Nutriflex Lipid Peri

Arginine:

• Nutriflex Lipid Peri (Arginine) reviews

Nutritive Wound - Skin Cream

For Minor Cuts and Wounds

- Eases Discomfort

- Soothing Cream

CONTAINS:

Nutriflex Lipid Peri (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
• Nutriflex Lipid Peri (Calcium Chloride Dihydrate) reviews

1 INDICATIONS AND USAGE

Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Calcium Chloride Dihydrate) acetate capsule.

- Capsule: 667 mg Nutriflex Lipid Peri (Calcium Chloride Dihydrate) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

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

An overdose of Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Calcium Chloride Dihydrate) levels twice weekly. Should hypercalcemia develop, reduce the Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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, Nutriflex Lipid Peri (Calcium Chloride Dihydrate) acetate has been generally well tolerated.

Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Calcium Chloride Dihydrate) acetate N=167 N (%)	3 month, open label study of Nutriflex Lipid Peri (Calcium Chloride Dihydrate) acetate N=98 N (%)	Double blind, placebo-controlled, cross-over study of liquid Nutriflex Lipid Peri (Calcium Chloride Dihydrate) acetate N=69
			Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Calcium Chloride Dihydrate) concentration could reduce the incidence and severity of Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Calcium Chloride Dihydrate) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Nutriflex Lipid Peri acetate is characterized by the potential of Nutriflex Lipid Peri (Calcium Chloride Dihydrate) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Calcium Chloride Dihydrate) acetate and most concomitant drugs. When administering an oral medication with Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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:

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

8.2 Labor and Delivery

The effects of Nutriflex Lipid Peri (Calcium Chloride Dihydrate) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

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

11 DESCRIPTION

Nutriflex Lipid Peri (Calcium Chloride Dihydrate) acetate acts as a phosphate binder. Its chemical name is Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Calcium Chloride Dihydrate) acetate USP (anhydrous; Ca(CH₃COO)₂; MW=158.17 grams) equal to 169 mg (8.45 mEq) Nutriflex Lipid Peri (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.

Nutriflex Lipid Peri (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 Nutriflex Lipid Peri resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Nutriflex Lipid Peri (Calcium Chloride Dihydrate) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Nutriflex Lipid Peri (Calcium Chloride Dihydrate) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Calcium Chloride Dihydrate) acetate.

14 CLINICAL STUDIES

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

* ANOVA of Nutriflex Lipid Peri (Calcium Chloride Dihydrate) acetate vs. placebo after 2 weeks of treatment. † Values expressed as mean ± SEM.
Parameter	Pre-Study	Post-Treatment		p-value*
		Nutriflex Lipid Peri (Calcium Chloride Dihydrate) Acetate	Placebo
Phosphorus (mg/dL)†	7.3 ± 0.18	5.9 ± 0.24	7.8 ± 0.22	<0.01
Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Calcium Chloride Dihydrate) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Nutriflex Lipid Peri (Calcium Chloride Dihydrate) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Calcium Chloride Dihydrate) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Calcium Chloride Dihydrate) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Glycine:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Im-1453
• Nutriflex Lipid Peri (Glycine) reviews

INDICATIONS AND USAGE

1.5% Nutriflex Lipid Peri (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, Nutriflex Lipid Peri (Glycine) irrigating solution must be regarded as a systemic drug. Absorption of large amounts of fluids containing Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Glycine) Irrigation, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.

Nursing Mothers: Caution should be exercised when Nutriflex Lipid Peri (Glycine) Irrigation, USP is administered to a nursing woman.

Pregnancy: Teratogenic Effects.

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

Pediatric Use: The safety and effectiveness of Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Glycine). Large intravenous doses of Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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% Nutriflex Lipid Peri (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% Nutriflex Lipid Peri (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
• Nutriflex Lipid Peri (Lysine Hydrochloride) reviews

BOXED WARNING

Pharmacy Bulk Package

Not For Direct Infusion

DESCRIPTION

Nutriflex Lipid Peri (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.

Nutriflex Lipid Peri (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
Nutriflex Lipid Peri (Lysine Hydrochloride) (from Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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

Nutriflex Lipid Peri (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, Nutriflex Lipid Peri (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)

Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Lysine Hydrochloride)^®15%-dextrose-fatregimen.

INDICATIONS AND USAGE

Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Lysine Hydrochloride)^® 15%. It is also not known whether Nutriflex Lipid Peri (Lysine Hydrochloride)^® 15% can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Nutriflex Lipid Peri (Lysine Hydrochloride)^® 15% should be given to a pregnant woman only if clearly needed.

E. Nursing Mothers

Caution should be exercised when Nutriflex Lipid Peri (Lysine Hydrochloride)^® 15% is administered to a nursing woman.

F. Pediatric Use

Safety and effectiveness of Nutriflex Lipid Peri (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

Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Lysine Hydrochloride)^® 15%in patients with a need for fluid volume restriction, it can be diluted asfollows:

	Volume	Amount	FinalConcentration
Nutriflex Lipid Peri (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
Nutriflex Lipid Peri (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
Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Lysine Hydrochloride)^® 15%plus non-protein calorie sources. Dilution of 250 mL Nutriflex Lipid Peri (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

Nutriflex Lipid Peri (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 Acetate:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Nutriflex Lipid Peri (Potassium Acetate) reviews

Nutriflex Lipid Peri (Potassium Acetate) CHLORIDE EXTENDED RELEASE TABLETS USP 20 mEq K

Rx Only

DESCRIPTION

The Nutriflex Lipid Peri (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq product is an immediately dispersing extended release oral dosage form of Nutriflex Lipid Peri (Potassium Acetate) chloride containing 1500 mg of microencapsulated Nutriflex Lipid Peri (Potassium Acetate) chloride, USP equivalent to 20 mEq of Nutriflex Lipid Peri (Potassium Acetate) in a tablet.

These formulations are intended to slow the release of Nutriflex Lipid Peri (Potassium Acetate) so that the likelihood of a high localized concentration of Nutriflex Lipid Peri (Potassium Acetate) chloride within the gastrointestinal tract is reduced.

Nutriflex Lipid Peri (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq is an electrolyte replenisher. The chemical name of the active ingredient is Nutriflex Lipid Peri (Potassium Acetate) chloride, and the structural formula is KCl. Nutriflex Lipid Peri (Potassium Acetate) 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.

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

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

CLINICAL PHARMACOLOGY

The Nutriflex Lipid Peri (Potassium Acetate) ion is the principal intracellular cation of most body tissues. Nutriflex Lipid Peri (Potassium Acetate) 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 Nutriflex Lipid Peri (Potassium Acetate) 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.

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

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

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

INDICATIONS AND USAGE

BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND BLEEDING WITH CONTROLLED-RELEASE Nutriflex Lipid Peri (Potassium Acetate) CHLORIDE PREPARATIONS, THESE DRUGS SHOULD BE RESERVED FOR THOSE PATIENTS WHO CANNOT TOLERATE OR REFUSE TO TAKE LIQUID OR EFFERVESCENT Nutriflex Lipid Peri (Potassium Acetate) 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 Nutriflex Lipid Peri (Potassium Acetate) 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 Nutriflex Lipid Peri (Potassium Acetate) 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 Nutriflex Lipid Peri (Potassium Acetate) salts may be indicated.

CONTRAINDICATIONS

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

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

Interaction with Potassium-Sparing Diuretics

Hypokalemia should not be treated by the concomitant administration of Nutriflex Lipid Peri (Potassium Acetate) 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 Nutriflex Lipid Peri (Potassium Acetate) retention by inhibiting aldosterone production. Nutriflex Lipid Peri (Potassium Acetate) supplements should be given to patients receiving ACE inhibitors only with close monitoring.

Gastrointestinal Lesions

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

PRECAUTIONS

General

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

Information for Patients

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

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

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

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

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

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

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

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

Aqueous suspension of Nutriflex Lipid Peri (Potassium Acetate) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending Nutriflex Lipid Peri (Potassium Acetate) 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 Nutriflex Lipid Peri it is important to recognize that artifactual elevations can occur after improper venipuncture technique or as a result of in vitro hemolysis of the sample.

Drug Interactions

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

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Pregnancy Category C

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

Nursing Mothers

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

Nutriflex Lipid Peri (Potassium Acetate) 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 Nutriflex Lipid Peri (Potassium Acetate) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending Nutriflex Lipid Peri (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq is not recommended.

HOW SUPPLIED

Nutriflex Lipid Peri (Potassium Acetate) 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

Nutriflex Lipid Peri (Potassium Acetate) 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
• Nutriflex Lipid Peri (Sodium Acetate Trihydrate) reviews

1 INDICATIONS AND USAGE

Nutriflex Lipid Peri nitrite is indicated for sequential use with Nutriflex Lipid Peri (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

Nutriflex Lipid Peri (Sodium Acetate Trihydrate) Nitrite Injection is indicated for sequential use with Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri 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, Nutriflex Lipid Peri (Sodium Acetate Trihydrate) Nitrite Injection and Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) thiosulfate, simultaneously with Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) thiosulfate, with Nutriflex Lipid Peri (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 Nutriflex Lipid Peri Nitrite and Nutriflex Lipid Peri (Sodium Acetate Trihydrate) Thiosulfate
Adults	Nutriflex Lipid Peri (Sodium Acetate Trihydrate) Nitrite -10 mL of Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite at the rate of 2.5 to 5 mL/minute Nutriflex Lipid Peri (Sodium Acetate Trihydrate) Thiosulfate - 50 mL of Nutriflex Lipid Peri (Sodium Acetate Trihydrate) thiosulfate immediately following administration of Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite.
Children	Nutriflex Lipid Peri (Sodium Acetate Trihydrate) Nitrite - 0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite.

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite and Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite, followed by Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite and Nutriflex Lipid Peri (Sodium Acetate Trihydrate) thiosulfate.

Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite injection and Nutriflex Lipid Peri (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. Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite should be administered first, followed immediately by Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) Nitrite and Nutriflex Lipid Peri (Sodium Acetate Trihydrate) Thiosulfate
Adults	Nutriflex Lipid Peri (Sodium Acetate Trihydrate) Nitrite -10 mL of Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite at the rate of 2.5 to 5 mL/minute Nutriflex Lipid Peri (Sodium Acetate Trihydrate) Thiosulfate - 50 mL of Nutriflex Lipid Peri (Sodium Acetate Trihydrate) thiosulfate immediately following administration of Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite.
Children	Nutriflex Lipid Peri (Sodium Acetate Trihydrate) Nitrite -0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite and Nutriflex Lipid Peri (Sodium Acetate Trihydrate) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Nutriflex Lipid Peri (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 Nutriflex Lipid Peri 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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) thiosulfate and Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Nutriflex Lipid Peri (Sodium Acetate Trihydrate) Nitrite Injection consists of:

• One vial of Nutriflex Lipid Peri (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: Nutriflex Lipid Peri 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 Nutriflex Lipid Peri (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. Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite whenever possible. When Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite administered to an adult. Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Nutriflex Lipid Peri 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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri 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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite.

5.7 Use with Other Drugs

Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite.

The medical literature has reported the following adverse events in association with Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Nutriflex Lipid Peri 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. Nutriflex Lipid Peri (Sodium Acetate Trihydrate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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, Nutriflex Lipid Peri (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, Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Nutriflex Lipid Peri (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, Nutriflex Lipid Peri 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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite is excreted in human milk. Because Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite. In studies conducted with Long-Evans rats, Nutriflex Lipid Peri (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 Nutriflex Lipid Peri nitrite in conjunction with Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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.

Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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

Nutriflex Lipid Peri (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

Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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

Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite has the chemical name nitrous acid Nutriflex Lipid Peri (Sodium Acetate Trihydrate) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Nutriflex Lipid Peri (Sodium Acetate Trihydrate) Nitrite

Nutriflex Lipid Peri (Sodium Acetate Trihydrate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite injection.

Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite in 10 mL solution (30 mg/mL). Nutriflex Lipid Peri (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 Nutriflex Lipid Peri nitrite and Nutriflex Lipid Peri (Sodium Acetate Trihydrate) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Nutriflex Lipid Peri (Sodium Acetate Trihydrate) Nitrite

Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite. It has been suggested that Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Nutriflex Lipid Peri (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. Nutriflex Lipid Peri (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

Nutriflex Lipid Peri (Sodium Acetate Trihydrate) Nitrite

When 4 mg/kg Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Nutriflex Lipid Peri (Sodium Acetate Trihydrate) Nitrite

Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite in humans have not been well studied. It has been reported that approximately 40% of Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite and Nutriflex Lipid Peri (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 Nutriflex Lipid Peri nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Nutriflex Lipid Peri (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. Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Nutriflex Lipid Peri (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. Nutriflex Lipid Peri (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. Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite and Nutriflex Lipid Peri (Sodium Acetate Trihydrate) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite or 1 g/kg Nutriflex Lipid Peri (Sodium Acetate Trihydrate) thiosulfate alone or in sequence immediately after subcutaneous injection of Nutriflex Lipid Peri (Sodium Acetate Trihydrate) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite and/or 0.5 g/kg Nutriflex Lipid Peri (Sodium Acetate Trihydrate) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Nutriflex Lipid Peri (Sodium Acetate Trihydrate) cyanide required to cause death, and when administered together, Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite and Nutriflex Lipid Peri (Sodium Acetate Trihydrate) thiosulfate resulted in a synergistic effect in raising the lethal dose of Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite and Nutriflex Lipid Peri (Sodium Acetate Trihydrate) thiosulfate in the treatment of cyanide poisoning.

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

14 CLINICAL STUDIES

The human data supporting the use of Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) thiosulfate report its use in conjunction with Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (Sodium Acetate Trihydrate) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Nutriflex Lipid Peri (Sodium Acetate Trihydrate) nitrite injection 30 mg/mL (containing 300 mg of Nutriflex Lipid Peri (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: Nutriflex Lipid Peri (Sodium Acetate Trihydrate) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Nutriflex Lipid Peri 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

Nutriflex Lipid Peri (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

Nutriflex Lipid Peri (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

Sodium Chloride:

• 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
• Nutriflex Lipid Peri (Sodium Chloride) reviews

1 INDICATIONS AND USAGE

Nutriflex Lipid Peri nitrite is indicated for sequential use with Nutriflex Lipid Peri (Sodium Chloride) 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

Nutriflex Lipid Peri (Sodium Chloride) Nitrite Injection is indicated for sequential use with Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri 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, Nutriflex Lipid Peri (Sodium Chloride) Nitrite Injection and Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) thiosulfate, simultaneously with Nutriflex Lipid Peri (Sodium Chloride) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Nutriflex Lipid Peri (Sodium Chloride) thiosulfate, with Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri Nitrite and Nutriflex Lipid Peri (Sodium Chloride) Thiosulfate
Adults	Nutriflex Lipid Peri (Sodium Chloride) Nitrite -10 mL of Nutriflex Lipid Peri (Sodium Chloride) nitrite at the rate of 2.5 to 5 mL/minute Nutriflex Lipid Peri (Sodium Chloride) Thiosulfate - 50 mL of Nutriflex Lipid Peri (Sodium Chloride) thiosulfate immediately following administration of Nutriflex Lipid Peri (Sodium Chloride) nitrite.
Children	Nutriflex Lipid Peri (Sodium Chloride) Nitrite - 0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Nutriflex Lipid Peri (Sodium Chloride) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) nitrite.

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Nutriflex Lipid Peri (Sodium Chloride) nitrite and Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) nitrite, followed by Nutriflex Lipid Peri (Sodium Chloride) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Nutriflex Lipid Peri (Sodium Chloride) nitrite and Nutriflex Lipid Peri (Sodium Chloride) thiosulfate.

Nutriflex Lipid Peri (Sodium Chloride) nitrite injection and Nutriflex Lipid Peri (Sodium Chloride) 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. Nutriflex Lipid Peri (Sodium Chloride) nitrite should be administered first, followed immediately by Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) Nitrite and Nutriflex Lipid Peri (Sodium Chloride) Thiosulfate
Adults	Nutriflex Lipid Peri (Sodium Chloride) Nitrite -10 mL of Nutriflex Lipid Peri (Sodium Chloride) nitrite at the rate of 2.5 to 5 mL/minute Nutriflex Lipid Peri (Sodium Chloride) Thiosulfate - 50 mL of Nutriflex Lipid Peri (Sodium Chloride) thiosulfate immediately following administration of Nutriflex Lipid Peri (Sodium Chloride) nitrite.
Children	Nutriflex Lipid Peri (Sodium Chloride) Nitrite -0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Nutriflex Lipid Peri (Sodium Chloride) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) nitrite.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Nutriflex Lipid Peri (Sodium Chloride) nitrite and Nutriflex Lipid Peri (Sodium Chloride) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri 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 Nutriflex Lipid Peri (Sodium Chloride) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Nutriflex Lipid Peri (Sodium Chloride) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Nutriflex Lipid Peri (Sodium Chloride) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Nutriflex Lipid Peri (Sodium Chloride) thiosulfate and Nutriflex Lipid Peri (Sodium Chloride) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Nutriflex Lipid Peri (Sodium Chloride) Nitrite Injection consists of:

• One vial of Nutriflex Lipid Peri (Sodium Chloride) 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: Nutriflex Lipid Peri 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 Nutriflex Lipid Peri (Sodium Chloride) 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. Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Nutriflex Lipid Peri (Sodium Chloride) nitrite whenever possible. When Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) nitrite administered to an adult. Nutriflex Lipid Peri (Sodium Chloride) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Nutriflex Lipid Peri 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 Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri 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 Nutriflex Lipid Peri (Sodium Chloride) nitrite.

5.7 Use with Other Drugs

Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) nitrite.

The medical literature has reported the following adverse events in association with Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Nutriflex Lipid Peri 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. Nutriflex Lipid Peri (Sodium Chloride) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) 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, Nutriflex Lipid Peri (Sodium Chloride) 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, Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Nutriflex Lipid Peri (Sodium Chloride) 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, Nutriflex Lipid Peri 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 Nutriflex Lipid Peri (Sodium Chloride) nitrite is excreted in human milk. Because Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Nutriflex Lipid Peri (Sodium Chloride) nitrite. In studies conducted with Long-Evans rats, Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri nitrite in conjunction with Nutriflex Lipid Peri (Sodium Chloride) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Nutriflex Lipid Peri (Sodium Chloride) 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.

Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) 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

Nutriflex Lipid Peri (Sodium Chloride) 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

Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) 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

Nutriflex Lipid Peri (Sodium Chloride) nitrite has the chemical name nitrous acid Nutriflex Lipid Peri (Sodium Chloride) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Nutriflex Lipid Peri (Sodium Chloride) Nitrite

Nutriflex Lipid Peri (Sodium Chloride) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Nutriflex Lipid Peri (Sodium Chloride) nitrite injection.

Nutriflex Lipid Peri (Sodium Chloride) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Nutriflex Lipid Peri (Sodium Chloride) nitrite in 10 mL solution (30 mg/mL). Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri nitrite and Nutriflex Lipid Peri (Sodium Chloride) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Nutriflex Lipid Peri (Sodium Chloride) Nitrite

Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) nitrite. It has been suggested that Nutriflex Lipid Peri (Sodium Chloride) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Nutriflex Lipid Peri (Sodium Chloride) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Nutriflex Lipid Peri (Sodium Chloride) 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. Nutriflex Lipid Peri (Sodium Chloride) 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

Nutriflex Lipid Peri (Sodium Chloride) Nitrite

When 4 mg/kg Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Nutriflex Lipid Peri (Sodium Chloride) Nitrite

Nutriflex Lipid Peri (Sodium Chloride) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Nutriflex Lipid Peri (Sodium Chloride) nitrite in humans have not been well studied. It has been reported that approximately 40% of Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) nitrite and Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Nutriflex Lipid Peri (Sodium Chloride) 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. Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Nutriflex Lipid Peri (Sodium Chloride) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Nutriflex Lipid Peri (Sodium Chloride) 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. Nutriflex Lipid Peri (Sodium Chloride) 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. Nutriflex Lipid Peri (Sodium Chloride) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Nutriflex Lipid Peri (Sodium Chloride) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) nitrite and Nutriflex Lipid Peri (Sodium Chloride) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Nutriflex Lipid Peri (Sodium Chloride) nitrite or 1 g/kg Nutriflex Lipid Peri (Sodium Chloride) thiosulfate alone or in sequence immediately after subcutaneous injection of Nutriflex Lipid Peri (Sodium Chloride) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Nutriflex Lipid Peri (Sodium Chloride) nitrite and/or 0.5 g/kg Nutriflex Lipid Peri (Sodium Chloride) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Nutriflex Lipid Peri (Sodium Chloride) cyanide required to cause death, and when administered together, Nutriflex Lipid Peri (Sodium Chloride) nitrite and Nutriflex Lipid Peri (Sodium Chloride) thiosulfate resulted in a synergistic effect in raising the lethal dose of Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) nitrite and Nutriflex Lipid Peri (Sodium Chloride) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Nutriflex Lipid Peri (Sodium Chloride) nitrite and Nutriflex Lipid Peri (Sodium Chloride) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Nutriflex Lipid Peri (Sodium Chloride) nitrite, with or without Nutriflex Lipid Peri (Sodium Chloride) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) thiosulfate report its use in conjunction with Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) 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 Nutriflex Lipid Peri (Sodium Chloride) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Nutriflex Lipid Peri (Sodium Chloride) nitrite injection 30 mg/mL (containing 300 mg of Nutriflex Lipid Peri (Sodium Chloride) 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: Nutriflex Lipid Peri (Sodium Chloride) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Nutriflex Lipid Peri 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

Nutriflex Lipid Peri (Sodium Chloride) 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

Nutriflex Lipid Peri (Sodium Chloride) 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

Sodium Hydroxide:

• 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
• Nutriflex Lipid Peri (Sodium Hydroxide) reviews

1 INDICATIONS AND USAGE

Nutriflex Lipid Peri nitrite is indicated for sequential use with Nutriflex Lipid Peri (Sodium Hydroxide) 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

Nutriflex Lipid Peri (Sodium Hydroxide) Nitrite Injection is indicated for sequential use with Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri 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, Nutriflex Lipid Peri (Sodium Hydroxide) Nitrite Injection and Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) thiosulfate, simultaneously with Nutriflex Lipid Peri (Sodium Hydroxide) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Nutriflex Lipid Peri (Sodium Hydroxide) thiosulfate, with Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri Nitrite and Nutriflex Lipid Peri (Sodium Hydroxide) Thiosulfate
Adults	Nutriflex Lipid Peri (Sodium Hydroxide) Nitrite -10 mL of Nutriflex Lipid Peri (Sodium Hydroxide) nitrite at the rate of 2.5 to 5 mL/minute Nutriflex Lipid Peri (Sodium Hydroxide) Thiosulfate - 50 mL of Nutriflex Lipid Peri (Sodium Hydroxide) thiosulfate immediately following administration of Nutriflex Lipid Peri (Sodium Hydroxide) nitrite.
Children	Nutriflex Lipid Peri (Sodium Hydroxide) Nitrite - 0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Nutriflex Lipid Peri (Sodium Hydroxide) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) nitrite.

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Nutriflex Lipid Peri (Sodium Hydroxide) nitrite and Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) nitrite, followed by Nutriflex Lipid Peri (Sodium Hydroxide) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Nutriflex Lipid Peri (Sodium Hydroxide) nitrite and Nutriflex Lipid Peri (Sodium Hydroxide) thiosulfate.

Nutriflex Lipid Peri (Sodium Hydroxide) nitrite injection and Nutriflex Lipid Peri (Sodium Hydroxide) 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. Nutriflex Lipid Peri (Sodium Hydroxide) nitrite should be administered first, followed immediately by Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) Nitrite and Nutriflex Lipid Peri (Sodium Hydroxide) Thiosulfate
Adults	Nutriflex Lipid Peri (Sodium Hydroxide) Nitrite -10 mL of Nutriflex Lipid Peri (Sodium Hydroxide) nitrite at the rate of 2.5 to 5 mL/minute Nutriflex Lipid Peri (Sodium Hydroxide) Thiosulfate - 50 mL of Nutriflex Lipid Peri (Sodium Hydroxide) thiosulfate immediately following administration of Nutriflex Lipid Peri (Sodium Hydroxide) nitrite.
Children	Nutriflex Lipid Peri (Sodium Hydroxide) Nitrite -0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Nutriflex Lipid Peri (Sodium Hydroxide) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) nitrite.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Nutriflex Lipid Peri (Sodium Hydroxide) nitrite and Nutriflex Lipid Peri (Sodium Hydroxide) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri 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 Nutriflex Lipid Peri (Sodium Hydroxide) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Nutriflex Lipid Peri (Sodium Hydroxide) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Nutriflex Lipid Peri (Sodium Hydroxide) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Nutriflex Lipid Peri (Sodium Hydroxide) thiosulfate and Nutriflex Lipid Peri (Sodium Hydroxide) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Nutriflex Lipid Peri (Sodium Hydroxide) Nitrite Injection consists of:

• One vial of Nutriflex Lipid Peri (Sodium Hydroxide) 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: Nutriflex Lipid Peri 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 Nutriflex Lipid Peri (Sodium Hydroxide) 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. Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Nutriflex Lipid Peri (Sodium Hydroxide) nitrite whenever possible. When Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) nitrite administered to an adult. Nutriflex Lipid Peri (Sodium Hydroxide) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Nutriflex Lipid Peri 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 Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri 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 Nutriflex Lipid Peri (Sodium Hydroxide) nitrite.

5.7 Use with Other Drugs

Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) nitrite.

The medical literature has reported the following adverse events in association with Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Nutriflex Lipid Peri 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. Nutriflex Lipid Peri (Sodium Hydroxide) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) 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, Nutriflex Lipid Peri (Sodium Hydroxide) 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, Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Nutriflex Lipid Peri (Sodium Hydroxide) 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, Nutriflex Lipid Peri 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 Nutriflex Lipid Peri (Sodium Hydroxide) nitrite is excreted in human milk. Because Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Nutriflex Lipid Peri (Sodium Hydroxide) nitrite. In studies conducted with Long-Evans rats, Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri nitrite in conjunction with Nutriflex Lipid Peri (Sodium Hydroxide) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Nutriflex Lipid Peri (Sodium Hydroxide) 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.

Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) 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

Nutriflex Lipid Peri (Sodium Hydroxide) 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

Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) 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

Nutriflex Lipid Peri (Sodium Hydroxide) nitrite has the chemical name nitrous acid Nutriflex Lipid Peri (Sodium Hydroxide) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Nutriflex Lipid Peri (Sodium Hydroxide) Nitrite

Nutriflex Lipid Peri (Sodium Hydroxide) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Nutriflex Lipid Peri (Sodium Hydroxide) nitrite injection.

Nutriflex Lipid Peri (Sodium Hydroxide) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Nutriflex Lipid Peri (Sodium Hydroxide) nitrite in 10 mL solution (30 mg/mL). Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri nitrite and Nutriflex Lipid Peri (Sodium Hydroxide) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Nutriflex Lipid Peri (Sodium Hydroxide) Nitrite

Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) nitrite. It has been suggested that Nutriflex Lipid Peri (Sodium Hydroxide) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Nutriflex Lipid Peri (Sodium Hydroxide) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Nutriflex Lipid Peri (Sodium Hydroxide) 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. Nutriflex Lipid Peri (Sodium Hydroxide) 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

Nutriflex Lipid Peri (Sodium Hydroxide) Nitrite

When 4 mg/kg Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Nutriflex Lipid Peri (Sodium Hydroxide) Nitrite

Nutriflex Lipid Peri (Sodium Hydroxide) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Nutriflex Lipid Peri (Sodium Hydroxide) nitrite in humans have not been well studied. It has been reported that approximately 40% of Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) nitrite and Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Nutriflex Lipid Peri (Sodium Hydroxide) 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. Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Nutriflex Lipid Peri (Sodium Hydroxide) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Nutriflex Lipid Peri (Sodium Hydroxide) 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. Nutriflex Lipid Peri (Sodium Hydroxide) 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. Nutriflex Lipid Peri (Sodium Hydroxide) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Nutriflex Lipid Peri (Sodium Hydroxide) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) nitrite and Nutriflex Lipid Peri (Sodium Hydroxide) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Nutriflex Lipid Peri (Sodium Hydroxide) nitrite or 1 g/kg Nutriflex Lipid Peri (Sodium Hydroxide) thiosulfate alone or in sequence immediately after subcutaneous injection of Nutriflex Lipid Peri (Sodium Hydroxide) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Nutriflex Lipid Peri (Sodium Hydroxide) nitrite and/or 0.5 g/kg Nutriflex Lipid Peri (Sodium Hydroxide) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Nutriflex Lipid Peri (Sodium Hydroxide) cyanide required to cause death, and when administered together, Nutriflex Lipid Peri (Sodium Hydroxide) nitrite and Nutriflex Lipid Peri (Sodium Hydroxide) thiosulfate resulted in a synergistic effect in raising the lethal dose of Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) nitrite and Nutriflex Lipid Peri (Sodium Hydroxide) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Nutriflex Lipid Peri (Sodium Hydroxide) nitrite and Nutriflex Lipid Peri (Sodium Hydroxide) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Nutriflex Lipid Peri (Sodium Hydroxide) nitrite, with or without Nutriflex Lipid Peri (Sodium Hydroxide) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) thiosulfate report its use in conjunction with Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) 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 Nutriflex Lipid Peri (Sodium Hydroxide) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Nutriflex Lipid Peri (Sodium Hydroxide) nitrite injection 30 mg/mL (containing 300 mg of Nutriflex Lipid Peri (Sodium Hydroxide) 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: Nutriflex Lipid Peri (Sodium Hydroxide) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Nutriflex Lipid Peri 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

Nutriflex Lipid Peri (Sodium Hydroxide) 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

Nutriflex Lipid Peri (Sodium Hydroxide) 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

Soybean Oil:

• Warnings
• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdose section
• Dosage and administration
• How supplied
• Storage and handling
• Limited warranty
• References
• Nutriflex Lipid Peri (Soybean Oil) reviews

WARNINGS

This product is intended for use only by licensed medical personnel experienced in administering allergenic extracts and trained to provide immediate emergency treatment in the event of a life-threatening reaction. Allergenic extracts may potentially elicit a severe life-threatening systemic reaction, rarely resulting in death.1

Therefore, emergency measures and personnel trained in their use must be available immediately in the event of such a reaction.

Patients should be instructed to recognize adverse reaction symptoms, be observed in the office for at least 30 minutes after skin testing or treatment, and be cautioned to contact the physician's office if symptoms occur. See ADVERSE REACTION section of this package insert regarding adverse event reporting.

Standardized glycerinated extracts may be more potent than regular extracts and therefore are not directly interchangeable with non-standardized extracts, or other manufacturers' products.

Patients with cardiovascular diseases and/or pulmonary diseases such as symptomatic unstable, steroid dependent asthma, and/or those who are receiving cardiovascular drugs such as beta blockers, may be at higher risk for severe adverse reactions. These patients may also be more refractory to the normal allergy treatment regimen. Patients should be treated only if the benefit of treatment outweighs the risks.1

Patients on beta blockers may be more reactive to allergens given for testing or treatment and may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. 2

This product should never be injected intravenously.

Refer to the WARNINGS, PRECAUTIONS, ADVERSE REACTIONS and OVERDOSE Sections for further discussion.

DESCRIPTION

The allergenic extract in this vial is referred to as a "bulk" extract or stock concentrate since it is designed primarily for the physician equipped to prepare dilutions and mixtures as required. The extract is sterile and intended for subcutaneous injection for immunotherapy and scratch, prick or puncture for diagnosis. Unless specified otherwise, the concentration of extract supplied will in most cases be expressed in weight to volume (e.g., 1:10 or 1:20 w/v) and will be the strongest available. Where mixtures of pollens and non-pollens have been ordered, the mixed extract will be treated as a pollen mixture. To insure maximum potency for the entire dating period, all bulk concentrates will contain 50% volume to volume (v/v) glycerin unless otherwise requested. Dilutions will also be prepared with 50% (v/v) glycerin unless another diluent is specified.

Source materials utilized in allergenic extract products include pollens, molds, animal epidermals, insects, foods and environmental materials.

Pollens are collected using techniques such as waterset or vacuuming, cleaned and purified to greater than 99% single specie pollen (less than 1% foreign particle presence).

Molds are typically grown on synthetic nutrient medias and are derived from the surface growth (mycelia).

Animal source materials are collected from animals deemed to be healthy at the time of collection by a veterinarian or individual trained and certified by a veterinarian. Epidermals include feathers, hair and dander, or the whole epidermal (pelt) as described on product labeling.

Regular process epidermals are extractions of the source material without additional processing, except that certain materials are defatted. AP (acetone precipitated) epidermal source materials are derived from the precipitate formed when acetone is added to an aqueous extract. The resulting precipitate is dried, and becomes the source material for the AP product.

Insects are collected in whole body form. Extractions take place as whole body or ground insects.

Information on Foods and other Environmental source materials can be obtained by contacting our Customer Service Department.

The following is a brief summary of the six methods of describing allergenic product concentration.

1. Weight to volume (w/v). Weight to volume (w/v) describes the weight of allergenic source material added to a given volume of extracting fluid. A 1:10 w/v extract, e.g., indicates that the solution contains the extractable material from one gram of raw material added to each 10 mL Glycero-Coca's or 10 mL Coca's extracting fluid. The amount and composition of extracted materials will vary with the type of antigen, the extracting fluid, duration of extraction, pH, temperature, and other variables. Pollens are typically extracted at a 1:20 w/v ratio in Glycero-Coca's while Coca's extracts are 1:10 w/v. Epidermal, environmental, regular molds and insect products are typically extracted at 1:10 w/v. AP (acetone precipitated) epidermal products are prepared at a 1:50 w/v concentration (i.e., 1 gram of dried precipitate in 50 mL of reconstitution fluid). AP Dog Hair-Dander is prepared at 1:100 w/v concentration. (i.e., 1 gram of dried precipitate in 100 mL of reconstitution fluid.)

2. Protein Nitrogen Units per mL (PNU/mL). One protein nitrogen unit represents 0.00001 mg phosphotungstic acid precipitable protein nitrogen dissolved in one mL of antigen extract. The PNU content of extracts of the same antigen may vary according to the method of measuring the PNU. Thus, the PNU content of extracts from different manufacturers is not comparable unless the PNU method is known to be the same and is reproducible from lot to lot. The amount of protein nitrogen extracted from the source material is influenced by such factors as the type of antigen, the extracting fluid, duration of extraction, pH, temperature and other variables. Allergenic materials make up a variable proportion of the total protein of an extract. Most allergenic extracts are assayed for PNU. Specific PNU information is available upon request.

3. Amb a 1. Of the many allergens from Short Ragweed which have been purified and characterized [Amb a 1 3 (also known as Antigen E), Amb a 2 3 (also known as Antigen K), Ra3 4, Ra4 (BPA-R) 5, Ra5 6, Ra6, Ra7, Ra87, and cytochrome C 8], Amb a 1 is considered the most important and has been selected as the basis for standardization. Extracts of Short Ragweed containing Amb a 1 are diffused in agar against standard anti-serum to Amb a 1, and compared to the diffusion of standard Amb a 1 solutions. The amount of Amb a 1 is expressed as units of Amb a 1 per mL of extract. A Short Ragweed pollen extracted at 1:20 (w/v) usually assays within a range of 50,000 to 70,000 PNU/mL and 100 to 300 units of Amb a 1 per mL.

The Amb a 1 concentration of any Short Ragweed extract which is diluted with a diluent or other allergenic extracts is determined by calculation. The resulting Amb a 1 value does not reflect the total potency of the product if Short Ragweed extract is mixed with another allergenic extract.

4. Allergy Units per mL (AU/mL). The potency of extracts labeled in Allergy Units (AU)/mL is determined by in vitro comparison to a reference standard established by the Center for Biologics Evaluation and Research (CBER) of the Food and Drug Administration (FDA).

5. Bioequivalent Allergy Units per mL (BAU/mL). Other standardized allergenic extracts are labeled in Bioequivalent Allergy Units/mL (BAU/mL) based on their comparison (by in vitro assay or major allergen content) to CBER, FDA Reference Preparations. The FDA reference extracts have been assigned Bioequivalent Allergy Units based on the CBER ID₅₀EAL method.9 Briefly, highly sensitive patients are skin tested to the reference preparation using an intradermal technique employing 3-fold extract dilutions. Depending on the dilution which elicits a summation of erythema diameter of 50, Bioequivalent Allergy Units are assigned as follows:

BAU/mL	D50 Range
100,000	13.9 - 15.9
10,000	10.9 - 12.9
1,000	8.8 - 10.8
100	6.7 - 8.7

References labeled 10,000 BAU/mL can be diluted one to a half million fold, and references labeled 100,000 BAU/mL can be diluted one to 5 million fold and produce a sum of erythema diameter of 50 mm when Intradermal testing highly reactive subjects.

6. Concentrate. Concentrate label terminology applies to allergenic extract mixtures, where the individual allergens being combined vary in strength or the designation of strength.

e.g. Concentrate

50% Short Ragweed 1:20 w/v

25% Std. Cat Pelt 10,000 BAU/mL

25% Mite D. farinae 10,000 AU/mL

Should the physician choose to calculate the actual strength of each component in the "Concentrate" mixture, the following formulation may be used:

Actual Allergen Strength in Concentrate	=	Allergen Manufacturing Strength	X	% Allergen in Formulation (by volume or parts)

Ingredients: Active ingredients are the allergen(s) noted on the vial label. Preservative is 50% (v/v) glycerin, or 0.4% phenol, as indicated on the vial label. Additional ingredients are 0.5% sodium chloride, and 0.275% sodium bicarbonate.

CLINICAL PHARMACOLOGY

The mechanism by which hyposensitization is achieved is not known completely. It has been shown that repeated injections of appropriate allergenic extracts will ameliorate the intensity of allergic symptoms upon contact with the allergen.11, 12, 13, 14 Clinical studies which address the efficacy of immunotherapy are available. The allergens which have been studied are cat, mite, and some pollen extracts.10, 15, 16, 17, 18, 19

IgE antibodies bound to receptors on mast cell membranes are required for the allergic reaction, and their level is probably related to serum IgE concentrations. Immunotherapy has been associated with decreased levels of IgE, and also with increases in allergen specific IgG "blocking" antibody.

The histamine release response of circulating basophils to a specific allergen is reduced in some patients by immunotherapy, but the mechanism of this change is not clear.

Further study and clarification of the relationships among changes in blocking antibody, reaginic antibody, and mediator-releasing cells, and between these three factors and successful immunotherapy, is needed.

INDICATIONS AND USAGE

20,21,22,23

Allergenic extracts are indicated for use in diagnosis and immunotherapy of patients presenting symptoms of allergy (hay fever, rhinitis, etc.) to specific environmental allergens. The selection of allergenic extracts to be used should be based on a thorough and carefully taken history of hypersensitivity, and confirmed by skin testing.

The use of mixed or unrelated antigens for skin testing is not recommended since, in the case of a positive reaction, it does not indicate which component of the mix is responsible for the reaction, while, in the case of a negative reaction, it fails to indicate whether the individual antigens at full concentration would give a positive reaction. Utilization of such mixes for compounding a treatment may result, in the former case, in administering unnecessary antigens and, in the latter case, in the omission of a needed antigen.

Avoidance of allergens is to be advocated if possible, but cannot always be attained, e.g., allergy to dog dander in kennel owners and employees, dog breeders, research workers, veterinarians, etc.

Allergens to which a patient is extremely sensitive should not be included in treatment mixes with allergens to which there is much less sensitivity, but should be administered separately. This allows individualized and better control of dosage increases, including adjustments in dosage becoming necessary after severe reactions which may occur with the highly reactive allergen.

CONTRAINDICATIONS

There are no known absolute contraindications to immunotherapy. See PRECAUTIONS and WARNINGS.

Patients with cardiovascular diseases and/or pulmonary diseases such as symptomatic unstable, steroid-dependent asthma, and/or those who are receiving cardiovascular drugs such as beta blockers, may be at higher risk for severe adverse reactions. These patients may also be more refractory to the normal allergy treatment regimen. Patients should be treated only if the benefit of treatment outweighs the risks.1

Treat patients only with allergens to which they are allergic by skin test reaction, have a history of symptoms on exposure, and are likely to be exposed to again.

Any injections, including immunotherapy, should be avoided in patients with a bleeding tendency. Patients on beta blockers may be more reactive to allergens given for testing or treatment and may be unresponsive to the usual doses of epinephrine used to treat systemic reactions.2

Since there are differences of opinion concerning the possibility of routine immunizations exacerbating autoimmune diseases, immunotherapy should be given cautiously to patients with other immunologic diseases and only if the risk from exposure is greater than the risk of exacerbating the underlying disorder.

WARNINGS

Allergenic extracts must be temporarily withheld from patients or the dose adjusted downward if any of the following conditions exist: (1) severe symptoms of rhinitis and/or asthma; (2) infection or flu accompanied by fever; (3) any evidence of an excessively large local or any generalized reaction during the initial stages of immunotherapy or during maintenance therapy, and/or (4) exposure to excessive amounts of clinically relevant allergen prior to a scheduled injection. Do not administer immunotherapy during a period of symptoms due to exposure. Since the individual components of the extract are those to which the patient is allergic, and to which s/he will be exposed, typical allergic symptoms may follow shortly after the injection, particularly when the antigen load from exposure plus the injected antigen exceeds the patient's antigen tolerance.

THE CONCENTRATE MUST NOT BE INJECTED AT ANY TIME UNLESS TOLERANCE HAS BEEN ESTABLISHED. DILUTE CONCENTRATED EXTRACTS WITH STERILE DILUENT FOR SKIN TESTING AND IMMUNOTHERAPY.

INJECTIONS MUST NEVER BE GIVEN INTRAVENOUSLY. Subcutaneous injection is recommended. Intracutaneous or intramuscular injection may produce large local reactions or be excessively painful.

AFTER INSERTING NEEDLE SUBCUTANEOUSLY, BUT BEFORE INJECTING, ALWAYS WITHDRAW THE PLUNGER SLIGHTLY. IF BLOOD APPEARS IN THE SYRINGE, CHANGE NEEDLE AND GIVE THE INJECTION IN ANOTHER SITE.

IF CHANGING TO A DIFFERENT LOT OF EXTRACT: All extracts lose potency over time, and a fresh extract could have an effective potency that is substantially greater than that of the old extract. Even though it is the same formula and concentration, the first dose from the new vial should not exceed 50% of the previous dose.

IF THE EXTRACT PREVIOUSLY USED WAS FROM ANOTHER MANUFACTURER: Since manufacturing processes and sources of raw materials differ among manufacturers, the interchangeability of extracts from different manufacturers cannot be insured. The starting dose of the extract therefore should be greatly decreased even though the extract is the same formula and dilution. In general, a dose reduction to 50% of the previous product dose should be adequate, but each situation must be evaluated separately considering the patient's history of sensitivity, tolerance of previous injections, and other factors. If the patient tolerates a 50% decrease, the next dose could be raised to the previous dose amount. If the decrease is greater than 50%, the next dose would need to be determined by the allergist, depending on the situation. Dose intervals should not exceed one week when rebuilding dose. See DOSAGE AND ADMINISTRATION.

IF A PROLONGED PERIOD OF TIME HAS ELAPSED SINCE THE LAST INJECTION: Patients may lose tolerance for allergen injections during prolonged periods between doses. The duration of tolerance is an individual characteristic and varies from patient to patient. In general, the longer the lapse in the injection schedule, the greater dose reduction required. If the interval since last dose is over four weeks, perform skin tests to determine starting dose. See DOSAGE AND ADMINISTRATION.

IF THE PREVIOUS EXTRACT WAS OUTDATED: The dating period for allergenic extracts indicates the time that they can be expected to remain potent under refrigerated storage conditions (2° - 8°C). During the storage of extracts, even under ideal conditions, some loss of potency occurs. For this reason, extracts should not be used beyond their expiration date. If a patient has been receiving injections of an outdated extract, s/he may experience excessive local or systemic reactions when changed to a new and possibly more potent extract. In general, the longer the material has been outdated, the greater the dose reduction necessary for the fresh extract.

IF CHANGING FROM ALUM-ADSORBED TO AQUEOUS OR GLYCERINATED EXTRACTS: When the patient was previously receiving alum-adsorbed or alum-precipitated extract, the safest course is to start over as though the patient had not been receiving immunotherapy. See DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS.

IF ANY OTHER CHANGES HAVE BEEN MADE IN THE EXTRACT CONCENTRATE FORMULA: Changes other than those listed above may include situations such as a redistribution of component parts or percentages, a difference in extracting fluid (i.e., change from non-glycerin extracts to 50% glycerin extracts), combining two or more stock concentrates, or any other change. It should be recognized that any change in formula can affect a patient's tolerance of the treatment. The usual 1/2 of the previous dose for a new extract may produce an adverse reaction; extra dilutions are recommended whenever starting a revised formula. The greater the change, the greater the number of dilutions required.

Proper selection of the dose and careful injection should prevent most systemic reactions. It must be remembered that allergenic extracts are highly potent in sensitive individuals, and that systemic reactions of varying degrees of severity may occur, including urticaria, rhinitis, conjunctivitis, wheezing, coughing, angioedema, hypotension, bradycardia, pallor, laryngeal edema, fainting, or even anaphylactic shock and death, as described under ADVERSE REACTIONS. Patients should be informed of this, and the precautions should be discussed prior to immunotherapy. Severe systemic reactions should be treated as indicated in ADVERSE REACTIONS. Refer to WARNINGS box.

PRECAUTIONS

1. General

The presence of asthmatic signs and symptoms appear to be an indicator for severe reactions following allergy injections. An assessment of airway obstruction either by measurement of peak flow or an alternate procedure may provide a useful indicator as to the advisability of administering an allergy injection.1, 24, 25, 26, 27

Concentrated extracts must not be injected unless tolerance has been established. Concentrated extracts must be diluted prior to use: See DOSAGE and ADMINISTRATION for detailed instructions on the dilution of allergenic extracts.

Any evidence of a local or generalized reaction requires a reduction in dosage during the initial stages of immunotherapy, as well as during maintenance therapy.

Allergenic extracts diluted with sterile Albumin Saline with Phenol may be more potent than extracts diluted with diluents which do not contain stabilizers. When switching from non-stabilized to stabilized diluent, consider weaker initial dilutions for both intradermal testing and immunotherapy.

Sterile solutions, vials, syringes, etc. should be used and aseptic precautions observed in making dilutions.

To avoid cross-contamination, do not use the same needle to withdraw materials from vials of more than one extract, or extract followed by diluent.

A sterile tuberculin syringe graduated in 0.01 mL units and with a needle at least 5/8" long should be used to measure each dose from the appropriate dilution.

Aseptic techniques should always be employed when injections of allergenic extracts are being administered. A separate sterile syringe should be used for each patient to prevent transmission of hepatitis and other infectious agents from one person to another.

Patient reactions to previous injections should be reviewed before each new injection, so that dosage can be adjusted accordingly. See ADVERSE REACTIONS and WARNINGS.

Rarely, a patient is encountered who develops systemic reactions to minute doses of allergen and does not demonstrate increasing tolerance to injections after several months of treatment. If systemic reactions or excessive local responses occur persistently at very small doses, efforts at immunotherapy should be stopped.

PATIENTS SHOULD BE OBSERVED IN THE OFFICE FOR AT LEAST 30 MINUTES AFTER SKIN TESTING AND EACH TREATMENT INJECTION. Most severe reactions will occur within this time period, and rapid treatment measures should be instituted. See ADVERSE REACTIONS for such treatment measures.

In order to avoid darkening and possible precipitation, do not dilute the following extracts with solutions containing phenol: Privet pollen and food extracts of White Potato, Corn, Oat, Rye, and Wheat. Injections of such extracts discolored by reaction with phenol may produce a lasting tattoo-like discoloration of the skin.

2. Information for Patients

Patients should be instructed in the recognition of adverse reactions to immunotherapy, and in particular, to the symptoms of shock. Patients should be made to understand the importance of a 30 minute observation period, and be cautioned to return to the office promptly if symptoms occur after leaving. Patients should be instructed to report any symptoms of exposure to the allergen, so the physician can adjust the dosage appropriately.

3. Drug Interactions

Patientswith cardiovascular diseases and/or pulmonary diseases such assymptomatic unstable, steroid-dependent asthma, and/or those who arereceiving cardiovascular drugs such as beta blockers, may be at higherrisk for severe adverse reactions. These patients may also be morerefractory to the normal allergy treatment regimen. Patients should betreated only if the benefit of treatment outweighs the risks.1

Patientson beta blockers may be more reactive to allergens given for testing ortreatment and may be unresponsive to the usual doses of epinephrineused to treat allergic reactions.2. Certain medications may lessen the skin test wheal anderythema responses elicited by allergens and histamine for varying timeperiods. Conventional antihistamines should be discontinued at least 5days before skin testing. Long acting antihistamines should bediscontinued for at least 3 weeks prior to skin testing. 28 Topical steroids should be discontinued at the skin test site for at least 2-3 weeks before skin testing.28, 29

Tricyclic antidepressants such as Doxepin should be withheld for at least 7 days before skin testing. 30 Topical local anesthetics may suppress the flare responses and should be avoided in skin test sites.31

4. Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been conducted with allergenic extracts to determine their potential for carcinogenicity, mutagenicity or impairment of fertility.

5. Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with allergenic extracts. It is also not known whether allergenic extracts can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Allergenic extracts should be given to a pregnant woman only if clearly needed. The physician must carefully consider the benefit-to-risk ratio to both patient and fetus, of performing skin testing or continuing immunotherapy during pregnancy. The recommended precautions for preventing adverse reactions are especially important in the pregnant patient. Based on the physician's discretion, immunotherapy maintenance doses may be continued during pregnancy if the patient has not experienced adverse side effects. Immunotherapy is generally not initiated during pregnancy due to the risks associated with systemic reactions and their treatment. 33

6. Nursing Mothers

There are no current studies on the secretion of allergenic extract components in human milk or their effect on the nursing infant. Because many drugs are excreted in human milk, caution should be exercised when allergenic extracts are administered to a nursing woman.

7. Pediatric Use

Since dosage for the pediatric population is the same as for adults 34, 35 larger volumes of solution may produce excessive discomfort. Therefore, in order to achieve the total dose required, the volume of the dose may need to be divided into more than one injection per visit.

8. Geriatric Use

The reactions from immunotherapy can be expected to be the same in elderly patients as in younger ones. Elderly patients may be more likely to be on medication that could block the effect of epinephrine which could be used to treat serious reactions, or they could be more sensitive to the cardiovascular side effect of epinephrine because of pre-existing cardiovascular disease. 36

ADVERSE REACTIONS

Physicians administering allergenic extract testing or treatment materials should be experienced in the treatment of severe systemic reactions. See WARNINGS box at the beginning of this package insert.

1. Local Reactions

Some erythema, swelling or pruritus at the site of injection are common, the extent varying with the patient. Such reactions should not be considered significant unless they persist for at least 24 hours. Local reactions (erythema or swelling) which exceed 4-5 cm in diameter are not only uncomfortable, but also indicate the possibility of a systemic reaction if dosage is increased. In such cases the dosage should be reduced to the last level not causing the reaction and maintained at this level for two or three treatments before cautiously increasing again. Large persistent local reactions may be treated by local cold, wet dressings and/or the use of oral antihistamines. They should be considered a warning of possible severe systemic reactions and an indication of the need for temporarily reduced dosages. A mild burning immediately after the injection is to be expected. This usually subsides in 10 to 20 seconds.

2. Systemic Reactions

With careful attention to dosage and administration, systemic reactions occur infrequently, but it cannot be overemphasized that in sensitive individuals, any injection could result in anaphylactic shock. Therefore, it is imperative that physicians administering allergenic extracts understand and be prepared for the treatment of severe reactions.

Most severe systemic reactions will begin within a 30 minute time period, but systemic reactions may occur at any time after skin tests or immunotherapy. Symptoms may range from mild to life-threatening (due to anaphylaxis)as described below.

Other possible systemic reactions which may occur in varying degrees of severity are laryngeal edema, fainting, pallor, bradycardia, hypotension, angioedema, cough, wheezing, conjunctivitis, rhinitis, and urticaria. Adverse reaction frequency data for allergenic extract administration for testing and treatment show that risk is low. 1, 37

If a systemic or anaphylactic reaction does occur, apply a tourniquet above the site of injection and inject 1:1,000 epinephrine-hydrochloride intramuscularly or subcutaneously into the opposite arm. Loosen the tourniquet at least every 10 minutes. Do not obstruct arterial blood flow with the tourniquet.

EPINEPHRINE

Dosage:

ADULT: 0.3 to 0.5 mL should be injected. Repeat in 5 to 10 minutes if necessary.

PEDIATRIC: The usual initial dose is 0.01 mg (mL) per kg body weight or 0.3 mg (mL) per square meter of body surface area. Suggested dosage for infants to 2 years of age is 0.05 mL to 0.1 mL; for children 2 to 6 years, 0.15 mL; and children 6 to 12 years, 0.2 mL. Single pediatric doses should not exceed 0.3 mg (mL). Doses may be repeated as frequently as every 20 minutes, depending on the severity of the condition and the response of the patient. After administration of epinephrine, profound shock or vasomotor collapse should be treated with intravenous fluids, and possibly vasoactive drugs. Airway patency should be insured. Oxygen should be given by mask. Intravenous antihistamine, inhaled bronchodilators, theophylline and/or adrenal corticosteroids may be used if necessary after adequate epinephrine and circulatory support has been given. Emergency resuscitation measures and personnel trained in their use must be available immediately in the event of a serious systemic or anaphylactic reaction not responsive to the above measures [Ref. J. Allergy and Clinical Immunology, 77(2):p. 271-273, 1986].

Rarely are all of the above measures necessary; the tourniquet and epinephrine usually produce prompt responses. However, the physician should be prepared in advance for all contingencies. Promptness in beginning emergency treatment measures is of utmost importance.

Severe systemic reactions mandate a decrease of at least 50% in the next dose, followed by cautious increases. Repeated systemic reactions, even of a mild nature, are sufficient reason for the cessation of further attempts to increase the reaction-causing dose.

3. Adverse Event Reporting

Report all adverse events to Jubilant HollisterStier LLC, Customer Technical Services Department at 1 (800) 992-1120. A voluntary adverse event reporting system for health professionals is available through the FDA MEDWATCH program. Preprinted forms (FDA Form 3500) are available from the FDA by calling 1 (800) FDA-1088. Completed forms should be mailed to MEDWATCH, 5600 Fisher Lane, Rockville, MD 20852-9787 or Fax to: 1 (800) FDA-0178.

OVERDOSE SECTION

See ADVERSE REACTIONS.

DOSAGE AND ADMINISTRATION

1. General

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

Dosage of allergenic extracts is a highly individualized matter and varies according to the degree of sensitivity of the patient, his clinical response, and tolerance to the extract administered during the early phases of an injection regimen.

Allergen extracts should be administered using a sterile syringe with 0.01 mL gradations and a 25-27 gauge x 1/2" to 5/8" needle. The injections are given subcutaneously. The most common sites of injection are the lateral aspect of the upper arm or thigh. Intracutaneous or intramuscular injections may produce large local reactions and may be very painful.

Sterile aqueous diluent containing human serum albumin [Albumin Saline with Phenol ] or diluent of 50% glycerin may be used when preparing dilutions of the concentrate for immunotherapy. Dilutions should be made accurately and aseptically, using sterile diluent, vials, syringes, etc. Mix thoroughly and gently by rocking or swirling. Maintain stock solutions and dilutions constantly at 2° - 8°C. To prepare dilutions for intradermal and therapeutic use, make a 1:10 dilution by adding 1.0 mL of the Concentrate to 9.0 mL of sterile aqueous diluent. Subsequent serial dilutions are made in a similar manner.

Following is a suggested schedule for average patients and will be satisfactory in most cases. However, the degree of sensitivity varies in many patients. The size of the dose should be adjusted according to the patient's tolerance and reaction. Decrease the size of the dose if the previous injection resulted in marked local or the slightest general reaction. Another dose should never be given until all reactions resulting from the previous dose have disappeared.

The starting dose should be based on skin tests of the extract to be used for immunotherapy. To determine the starting dose, begin intradermal testing with the most dilute extract preparation. Inject 0.02 mL and read the reaction after 15 minutes. Intradermal testing is continued with increasing concentrations of the extract until a reaction of 10-20 mm erythema ( ∑ E 0-40 mm) and/or a 5 mm wheal occurs. This concentration at a dose of 0.03 mL then can serve as a starting dose for immunotherapy. Subsequent doses can be increased by 0.03 mL to as high as 0.12 mL increments each time until 0.3 mL is reached, at which time a dilution 10 times as strong can be used, starting with 0.03 mL. Proceed in this way until a tolerance dose is reached or symptoms are controlled. Suggested maintenance dose for a pollen extract is 0.2 mL of the Concentrate, while for a non-pollen extract the maximum suggested dose is 0.5 mL of the Concentrate. Occasionally, higher doses are necessary to relieve symptoms. Special caution is required in administering doses greater than 0.2 mL. The interval between doses is normally 3 to 7 days during dose building regimen.

Normally immunotherapy can be started with a 1:100,000 dilution of extracts labeled in weight/volume. Certain therapeutic mixtures are labeled as Concentrate, (v/v) dilutions of Concentrate, Amb a 1, Allergy units/mL or Bioequivalent Allergy Units/mL. (See DESCRIPTION.) Strength of each antigen in the mixture is indicated in the product labeling. For beginning treatment, use at least a 1,000-fold dilution of the Concentrate extract for non-pollens, and at least a 10,000-fold dilution of the Concentrate extract for pollens.

In some patients, the dosage may be increased more rapidly than recommended above. In seasonal allergies, treatment should be started and the interval between doses regulated so that at least the first twenty doses will have been administered by the time symptoms are expected. Thus, the shorter the interval between the start of immunotherapy and the expected onset of symptoms, the shorter the interval between each dose. Some patients may even tolerate daily doses.

Should symptoms develop before the next injection is scheduled, the interval between doses should be decreased. Should allergic symptoms or local reactions develop shortly after the dose is administered, the size of the dose should be decreased. In seasonal allergies, it is often advisable to decrease the dose to one-half or one-quarter of the maximum dose previously attained if the patient has any seasonal symptoms.

A maintenance dose, the largest dose tolerated by the patient that relieves symptoms without producing undesirable local or general reactions, is recommended for most patients. The upper limits of dosage have not been established; however, doses larger than 0.2 mL of extract may be painful if glycerin is present. The dosage of allergenic extract does not vary significantly with the respiratory allergic disease under treatment. The size of this dose and the interval between doses will vary and can be adjusted as necessary.

The interval between maintenance doses can be increased gradually from one week to 10 days, to two weeks, to three weeks, or even to four weeks, if tolerated. Repeat the doses at a given interval three or four times to check for untoward reactions before further increasing the interval. Protection is lost rapidly if the interval between doses is more than four weeks. (See WARNINGS.)

The usual duration of treatment has not been established. A period of two or three years of injection therapy constitutes an average minimum course of treatment.

2. Pediatric Use

The dose for the pediatric population is the same as for adults.

3. Geriatric Use

The dose for elderly patients is the same as for adult patients under 65.36

HOW SUPPLIED

In 10 mL, 30 mL and 50 mL vials at the w/v, Concentrate, v/v dilution of Concentrate, AU/mL (Standardized Mite Extracts: D. farinae, D. pteronyssinus 10,000 and 30,000 AU/mL; Mite Mixtures: 5,000 AU/mL each species, or 15,000 AU/mL each species), BAU/mL (Standardized Cat Hair and Cat Pelt extracts: 10,000 BAU/mL; Standardized Grass extracts: 10,000 and 100,000 BAU/mL); Amb a 1 units/mL; or PNU/mL ordered by the physician. Please see the current Allergy Product Catalog.

STORAGE AND HANDLING

The expiration date is listed on the container label. To ensure the maximum potency, the extract and its dilutions should be stored at 2° - 8°C, and kept in this temperature range at all times, even during use. Dilutions are less stable than concentrates. If loss of potency is suspected, dilutions should be checked by skin testing with equal v/v dilutions of a freshly prepared dilution on individuals known to be allergic to the specific allergen.

LIMITED WARRANTY

A number of factors beyond our control could reduce the efficacy of this product or even result in an ill effect following its use. These include storage and handling of the product after it leaves our hands, diagnosis, dosage, method of administration and biological differences in individual patients. Because of these factors, it is important that this product be stored properly and that the directions be followed carefully during use. No warranty, express or implied, including any warranty of merchantability or fitness, is made. Representatives of the Company are not authorized to vary the terms or the contents of any printed labeling, including the package insert, for this product except by printed notice from the Company's headquarters. The prescriber and user of this product must accept the terms hereof.

REFERENCES

1. Lockey, R.F., L.M. Benedict, P.C. Turkletaub, S.C. Bukantz. Fatalities from immunotherapy (IT) and skin testing (ST). J. Allergy Clin. Immunol., 79 (4): 660-677, 1987.

2. Jacobs, R.L., G.W. Rake, Jr., et al. Potentiated anaphylaxis in patients with drug-induced beta-adrenergic blockade. J. Allergy Clin. Immunol., 68 (2): 125-127, August 1981.

3. Griffith, I.J., J. Pollock, D.G. Klapper, B.L. Rogers and A.K. Nault. Sequence Polymorphism of Amb a I and Amb a II, the Major Allergens in Ambrosia artemisiifolia (Short Ragweed). Int. Arch. Allergy Apply. Immunol., 96: 296-304, 1991.

4. Underdown, B. J. and L. Goodfriend. Isolation and characterization of an allergen from short ragweed pollen. Biochem. 8 (3): 980-989, 1969.

5. Griffiths, B. W and R. Brunet. Isolation of a basic protein antigen of low ragweed pollen. Can. J. Biochem. 49 (3): 396-400, 1971.

6. Lapkoff, C. B. and L. Goodfriend. Isolation of a low molecular weight ragweed allergen: Ra5. Int. Arch. Allergy Appl. Immunol. 46 (2): 215-229, 1974.

7. Hussain, R. and D. G. March. Characterization and allergenic activity of ragweed allergens Ra6, Ra7, Ra8. J. Allergy Clin. Immunol. 65 (3): 230, abstr. 218, 1980

8. Goodfriend, L., A. M. Choudhury, J. Del Carpio and T. P. King. Cytochrome C: New ragweed pollen allergen. Fed. Proc. 38 (3, part II): 1415, abstr. 6261, 1979.

9. Turkeltaub, P.C., MD, and S.C. Rastogi, PhD. Quantitative intradermal test procedure for evaluation of subject sensitivity to standardized allergenic extracts and for assignment of bioequivalent allergy units to reference preparations using the ID₅₀EAL method. Allergenics Products Testing Laboratory, Center for Biologics Evaluation and Research (CBER), FDA. Revised: November, 1994.

10. Norman, P. S. Postgraduate Course Presentation. An overview of immunotherapy, implications for the future. J. Allergy Clin. Immunol., 65 (2): 87-96, 1980.

11. Lowell, F. C. and W. Franklin. A "double-blind" study of treatment with aqueous allergenic extracts in cases of allergic rhinitis. J. Allergy, 34 (2):165-182, 1963.

12. Lowell, F. C. and W. Franklin. A double-blind study of the effectiveness and specificity of injection therapy in ragweed hay fever. N. Eng. J. Med. 273 (13): 675-679, 1965.

13. Zavazal, V. and A. Stajner. Immunologic changes during specific treatment of the atopic state. II. Acta. Allergol. 25 (1): 11-17, 1970.

14. Reisman, R. E., J. I. Wypych, and E. E. Arbesman. Relationship of immunotherapy, seasonal pollen exposure and clinical response to serum concentrations of total IgE and ragweed-specific IgE. Int. Arch. Allergy Appl. Immunol. 48 (6): 721-730, 1975.

15. Taylor, W. W., J. L. Ohman, F. C. Lowell. Immunotherapy in cat-induced asthma; double-blind trial with evaluation of bronchial responses to cat allergen and histamine. J. Allergy Clin. Immunol., 61 (5): 283-287, 1978.

16. Smith, A. P. Hyposensitization with Dermatophagoides pteronyssinus antigen: Trial in asthma induced by house dust. Br. Med. J., 4: 204-206, 1971.

17. Chapman, M. D., T. A. E. Platts-Mills, M. Gabriel, H. K. Ng, W. G. L. Allen, L. E.Hill, A. J. Nunn. Antibody response following prolonged hyposensitization with Dermatophagoides pteronyssinus extract. Int. Arch. Allergy Appl. Immunol., 61:431-440, 1980.

18. Norman, P. S., W. L. Winkenwerder. Maintenance immunotherapy in ragweed hay fever. J. Allergy, 74: 273-282, 1971.

19. Norman, P. S., W. L. Winkenwerder, L. M. Lichtenstein. Immunotherapy of hay fever with ragweed Antigen E; comparisons with whole pollen extract and placebos. J. Allergy, 42: 93-108, 1968.

20. Middleton, E., C. E. Reed and E. F. Ellis, editors. Allergy Principles and Practice. C. V. Mosby Co., St. Louis, 1978, pp. 877-898.

21. Sheldon, J. M., R. G. Lovell and K. P. Mathews. A Manual of Clinical Allergy, Second Edition. W. B. Saunders. Philadelphia, 1967, pp. 107-112.

22. Sherman, W. B. Hypersensitivity Mechanisms and Management. W. B. Saunders. Philadelphia, 1968, pp. 169-172.

23. Swineford, O. Asthma and Hay Fever. Charles C. Thomas. Springfield, IL, 1971, pp. 148-155.

24. Reid, M.J., R.F. Lockey, P.C. Turkletaub, T.A.E., Platts-Mills. Survey of fatalities from skin testing and immunotherapy. J. 0 Clin. Immunol. 92 (1): 6-15, July 1993.

25. Reid, M.J., G. Gurka. Deaths associated with skin testing and immunotherapy. J. Allergy Clin. Immunol. 97(1) Part 3:231, Abstract 195, January 1996.

26. Thompson, R.A., et al, report of a WHO/IUIS working group. The current status of allergen immunotherapy (hyposensitization). Allergy. 44: 369-379, 1989.

27. Malling, H.J., B. Weeke, et al, The European Academy of Allergology and Clinical Immunology. Position Papers. Allergy. 48 (Supplement 14): 9-82, 1993.

28. Pipkorn, U. Pharmacological influence of anti-allergic medication on In Vivo allergen testing. Allergy. 43: 81-86,1988.

29. Andersson, M. and U. Pipkorn. Inhibition of the dermal immediate allergic reaction through prolonged treatment with topical glucocorticosteroids. J. Allergy Clin. Immunol. 79 (2): 345-349, February 1987.

30. Rao, K.S., et al. Duration of suppressive effect of tricyclic anti-depressants on histamine induced wheal and flare reactions on human skin. J. Allergy Clin. Immunol. 82: 752-757, November 1988.

31. Pipkorn, U., and M. Andersson. Topical dermal anesthesia inhibits the flare but not the wheal response to allergen and histamine in the skin prick test. Clinical Allergy. 17: 307-311, 1987.

32. DuBuske, L.M., C.J. Ling and A.L. Sheffer. Special problems regarding allergen immunotherapy. Immunol. Allergy Clin. North Am. (USA). 12(1): 145-175, 1992.

33. Li, J.T., R.F. Lockey, I.L. Bernstein, J.M. Ortnoy, R.A. Nicklas. Allergen Immunotherapy: A Practice Parameter. Ann. Allergy, Asthma and Immunotherapy 90 (1): 26, 2003.

34. Patterson, R., et al. Allergy Principles and Practice, 2nd ed. E. Middleton, Jr., C. E. Reed, E. F. Ellis, Ed., C. V. Mosby Co., 1983, St. Louis, MO, 1983, Chapter 52

35. Levy, D. A., L. M. Lichtenstein, E. O. Goldstein, and K. Ishizaka. Immunologic and cellular changes accompanying the therapy of pollen allergy. J. Clinical Investigation, 50:360, 1971.

36. Peebles, R.S., Jr., B. Bochner, Howard J. Zeitz, ed. Anaphylaxis in the elderly. Immunology and Allergy Clinics of North America. 13 (3): 627-646, August 1993.

37. Turkeltaub, P.C., MD, and P.J. Gergen, MD. The risk of adverse reactions from percutaneous prick-puncture allergen skin testing, venipuncture, and body measurements: Data from the second National Health and Nutrition Examination Survey 1976-80 (NHANES II). J. Allergy Clin. Immunol. 84(6): 886-890, Dec. 1989.

Tryptophan:

• Nutriflex Lipid Peri (Tryptophan) reviews

In Canada, Nutriflex Lipid Peri (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. Nutriflex Lipid Peri (Tryptophan) is a natural substance (amino acid) found in high-protein foods and milk. In the US, Nutriflex Lipid Peri (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 Nutriflex Lipid Peri (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.

Zinc Acetate Dihydrate:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Overdosage
• Dosage and administration
• How supplied
• Nutriflex Lipid Peri (Zinc Acetate Dihydrate) reviews

INDICATIONS AND USAGE

Nutriflex Lipid Peri (Zinc Acetate Dihydrate) 1 mg/mL (Zinc Chloride Injection, USP) is indicated for use as a supplement to intravenous solutions given for TPN. Administration helps to maintain Nutriflex Lipid Peri (Zinc Acetate Dihydrate) serum levels and to prevent depletion of endogenous stores, and subsequent deficiency symptoms.

CONTRAINDICATIONS

None known.

WARNINGS

Direct intramuscular or intravenous injection of Nutriflex Lipid Peri (Zinc Acetate Dihydrate) 1 mg/mL (Zinc Chloride Injection, USP) is contraindicated as the acidic pH of the solution (2) may cause considerable tissue irritation.

Severe kidney disease may make it necessary to reduce or omit chromium and Nutriflex Lipid Peri (Zinc Acetate Dihydrate) doses because these elements are primarily eliminated in the urine.

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

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

PRECAUTIONS

General

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

Zinc 1 mg/mL should only be used in conjunction with a pharmacy directed admixture program using aseptic technique in a laminar flow environment; it should be used promptly and in a single operation without any repeated penetrations. Solution contains no preservatives; discard unused portion immediately after admixture procedure is completed.

Zinc should not be given undiluted by direct injection into a peripheral vein because of the likelihood of infusion phlebitis and the potential for increased excretory loss of Nutriflex Lipid Peri (Zinc Acetate Dihydrate) from a bolus injection. Administration of Nutriflex Lipid Peri (Zinc Acetate Dihydrate) in the absence of copper may cause a decrease in serum copper levels.

Laboratory Tests

Periodic determinations of serum copper as well as Nutriflex Lipid Peri (Zinc Acetate Dihydrate) are suggested as a guideline for subsequent Nutriflex Lipid Peri (Zinc Acetate Dihydrate) administration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of Nutriflex Lipid Peri 1 mg/mL (Zinc Chloride Injection, USP) have not been performed, nor have studies been done to assess mutagenesis or impairment of fertility.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Nutriflex Lipid Peri (Zinc Acetate Dihydrate) 1 mg/mL (Zinc Chloride Injection, USP) is administered to a nursing woman.

Pediatric Use

Pregnancy Category C. Animal reproduction studies have not been conducted with Nutriflex Lipid Peri chloride. It is also not known whether Nutriflex Lipid Peri (Zinc Acetate Dihydrate) chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Nutriflex Lipid Peri (Zinc Acetate Dihydrate) chloride should be given to a pregnant woman only if clearly needed.

Geriatric Use

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

ADVERSE REACTIONS

None known.

DRUG ABUSE AND DEPENDENCE

None known.

OVERDOSAGE

Single intravenous doses of 1 to 2 mg zinc/kg body weight have been given to adult leukemic patients without toxic manifestations. However, acute toxicity was reported in an adult when 10 mg Nutriflex Lipid Peri (Zinc Acetate Dihydrate) was infused over a period of one hour on each of four consecutive days. Profuse sweating, decreased level of consciousness, blurred vision, tachycardia (140/min), and marked hypothermia (94.2° F) on the fourth day were accompanied by a serum Nutriflex Lipid Peri (Zinc Acetate Dihydrate) concentration of 207 mcg/dl. Symptoms abated within three hours.

Hyperamylasemia may be a sign of impending Nutriflex Lipid Peri (Zinc Acetate Dihydrate) overdosage; patients receiving an inadvertent overdose (25 mg zinc/liter of TPN solution, equivalent to 50 to 70 mg zinc/day) developed hyperamylasemia (557 to 1850 Klein units; normal: 130 to 310).

Death resulted from an overdosage in which 1683 mg Nutriflex Lipid Peri (Zinc Acetate Dihydrate) was delivered intravenously over the course of 60 hours to a 72 year old patient.

Symptoms of Nutriflex Lipid Peri (Zinc Acetate Dihydrate) toxicity included hypotension (80/40 mm Hg), pulmonary edema, diarrhea, vomiting, jaundice, and oliguria, with a serum Nutriflex Lipid Peri (Zinc Acetate Dihydrate) level of 4184 mcg/dl.

Calcium supplements may confer a protective effect against Nutriflex Lipid Peri (Zinc Acetate Dihydrate) toxicity.

DOSAGE AND ADMINISTRATION

Nutriflex Lipid Peri (Zinc Acetate Dihydrate) 1 mg/mL (Zinc Chloride Injection, USP) contains 1 mg zinc/mL and is administered intravenously only after dilution. The additive should be diluted prior to administration in a volume of fluid not less than 100 mL. For the metabolically stable adult receiving TPN, the suggested intravenous dosage is 2.5 to 4 mg zinc/day (2.5 to 4 mL/day). An additional 2 mg zinc/day (2 mL/day) is suggested for acute catabolic states. For the stable adult with fluid loss from the small bowel, an additional 12.2 mg zinc/liter of small bowel fluid lost (12.2 mL/liter of small bowel fluid lost), or an additional 17.1 mg zinc/kg of stool or ileostomy output (17.1 mL/kg of stool or ileostomy output) is recommended. Frequent monitoring of Nutriflex Lipid Peri (Zinc Acetate Dihydrate) blood levels is suggested for patients receiving more than the usual maintenance dosage level of Nutriflex Lipid Peri (Zinc Acetate Dihydrate).

For full term infants and children up to 5 years of age, 100 mcg zinc/kg/day (0.1 mL/kg/day) is recommended. For premature infants (birth weight less than 1500 g) up to 3 kg in body weight, 300 mcg zinc/kg/day (0.3 mL/kg/day) is suggested.

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

HOW SUPPLIED

Nutriflex Lipid Peri (Zinc Acetate Dihydrate) 1 mg/mL (Zinc Chloride Injection, USP) is supplied in 10 mL Plastic Vials (List No. 4090).

Store at 20 to 25°C (68 to 77°F).

Revised: October, 2004

© Hospira 2004 EN-0488 Printed in USA

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

10 mL Vial

Nutriflex Lipid Peri (Zinc Acetate Dihydrate)

1 mg/mL

Nutriflex Lipid Peri (Zinc Acetate Dihydrate) Chloride Inj., USP

Rx only

FOR I.V. USE ONLY AFTER DILUTION.

HOSPIRA, INC., LAKE FOREST, IL 60045 USA