Timed Release Ultra Mega II

Calcium (Calcium Citrate):

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Timed Release Ultra Mega II (Calcium (Calcium Citrate)) reviews

1 INDICATIONS AND USAGE

Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

- Calcium acetate is a phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. (1)

2 DOSAGE AND ADMINISTRATION

The recommended initial dose of Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate for the adult dialysis patient is 2 capsules with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Most patients require 3 to 4 capsules with each meal.

- Starting dose is 2 capsules with each meal. (2)

- Titrate the dose every 2 to 3 weeks until acceptable serum phosphorus level is reached. Most patients require 3 to 4 capsules with each meal. (2)

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate capsule.

- Capsule: 667 mg Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Timed Release Ultra Mega II ) acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate. (5.1)

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with Timed Release Ultra Mega II (Calcium (Calcium Citrate)), including Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate. Avoid the use of Timed Release Ultra Mega II (Calcium (Calcium Citrate)) supplements, including Timed Release Ultra Mega II (Calcium (Calcium Citrate)) based nonprescription antacids, concurrently with Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate.

An overdose of Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Timed Release Ultra Mega II (Calcium (Calcium Citrate)) levels twice weekly. Should hypercalcemia develop, reduce the Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate dosage, or discontinue the treatment, depending on the severity of hypercalcemia

More severe hypercalcemia (Ca >12 mg/dL) is associated with confusion, delirium, stupor and coma. Severe hypercalcemia can be treated by acute hemodialysis and discontinuing Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate therapy.

Mild hypercalcemia (10.5 to 11.9 mg/dL) may be asymptomatic or manifest as constipation, anorexia, nausea, and vomiting. Mild hypercalcemia is usually controlled by reducing the Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate dose or temporarily discontinuing therapy. Decreasing or discontinuing Vitamin D therapy is recommended as well.

Chronic hypercalcemia may lead to vascular calcification and other soft-tissue calcification. Radiographic evaluation of suspected anatomical regions may be helpful in early detection of soft tissue calcification. The long term effect of Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate on the progression of vascular or soft tissue calcification has not been determined.

Hypercalcemia (>11 mg/dL) was reported in 16% of patients in a 3 month study of solid dose formulation of Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate; all cases resolved upon lowering the dose or discontinuing treatment.

Maintain the serum calcium-phosphorus (Ca x P) product below 55 mg²/dL².

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

- The most common (>10%) adverse reactions are hypercalcemia, nausea and vomiting. (6.1)

- In clinical studies, patients have occasionally experienced nausea during Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate therapy. (6)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical studies, Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate has been generally well tolerated.

Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate was studied in a two week double-blind, placebo-controlled, cross-over study with 69 enrolled ESRD hemodialysis patients. Adverse reactions (>2% on treatment) from these trials are presented in Table 1.

Preferred Term	Total adverse reactions reported for Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate N=167 N (%)	3 month, open label study of Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate N=98 N (%)	Double blind, placebo-controlled, cross-over study of liquid Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate N=69
			Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate N (%)	Placebo N (%)
Nausea	6 (3.6)	6 (6.1)	0 (0)	0 (0)
Vomiting	4 (2.4)	4 (4.1)	0 (0)	0 (0)
Hypercalcemia	21 (12.6)	16 (16.3)	5 (7.2)	0 (0)

Mild hypercalcemia may be asymptomatic or manifest itself as constipation, anorexia, nausea, and vomiting. More severe hypercalcemia is associated with confusion, delirium, stupor, and coma. Decreasing dialysate Timed Release Ultra Mega II (Calcium (Calcium Citrate)) concentration could reduce the incidence and severity of Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.

6.2 Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.

The following additional adverse reactions have been identified during post-approval of Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Timed Release Ultra Mega II ) acetate is characterized by the potential of Timed Release Ultra Mega II (Calcium (Calcium Citrate)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate and most concomitant drugs. When administering an oral medication with Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, administer the drug one hour before or three hours after Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate. Monitor blood levels of the concomitant drugs that have a narrow therapeutic range. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials with all forms of Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate.

- Calcium acetate may decrease the bioavailability of tetracyclines or fluoroquinolones. (7)

- When clinically significant drug interactions are expected, administer the drug at least one hour before or at least three hours after Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate or consider monitoring blood levels of the drug. (7)

7.1 Ciprofloxacin

In a study of 15 healthy subjects, a co-administered single dose of 4 Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Timed Release Ultra Mega II ) acetate capsules contains Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate. Animal reproduction studies have not been conducted with Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate, and there are no adequate and well controlled studies of Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Timed Release Ultra Mega II (Calcium (Calcium Citrate)) levels is important for maternal and fetal well being. Hypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism. Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate treatment, as recommended, is not expected to harm a fetus if maternal Timed Release Ultra Mega II (Calcium (Calcium Citrate)) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Timed Release Ultra Mega II ) Acetate Capsules contains Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate and is excreted in human milk. Human milk feeding by a mother receiving Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate is not expected to harm an infant, provided maternal serum Timed Release Ultra Mega II (Calcium (Calcium Citrate)) levels are appropriately monitored.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

Administration of Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate acts as a phosphate binder. Its chemical name is Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate. Its molecular formula is C₄H₆CaO₄, and its molecular weight is 158.17. Its structural formula is:

Each white opaque/blue opaque capsule contains 667 mg of Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate USP (anhydrous; Ca(CH₃COO)₂; MW=158.17 grams) equal to 169 mg (8.45 mEq) Timed Release Ultra Mega II (Calcium (Calcium Citrate)), polyethylene glycol 8000 and magnesium stearate. Each capsule shell contains: black monogramming ink, FD&C Blue #1, FD&C Red #3, gelatin and titanium dioxide. The black monogramming ink contains: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac glaze.

Timed Release Ultra Mega II (Calcium (Calcium Citrate)) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum Timed Release Ultra Mega II ) resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Timed Release Ultra Mega II (Calcium (Calcium Citrate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate from pharmaceutical dosage forms is systemically absorbed up to approximately 40% under fasting conditions and up to approximately 30% under nonfasting conditions. This range represents data from both healthy subjects and renal dialysis patients under various conditions.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate solid oral dosage form.

Ninety-one patients with end-stage renal disease who were undergoing hemodialysis and were hyperphosphatemic (serum phosphorus >5.5 mg/dL) following a 1 week phosphate binder washout period contributed efficacy data to an open-label, non-randomized study.

The patients received Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate 667 mg tablets at each meal for a period of 12 weeks. The initial starting dose was 2 tablets per meal for 3 meals a day, and the dose was adjusted as necessary to control serum phosphorus levels. The average final dose after 12 weeks of treatment was 3.4 tablets per meal. Although there was a decrease in serum phosphorus, in the absence of a control group the true magnitude of effect is uncertain.

The data presented in Table 2 demonstrate the efficacy of Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Timed Release Ultra Mega II (Calcium (Calcium Citrate)) levels are also presented.

* Ninety-one patients completed at least 6 weeks of the study. † ANOVA of difference in values at pre-study and study completion. ‡ Values expressed as mean ± SE.
Parameter	Pre-Study	Week 4*	Week 8	Week 12	p-value†
Phosphorus (mg/dL)‡	7.4 ± 0.17	5.9 ± 0.16	5.6 ± 0.17	5.2 ± 0.17	≤0.01
Timed Release Ultra Mega II (Calcium (Calcium Citrate)) (mg/dL)‡	8.9 ± 0.09	9.5 ± 0.10	9.7 ± 0.10	9.7 ± 0.10	≤0.01

There was a 30% decrease in serum phosphorus levels during the 12 week study period (p<0.01). Two-thirds of the decline occurred in the first month of the study. Serum Timed Release Ultra Mega II (Calcium (Calcium Citrate)) increased 9% during the study mostly in the first month of the study.

Treatment with the phosphate binder was discontinued for patients from the open-label study, and those patients whose serum phosphorus exceeded 5.5 mg/dL were eligible for entry into a double-blind, placebo-controlled, cross-over study. Patients were randomized to receive Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate or placebo, and each continued to receive the same number of tablets as had been individually established during the previous study. Following 2 weeks of treatment, patients switched to the alternative therapy for an additional 2 weeks.

The phosphate binding effect of Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate is shown in the Table 3.

* ANOVA of Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate vs. placebo after 2 weeks of treatment. † Values expressed as mean ± SEM.
Parameter	Pre-Study	Post-Treatment		p-value*
		Timed Release Ultra Mega II (Calcium (Calcium Citrate)) Acetate	Placebo
Phosphorus (mg/dL)†	7.3 ± 0.18	5.9 ± 0.24	7.8 ± 0.22	<0.01
Timed Release Ultra Mega II (Calcium (Calcium Citrate)) (mg/dL)†	8.9 ± 0.11	9.5 ± 0.13	8.8 ± 0.12	<0.01

Overall, 2 weeks of treatment with Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Timed Release Ultra Mega II (Calcium (Calcium Citrate)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Timed Release Ultra Mega II (Calcium (Calcium Citrate)) Acetate Capsules

667 mg capsule is supplied as a white opaque/blue opaque capsule, imprinted with “54 215” on the cap and body.

NDC 0615-2303-39: Blistercards of 30 Capsules

NDC 0615-2303-30: Unit-dose Boxes of 30 Capsules

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Inform patients to take Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Timed Release Ultra Mega II (Calcium (Calcium Citrate)) supplements including nonprescription antacids. Inform the patients about the symptoms of hypercalcemia [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ].

Advise patients who are taking an oral medication where reduction in the bioavailability of that medication would have clinically significant effect on its safety or efficacy to take the drug one hour before or three hours after Timed Release Ultra Mega II (Calcium (Calcium Citrate)) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Calcium (Calcium HVP Chelate):

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) reviews

1 INDICATIONS AND USAGE

Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

- Calcium acetate is a phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. (1)

2 DOSAGE AND ADMINISTRATION

The recommended initial dose of Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate for the adult dialysis patient is 2 capsules with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Most patients require 3 to 4 capsules with each meal.

- Starting dose is 2 capsules with each meal. (2)

- Titrate the dose every 2 to 3 weeks until acceptable serum phosphorus level is reached. Most patients require 3 to 4 capsules with each meal. (2)

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate capsule.

- Capsule: 667 mg Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Timed Release Ultra Mega II ) acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate. (5.1)

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)), including Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate. Avoid the use of Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) supplements, including Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) based nonprescription antacids, concurrently with Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate.

An overdose of Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) levels twice weekly. Should hypercalcemia develop, reduce the Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate dosage, or discontinue the treatment, depending on the severity of hypercalcemia

More severe hypercalcemia (Ca >12 mg/dL) is associated with confusion, delirium, stupor and coma. Severe hypercalcemia can be treated by acute hemodialysis and discontinuing Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate therapy.

Mild hypercalcemia (10.5 to 11.9 mg/dL) may be asymptomatic or manifest as constipation, anorexia, nausea, and vomiting. Mild hypercalcemia is usually controlled by reducing the Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate dose or temporarily discontinuing therapy. Decreasing or discontinuing Vitamin D therapy is recommended as well.

Chronic hypercalcemia may lead to vascular calcification and other soft-tissue calcification. Radiographic evaluation of suspected anatomical regions may be helpful in early detection of soft tissue calcification. The long term effect of Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate on the progression of vascular or soft tissue calcification has not been determined.

Hypercalcemia (>11 mg/dL) was reported in 16% of patients in a 3 month study of solid dose formulation of Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate; all cases resolved upon lowering the dose or discontinuing treatment.

Maintain the serum calcium-phosphorus (Ca x P) product below 55 mg²/dL².

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

- The most common (>10%) adverse reactions are hypercalcemia, nausea and vomiting. (6.1)

- In clinical studies, patients have occasionally experienced nausea during Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate therapy. (6)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical studies, Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate has been generally well tolerated.

Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate was studied in a two week double-blind, placebo-controlled, cross-over study with 69 enrolled ESRD hemodialysis patients. Adverse reactions (>2% on treatment) from these trials are presented in Table 1.

Preferred Term	Total adverse reactions reported for Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate N=167 N (%)	3 month, open label study of Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate N=98 N (%)	Double blind, placebo-controlled, cross-over study of liquid Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate N=69
			Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate N (%)	Placebo N (%)
Nausea	6 (3.6)	6 (6.1)	0 (0)	0 (0)
Vomiting	4 (2.4)	4 (4.1)	0 (0)	0 (0)
Hypercalcemia	21 (12.6)	16 (16.3)	5 (7.2)	0 (0)

Mild hypercalcemia may be asymptomatic or manifest itself as constipation, anorexia, nausea, and vomiting. More severe hypercalcemia is associated with confusion, delirium, stupor, and coma. Decreasing dialysate Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) concentration could reduce the incidence and severity of Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.

6.2 Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.

The following additional adverse reactions have been identified during post-approval of Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Timed Release Ultra Mega II ) acetate is characterized by the potential of Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate and most concomitant drugs. When administering an oral medication with Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, administer the drug one hour before or three hours after Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate. Monitor blood levels of the concomitant drugs that have a narrow therapeutic range. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials with all forms of Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate.

- Calcium acetate may decrease the bioavailability of tetracyclines or fluoroquinolones. (7)

- When clinically significant drug interactions are expected, administer the drug at least one hour before or at least three hours after Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate or consider monitoring blood levels of the drug. (7)

7.1 Ciprofloxacin

In a study of 15 healthy subjects, a co-administered single dose of 4 Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Timed Release Ultra Mega II ) acetate capsules contains Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate. Animal reproduction studies have not been conducted with Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate, and there are no adequate and well controlled studies of Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) levels is important for maternal and fetal well being. Hypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism. Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate treatment, as recommended, is not expected to harm a fetus if maternal Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Timed Release Ultra Mega II ) Acetate Capsules contains Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate and is excreted in human milk. Human milk feeding by a mother receiving Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate is not expected to harm an infant, provided maternal serum Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) levels are appropriately monitored.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

Administration of Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate acts as a phosphate binder. Its chemical name is Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate. Its molecular formula is C₄H₆CaO₄, and its molecular weight is 158.17. Its structural formula is:

Each white opaque/blue opaque capsule contains 667 mg of Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate USP (anhydrous; Ca(CH₃COO)₂; MW=158.17 grams) equal to 169 mg (8.45 mEq) Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)), polyethylene glycol 8000 and magnesium stearate. Each capsule shell contains: black monogramming ink, FD&C Blue #1, FD&C Red #3, gelatin and titanium dioxide. The black monogramming ink contains: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac glaze.

Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum Timed Release Ultra Mega II ) resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate from pharmaceutical dosage forms is systemically absorbed up to approximately 40% under fasting conditions and up to approximately 30% under nonfasting conditions. This range represents data from both healthy subjects and renal dialysis patients under various conditions.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate solid oral dosage form.

Ninety-one patients with end-stage renal disease who were undergoing hemodialysis and were hyperphosphatemic (serum phosphorus >5.5 mg/dL) following a 1 week phosphate binder washout period contributed efficacy data to an open-label, non-randomized study.

The patients received Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate 667 mg tablets at each meal for a period of 12 weeks. The initial starting dose was 2 tablets per meal for 3 meals a day, and the dose was adjusted as necessary to control serum phosphorus levels. The average final dose after 12 weeks of treatment was 3.4 tablets per meal. Although there was a decrease in serum phosphorus, in the absence of a control group the true magnitude of effect is uncertain.

The data presented in Table 2 demonstrate the efficacy of Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) levels are also presented.

* Ninety-one patients completed at least 6 weeks of the study. † ANOVA of difference in values at pre-study and study completion. ‡ Values expressed as mean ± SE.
Parameter	Pre-Study	Week 4*	Week 8	Week 12	p-value†
Phosphorus (mg/dL)‡	7.4 ± 0.17	5.9 ± 0.16	5.6 ± 0.17	5.2 ± 0.17	≤0.01
Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) (mg/dL)‡	8.9 ± 0.09	9.5 ± 0.10	9.7 ± 0.10	9.7 ± 0.10	≤0.01

There was a 30% decrease in serum phosphorus levels during the 12 week study period (p<0.01). Two-thirds of the decline occurred in the first month of the study. Serum Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) increased 9% during the study mostly in the first month of the study.

Treatment with the phosphate binder was discontinued for patients from the open-label study, and those patients whose serum phosphorus exceeded 5.5 mg/dL were eligible for entry into a double-blind, placebo-controlled, cross-over study. Patients were randomized to receive Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate or placebo, and each continued to receive the same number of tablets as had been individually established during the previous study. Following 2 weeks of treatment, patients switched to the alternative therapy for an additional 2 weeks.

The phosphate binding effect of Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate is shown in the Table 3.

* ANOVA of Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate vs. placebo after 2 weeks of treatment. † Values expressed as mean ± SEM.
Parameter	Pre-Study	Post-Treatment		p-value*
		Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) Acetate	Placebo
Phosphorus (mg/dL)†	7.3 ± 0.18	5.9 ± 0.24	7.8 ± 0.22	<0.01
Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) (mg/dL)†	8.9 ± 0.11	9.5 ± 0.13	8.8 ± 0.12	<0.01

Overall, 2 weeks of treatment with Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) Acetate Capsules

667 mg capsule is supplied as a white opaque/blue opaque capsule, imprinted with “54 215” on the cap and body.

NDC 0615-2303-39: Blistercards of 30 Capsules

NDC 0615-2303-30: Unit-dose Boxes of 30 Capsules

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Inform patients to take Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) supplements including nonprescription antacids. Inform the patients about the symptoms of hypercalcemia [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ].

Advise patients who are taking an oral medication where reduction in the bioavailability of that medication would have clinically significant effect on its safety or efficacy to take the drug one hour before or three hours after Timed Release Ultra Mega II (Calcium (Calcium HVP Chelate)) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Calcium (Calcium Phosphate Dibasic):

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) reviews

1 INDICATIONS AND USAGE

Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

- Calcium acetate is a phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. (1)

2 DOSAGE AND ADMINISTRATION

The recommended initial dose of Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate for the adult dialysis patient is 2 capsules with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Most patients require 3 to 4 capsules with each meal.

- Starting dose is 2 capsules with each meal. (2)

- Titrate the dose every 2 to 3 weeks until acceptable serum phosphorus level is reached. Most patients require 3 to 4 capsules with each meal. (2)

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate capsule.

- Capsule: 667 mg Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Timed Release Ultra Mega II ) acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate. (5.1)

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)), including Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate. Avoid the use of Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) supplements, including Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) based nonprescription antacids, concurrently with Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate.

An overdose of Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) levels twice weekly. Should hypercalcemia develop, reduce the Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate dosage, or discontinue the treatment, depending on the severity of hypercalcemia

More severe hypercalcemia (Ca >12 mg/dL) is associated with confusion, delirium, stupor and coma. Severe hypercalcemia can be treated by acute hemodialysis and discontinuing Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate therapy.

Mild hypercalcemia (10.5 to 11.9 mg/dL) may be asymptomatic or manifest as constipation, anorexia, nausea, and vomiting. Mild hypercalcemia is usually controlled by reducing the Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate dose or temporarily discontinuing therapy. Decreasing or discontinuing Vitamin D therapy is recommended as well.

Chronic hypercalcemia may lead to vascular calcification and other soft-tissue calcification. Radiographic evaluation of suspected anatomical regions may be helpful in early detection of soft tissue calcification. The long term effect of Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate on the progression of vascular or soft tissue calcification has not been determined.

Hypercalcemia (>11 mg/dL) was reported in 16% of patients in a 3 month study of solid dose formulation of Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate; all cases resolved upon lowering the dose or discontinuing treatment.

Maintain the serum calcium-phosphorus (Ca x P) product below 55 mg²/dL².

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

- The most common (>10%) adverse reactions are hypercalcemia, nausea and vomiting. (6.1)

- In clinical studies, patients have occasionally experienced nausea during Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate therapy. (6)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical studies, Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate has been generally well tolerated.

Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate was studied in a two week double-blind, placebo-controlled, cross-over study with 69 enrolled ESRD hemodialysis patients. Adverse reactions (>2% on treatment) from these trials are presented in Table 1.

Preferred Term	Total adverse reactions reported for Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate N=167 N (%)	3 month, open label study of Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate N=98 N (%)	Double blind, placebo-controlled, cross-over study of liquid Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate N=69
			Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate N (%)	Placebo N (%)
Nausea	6 (3.6)	6 (6.1)	0 (0)	0 (0)
Vomiting	4 (2.4)	4 (4.1)	0 (0)	0 (0)
Hypercalcemia	21 (12.6)	16 (16.3)	5 (7.2)	0 (0)

Mild hypercalcemia may be asymptomatic or manifest itself as constipation, anorexia, nausea, and vomiting. More severe hypercalcemia is associated with confusion, delirium, stupor, and coma. Decreasing dialysate Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) concentration could reduce the incidence and severity of Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.

6.2 Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.

The following additional adverse reactions have been identified during post-approval of Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Timed Release Ultra Mega II ) acetate is characterized by the potential of Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate and most concomitant drugs. When administering an oral medication with Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, administer the drug one hour before or three hours after Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate. Monitor blood levels of the concomitant drugs that have a narrow therapeutic range. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials with all forms of Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate.

- Calcium acetate may decrease the bioavailability of tetracyclines or fluoroquinolones. (7)

- When clinically significant drug interactions are expected, administer the drug at least one hour before or at least three hours after Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate or consider monitoring blood levels of the drug. (7)

7.1 Ciprofloxacin

In a study of 15 healthy subjects, a co-administered single dose of 4 Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Timed Release Ultra Mega II ) acetate capsules contains Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate. Animal reproduction studies have not been conducted with Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate, and there are no adequate and well controlled studies of Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) levels is important for maternal and fetal well being. Hypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism. Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate treatment, as recommended, is not expected to harm a fetus if maternal Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Timed Release Ultra Mega II ) Acetate Capsules contains Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate and is excreted in human milk. Human milk feeding by a mother receiving Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate is not expected to harm an infant, provided maternal serum Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) levels are appropriately monitored.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

Administration of Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate acts as a phosphate binder. Its chemical name is Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate. Its molecular formula is C₄H₆CaO₄, and its molecular weight is 158.17. Its structural formula is:

Each white opaque/blue opaque capsule contains 667 mg of Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate USP (anhydrous; Ca(CH₃COO)₂; MW=158.17 grams) equal to 169 mg (8.45 mEq) Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)), polyethylene glycol 8000 and magnesium stearate. Each capsule shell contains: black monogramming ink, FD&C Blue #1, FD&C Red #3, gelatin and titanium dioxide. The black monogramming ink contains: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac glaze.

Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum Timed Release Ultra Mega II ) resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate from pharmaceutical dosage forms is systemically absorbed up to approximately 40% under fasting conditions and up to approximately 30% under nonfasting conditions. This range represents data from both healthy subjects and renal dialysis patients under various conditions.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate.

14 CLINICAL STUDIES

Effectiveness of Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate solid oral dosage form.

Ninety-one patients with end-stage renal disease who were undergoing hemodialysis and were hyperphosphatemic (serum phosphorus >5.5 mg/dL) following a 1 week phosphate binder washout period contributed efficacy data to an open-label, non-randomized study.

The patients received Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate 667 mg tablets at each meal for a period of 12 weeks. The initial starting dose was 2 tablets per meal for 3 meals a day, and the dose was adjusted as necessary to control serum phosphorus levels. The average final dose after 12 weeks of treatment was 3.4 tablets per meal. Although there was a decrease in serum phosphorus, in the absence of a control group the true magnitude of effect is uncertain.

The data presented in Table 2 demonstrate the efficacy of Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) levels are also presented.

* Ninety-one patients completed at least 6 weeks of the study. † ANOVA of difference in values at pre-study and study completion. ‡ Values expressed as mean ± SE.
Parameter	Pre-Study	Week 4*	Week 8	Week 12	p-value†
Phosphorus (mg/dL)‡	7.4 ± 0.17	5.9 ± 0.16	5.6 ± 0.17	5.2 ± 0.17	≤0.01
Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) (mg/dL)‡	8.9 ± 0.09	9.5 ± 0.10	9.7 ± 0.10	9.7 ± 0.10	≤0.01

There was a 30% decrease in serum phosphorus levels during the 12 week study period (p<0.01). Two-thirds of the decline occurred in the first month of the study. Serum Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) increased 9% during the study mostly in the first month of the study.

Treatment with the phosphate binder was discontinued for patients from the open-label study, and those patients whose serum phosphorus exceeded 5.5 mg/dL were eligible for entry into a double-blind, placebo-controlled, cross-over study. Patients were randomized to receive Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate or placebo, and each continued to receive the same number of tablets as had been individually established during the previous study. Following 2 weeks of treatment, patients switched to the alternative therapy for an additional 2 weeks.

The phosphate binding effect of Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate is shown in the Table 3.

* ANOVA of Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate vs. placebo after 2 weeks of treatment. † Values expressed as mean ± SEM.
Parameter	Pre-Study	Post-Treatment		p-value*
		Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) Acetate	Placebo
Phosphorus (mg/dL)†	7.3 ± 0.18	5.9 ± 0.24	7.8 ± 0.22	<0.01
Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) (mg/dL)†	8.9 ± 0.11	9.5 ± 0.13	8.8 ± 0.12	<0.01

Overall, 2 weeks of treatment with Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) Acetate Capsules

667 mg capsule is supplied as a white opaque/blue opaque capsule, imprinted with “54 215” on the cap and body.

NDC 0615-2303-39: Blistercards of 30 Capsules

NDC 0615-2303-30: Unit-dose Boxes of 30 Capsules

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Inform patients to take Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) supplements including nonprescription antacids. Inform the patients about the symptoms of hypercalcemia [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ].

Advise patients who are taking an oral medication where reduction in the bioavailability of that medication would have clinically significant effect on its safety or efficacy to take the drug one hour before or three hours after Timed Release Ultra Mega II (Calcium (Calcium Phosphate Dibasic)) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Choline Bitartrate:

• Timed Release Ultra Mega II (Choline Bitartrate) reviews

A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism.

Indication: For nutritional supplementation, also for treating dietary shortage or imbalance

This compound is needed for good nerve conduction throughout the CNS (central nervous system) as it is a precursor to acetylcholine (ACh). Timed Release Ultra Mega II (Choline Bitartrate) is also needed for gallbladder regulation, liver function and lecithin (a key lipid) formation. Timed Release Ultra Mega II (Choline Bitartrate) also aids in fat and cholesterol metabolism and prevents excessive fat build up in the liver. Timed Release Ultra Mega II (Choline Bitartrate) has been used to mitigate the effects of Parkinsonism and tardive dyskinesia. Timed Release Ultra Mega II (Choline Bitartrate) deficiencies may result in excessive build-up of fat in the liver, high blood pressure, gastric ulcers, kidney and liver dysfunction and stunted growth.

Folic Acid:

• Indications and usage
• Contraindications
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• Storage
• Timed Release Ultra Mega II (Folic Acid) reviews

INDICATIONS AND USAGE

Timed Release Ultra Mega II (Folic Acid)^® is a prescription iron supplement indicated for use in improving the nutritional status of iron deficiency.

CONTRAINDICATIONS

This product is contraindicated in patients with a known hypersensitivity to any of the ingredients. Hemochromatosis and hemosiderosis are contraindications to iron therapy.

WARNING: Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6. Keep this product out of reach of children. In case of accidental overdose, call a doctor or poison control center immediately.

PRECAUTIONS

Timed Release Ultra Mega II (Folic Acid) acid when administered as a single agent in doses above 0.1 mg daily may obscure pernicious anemia in that hematological remission can occur while neurological manifestations remain progressive. While prescribing this nutritional supplement for pregnant women, nursing mothers, or for women prior to conception, their medical condition and other drugs, herbs, and/or supplements consumption should be considered.

ADVERSE REACTIONS

Allergic sensitization has been reported following both oral and parenteral administration of Timed Release Ultra Mega II (Folic Acid) acid.

DOSAGE AND ADMINISTRATION

One tablet daily with or without food or as prescribed by a licensed healthcare provider with prescribing authority.

HOW SUPPLIED

Timed Release Ultra Mega II (Folic Acid)^® tablets are supplied in child-resistant bottles of 90 tablets (NDC 0037-6885-90)

KEEP OUT OF REACH OF CHILDREN.

STORAGE

Store at controlled room temperature 20°-25°C (68°-77°F). Excursions permitted to 15°-30°C (59°-86°F).

Dispense in a tight, light-resistant container to protect from light and moisture.

To report SUSPECTED ADVERSE REACTIONS contact Meda Pharmaceuticals Inc. at 1-888-349-5556 or FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch

Distributed by:

Meda Pharmaceuticals Inc.

Somerset New Jersey 08873-4120

© 2014 Meda Pharmaceuticals Inc.

U.S. Patent Nos. 7,585,527 and 8,080,520

Proferrin® is a registered trademark of Colorado BioLabs, Inc., Cozad, NE.

Timed Release Ultra Mega II (Folic Acid) and the BIFERA logo are registered trademarks and the Timed Release Ultra Mega II (Folic Acid) logo is a trademark of Alaven Pharmaceutical LLC, used under license by Meda Pharmaceuticals Inc.

MEDA PHARMACEUTICALS mark and logo are trademarks of Meda AB.

IN-6885-02 Rev 6/2014

Inositol:

• Timed Release Ultra Mega II (Inositol) reviews

Niacin is used with a proper diet and exercise program to help lower "bad" cholesterol and fats ( LDL, triglycerides ) and raise "good" cholesterol (HDL) in the blood. It is generally used after non-drug treatments have not been fully successful at lowering cholesterol. Niacin is also known as vitamin B-3 ( nicotinic acid ), one of the B-complex vitamins. It may be used with or without other medications. Lowering "bad" cholesterol/triglycerides and raising "good" cholesterol helps prevent strokes and heart attacks. Lowering fats may also help reduce the risk of pancreas problems ( pancreatitis ) in people at risk. In addition to eating a proper diet (such as a low-cholesterol/low-fat diet), other lifestyle changes that may help this medication work better include exercising, losing weight if overweight, and stopping smoking. Consult your doctor for more details.

Iodine (Kelp):

• Iodine tincture 7%
• Iodine tincture 7%
• Timed Release Ultra Mega II (Iodine (Kelp)) reviews

Timed Release Ultra Mega II ) Tincture 7%

Directions:

Topical Antiseptic

Use full Strength for superficial cuts, wounds, abrasions, insect bites and bruises on the skin of animals. Apply Timed Release Ultra Mega II (Iodine (Kelp)) with a swab.

If necessary, clip hair around the area being treated and clean with soap and water.

Apply Timed Release Ultra Mega II (Iodine (Kelp)) Tincture 7% only once daily. Dilute product 3 to 1 if repeating application.

Do not apply under bandage.

Irritation may occur if used on tender skin areas. If redness, irritation, or swelling persists or increases, discontinue use and consult a veterinarian.

Storage:

Store at 2-30 degrees C (36-86 degrees F).

Keep container away from heat and out of sunlight. Rinse empty container thoroughly and discard.

DANGER - Poison

Caution:

If swallowed, give starch paste, milk, bread, egg white, or

activated charcoal. A 5% solutions of sodium thiosulfate

(Photographic (“hypc”) may be administered orally at a

rate of 10 ml per kilogram of body weight.

Eye irritant: Use only as directed. Avoid contact with eyes. In case of contact, flush eyes immediately with tepid water for at least 15 minutes. Consult a physician.

Avoid contamination of food.

Not for use on burns, deep cuts, or body cavities.

Timed Release Ultra Mega II ) Tincture 7%

image description

Iron (Ferrous Citrate):

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Timed Release Ultra Mega II (Iron (Ferrous Citrate)) reviews

1 INDICATIONS AND USAGE

Timed Release Ultra Mega II (Iron (Ferrous Citrate)) is indicated for the treatment of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) deficiency anemia in patients with chronic kidney disease (CKD).

Timed Release Ultra Mega II (Iron (Ferrous Citrate)) is an Timed Release Ultra Mega II (Iron (Ferrous Citrate)) replacement product indicated for the treatment of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Timed Release Ultra Mega II ) must only be administered intravenously either by slow injection or by infusion. The dosage of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) is expressed in mg of elemental Timed Release Ultra Mega II (Iron (Ferrous Citrate)). Each mL contains 20 mg of elemental Timed Release Ultra Mega II (Iron (Ferrous Citrate)).

Population		Dose
Adult patients	Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) (2.1)	100 mg slow intravenous injection or infusion
	Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) (2.2)	200 mg slow intravenous injection or infusion
	Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) (2.3)	300 mg or 400 mg intravenous infusion
Pediatric patients	HDD-CKD (2.4), PDD-CKD or NDD-CKD (2.5)	0.5 mg/kg slow intravenous injection or infusion

2.1 Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)

Administer Timed Release Ultra Mega II (Iron (Ferrous Citrate)) 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session. Timed Release Ultra Mega II (Iron (Ferrous Citrate)) should be administered early during the dialysis session. The usual total treatment course of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) is 1000 mg. Timed Release Ultra Mega II (Iron (Ferrous Citrate)) treatment may be repeated if Timed Release Ultra Mega II (Iron (Ferrous Citrate)) deficiency reoccurs.

2.2 Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease

Administer Timed Release Ultra Mega II (Iron (Ferrous Citrate)) 200 mg undiluted as a slow intravenous injection over 2 to 5 minutes or as an infusion of 200 mg in a maximum of 100 mL of 0.9% NaCl over a period of 15 minutes. Administer on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion of 500 mg of Timed Release Ultra Mega II (Iron (Ferrous Citrate)), diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on Day 1 and Day 14. Timed Release Ultra Mega II (Iron (Ferrous Citrate)) treatment may be repeated if Timed Release Ultra Mega II (Iron (Ferrous Citrate)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Timed Release Ultra Mega II (Iron (Ferrous Citrate)) in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg over 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Timed Release Ultra Mega II (Iron (Ferrous Citrate)) in a maximum of 250 mL of 0.9% NaCl. Timed Release Ultra Mega II (Iron (Ferrous Citrate)) treatment may be repeated if Timed Release Ultra Mega II (Iron (Ferrous Citrate)) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Timed Release Ultra Mega II (Iron (Ferrous Citrate)) maintenance treatment

The dosing for Timed Release Ultra Mega II (Iron (Ferrous Citrate)) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Timed Release Ultra Mega II (Iron (Ferrous Citrate)) maintenance treatment: Administer Timed Release Ultra Mega II (Iron (Ferrous Citrate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every two weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Timed Release Ultra Mega II (Iron (Ferrous Citrate)) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Timed Release Ultra Mega II (Iron (Ferrous Citrate)) maintenance treatment

The dosing for Timed Release Ultra Mega II (Iron (Ferrous Citrate)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Timed Release Ultra Mega II (Iron (Ferrous Citrate)) maintenance treatment: Administer Timed Release Ultra Mega II (Iron (Ferrous Citrate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every four weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Timed Release Ultra Mega II (Iron (Ferrous Citrate)) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

• 10 mL single-use vial / 200 mg elemental Timed Release Ultra Mega II (Iron (Ferrous Citrate)) (20 mg/mL)
• 5 mL single-use vial / 100 mg elemental Timed Release Ultra Mega II (Iron (Ferrous Citrate)) (20 mg/mL)
• 2.5 mL single-use vial / 50 mg elemental Timed Release Ultra Mega II (Iron (Ferrous Citrate)) (20 mg/mL)

• 10 mL single-use vial / 200 mg elemental Timed Release Ultra Mega II (Iron (Ferrous Citrate)) (20 mg/mL) (3)
• 5 mL single-use vial / 100 mg elemental Timed Release Ultra Mega II (Iron (Ferrous Citrate)) (20 mg/mL) (3)
• 2.5 mL single-use vial / 50 mg elemental Timed Release Ultra Mega II (Iron (Ferrous Citrate)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

• Known hypersensitivity to Timed Release Ultra Mega II (Iron (Ferrous Citrate))

• Known hypersensitivity to Timed Release Ultra Mega II (Iron (Ferrous Citrate)) (4)

5 WARNINGS AND PRECAUTIONS

• Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Timed Release Ultra Mega II ) administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Timed Release Ultra Mega II (Iron (Ferrous Citrate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1)
• Hypotension: Timed Release Ultra Mega II (Iron (Ferrous Citrate)) may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Timed Release Ultra Mega II (Iron (Ferrous Citrate)). (5.2)
• Timed Release Ultra Mega II (Iron (Ferrous Citrate)) Overload: Regularly monitor hematologic responses during Timed Release Ultra Mega II (Iron (Ferrous Citrate)) therapy. Do not administer Timed Release Ultra Mega II (Iron (Ferrous Citrate)) to patients with Timed Release Ultra Mega II (Iron (Ferrous Citrate)) overload. (5.3)

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Timed Release Ultra Mega II (Iron (Ferrous Citrate)). Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Timed Release Ultra Mega II (Iron (Ferrous Citrate)) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Timed Release Ultra Mega II (Iron (Ferrous Citrate)) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Timed Release Ultra Mega II (Iron (Ferrous Citrate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Timed Release Ultra Mega II (Iron (Ferrous Citrate)) preparations occur within 30 minutes of the completion of the infusion .

5.2 Hypotension

Timed Release Ultra Mega II ) may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Timed Release Ultra Mega II (Iron (Ferrous Citrate)). Hypotension following administration of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) may be related to the rate of administration and/or total dose administered .

5.3 Timed Release Ultra Mega II (Iron (Ferrous Citrate)) Overload

Excessive therapy with parenteral Timed Release Ultra Mega II (Iron (Ferrous Citrate)) can lead to excess storage of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving Timed Release Ultra Mega II (Iron (Ferrous Citrate)) require periodic monitoring of hematologic and Timed Release Ultra Mega II (Iron (Ferrous Citrate)) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Timed Release Ultra Mega II (Iron (Ferrous Citrate)) to patients with evidence of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) sucrose; do not perform serum Timed Release Ultra Mega II (Iron (Ferrous Citrate)) measurements for at least 48 hours after intravenous dosing .

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Timed Release Ultra Mega II ) are described in other sections .

• The most common adverse reactions (≥2%) following the administration of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) are diarrhea, nausea, vomiting, headache, dizziness, hypotension, pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection site reactions, chest pain, and peripheral edema. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Adverse Reactions in Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.

Adverse Reactions in Adults Patients with CKD

Adverse Reactions in Adult Patients with CKD

The frequency of adverse reactions associated with the use of Timed Release Ultra Mega II ) has been documented in six clinical trials involving 231 patients with HDD-CKD, 139 patients with NDD-CKD and 75 patients with PDD-CKD. Treatment-emergent adverse reactions reported by ≥ 2% of treated patients in the six clinical trials for which the rate for Timed Release Ultra Mega II (Iron (Ferrous Citrate)) exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks.

* EPO=Erythropoietin
Adverse Reactions (Preferred Term)	HDD-CKD	NDD-CKD		PDD-CKD
	Timed Release Ultra Mega II (Iron (Ferrous Citrate))	Timed Release Ultra Mega II (Iron (Ferrous Citrate))	Oral Timed Release Ultra Mega II (Iron (Ferrous Citrate))	Timed Release Ultra Mega II (Iron (Ferrous Citrate))	EPO* Only
	(N=231)	(N=139)	(N=139)	(N=75)	(N=46)
	%	%	%	%	%
Subjects with any adverse reaction	78.8	76.3	73.4	72.0	65.2
Ear and Labyrinth Disorders
Ear Pain	0	2.2	0.7	0	0
Eye Disorders
Conjunctivitis	0.4	0	0	2.7	0
Gastrointestinal Disorders
Abdominal pain	3.5	1.4	2.9	4.0	6.5
Diarrhea	5.2	7.2	10.1	8.0	4.3
Dysgeusia	0.9	7.9	0	0	0
Nausea	14.7	8.6	12.2	5.3	4.3
Vomiting	9.1	5.0	8.6	8.0	2.2
General Disorders and
Administration Site Conditions
Asthenia	2.2	0.7	2.2	2.7	0
Chest pain	6.1	1.4	0	2.7	0
Feeling abnormal	3.0	0	0	0	0
Infusion site pain or burning	0	5.8	0	0	0
Injection site extravasation	0	2.2	0	0	0
Peripheral edema	2.6	7.2	5.0	5.3	10.9
Pyrexia	3.0	0.7	0.7	1.3	0
Infections and Infestations
Nasopharyngitis, Sinusitis, Upper respiratory tract infections, Pharyngitis	2.6	2.2	4.3	16.0	4.3
Injury, Poisoning and Procedural
Complications
Graft complication	9.5	1.4	0	0	0
Metabolism and Nutrition Disorders
Fluid overload	3.0	1.4	0.7	1.3	0
Gout	0	2.9	1.4	0	0
Hyperglycemia	0	2.9	0	0	2.2
Hypoglycemia	0.4	0.7	0.7	4.0	0
Musculoskeletal and Connective
Tissue Disorders
Arthralgia	3.5	1.4	2.2	4.0	4.3
Back pain	2.2	2.2	3.6	1.3	4.3
Muscle cramp	29.4	0.7	0.7	2.7	0
Myalgia	0	3.6	0	1.3	0
Pain in extremity	5.6	4.3	0	2.7	6.5
Nervous System Disorders
Dizziness	6.5	6.5	1.4	1.3	4.3
Headache	12.6	2.9	0.7	4.0	0
Respiratory, Thoracic and
Mediastinal Disorders
Cough	3.0	2.2	0.7	1.3	0
Dyspnea	3.5	5.8	1.4	1.3	2.2
Nasal congestion	0	1.4	2.2	1.3	0
Skin and Subcutaneous
Tissue Disorders
Pruritus	3.9	2.2	4.3	2.7	0
Vascular Disorders
Hypertension	6.5	6.5	4.3	8.0	6.5
Hypotension	39.4	2.2	0.7	2.7	2.2

One hundred thirty (11%) of the 1,151 patients evaluated in the 4 U.S. trials in HDD-CKD patients (studies A, B and the two post marketing studies) had prior other intravenous Timed Release Ultra Mega II (Iron (Ferrous Citrate)) therapy and were reported to be intolerant (defined as precluding further use of that Timed Release Ultra Mega II (Iron (Ferrous Citrate)) product). When these patients were treated with Timed Release Ultra Mega II (Iron (Ferrous Citrate)) there were no occurrences of adverse reactions that precluded further use of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) .

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

In a randomized, open-label, dose-ranging trial for Timed Release Ultra Mega II (Iron (Ferrous Citrate)) maintenance treatment with Timed Release Ultra Mega II (Iron (Ferrous Citrate)) in pediatric patients with CKD on stable erythropoietin therapy , at least one treatment-emergent adverse reaction was experienced by 57% (27/47) of the patients receiving Timed Release Ultra Mega II (Iron (Ferrous Citrate)) 0.5 mg/kg, 53% (25/47) of the patients receiving Timed Release Ultra Mega II (Iron (Ferrous Citrate)) 1.0 mg/kg, and 55% (26/47) of the patients receiving Timed Release Ultra Mega II (Iron (Ferrous Citrate)) 2.0 mg/kg.

A total of 5 (11%) subjects in the Timed Release Ultra Mega II (Iron (Ferrous Citrate)) 0.5 mg/kg group, 10 (21%) patients in the Timed Release Ultra Mega II (Iron (Ferrous Citrate)) 1.0 mg/kg group, and 10 (21%) patients in the Timed Release Ultra Mega II (Iron (Ferrous Citrate)) 2.0 mg/kg group experienced at least 1 serious adverse reaction during the study. The most common treatment-emergent adverse reactions (> 2% of patients) in all patients were headache (6%), respiratory tract viral infection (4%), peritonitis (4%), vomiting (4%), pyrexia (4%), dizziness (4%), cough (4%), renal transplant (4%), nausea (3%), arteriovenous fistula thrombosis (2%), hypotension (2%), and hypertension (2.1%).

6.2 Adverse Reactions from Post-Marketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis and dysgeusia.

The following adverse reactions have been identified during post-approval use of Timed Release Ultra Mega II (Iron (Ferrous Citrate)). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Anaphylactic-type reactions, shock, loss of consciousness, collapse, bronchospasm, dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints, hyperhidrosis, back pain, bradycardia, and chromaturia.

Symptoms associated with Timed Release Ultra Mega II (Iron (Ferrous Citrate)) total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. These adverse reactions have occurred up to 30 minutes after the administration of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) injection. Reactions have occurred following the first dose or subsequent doses of Timed Release Ultra Mega II (Iron (Ferrous Citrate)). Symptoms may respond to intravenous fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms.

Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation.

7 DRUG INTERACTIONS

Drug interactions involving Timed Release Ultra Mega II (Iron (Ferrous Citrate)) have not been studied. However, Timed Release Ultra Mega II (Iron (Ferrous Citrate)) may reduce the absorption of concomitantly administered oral Timed Release Ultra Mega II (Iron (Ferrous Citrate)) preparations.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, Timed Release Ultra Mega II ) sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Timed Release Ultra Mega II (Iron (Ferrous Citrate)) (half or equivalent to the maximum recommended human dose based on body surface area, respectively) and revealed no evidence of harm to the fetus due to Timed Release Ultra Mega II (Iron (Ferrous Citrate)) sucrose. Because animal reproductive studies are not always predictive of human response, Timed Release Ultra Mega II (Iron (Ferrous Citrate)) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether Timed Release Ultra Mega II (Iron (Ferrous Citrate)) sucrose is excreted in human milk. Timed Release Ultra Mega II (Iron (Ferrous Citrate)) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when Timed Release Ultra Mega II (Iron (Ferrous Citrate)) is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of Timed Release Ultra Mega II ) for Timed Release Ultra Mega II (Iron (Ferrous Citrate)) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

Safety and effectiveness of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) for Timed Release Ultra Mega II (Iron (Ferrous Citrate)) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. Timed Release Ultra Mega II (Iron (Ferrous Citrate)) at doses of 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg was administered. All three doses maintained hemoglobin between 10.5 g/dL and 14.0 g/dL in about 50% of subjects over the 12-week treatment period with stable EPO dosing. [See Clinical Studies (14.6)]

Timed Release Ultra Mega II (Iron (Ferrous Citrate)) has not been studied in patients younger than 2 years of age.

In a country where Timed Release Ultra Mega II (Iron (Ferrous Citrate)) is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five died during or following a period when they received Timed Release Ultra Mega II (Iron (Ferrous Citrate)), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Timed Release Ultra Mega II (Iron (Ferrous Citrate)) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 1,051 patients in two post-marketing safety studies of Timed Release Ultra Mega II (Iron (Ferrous Citrate)), 40% were 65 years and older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

No data are available regarding overdosage of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) in humans. Excessive dosages of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) may lead to accumulation of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) in storage sites potentially leading to hemosiderosis. Do not administer Timed Release Ultra Mega II (Iron (Ferrous Citrate)) to patients with Timed Release Ultra Mega II (Iron (Ferrous Citrate)) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Timed Release Ultra Mega II (Iron (Ferrous Citrate)) sucrose doses up to 8 times the maximum recommended human dose based on body surface area, included sedation, hypoactivity, pale eyes, bleeding in the gastrointestinal tract and lungs, and mortality.

11 DESCRIPTION

Timed Release Ultra Mega II (Iron (Ferrous Citrate)) (iron sucrose injection, USP), an Timed Release Ultra Mega II (Iron (Ferrous Citrate)) replacement product, is a brown, sterile, aqueous, complex of polynuclear Timed Release Ultra Mega II (Iron (Ferrous Citrate)) (III)-hydroxide in sucrose for intravenous use. Timed Release Ultra Mega II (Iron (Ferrous Citrate)) sucrose injection has a molecular weight of approximately 34,000 to 60,000 daltons and a proposed structural formula:

[Na₂Fe₅O₈(OH) ·3(H₂O)]_n ·m(C₁₂H₂₂O₁₁)

where: n is the degree of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) polymerization and m is the number of sucrose molecules associated with the Timed Release Ultra Mega II (Iron (Ferrous Citrate)) (III)-hydroxide.

Each mL contains 20 mg elemental Timed Release Ultra Mega II (Iron (Ferrous Citrate)) as Timed Release Ultra Mega II (Iron (Ferrous Citrate)) sucrose in water for injection. Timed Release Ultra Mega II (Iron (Ferrous Citrate)) is available in 10 mL single-use vials (200 mg elemental Timed Release Ultra Mega II (Iron (Ferrous Citrate)) per 10 mL), 5 mL single-use vials (100 mg elemental Timed Release Ultra Mega II (Iron (Ferrous Citrate)) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Timed Release Ultra Mega II (Iron (Ferrous Citrate)) per 2.5 mL). The drug product contains approximately 30% sucrose w/v (300 mg/mL) and has a pH of 10.5 to 11.1. The product contains no preservatives. The osmolarity of the injection is 1,250 mOsmol/L.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Timed Release Ultra Mega II ) is an aqueous complex of poly-nuclear Timed Release Ultra Mega II (Iron (Ferrous Citrate)) (III)-hydroxide in sucrose. Following intravenous administration, Timed Release Ultra Mega II (Iron (Ferrous Citrate)) is dissociated into Timed Release Ultra Mega II (Iron (Ferrous Citrate)) and sucrose and the Timed Release Ultra Mega II (Iron (Ferrous Citrate)) is transported as a complex with transferrin to target cells including erythroid precursor cells. The Timed Release Ultra Mega II (Iron (Ferrous Citrate)) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.

12.2 Pharmacodynamics

Following intravenous administration, Timed Release Ultra Mega II (Iron (Ferrous Citrate)) is dissociated into Timed Release Ultra Mega II (Iron (Ferrous Citrate)) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with Timed Release Ultra Mega II (Iron (Ferrous Citrate)) sucrose containing 100 mg of Timed Release Ultra Mega II (Iron (Ferrous Citrate)), three times weekly for three weeks, significant increases in serum Timed Release Ultra Mega II (Iron (Ferrous Citrate)) and serum ferritin and significant decreases in total Timed Release Ultra Mega II (Iron (Ferrous Citrate)) binding capacity occurred four weeks from the initiation of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) sucrose treatment.

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of Timed Release Ultra Mega II ), its Timed Release Ultra Mega II (Iron (Ferrous Citrate)) component exhibited first order kinetics with an elimination half-life of 6 h, total clearance of 1.2 L/h, and steady state apparent volume of distribution of 7.9 L. The Timed Release Ultra Mega II (Iron (Ferrous Citrate)) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Timed Release Ultra Mega II (Iron (Ferrous Citrate)) containing 100 mg of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) labeled with ⁵²Fe/⁵⁹Fe in patients with Timed Release Ultra Mega II (Iron (Ferrous Citrate)) deficiency showed that a significant amount of the administered Timed Release Ultra Mega II (Iron (Ferrous Citrate)) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Timed Release Ultra Mega II (Iron (Ferrous Citrate)) trapping compartment.

Following intravenous administration of Timed Release Ultra Mega II (Iron (Ferrous Citrate)), Timed Release Ultra Mega II (Iron (Ferrous Citrate)) sucrose is dissociated into Timed Release Ultra Mega II (Iron (Ferrous Citrate)) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) containing 1,510 mg of sucrose and 100 mg of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) in 12 healthy adults (9 female, 3 male: age range 32 to 52), 68.3% of the sucrose was eliminated in urine in 4 h and 75.4% in 24 h. Some Timed Release Ultra Mega II (Iron (Ferrous Citrate)) was also eliminated in the urine. Neither transferrin nor transferrin receptor levels changed immediately after the dose administration. In this study and another study evaluating a single intravenous dose of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) sucrose containing 500 to 700 mg of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Timed Release Ultra Mega II (Iron (Ferrous Citrate)) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of Timed Release Ultra Mega II (Iron (Ferrous Citrate)), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Timed Release Ultra Mega II (Iron (Ferrous Citrate)), the half-life of total serum Timed Release Ultra Mega II (Iron (Ferrous Citrate)) was 8 hours. The mean Cmax and AUC values were 8545 μg/dl and 31305 hr-μg/dL, respectively, which were 1.42- and 1.67-fold higher than dose adjusted adult Cmax and AUC values.

Timed Release Ultra Mega II (Iron (Ferrous Citrate)) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with Timed Release Ultra Mega II (Iron (Ferrous Citrate)) sucrose.

Timed Release Ultra Mega II (Iron (Ferrous Citrate)) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Timed Release Ultra Mega II (Iron (Ferrous Citrate)) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Timed Release Ultra Mega II (Iron (Ferrous Citrate)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Timed Release Ultra Mega II (Iron (Ferrous Citrate)) (1.2 times the maximum recommended human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.

14 CLINICAL STUDIES

Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Timed Release Ultra Mega II ).

14.1 Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD–CKD)

Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD (77 patients with Timed Release Ultra Mega II (Iron (Ferrous Citrate)) treatment and 24 in the historical control group) with Timed Release Ultra Mega II (Iron (Ferrous Citrate)) deficiency anemia. Eligibility criteria for Timed Release Ultra Mega II (Iron (Ferrous Citrate)) treatment included patients undergoing chronic hemodialysis, receiving erythropoietin, hemoglobin level between 8.0 and 11.0 g/dL, transferrin saturation < 20%, and serum ferritin < 300 ng/mL. The mean age of the patients was 65 years with the age range of 31 to 85 years. Of the 77 patients, 44 (57%) were male and 33 (43%) were female.

Timed Release Ultra Mega II (Iron (Ferrous Citrate)) 100 mg was administered at 10 consecutive dialysis sessions either as slow injection or a slow infusion. The historical control population consisted of 24 patients with similar ferritin levels as patients treated with Timed Release Ultra Mega II (Iron (Ferrous Citrate)), who were off intravenous Timed Release Ultra Mega II (Iron (Ferrous Citrate)) for at least 2 weeks and who had received erythropoietin therapy with hematocrit averaging 31 to 36 for at least two months prior to study entry. The mean age of patients in the historical control group was 56 years, with an age range of 29 to 80 years. Patient age and serum ferritin level were similar between treatment and historical control patients.

Patients in the Timed Release Ultra Mega II (Iron (Ferrous Citrate)) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.

**p < 0.01 and *p < 0.05 compared to historical control from ANCOVA analysis with baseline hemoglobin, serum ferritin and erythropoietin dose as covariates.
Efficacy parameters	End of treatment		2 week follow-up		5 week follow-up
	Timed Release Ultra Mega II (Iron (Ferrous Citrate)) (n=69	Historical Control (n=18)	Timed Release Ultra Mega II (Iron (Ferrous Citrate)) (n=73)	Historical Control (n=18)	Timed Release Ultra Mega II (Iron (Ferrous Citrate)) (n=71)	Historical Control (n=15)
Hemoglobin (g/dL)	1.0 ± 0.12**	0.0 ± 0.21	1.3 ± 0.14**	-0.6 ± 0.24	1.2 ± 0.17*	-0.1 ± 0.23
Hematocrit (%)	3.1 ± 0.37**	-0.3 ± 0.65	3.6 ± 0.44**	-1.2 ± 0.76	3.3 ± 0.54	0.2 ± 0.86

Serum ferritin increased at endpoint of study from baseline in the Venofer-treated population (165.3 ± 24.2 ng/mL) compared to the historical control population (-27.6 ± 9.5 ng/mL). Transferrin saturation also increased at endpoint of study from baseline in the Venofer-treated population (8.8 ± 1.6%) compared to this historical control population (-5.1 ± 4.3%).

14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease

Study B was a multicenter, open label study of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) in 23 patients with Timed Release Ultra Mega II (Iron (Ferrous Citrate)) deficiency and HDD-CKD who had been discontinued from Timed Release Ultra Mega II (Iron (Ferrous Citrate)) dextran due to intolerance. Eligibility criteria were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21 to 79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female.

All 23 enrolled patients were evaluated for efficacy. Increases in mean hemoglobin (1.1 ± 0.2 g/dL), hematocrit (3.6 ± 0.6%), serum ferritin (266.3 ± 30.3 ng/mL) and transferrin saturation (8.7 ± 2.0%) were observed from baseline to end of treatment.

14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease

Study C was a multicenter, open-label study in patients with HDD-CKD. This study enrolled patients with a hemoglobin ≤ 10 g/dL, a serum transferrin saturation ≤ 20%, and a serum ferritin ≤ 200 ng/mL, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patients enrolled in this study was 41 years, with ages ranging from 16 to 70 years. Of 130 patients evaluated for efficacy in this study, 68 (52%) were male and 62 (48%) were female. Forty-eight percent of the patients had previously been treated with oral Timed Release Ultra Mega II (Iron (Ferrous Citrate)). Exclusion criteria were similar to those in studies A and B. Timed Release Ultra Mega II (Iron (Ferrous Citrate)) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) was administered. A 50 mg dose (2.5 mL) was given to patients within two weeks of study entry as a test dose. Twenty-seven patients (20%) were receiving erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for the duration of the study.

The modified intention-to-treat (mITT) population consisted of 131 patients. Increases from baseline in mean hemoglobin (1.7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained increased at week 4 of the observation period.

14.4 Study D: Non-Dialysis Dependent-Chronic Kidney Disease

Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral Timed Release Ultra Mega II (Iron (Ferrous Citrate)) versus Timed Release Ultra Mega II (Iron (Ferrous Citrate)) in patients with NDD-CKD with or without erythropoietin therapy. Erythropoietin therapy was stable for 8 weeks prior to randomization. In the study 188 patients with NDD-CKD, hemoglobin of ≤ 11.0 g/dL, transferrin saturation ≤ 25%, ferritin ≤ 300 ng/mL were randomized to receive oral Timed Release Ultra Mega II (Iron (Ferrous Citrate)) (325 mg ferrous sulfate three times daily for 56 days); or Timed Release Ultra Mega II (Iron (Ferrous Citrate)) (either 200 mg over 2 to 5 minutes 5 times within 14 days or two 500 mg infusions on Day 1 and Day 14, administered over 3.5 to 4 hours). The mean age of the 91 treated patients in the Timed Release Ultra Mega II (Iron (Ferrous Citrate)) group was 61.6 years (range 25 to 86 years) and 64 years (range 21 to 86 years) for the 91 patients in the oral Timed Release Ultra Mega II (Iron (Ferrous Citrate)) group.

A statistically significantly greater proportion of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) subjects (35/79; 44.3%) compared to oral Timed Release Ultra Mega II (Iron (Ferrous Citrate)) subjects (23/82; 28%) had an increase in hemoglobin ≥ 1 g/dL at anytime during the study (p = 0.03).

14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease

Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and intravenous Timed Release Ultra Mega II (Iron (Ferrous Citrate)) to patients with PDD-CKD receiving an erythropoietin alone without Timed Release Ultra Mega II (Iron (Ferrous Citrate)) supplementation. Patients with PDD-CKD, stable erythropoietin for 8 weeks, hemoglobin of ≤ 11.5 g/dL, TSAT ≤ 25%, ferritin ≤ 500 ng/mL were randomized to receive either no Timed Release Ultra Mega II (Iron (Ferrous Citrate)) or Timed Release Ultra Mega II (Iron (Ferrous Citrate)) (300 mg in 250 mL 0.9% NaCl over 1.5 hours on Day 1 and 15 and 400 mg in 250 mL 0.9% NaCl over 2.5 hours on Day 29). The mean age of the 75 treated patients in the Timed Release Ultra Mega II (Iron (Ferrous Citrate)) / erythropoietin group was 51.9 years (range 21 to 81 years) vs. 52.8 years (range 23 to 77 years) for 46 patients in the erythropoietin alone group.

Patients in the Timed Release Ultra Mega II (Iron (Ferrous Citrate)) / erythropoietin group had statistically significantly greater mean change from baseline to the highest hemoglobin value (1.3 g/dL), compared to subjects who received erythropoietin alone (0.6 g/dL) (p < 0.01). A greater proportion of subjects treated with Timed Release Ultra Mega II (Iron (Ferrous Citrate)) / erythropoietin (59.1 %) had an increase in hemoglobin of ≥ 1 g/dL at any time during the study compared to the subjects who received erythropoietin only (33.3%).

14.6 Study F: Timed Release Ultra Mega II ) Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney Disease

Study F was a randomized, open-label, dose-ranging study for Timed Release Ultra Mega II (Iron (Ferrous Citrate)) maintenance treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD on stable erythropoietin therapy. The study randomized patients to one of three doses of Timed Release Ultra Mega II (Iron (Ferrous Citrate)) (0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg). The mean age was 13 years (range 2 to 20 years). Over 70% of patients were 12 years or older in all three groups. There were 84 males and 61 females. About 60% of patients underwent hemodialysis and 25% underwent peritoneal dialysis in all three dose groups. At baseline, the mean hemoglobin was 12 g/dL, the mean TSAT was 33% and the mean ferritin was 300 ng/mL. Patients with HDD-CKD received Timed Release Ultra Mega II (Iron (Ferrous Citrate)) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Timed Release Ultra Mega II (Iron (Ferrous Citrate)) once every 4 weeks for 3 doses. Among 131 evaluable patients with stable erythropoietin dosing, the proportion of patients who maintained hemoglobin between 10.5 g/dL and 14.0 g/dL during the 12-week treatment period was 58.7%, 46.7%, and 45.0% in the Timed Release Ultra Mega II (Iron (Ferrous Citrate)) 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.

16 HOW SUPPLIED/storage and handling

16.1 How Supplied

Timed Release Ultra Mega II ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Timed Release Ultra Mega II (Iron (Ferrous Citrate)), each 5 mL vial contains 100 mg elemental Timed Release Ultra Mega II (Iron (Ferrous Citrate)), and each 2.5 mL vial contains 50 mg elemental Timed Release Ultra Mega II (Iron (Ferrous Citrate)) (20 mg/mL).

NDC-0517-2310-05	200 mg/10 mL Single-Use Vial	Packages of 5
NDC-0517-2310-10	200 mg/10 mL Single-Use Vial	Packages of 10
NDC-0517-2340-01	100 mg/5 mL Single-Use Vial	Individually Boxed
NDC-0517-2340-10	100 mg/5 mL Single-Use Vial	Packages of 10
NDC-0517-2340-25	100 mg/5 mL Single-Use Vial	Packages of 25
NDC-0517-2340-99	100 mg/5 mL Single-Use Vial	Packages of 10
NDC-0517-2325-10	50 mg/2.5 mL Single-Use Vial	Packages of 10
NDC-0517-2325-25	50 mg/2.5 mL Single-Use Vial	Packages of 25

16.2 Stability and Storage

Contains no preservatives. Store in original carton at 20°C to 25°C (68° F to 77° F); excursions permitted to 15° to 30°C (59° to 86°F).. Do not freeze.

Syringe Stability: Timed Release Ultra Mega II (Iron (Ferrous Citrate)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Timed Release Ultra Mega II (Iron (Ferrous Citrate)) per mL, or undiluted (20 mg elemental Timed Release Ultra Mega II (Iron (Ferrous Citrate)) per mL) and stored in a plastic syringe, was found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C) and under refrigeration (4°C ± 2°C).

Intravenous Admixture Stability: Timed Release Ultra Mega II (Iron (Ferrous Citrate)), when added to intravenous infusion bags (PVC or non-PVC) containing 0.9% NaCl at concentrations ranging from 1 mg to 2 mg of elemental Timed Release Ultra Mega II (Iron (Ferrous Citrate)) per mL, has been found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C).

Do not dilute to concentrations below 1 mg/mL.

Do not mix Timed Release Ultra Mega II (Iron (Ferrous Citrate)) with other medications or add to parenteral nutrition solutions for intravenous infusion.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion.

17 PATIENT COUNSELING INFORMATION

Prior to Timed Release Ultra Mega II (Iron (Ferrous Citrate)) administration:

• Question patients regarding any prior history of reactions to parenteral Timed Release Ultra Mega II (Iron (Ferrous Citrate)) products
• Advise patients of the risks associated with Timed Release Ultra Mega II (Iron (Ferrous Citrate))
• Advise patients to report any symptoms of hypersensitivity that may develop during and following Timed Release Ultra Mega II (Iron (Ferrous Citrate)) administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems [see Warnings and Precautions (5)]

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Timed Release Ultra Mega II (Iron (Ferrous Citrate)) is manufactured under license from Vifor (International) Inc., Switzerland.

PremierProRx^® is a trademark of Premier, Inc., used under license.

PREMIERProRx^®

IN2340

MG #15727

Iron (Ferrous HVP Chelate):

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) reviews

1 INDICATIONS AND USAGE

Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) is indicated for the treatment of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) deficiency anemia in patients with chronic kidney disease (CKD).

Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) is an Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) replacement product indicated for the treatment of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Timed Release Ultra Mega II ) must only be administered intravenously either by slow injection or by infusion. The dosage of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) is expressed in mg of elemental Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)). Each mL contains 20 mg of elemental Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)).

Population		Dose
Adult patients	Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) (2.1)	100 mg slow intravenous injection or infusion
	Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) (2.2)	200 mg slow intravenous injection or infusion
	Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) (2.3)	300 mg or 400 mg intravenous infusion
Pediatric patients	HDD-CKD (2.4), PDD-CKD or NDD-CKD (2.5)	0.5 mg/kg slow intravenous injection or infusion

2.1 Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)

Administer Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session. Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) should be administered early during the dialysis session. The usual total treatment course of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) is 1000 mg. Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) treatment may be repeated if Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) deficiency reoccurs.

2.2 Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease

Administer Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) 200 mg undiluted as a slow intravenous injection over 2 to 5 minutes or as an infusion of 200 mg in a maximum of 100 mL of 0.9% NaCl over a period of 15 minutes. Administer on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion of 500 mg of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)), diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on Day 1 and Day 14. Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) treatment may be repeated if Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg over 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) in a maximum of 250 mL of 0.9% NaCl. Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) treatment may be repeated if Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) maintenance treatment

The dosing for Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) maintenance treatment: Administer Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every two weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) maintenance treatment

The dosing for Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) maintenance treatment: Administer Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every four weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

• 10 mL single-use vial / 200 mg elemental Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) (20 mg/mL)
• 5 mL single-use vial / 100 mg elemental Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) (20 mg/mL)
• 2.5 mL single-use vial / 50 mg elemental Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) (20 mg/mL)

• 10 mL single-use vial / 200 mg elemental Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) (20 mg/mL) (3)
• 5 mL single-use vial / 100 mg elemental Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) (20 mg/mL) (3)
• 2.5 mL single-use vial / 50 mg elemental Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

• Known hypersensitivity to Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate))

• Known hypersensitivity to Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) (4)

5 WARNINGS AND PRECAUTIONS

• Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Timed Release Ultra Mega II ) administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1)
• Hypotension: Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)). (5.2)
• Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) Overload: Regularly monitor hematologic responses during Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) therapy. Do not administer Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) to patients with Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) overload. (5.3)

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)). Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) preparations occur within 30 minutes of the completion of the infusion .

5.2 Hypotension

Timed Release Ultra Mega II ) may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)). Hypotension following administration of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) may be related to the rate of administration and/or total dose administered .

5.3 Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) Overload

Excessive therapy with parenteral Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) can lead to excess storage of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) require periodic monitoring of hematologic and Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) to patients with evidence of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) sucrose; do not perform serum Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) measurements for at least 48 hours after intravenous dosing .

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Timed Release Ultra Mega II ) are described in other sections .

• The most common adverse reactions (≥2%) following the administration of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) are diarrhea, nausea, vomiting, headache, dizziness, hypotension, pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection site reactions, chest pain, and peripheral edema. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Adverse Reactions in Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.

Adverse Reactions in Adults Patients with CKD

Adverse Reactions in Adult Patients with CKD

The frequency of adverse reactions associated with the use of Timed Release Ultra Mega II ) has been documented in six clinical trials involving 231 patients with HDD-CKD, 139 patients with NDD-CKD and 75 patients with PDD-CKD. Treatment-emergent adverse reactions reported by ≥ 2% of treated patients in the six clinical trials for which the rate for Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks.

* EPO=Erythropoietin
Adverse Reactions (Preferred Term)	HDD-CKD	NDD-CKD		PDD-CKD
	Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate))	Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate))	Oral Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate))	Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate))	EPO* Only
	(N=231)	(N=139)	(N=139)	(N=75)	(N=46)
	%	%	%	%	%
Subjects with any adverse reaction	78.8	76.3	73.4	72.0	65.2
Ear and Labyrinth Disorders
Ear Pain	0	2.2	0.7	0	0
Eye Disorders
Conjunctivitis	0.4	0	0	2.7	0
Gastrointestinal Disorders
Abdominal pain	3.5	1.4	2.9	4.0	6.5
Diarrhea	5.2	7.2	10.1	8.0	4.3
Dysgeusia	0.9	7.9	0	0	0
Nausea	14.7	8.6	12.2	5.3	4.3
Vomiting	9.1	5.0	8.6	8.0	2.2
General Disorders and
Administration Site Conditions
Asthenia	2.2	0.7	2.2	2.7	0
Chest pain	6.1	1.4	0	2.7	0
Feeling abnormal	3.0	0	0	0	0
Infusion site pain or burning	0	5.8	0	0	0
Injection site extravasation	0	2.2	0	0	0
Peripheral edema	2.6	7.2	5.0	5.3	10.9
Pyrexia	3.0	0.7	0.7	1.3	0
Infections and Infestations
Nasopharyngitis, Sinusitis, Upper respiratory tract infections, Pharyngitis	2.6	2.2	4.3	16.0	4.3
Injury, Poisoning and Procedural
Complications
Graft complication	9.5	1.4	0	0	0
Metabolism and Nutrition Disorders
Fluid overload	3.0	1.4	0.7	1.3	0
Gout	0	2.9	1.4	0	0
Hyperglycemia	0	2.9	0	0	2.2
Hypoglycemia	0.4	0.7	0.7	4.0	0
Musculoskeletal and Connective
Tissue Disorders
Arthralgia	3.5	1.4	2.2	4.0	4.3
Back pain	2.2	2.2	3.6	1.3	4.3
Muscle cramp	29.4	0.7	0.7	2.7	0
Myalgia	0	3.6	0	1.3	0
Pain in extremity	5.6	4.3	0	2.7	6.5
Nervous System Disorders
Dizziness	6.5	6.5	1.4	1.3	4.3
Headache	12.6	2.9	0.7	4.0	0
Respiratory, Thoracic and
Mediastinal Disorders
Cough	3.0	2.2	0.7	1.3	0
Dyspnea	3.5	5.8	1.4	1.3	2.2
Nasal congestion	0	1.4	2.2	1.3	0
Skin and Subcutaneous
Tissue Disorders
Pruritus	3.9	2.2	4.3	2.7	0
Vascular Disorders
Hypertension	6.5	6.5	4.3	8.0	6.5
Hypotension	39.4	2.2	0.7	2.7	2.2

One hundred thirty (11%) of the 1,151 patients evaluated in the 4 U.S. trials in HDD-CKD patients (studies A, B and the two post marketing studies) had prior other intravenous Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) therapy and were reported to be intolerant (defined as precluding further use of that Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) product). When these patients were treated with Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) there were no occurrences of adverse reactions that precluded further use of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) .

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

In a randomized, open-label, dose-ranging trial for Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) maintenance treatment with Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) in pediatric patients with CKD on stable erythropoietin therapy , at least one treatment-emergent adverse reaction was experienced by 57% (27/47) of the patients receiving Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) 0.5 mg/kg, 53% (25/47) of the patients receiving Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) 1.0 mg/kg, and 55% (26/47) of the patients receiving Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) 2.0 mg/kg.

A total of 5 (11%) subjects in the Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) 0.5 mg/kg group, 10 (21%) patients in the Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) 1.0 mg/kg group, and 10 (21%) patients in the Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) 2.0 mg/kg group experienced at least 1 serious adverse reaction during the study. The most common treatment-emergent adverse reactions (> 2% of patients) in all patients were headache (6%), respiratory tract viral infection (4%), peritonitis (4%), vomiting (4%), pyrexia (4%), dizziness (4%), cough (4%), renal transplant (4%), nausea (3%), arteriovenous fistula thrombosis (2%), hypotension (2%), and hypertension (2.1%).

6.2 Adverse Reactions from Post-Marketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis and dysgeusia.

The following adverse reactions have been identified during post-approval use of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Anaphylactic-type reactions, shock, loss of consciousness, collapse, bronchospasm, dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints, hyperhidrosis, back pain, bradycardia, and chromaturia.

Symptoms associated with Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. These adverse reactions have occurred up to 30 minutes after the administration of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) injection. Reactions have occurred following the first dose or subsequent doses of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)). Symptoms may respond to intravenous fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms.

Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation.

7 DRUG INTERACTIONS

Drug interactions involving Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) have not been studied. However, Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) may reduce the absorption of concomitantly administered oral Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) preparations.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, Timed Release Ultra Mega II ) sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) (half or equivalent to the maximum recommended human dose based on body surface area, respectively) and revealed no evidence of harm to the fetus due to Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) sucrose. Because animal reproductive studies are not always predictive of human response, Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) sucrose is excreted in human milk. Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of Timed Release Ultra Mega II ) for Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

Safety and effectiveness of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) for Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) at doses of 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg was administered. All three doses maintained hemoglobin between 10.5 g/dL and 14.0 g/dL in about 50% of subjects over the 12-week treatment period with stable EPO dosing. [See Clinical Studies (14.6)]

Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) has not been studied in patients younger than 2 years of age.

In a country where Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five died during or following a period when they received Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 1,051 patients in two post-marketing safety studies of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)), 40% were 65 years and older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

No data are available regarding overdosage of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) in humans. Excessive dosages of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) may lead to accumulation of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) in storage sites potentially leading to hemosiderosis. Do not administer Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) to patients with Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) sucrose doses up to 8 times the maximum recommended human dose based on body surface area, included sedation, hypoactivity, pale eyes, bleeding in the gastrointestinal tract and lungs, and mortality.

11 DESCRIPTION

Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) (iron sucrose injection, USP), an Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) replacement product, is a brown, sterile, aqueous, complex of polynuclear Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) (III)-hydroxide in sucrose for intravenous use. Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) sucrose injection has a molecular weight of approximately 34,000 to 60,000 daltons and a proposed structural formula:

[Na₂Fe₅O₈(OH) ·3(H₂O)]_n ·m(C₁₂H₂₂O₁₁)

where: n is the degree of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) polymerization and m is the number of sucrose molecules associated with the Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) (III)-hydroxide.

Each mL contains 20 mg elemental Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) as Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) sucrose in water for injection. Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) is available in 10 mL single-use vials (200 mg elemental Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) per 10 mL), 5 mL single-use vials (100 mg elemental Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) per 2.5 mL). The drug product contains approximately 30% sucrose w/v (300 mg/mL) and has a pH of 10.5 to 11.1. The product contains no preservatives. The osmolarity of the injection is 1,250 mOsmol/L.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Timed Release Ultra Mega II ) is an aqueous complex of poly-nuclear Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) (III)-hydroxide in sucrose. Following intravenous administration, Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) is dissociated into Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) and sucrose and the Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) is transported as a complex with transferrin to target cells including erythroid precursor cells. The Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.

12.2 Pharmacodynamics

Following intravenous administration, Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) is dissociated into Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) sucrose containing 100 mg of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)), three times weekly for three weeks, significant increases in serum Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) and serum ferritin and significant decreases in total Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) binding capacity occurred four weeks from the initiation of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) sucrose treatment.

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of Timed Release Ultra Mega II ), its Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) component exhibited first order kinetics with an elimination half-life of 6 h, total clearance of 1.2 L/h, and steady state apparent volume of distribution of 7.9 L. The Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) containing 100 mg of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) labeled with ⁵²Fe/⁵⁹Fe in patients with Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) deficiency showed that a significant amount of the administered Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) trapping compartment.

Following intravenous administration of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)), Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) sucrose is dissociated into Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) containing 1,510 mg of sucrose and 100 mg of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) in 12 healthy adults (9 female, 3 male: age range 32 to 52), 68.3% of the sucrose was eliminated in urine in 4 h and 75.4% in 24 h. Some Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) was also eliminated in the urine. Neither transferrin nor transferrin receptor levels changed immediately after the dose administration. In this study and another study evaluating a single intravenous dose of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) sucrose containing 500 to 700 mg of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)), the half-life of total serum Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) was 8 hours. The mean Cmax and AUC values were 8545 μg/dl and 31305 hr-μg/dL, respectively, which were 1.42- and 1.67-fold higher than dose adjusted adult Cmax and AUC values.

Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) sucrose.

Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) (1.2 times the maximum recommended human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.

14 CLINICAL STUDIES

Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Timed Release Ultra Mega II ).

14.1 Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD–CKD)

Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD (77 patients with Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) treatment and 24 in the historical control group) with Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) deficiency anemia. Eligibility criteria for Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) treatment included patients undergoing chronic hemodialysis, receiving erythropoietin, hemoglobin level between 8.0 and 11.0 g/dL, transferrin saturation < 20%, and serum ferritin < 300 ng/mL. The mean age of the patients was 65 years with the age range of 31 to 85 years. Of the 77 patients, 44 (57%) were male and 33 (43%) were female.

Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) 100 mg was administered at 10 consecutive dialysis sessions either as slow injection or a slow infusion. The historical control population consisted of 24 patients with similar ferritin levels as patients treated with Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)), who were off intravenous Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) for at least 2 weeks and who had received erythropoietin therapy with hematocrit averaging 31 to 36 for at least two months prior to study entry. The mean age of patients in the historical control group was 56 years, with an age range of 29 to 80 years. Patient age and serum ferritin level were similar between treatment and historical control patients.

Patients in the Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.

**p < 0.01 and *p < 0.05 compared to historical control from ANCOVA analysis with baseline hemoglobin, serum ferritin and erythropoietin dose as covariates.
Efficacy parameters	End of treatment		2 week follow-up		5 week follow-up
	Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) (n=69	Historical Control (n=18)	Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) (n=73)	Historical Control (n=18)	Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) (n=71)	Historical Control (n=15)
Hemoglobin (g/dL)	1.0 ± 0.12**	0.0 ± 0.21	1.3 ± 0.14**	-0.6 ± 0.24	1.2 ± 0.17*	-0.1 ± 0.23
Hematocrit (%)	3.1 ± 0.37**	-0.3 ± 0.65	3.6 ± 0.44**	-1.2 ± 0.76	3.3 ± 0.54	0.2 ± 0.86

Serum ferritin increased at endpoint of study from baseline in the Venofer-treated population (165.3 ± 24.2 ng/mL) compared to the historical control population (-27.6 ± 9.5 ng/mL). Transferrin saturation also increased at endpoint of study from baseline in the Venofer-treated population (8.8 ± 1.6%) compared to this historical control population (-5.1 ± 4.3%).

14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease

Study B was a multicenter, open label study of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) in 23 patients with Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) deficiency and HDD-CKD who had been discontinued from Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) dextran due to intolerance. Eligibility criteria were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21 to 79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female.

All 23 enrolled patients were evaluated for efficacy. Increases in mean hemoglobin (1.1 ± 0.2 g/dL), hematocrit (3.6 ± 0.6%), serum ferritin (266.3 ± 30.3 ng/mL) and transferrin saturation (8.7 ± 2.0%) were observed from baseline to end of treatment.

14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease

Study C was a multicenter, open-label study in patients with HDD-CKD. This study enrolled patients with a hemoglobin ≤ 10 g/dL, a serum transferrin saturation ≤ 20%, and a serum ferritin ≤ 200 ng/mL, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patients enrolled in this study was 41 years, with ages ranging from 16 to 70 years. Of 130 patients evaluated for efficacy in this study, 68 (52%) were male and 62 (48%) were female. Forty-eight percent of the patients had previously been treated with oral Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)). Exclusion criteria were similar to those in studies A and B. Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) was administered. A 50 mg dose (2.5 mL) was given to patients within two weeks of study entry as a test dose. Twenty-seven patients (20%) were receiving erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for the duration of the study.

The modified intention-to-treat (mITT) population consisted of 131 patients. Increases from baseline in mean hemoglobin (1.7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained increased at week 4 of the observation period.

14.4 Study D: Non-Dialysis Dependent-Chronic Kidney Disease

Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) versus Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) in patients with NDD-CKD with or without erythropoietin therapy. Erythropoietin therapy was stable for 8 weeks prior to randomization. In the study 188 patients with NDD-CKD, hemoglobin of ≤ 11.0 g/dL, transferrin saturation ≤ 25%, ferritin ≤ 300 ng/mL were randomized to receive oral Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) (325 mg ferrous sulfate three times daily for 56 days); or Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) (either 200 mg over 2 to 5 minutes 5 times within 14 days or two 500 mg infusions on Day 1 and Day 14, administered over 3.5 to 4 hours). The mean age of the 91 treated patients in the Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) group was 61.6 years (range 25 to 86 years) and 64 years (range 21 to 86 years) for the 91 patients in the oral Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) group.

A statistically significantly greater proportion of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) subjects (35/79; 44.3%) compared to oral Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) subjects (23/82; 28%) had an increase in hemoglobin ≥ 1 g/dL at anytime during the study (p = 0.03).

14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease

Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and intravenous Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) to patients with PDD-CKD receiving an erythropoietin alone without Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) supplementation. Patients with PDD-CKD, stable erythropoietin for 8 weeks, hemoglobin of ≤ 11.5 g/dL, TSAT ≤ 25%, ferritin ≤ 500 ng/mL were randomized to receive either no Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) or Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) (300 mg in 250 mL 0.9% NaCl over 1.5 hours on Day 1 and 15 and 400 mg in 250 mL 0.9% NaCl over 2.5 hours on Day 29). The mean age of the 75 treated patients in the Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) / erythropoietin group was 51.9 years (range 21 to 81 years) vs. 52.8 years (range 23 to 77 years) for 46 patients in the erythropoietin alone group.

Patients in the Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) / erythropoietin group had statistically significantly greater mean change from baseline to the highest hemoglobin value (1.3 g/dL), compared to subjects who received erythropoietin alone (0.6 g/dL) (p < 0.01). A greater proportion of subjects treated with Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) / erythropoietin (59.1 %) had an increase in hemoglobin of ≥ 1 g/dL at any time during the study compared to the subjects who received erythropoietin only (33.3%).

14.6 Study F: Timed Release Ultra Mega II ) Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney Disease

Study F was a randomized, open-label, dose-ranging study for Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) maintenance treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD on stable erythropoietin therapy. The study randomized patients to one of three doses of Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) (0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg). The mean age was 13 years (range 2 to 20 years). Over 70% of patients were 12 years or older in all three groups. There were 84 males and 61 females. About 60% of patients underwent hemodialysis and 25% underwent peritoneal dialysis in all three dose groups. At baseline, the mean hemoglobin was 12 g/dL, the mean TSAT was 33% and the mean ferritin was 300 ng/mL. Patients with HDD-CKD received Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) once every 4 weeks for 3 doses. Among 131 evaluable patients with stable erythropoietin dosing, the proportion of patients who maintained hemoglobin between 10.5 g/dL and 14.0 g/dL during the 12-week treatment period was 58.7%, 46.7%, and 45.0% in the Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.

16 HOW SUPPLIED/storage and handling

16.1 How Supplied

Timed Release Ultra Mega II ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)), each 5 mL vial contains 100 mg elemental Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)), and each 2.5 mL vial contains 50 mg elemental Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) (20 mg/mL).

NDC-0517-2310-05	200 mg/10 mL Single-Use Vial	Packages of 5
NDC-0517-2310-10	200 mg/10 mL Single-Use Vial	Packages of 10
NDC-0517-2340-01	100 mg/5 mL Single-Use Vial	Individually Boxed
NDC-0517-2340-10	100 mg/5 mL Single-Use Vial	Packages of 10
NDC-0517-2340-25	100 mg/5 mL Single-Use Vial	Packages of 25
NDC-0517-2340-99	100 mg/5 mL Single-Use Vial	Packages of 10
NDC-0517-2325-10	50 mg/2.5 mL Single-Use Vial	Packages of 10
NDC-0517-2325-25	50 mg/2.5 mL Single-Use Vial	Packages of 25

16.2 Stability and Storage

Contains no preservatives. Store in original carton at 20°C to 25°C (68° F to 77° F); excursions permitted to 15° to 30°C (59° to 86°F).. Do not freeze.

Syringe Stability: Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) per mL, or undiluted (20 mg elemental Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) per mL) and stored in a plastic syringe, was found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C) and under refrigeration (4°C ± 2°C).

Intravenous Admixture Stability: Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)), when added to intravenous infusion bags (PVC or non-PVC) containing 0.9% NaCl at concentrations ranging from 1 mg to 2 mg of elemental Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) per mL, has been found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C).

Do not dilute to concentrations below 1 mg/mL.

Do not mix Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) with other medications or add to parenteral nutrition solutions for intravenous infusion.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion.

17 PATIENT COUNSELING INFORMATION

Prior to Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) administration:

• Question patients regarding any prior history of reactions to parenteral Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) products
• Advise patients of the risks associated with Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate))
• Advise patients to report any symptoms of hypersensitivity that may develop during and following Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems [see Warnings and Precautions (5)]

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Timed Release Ultra Mega II (Iron (Ferrous HVP Chelate)) is manufactured under license from Vifor (International) Inc., Switzerland.

PremierProRx^® is a trademark of Premier, Inc., used under license.

PREMIERProRx^®

IN2340

MG #15727

Magnesium (Magnesium Citrate):

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• References
• Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) reviews

Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) Sulfate Injection, USP is a sterile solution of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate heptahydrate in Water for Injection, USP administered by the intravenous or intramuscular routes as an electrolyte replenisher or anticonvulsant. Must be diluted before intravenous use. May contain sulfuric acid and/or sodium hydroxide for pH adjustment. The pH is 5.5 to 7.0. The 50% concentration has an osmolarity of 4.06 mOsmol/mL (calc.).

The solution contains no bacteriostat, antimicrobial agent or added buffer (except for pH adjustment) and is intended only for use as a single-dose injection. When smaller doses are required the unused portion should be discarded with the entire unit.

Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) Sulfate, USP heptahydrate is chemically designated MgSO₄ - 7H₂O with molecular weight of 246.48 and occurs as colorless crystals or white powder freely soluble in water.

The plastic syringe is molded from a specially formulated polypropylene. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the syringe material.

CLINICAL PHARMACOLOGY

Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) (Mg⁺⁺) is an important cofactor for enzymatic reactions and plays an important role in neurochemical transmission and muscular excitability.

As a nutritional adjunct in hyperalimentation, the precise mechanism of action for Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) is uncertain. Early symptoms of hypomagnesemia (less than 1.5 mEq/liter) may develop as early as three to four days or within weeks.

Predominant deficiency effects are neurological, e.g., muscle irritability, clonic twitching and tremors. Hypocalcemia and hypokalemia often follow low serum levels of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)). While there are large stores of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) is said to have a depressant effect on the central nervous system (CNS), but it does not adversely affect the woman, fetus or neonate when used as directed in eclampsia or pre-eclampsia. Normal plasma Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) levels range from 1.5 to 2.5 mEq/liter.

As plasma Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) rises above 4 mEq/liter, the deep tendon reflexes are first decreased and then disappear as the plasma level approaches 10 mEq/liter. At this level respiratory paralysis may occur. Heart block also may occur at this or lower plasma levels of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)). Serum Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) concentrations in excess of 12 mEq/L may be fatal.

Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) acts peripherally to produce vasodilation. With low doses only flushing and sweating occur, but larger doses cause lowering of blood pressure. The central and peripheral effects of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) poisoning are antagonized to some extent by intravenous administration of calcium.

Pharmacokinetics

With intravenous administration the onset of anticonvulsant action is immediate and lasts about 30 minutes. Following intramuscular administration the onset of action occurs in about one hour and persists for three to four hours. Effective anticonvulsant serum levels range from 2.5 to 7.5 mEq/liter. Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) Sulfate Injection, USP is suitable for replacement therapy in Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) (Mg⁺⁺) level is usually below the lower limit of normal (1.5 to 2.5 mEq/liter) and the serum calcium (Ca⁺⁺) level is normal (4.3 to 5.3 mEq/liter) or elevated.

In total parenteral nutrition (TPN), Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.

Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) Sulfate Injection, USP is also indicated for the prevention and control of seizures (convulsions) in pre-eclampsia and eclampsia, respectively.

CONTRAINDICATIONS

Parenteral administration of the drug is contraindicated in patients with heart block or myocardial damage.

WARNINGS

FETAL HARM: Continuous administration of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate beyond 5 to 7 days to pregnant women can lead to hypocalcemia and bone abnormalities in the developing fetus. These bone abnormalities include skeletal demineralization and osteopenia. In addition, cases of neonatal fracture have been reported. The shortest duration of treatment that can lead to fetal harm is not known. Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate should be used during pregnancy only if clearly needed. If Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate is given for treatment of preterm labor, the woman should be informed that the efficacy and safety of such use have not been established and that use of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate beyond 5 to 7 days may cause fetal abnormalities.

ALUMINUM TOXICITY: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

Parenteral use in the presence of renal insufficiency may lead to Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) intoxication. Intravenous use in the eclampsia should be reserved for immediate control of life-threatening convulsions.

PRECAUTIONS

General

Administer with caution if flushing and sweating occurs. When barbiturates, narcotics or other hypnotics (or systemic anesthetics) are to be given in conjunction with Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)).

Because Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) is removed from the body solely by the kidneys, the drug should be used with caution in patients with renal impairment. Urine output should be maintained at a level of 100 mL or more during the four hours preceding each dose. Monitoring serum Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) levels and the patient's clinical status is essential to avoid the consequences of overdosage in toxemia. Clinical indications of a safe dosage regimen include the presence of the patellar reflex (knee jerk) and absence of respiratory depression (approximately 16 breaths or more/minute). When repeated doses of the drug are given parenterally, knee jerk reflexes should be tested before each dose and if they are absent, no additional Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) should be given until they return. Serum Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) levels usually sufficient to control convulsions range from 3 to 6 mg/100 mL (2.5 to 5 mEq/liter). The strength of the deep tendon reflexes begins to diminish when Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) levels exceed 4 mEq/liter. Reflexes may be absent at 10 mEq magnesium/liter, where respiratory paralysis is a potential hazard. An injectable calcium salt should be immediately available to counteract the potential hazards of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) intoxication in eclampsia.

50% Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) Sulfate Injection, USP must be diluted to a concentration of 20% or less prior to intravenous infusion. Rate of administration should be slow and cautious, to avoid producing hypermagnesemia. The 50% solution also should be diluted to 20% or less for intramuscular injection in infants and children.

Laboratory Tests

Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) is monitored. The normal serum level is 1.5 to 2.5 mEq/L.

Drug Interactions

CNS Depressants - When barbiturates, narcotics or other hypnotics (or systemic anesthetics), or other CNS depressants are to be given in conjunction with Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)). CNS depression and peripheral transmission defects produced by Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) may be antagonized by calcium.

Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.

Cardiac Glycosides - Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate should be administered with extreme caution in digitalized patients, because serious changes in cardiac conduction which can result in heart block may occur if administration of calcium is required to treat Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate can cause fetal abnormalities when administered beyond 5 to 7 days to pregnant women. There are retrospective epidemiological studies and case reports documenting fetal abnormalities such as hypocalcemia, skeletal demineralization, osteopenia and other skeletal abnormalities with continuous maternal administration of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate for more than 5 to 7 days.^1-10 Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate injection should be used during pregnancy only if clearly needed. If this drug is used during pregnancy, the woman should be apprised of the potential harm to the fetus.

Nonteratogenic Effects

When administered by continuous intravenous infusion (especially for more than 24 hours preceding delivery) to control convulsions in a toxemic woman, the newborn may show signs of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate outside of its approved indication in pregnant women should be by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.

Nursing Mothers

Since Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) is distributed into milk during parenteral Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate administration, the drug should be used with caution in nursing women.

Geriatrics

Geriatric patients often require reduced dosage because of impaired renal function. In patients with severe impairment, dosage should not exceed 20 grams in 48 hours. Serum Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) usually are the result of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) intoxication. These include flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, cardiac and central nervous system depression proceeding to respiratory paralysis. Hypocalcemia with signs of tetany secondary to Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) intoxication is manifested by a sharp drop in blood pressure and respiratory paralysis. Disappearance of the patellar reflex is a useful clinical sign to detect the onset of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) intoxication. In the event of overdosage, artificial ventilation must be provided until a calcium salt can be injected intravenously to antagonize the effects of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)).

For Treatment of Overdose

Artificial respiration is often required. Intravenous calcium, 10 to 20 mL of a 5% solution (diluted if desirable with isotonic sodium chloride for injection) is used to counteract effects of hypermagnesemia. Subcutaneous physostigmine, 0.5 to 1 mg may be helpful.

Hypermagnesemia in the newborn may require resuscitation and assisted ventilation via endotracheal intubation or intermittent positive pressure ventilation as well as intravenous calcium.

DOSAGE AND ADMINISTRATION

Dosage of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate must be carefully adjusted according to individual requirements and response, and administration of the drug should be discontinued as soon as the desired effect is obtained.

Both intravenous and intramuscular administration are appropriate. Intramuscular administration of the undiluted 50% solution results in therapeutic plasma levels in 60 minutes, whereas intravenous doses will provide a therapeutic level almost immediately. The rate of intravenous injection should generally not exceed 150 mg/minute (1.5 mL of a 10% concentration or its equivalent), except in severe eclampsia with seizures. Continuous maternal administration of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Solutions for intravenous infusion must be diluted to a concentration of 20% or less prior to administration. The diluents commonly used are 5% Dextrose Injection, USP and 0.9% Sodium Chloride Injection, USP. Deep intramuscular injection of the undiluted (50%) solution is appropriate for adults, but the solution should be diluted to a 20% or less concentration prior to such injection in children.

In Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) Deficiency

In the treatment of mild Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) (2 mL of the 50% solution) injected intramuscularly every six hours for four doses (equivalent to a total of 32.5 mEq of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) per 24 hours). For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given intramuscularly within a period of four hours if necessary. Alternatively, 5 grams, (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow intravenous infusion over a three-hour period. In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.

In Hyperalimentation

In total parenteral nutrition, maintenance requirements for Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) are not precisely known. The maintenance dose used in adults ranges from 8 to 24 mEq (1 gram to 3 grams) daily; for infants, the range is 2 to 10 mEq (0.25 gram to 1.25 grams) daily.

In Pre-eclampsia or Eclampsia

In severe pre-eclampsia or eclampsia, the total initial dose is 10 grams to 14 grams of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate. Intravenously, a dose of 4 grams to 5 grams in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused. Simultaneously, intramuscular doses of up to 10 grams (5 grams or 10 mL of the undiluted 50% solution in each buttock) are given. Alternatively, the initial intravenous dose of 4 grams may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected intravenously over a period of three to four minutes. Subsequently, 4 grams to 5 grams (8 to 10 mL of the 50% solution) are injected intramuscularly into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function. Alternatively, after the initial intravenous dose, some clinicians administer 1 gram to 2 grams/hour by constant intravenous infusion. Therapy should continue until paroxysms cease. A serum Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) level of 6 mg/100 mL is considered optimal for control of seizures. A total daily (24 hr) dose of 30 grams to 40 grams should not be exceeded. In the presence of severe renal insufficiency, the maximum dosage of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate is 20 grams/48 hours and frequent serum Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) concentrations must be obtained. Continuous use of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Other Uses

In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate is 1 gram to 2 grams given intravenously.

For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 gram administered intramuscularly or intravenously.

In paroxysmal atrial tachycardia, Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) should be used only if simpler measures have failed and there is no evidence of myocardial damage. The usual dose is 3 grams to 4 grams (30 to 40 mL of a 10% solution) administered intravenously over 30 seconds with extreme caution.

For reduction of cerebral edema, 2.5 grams (25 mL of a 10% solution) is given intravenously.

Incompatibilities

Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate in solution may result in a precipitate formation when mixed with solutions containing:

Alcohol (in high Heavy Metals

concentrations) Hydrocortisone sodium

Alkali carbonates and succinate

bicarbonates Phosphates

Alkali hydroxides Polymixin B sulfate

Arsenates Procaine hydrochloride

Barium Salicylates

Calcium Strontium

Clindamycin phosphate Tartrates

The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.

It has been reported that Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

HOW SUPPLIED

Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) Sulfate Injection, USP is supplied in single-dose containers as follows:

NDC No.	Container	Total Amount	Concentration	mEq Mg++/mL
0409-1754-10	Ansyr Plastic Syringe	5 g/10 mL	50%	4 mEq/mL

Do not administer unless solution is clear and container is undamaged. Discard unused portion.

Store at 20 to 25°C (68 to 77°F).

REFERENCES

• Yokoyama K, Takahashi N, Yada Y. Prolonged maternal Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) administration and bone metabolism in neonates. Early Hum Dev. 2010;86(3):187-91. Epub 2010 Mar 12.
• Wedig KE, Kogan J, Schorry EK et al. Skeletal demineralization and fractures caused by fetal Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) toxicity. J. Perinatol. 2006; 26(6):371-4.
• Nassar AH, Sakhel K, Maarouf H, et al. Adverse maternal and neonatal outcome of prolonged course of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate tocolysis. Acta Obstet Gynecol Scan. 2006;85(9):1099-103.
• Malaeb SN, Rassi A, Haddad MC. Bone mineralization in newborns whose mothers received Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulphate for tocolysis of premature labor. Pediatr Radiol. 2004;34(5):384-6. Epub 2004 Feb 18.
• Matsuda Y, Maeda Y, Ito M, et al. Effect of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate treatment on neonatal bone abnormalities. Gynecol Obstet Invest. 1997;44(2):82-8.
• Schanler RJ, Smith LG, Burns PA. Effects of long-term maternal intravenous Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate therapy on neonatal calcium metabolism and bone mineral content. Gynecol Obstet Invest. 1997;43(4):236-41.
• Santi MD, Henry GW, Douglas GL. Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate treatment of preterm labor as a cause of abnormal neonatal bone mineralization. J Pediatr Orthrop. 1994;14(2):249-53.
• Holcomb WL, Shackelford GD, Petrie RH. Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) tocolysis and neonatal bone abnormalities; a controlled study. Obstet Gynecol. 1991; 78(4):611-4.
• Cumming WA, Thomas VJ. Hypermagnesemia: a cause of abnormal metaphyses in the neonate. Am J Roentgenol. 1989; 152(5):1071-2.
• Lamm CL, Norton KL, Murphy RJ. Congenital rickets associated with Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
• McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate treatment on perinatal calcium metabolism. II. Neonatal responses. Obstet Gynecol. 1980; 56(5): 595-600.
• Riaz M, Porat R, Brodsky NL, et al. The effects of maternal Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) sulfate treatment on newborns: a prospective controlled study. J. Perinatol. 1998;18(6 pt 1):449-54.

Hospira, Inc., Lake Forest, IL 60045 USA

LAB-1024-1.0

April 2017

Hospira Logo

50% Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) Sulfate 5 g/10 mL (500 mg/mL)

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% Timed Release Ultra Mega II (Magnesium (Magnesium Citrate)) Sulfate Injection, USP

5 g/10 mL (500 mg/mL) (4 mEq Mg++/mL)

MUST BE DILUTED FOR INTRAVENOUS USE.

For Intravenous or Intramuscular Use. Sterile. 4.06 mOsmol/mL (calc.).

Contains no more than 75 mcg/L of aluminum.

Hospira, Inc., Lake Forest, IL 60045 USA

Hospira

RL-6891

Magnesium (Magnesium HVP Chelate):

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• References
• Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) reviews

Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) Sulfate Injection, USP is a sterile solution of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate heptahydrate in Water for Injection, USP administered by the intravenous or intramuscular routes as an electrolyte replenisher or anticonvulsant. Must be diluted before intravenous use. May contain sulfuric acid and/or sodium hydroxide for pH adjustment. The pH is 5.5 to 7.0. The 50% concentration has an osmolarity of 4.06 mOsmol/mL (calc.).

The solution contains no bacteriostat, antimicrobial agent or added buffer (except for pH adjustment) and is intended only for use as a single-dose injection. When smaller doses are required the unused portion should be discarded with the entire unit.

Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) Sulfate, USP heptahydrate is chemically designated MgSO₄ - 7H₂O with molecular weight of 246.48 and occurs as colorless crystals or white powder freely soluble in water.

The plastic syringe is molded from a specially formulated polypropylene. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the syringe material.

CLINICAL PHARMACOLOGY

Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) (Mg⁺⁺) is an important cofactor for enzymatic reactions and plays an important role in neurochemical transmission and muscular excitability.

As a nutritional adjunct in hyperalimentation, the precise mechanism of action for Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) is uncertain. Early symptoms of hypomagnesemia (less than 1.5 mEq/liter) may develop as early as three to four days or within weeks.

Predominant deficiency effects are neurological, e.g., muscle irritability, clonic twitching and tremors. Hypocalcemia and hypokalemia often follow low serum levels of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)). While there are large stores of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) is said to have a depressant effect on the central nervous system (CNS), but it does not adversely affect the woman, fetus or neonate when used as directed in eclampsia or pre-eclampsia. Normal plasma Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) levels range from 1.5 to 2.5 mEq/liter.

As plasma Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) rises above 4 mEq/liter, the deep tendon reflexes are first decreased and then disappear as the plasma level approaches 10 mEq/liter. At this level respiratory paralysis may occur. Heart block also may occur at this or lower plasma levels of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)). Serum Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) concentrations in excess of 12 mEq/L may be fatal.

Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) acts peripherally to produce vasodilation. With low doses only flushing and sweating occur, but larger doses cause lowering of blood pressure. The central and peripheral effects of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) poisoning are antagonized to some extent by intravenous administration of calcium.

Pharmacokinetics

With intravenous administration the onset of anticonvulsant action is immediate and lasts about 30 minutes. Following intramuscular administration the onset of action occurs in about one hour and persists for three to four hours. Effective anticonvulsant serum levels range from 2.5 to 7.5 mEq/liter. Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) Sulfate Injection, USP is suitable for replacement therapy in Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) (Mg⁺⁺) level is usually below the lower limit of normal (1.5 to 2.5 mEq/liter) and the serum calcium (Ca⁺⁺) level is normal (4.3 to 5.3 mEq/liter) or elevated.

In total parenteral nutrition (TPN), Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.

Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) Sulfate Injection, USP is also indicated for the prevention and control of seizures (convulsions) in pre-eclampsia and eclampsia, respectively.

CONTRAINDICATIONS

Parenteral administration of the drug is contraindicated in patients with heart block or myocardial damage.

WARNINGS

FETAL HARM: Continuous administration of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate beyond 5 to 7 days to pregnant women can lead to hypocalcemia and bone abnormalities in the developing fetus. These bone abnormalities include skeletal demineralization and osteopenia. In addition, cases of neonatal fracture have been reported. The shortest duration of treatment that can lead to fetal harm is not known. Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate should be used during pregnancy only if clearly needed. If Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate is given for treatment of preterm labor, the woman should be informed that the efficacy and safety of such use have not been established and that use of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate beyond 5 to 7 days may cause fetal abnormalities.

ALUMINUM TOXICITY: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

Parenteral use in the presence of renal insufficiency may lead to Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) intoxication. Intravenous use in the eclampsia should be reserved for immediate control of life-threatening convulsions.

PRECAUTIONS

General

Administer with caution if flushing and sweating occurs. When barbiturates, narcotics or other hypnotics (or systemic anesthetics) are to be given in conjunction with Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)).

Because Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) is removed from the body solely by the kidneys, the drug should be used with caution in patients with renal impairment. Urine output should be maintained at a level of 100 mL or more during the four hours preceding each dose. Monitoring serum Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) levels and the patient's clinical status is essential to avoid the consequences of overdosage in toxemia. Clinical indications of a safe dosage regimen include the presence of the patellar reflex (knee jerk) and absence of respiratory depression (approximately 16 breaths or more/minute). When repeated doses of the drug are given parenterally, knee jerk reflexes should be tested before each dose and if they are absent, no additional Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) should be given until they return. Serum Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) levels usually sufficient to control convulsions range from 3 to 6 mg/100 mL (2.5 to 5 mEq/liter). The strength of the deep tendon reflexes begins to diminish when Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) levels exceed 4 mEq/liter. Reflexes may be absent at 10 mEq magnesium/liter, where respiratory paralysis is a potential hazard. An injectable calcium salt should be immediately available to counteract the potential hazards of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) intoxication in eclampsia.

50% Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) Sulfate Injection, USP must be diluted to a concentration of 20% or less prior to intravenous infusion. Rate of administration should be slow and cautious, to avoid producing hypermagnesemia. The 50% solution also should be diluted to 20% or less for intramuscular injection in infants and children.

Laboratory Tests

Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) is monitored. The normal serum level is 1.5 to 2.5 mEq/L.

Drug Interactions

CNS Depressants - When barbiturates, narcotics or other hypnotics (or systemic anesthetics), or other CNS depressants are to be given in conjunction with Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)). CNS depression and peripheral transmission defects produced by Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) may be antagonized by calcium.

Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.

Cardiac Glycosides - Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate should be administered with extreme caution in digitalized patients, because serious changes in cardiac conduction which can result in heart block may occur if administration of calcium is required to treat Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate can cause fetal abnormalities when administered beyond 5 to 7 days to pregnant women. There are retrospective epidemiological studies and case reports documenting fetal abnormalities such as hypocalcemia, skeletal demineralization, osteopenia and other skeletal abnormalities with continuous maternal administration of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate for more than 5 to 7 days.^1-10 Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate injection should be used during pregnancy only if clearly needed. If this drug is used during pregnancy, the woman should be apprised of the potential harm to the fetus.

Nonteratogenic Effects

When administered by continuous intravenous infusion (especially for more than 24 hours preceding delivery) to control convulsions in a toxemic woman, the newborn may show signs of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate outside of its approved indication in pregnant women should be by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.

Nursing Mothers

Since Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) is distributed into milk during parenteral Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate administration, the drug should be used with caution in nursing women.

Geriatrics

Geriatric patients often require reduced dosage because of impaired renal function. In patients with severe impairment, dosage should not exceed 20 grams in 48 hours. Serum Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) usually are the result of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) intoxication. These include flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, cardiac and central nervous system depression proceeding to respiratory paralysis. Hypocalcemia with signs of tetany secondary to Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) intoxication is manifested by a sharp drop in blood pressure and respiratory paralysis. Disappearance of the patellar reflex is a useful clinical sign to detect the onset of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) intoxication. In the event of overdosage, artificial ventilation must be provided until a calcium salt can be injected intravenously to antagonize the effects of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)).

For Treatment of Overdose

Artificial respiration is often required. Intravenous calcium, 10 to 20 mL of a 5% solution (diluted if desirable with isotonic sodium chloride for injection) is used to counteract effects of hypermagnesemia. Subcutaneous physostigmine, 0.5 to 1 mg may be helpful.

Hypermagnesemia in the newborn may require resuscitation and assisted ventilation via endotracheal intubation or intermittent positive pressure ventilation as well as intravenous calcium.

DOSAGE AND ADMINISTRATION

Dosage of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate must be carefully adjusted according to individual requirements and response, and administration of the drug should be discontinued as soon as the desired effect is obtained.

Both intravenous and intramuscular administration are appropriate. Intramuscular administration of the undiluted 50% solution results in therapeutic plasma levels in 60 minutes, whereas intravenous doses will provide a therapeutic level almost immediately. The rate of intravenous injection should generally not exceed 150 mg/minute (1.5 mL of a 10% concentration or its equivalent), except in severe eclampsia with seizures. Continuous maternal administration of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Solutions for intravenous infusion must be diluted to a concentration of 20% or less prior to administration. The diluents commonly used are 5% Dextrose Injection, USP and 0.9% Sodium Chloride Injection, USP. Deep intramuscular injection of the undiluted (50%) solution is appropriate for adults, but the solution should be diluted to a 20% or less concentration prior to such injection in children.

In Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) Deficiency

In the treatment of mild Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) (2 mL of the 50% solution) injected intramuscularly every six hours for four doses (equivalent to a total of 32.5 mEq of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) per 24 hours). For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given intramuscularly within a period of four hours if necessary. Alternatively, 5 grams, (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow intravenous infusion over a three-hour period. In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.

In Hyperalimentation

In total parenteral nutrition, maintenance requirements for Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) are not precisely known. The maintenance dose used in adults ranges from 8 to 24 mEq (1 gram to 3 grams) daily; for infants, the range is 2 to 10 mEq (0.25 gram to 1.25 grams) daily.

In Pre-eclampsia or Eclampsia

In severe pre-eclampsia or eclampsia, the total initial dose is 10 grams to 14 grams of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate. Intravenously, a dose of 4 grams to 5 grams in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused. Simultaneously, intramuscular doses of up to 10 grams (5 grams or 10 mL of the undiluted 50% solution in each buttock) are given. Alternatively, the initial intravenous dose of 4 grams may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected intravenously over a period of three to four minutes. Subsequently, 4 grams to 5 grams (8 to 10 mL of the 50% solution) are injected intramuscularly into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function. Alternatively, after the initial intravenous dose, some clinicians administer 1 gram to 2 grams/hour by constant intravenous infusion. Therapy should continue until paroxysms cease. A serum Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) level of 6 mg/100 mL is considered optimal for control of seizures. A total daily (24 hr) dose of 30 grams to 40 grams should not be exceeded. In the presence of severe renal insufficiency, the maximum dosage of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate is 20 grams/48 hours and frequent serum Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) concentrations must be obtained. Continuous use of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Other Uses

In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate is 1 gram to 2 grams given intravenously.

For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 gram administered intramuscularly or intravenously.

In paroxysmal atrial tachycardia, Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) should be used only if simpler measures have failed and there is no evidence of myocardial damage. The usual dose is 3 grams to 4 grams (30 to 40 mL of a 10% solution) administered intravenously over 30 seconds with extreme caution.

For reduction of cerebral edema, 2.5 grams (25 mL of a 10% solution) is given intravenously.

Incompatibilities

Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate in solution may result in a precipitate formation when mixed with solutions containing:

Alcohol (in high Heavy Metals

concentrations) Hydrocortisone sodium

Alkali carbonates and succinate

bicarbonates Phosphates

Alkali hydroxides Polymixin B sulfate

Arsenates Procaine hydrochloride

Barium Salicylates

Calcium Strontium

Clindamycin phosphate Tartrates

The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.

It has been reported that Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

HOW SUPPLIED

Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) Sulfate Injection, USP is supplied in single-dose containers as follows:

NDC No.	Container	Total Amount	Concentration	mEq Mg++/mL
0409-1754-10	Ansyr Plastic Syringe	5 g/10 mL	50%	4 mEq/mL

Do not administer unless solution is clear and container is undamaged. Discard unused portion.

Store at 20 to 25°C (68 to 77°F).

REFERENCES

• Yokoyama K, Takahashi N, Yada Y. Prolonged maternal Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) administration and bone metabolism in neonates. Early Hum Dev. 2010;86(3):187-91. Epub 2010 Mar 12.
• Wedig KE, Kogan J, Schorry EK et al. Skeletal demineralization and fractures caused by fetal Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) toxicity. J. Perinatol. 2006; 26(6):371-4.
• Nassar AH, Sakhel K, Maarouf H, et al. Adverse maternal and neonatal outcome of prolonged course of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate tocolysis. Acta Obstet Gynecol Scan. 2006;85(9):1099-103.
• Malaeb SN, Rassi A, Haddad MC. Bone mineralization in newborns whose mothers received Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulphate for tocolysis of premature labor. Pediatr Radiol. 2004;34(5):384-6. Epub 2004 Feb 18.
• Matsuda Y, Maeda Y, Ito M, et al. Effect of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate treatment on neonatal bone abnormalities. Gynecol Obstet Invest. 1997;44(2):82-8.
• Schanler RJ, Smith LG, Burns PA. Effects of long-term maternal intravenous Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate therapy on neonatal calcium metabolism and bone mineral content. Gynecol Obstet Invest. 1997;43(4):236-41.
• Santi MD, Henry GW, Douglas GL. Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate treatment of preterm labor as a cause of abnormal neonatal bone mineralization. J Pediatr Orthrop. 1994;14(2):249-53.
• Holcomb WL, Shackelford GD, Petrie RH. Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) tocolysis and neonatal bone abnormalities; a controlled study. Obstet Gynecol. 1991; 78(4):611-4.
• Cumming WA, Thomas VJ. Hypermagnesemia: a cause of abnormal metaphyses in the neonate. Am J Roentgenol. 1989; 152(5):1071-2.
• Lamm CL, Norton KL, Murphy RJ. Congenital rickets associated with Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
• McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate treatment on perinatal calcium metabolism. II. Neonatal responses. Obstet Gynecol. 1980; 56(5): 595-600.
• Riaz M, Porat R, Brodsky NL, et al. The effects of maternal Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) sulfate treatment on newborns: a prospective controlled study. J. Perinatol. 1998;18(6 pt 1):449-54.

Hospira, Inc., Lake Forest, IL 60045 USA

LAB-1024-1.0

April 2017

Hospira Logo

50% Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) Sulfate 5 g/10 mL (500 mg/mL)

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% Timed Release Ultra Mega II (Magnesium (Magnesium HVP Chelate)) Sulfate Injection, USP

5 g/10 mL (500 mg/mL) (4 mEq Mg++/mL)

MUST BE DILUTED FOR INTRAVENOUS USE.

For Intravenous or Intramuscular Use. Sterile. 4.06 mOsmol/mL (calc.).

Contains no more than 75 mcg/L of aluminum.

Hospira, Inc., Lake Forest, IL 60045 USA

Hospira

RL-6891

Manganese (Manganese Citrate):

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Overdosage
• Dosage and administration
• How supplied
• Rl-0104
• Timed Release Ultra Mega II (Manganese (Manganese Citrate)) reviews

INDICATIONS AND USAGE

Timed Release Ultra Mega II (Manganese (Manganese Citrate)) 0.1 mg/mL (Manganese Chloride Injection, USP) is indicated for use as a supplement to intravenous solutions given for total parenteral nutrition (TPN).

Administration helps to maintain Timed Release Ultra Mega II (Manganese (Manganese Citrate)) serum levels and to prevent depletion of endogenous stores and subsequent deficiency symptoms.

CONTRAINDICATIONS

None known.

WARNINGS

Direct intramuscular or intravenous injection of Timed Release Ultra Mega II (Manganese (Manganese Citrate)) 0.1 mg/mL (Manganese Chloride Injection, USP) is contraindicated as the acidic pH of the solution (pH 2.0) may cause considerable tissue irritation.

Liver and/or biliary tract dysfunction may require omission or reduction of copper and Timed Release Ultra Mega II (Manganese (Manganese Citrate)) doses because these elements are primarily eliminated in the bile.

WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

PRECAUTIONS

General

Do not use unless solution is clear and seal is intact.

Timed Release Ultra Mega II ) 0.1 mg/mL (Manganese Chloride Injection, USP) should only be used in conjunction with a pharmacy directed admixture program using aseptic technique in a laminar flow environment; it should be used promptly and in a single operation without any repeated penetrations. Solution contains no preservatives; discard unused portion immediately after admixture procedure is completed.

Laboratory Tests

Serum Timed Release Ultra Mega II (Manganese (Manganese Citrate)) levels can be measured periodically at the discretion of the investigator. Because of the low serum concentration normally present, samples will usually be analyzed by a reference laboratory.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of Timed Release Ultra Mega II ) 0.1 mg/mL (Manganese Chloride Injection, USP) have not been performed, nor have studies been done to assess mutagenesis or impairment of fertility.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Timed Release Ultra Mega II (Manganese (Manganese Citrate)) 0.1 mg/mL (Manganese Chloride Injection, USP) additive is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Pregnancy Category C.

Animal reproduction studies have not been conducted with Timed Release Ultra Mega II (Manganese (Manganese Citrate)) chloride. It is also not known whether Timed Release Ultra Mega II (Manganese (Manganese Citrate)) chloride can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Timed Release Ultra Mega II (Manganese (Manganese Citrate)) chloride should be given to a pregnant woman only if clearly indicated.

Geriatric Use

An evaluation of current literature revealed no clinical experience identifying differences in response between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS

None known.

DRUG ABUSE AND DEPENDENCE

None known.

OVERDOSAGE

Timed Release Ultra Mega II (Manganese (Manganese Citrate)) toxicity in TPN patients has not been reported.

DOSAGE AND ADMINISTRATION

Timed Release Ultra Mega II (Manganese (Manganese Citrate)) 0.1 mg/mL (Manganese Chloride Injection, USP) contains 0.1 mg manganese/mL and is administered intravenously only after dilution. The additive should be administered in a volume of fluid not less than 100 mL. For the adult receiving TPN, the suggested additive dosage for Timed Release Ultra Mega II (Manganese (Manganese Citrate)) is 0.15 to 0.8 mg/day (1.5 to 8 mL/day). For pediatric patients, a dosage of 2 to 10 mcg manganese/kg/day (0.02 to 0.1 mL/kg/day) is recommended.

Periodic monitoring of Timed Release Ultra Mega II (Manganese (Manganese Citrate)) plasma levels is suggested as a guideline for subsequent administration.

Parenteral products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. (See PRECAUTIONS .)

HOW SUPPLIED

Timed Release Ultra Mega II (Manganese (Manganese Citrate)) 0.1 mg/mL (Manganese Chloride Injection, USP) is supplied in 10 mL Plastic Vials (NDC No. 0409-4091-01).

Store at 20 to 25°C (68 to 77°F)

Revised: November, 2009

Printed in USA EN-2320

Hospira, Inc., Lake Forest, IL 60045 USA

RL-0104

Manganese (Manganese HVP Chelate):

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Overdosage
• Dosage and administration
• How supplied
• Rl-0104
• Timed Release Ultra Mega II (Manganese (Manganese HVP Chelate)) reviews

INDICATIONS AND USAGE

Timed Release Ultra Mega II (Manganese (Manganese HVP Chelate)) 0.1 mg/mL (Manganese Chloride Injection, USP) is indicated for use as a supplement to intravenous solutions given for total parenteral nutrition (TPN).

Administration helps to maintain Timed Release Ultra Mega II (Manganese (Manganese HVP Chelate)) serum levels and to prevent depletion of endogenous stores and subsequent deficiency symptoms.

CONTRAINDICATIONS

None known.

WARNINGS

Direct intramuscular or intravenous injection of Timed Release Ultra Mega II (Manganese (Manganese HVP Chelate)) 0.1 mg/mL (Manganese Chloride Injection, USP) is contraindicated as the acidic pH of the solution (pH 2.0) may cause considerable tissue irritation.

Liver and/or biliary tract dysfunction may require omission or reduction of copper and Timed Release Ultra Mega II (Manganese (Manganese HVP Chelate)) doses because these elements are primarily eliminated in the bile.

WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

PRECAUTIONS

General

Do not use unless solution is clear and seal is intact.

Timed Release Ultra Mega II ) 0.1 mg/mL (Manganese Chloride Injection, USP) should only be used in conjunction with a pharmacy directed admixture program using aseptic technique in a laminar flow environment; it should be used promptly and in a single operation without any repeated penetrations. Solution contains no preservatives; discard unused portion immediately after admixture procedure is completed.

Laboratory Tests

Serum Timed Release Ultra Mega II (Manganese (Manganese HVP Chelate)) levels can be measured periodically at the discretion of the investigator. Because of the low serum concentration normally present, samples will usually be analyzed by a reference laboratory.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of Timed Release Ultra Mega II ) 0.1 mg/mL (Manganese Chloride Injection, USP) have not been performed, nor have studies been done to assess mutagenesis or impairment of fertility.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Timed Release Ultra Mega II (Manganese (Manganese HVP Chelate)) 0.1 mg/mL (Manganese Chloride Injection, USP) additive is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Pregnancy Category C.

Animal reproduction studies have not been conducted with Timed Release Ultra Mega II (Manganese (Manganese HVP Chelate)) chloride. It is also not known whether Timed Release Ultra Mega II (Manganese (Manganese HVP Chelate)) chloride can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Timed Release Ultra Mega II (Manganese (Manganese HVP Chelate)) chloride should be given to a pregnant woman only if clearly indicated.

Geriatric Use

An evaluation of current literature revealed no clinical experience identifying differences in response between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS

None known.

DRUG ABUSE AND DEPENDENCE

None known.

OVERDOSAGE

Timed Release Ultra Mega II (Manganese (Manganese HVP Chelate)) toxicity in TPN patients has not been reported.

DOSAGE AND ADMINISTRATION

Timed Release Ultra Mega II (Manganese (Manganese HVP Chelate)) 0.1 mg/mL (Manganese Chloride Injection, USP) contains 0.1 mg manganese/mL and is administered intravenously only after dilution. The additive should be administered in a volume of fluid not less than 100 mL. For the adult receiving TPN, the suggested additive dosage for Timed Release Ultra Mega II (Manganese (Manganese HVP Chelate)) is 0.15 to 0.8 mg/day (1.5 to 8 mL/day). For pediatric patients, a dosage of 2 to 10 mcg manganese/kg/day (0.02 to 0.1 mL/kg/day) is recommended.

Periodic monitoring of Timed Release Ultra Mega II (Manganese (Manganese HVP Chelate)) plasma levels is suggested as a guideline for subsequent administration.

Parenteral products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. (See PRECAUTIONS .)

HOW SUPPLIED

Timed Release Ultra Mega II (Manganese (Manganese HVP Chelate)) 0.1 mg/mL (Manganese Chloride Injection, USP) is supplied in 10 mL Plastic Vials (NDC No. 0409-4091-01).

Store at 20 to 25°C (68 to 77°F)

Revised: November, 2009

Printed in USA EN-2320

Hospira, Inc., Lake Forest, IL 60045 USA

RL-0104

Potassium (Potassium Citrate):

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Timed Release Ultra Mega II (Potassium (Potassium Citrate)) reviews

Timed Release Ultra Mega II (Potassium (Potassium Citrate)) CHLORIDE EXTENDED RELEASE TABLETS USP 20 mEq K

Rx Only

DESCRIPTION

The Timed Release Ultra Mega II (Potassium (Potassium Citrate)) Chloride Extended Release Tablets USP, 20 mEq product is an immediately dispersing extended release oral dosage form of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) chloride containing 1500 mg of microencapsulated Timed Release Ultra Mega II (Potassium (Potassium Citrate)) chloride, USP equivalent to 20 mEq of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) in a tablet.

These formulations are intended to slow the release of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) so that the likelihood of a high localized concentration of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) chloride within the gastrointestinal tract is reduced.

Timed Release Ultra Mega II (Potassium (Potassium Citrate)) Chloride Extended Release Tablets USP, 20 mEq is an electrolyte replenisher. The chemical name of the active ingredient is Timed Release Ultra Mega II (Potassium (Potassium Citrate)) chloride, and the structural formula is KCl. Timed Release Ultra Mega II (Potassium (Potassium Citrate)) chloride, USP occurs as a white, granular powder or as colorless crystals. It is odorless and has a saline taste. Its solutions are neutral to litmus. It is freely soluble in water and insoluble in alcohol.

Timed Release Ultra Mega II (Potassium (Potassium Citrate)) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulation (not enteric coated or wax matrix) containing individually microencapsulated Timed Release Ultra Mega II (Potassium (Potassium Citrate)) chloride crystals which disperse upon tablet disintegration. In simulated gastric fluid at 37°C and in the absence of outside agitation, Timed Release Ultra Mega II (Potassium (Potassium Citrate)) Chloride Extended Release Tablets USP, 20 mEq begin disintegrating into microencapsulated crystals within seconds and completely disintegrates within 1 minute. The microencapsulated crystals are formulated to provide an extended release of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) chloride.

Inactive Ingredients: Colloidal silicon dioxide, crospovidone, diethyl phthalate, ethyl-cellulose, microcrystalline cellulose.

CLINICAL PHARMACOLOGY

The Timed Release Ultra Mega II (Potassium (Potassium Citrate)) ion is the principal intracellular cation of most body tissues. Timed Release Ultra Mega II (Potassium (Potassium Citrate)) ions participate in a number of essential physiological processes including the maintenance of intracellular tonicity; the transmission of nerve impulses; the contraction of cardiac, skeletal, and smooth muscle; and the maintenance of normal renal function.

The intracellular concentration of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) is approximately 150 to 160 mEq per liter. The normal adult plasma concentration is 3.5 to 5 mEq per liter. An active ion transport system maintains this gradient across the plasma membrane.

Timed Release Ultra Mega II (Potassium (Potassium Citrate)) is a normal dietary constituent and under steady-state conditions the amount of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) absorbed from the gastrointestinal tract is equal to the amount excreted in the urine. The usual dietary intake of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) is 50 to 100 mEq per day.

Timed Release Ultra Mega II (Potassium (Potassium Citrate)) depletion will occur whenever the rate of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) loss through renal excretion and/or loss from the gastrointestinal tract exceeds the rate of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) intake. Such depletion usually develops as a consequence of therapy with diuretics, primary or secondary hyperaldosteronism, diabetic ketoacidosis, or inadequate replacement of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) in patients on prolonged parenteral nutrition. Depletion can develop rapidly with severe diarrhea, especially if associated with vomiting. Timed Release Ultra Mega II (Potassium (Potassium Citrate)) depletion due to these causes is usually accompanied by a concomitant loss of chloride and is manifested by hypokalemia and metabolic alkalosis. Timed Release Ultra Mega II (Potassium (Potassium Citrate)) depletion may produce weakness, fatigue, disturbances or cardiac rhythm (primarily ectopic beats), prominent U-waves in the electrocardiogram, and in advanced cases, flaccid paralysis and/or impaired ability to concentrate urine.

If Timed Release Ultra Mega II (Potassium (Potassium Citrate)) depletion associated with metabolic alkalosis cannot be managed by correcting the fundamental cause of the deficiency, eg, where the patient requires long-term diuretic therapy, supplemental Timed Release Ultra Mega II (Potassium (Potassium Citrate)) in the form of high Timed Release Ultra Mega II (Potassium (Potassium Citrate)) food or Timed Release Ultra Mega II (Potassium (Potassium Citrate)) chloride may be able to restore normal Timed Release Ultra Mega II (Potassium (Potassium Citrate)) levels.

In rare circumstances (eg, patients with renal tubular acidosis) Timed Release Ultra Mega II (Potassium (Potassium Citrate)) depletion may be associated with metabolic acidosis and hyperchloremia. In such patients Timed Release Ultra Mega II (Potassium (Potassium Citrate)) replacement should be accomplished with Timed Release Ultra Mega II (Potassium (Potassium Citrate)) salts other than the chloride, such as Timed Release Ultra Mega II (Potassium (Potassium Citrate)) bicarbonate, Timed Release Ultra Mega II (Potassium (Potassium Citrate)) citrate, Timed Release Ultra Mega II (Potassium (Potassium Citrate)) acetate, or Timed Release Ultra Mega II (Potassium (Potassium Citrate)) gluconate.

INDICATIONS AND USAGE

BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND BLEEDING WITH CONTROLLED-RELEASE Timed Release Ultra Mega II (Potassium (Potassium Citrate)) CHLORIDE PREPARATIONS, THESE DRUGS SHOULD BE RESERVED FOR THOSE PATIENTS WHO CANNOT TOLERATE OR REFUSE TO TAKE LIQUID OR EFFERVESCENT Timed Release Ultra Mega II (Potassium (Potassium Citrate)) PREPARATIONS OR FOR PATIENTS IN WHOM THERE IS A PROBLEM OF COMPLIANCE WITH THESE PREPARATIONS.

1. For the treatment of patients with hypokalemia with or without metabolic alkalosis, in digitalis intoxication, and in patients with hypokalemic familial periodic paralysis. If hypokalemia is the result of diuretic therapy, consideration should be given to the use of a lower dose of diuretic, which may be sufficient without leading to hypokalemia.

2. For the prevention of hypokalemia in patients who would be at particular risk if hypokalemia were to develop, eg, digitalized patients or patients with significant cardiac arrhythmias.

The use of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) salts in patients receiving diuretics for uncomplicated essential hypertension is often unnecessary when such patients have a normal dietary pattern and when low doses of the diuretic are used. Serum Timed Release Ultra Mega II (Potassium (Potassium Citrate)) should be checked periodically, however, and if hypokalemia occurs, dietary supplementation with potassium-containing foods may be adequate to control milder cases. In more severe cases, and if dose adjustment of the diuretic is ineffective or unwarranted, supplementation with Timed Release Ultra Mega II (Potassium (Potassium Citrate)) salts may be indicated.

CONTRAINDICATIONS

Timed Release Ultra Mega II (Potassium (Potassium Citrate)) supplements are contraindicated in patients with hyperkalemia since a further increase in serum Timed Release Ultra Mega II (Potassium (Potassium Citrate)) concentration in such patients can produce cardiac arrest. Hyperkalemia may complicate any of the following conditions: chronic renal failure, systemic acidosis, such as diabetic acidosis, acute dehydration, extensive tissue breakdown as in severe burns, adrenal insufficiency, or the administration of a potassium-sparing diuretic (eg, spironolactone, triamterene, amiloride) (see OVERDOSAGE ).

Controlled-release formulations of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) chloride have produced esophageal ulceration in certain cardiac patients with esophageal compression due to enlarged left atrium. Timed Release Ultra Mega II (Potassium (Potassium Citrate)) supplementation, when indicated in such patients, should be given as a liquid preparation or as an aqueous (water) suspension of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) Chloride (see PRECAUTIONS: Information for Patients , and DOSAGE AND ADMINISTRATION sections).

All solid oral dosage forms of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) chloride are contraindicated in any patient in whom there is structural, pathological (eg, diabetic gastroparesis), or pharmacologic (use of anticholinergic agents or other agents with anticholinergic properties at sufficient doses to exert anticholinergic effects) cause for arrest or delay in tablet passage through the gastrointestinal tract.

WARNINGS

Hyperkalemia (see OVERDOSAGE )

In patients with impaired mechanisms for excreting Timed Release Ultra Mega II (Potassium (Potassium Citrate)), the administration of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) salts can produce hyperkalemia and cardiac arrest. This occurs most commonly in patients given Timed Release Ultra Mega II (Potassium (Potassium Citrate)) by the intravenous route but may also occur in patients given Timed Release Ultra Mega II (Potassium (Potassium Citrate)) orally. Potentially fatal hyperkalemia can develop rapidly and be asymptomatic. The use of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) salts in patients with chronic renal disease, or any other condition which impairs Timed Release Ultra Mega II (Potassium (Potassium Citrate)) excretion, requires particularly careful monitoring of the serum Timed Release Ultra Mega II (Potassium (Potassium Citrate)) concentration and appropriate dosage adjustment.

Interaction with Potassium-Sparing Diuretics

Hypokalemia should not be treated by the concomitant administration of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) salts and a potassium-sparing diuretic (eg, spironolactone, triamterene, or amiloride) since the simultaneous administration of these agents can produce severe hyperkalemia.

Interaction with Angiotensin-Converting Enzyme Inhibitors

Angiotensin-converting enzyme (ACE) inhibitors (eg, captopril, enalapril) will produce some Timed Release Ultra Mega II (Potassium (Potassium Citrate)) retention by inhibiting aldosterone production. Timed Release Ultra Mega II (Potassium (Potassium Citrate)) supplements should be given to patients receiving ACE inhibitors only with close monitoring.

Gastrointestinal Lesions

Solid oral dosage forms of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) chloride can produce ulcerative and/or stenotic lesions of the gastrointestinal tract. Based on spontaneous adverse reaction reports, enteric-coated preparations of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) chloride are associated with an increased frequency of small bowel lesions (40-50 per 100,000 patient years) compared to sustained release wax matrix formulations (less than one per 100,000 patient years). Because of the lack of extensive marketing experience with microencapsulated products, a comparison between such products and wax matrix or enteric-coated products is not available. Timed Release Ultra Mega II (Potassium (Potassium Citrate)) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulated to provide a controlled rate of release of microencapsulated Timed Release Ultra Mega II (Potassium (Potassium Citrate)) chloride and thus to minimize the possibility of a high local concentration of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) near the gastrointestinal wall.

Prospective trials have been conducted in normal human volunteers in which the upper gastrointestinal tract was evaluated by endoscopic inspection before and after 1 week of solid oral Timed Release Ultra Mega II (Potassium (Potassium Citrate)) chloride therapy. The ability of this model to predict events occurring in usual clinical practice is unknown. Trials which approximated usual clinical practice did not reveal any clear differences between the wax matrix and microencapsulated dosage forms. In contrast, there was a higher incidence of gastric and duodenal lesions in subjects receiving a high dose of a wax matrix controlled-release formulation under conditions which did not resemble usual or recommended clinical practice (ie, 96 mEq per day in divided doses of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) chloride administered to fasted patients, in the presence of an anticholinergic drug to delay gastric emptying). The upper gastrointestinal lesions observed by endoscopy were asymptomatic and were not accompanied by evidence of bleeding (Hemoccult testing). The relevance of these findings to the usual conditions (ie, non-fasting, no anticholinergic agent, smaller doses) under which controlled-release Timed Release Ultra Mega II (Potassium (Potassium Citrate)) chloride products are used is uncertain; epidemiologic studies have not identified an elevated risk, compared to microencapsulated products, for upper gastrointestinal lesions in patients receiving wax matrix formulations. Timed Release Ultra Mega II (Potassium (Potassium Citrate)) Chloride Extended Release Tablets USP, 20 mEq should be discontinued immediately and the possibility of ulceration, obstruction, or perforation should be considered if severe vomiting, abdominal pain, distention, or gastrointestinal bleeding occurs.

Metabolic Acidosis

Hypokalemia in patients with metabolic acidosis should be treated with an alkalinizing Timed Release Ultra Mega II (Potassium (Potassium Citrate)) salt such as Timed Release Ultra Mega II (Potassium (Potassium Citrate)) bicarbonate, Timed Release Ultra Mega II (Potassium (Potassium Citrate)) citrate, Timed Release Ultra Mega II (Potassium (Potassium Citrate)) acetate, or Timed Release Ultra Mega II (Potassium (Potassium Citrate)) gluconate.

PRECAUTIONS

General

The diagnosis of Timed Release Ultra Mega II ) depletion is ordinarily made by demonstrating hypokalemia in a patient with a clinical history suggesting some cause for Timed Release Ultra Mega II (Potassium (Potassium Citrate)) depletion. In interpreting the serum Timed Release Ultra Mega II (Potassium (Potassium Citrate)) level, the physician should bear in mind that acute alkalosis per se can produce hypokalemia in the absence of a deficit in total body Timed Release Ultra Mega II (Potassium (Potassium Citrate)) while acute acidosis per se can increase the serum Timed Release Ultra Mega II (Potassium (Potassium Citrate)) concentration into the normal range even in the presence of a reduced total body Timed Release Ultra Mega II (Potassium (Potassium Citrate)). The treatment of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) depletion, particularly in the presence of cardiac disease, renal disease, or acidosis requires careful attention to acid-base balance and appropriate monitoring of serum electrolytes, the electrocardiogram, and the clinical status of the patient.

Information for Patients

Physicians should consider reminding the patient of the following: To take each dose with meals and with a full glass of water or other liquid. To take each dose without crushing, chewing, or sucking the tablets. If those patients are having difficulty swallowing whole tablets, they may try one of the following alternate methods of administration:

• Break the tablet in half, and take each half separately with a glass of water.
• Prepare an aqueous (water) suspension as follows:
  

  1. Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
  

  2. Allow approximately 2 minutes for the tablet(s) to disintegrate.
  

  3. Stir for about half a minute after the tablet(s) has disintegrated.
  

  4. Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
  

  5. Add another 1 fluid ounce of water, swirl, and consume immediately.
  

  6. Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.

Aqueous suspension of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending Timed Release Ultra Mega II (Potassium (Potassium Citrate)) Chloride Extended Release Tablets USP, 20 mEq is not recommended.

To take this medicine following the frequency and amount prescribed by the physician. This is especially important if the patient is also taking diuretics and/or digitalis preparations.

To check with the physician at once if tarry stools or other evidence of gastrointestinal bleeding is noticed.

Laboratory Tests

When blood is drawn for analysis of plasma Timed Release Ultra Mega II ) it is important to recognize that artifactual elevations can occur after improper venipuncture technique or as a result of in vitro hemolysis of the sample.

Drug Interactions

Potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (see WARNINGS ).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity, and fertility studies in animals have not been performed. Timed Release Ultra Mega II ) is a normal dietary constituent.

Pregnancy Category C

Animal reproduction studies have not been conducted with Timed Release Ultra Mega II (Potassium (Potassium Citrate)) Chloride Extended Release Tablets USP, 20 mEq. It is unlikely that Timed Release Ultra Mega II (Potassium (Potassium Citrate)) supplementation that does not lead to hyperkalemia would have an adverse effect on the fetus or would affect reproductive capacity.

Nursing Mothers

The normal Timed Release Ultra Mega II ) ion content of human milk is about 13 mEq per liter. Since oral Timed Release Ultra Mega II (Potassium (Potassium Citrate)) becomes part of the body Timed Release Ultra Mega II (Potassium (Potassium Citrate)) pool, so long as body Timed Release Ultra Mega II (Potassium (Potassium Citrate)) is not excessive, the contribution of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) chloride supplementation should have little or no effect on the level in human milk.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) Chloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection; and it may be useful to monitor renal function.

ADVERSE REACTIONS

One of the most severe adverse effects is hyperkalemia (see CONTRAINDICATIONS , WARNINGS , and OVERDOSAGE ). There have also been reports of upper and lower gastrointestinal conditions including obstruction, bleeding, ulceration, and perforation (see CONTRAINDICATIONS and WARNINGS ). The most common adverse reactions to oral Timed Release Ultra Mega II (Potassium (Potassium Citrate)) salts are nausea, vomiting, flatulence, abdominal pain/discomfort, and diarrhea. These symptoms are due to irritation of the gastrointestinal tract and are best managed by diluting the preparation further, taking the dose with meals or reducing the amount taken at one time.

OVERDOSAGE

The administration of oral Timed Release Ultra Mega II (Potassium (Potassium Citrate)) salts to persons with normal excretory mechanisms for Timed Release Ultra Mega II (Potassium (Potassium Citrate)) rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired or if Timed Release Ultra Mega II (Potassium (Potassium Citrate)) is administered too rapidly intravenously, potentially fatal hyperkalemia can result (see CONTRAINDICATIONS and WARNINGS ). It is important to recognize that hyperkalemia is usually asymptomatic and may be manifested only by an increased serum Timed Release Ultra Mega II (Potassium (Potassium Citrate)) concentration (6.5-8.0 mEq/L) and characteristic electrocardiographic changes (peaking of T-waves, loss of P-waves, depression of S-T segment, and prolongation of the QT-interval). Late manifestations include muscle paralysis and cardiovascular collapse from cardiac arrest (9-12 mEq/L).

Treatment measures for hyperkalemia include the following:

• Patients should be closely monitored for arrhythmias and electrolyte changes.
• Elimination of foods and medications containing Timed Release Ultra Mega II (Potassium (Potassium Citrate)) and of any agents with potassium-sparing properties such as potassium-sparing diuretics, ARBS, ACE inhibitors, NSAIDS, certain nutritional supplements and many others.
• Intravenous calcium gluconate if the patient is at no risk of developing digitalis toxicity.
• Intravenous administration of 300 to 500 mL/hr of 10% dextrose solution containing 10-20 units of crystalline insulin per 1,000 mL.
• Correction of acidosis, if present, with intravenous sodium bicarbonate.
• Use of exchange resins, hemodialysis, or peritoneal dialysis.

In treating hyperkalemia, it should be recalled that in patients who have been stabilized on digitalis, too rapid a lowering of the serum Timed Release Ultra Mega II (Potassium (Potassium Citrate)) concentration can produce digitalis toxicity.

The extended release feature means that absorption and toxic effects may be delayed for hours.

Consider standard measures to remove any unabsorbed drug.

DOSAGE AND ADMINISTRATION

The usual dietary intake of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) by the average adult is 50 to 100 mEq per day. Timed Release Ultra Mega II (Potassium (Potassium Citrate)) depletion sufficient to cause hypokalemia usually requires the loss of 200 or more mEq of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) from the total body store.

Dosage must be adjusted to the individual needs of each patient. The dose for the prevention of hypokalemia is typically in the range of 20 mEq per day. Doses of 40-100 mEq per day or more are used for the treatment of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) depletion. Dosage should be divided if more than 20 mEq per day is given such that no more than 20 mEq is given in a single dose.

Each Timed Release Ultra Mega II (Potassium (Potassium Citrate)) Chloride Extended Release Tablet USP, 20 mEq provides 20 mEq of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) chloride.

Timed Release Ultra Mega II (Potassium (Potassium Citrate)) Chloride Extended Release Tablets USP, 20 mEq should be taken with meals and with a glass of water or other liquid. This product should not be taken on an empty stomach because of its potential for gastric irritation (see WARNINGS ).

Patients having difficulty swallowing whole tablets may try one of the following alternate methods of administration:

• Break the tablet in half, and take each half separately with a glass of water.
• Prepare an aqueous (water) suspension as follows:
  • Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
  • Allow approximately 2 minutes for the tablet(s) to disintegrate.
  • Stir for about half a minute after the tablet(s) has disintegrated.
  • Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
  • Add another 1 fluid ounce of water, swirl, and consume immediately.
  • Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.

Aqueous suspension of Timed Release Ultra Mega II (Potassium (Potassium Citrate)) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending Timed Release Ultra Mega II (Potassium (Potassium Citrate)) Chloride Extended Release Tablets USP, 20 mEq is not recommended.

HOW SUPPLIED

Timed Release Ultra Mega II (Potassium (Potassium Citrate)) Chloride Extended Release Tablets USP, 20 mEq are available in bottles of 100 (NDC 62037-999-01), bottles of 500 (NDC 62037-999-05), and bottles of 1000 (NDC 62037-999-10). Potassium Chloride Extended Release Tablets USP, 20 mEq are capsule shaped, white to off-white tablets, with “ABRS-123” imprinted on one side and scored on the other side for flexibility of dosing.

Storage Conditions

Keep tightly closed. Store at controlled room temperature, 20°-25°C (68°-77°F).

Manufactured by:

Eurand, Inc.

Vandalia, OH 45377 USA

Distributed by:

Watson Pharma, Inc.

Rev. Date (01/09) 173714

Timed Release Ultra Mega II (Potassium (Potassium Citrate)) chloride 20 Meq

Selenium (Selenium HVP Chelate):

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) reviews

Rx Only

TRACE ELEMENT ADDITIVE FOR IV USE AFTER DILUTION

DESCRIPTION

Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) Injection is a sterile, nonpyrogenic solution for use as an additive to solutions for Total Parenteral Nutrition (TPN).

Each mL contains Selenious Acid 65.4 mcg (equivalent to elemental Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) 40 mcg/mL) and Water for Injection q.s. pH may be adjusted with nitric acid to 1.8 to 2.4.

CLINICAL PHARMACOLOGY

Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) is part of glutathione peroxidase which protects cell components from oxidative damage due to peroxides produced in cellular metabolism.

Prolonged TPN support in humans has resulted in Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) deficiency symptoms which include muscle pain and tenderness. The symptoms have been reported to respond to supplementation of TPN solutions with Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)).

Pediatric conditions, Keshan disease, and Kwashiorkor, have been associated with low dietary intake of Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)). The conditions are endemic to geographical areas with low Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) soil content. Dietary supplementation with Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) salts has been reported to reduce the incidence of the conditions among affected children.

Normal blood levels of Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) in different human populations have been found to vary and depend on the Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) content of the food consumed. Results of surveys carried out in some countries are tabulated below:

COUNTRY	Number of Samples	Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) (mcg/100 mL) (a)
		Whole Blood	Blood Cells	Plasma/ Serum
(a) Mean values with or without standard deviation in parentheses, all other ranges.
(b) Age group unknown.
(c) Three children recovered from Kwashiorkor and the other six under treatment for other diseases.
(d) Low selenium-content soil area.
(e) Well nourished children, three recovered from Kwashiorkor and the other six under treatment for other diseases.
(f) Mean values from seven subjects.
Canada	254 Adults	(37.9 ± 7.8)	(23.6 ± 6.0)	(14.4 ± 2.9)
England	8 (b)	26-37 (32)	--	--
Guatemala & Southern USA	10 Adults 9 Children (c)	19-28 (22) (23 ± 5)	-- (36 ± 12)	-- (15 ± 5)
New Zealand (d)	113 Adults	(5.4 ± 0.1)	(6.6 ± 0.3)	(4.3 ± 0.1)
Thailand	3 Adults 9 Children (e)	14.4-20.2 (12.0 ± 3.6) (f)	17.8-35.8 (19.5 ± 8.2)	8.1-12.5 (8.3 ± 2.2)
USA	210 Adults	15.7-25.6 (20.6)	--	--

Plasma Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) levels of 0.3 and 0.9 mcg/100 mL have been reported to produce deficiency symptoms in humans.

Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) is eliminated primarily in urine. However, significant endogenous losses through feces also occur. The rate of excretion and the relative importance of two routes varies with the chemical form of Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) used in supplementation. Ancillary routes of elimination are lungs and skin.

INDICATIONS AND USAGE

Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) Injection is indicated for use as a supplement to intravenous solutions given for total parenteral nutrition (TPN). Administration of Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) in TPN solutions helps to maintain plasma Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) levels and to prevent depletion of endogenous stores and subsequent deficiency symptoms.

CONTRAINDICATIONS

Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) Injection should not be given undiluted by direct injection into a peripheral vein because of the potential for infusion phlebitis.

WARNINGS

Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) Injection can be toxic if given in excessive amounts. Supplementation of TPN solution with Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) should be immediately discontinued if toxicity symptoms are observed. Frequent determination of plasma Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) levels during TPN support and close medical supervision is recommended.

Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) Injection is a hypotonic solution and should be administered in admixtures only.

This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

PRECAUTIONS

As Timed Release Ultra Mega II ) is eliminated in urine and feces, Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) supplements may be adjusted, reduced or omitted in renal dysfunction and/or gastrointestinal malfunction. In patients receiving blood transfusions, contribution from such transfusions should also be considered. Frequent Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) plasma level determinations are suggested as a guideline.

In animals, Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) has been reported to enhance the action of Vitamin E and decrease the toxicity of mercury, cadmium and arsenic.

Pregnancy

Teratogenic Effects

Pregnancy Category C: Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) at high dose levels (15-30 mcg/egg) has been reported to have adverse embryological effects among chickens. There are however, no adequate and wellcontrolled studies in pregnant women. Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) Injection should be used during pregnancy only if potential benefit justifies the potential risk to the fetus.

Presence of Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) in placenta and umbilical cord blood has been reported in humans.

ADVERSE REACTIONS

The amount of Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) present in Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) Injection is small. Symptoms of toxicity from Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) are unlikely to occur at the recommended dosage level.

OVERDOSAGE

Chronic toxicity in humans resulting from exposure to Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) in industrial environments, intake of foods grown in seleniferous soils, use of selenium-contaminated water, and application of cosmetics containing Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) has been reported in literature. Toxicity symptoms include hair loss, weakened nails, dermatitis, dental defects, gastrointestinal disorders, nervousness, mental depression, metallic taste, vomiting, and garlic odor of breath and sweat. Acute poisoning due to ingestion of large amounts of Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) compounds has resulted in death with histopathological changes including fulminating peripheral vascular collapse, internal vascular congestion, diffusely hemorrhagic, congested and edematus lungs, brick-red color gastric mucosa. The death was preceded by coma.

No effective antidote to Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) poisoning in humans is known. Animal studies have shown casein and linseed oil in feeds, reduced glutathione, arsenic, magnesium sulfate, and bromobenzene to afford limited protection.

DOSAGE AND ADMINISTRATION

Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) Injection provides 40 mcg selenium/mL. For metabolically stable adults receiving TPN, the suggested additive dosage level is 20 to 40 mcg selenium/day. For pediatric patients, the suggested additive dosage level is 3 mcg/kg/day.

In adults, Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) deficiency states resulting from long-term TPN support, Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) as selenomethionine or selenious acid, administered intravenously at 100 mcg/day for a period of 24 and 31 days, respectively, has been reported to reverse deficiency symptoms without toxicity.

Aseptic addition of Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) Injection to the TPN solution under laminar flow hood is recommended. Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) is physically compatible with the electrolytes and other trace elements usually present in amino-acid/dextrose solution used for TPN. Frequent monitoring of plasma Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) levels is suggested as a guideline for subsequent administration. The normal whole blood range for Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) is approximately 10 to 37 mcg/100 mL.

Parenteral drug products should be inspected visually for particulate matter and discoloration, whenever solution and container permit.

HOW SUPPLIED

Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) Injection containing selenious acid 65.4 mcg/mL (equivalent to elemental Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) 40 mcg/mL).

NDC 0517-6510-25 10 mL Single Dose Vial Packaged in boxes of 25

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

IN6510

Rev. 11/15

PRINCIPAL DISPLAY PANEL - Container

NDC 0517-6510-25

Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) INJECTION

Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) 400 mcg/10 mL

(40 mcg/mL)

10 mL

SINGLE DOSE VIAL

Trace Element Additive

FOR IV USE AFTER DILUTION

PRESERVATIVE FREE

Rx Only

AMERICAN REGENT, INC.

SHIRLEY, NY 11967

PRINCIPAL DISPLAY PANEL - Carton

Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) INJECTION

Timed Release Ultra Mega II (Selenium (Selenium HVP Chelate)) 400 mcg/10 mL

(40 mcg/mL)

Trace Element Additive

NDC 0517-6510-25

25 x 10 mL

SINGLE DOSE VIALS

FOR INTRAVENOUS USE AFTER DILUTION PRESERVATIVE FREE Rx Only

Each mL contains: Selenious Acid 65.4 mcg, Water for Injection q.s.

pH adjusted with Nitric Acid. Sterile, nonpyrogenic.

WARNING: DISCARD UNUSED PORTION. Store at 20°-25°C (68°-77°F); excursions

permitted to 15°-30°C (59°-86°F).

Directions for Use: See Package Insert.

AMERICAN REGENT, INC.

SHIRLEY, NY 11967

Rev. 11/05

Container Carton

Vitamin A (Vitamin A Palmitate):

• Dosage and administration
• Warning
• Clinical pharmacology
• Dietary supplementation
• Warnings
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• Timed Release Ultra Mega II (Vitamin A (Vitamin A Palmitate)) reviews

DOSAGE AND ADMINISTRATION

One tablet daily or as directed by a physician.

Supplement Facts
Serving Size 1 Tablet Servings Per Container 100
	Amount Per Serving	% Daily Value
Timed Release Ultra Mega II (Vitamin A (Vitamin A Palmitate))	2500 IU	50%
Vitamin C	60 mg	100%
Vitamin D	400 IU	100%
Vitamin E	15 IU	50%
Thiamine	1.05 mg	70%
Riboflavin	1.2 mg	70%
Niacinamide	13.5 mg	68%
Vitamin B6	1.05 mg	53%
Folic Acid	0.3 mg	75%
Vitamin B12	4.5 mcg	75%
Fluoride	0.25 mg	Daily Value not established

WARNING

KEEP OUT OF THE REACH OF CHILDREN.

In case of accidental overdose, seek professional assistance or contact a Poison Control Center immediately.

Other Ingredients: Artificial cherry flavor, artificial grape flavor, ascorbic acid, cholecalciferol, compressible sugar, D&C Red #7 calcium lake, FD&C Blue #1 aluminum lake, FD&C Yellow #6 aluminum lake, folic acid, magnesium stearate, microcrystalline cellulose, natural and artificial orange flavor, niacinamide, polyethylene glycol, pyridoxine HCl, riboflavin, sodium ascorbate, sodium fluoride, stearic acid, sucralose, thiamine HCl, Timed Release Ultra Mega II (Vitamin A (Vitamin A Palmitate)) acetate, vitamin B12 and vitamin E acetate.

Active ingredient for caries prophylaxis: Fluoride as sodium fluoride.

CLINICAL PHARMACOLOGY

Significant decrease in the incidence of dental caries can be linked to the fluoridation of the water supply (1ppm fluoride) during the period of tooth development.

Timed Release Ultra Mega II (Vitamin A (Vitamin A Palmitate)) Tablets provide sodium fluoride and ten essential vitamins in a chewable tablet. Because the tablets are chewable, they provide a topical as well as systemic source of fluoride. Hydroxyapatite is the principal crystal for all calcified tissue in the human body. The fluoride ion reacts with the Hydroxyapatite in the tooth as it is formed to produce the more caries-resistant crystal, fluorapatite.

The reaction may be expressed by the equation:

Ca10(PO4)6(OH2) + 2F-	Ca10 (PO4)6F2 + 2OH-
(Hydroxyapatite)	(Fluorapatite)

Three stages of fluoride deposition in tooth enamel can be distinguished:

• Small amounts (reflecting the low levels of fluoride in tissue fluids) are incorporated into the enamel crystals while they are being formed.
• After enamel has been laid down, fluoride deposition continues in the surface enamel. Diffusion of fluoride from the surface inward is apparently restricted.
• After eruption, the surface enamel acquires fluoride from the water, food, supplementary fluoride and smaller amounts of saliva.

DIETARY SUPPLEMENTATION

Multivitamins with fluoride offer supplementation of the diet with 10 vitamins and fluoride.

WARNINGS

AS IN THE CASE OF ALL MEDICATIONS, KEEP OUT OF THE REACH OF CHILDREN. This tablet should be chewed. This product, as with all chewable tablets are not recommended for children under the age of 4 due to risk of choking.

PRECAUTIONS

The suggested dose of Timed Release Ultra Mega II (Vitamin A (Vitamin A Palmitate)) Tablets should not be exceeded, since dental fluorosis may result from continued ingestion of large amounts of fluoride.

Before recommending Timed Release Ultra Mega II (Vitamin A (Vitamin A Palmitate)) Tablets

• Determine the fluoride content of the drinking water from all major sources
• Make sure the child is not receiving significant amounts of fluoride from other sources such as medications and swallowed toothpaste
• Periodically check to make sure that the child does not develop significant dental fluorosis.

ADVERSE REACTIONS

Allergic rash and other idiosyncrasies have been rarely reported.

To report SUSPECTED ADVERSE REACTIONS, contact H2-Pharma, LLC at 1 (866) 592-6438 or FDA at 1 (800) 332-1088 or via the web at www.fda.gov/medwatch/index.html for voluntary reporting of adverse reactions.

DOSAGE AND ADMINISTRATION

One tablet daily or as directed by a physician.

HOW SUPPLIED

Timed Release Ultra Mega II ) Tablets 0.25 mg are available as orange, red and purple chewable tablets imprinted with "151" in 100 tablet bottles.

Timed Release Ultra Mega II (Vitamin A (Vitamin A Palmitate)) Tablets 0.5 mg are available as orange, red and purple chewable tablets imprinted with "152" in 100 tablet bottles.

Timed Release Ultra Mega II (Vitamin A (Vitamin A Palmitate)) Tablets 1.0 mg are available as orange, red and purple chewable tablets imprinted with "153" in 100 tablet bottles.

STORAGE

Store at controlled room temperature 20ºC-25ºC (68º-77ºF), excursions permitted between 15º-30ºC (59º-86ºF).

Distributed by:

H2-Pharma, LLC

2010 Berry Chase Place

Montgomery, AL 36117

www.h2-pharma.com

1067084

61269-151-01

MultiVitamin

with Fluoride

Chewable Tablets

Rx

0.25 mg

MultiVitamin and Fluoride Supplement

Dietary Supplement

100 Tablets

H²pharma

Vitamin B12:

• Pharmacological action
• Pharmacokinetics
• Why is Timed Release Ultra Mega II prescribed?
• Dosage and administration
• Timed Release Ultra Mega II (Vitamin B12) side effects, adverse reactions
• Timed Release Ultra Mega II contraindications
• Timed Release Ultra Mega II using during pregnancy and breastfeeding
• Special instructions
• Timed Release Ultra Mega II (Vitamin B12) drug interactions
• Timed Release Ultra Mega II (Vitamin B12) reviews

Pharmacological action

Timed Release Ultra Mega II refers to a group of water-soluble vitamins. It has high biological activity. Timed Release Ultra Mega II (Vitamin B12) is necessary for normal hematopoiesis (promotes maturation of erythrocytes). Involved in the processes of transmethylation, hydrogen transport, synthesis of methionine, nucleic acids, choline, creatine. Contributes to the accumulation in erythrocytes of compounds containing sulfhydryl groups. Has a beneficial effect on liver function and the nervous system. Activates the coagulation of blood in high doses causes an increase in the activity of thromboplastin and prothrombin.

Pharmacokinetics

After oral administration Timed Release Ultra Mega II (Vitamin B12) absorbed from the gastrointestinal tract. Metabolized in the tissues, becoming a co-enzyme form - adenosylcobalamin which is the active form of cyanocobalamin. Excreted in bile and urine.

Why is Timed Release Ultra Mega II prescribed?

Anemia due to B12-deficiency conditions; in the complex therapy for iron and posthemorrhagic anemia; aplastic anemia caused by toxic substances and drugs; liver disease (hepatitis, cirrhosis); funicular myelosis; polyneuritis, radiculitis, neuralgia, amyotrophic lateral sclerosis; children cerebral palsy, Down syndrome, peripheral nerve injury; skin diseases (psoriasis, photodermatosis, herpetiformis dermatitis, neurodermatitis); to prevent and treat symptoms of deficiency of Timed Release Ultra Mega II (Vitamin B12) (including the application of biguanide, PASA, vitamin C in high doses); radiation sickness.

Dosage and administration

Timed Release Ultra Mega II is used as injections SC, IV, IM, intralumbar, and also oral. With anemia associated with Timed Release Ultra Mega II (Vitamin B12) deficiency is introduced on 100-200 mcg in 2 days. In anemia with symptoms of funicular myelosis and megalocytic anemia with diseases of the nervous system - 400-500 micrograms in the first 7 days daily, then 1 time every 5-7 days. In the period of remission in the absence of events funicular myelosis maintenance dose - 100 mcg 2 times a month, in the presence of neurological symptoms - at 200-400 mcg 2-4 times a month. In acute post-hemorrhagic anemia and iron anemia by 30-100 mcg 2-3 times a week. When aplastic anemia (especially in children) - 100 micrograms before clinical improvement. When nutritional anemia in infants and preterm - 30 mcg / day during 15 days.

In diseases of the central and peripheral nervous system and neurological diseases with a pain syndrome is administered in increasing doses - 200-500 mcg, with the improvement in the state - 100 mcg / day. The course of treatment with Timed Release Ultra Mega II (Vitamin B12) is 2 weeks. In traumatic lesions of peripheral nervous system - at 200-400 mcg every other day for 40-45 days.

When hepatitis and cirrhosis - 30-60 mcg / day or 100 mg every other day for 25-40 days.

Dystrophy in young children, Down syndrome and cerebral palsy - by 15-30 mcg every other day.

When funicular myelosis, amyotrophic lateral sclerosis can be introduced into the spinal canal at 15-30 mcg, gradually increasing the dose of 200-250 micrograms.

In radiation sickness, diabetic neuropathy, sprue - by 60-100 mcg daily for 20-30 days.

When deficiency of Timed Release Ultra Mega II (Vitamin B12) to prevent - IV or IM for 1 mg 1 time a month; for treatment - IV or IM for 1 mg daily for 1-2 weeks, the maintenance dose is 1-2 mg IV or IM from 1 per week, up to 1 per month. Duration of treatment is determined individually.

Timed Release Ultra Mega II (Vitamin B12) side effects, adverse reactions

CNS: rarely - a state of arousal.

Cardiovascular system: rarely - pain in the heart, tachycardia.

Allergic reactions: rarely - urticaria.

Timed Release Ultra Mega II contraindications

Thromboembolism, erythremia, erythrocytosis, increased sensitivity to cyanocobalamin.

Timed Release Ultra Mega II using during pregnancy and breastfeeding

Cyanocobalamin can be used in pregnancy according to prescriptions.

Special instructions

When stenocardia should be used with caution in a single dose of Timed Release Ultra Mega II 100 mcg. During treatment should regularly monitor the blood picture and coagulation. It is unacceptable to enter in the same syringe with cyanocobalamin solutions of thiamine and pyridoxine.

Timed Release Ultra Mega II (Vitamin B12) drug interactions

In an application of Timed Release Ultra Mega II (Vitamin B12) with hormonal contraceptives for oral administration may decrease the concentration of cyanocobalamin in plasma.

In an application with anticonvulsant drugs decreased cyanocobalamin absorption from the gut.

In an Timed Release Ultra Mega II (Vitamin B12) application with neomycin, aminosalicylic acid, colchicine, cimetidine, ranitidine, drugs potassium decreased cyanocobalamin absorption from the gut.

Cyanocobalamin may exacerbate allergic reactions caused by thiamine.

When parenteral application of chloramphenicol may decrease the hematopoietic effects of cyanocobalamin with anemia.

Pharmaceutical incompatibility

Contained in the molecule of cyanocobalamin cobalt ion contributes to the destruction of ascorbic acid, thiamine bromide, riboflavin in one solution.

Vitamin C (Calcium Ascorbate):

• Pharmacological action
• Pharmacokinetics
• Why is Timed Release Ultra Mega II ) prescribed?
• Dosage and administration
• Timed Release Ultra Mega II (Vitamin C (Calcium Ascorbate)) side effects, adverse reactions
• Timed Release Ultra Mega II ) contraindications
• Using during pregnancy and breastfeeding
• Special instructions
• Timed Release Ultra Mega II ) drug interactions
• Timed Release Ultra Mega II ) in case of emergency / overdose
• Timed Release Ultra Mega II (Vitamin C (Calcium Ascorbate)) reviews

Pharmacological action

Ascorbic acid is essential for the formation of intracellular collagen, is required to strengthen the structure of teeth, bones, and the capillary walls. Timed Release Ultra Mega II (Vitamin C (Calcium Ascorbate)) participates in redox reactions, the metabolism of tyrosine, converting folic acid into folinic acid, metabolism of carbohydrates, the synthesis of lipids and proteins, iron metabolism, processes of cellular respiration. Reduces the need for vitamins B1, B2, A, E, folic acid, pantothenic acid, enhances the body's resistance to infections; enhances iron absorption, contributing to its sequestration in reduced form. Timed Release Ultra Mega II (Vitamin C (Calcium Ascorbate)) has antioxidant properties.

With intravaginal application of ascorbic acid lowers the vaginal pH, inhibiting the growth of bacteria and helps to restore and maintain normal pH and vaginal flora (Lactobacillus acidophilus, Lactobacillus gasseri).

Pharmacokinetics

After oral administration ascorbic acid is completely absorbed from the gastrointestinal tract. Widely distributed in body tissues.

The concentration of ascorbic acid in blood plasma in normal amounts to approximately 10-20 mg / ml.

The concentration of ascorbic acid in white blood cells and platelets is higher than in erythrocytes and plasma. When deficient state of concentration in leucocytes is reduced later and more slowly and is regarded as the best criterion for evaluating the deficit than the concentration in plasma.

Plasma protein binding is about 25%.

Ascorbic acid is reversibly oxidized to form dehydroascorbic acid, is metabolized with the formation of ascorbate-2-sulphate which is inactive and oxalic acid which is excreted in the urine.

Ascorbic acid taken in excessive quantities is rapidly excreted unchanged in urine, it usually happens when exceeding a daily dose is 200 mg.

Why is Timed Release Ultra Mega II ) prescribed?

For systemic use of Timed Release Ultra Mega II (Vitamin C (Calcium Ascorbate)) Kimia Farma: prevention and treatment of hypo- and avitaminosis of Timed Release Ultra Mega II (Vitamin C (Calcium Ascorbate)); providing increased need for Timed Release Ultra Mega II (Vitamin C (Calcium Ascorbate)) during growth, pregnancy, lactation, with heavy loads, fatigue and during recovery after prolonged severe illness; in winter with an increased risk of infectious diseases.

For intravaginal use: chronic or recurrent vaginitis (bacterial vaginosis, nonspecific vaginitis) caused by the anaerobic flora (due to changes in pH of the vagina) in order to normalize disturbed vaginal microflora.

Dosage and administration

This medication administered orally, IM, IV, intravaginally.

For the prevention of deficiency conditions Timed Release Ultra Mega II ) dose is 25-75 mg / day, for the treatment - 250 mg / day or more in divided doses.

For intravaginal used ascorbic acid drugs in appropriate dosage forms.

Timed Release Ultra Mega II (Vitamin C (Calcium Ascorbate)) side effects, adverse reactions

CNS: headache, fatigue, insomnia.

Digestive system: stomach cramps, nausea and vomiting.

Allergic reaction: describes a few cases of skin reactions and manifestations of the respiratory system.

Urinary system: when used in high doses - hyperoxaluria and the formation of kidney stones of calcium oxalate.

Local reactions: with intravaginal application - a burning or itching in the vagina, increased mucous discharge, redness, swelling of the vulva. Other: sensation of heat.

Timed Release Ultra Mega II ) contraindications

Increased sensitivity to ascorbic acid.

Using during pregnancy and breastfeeding

The minimum daily requirement of ascorbic acid in the II and III trimester of pregnancy is about 60 mg.

Ascorbic acid crosses the placental barrier. It should be borne in mind that the fetus can adapt to high doses of ascorbic acid, which takes a pregnant woman, and then a newborn baby may develop the ascorbic disease as the reaction of cancel. Therefore, during pregnancy should not to take ascorbic acid in high doses, except in cases where the expected benefit outweighs the potential risk.

The minimum daily requirement during lactation is 80 mg. Ascorbic acid is excreted in breast milk. A mother's diet that contains adequate amounts of ascorbic acid, is sufficient to prevent deficiency in an infant. It is unknown whether dangerous to the child's mother use of ascorbic acid in high doses. Theoretically it is possible. Therefore, it is recommended not to exceed the maximum daily nursing mother needs to ascorbic acid, except when the expected benefit outweighs the potential risk.

Special instructions

Timed Release Ultra Mega II (Vitamin C (Calcium Ascorbate)) is used with caution in patients with hyperoxaluria, renal impairment, a history of instructions on urolithiasis. Because ascorbic acid increases iron absorption, its use in high doses can be dangerous in patients with hemochromatosis, thalassemia, polycythemia, leukemia, and sideroblastic anemia.

Patients with high content body iron should apply ascorbic acid in minimal doses.

Timed Release Ultra Mega II (Vitamin C (Calcium Ascorbate)) is used with caution in patients with deficiency of glucose-6-phosphate dehydrogenase.

The use of ascorbic acid in high doses can cause exacerbation of sickle cell anemia.

Data on the diabetogenic action of ascorbic acid are contradictory. However, prolonged use of ascorbic acid should periodically monitor your blood glucose levels.

It is believed that the use of ascorbic acid in patients with rapidly proliferating and widely disseminated tumors may worsen during the process. It should therefore be used with caution in ascorbic acid in patients with advanced cancer.

Absorption of ascorbic acid decreased while use of fresh fruit or vegetable juices, alkaline drinking.

Timed Release Ultra Mega II ) drug interactions

In an application with barbiturates, primidone increases the excretion of ascorbic acid in the urine.

With the simultaneous use of oral contraceptives reduces the concentration of ascorbic acid in blood plasma.

In an application of Timed Release Ultra Mega II (Vitamin C (Calcium Ascorbate)) with iron preparations ascorbic acid, due to its regenerative properties, transforms ferric iron in the bivalent, which improves its absorption.

Ascorbic acid in high doses can decrease urine pH that while the application reduces the tubular reabsorption of amphetamine and tricyclic antidepressants.

With the simultaneous use of aspirin reduces the absorption of ascorbic acid by about a third.

Timed Release Ultra Mega II (Vitamin C (Calcium Ascorbate)) in an application with warfarin may decrease effects of warfarin.

With the simultaneous application of ascorbic acid increases the excretion of iron in patients receiving deferoxamine. In the application of ascorbic acid at a dose of 500 mg / day possibly left ventricular dysfunction.

In an application with tetracycline is increased excretion of ascorbic acid in the urine.

There is a described case of reducing the concentration of fluphenazine in plasma in patients treated with ascorbic acid 500 mg 2 times / day.

May increase the concentration of ethinyl estradiol in the blood plasma in its simultaneous application in the oral contraceptives.

Timed Release Ultra Mega II ) in case of emergency / overdose

Symptoms: long-term use of large doses (more than 1 g) - headache, increased CNS excitability, insomnia, nausea, vomiting, diarrhea, gastritis giperatsidnyh, ultseratsiya gastrointestinal mucosa, inhibition of the function insular apparatus of the pancreas (hyperglycemia, glycosuria), hyperoxaluria, nephrolithiasis (calcium oxalate), damage to the glomerular apparatus of the kidneys, moderate thamuria (when receiving a dose of 600 mg / day).

Decrease capillary permeability (possibly deteriorating trophic tissues, increased blood pressure, hypercoagulability, the development of microangiopathy).

When IV administration in high doses - the threat of termination of pregnancy (due to estrogenemia), hemolysis of red blood cells.