OliClinomel N4-550E

Arginine:

• OliClinomel N4-550E (Arginine) reviews

Nutritive Wound - Skin Cream

For Minor Cuts and Wounds

- Eases Discomfort

- Soothing Cream

CONTAINS:

OliClinomel N4-550E (Arginine) Aminobenzoate 2.5% Patent # 5734080

In a cream base with Safflower Oil, Apricot Kernel Oil, Mixed Tocopherols, Glycerin, Coconut Oil, Borage Oil, Tea Tree Oil, Camphor, Thymine, Lecithin, Grapefruit Extract, Lemon Oil and Aloe Vera.

DIRECTIONS:

Apply topically as needed to superficial wounds and abrasions.

INDICATIONS FOR USE:

FelineAid can be used on minor cuts, abrasions and irritations as well as superficial wounds and skin lesions on cats.

CAUTIONS:

Avoid contact with eyes. If contact occurs, flush with copious amounts of water. If condition persists or worsens discontinue use.

Shake Well

Store at room temperature.

For Veterinary Use Only

Calcium Chloride Dihydrate:

• 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
• OliClinomel N4-550E (Calcium Chloride Dihydrate) reviews

1 INDICATIONS AND USAGE

OliClinomel N4-550E (Calcium Chloride Dihydrate) 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 OliClinomel N4-550E (Calcium Chloride Dihydrate) 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 OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate capsule.

- Capsule: 667 mg OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting OliClinomel N4-550E acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of OliClinomel N4-550E (Calcium Chloride Dihydrate) 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 OliClinomel N4-550E (Calcium Chloride Dihydrate), including OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate. Avoid the use of OliClinomel N4-550E (Calcium Chloride Dihydrate) supplements, including OliClinomel N4-550E (Calcium Chloride Dihydrate) based nonprescription antacids, concurrently with OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate.

An overdose of OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum OliClinomel N4-550E (Calcium Chloride Dihydrate) levels twice weekly. Should hypercalcemia develop, reduce the OliClinomel N4-550E (Calcium Chloride Dihydrate) 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 OliClinomel N4-550E (Calcium Chloride Dihydrate) 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 OliClinomel N4-550E (Calcium Chloride Dihydrate) 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 OliClinomel N4-550E (Calcium Chloride Dihydrate) 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 OliClinomel N4-550E (Calcium Chloride Dihydrate) 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 OliClinomel N4-550E (Calcium Chloride Dihydrate) 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, OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate has been generally well tolerated.

OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of OliClinomel N4-550E (Calcium Chloride Dihydrate) 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 OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate N=167 N (%)	3 month, open label study of OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate N=98 N (%)	Double blind, placebo-controlled, cross-over study of liquid OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate N=69
			OliClinomel N4-550E (Calcium Chloride Dihydrate) 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 OliClinomel N4-550E (Calcium Chloride Dihydrate) concentration could reduce the incidence and severity of OliClinomel N4-550E (Calcium Chloride Dihydrate) 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 OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of OliClinomel N4-550E acetate is characterized by the potential of OliClinomel N4-550E (Calcium Chloride Dihydrate) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate and most concomitant drugs. When administering an oral medication with OliClinomel N4-550E (Calcium Chloride Dihydrate) 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 OliClinomel N4-550E (Calcium Chloride Dihydrate) 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 OliClinomel N4-550E (Calcium Chloride Dihydrate) 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 OliClinomel N4-550E (Calcium Chloride Dihydrate) 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 OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

OliClinomel N4-550E acetate capsules contains OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate. Animal reproduction studies have not been conducted with OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate, and there are no adequate and well controlled studies of OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum OliClinomel N4-550E (Calcium Chloride Dihydrate) 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. OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate treatment, as recommended, is not expected to harm a fetus if maternal OliClinomel N4-550E (Calcium Chloride Dihydrate) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

OliClinomel N4-550E Acetate Capsules contains OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate and is excreted in human milk. Human milk feeding by a mother receiving OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate is not expected to harm an infant, provided maternal serum OliClinomel N4-550E (Calcium Chloride Dihydrate) 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 OliClinomel N4-550E (Calcium Chloride Dihydrate) 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 OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate acts as a phosphate binder. Its chemical name is OliClinomel N4-550E (Calcium Chloride Dihydrate) 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 OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate USP (anhydrous; Ca(CH₃COO)₂; MW=158.17 grams) equal to 169 mg (8.45 mEq) OliClinomel N4-550E (Calcium Chloride Dihydrate), 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.

OliClinomel N4-550E (Calcium Chloride Dihydrate) 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 OliClinomel N4-550E resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate, when taken with meals, combines with dietary phosphate to form an insoluble OliClinomel N4-550E (Calcium Chloride Dihydrate) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered OliClinomel N4-550E (Calcium Chloride Dihydrate) 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 OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate.

14 CLINICAL STUDIES

Effectiveness of OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate in decreasing serum phosphorus has been demonstrated in two studies of the OliClinomel N4-550E (Calcium Chloride Dihydrate) 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 OliClinomel N4-550E (Calcium Chloride Dihydrate) 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 OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum OliClinomel N4-550E (Calcium Chloride Dihydrate) 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
OliClinomel N4-550E (Calcium Chloride Dihydrate) (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 OliClinomel N4-550E (Calcium Chloride Dihydrate) 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 OliClinomel N4-550E (Calcium Chloride Dihydrate) 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 OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate is shown in the Table 3.

* ANOVA of OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate vs. placebo after 2 weeks of treatment. † Values expressed as mean ± SEM.
Parameter	Pre-Study	Post-Treatment		p-value*
		OliClinomel N4-550E (Calcium Chloride Dihydrate) Acetate	Placebo
Phosphorus (mg/dL)†	7.3 ± 0.18	5.9 ± 0.24	7.8 ± 0.22	<0.01
OliClinomel N4-550E (Calcium Chloride Dihydrate) (mg/dL)†	8.9 ± 0.11	9.5 ± 0.13	8.8 ± 0.12	<0.01

Overall, 2 weeks of treatment with OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum OliClinomel N4-550E (Calcium Chloride Dihydrate) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

OliClinomel N4-550E (Calcium Chloride Dihydrate) 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 OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of OliClinomel N4-550E (Calcium Chloride Dihydrate) 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 OliClinomel N4-550E (Calcium Chloride Dihydrate) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Dextrose Monohydrate:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• Directions for use of pharmacy bulk package container
• How supplied
• OliClinomel N4-550E (Dextrose Monohydrate) reviews

INDICATIONS AND USAGE

70% OliClinomel N4-550E (Dextrose Monohydrate) Injection USP is indicated as a caloric component in a parenteral nutrition regimen. 70% OliClinomel N4-550E (Dextrose Monohydrate) Injection USP is used with an appropriate protein (nitrogen) source in the prevention of nitrogen loss or in the treatment of negative nitrogen balance in patients where: (1) the alimentary tract cannot or should not be used, (2) gastrointestinal absorption of protein is impaired, or (3) metabolic requirements for protein are substantially increased, as with extensive burns.

CONTRAINDICATIONS

The infusion of 70% OliClinomel N4-550E (Dextrose Monohydrate) Injection USP is contraindicated in patients having intracranial or intraspinal hemorrhage, in patients who are severely dehydrated, in patients who are anuric, and in patients in hepatic coma.

Solutions containing OliClinomel N4-550E (Dextrose Monohydrate) may be contraindicated in patients with hypersensitivity to corn products.

WARNINGS

This injection is for compounding only, not for direct infusion.

Dilute before use to a concentration which will, when administered with an amino acid (nitrogen) source, result in an appropriate calorie to gram of nitrogen ratio and which has an osmolarity consistent with the route of administration.

Unless appropriately diluted, the infusion of hypertonic OliClinomel N4-550E (Dextrose Monohydrate) injection into a peripheral vein may result in vein irritation, vein damage, and thrombosis. Strongly hypertonic nutrient solutions should only be administered through an indwelling intravenous catheter with the tip located in a large central vein such as the superior vena cava.

Use of 70% OliClinomel N4-550E (Dextrose Monohydrate) Injection USP to prepare parenteral nutritional admixtures may be incompatible with other components, especially calcium and phosphate salts and lipid emulsions. Incompatibility of admixed components can produce precipitates which may cause particulate emboli. Use 70% OliClinomel N4-550E (Dextrose Monohydrate) Injection USP only to prepare formulations that are known to be stable: refer to standard texts for further information.

The administration of intravenous solutions can cause fluid and/or solute overload resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentration.

WARNING: 70% OliClinomel N4-550E (Dextrose Monohydrate) Injection USP 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 µg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

Prolonged infusion of isotonic or hypotonic OliClinomel N4-550E (Dextrose Monohydrate) in water may increase the volume of extracellular fluid and cause water intoxication.

Solutions containing OliClinomel N4-550E (Dextrose Monohydrate) without electrolytes should not be administered simultaneously with blood through the same infusion set because of the possibility of agglomeration.

Excessive administration of potassium-free OliClinomel N4-550E (Dextrose Monohydrate) solutions may result in significant hypokalemia. Serum potassium levels should be maintained and potassium supplemented as required.

In very low birth weight infants, excessive or rapid administration of OliClinomel N4-550E (Dextrose Monohydrate) injection may result in increased serum osmolality and possible intracerebral hemorrhage.

PRECAUTIONS

General

This solution should be used with care in patients with hypervolemia, renal insufficiency, urinary tract obstruction, or impending or frank cardiac decompensation.

Solutions containing OliClinomel N4-550E should be used with caution in patients with overt or known subclinical diabetes mellitus or carbohydrate intolerance for any reason.

Essential electrolytes, minerals, and vitamins should be supplied as needed.

Hypokalemia may develop during parenteral administration of hypertonic OliClinomel N4-550E (Dextrose Monohydrate) solutions. Sufficient amounts of potassium should be added to OliClinomel N4-550E (Dextrose Monohydrate) solutions administered to fasting patients with good renal function, especially those on digitalis therapy.

To minimize the risk of possible incompatibilities arising from mixing this solution with other additives that may be prescribed, the final infusate should be inspected for cloudiness or precipitation immediately after mixing, prior to administration, and periodically during administration. See WARNINGS .

Do not use plastic container in series connection.

If administration of 70% OliClinomel N4-550E (Dextrose Monohydrate) Injection USP after admixture or dilution is controlled by a pumping device, care must be taken to discontinue pumping action before the container runs dry or air embolism may result. If administration is not controlled by a pumping device, refrain from applying excessive pressure (>300mmHg) causing distortion to the container such as wringing or twisting. Such handling could result in breakage of the container.

This solution is intended for intravenous administration after admixture or dilution using sterile equipment. When using an automated compounding device replace all disposable components as recommended by manufacturer and at least every 24 hours.

Aseptic technique is essential with the use of sterile preparations for compounding nutritional admixtures. Discard container within 4 hours of entering closure.

Administration of hypertonic OliClinomel N4-550E (Dextrose Monohydrate) and amino acid solutions via central venous catheter may be associated with complications which can be prevented or minimized by careful attention to all aspects of the procedure. This includes attention to solution preparation, administration and patient monitoring.

It is essential that a carefully prepared protocol, based upon current medical practice, be followed, preferably by an experienced team. The package insert of the protein (nitrogen) source should be consulted for dosage and all precautionary information.

Use only if solution is clear and container and seals are intact.

70% OliClinomel N4-550E (Dextrose Monohydrate) Injection USP contains no more than 25 µg/L of aluminum.

Laboratory Tests

Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid-base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Significant deviations from normal concentrations may require tailoring of the electrolyte pattern, in these or alternative solutions.

Drug Interactions

Caution must be exercised in the administration of 70% OliClinomel N4-550E Injection USP to patients receiving corticosteroids or corticotropin. Some additives may be incompatible. Consult with pharmacist. When introducing additives, use aseptic techniques. Mix thoroughly. Do not store. Dispose of any unused product. See WARNINGS .

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies with OliClinomel N4-550E (Dextrose Monohydrate) Injections USP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.

Pregnancy

Pregnancy Category C

There are no adequate and well controlled studies with OliClinomel N4-550E Injections, USP in pregnant women and animal reproduction studies have not been conducted with this drug. Therefore, it is not known whether OliClinomel N4-550E (Dextrose Monohydrate) Injections USP can cause fetal harm when administered to a pregnant woman. OliClinomel N4-550E (Dextrose Monohydrate) Injections USP should be given during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery

Intrapartum maternal intravenous infusion of glucose-containing solutions may produce maternal hyperglycemia with subsequent fetal hyperglycemia and fetal metabolic acidosis. Fetal hyperglycemia can result in increased fetal insulin levels which may result in neonatal hypoglycemia following delivery. Consider the potential risks and benefits for each specific patient before administering OliClinomel N4-550E (Dextrose Monohydrate) Injection, USP.

Nursing Mothers

It is not known if this drug is present in human milk. Because many drugs are present in human milk, caution should be exercised when OliClinomel N4-550E Injections USP are administered to a nursing woman.

Pediatric Use

The use of OliClinomel N4-550E (Dextrose Monohydrate) in pediatric patients is based on clinical practice (see DOSAGE AND ADMINISTRATION ). Because of their hypertonicity, 70% OliClinomel N4-550E (Dextrose Monohydrate) Injections must be diluted prior to administration.

Newborns – especially those born premature and with low birth weight - are at increased risk of developing hypo- or hyperglycemia and therefore need close monitoring during treatment with intravenous glucose solutions to ensure adequate glycemic control in order to avoid potential long term adverse effects. Hypoglycemia in the newborn can cause prolonged seizures, coma and brain damage. Hyperglycemia has been associated with intraventricular hemorrhage, late onset bacterial and fungal infection, retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, prolonged length of hospital stay, and death.

Geriatric Use

An evaluation of literature revealed no clinical experience identifying 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.

See WARNINGS .

ADVERSE REACTIONS

Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. Incompatibility of admixed components can produce precipitates which may cause particulate emboli.

Hyperosmolar syndrome, resulting from excessively rapid administration of concentrated OliClinomel N4-550E (Dextrose Monohydrate) may cause hypovolemia, dehydration, mental confusion and/or loss of consciousness. Too rapid infusion of hypertonic solutions may cause local pain and venous irritation. Rate of administration should be adjusted according to tolerance. Use of the largest peripheral vein and a small bore needle is recommended. (See DOSAGE AND ADMINISTRATION .)

Hypersensitivity reactions, including anaphylaxis and chills.

If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.

OVERDOSAGE

In the event of a fluid or solute overload during parenteral therapy, reevaluate the patient’s condition and institute appropriate corrective treatment.

DOSAGE AND ADMINISTRATION

This solution is for intravenous use only after admixture or dilution.

70% OliClinomel N4-550E Injection USP is designed for use with automated compounding devices for preparing intravenous nutritional admixtures or for the filling of empty sterile syringes. Dosages will be in accordance with the recommendation of the prescribing physician. 70% OliClinomel N4-550E (Dextrose Monohydrate) Injection USP is not intended for direct infusion. Admixtures should be made by, or under the direction of, a pharmacist using strict aseptic technique under a laminar flow hood. Compounded admixtures may be stored under refrigeration for up to 24 hours. Administration of admixtures should be completed within 24 hours after removal from refrigeration.

Dosage is to be directed by a physician and is dependent upon age, weight, clinical condition of the patient and laboratory determinations. Frequent laboratory determinations and clinical evaluation are essential to monitor changes in blood glucose and electrolyte concentrations, and fluid and electrolyte balance during prolonged parenteral therapy.

Fluid administration should be based on calculated maintenance or replacement fluid requirements for each patient.

Pediatric Use

The dosage selection and constant infusion rate of intravenous OliClinomel N4-550E (Dextrose Monohydrate) must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when OliClinomel N4-550E (Dextrose Monohydrate) is prescribed to pediatric patients, particularly neonates and low birth weight infants. The infusion rate and volume depends on the age, weight, clinical and metabolic conditions of the patient, concomitant therapy and should be determined by the consulting physician experienced in pediatric intravenous fluid therapy.

Directions for Use of Pharmacy Bulk Package Container

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration or admixture and final infusate should be inspected for cloudiness or precipitation immediately after mixing, prior to administration, and periodically during administration, whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions where possible.

70% OliClinomel N4-550E (Dextrose Monohydrate) Injection USP in the Pharmacy Bulk Package is intended for use in the preparation of sterile, intravenous admixtures.

Refer to standard texts and guidelines on the preparation of parenteral nutritional admixtures.

When compounding admixtures, use aseptic technique. Mix thoroughly.

Do not store any unused portion of 70% OliClinomel N4-550E (Dextrose Monohydrate) Injection USP.

TO OPEN:

• Inspect overwrap. Do not use if overwrap has been damaged.
• Do not use unless solution is clear and closure is intact.
• Tear overwrap starting from the tear notches. (Figure 1)
  

• Inspect the container for minute leaks by squeezing inner bag firmly. If leaks are found, discard the bag as sterility may be impaired.
• For compounding only. Do not use for direct infusion
  

  PREPARATION FOR ADMIXING
  

  Note: Important Admixing Information
  

  
  

• The Pharmacy Bulk Package is to be used only in a suitable work area such as a laminar air flow hood (or an equivalent clean air compounding area).
• The contents are restricted to the preparation of admixtures for infusion or, through a sterile transfer device, for the filling of empty sterile syringes.
• Additives may be incompatible with the fluid withdrawn from this container. When compounding admixtures, use aseptic technique, mix thoroughly and do not store.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution container permits. (see PRECAUTIONS, General )

• Do not use/penetrate blocked port.
  

• Remove aluminum foil of set port at the bottom of container.
• Attach suitable transfer device or compounding set (Figure 2). Refer to complete directions accompanying device.
• Hang bag on suitable fixture (Figure 3).
• Once container closure has been penetrated, withdrawal of content should be completed within 4 hours.

Bag Illustration Figure 1 Bag Hanger illustration Figure 2 Figure 3

HOW SUPPLIED

70% OliClinomel N4-550E (Dextrose Monohydrate) Injection USP is supplied in 2000 mL Pharmacy Bulk Package containers packaged 4 per case.

NDC REF SIZE

0264-7387-50 S8705 2000 mL

Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. It is recommended that the product be stored at room temperature (25°C); however, brief exposure up to 40°C does not adversely affect the product.

Rx only

Initiated: February 2015

B. Braun Medical Inc.

Bethlehem, PA 18018-3524 USA

1-800-227-2862

www.bbraun.com

Y36-002-865 LD-355-2

Glycine:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Im-1453
• OliClinomel N4-550E (Glycine) reviews

INDICATIONS AND USAGE

1.5% OliClinomel N4-550E (Glycine) Irrigation, USP is indicated for use as irrigating fluid during transurethral prostatic resection and other transurethral surgical procedures.

CONTRAINDICATIONS

NOT FOR INJECTION BY USUAL PARENTERAL ROUTES.

Do not use in patients with anuria.

WARNINGS

FOR UROLOGIC IRRIGATION ONLY.

Solutions for urologic irrigation must be used with caution in patients with severe cardiopulmonary or renal dysfunction. Irrigating fluids used during transurethral prostatectomy have been demonstrated to enter the systemic circulation in relatively large volumes. Thus, OliClinomel N4-550E (Glycine) irrigating solution must be regarded as a systemic drug. Absorption of large amounts of fluids containing OliClinomel N4-550E (Glycine) may significantly alter cardiopulmonary and renal dynamics.

Do not heat container over 66°C (150°F).

PRECAUTIONS

Cardiovascular status, especially of the patient with cardiac disease, should be carefully observed before and during transurethral resection of the prostate when using OliClinomel N4-550E (Glycine) irrigating solution, because the quantity of fluid absorbed into the systemic circulation by opened prostatic veins may produce significant expansion of the extracellular fluid and lead to fulminating congestive heart failure. Shift of sodium free intracellular fluid into the extracellular compartment following systemic absorption of solution may lower serum sodium concentration and aggravate pre-existing hyponatremia.

Care should be exercised if impaired liver function is known or suspected. Under such conditions, ammonia resulting from metabolism of OliClinomel N4-550E (Glycine) may accumulate in the blood.

Aseptic technique is essential with the use of sterile solutions for irrigation. The administration set should be attached promptly. Unused portions should be discarded and a fresh container of appropriate size used for the start-up of each cycle or repeat procedure.

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

Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies with OliClinomel N4-550E (Glycine) Irrigation, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.

Nursing Mothers: Caution should be exercised when OliClinomel N4-550E (Glycine) Irrigation, USP is administered to a nursing woman.

Pregnancy: Teratogenic Effects.

Pregnancy Category C. Animal reproduction studies have not been conducted with OliClinomel N4-550E (Glycine) Irrigation, USP. It is also not known whether OliClinomel N4-550E (Glycine) Irrigation, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. OliClinomel N4-550E (Glycine) Irrigation, USP should be given to a pregnant woman only if clearly needed.

Pediatric Use: The safety and effectiveness of OliClinomel N4-550E (Glycine) Irrigation have not been established. Its limited use in pediatric patients has been inadequate to fully define proper dosage and limitations for use.

ADVERSE REACTIONS

Adverse reactions may result from intravascular absorption of OliClinomel N4-550E (Glycine). Large intravenous doses of OliClinomel N4-550E (Glycine) are known to cause salivation, nausea and lightheadedness. Other consequences of absorption of urologic irrigating solutions include fluid and electrolyte disturbances such as acidosis, electrolyte loss, marked diuresis, urinary retention, edema, dryness of mouth, thirst, dehydration, coma from hyponatremia, secondary hyponatremia due to fluid overload, and hyper- ammonemia with resultant coma and/or encephalopathy; cardiovascular disorders such as hypotension, tachycardia, angina-like pains; pulmonary disorders such as pulmonary congestion; and other general reactions such as blurred vision, convulsions, nausea, vomiting, rhinitis, chills, vertigo, backache, transient blindness and urticaria. Allergic reactions from OliClinomel N4-550E (Glycine) are unknown or exceedingly rare.

Should any adverse reaction occur, discontinue the irrigant, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.

OVERDOSAGE

In the event of overhydration or solute overload, re-evaluate the patient and institute appropriate corrective measures. See WARNINGS, PRECAUTIONS and ADVERSE REACTIONS.

DOSAGE AND ADMINISTRATION

1.5% OliClinomel N4-550E (Glycine) Irrigation, USP should be administered only by transurethral instillation with appropriate urologic instrumentation. A disposable irrigation set should be used. The total volume of solution used for irrigation is solely at the discretion of the surgeon.

Height of container(s) above the operating table in excess of 60 cm (approx. 2 ft.) has been reported to increase intravascular absorption of the irrigating fluid.

Drug Interactions

Additives may be incompatible. Consult with pharmacist, if available. When introducing additives, use aseptic technique, mix thoroughly and do not store.

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

HOW SUPPLIED

1.5% OliClinomel N4-550E (Glycine) Irrigation, USP is supplied in single-dose 3000 mL flexible irrigation container ( List No. 7974).

Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. Store at 20 to 25°C (68 to 77°F).

Revised: October 2004

©Hospira 2004 EN-0577 Printed in USA

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

IM-1453

iv bag ndc 0409-7974-08

2

HDPE

TO OPEN TEAR AT NOTCH

DO NOT REMOVE FROM OVERWRAP UNTIL READY FOR USE. AFTER REMOVING

THE OVERWRAP, CHECK FOR MINUTE LEAKS BY SQUEEZING CONTAINER FIRMLY.

IF LEAKS ARE FOUND, DISCARD SOLUTION AS STERILITY MAY BE IMPAIRED.

RECOMMENDED STORAGE: ROOM TEMPERATURE (25°C). AVOID EXCESSIVE

HEAT. PROTECT FROM FREEZING. SEE INSERT.

98-4321-R14-3/98

Lysine Hydrochloride:

• Boxed warning
• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• OliClinomel N4-550E (Lysine Hydrochloride) reviews

BOXED WARNING

Pharmacy Bulk Package

Not For Direct Infusion

DESCRIPTION

OliClinomel N4-550E (Lysine Hydrochloride)^® 15% Amino Acids Injection in a Pharmacy Bulk Package is a sterile, clear, nonpyrogenic solution of essential and nonessential amino acids for intravenous infusion in parenteral nutrition following appropriate dilution.

OliClinomel N4-550E (Lysine Hydrochloride)^® 15% in a Pharmacy Bulk Package is not for direct infusion. It is a sterile dosage from which contains several single doses for use in a pharmacy admixture program in the preparation of intravenous parenteral fluids.

Each 100 mL contains:

Essential Amino Acids
OliClinomel N4-550E (Lysine Hydrochloride) (from OliClinomel N4-550E (Lysine Hydrochloride) Acetate, USP)……………………………………...1.18		g
Leucine, USP……………………………………………………………...1.04		g
Phenylalanine, USP……………………………………...1.04		g
Valine, USP……………………………………………………………...960		mg
Isoleucine, USP………………………………………...749		mg
Methionine, USP………………………………………...749		mg
Threonine, USP………………………………………...749		mg
Tryptophan, USP………………………………………...250		mg
Nonessential Amino Acids
Alanine, USP…………………………………………...2.17		g
Arginine, USP…………………………………………...1.47		g
Glycine, USP…………………………………………...1.04		g
Histidine, USP…………………………………………...894		mg
Proline, USP……………………………………………………………...894		mg
Glutamic Acid…………………………………………...749		mg
Serine, USP……………………………………………...592		mg
Aspartic Acid, USP……………………………………...434		mg
Tyrosine, USP…………………………………………...39		mg
Sodium Metabisulfite, NF added……………………………………………...30		mg
Water for Injection, USP……………………………………………………...		qs
Essential Amino Acids………………………………………………………...6.7		g
Nonessential Amino Acids…………………………………………………...8.3		g
Total Amino Acids…………………………………………………………...15.0		g
Total Nitrogen………………………………………………………………...2.37		g
Acetate*……………………………………………………...151		mEq/L
Osmolarity (calculated)……………………………………...1388		mOsmol/L
pH……………………………………………………………………………...5.6(5.2-6.0)
*Acetate from OliClinomel N4-550E (Lysine Hydrochloride) Acetate, USP and acetic acid used for pH adjustment.

The formulas for the individual amino acids are as follows:

Formulas for individual amino acids

CLINICAL PHARMACOLOGY

OliClinomel N4-550E (Lysine Hydrochloride)^® 15% Amino Acids Injection providesseventeen crystalline amino acids. This completely utilizable substrate promotesprotein synthesis and wound healing and reduces the rate of protein catabolism.

A.Total Parenteral Nutrition (Central Infusion)

When enteralfeeding is inadvisable, OliClinomel N4-550E (Lysine Hydrochloride)^® 15% given by central venousinfusion in combination with energy sources, vitamins, trace elements andelectrolytes, will completely satisfy the requirements for weight maintenanceor weight gain, depending upon the dose selected. The energy component inparenteral nutrition by central infusion may be derived solely from dextroseor may be provided by a combination of dextrose and intravenous fat emulsion. The addition of intravenous fat emulsion provides essential fatty acids andpermits a dietary balance of fat and carbohydrate, at the same time offeringthe option of reducing the dextrose load and/or increasing the total caloricinput. An adequate energy supply is essential for optimal utilization of aminoacids.

B. Total Parenteral Nutrition (Peripheral Infusion)

OliClinomel N4-550E (Lysine Hydrochloride)^® 15%can also be administered as part of a total parenteral nutrition program byperipheral vein when the enteral route is inadvisable and use of the centralvenous catheter is contraindicated.

Reduction of proteinloss can be achieved by use of diluted OliClinomel N4-550E (Lysine Hydrochloride)^® 15% in combinationwith dextrose or with dextrose and intravenous fat emulsion by peripheralinfusion. Complete peripheral intravenous nutrition can be achieved in patientswith low caloric requirements by a OliClinomel N4-550E (Lysine Hydrochloride)^®15%-dextrose-fatregimen.

INDICATIONS AND USAGE

OliClinomel N4-550E (Lysine Hydrochloride)^® 15% is indicated as an amino acid(nitrogen) source in parenteral nutrition regimens. This use is appropriatewhen the enteral route is inadvisable, inadequate or not possible, as when:

-Gastrointestinal absorption is impaired by obstruction, inflammatory diseaseor its complications, or antineoplastic therapy;

-Bowel rest is needed because of gastrointestinal surgery or its complicationssuch as ileus, fistulae or anastomotic leaks;

-Tube feeding methods alone cannot provide adequate nutrition.

CONTRAINDICATIONS

This solution should not be used in patients in hepatic coma,severe renal failure, metabolic disorders involving impaired nitrogen utilizationor hypersensitivity to one or more amino acids.

WARNINGS

Administration of amino acids solutions at excessive ratesor to patients with hepatic insufficiency may result in plasma amino acidimbalances, hyperammonemia, prerenal azotemia, stupor and coma. Conservativedoses of amino acids should be given to these patients, dictated by the nutritionalstatus of the patient. Should symptoms of hyperammonemia develop, amino acidadministration should be discontinued and the patient’s clinical statusre-evaluated.

Contains sodium metabisulfite, a sulfitethat may cause allergic-type reactions including anaphylactic symptoms andlife-threatening or less severe asthmatic episodes in certain susceptiblepeople. The overall prevalence of sulfite sensitivity in the general populationis unknown and probably low.

Sulfite sensitivity isseen more frequently in asthmatic than in nonasthmatic people.

WARNING: This product contains aluminum that maybe toxic. Aluminum may reach toxic levels with prolonged parenteral administrationif kidney function is impaired. Premature neonates are particularly at riskbecause their kidneys are immature, and they require large amounts of calciumand phosphate solutions, which contain aluminum.

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

PRECAUTIONS

A. GENERAL

It is essential to provide adequate calories concurrently if parenterally administered amino acids are to be retained by the body and utilized for protein synthesis.

The administration of OliClinomel N4-550E (Lysine Hydrochloride)^® 15% Amino Acids Injection as part of total parenteral nutrition (TPN) with large volumes of hyperosmotic fluids requires periodic monitoring of the patient for signs of hyperosmolarity, hyperglycemia, glycosuria and hypertriglyceridemia.

During parenteral nutrition with concentrated dextrose and amino acids solutions, essential fatty acid deficiency syndrome may develop but may not be clinically apparent. Early demonstration of this condition can only be accomplished by gas liquid chromatographic analysis of plasma lipids. The syndrome may be prevented or corrected by appropriate treatment with intravenous fat emulsions.

For complete nutritional support, TPN regimens must also include multiple vitamins and trace elements. Potentially incompatible ions such as calcium and phosphate may be added to alternate infusate bottles to avoid precipitation. Although the metabolizable acetate ion in OliClinomel N4-550E (Lysine Hydrochloride)^® 15% diminishes the risk of acidosis, the physician must be alert to the potential appearance of this disorder.

Initiation and termination of infusions of TPN fluids must be gradual to permit adjustment of endogenous insulin release.

Undiluted OliClinomel N4-550E (Lysine Hydrochloride)^® 15% should not be administered peripherally. When administered centrally, it should be diluted with appropriate diluents, e.g., dextrose, electrolytes and other nutrient components, to at least half strength. See DOSAGE AND ADMINISTRATION.

Caution against volume overload should be exercised.

Drug product contains no more than 25 mcg/L of aluminum.

B. Laboratory Tests

Infusion of OliClinomel N4-550E (Lysine Hydrochloride)^® 15% without concomitant infusion of an adequate number of non-protein calories may result in elevated BUN. Monitoring of BUN is required and the balance between OliClinomel N4-550E (Lysine Hydrochloride)^® 15% and the calorie source may require adjustment. Frequent clinical evaluations and laboratory determinations are required to prevent the complications which may occur during the administration of solutions used in TPN. Laboratory tests should include blood glucose, serum electrolytes, liver and kidney function, serum osmolarity, blood ammonia, serum protein, pH, hematocrit, WBC and urinary glucose. When OliClinomel N4-550E (Lysine Hydrochloride)^® 15% is combined with electrolytes, care should be used in administering this solution to patients with congestive heart failure, renal failure, edema, adrenal hyperactivity, acid-base imbalance and those receiving diuretics or antihypertensive therapy. Total volume infused should be closely monitored. Serum electrolytes should be monitored daily in these patients.

C. Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies with OliClinomel N4-550E (Lysine Hydrochloride)^® 15% have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.

D. Pregnancy Category C

Animal reproduction studies have not been conducted with OliClinomel N4-550E (Lysine Hydrochloride)^® 15%. It is also not known whether OliClinomel N4-550E (Lysine Hydrochloride)^® 15% can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. OliClinomel N4-550E (Lysine Hydrochloride)^® 15% should be given to a pregnant woman only if clearly needed.

E. Nursing Mothers

Caution should be exercised when OliClinomel N4-550E (Lysine Hydrochloride)^® 15% is administered to a nursing woman.

F. Pediatric Use

Safety and effectiveness of OliClinomel N4-550E (Lysine Hydrochloride)^® 15% Amino Acids Injection in pediatric patients have not been established by adequate and well-controlled studies. However, the use of amino acids injections in pediatric patients as an adjunct in the offsetting of nitrogen loss or in the treatment of negative nitrogen balance is referenced in the medical literature.

G. Special Precautions for Central Infusion

TPN delivered by indwelling catheter through a central or large peripheral vein is a special technique requiring a team effort by physician, nurse and pharmacist. The responsibility for administering this therapy should be confined to those trained in the procedures and alert to signs of complications. Complications known to occur from the placement of central venous catheter are pneumothorax, hemothorax, hydrothorax, artery puncture and transection, injury to the brachial plexus, malposition of the catheter, formation of arteriovenous fistula, phlebitis, thrombosis, and air/catheter emboli. The risk of sepsis is present during intravenous therapy, especially when using central venous catheters for prolonged periods. It is imperative that the preparation of admixtures and the placement and care of the catheters be accomplished under controlled aseptic conditions.

H. Admixtures

Admixtures should be prepared under a laminar flow hood using aseptic technique.

Admixtures should be stored under refrigeration and must be administered within 24 hours after removal from refrigerator.

Filters of less than 1.2 micron pore size must not be used with admixtures containing fat emulsion.

I. Do not administer unless solution is clear and the seal is intact.

IT IS ESSENTIAL THAT A CAREFULLY PREPARED PROTOCOL, BASED ON CURRENT MEDICAL PRACTICES, BE FOLLOWED, PREFERABLY BY AN EXPERIENCED TEAM.

ADVERSE REACTIONS

OVERDOSAGE

In the event of overhydration or solute overload, re-evaluatethe patient and institute appropriate corrective measures. See WARNINGS andPRECAUTIONS.

DOSAGE AND ADMINISTRATION

The appropriate daily dose of amino acids to be used withdextrose or with dextrose and intravenous fat emulsion will depend upon themetabolic status and clinical response of the patient as therapy proceeds. Doses which achieve nitrogen equilibrium or positive balance are the mostdesirable. The dosage on the first day should be approximately half the anticipatedoptimal dosage and should be increased gradually to minimize glycosuria; similarly,withdrawal should be accomplished gradually to avoid rebound hypoglycemia.

Fatemulsion coadministration should be considered when prolonged (more than 5days) parenteral nutrition is required in order to prevent essential fattyacid deficiency (EFAD). Serum lipids should be monitored for evidence of EFADin patients maintained on fat free TPN.

The amount administeredis dosed on the basis of amino acids/kg of body weight/day. In general, twoto three g/kg of body weight for neonates and infants with adequate caloriesare sufficient to satisfy protein needs and promote positive nitrogen balance. In pediatric patients, the final solution should not exceed twice normal serumosmolarity (718 mOsmol/L).

DIRECTIONSFOR PROPER USE OF PHARMACY BULK PACKAGE

OliClinomel N4-550E (Lysine Hydrochloride)^® 15%in a Pharmacy Bulk Package is not intended for direct infusion. The containerclosure may be penetrated only once using a suitable sterile transfer deviceor dispensing set which allows measured dispensing of the contents. The PharmacyBulk Package is to be used only in a suitable work area such as a laminarflow hood (or an equivalent clean air compounding area). Once the closureis penetrated, the contents should be dispensed as soon as possible; the transferof contents must be completed within 4 hours of closure entry. The bottlemay be stored at room temperature (25°C) after the closure has been entered. Date and time of container entry should be noted in the area designated onthe container label.

When using OliClinomel N4-550E (Lysine Hydrochloride)^® 15%in patients with a need for fluid volume restriction, it can be diluted asfollows:

	Volume	Amount	FinalConcentration
OliClinomel N4-550E (Lysine Hydrochloride)® 15%	500 mL	75 g	7.5%
Dextrose 70%	250 mL	175 g	17.5%
Intralipid® 20%	250 mL	50 g	5.0%

This will provide 1395 kilocalories (kcal) per 1000 mLof admixture with a ratio of 118 non-protein calories per gram of nitrogenand an osmolarity of 1561 mOsmol/L.

In patients wherethe need for fluid restriction is not so marked, either of the following regimensmay be used dependent upon the energy needs of the patient.

	Volume	Amount	FinalConcentration
OliClinomel N4-550E (Lysine Hydrochloride)® 15%	500 mL	75 g	3.75%
Dextrose 50%	1000 mL	500 g	25%
Intralipid® 20%	500 mL	100 g	5%

This will provide 1500 kcal per 1000 mL of admixture witha ratio of 228 non-protein calories per gram of nitrogen and an osmolarityof 1633 mOsmol/L.

	Volume	Amount	FinalConcentration
OliClinomel N4-550E (Lysine Hydrochloride)® 15%	500 mL	75 g	3.75%
Dextrose 30%	1000 mL	300 g	15%
Intralipid® 10%	500 mL	50 g	2.5%

This will provide 935 kcal per 1000 mL of admixture witha ratio of 158 non-protein calories per gram of nitrogen and an osmolarityof 1128.5 mOsmol/L.

A. Total Parenteral Nutrition (CentralInfusion)

In unstressed adult patients with no unusualnitrogen losses, a minimum dosage of 0.1 gram nitrogen (4.2 mL of OliClinomel N4-550E (Lysine Hydrochloride)^® 15%)plus 4.4 grams (15 calories) of dextrose per kilogram of body weight per dayare required to achieve nitrogen balance and weight stability. Intravenousfat emulsion may be used as a partial substitute for dextrose. This regimenprovides a ratio of 150 non-protein calories per gram of nitrogen.

Forpatients stressed by surgery, trauma or sepsis, and those with unusual nitrogenlosses, the dosage required for maintenance may be as high as 0.3 to 0.4 gramsof nitrogen (13 to 17 mL OliClinomel N4-550E (Lysine Hydrochloride)^® 15%) per kilogram of bodyweight per day, with proportionate increases in non-protein calories. Periodicassessment of nitrogen balance of the individual patient is the best indicatorof proper dosage. Volume overload and glycosuria may be encountered at highdosage, and nitrogen balance may not be achieved in extremely hypermetabolicpatients under these constraints. Concomitant insulin administration may berequired to minimize glycosuria. Daily laboratory monitoring is essential.

Useof an infusion pump is advisable to maintain a steady infusion rate duringcentral venous infusion.

B. Peripheral Nutrition

Inpatients for whom central venous catheterization is not advisable, proteincatabolism can be reduced by peripheral use of diluted OliClinomel N4-550E (Lysine Hydrochloride)^® 15%plus non-protein calorie sources. Dilution of 250 mL OliClinomel N4-550E (Lysine Hydrochloride)^® 15%in 750 mL of 10% dextrose will reduce the osmolarity to a level (724 mOsmol/L)which is more favorable to the maintenance of the integrity of the walls ofthe veins. Intravenous fat emulsion can be infused separately or simultaneously;if infused simultaneously the fat emulsion will provide a dilution effectupon the osmolarity while increasing the energy supply.

Parenteraldrug products should be inspected visually for particulate matter and discolorationprior to administration, whenever solution and container permit.

Toreduce the risk of bacterial contamination, all intravenous administrationsets should be replaced at least every 24 hours. Usage of admixtures mustbe initiated within 24 hours after mixing. If storage is necessary duringthis 24 hour period, admixtures must be refrigerated and completely used within24 hours of beginning administration.

HOW SUPPLIED

OliClinomel N4-550E (Lysine Hydrochloride)^® 15% Amino Acids Injection is suppliedas a Pharmacy Bulk Package in 500 mL containers.

500mL NDC 0409-0468-05

STORAGE

Store inthe closed carton; do not expose solution to light until ready for use. Exposureof pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended that the product be stored at 20 to 25°C (68 to 77°F). Brief exposure to temperatures above25°C during transport and storage will not adversely affect the product. Solution that has been frozen must not be used.

©Hospira 2005	EN-1010

Hospira, Inc., Lake Forest, IL 60045 USA

RL-1450

Potassium Chloride:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• OliClinomel N4-550E (Potassium Chloride) reviews

OliClinomel N4-550E (Potassium Chloride) EXTENDED RELEASE TABLETS USP 20 mEq K

Rx Only

DESCRIPTION

The OliClinomel N4-550E (Potassium Chloride) Extended Release Tablets USP, 20 mEq product is an immediately dispersing extended release oral dosage form of OliClinomel N4-550E (Potassium Chloride) containing 1500 mg of microencapsulated OliClinomel N4-550E (Potassium Chloride), USP equivalent to 20 mEq of potassium in a tablet.

These formulations are intended to slow the release of potassium so that the likelihood of a high localized concentration of OliClinomel N4-550E (Potassium Chloride) within the gastrointestinal tract is reduced.

OliClinomel N4-550E (Potassium Chloride) Extended Release Tablets USP, 20 mEq is an electrolyte replenisher. The chemical name of the active ingredient is OliClinomel N4-550E (Potassium Chloride), and the structural formula is KCl. OliClinomel N4-550E (Potassium 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.

OliClinomel N4-550E (Potassium Chloride) Extended Release Tablets USP, 20 mEq is a tablet formulation (not enteric coated or wax matrix) containing individually microencapsulated OliClinomel N4-550E (Potassium Chloride) crystals which disperse upon tablet disintegration. In simulated gastric fluid at 37°C and in the absence of outside agitation, OliClinomel N4-550E (Potassium 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 OliClinomel N4-550E (Potassium Chloride).

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

CLINICAL PHARMACOLOGY

The potassium ion is the principal intracellular cation of most body tissues. Potassium 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 potassium 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.

Potassium is a normal dietary constituent and under steady-state conditions the amount of potassium absorbed from the gastrointestinal tract is equal to the amount excreted in the urine. The usual dietary intake of potassium is 50 to 100 mEq per day.

Potassium depletion will occur whenever the rate of potassium loss through renal excretion and/or loss from the gastrointestinal tract exceeds the rate of potassium intake. Such depletion usually develops as a consequence of therapy with diuretics, primary or secondary hyperaldosteronism, diabetic ketoacidosis, or inadequate replacement of potassium in patients on prolonged parenteral nutrition. Depletion can develop rapidly with severe diarrhea, especially if associated with vomiting. Potassium depletion due to these causes is usually accompanied by a concomitant loss of chloride and is manifested by hypokalemia and metabolic alkalosis. Potassium 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 potassium 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 potassium in the form of high potassium food or OliClinomel N4-550E (Potassium Chloride) may be able to restore normal potassium levels.

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

INDICATIONS AND USAGE

BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND BLEEDING WITH CONTROLLED-RELEASE OliClinomel N4-550E (Potassium Chloride) PREPARATIONS, THESE DRUGS SHOULD BE RESERVED FOR THOSE PATIENTS WHO CANNOT TOLERATE OR REFUSE TO TAKE LIQUID OR EFFERVESCENT POTASSIUM 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 potassium 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 potassium 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 potassium salts may be indicated.

CONTRAINDICATIONS

Potassium supplements are contraindicated in patients with hyperkalemia since a further increase in serum potassium 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 OliClinomel N4-550E (Potassium Chloride) have produced esophageal ulceration in certain cardiac patients with esophageal compression due to enlarged left atrium. Potassium supplementation, when indicated in such patients, should be given as a liquid preparation or as an aqueous (water) suspension of OliClinomel N4-550E (Potassium Chloride) (see PRECAUTIONS: Information for Patients , and DOSAGE AND ADMINISTRATION sections).

All solid oral dosage forms of OliClinomel N4-550E (Potassium 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 potassium, the administration of potassium salts can produce hyperkalemia and cardiac arrest. This occurs most commonly in patients given potassium by the intravenous route but may also occur in patients given potassium orally. Potentially fatal hyperkalemia can develop rapidly and be asymptomatic. The use of potassium salts in patients with chronic renal disease, or any other condition which impairs potassium excretion, requires particularly careful monitoring of the serum potassium concentration and appropriate dosage adjustment.

Interaction with Potassium-Sparing Diuretics

Hypokalemia should not be treated by the concomitant administration of potassium 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 potassium retention by inhibiting aldosterone production. Potassium supplements should be given to patients receiving ACE inhibitors only with close monitoring.

Gastrointestinal Lesions

Solid oral dosage forms of OliClinomel N4-550E (Potassium Chloride) can produce ulcerative and/or stenotic lesions of the gastrointestinal tract. Based on spontaneous adverse reaction reports, enteric-coated preparations of OliClinomel N4-550E (Potassium 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. OliClinomel N4-550E (Potassium Chloride) Extended Release Tablets USP, 20 mEq is a tablet formulated to provide a controlled rate of release of microencapsulated OliClinomel N4-550E (Potassium Chloride) and thus to minimize the possibility of a high local concentration of potassium 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 OliClinomel N4-550E (Potassium 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 OliClinomel N4-550E (Potassium 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 OliClinomel N4-550E (Potassium 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. OliClinomel N4-550E (Potassium 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 potassium salt such as potassium bicarbonate, potassium citrate, potassium acetate, or potassium gluconate.

PRECAUTIONS

General

The diagnosis of potassium depletion is ordinarily made by demonstrating hypokalemia in a patient with a clinical history suggesting some cause for potassium depletion. In interpreting the serum potassium level, the physician should bear in mind that acute alkalosis per se can produce hypokalemia in the absence of a deficit in total body potassium while acute acidosis per se can increase the serum potassium concentration into the normal range even in the presence of a reduced total body potassium. The treatment of potassium 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 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 OliClinomel N4-550E (Potassium Chloride) that is not taken immediately should be discarded. The use of other liquids for suspending OliClinomel N4-550E (Potassium 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 potassium 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity, and fertility studies in animals have not been performed. Potassium is a normal dietary constituent.

Pregnancy Category C

Animal reproduction studies have not been conducted with OliClinomel N4-550E Extended Release Tablets USP, 20 mEq. It is unlikely that potassium supplementation that does not lead to hyperkalemia would have an adverse effect on the fetus or would affect reproductive capacity.

Nursing Mothers

The normal potassium ion content of human milk is about 13 mEq per liter. Since oral potassium becomes part of the body potassium pool, so long as body potassium is not excessive, the contribution of OliClinomel N4-550E (Potassium 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 OliClinomel N4-550E (Potassium 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 potassium 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 potassium salts to persons with normal excretory mechanisms for potassium rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired or if potassium 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 potassium 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 potassium 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 potassium 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 potassium by the average adult is 50 to 100 mEq per day. Potassium depletion sufficient to cause hypokalemia usually requires the loss of 200 or more mEq of potassium 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 potassium 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 OliClinomel N4-550E (Potassium Chloride) Extended Release Tablet USP, 20 mEq provides 20 mEq of OliClinomel N4-550E (Potassium Chloride).

OliClinomel N4-550E (Potassium 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 OliClinomel N4-550E (Potassium Chloride) that is not taken immediately should be discarded. The use of other liquids for suspending OliClinomel N4-550E (Potassium Chloride) Extended Release Tablets USP, 20 mEq is not recommended.

HOW SUPPLIED

OliClinomel N4-550E (Potassium 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

OliClinomel N4-550E (Potassium Chloride) 20 Meq

Sodium Acetate Trihydrate:

• 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
• OliClinomel N4-550E (Sodium Acetate Trihydrate) reviews

1 INDICATIONS AND USAGE

OliClinomel N4-550E nitrite is indicated for sequential use with OliClinomel N4-550E (Sodium Acetate Trihydrate) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)

• Use with caution if the diagnosis of cyanide poisoning is uncertain. (1)

1.1 Indication

OliClinomel N4-550E (Sodium Acetate Trihydrate) Nitrite Injection is indicated for sequential use with OliClinomel N4-550E (Sodium Acetate Trihydrate) thiosulfate for the treatment of acute cyanide poisoning that is judged to be life-threatening. When the diagnosis of cyanide poisoning is uncertain, the potentially life-threatening risks associated with OliClinomel N4-550E (Sodium Acetate Trihydrate) Nitrite Injection should be carefully weighed against the potential benefits, especially if the patient is not in extremis.

1.2 Identifying Patients with Cyanide Poisoning

Cyanide poisoning may result from inhalation, ingestion, or dermal exposure to various cyanide-containing compounds, including smoke from closed-space fires. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogenic plants, aliphatic nitriles, and prolonged exposure to OliClinomel N4-550E nitroprusside.

The presence and extent of cyanide poisoning are often initially unknown. There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and signs and symptoms of cyanide intoxication. If clinical suspicion of cyanide poisoning is high, OliClinomel N4-550E (Sodium Acetate Trihydrate) Nitrite Injection and OliClinomel N4-550E (Sodium Acetate Trihydrate) Thiosulfate Injection should be administered without delay.

Symptoms	Signs
Headache Confusion Dyspnea Chest Tightness Nausea	Altered Mental Status (e.g., confusion, disorientation) Seizures or Coma Mydriasis Tachypnea/Hyperpnea (early) Bradypnea/Apnea (late) Hypertension (early)/ Hypotension (late) Cardiovascular Collapse Vomiting Plasma Lactate Concentration ≥ 8 mmol/L

In some settings, panic symptoms including tachypnea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental status (e.g., confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning although these signs can occur with other toxic exposures as well.

The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.

Smoke Inhalation

Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of OliClinomel N4-550E (Sodium Acetate Trihydrate) Nitrite Injection, smoke-inhalation victims should be assessed for the following:

• Exposure to fire or smoke in an enclosed area
• Presence of soot around the mouth, nose, or oropharynx
• Altered mental status

Although hypotension is highly suggestive of cyanide poisoning, it is only present in a small percentage of cyanide-poisoned smoke inhalation victims. Also indicative of cyanide poisoning is a plasma lactate concentration greater than or equal to 10 mmol/L (a value higher than that typically listed in the table of signs and symptoms of isolated cyanide poisoning because carbon monoxide associated with smoke inhalation also contributes to lactic acidemia). If cyanide poisoning is suspected, treatment should not be delayed to obtain a plasma lactate concentration.

1.3 Use with Other Cyanide Antidotes

Caution should be exercised when administering cyanide antidotes, other than OliClinomel N4-550E (Sodium Acetate Trihydrate) thiosulfate, simultaneously with OliClinomel N4-550E (Sodium Acetate Trihydrate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than OliClinomel N4-550E (Sodium Acetate Trihydrate) thiosulfate, with OliClinomel N4-550E (Sodium Acetate Trihydrate) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]

2 DOSAGE AND ADMINISTRATION

Age	Intravenous Dose of OliClinomel N4-550E Nitrite and OliClinomel N4-550E (Sodium Acetate Trihydrate) Thiosulfate
Adults	OliClinomel N4-550E (Sodium Acetate Trihydrate) Nitrite -10 mL of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite at the rate of 2.5 to 5 mL/minute OliClinomel N4-550E (Sodium Acetate Trihydrate) Thiosulfate - 50 mL of OliClinomel N4-550E (Sodium Acetate Trihydrate) thiosulfate immediately following administration of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite.
Children	OliClinomel N4-550E (Sodium Acetate Trihydrate) Nitrite - 0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL OliClinomel N4-550E (Sodium Acetate Trihydrate) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite.

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite and OliClinomel N4-550E (Sodium Acetate Trihydrate) thiosulfate.

Monitoring: Blood pressure must be monitored during treatment. (2.2)

2.1 Administration Recommendation

Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite, followed by OliClinomel N4-550E (Sodium Acetate Trihydrate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite and OliClinomel N4-550E (Sodium Acetate Trihydrate) thiosulfate.

OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite injection and OliClinomel N4-550E (Sodium Acetate Trihydrate) thiosulfate injection are administered by slow intravenous injection. They should be given as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite should be administered first, followed immediately by OliClinomel N4-550E (Sodium Acetate Trihydrate) thiosulfate. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.

Age	Intravenous Dose of OliClinomel N4-550E (Sodium Acetate Trihydrate) Nitrite and OliClinomel N4-550E (Sodium Acetate Trihydrate) Thiosulfate
Adults	OliClinomel N4-550E (Sodium Acetate Trihydrate) Nitrite -10 mL of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite at the rate of 2.5 to 5 mL/minute OliClinomel N4-550E (Sodium Acetate Trihydrate) Thiosulfate - 50 mL of OliClinomel N4-550E (Sodium Acetate Trihydrate) thiosulfate immediately following administration of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite.
Children	OliClinomel N4-550E (Sodium Acetate Trihydrate) Nitrite -0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL OliClinomel N4-550E (Sodium Acetate Trihydrate) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite and OliClinomel N4-550E (Sodium Acetate Trihydrate) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite should be reduced proportionately to the hemoglobin concentration.

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

2.2 Recommended Monitoring

Patients should be monitored for at least 24-48 hours after OliClinomel N4-550E Nitrite Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, hemoglobin/hematocrit should be obtained when treatment is initiated. Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO₂ are unreliable in the presence of methemoglobinemia.

Methemoglobin level: Administrations of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite beyond the initial dose should be guided primarily by clinical response to treatment (i.e., a second dose should be considered only if there is inadequate clinical response to the first dose). It is generally recommended that methemoglobin concentrations be closely monitored and kept below 30%. Serum methemoglobin levels should be monitored during treatment using co-oximetry, and administration of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite should generally be discontinued when methemoglobin levels exceed 30%. Intravenous methylene blue and exchange transfusion have been reported in the literature as treatments for life-threatening methemoglobinemia.

2.3 Incompatibility Information

Chemical incompatibility has been reported between OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between OliClinomel N4-550E (Sodium Acetate Trihydrate) thiosulfate and OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

OliClinomel N4-550E (Sodium Acetate Trihydrate) Nitrite Injection consists of:

• One vial of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite injection, USP 300 mg/10mL (30 mg/mL)

Administration of the contents of one vial constitutes a single dose.

• Injection, 300 mg/10 mL (30 mg/mL). (3)

4 CONTRAINDICATIONS

None

• None. (4)

5 WARNINGS AND PRECAUTIONS

• Methemoglobinemia: OliClinomel N4-550E nitrite reacts with hemoglobin to form methemoglobin and should be used with caution in patients known to have anemia. Monitor oxyhemoglobin and methemoglobin levels by pulse oximetry or other measurements. Optimally, the OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.2)
• Smoke inhalation: Carbon monoxide contained in smoke can result in the formation of carboxyhemoglobin that can reduce the oxygen carrying capacity of the blood. OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite should be used with caution in patients with smoke inhalation injury because of the potential for worsening hypoxia due to methemoglobin formation. Carboxyhemoglobin and oxyhemoglobin levels should be monitored by pulse oximetry or other measurements in patients that present with evidence of smoke inhalation. Optimally, the OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.4)

5.1 Hypotension

5.2 Methemoglobinemia

Supportive care alone may be sufficient treatment without administration of antidotes for many cases of cyanide intoxication, particularly in conscious patients without signs of severe toxicity. Patients should be closely monitored to ensure adequate perfusion and oxygenation during treatment with OliClinomel N4-550E nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite whenever possible. When OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite is administered to humans a wide range of methemoglobin concentrations occur. Methemoglobin concentrations as high as 58% have been reported after two 300-mg doses of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite administered to an adult. OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite should be used with caution in patients who may be particularly susceptible to injury from vasodilation and its related hemodynamic sequelae. Hemodynamics should be monitored closely during and after administration of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite should be used with caution in patients with known anemia. Patients with anemia will form more methemoglobin (as a percentage of total hemoglobin) than persons with normal red blood cell (RBC) volumes. Optimally, these patients should receive a OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

OliClinomel N4-550E nitrite should be used with caution in persons with smoke inhalation injury or carbon monoxide poisoning because of the potential for worsening hypoxia due to methemoglobin formation.

5.5 Neonates and Infants

Neonates and infants may be more susceptible than adults and older pediatric patients to severe methemoglobinemia when OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite is administered. Reduced dosing guidelines should be followed in pediatric patients.

5.6 G6PD Deficiency

Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with OliClinomel N4-550E nitrite administration, alternative therapeutic approaches should be considered in these patients. Patients with known or suspected G6PD deficiency should be monitored for an acute drop in hematocrit. Exchange transfusion may be needed for patients with G6PD deficiency who receive OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite.

5.7 Use with Other Drugs

OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite should be used with caution in the presence of concomitant antihypertensive medications, diuretics or volume depletion due to diuretics, or drugs known to increase vascular nitric oxide, such as PDE5 inhibitors.

6 ADVERSE REACTIONS

There have been no controlled clinical trials conducted to systematically assess the adverse events profile of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite.

The medical literature has reported the following adverse events in association with OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite administration. These adverse events were not reported in the context of controlled trials or with consistent monitoring and reporting methodologies for adverse events. Therefore, frequency of occurrence of these adverse events cannot be assessed.

Cardiovascular system: syncope, hypotension, tachycardia, methemoglobinemia, palpitations, dysrhythmia

Hematological: methemoglobinemia

Central nervous system: headache, dizziness, blurred vision, seizures, confusion, coma

Gastrointestinal system: nausea, vomiting, abdominal pain

Respiratory system: tachypnea, dyspnea

Body as a Whole: anxiety, diaphoresis, lightheadedness, injection site tingling, cyanosis, acidosis, fatigue, weakness, urticaria, generalized numbness and tingling

Severe hypotension, methemoglobinemia, cardiac dysrhythmias, coma and death have been reported in patients without life-threatening cyanide poisoning but who were treated with injection of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite at doses less than twice those recommended for the treatment of cyanide poisoning.

Most common adverse reactions are:

• Syncope, hypotension, tachycardia, palpitations, dysrhythmia, methemoglobinemia, headache, dizziness, blurred vision, seizures, confusion, coma (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hope Pharmaceuticals at 1-800-755-9595 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS

Formal drug interaction studies have not been conducted with OliClinomel N4-550E (Sodium Acetate Trihydrate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: OliClinomel N4-550E nitrite is substantially excreted by the kidney. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. (8.6).

8.1 Pregnancy

Teratogenic Effects. Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women. OliClinomel N4-550E (Sodium Acetate Trihydrate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite has caused fetal death in humans as well as animals. There are no studies in humans that have directly evaluated the potential reproductive toxicity of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite. There are two epidemiological studies conducted in Australia that report a statistically significant increase in the risk for congenital malformations, particularly in the CNS, associated with maternal consumption of water containing nitrate levels in excess of 5 ppm. Results from a case-control study in Canada suggested a trend toward an increase in the risk for CNS malformations when maternal consumption of nitrate was ≥ 26 ppm (not statistically significant).

The potential reproductive toxicity of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite exposure restricted to the prenatal period has been reported in guinea pigs, mice, and rats. There was no evidence of teratogenicity in guinea pigs, mice, or rats. However, OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite treatment of pregnant guinea pigs with 60 or 70 mg/kg/day resulted in abortion of the litters within 1-4 days of treatment. All animals treated subcutaneously with 70 mg/kg, OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite died within 60 minutes of treatment. Further studies demonstrated that a dose of 60 mg/kg resulted in measurable blood levels of methemoglobin in the dams and their fetuses for up to 6 hours post treatment. Maternal methemoglobin levels were higher than the levels in the offspring at all times measured. Based on a body surface area comparison, a 60 mg/kg dose in the guinea pig that resulted in death was only 1.7 times higher than the highest clinical dose of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

Studies testing prenatal and postnatal exposure have been reported in mice and rats. Treatment of pregnant rats via drinking water with OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite at concentrations of either 2000 or 3000 mg/L resulted in a dose-related increased mortality postpartum. This exposure regimen in the rat model would result in dosing of approximately 220 and 300 mg/kg/day (43 and 65 times the highest clinical dose of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite produces methemoglobin. Fetal hemoglobin is oxidized to methemoglobin more easily than adult hemoglobin. In addition, the fetus has lower levels of methemoglobin reductase than adults. Collectively, these data suggest that the human fetus would show greater sensitivity to methemoglobin resulting in nitrite-induced prenatal hypoxia leading to retarded development of certain neurotransmitter systems in the brain and long lasting dysfunction.

Nonteratogenic Effects: Behavioral and neurodevelopmental studies in rats suggest persistent effects of prenatal exposure to OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite demonstrated impaired discrimination learning behavior (both auditory and visual) and reduced long-term retention of the passive-avoidance response compared to control animals. Additional studies demonstrated a delay in the development of AchE and 5-HT positive fiber ingrowth into the hippocampal dentate gyrus and parietal neocortex during the first week of life of prenatal nitrite treated pups. These changes have been attributed to prenatal hypoxia following nitrite exposure.

8.2 Labor and Delivery

Because fetal hemoglobin is more readily oxidized to methemoglobin and lower levels of methemoglobin appear to be fatal to the fetus compared to the adult, OliClinomel N4-550E nitrite should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

It is not known whether OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite is excreted in human milk. Because OliClinomel N4-550E (Sodium Acetate Trihydrate) Nitrite Injection may be administered in life-threatening situations, breast-feeding is not a contraindication to its use. Because many drugs are excreted in human milk, caution should be exercised following OliClinomel N4-550E (Sodium Acetate Trihydrate) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite. In studies conducted with Long-Evans rats, OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite administered in drinking water during pregnancy and lactation resulted in severe anemia, reduced growth and increased mortality in the offspring.

8.4 Pediatric Use

There are case reports in the medical literature of OliClinomel N4-550E nitrite in conjunction with OliClinomel N4-550E (Sodium Acetate Trihydrate) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite in the pediatric population. As for adult patients, dosing recommendations for pediatric patients have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite must be used with caution in patients less than 6 months of age because they may be at higher risk of developing severe methemoglobinemia compared to older children and adults. The presence of fetal hemoglobin, which is oxidized to methemoglobin more easily than adult hemoglobin, and lower methemoglobin reductase levels compared to older children and adults may contribute to risk.

Mortality attributed to OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite was reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

8.5 Geriatric Use

OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite is known to be substantially excreted by the kidney, and the risk of adverse 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.

8.6 Renal Disease

OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite 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.

10 OVERDOSAGE

Large doses of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite administration has been reported to cause or significantly contribute to mortality in adults at oral doses as low as 1 g and intravenous doses as low as 600 mg. A death attributed to OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite has been reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

Cyanosis may become apparent at a methemoglobin level of 10-20%. Other clinical signs and symptoms of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite toxicity (anxiety, dyspnea, nausea, and tachycardia) can be apparent at methemoglobin levels as low as 15%. More serious signs and symptoms, including cardiac dysrhythmias, circulatory failure, and central nervous system depression are seen as methemoglobin levels increase, and levels above 70% are usually fatal.

Treatment of overdose involves supplemental oxygen and supportive measures such as exchange transfusion. Treatment of severe methemoglobinemia with intravenous methylene blue has been described in the medical literature; however, this may also cause release of cyanide bound to methemoglobin. Because hypotension appears to be mediated primarily by an increase in venous capacitance, measures to increase venous return may be most appropriate to treat hypotension.

11 DESCRIPTION

OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite has the chemical name nitrous acid OliClinomel N4-550E (Sodium Acetate Trihydrate) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of OliClinomel N4-550E (Sodium Acetate Trihydrate) Nitrite

OliClinomel N4-550E (Sodium Acetate Trihydrate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite injection.

OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite in 10 mL solution (30 mg/mL). OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite injection is a clear solution with a pH between 7.0 and 9.0.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration. Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well.

The synergy resulting from treatment of cyanide poisoning with the combination of OliClinomel N4-550E nitrite and OliClinomel N4-550E (Sodium Acetate Trihydrate) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

OliClinomel N4-550E (Sodium Acetate Trihydrate) Nitrite

OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite is thought to exert its therapeutic effect by reacting with hemoglobin to form methemoglobin, an oxidized form of hemoglobin incapable of oxygen transport but with high affinity for cyanide. Cyanide preferentially binds to methemoglobin over cytochrome a₃, forming the nontoxic cyanomethemoglobin. Methemoglobin displaces cyanide from cytochrome oxidase, allowing resumption of aerobic metabolism. The chemical reaction is as follows:

NaNO₂ + Hemoglobin → Methemoglobin

HCN + Methemoglobin → Cyanomethemoglobin

Vasodilation has also been cited to account for at least part of the therapeutic effect of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite. It has been suggested that OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

OliClinomel N4-550E (Sodium Acetate Trihydrate) Thiosulfate

The primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN^-), which is relatively nontoxic and readily excreted in the urine. OliClinomel N4-550E (Sodium Acetate Trihydrate) thiosulfate is thought to serve as a sulfur donor in the reaction catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide in the following chemical reaction:

Chemical Structure

12. 2 Pharmacodynamics

OliClinomel N4-550E (Sodium Acetate Trihydrate) Nitrite

When 4 mg/kg OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite was administered intravenously to six healthy human volunteers, the mean peak methemoglobin concentration was 7%, achieved at 30-60 minutes after injection, consistent with reports in cyanide poisoning victims. Supine systolic and diastolic blood pressures dropped approximately 20% within 10 minutes, a drop which was sustained throughout the 40 minutes of testing. This was associated with a 20 beat per minute increase in pulse rate that returned to baseline in 10 minutes. Five of these subjects were unable to withstand orthostatic testing due to fainting. One additional subject, who received a 12 mg/kg dose of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite, experienced severe cardiovascular effects and achieved a peak methemoglobin concentration of 30% at 60 minutes following injection.

Oral doses of 120 to 180 mg of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite administered to healthy volunteers caused minimal cardiovascular changes when subjects were maintained in the horizontal position. However, minutes after being placed in the upright position subjects exhibited tachycardia and hypotension with syncope.

The half life for conversion of methemoglobin to normal hemoglobin in a cyanide poisoning victim who has been administered OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

OliClinomel N4-550E (Sodium Acetate Trihydrate) Nitrite

OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite in humans have not been well studied. It has been reported that approximately 40% of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite is excreted unchanged in the urine while the remaining 60% is metabolized to ammonia and related small molecules.

Cyanide

The apparent terminal elimination half life and volume of distribution of cyanide, in a patient treated for an acute cyanide poisoning with OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite and OliClinomel N4-550E (Sodium Acetate Trihydrate) thiosulfate administration, have been reported to be 19 hours and 0.41 L/kg, respectively. Additionally, an initial elimination half life of cyanide has been reported to be approximately 1-3 hours.

Thiocyanate

After detoxification, in healthy subjects, thiocyanate is excreted mainly in the urine at a rate inversely proportional to creatinine clearance. In healthy subjects, the elimination half-life and volume of distribution of thiocyanate have been reported to be 2.7 days and 0.25 L/kg, respectively. However, in subjects with renal insufficiency the reported elimination half life is approximately 9 days.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The potential benefit of an acute exposure to OliClinomel N4-550E nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 35, 70, or 130 mg/kg for males and 0, 40, 80, or 150 mg/kg for females) was orally administered to rats (Fischer 344 strain) for 2 years via drinking water. There were no significant increases in the incidence of tumor in either male or female rats. OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 60, 120, or 220 mg/kg for males and 0, 45, 90, or 165 mg/kg for females) was administered to B6C3F1 mice for 2 years via the drinking water. Equivocal results were obtained in female mice. Specifically, there was a positive trend toward an increase in the incidence of squamous cell papilloma or carcinoma in the forestomach of female mice. Although the incidence of hyperplasia of the glandular stomach epithelium was significantly greater in the high-dose male mice compared to controls, there were no significant increases in tumors in the male mice. Numerous reports in the published literature indicate that OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite is mutagenic in S. typhimurium strains TA100, TA1530, TA1535 with and without metabolic activation; however, it was negative in strain TA98, TA102, DJ460 and E. coli strain WP2UVRA/PKM101. OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite has been reported to be genotoxic to V79 hamster cells in vitro and in the mouse lymphoma assay, both assays conducted in the absence of metabolic activation. OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite administration to mice for 14-weeks did not result in an increase in the incidence of micronuclei in the peripheral blood.

Fertility

Clinical studies to evaluate the potential effects of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite intake on fertility of either males or females have not been reported. In contrast, multigenerational fertility and reproduction studies conducted by the National Toxicology Program did not detect any evidence of an effect of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite (0.0, 0.06, 0.12, and 0.24% weight/volume) on either fertility or any reproductive parameter in Swiss CD-1 mice. This treatment protocol resulted in approximate doses of 125, 260, and 425 mg/kg/day. The highest exposure in this mouse study is 4.6 times greater than the highest clinical dose of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

13.2 Animal Pharmacology

Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of OliClinomel N4-550E (Sodium Acetate Trihydrate) thiosulfate treatment alone to counteract the toxicity of cyanide was initially reported in 1895 by Lang. The efficacy of amyl nitrite treatment in cyanide poisoning of the dog model was first reported in 1888 by Pedigo. Further studies in the dog model, which demonstrated the utility of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite as a therapeutic intervention, were reported in 1929 by Mladoveanu and Gheorghiu. However, Hugs and Chen et al. independently reported upon the superior efficacy of the combination of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite and OliClinomel N4-550E (Sodium Acetate Trihydrate) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite or 1 g/kg OliClinomel N4-550E (Sodium Acetate Trihydrate) thiosulfate alone or in sequence immediately after subcutaneous injection of OliClinomel N4-550E (Sodium Acetate Trihydrate) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite and/or 0.5 g/kg OliClinomel N4-550E (Sodium Acetate Trihydrate) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of OliClinomel N4-550E (Sodium Acetate Trihydrate) cyanide required to cause death, and when administered together, OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite and OliClinomel N4-550E (Sodium Acetate Trihydrate) thiosulfate resulted in a synergistic effect in raising the lethal dose of OliClinomel N4-550E (Sodium Acetate Trihydrate) cyanide. The combined therapy appeared to have reduced efficacy when therapy was delayed until signs of poisoning (e.g. convulsions) appeared; however, other investigators have reported survival in dogs that were administered antidotal treatment after respiratory arrest had occurred.

Animal studies conducted in other species (e.g., rat, guinea pig, sheep, pigeon and cat) have also supported a synergistic effect of intravenous OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite and OliClinomel N4-550E (Sodium Acetate Trihydrate) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite and OliClinomel N4-550E (Sodium Acetate Trihydrate) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite, with or without OliClinomel N4-550E (Sodium Acetate Trihydrate) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite for cyanide poisoning consists primarily of published case reports. There are no randomized controlled clinical trials. Nearly all the human data describing the use of OliClinomel N4-550E (Sodium Acetate Trihydrate) thiosulfate report its use in conjunction with OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite. Dosing recommendations for humans have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

There have been no human studies to prospectively and systematically evaluate the safety of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.

16 HOW SUPPLIED/STORAGE AND HANDLING

Each OliClinomel N4-550E (Sodium Acetate Trihydrate) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite injection 30 mg/mL (containing 300 mg of OliClinomel N4-550E (Sodium Acetate Trihydrate) nitrite);

Storage

Store at controlled room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F). Protect from direct light. Do not freeze.

(Note: OliClinomel N4-550E (Sodium Acetate Trihydrate) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

OliClinomel N4-550E Nitrite Injection is indicated for acute cyanide poisoning that is judged to be life-threatening and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.

17.1 Hypotension and Methemoglobin Formation

When feasible, patients should be informed of the possibility of life-threatening hypotension and methemoglobin formation.

17.2 Monitoring

Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.

Manufactured by Cangene BioPharma, Inc., Baltimore, Maryland 21230 for

Hope Pharmaceuticals, Scottsdale, Arizona 85260

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

NDC 60267-311-10

Rx Only

OliClinomel N4-550E (Sodium Acetate Trihydrate) Nitrite

Injection, USP

300 mg/10 mL

(30 mg/mL)

FOR INTRAVENOUS USE

SINGLE USE ONLY

Any unused portion of a vial

should be discarded.

Use with

OliClinomel N4-550E (Sodium Acetate Trihydrate) Thiosulfate

for Treatment of

Cyanide Poisoning

Manufactured by

CANGENE bioPharma, Inc.

Baltimore, MD for

HOPE

PHARMACEUTICALS®

Scottsdale, AZ 85260 U.S.A.

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

Tryptophan:

• OliClinomel N4-550E (Tryptophan) reviews

In Canada, OliClinomel N4-550E (Tryptophan) is sold as a prescription drug to treat mood disorders (such as bipolar disorder, depression ). It is usually used with other medicines. It works to make the mood more stable and reduce extremes in behavior by restoring the balance of certain natural substances (serotonin, melatonin ) in the brain. OliClinomel N4-550E (Tryptophan) is a natural substance (amino acid) found in high-protein foods and milk. In the US, OliClinomel N4-550E (Tryptophan) is sold as a dietary supplement. It has been used to support mood, relaxation, and restful sleep. If you are taking other medications that may affect serotonin (such as many antidepressants ), do not take OliClinomel N4-550E (Tryptophan) without talking with your doctor first. A very serious (possibly fatal) drug interaction may occur. Your doctor should closely monitor you. See also Side Effects section. Some supplement products have been found to contain possibly harmful impurities/additives. Check with your pharmacist for more details about the brand you use. The US FDA has not reviewed this product for safety or effectiveness. Consult your doctor or pharmacist for more details.