Olimel 5.7% E

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
• Olimel 5.7% E (Calcium Chloride Dihydrate) reviews

1 INDICATIONS AND USAGE

Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (Calcium Chloride Dihydrate) acetate capsule.

- Capsule: 667 mg Olimel 5.7% E (Calcium Chloride Dihydrate) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Olimel 5.7% E acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Olimel 5.7% E (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 Olimel 5.7% E (Calcium Chloride Dihydrate), including Olimel 5.7% E (Calcium Chloride Dihydrate) acetate. Avoid the use of Olimel 5.7% E (Calcium Chloride Dihydrate) supplements, including Olimel 5.7% E (Calcium Chloride Dihydrate) based nonprescription antacids, concurrently with Olimel 5.7% E (Calcium Chloride Dihydrate) acetate.

An overdose of Olimel 5.7% E (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 Olimel 5.7% E (Calcium Chloride Dihydrate) levels twice weekly. Should hypercalcemia develop, reduce the Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (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, Olimel 5.7% E (Calcium Chloride Dihydrate) acetate has been generally well tolerated.

Olimel 5.7% E (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 Olimel 5.7% E (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.

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 Olimel 5.7% E (Calcium Chloride Dihydrate) concentration could reduce the incidence and severity of Olimel 5.7% E (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 Olimel 5.7% E (Calcium Chloride Dihydrate) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Olimel 5.7% E acetate is characterized by the potential of Olimel 5.7% E (Calcium Chloride Dihydrate) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Olimel 5.7% E (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 Olimel 5.7% E (Calcium Chloride Dihydrate) acetate and most concomitant drugs. When administering an oral medication with Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (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:

Olimel 5.7% E acetate capsules contains Olimel 5.7% E (Calcium Chloride Dihydrate) acetate. Animal reproduction studies have not been conducted with Olimel 5.7% E (Calcium Chloride Dihydrate) acetate, and there are no adequate and well controlled studies of Olimel 5.7% E (Calcium Chloride Dihydrate) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Olimel 5.7% E (Calcium Chloride Dihydrate) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Olimel 5.7% E (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. Olimel 5.7% E (Calcium Chloride Dihydrate) acetate treatment, as recommended, is not expected to harm a fetus if maternal Olimel 5.7% E (Calcium Chloride Dihydrate) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Olimel 5.7% E (Calcium Chloride Dihydrate) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Olimel 5.7% E Acetate Capsules contains Olimel 5.7% E (Calcium Chloride Dihydrate) acetate and is excreted in human milk. Human milk feeding by a mother receiving Olimel 5.7% E (Calcium Chloride Dihydrate) acetate is not expected to harm an infant, provided maternal serum Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (Calcium Chloride Dihydrate) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Olimel 5.7% E (Calcium Chloride Dihydrate) acetate acts as a phosphate binder. Its chemical name is Olimel 5.7% E (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 Olimel 5.7% E (Calcium Chloride Dihydrate) acetate USP (anhydrous; Ca(CH₃COO)₂; MW=158.17 grams) equal to 169 mg (8.45 mEq) Olimel 5.7% E (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.

Olimel 5.7% E (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 Olimel 5.7% E resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Olimel 5.7% E (Calcium Chloride Dihydrate) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Olimel 5.7% E (Calcium Chloride Dihydrate) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Olimel 5.7% E (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 Olimel 5.7% E (Calcium Chloride Dihydrate) acetate.

14 CLINICAL STUDIES

Effectiveness of Olimel 5.7% E (Calcium Chloride Dihydrate) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (Calcium Chloride Dihydrate) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Olimel 5.7% E (Calcium Chloride Dihydrate) levels are also presented.

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 Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (Calcium Chloride Dihydrate) acetate is shown in the Table 3.

Overall, 2 weeks of treatment with Olimel 5.7% E (Calcium Chloride Dihydrate) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Olimel 5.7% E (Calcium Chloride Dihydrate) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Olimel 5.7% E (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 Olimel 5.7% E (Calcium Chloride Dihydrate) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Olimel 5.7% E (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 Olimel 5.7% E (Calcium Chloride Dihydrate) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Glycerol:

• 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
• Olimel 5.7% E (Glycerol) reviews

Olimel 5.7% E (Glycerol) is indicated for use as a nitrogen-binding agent for chronic management of patients 2 months of age and older with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. Olimel 5.7% E (Glycerol) must be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements).

Limitations of Use:

• Olimel 5.7% E (Glycerol) is not indicated for the treatment of acute hyperammonemia in patients with UCDs because more rapidly acting interventions are essential to reduce plasma ammonia levels.
• The safety and efficacy of Olimel 5.7% E (Glycerol) for the treatment of N-acetylglutamate synthase (NAGS) deficiency has not been established.

Olimel 5.7% E (Glycerol) is a nitrogen-binding agent indicated for chronic management of patients 2 months of age and older with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. Olimel 5.7% E (Glycerol) must be used with dietary protein restriction and, in some cases, dietary supplements. (1)

Limitations of Use:

• Olimel 5.7% E (Glycerol) is not indicated for treatment of acute hyperammonemia in patients with UCDs. (1)
• Safety and efficacy for treatment of N-acetylglutamate synthase (NAGS) deficiency has not been established. (1)

2 DOSAGE AND ADMINISTRATION

• Olimel 5.7% E should be prescribed by a physician experienced in management of UCDs. For administration and preparation, see full prescribing information. (2.1, 2.6)

Switching From Sodium Phenylbutyrate Tablets or Powder to Olimel 5.7% E (Glycerol):

• Patients should receive the dosage of Olimel 5.7% E (Glycerol) that contains the same amount of phenylbutyric acid, see full prescribing information for conversion. (2.2)

Initial Dosage in Phenylbutyrate-Naïve Patients (2.3):

• Recommended dosage range is 4.5 to 11.2 mL/m²/day (5 to 12.4 g/m²/day).
• For patients with some residual enzyme activity not adequately controlled with dietary restriction, the recommended starting dose is 4.5 mL/m²/day.
• Take into account patient's estimated urea synthetic capacity, dietary protein intake, and diet adherence.

Dosage Adjustment and Monitoring:

• Follow plasma ammonia levels to determine the need for dosage titration. (2.4)

Dosage Modifications in Patients with Hepatic Impairment:

• Start dosage at lower end of range. (2.5, 8.6)

2.1 Important Administration Instructions

Olimel 5.7% E (Glycerol) should be prescribed by a physician experienced in the management of UCDs.

• Instruct patients to take Olimel 5.7% E (Glycerol) with food or formula and to administer directly into the mouth via oral syringe or dosing cup.
• For patients who cannot swallow, see the instructions on administration of Olimel 5.7% E (Glycerol) by nasogastric tube or gastrostomy tube .
• For patients who require a volume of less than 1 mL per dose via nasogastric or gastrostomy tube, the delivered dose may be less than anticipated. Closely monitor these patients using ammonia levels .
• The recommended dosages for patients switching from sodium phenylbutyrate to Olimel 5.7% E (Glycerol) and patients naïve to phenylbutyric acid are different . For both subpopulations:
  • Patients 2 years of age and older: Give Olimel 5.7% E (Glycerol) in 3 equally divided dosages, each rounded up to the nearest 0.5 mL
  • Patients 2 months of age to less than 2 years: Give Olimel 5.7% E (Glycerol) in 3 or more equally divided dosages, each rounded up to the nearest 0.1 mL.
  • The maximum total daily dosage is 17.5 mL (19 g).
  • Olimel 5.7% E (Glycerol) must be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements).

2.2 Switching From Sodium Phenylbutyrate to Olimel 5.7% E

Patients switching from sodium phenylbutyrate to Olimel 5.7% E (Glycerol) should receive the dosage of Olimel 5.7% E (Glycerol) that contains the same amount of phenylbutyric acid. The conversion is as follows:

Total daily dosage of Olimel 5.7% E (Glycerol) (mL) = total daily dosage of sodium phenylbutyrate tablets (g) × 0.86

Total daily dosage of Olimel 5.7% E (Glycerol) (mL) = total daily dosage of sodium phenylbutyrate powder (g) × 0.81

2.3 Initial Dosage in Phenylbutyrate-Naïve Patients

The recommended dosage range, based upon body surface area, in patients naïve to phenylbutyrate is 4.5 to 11.2 mL/m²/day (5 to 12.4 g/m²/day). For patients with some residual enzyme activity who are not adequately controlled with protein restriction, the recommended starting dosage is 4.5 mL/m²/day.

In determining the starting dosage of Olimel 5.7% E (Glycerol) in treatment-naïve patients, consider the patient's residual urea synthetic capacity, dietary protein requirements, and diet adherence. Dietary protein is approximately 16% nitrogen by weight. Given that approximately 47% of dietary nitrogen is excreted as waste and approximately 70% of an administered PBA dose will be converted to urinary phenylacetylglutamine (U-PAGN), an initial estimated Olimel 5.7% E (Glycerol) dose for a 24-hour period is 0.6 mL Olimel 5.7% E (Glycerol) per gram of dietary protein ingested per 24-hour period. The total daily dosage should not exceed 17.5 mL.

2.4 Dosage Adjustment and Monitoring

During treatment with Olimel 5.7% E (Glycerol), patients should be followed clinically and with plasma ammonia levels to determine the need for dosage titration. Closely monitor ammonia levels after changing the dosage of Olimel 5.7% E (Glycerol).

Normal Ammonia Levels

If patients experience symptoms of vomiting, nausea, headache, somnolence or confusion in the absence of high ammonia levels or other intercurrent illnesses, reduce the Olimel 5.7% E (Glycerol) dosage and monitor patients clinically. If available, obtain measurements of plasma phenylacetate (PAA) concentrations and the ratio of plasma PAA to PAGN to guide dosing. A high PAA to PAGN ratio may indicate the saturation of the conjugation reaction to form PAGN. The PAA to PAGN ratio has been observed to be generally less than 1 in patients with UCDs without significant PAA accumulation .

Elevated Ammonia Levels

When plasma ammonia is elevated, increase the Olimel 5.7% E (Glycerol) dosage to reduce the fasting ammonia level to less than half the upper limit of normal (ULN) in patients 6 years and older. In infants and pediatric patients (generally below 6 years of age), where obtaining fasting ammonia is problematic due to frequent feedings, adjust the dosage to keep the first ammonia of the morning below the ULN.

Urinary Phenylacetylglutamine: If available, U-PAGN measurements may be used to help guide Olimel 5.7% E (Glycerol) dosage adjustment. Each gram of U-PAGN excreted over 24 hours covers waste nitrogen generated from 1.4 grams of dietary protein. If U-PAGN excretion is insufficient to cover daily dietary protein intake and the fasting ammonia is greater than half the ULN, the Olimel 5.7% E (Glycerol) dosage should be adjusted upward. The amount of dosage adjustment should factor in the amount of dietary protein that has not been covered, as indicated by the 24-hour U-PAGN level and the estimated Olimel 5.7% E (Glycerol) dose needed per gram of dietary protein ingested and the maximum total daily dosage (i.e., 17.5 mL).

Consider a patient's use of concomitant medications, such as probenecid, when making dosage adjustment decisions based on U-PAGN. Probenecid may result in a decrease of the urinary excretion of PAGN .

Plasma Phenylacetate and Phenylacetylglutamine: If available, the ratio of PAA to PAGN in plasma may provide additional information to assist in dosage adjustment decisions. In patients with a high PAA to PAGN ratio, a further increase in Olimel 5.7% E (Glycerol) dosage may not increase PAGN formation, even if plasma PAA concentrations are increased, due to saturation of the conjugation reaction .

2.5 Dosage Modifications in Patients with Hepatic Impairment

For patients with moderate to severe hepatic impairment, the recommended starting dosage is at the lower end of the recommended dosing range and kept at the lowest dose necessary to control the patient's ammonia levels .

2.6 Preparation for Nasogastric Tube or Gastrostomy Tube Administration

It is recommended that all patients who can swallow take Olimel 5.7% E (Glycerol) orally, even those with nasogastric and/or gastrostomy tubes. However, for patients who cannot swallow, a nasogastric tube or gastrostomy tube may be used to administer Olimel 5.7% E (Glycerol) as follows:

• Utilize an oral syringe to withdraw the prescribed dosage of Olimel 5.7% E (Glycerol) from the bottle.
• Place the tip of the syringe into the nasogastric/gastrostomy tube.
• Utilizing the plunger of the syringe, administer Olimel 5.7% E (Glycerol) into the tube.
• Flush once with 10 mL of water or formula and allow the flush to drain.
• If needed, flush a second time with an additional 10 mL of water or formula to clear the tube.

For patients who require a volume of less than 1 mL per dose via nasogastric or gastrostomy tube, the delivered dosage may be less than anticipated due to adherence of Olimel 5.7% E (Glycerol) to the plastic tubing. Therefore, these patients should be closely monitored using ammonia levels following initiation of Olimel 5.7% E (Glycerol) dosing or dosage adjustments.

3 DOSAGE FORMS AND STRENGTHS

Oral liquid: colorless to pale yellow, 1.1 g/mL of Olimel 5.7% E (Glycerol) phenylbutyrate (delivers 1.02 g/mL of phenylbutyrate).

Oral liquid: 1.1 g/mL. (3)

4 CONTRAINDICATIONS

Olimel 5.7% E (Glycerol) is contraindicated in patients

• Less than 2 months of age. Pediatric patients less than 2 months of age may have immature pancreatic exocrine function, which could impair hydrolysis of Olimel 5.7% E (Glycerol), leading to impaired absorption of phenylbutyrate and hyperammonemia .
• With known hypersensitivity to phenylbutyrate. Signs of hypersensitivity include wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash.

• Patients less than 2 months of age. (4)
• Known hypersensitivity to phenylbutyrate. (4)

5 WARNINGS AND PRECAUTIONS

• Neurotoxicity: Phenylacetate, the active moiety of Olimel 5.7% E (Glycerol), may be toxic; reduce dosage for symptoms of neurotoxicity. (5.1)
• Reduced Phenylbutyrate Absorption in Pancreatic Insufficiency or Intestinal Malabsorption: Monitor ammonia levels closely. (5.2)

5.1 Neurotoxicity

The major metabolite of Olimel 5.7% E (Glycerol), PAA, is associated with neurotoxicity. Signs and symptoms of PAA neurotoxicity, including somnolence, fatigue, lightheadedness, headache, dysgeusia, hypoacusis, disorientation, impaired memory, and exacerbation of preexisting neuropathy, were observed at plasma PAA concentrations of 500 micrograms/mL in a study of adult cancer patients who were administered PAA intravenously. In this study, adverse reactions were reversible.

In healthy subjects, after administration of 4 mL and 6 mL Olimel 5.7% E (Glycerol) 3 times daily for 3 days, a dose-dependent increase in all-grade nervous system adverse reactions was observed, even at exposure levels of PAA less than 100 micrograms/mL.

In clinical trials in patients with UCDs who had been on sodium phenylbutyrate prior to administration of Olimel 5.7% E (Glycerol), peak PAA concentrations after dosing with Olimel 5.7% E (Glycerol) ranged from 1.6 to 178 micrograms/mL (mean: 39 micrograms/mL) in adult patients, from 1 to 410 micrograms/mL (mean: 70 micrograms/mL; median: 50 micrograms/mL) in pediatric patients ages 2 years and older, and from 1 to 1215 micrograms/mL (mean: 142 micrograms/mL; median: 35 micrograms/mL) in pediatric patients ages 2 months to less than 2 years. Some patients with UCDs experienced headache, fatigue, symptoms of peripheral neuropathy, seizures, tremor and/or dizziness. No correlation between PAA levels and neurotoxicity symptoms was identified but PAA levels were generally not measured at the time of neurotoxicity symptoms.

If symptoms of vomiting, nausea, headache, somnolence or confusion, are present in the absence of high ammonia or other intercurrent illnesses, reduce the Olimel 5.7% E (Glycerol) dosage .

5.2 Reduced Phenylbutyrate Absorption in Pancreatic Insufficiency or Intestinal Malabsorption

Exocrine pancreatic enzymes hydrolyze Olimel 5.7% E (Glycerol) in the small intestine, separating the active moiety, phenylbutyrate, from Olimel 5.7% E (Glycerol). This process allows phenylbutyrate to be absorbed into the circulation. Low or absent pancreatic enzymes or intestinal disease resulting in fat malabsorption may result in reduced or absent digestion of Olimel 5.7% E (Glycerol) and/or absorption of phenylbutyrate and reduced control of plasma ammonia. Monitor ammonia levels closely in patients with pancreatic insufficiency or intestinal malabsorption.

6 ADVERSE REACTIONS

Most common adverse reactions in adults are: diarrhea, flatulence, and headache. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Horizon Therapeutics at 1-855-823-7878 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials 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 clinical practice.

Assessment of adverse reactions was based on exposure of 45 adult patients (31 female and 14 male) with UCD subtype deficiencies of ornithine transcarbamylase (OTC, n=40), carbamyl phosphate synthetase (CPS, n=2), and argininosuccinate synthetase (ASS, n=1) in a randomized, double-blind, active-controlled (RAVICTI vs sodium phenylbutyrate), crossover, 4-week study (Study 1) that enrolled patients 18 years of age and older . One of the 45 patients received only sodium phenylbutyrate prior to withdrawing on day 1 of the study due to an adverse reaction.

The most common adverse reactions (occurring in at least 10% of patients) reported during short-term treatment with Olimel 5.7% E (Glycerol) were diarrhea, flatulence, and headache. Table 1 summarizes adverse reactions occurring in 2 or more patients treated with Olimel 5.7% E (Glycerol) or sodium phenylbutyrate (incidence of at least 4% in either treatment arm).

Other Adverse Reactions

Olimel 5.7% E (Glycerol) has been evaluated in 77 patients with UCDs (51 adult and 26 pediatric patients ages 2 years to 17 years) in 2 open-label long-term studies, in which 69 patients completed 12 months of treatment with Olimel 5.7% E (Glycerol) (median exposure = 51 weeks). During these studies there were no deaths.

Adverse reactions occurring in at least 10% of adult patients were nausea, vomiting, diarrhea, decreased appetite, dizziness, headache, and fatigue.

Adverse reactions occurring in at least 10% of pediatric patients ages 2 years to 17 years were upper abdominal pain, rash, nausea, vomiting, diarrhea, decreased appetite, and headache.

Olimel 5.7% E (Glycerol) has also been evaluated in 17 patients with UCDs ages 2 months to less than 2 years in 3 open-label studies. The median exposure was 6 months (range 0.2 to 18 months). Adverse reactions occurring in at least 10% of pediatric patients aged 2 months to less than 2 years were neutropenia, vomiting, diarrhea, pyrexia, hypophagia, cough, nasal congestion, rhinorrhea, rash and papule.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Olimel 5.7% E (Glycerol). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

• Abnormal body odor, including from skin, hair and urine
• Retching and gagging
• Dysgeusia or burning sensation in mouth

7 DRUG INTERACTIONS

• Corticosteroids, valproic acid, or haloperidol: May increase plasma ammonia level; monitor ammonia levels closely.
• Probenecid: May affect renal excretion of metabolites of Olimel 5.7% E (Glycerol), including phenylacetylglutamine (PAGN) and PAA. (7.2)
• CYP3A4 Substrates with narrow therapeutic index (e.g., alfentanil, quinidine, cyclosporine): Olimel 5.7% E (Glycerol) may decrease exposure; monitor for decreased efficacy of the narrow therapeutic index drug. (7.3)
• Midazolam: Decreased exposure; monitor for suboptimal effect of midazolam. (7.3)

7.1 Potential for Other Drugs to Affect Ammonia

Corticosteroids

Use of corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels. Monitor ammonia levels closely when corticosteroids and Olimel 5.7% E (Glycerol) are used concomitantly.

Valproic Acid and Haloperidol

Hyperammonemia may be induced by haloperidol and by valproic acid. Monitor ammonia levels closely when use of valproic acid or haloperidol is necessary in patients with UCDs.

7.2 Potential for Other Drugs to Affect Olimel 5.7% E

Probenecid

Probenecid may inhibit the renal excretion of metabolites of Olimel 5.7% E (Glycerol) including PAGN and PAA.

7.3 Potential for Olimel 5.7% E to Affect Other Drugs

Drugs with narrow therapeutic index that are substrates of CYP3A4

Olimel 5.7% E (Glycerol) is a weak inducer of CYP3A4 in humans. Concomitant use of Olimel 5.7% E (Glycerol) may decrease the systemic exposure to drugs that are substrates of CYP3A4. Monitor for decreased efficacy of drugs with narrow therapeutic index (e.g., alfentanil, quinidine, cyclosporine) .

Midazolam

Concomitant use of Olimel 5.7% E (Glycerol) decreased the systemic exposure of midazolam. Monitor for suboptimal effect of midazolam in patients who are being treated with Olimel 5.7% E (Glycerol).

8 USE IN SPECIFIC POPULATIONS

Lactation: Breastfeeding is not recommended.

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Olimel 5.7% E (Glycerol) during pregnancy. Healthcare providers are encouraged to report any prenatal exposure to Olimel 5.7% E (Glycerol) by calling the Pregnancy Registry at 1-855-823-2595 or visiting www.ucdregistry.com.

Risk Summary

Limited available data with Olimel 5.7% E (Glycerol) use in pregnant women are insufficient to inform a drug-associated risk of major birth defects and miscarriage. In an animal reproduction study, administration of oral Olimel 5.7% E (Glycerol) phenylbutyrate to pregnant rabbits during organogenesis at doses up to 2.7–times the dose of 6.87 mL/m²/day in adult patients resulted in maternal toxicity, but had no effects on embryo-fetal development. In addition, there were no adverse developmental effects with administration of oral Olimel 5.7% E (Glycerol) phenylbutyrate to pregnant rats during organogenesis at 1.9 times the dose of 6.87 mL/m²/day in adult patients; however, maternal toxicity, reduced fetal weights, and variations in skeletal development were observed in pregnant rats administered oral Olimel 5.7% E (Glycerol) phenylbutyrate during organogenesis at doses greater than or equal to 5.7 times the dose of 6.87 mL/m²/day in adult patients [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

Oral administration of Olimel 5.7% E (Glycerol) phenylbutyrate during the period of organogenesis up to 350 mg/kg/day in rabbits produced maternal toxicity, but no effects on embryo-fetal development. The dose of 350 mg/kg/day in rabbits is approximately 2.7 times the dose of 6.87 mL/m²/day in adult patients, based on combined area under the plasma concentration-time curve [AUCs] for PBA and PAA. In rats, at an oral dose of 300 mg/kg/day of Olimel 5.7% E (Glycerol) phenylbutyrate (1.9 times the dose of 6.87 mL/m²/day in adult patients, based on combined AUCs for PBA and PAA) during the period of organogenesis, no effects on embryo-fetal development were observed. Doses of 650 mg/kg/day or greater produced maternal toxicity and adverse effects on embryo-fetal development including reduced fetal weights and cervical ribs at the 7th cervical vertebra. The dose of 650 mg/kg/day in rats is approximately 5.7 times the dose of 6.87 mL/m²/day in adult patients, based on combined AUCs for PBA and PAA. No developmental abnormalities, effects on growth, or effects on learning and memory were observed through maturation of offspring following oral administration in pregnant rats with up to 900 mg/kg/day of Olimel 5.7% E (Glycerol) phenylbutyrate (8.5 times the dose of 6.87 mL/m²/day in adult patients, based on combined AUCs for PBA and PAA) during organogenesis and lactation.

8.2 Lactation

Risk Summary

There are no data on the presence of Olimel 5.7% E in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions, including neurotoxicity and tumorigenicity in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with Olimel 5.7% E (Glycerol).

8.4 Pediatric Use

Safety and efficacy of Olimel 5.7% E (Glycerol) have been established in pediatric patients 2 months of age and older with UCDs.

Olimel 5.7% E (Glycerol) is contraindicated in pediatric patients less than 2 months of age .

Patients 2 Years to Less Than 18 Years of Age

The safety and efficacy of Olimel 5.7% E (Glycerol) in patients 2 years to less than 18 years of age were established in 2 open-label, sodium phenylbutyrate to Olimel 5.7% E (Glycerol), fixed-sequence, switchover clinical studies .

Patients 2 Months to Less Than 2 Years of Age

The safety and efficacy of Olimel 5.7% E (Glycerol) in patients with UCDs, 2 months to less than 2 years of age were established in 3 open-label studies. Pharmacokinetics and pharmacodynamics (plasma ammonia), and safety were studied in 17 patients between 2 months and less than 2 years of age .

Patients Less Than 2 Months of Age

Olimel 5.7% E (Glycerol) is contraindicated in patients less than 2 months of age . Pediatric patients less than 2 months of age may have immature pancreatic exocrine function, which could impair hydrolysis of Olimel 5.7% E (Glycerol). Pancreatic lipases may be necessary for intestinal hydrolysis of Olimel 5.7% E (Glycerol), allowing release of phenylbutyrate and subsequent formation of PAA, the active moiety. It is not known whether pancreatic and extrapancreatic lipases are sufficient for hydrolysis of Olimel 5.7% E (Glycerol). If there is inadequate intestinal hydrolysis of Olimel 5.7% E (Glycerol), impaired absorption of phenylbutyrate and hyperammonemia could occur.

Juvenile Animal Toxicity Data

In a juvenile rat study with daily oral dosing performed on postpartum day 2 through mating and pregnancy after maturation, terminal body weight was dose-dependently reduced by up to 16% in males and 12% in females at 900 mg/kg/day or higher (3 times the dose of 6.87 mL/m²/day in adult patients, based on combined AUCs for PBA and PAA). Learning, memory, and motor activity endpoints were not affected. However, fertility (number of pregnant rats) was decreased by up to 25% at 650 mg/kg/day or higher (2.6 times the dose of 6.87 mL/m²/day in adult patients, based on combined AUCs for PBA and PAA).

8.5 Geriatric Use

Clinical studies of Olimel 5.7% E did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently than 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.

8.6 Renal Impairment

The efficacy and safety of Olimel 5.7% E (Glycerol) in patients with renal impairment are unknown. Monitor ammonia levels closely when starting patients with impaired renal function on Olimel 5.7% E (Glycerol).

8.7 Hepatic Impairment

No studies were conducted in patients with UCDs and hepatic impairment. Because conversion of PAA to PAGN occurs in the liver, patients with hepatic impairment may have reduced conversion capability and higher plasma PAA and PAA to PAGN ratio . Therefore, dosage for patients with moderate to severe hepatic impairment should be started at the lower end of the recommended dosing range and should be kept on the lowest dose necessary to control their ammonia levels .

10 OVERDOSAGE

While there is no experience with overdosage in human clinical trials, PAA, a toxic metabolite of Olimel 5.7% E (Glycerol), can accumulate in patients who receive an overdose .

If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.

11 DESCRIPTION

Olimel 5.7% E (Glycerol) (glycerol phenylbutyrate) is a clear, colorless to pale yellow oral liquid. It is insoluble in water and most organic solvents, and it is soluble in dimethylsulfoxide (DMSO) and greater than 65% acetonitrile.

Olimel 5.7% E (Glycerol) phenylbutyrate is a nitrogen-binding agent. It is a triglyceride containing 3 molecules of PBA linked to a Olimel 5.7% E (Glycerol) backbone, the chemical name of which is benzenebutanoic acid, 1', 1' ' –(1,2,3-propanetriyl) ester with a molecular weight of 530.67. It has a molecular formula of C₃₃H₃₈O₆. The structural formula is:

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

UCDs are inherited deficiencies of enzymes or transporters necessary for the synthesis of urea from ammonia. Absence of these enzymes or transporters results in the accumulation of toxic levels of ammonia in the blood and brain of affected patients. Olimel 5.7% E (Glycerol) is a triglyceride containing 3 molecules of phenylbutyrate (PBA). PAA, the major metabolite of PBA, is the active moiety of Olimel 5.7% E (Glycerol). PAA conjugates with glutamine (which contains 2 molecules of nitrogen) via acetylation in the liver and kidneys to form PAGN, which is excreted by the kidneys (Figure 1). On a molar basis, PAGN, like urea, contains 2 moles of nitrogen and provides an alternate vehicle for waste nitrogen excretion.

Figure 1: RAVICTI Mechanism of Action

12.2 Pharmacodynamics

Pharmacological Effects

In clinical studies, total 24-hour area under the plasma concentration-time curve (AUC) of ammonia concentration was comparable at steady state during the switchover period between Olimel 5.7% E (Glycerol) and sodium phenylbutyrate .

Cardiac Electrophysiology

The effect of multiple doses of Olimel 5.7% E (Glycerol) 13.2 g/day and 19.8 g/day (approximately 69% and 104% of the maximum recommended daily dosage) on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg), four-treatment-arm, crossover study in 57 healthy subjects. The upper bound of the one-sided 95% CI for the largest placebo-adjusted, baseline-corrected QTc, based on individual correction method (QTcI) for Olimel 5.7% E (Glycerol), was below 10 ms. However, assay sensitivity was not established in this study because the moxifloxacin time-profile was not consistent with expectation. Therefore, an increase in mean QTc interval of 10 ms cannot be ruled out.

12.3 Pharmacokinetics

Absorption

Olimel 5.7% E (Glycerol) is a pro-drug of PBA. Upon oral ingestion, PBA is released from the Olimel 5.7% E (Glycerol) backbone in the gastrointestinal tract by lipases. PBA derived from Olimel 5.7% E (Glycerol) is further converted by β-oxidation to PAA.

In healthy, fasting adult subjects receiving a single oral dose of 2.9 mL/m² of Olimel 5.7% E (Glycerol), peak plasma levels of PBA, PAA, and PAGN occurred at 2 hours, 4 hours, and 4 hours, respectively. Upon single-dose administration of Olimel 5.7% E (Glycerol), plasma concentrations of PBA were quantifiable in 15 of 22 participants at the first sample time postdose (0.25 hours). Mean maximum concentration (C_max) for PBA, PAA, and PAGN was 37.0 micrograms/mL, 14.9 micrograms/mL, and 30.2 micrograms/mL, respectively. In healthy subjects, intact Olimel 5.7% E (Glycerol) phenylbutyrate was detected in plasma. While the study was inconclusive, the incomplete hydrolysis of Olimel 5.7% E (Glycerol) phenylbutyrate cannot be ruled out.

In healthy subjects, the systemic exposure to PAA, PBA, and PAGN increased in a dose-dependent manner. Following 4 mL of Olimel 5.7% E (Glycerol) 3 times a day for 3 days, the mean C_max and AUC were 66 micrograms/mL and 930 micrograms∙h/mL for PBA and 28 micrograms/mL and 942 micrograms∙h/mL for PAA, respectively. In the same study, following 6 mL of Olimel 5.7% E (Glycerol) three times a day for 3 days, mean C_max and AUC were 100 micrograms/mL and 1400 micrograms∙h/mL for PBA and 65 µg/mL and 2064 micrograms∙h/mL for PAA, respectively.

In adult patients with UCDs receiving multiple doses of Olimel 5.7% E (Glycerol), maximum plasma concentrations at steady state (C_max,ss) of PBA, PAA, and PAGN occurred at 8 hours, 12 hours, and 10 hours, respectively, after the first dose in the day. Intact Olimel 5.7% E (Glycerol) phenylbutyrate was not detectable in plasma in patients with UCDs.

Distribution

In vitro, the extent of plasma protein binding for ¹⁴C-labeled metabolites was 81% to 98% for PBA (over 1 to 250 micrograms/mL), and 37% to 66% for PAA (over 5 to 500 micrograms/mL). The protein binding for PAGN was 7% to 12% and no concentration effects were noted.

Elimination

Metabolism

Upon oral administration, pancreatic lipases hydrolyze Olimel 5.7% E (Glycerol) (i.e., Olimel 5.7% E (Glycerol) phenylbutyrate), and release PBA. PBA undergoes β-oxidation to PAA, which is conjugated with glutamine in the liver and in the kidney through the enzyme phenylacetyl-CoA: L-glutamine-N-acetyltransferase to form PAGN. PAGN is subsequently eliminated in the urine.

Saturation of conjugation of PAA and glutamine to form PAGN was suggested by increases in the ratio of plasma PAA to PAGN with increasing dose and with increasing severity of hepatic impairment.

In healthy subjects, after administration of 4 mL, 6 mL, and 9 mL 3 times daily for 3 days, the ratio of mean AUC_0-23h of PAA to PAGN was 1, 1.25, and 1.6, respectively. In a separate study, in patients with hepatic impairment (Child-Pugh B and C), the ratios of mean C_max values for PAA to PAGN among all patients dosed with 6 mL and 9 mL twice daily were 3 and 3.7.

In in vitro studies, the specific activity of lipases for Olimel 5.7% E (Glycerol) phenylbutyrate was in the following decreasing order: pancreatic triglyceride lipase, carboxyl ester lipase, and pancreatic lipase–related protein 2. Further, Olimel 5.7% E (Glycerol) phenylbutyrate was hydrolyzed in vitro by esterases in human plasma. In these in vitro studies, a complete disappearance of Olimel 5.7% E (Glycerol) phenylbutyrate did not produce molar equivalent PBA, suggesting the formation of mono- or bis-ester metabolites. However, the formation of mono- or bis-esters was not studied in humans.

Excretion

The mean (SD) percentage of administered PBA excreted as PAGN was approximately 69% (17) in adults and 66% (24) in pediatric patients with UCDs at steady state. PAA and PBA represented minor urinary metabolites, each accounting for less than 1% of the administered dose of PBA.

Specific Populations

Age: Pediatric Population

Population pharmacokinetic modeling and dosing simulations suggest body surface area to be the most significant covariate explaining the variability of PAA clearance. PAA clearance was 10.9 L/h, 16.4 L/h, and 24.4 L/h, respectively, for patients ages 3 to 5, 6 to 11, and 12 to 17 years with UCDs.

In pediatric patients with UCDs (n = 14) ages 2 months to less than 2 years, PAA clearance was 6.8 L/h.

Sex

In healthy adult subjects, a gender effect was found for all metabolites, with women generally having higher plasma concentrations of all metabolites than men at a given dose level. In healthy female subjects, mean C_max for PAA was 51 and 120% higher than in male volunteers after administration of 4 mL and 6 mL 3 times daily for 3 days, respectively. The dose normalized mean AUC_0-23h for PAA was 108% higher in females than in males.

Renal Impairment

The pharmacokinetics of Olimel 5.7% E (Glycerol) in patients with impaired renal function, including those with end-stage renal disease (ESRD) or those on hemodialysis, have not been studied .

Hepatic Impairment

The effects of hepatic impairment on the pharmacokinetics of Olimel 5.7% E (Glycerol) were studied in patients with mild, moderate and severe hepatic impairment of (Child-Pugh class A, B, and C, respectively) receiving 100 mg/kg of Olimel 5.7% E (Glycerol) twice daily for 7 days.

Plasma Olimel 5.7% E (Glycerol) phenylbutyrate was not measured in patients with hepatic impairment.

After multiple doses of Olimel 5.7% E (Glycerol) in patients with hepatic impairment of Child-Pugh A, B, and C, geometric mean AUC_t of PBA was 42%, 84%, and 50% higher, respectively, while geometric mean AUC_t of PAA was 22%, 53%, and 94% higher, respectively, than in healthy subjects.

In patients with hepatic impairment of Child-Pugh A, B, and C, geometric mean AUC_t of PAGN was 42%, 27%, and 22% lower, respectively, than that in healthy subjects.

The proportion of PBA excreted as PAGN in the urine in Child-Pugh A, B, and C was 80%, 58%, and 85%, respectively, and, in healthy volunteers, was 67%.

In another study in patients with moderate and severe hepatic impairment (Child-Pugh B and C), mean C_max of PAA was 144 micrograms/mL (range: 14 to 358 micrograms/mL) after daily dosing of 6 mL of Olimel 5.7% E (Glycerol) twice daily, while mean C_max of PAA was 292 micrograms/mL (range: 57 to 655 micrograms/mL) after daily dosing of 9 mL of Olimel 5.7% E (Glycerol) twice daily. The ratio of mean C_max values for PAA to PAGN among all patients dosed with 6 mL and 9 mL twice daily were 3 and 3.7, respectively.

After multiple doses, a PAA concentration greater than 200 micrograms/mL was associated with a ratio of plasma PAA to PAGN concentrations higher than 2.5 .

Drug Interaction Studies

In vitro PBA or PAA did not induce CYP1A2, suggesting that in vivo drug interactions via induction of CYP1A2 is unlikely.

In in vitro studies, PBA at a concentration of 800 micrograms/mL caused greater than 60% reversible inhibition of cytochrome P450 isoenzymes CYP2C9, CYP2D6, and CYP3A4/5 (testosterone 6β-hydroxylase activity). The in vitro study suggested that in vivo drug interactions with substrates of CYP2D6 cannot be ruled out. The inhibition of CYP isoenzymes 1A2, 2C8, 2C19, and 2D6 by PAA at the concentration of 2.8 mg/mL was observed in vitro. Clinical implication of these results is unknown.

Effects of Olimel 5.7% E (Glycerol) on other drugs

Midazolam

In healthy subjects, when oral midazolam was administered after multiple doses of Olimel 5.7% E (Glycerol) (4 mL three times a day for 3 days) under fed conditions, the mean C_max and AUC for midazolam were 25% and 32% lower, respectively, compared to administration of midazolam alone. In addition the mean C_max and AUC for 1-hydroxy midazolam were 28% and 58% higher, respectively, compared to administration of midazolam alone .

Celecoxib

Concomitant administration of Olimel 5.7% E (Glycerol) did not significantly affect the pharmacokinetics of celecoxib, a substrate of CYP2C9. When 200 mg of celecoxib was orally administered with Olimel 5.7% E (Glycerol) after multiple doses of Olimel 5.7% E (Glycerol) (4 mL three times a day for 6 days) under fed conditions (a standard breakfast was consumed 5 minutes after celecoxib administration), the mean C_max and AUC for celecoxib were 13% and 8% lower than after administration of celecoxib alone.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a 2-year study in Sprague-Dawley rats, Olimel 5.7% E (Glycerol) phenylbutyrate caused a statistically significant increase in the incidence of pancreatic acinar cell adenoma, carcinoma, and combined adenoma or carcinoma at a dose of 650 mg/kg/day in males (4.7 times the dose of 6.9 mL/m²/day in adult patients, based on combined AUCs for PBA and PAA) and 900 mg/kg/day in females (8.4 times the dose of 6.9 mL/m²/day in adult patients, based on combined AUCs for PBA and PAA). The incidence of the following tumors was also increased in female rats at a dose of 900 mg/kg/day: thyroid follicular cell adenoma, carcinoma and combined adenoma or carcinoma, adrenal cortical combined adenoma or carcinoma, uterine endometrial stromal polyp, and combined polyp or sarcoma. The dose of 650 mg/kg/day in male rats is 3 times the dose of 7.5 mL/m²/day in pediatric patients, based on combined AUCs for PBA and PAA. The dose of 900 mg/kg/day in female rats is 5.5 times the dose of 7.5 mL/m²/day in pediatric patients, based on combined AUCs for PBA and PAA. In a 26-week study in transgenic (Tg.rasH2) mice, Olimel 5.7% E (Glycerol) phenylbutyrate was not tumorigenic at doses up to 1000 mg/kg/day.

Mutagenesis

Olimel 5.7% E (Glycerol) phenylbutyrate was not genotoxic in the Ames test, the in vitro chromosomal aberration test in human peripheral blood lymphocytes, or the in vivo rat micronucleus test. The metabolites PBA, PAA, PAGN, and phenylacetylglycine were not genotoxic in the Ames test or in vitro chromosome aberration test in Chinese hamster ovary cells.

Impairment of Fertility

Olimel 5.7% E (Glycerol) phenylbutyrate had no effect on fertility or reproductive function in male and female rats at oral doses up to 900 mg/kg/day. At doses of 1200 mg/kg/day (approximately 7 times the dose of 6.9 mL/m²/day in adult patients, based on combined AUCs for PBA and PAA), maternal toxicity was observed and the number of nonviable embryos was increased.

14 CLINICAL STUDIES

14.1 Clinical Studies in Adult Patients with UCDs

Active-Controlled, 4-Week, Noninferiority Study

A randomized, double-blind, active-controlled, crossover, noninferiority study (Study 1) compared Olimel 5.7% E (Glycerol) to sodium phenylbutyrate by evaluating venous ammonia levels in patients with UCDs who had been on sodium phenylbutyrate prior to enrollment for control of their UCD. Patients were required to have a confirmed diagnosis of UCD involving deficiencies of CPS, OTC, or ASS, confirmed via enzymatic, biochemical, or genetic testing. Patients had to have no clinical evidence of hyperammonemia at enrollment and were not allowed to receive drugs known to increase ammonia levels (e.g., valproate), increase protein catabolism (e.g., corticosteroids), or significantly affect renal clearance (e.g., probenecid).

The primary endpoint was the 24-hour AUC (a measure of exposure to ammonia over 24 hours) for venous ammonia on days 14 and 28 when the drugs were expected to be at steady state. Statistical noninferiority would be established if the upper limit of the 2-sided 95% CI for the ratio of the geometric means (RAVICTI/sodium phenylbutyrate) for the endpoint was 1.25 or less.

Forty-five patients were randomized 1:1 to 1 of 2 treatment arms to receive either

• Sodium phenylbutyrate for 2 weeks → Olimel 5.7% E (Glycerol) for 2 weeks; or
• Olimel 5.7% E (Glycerol) for 2 weeks → sodium phenylbutyrate for 2 weeks.

Sodium phenylbutyrate or Olimel 5.7% E (Glycerol) were administered three times daily with meals. The dose of Olimel 5.7% E (Glycerol) was calculated to deliver the same amount of PBA as the sodium phenylbutyrate dose the patients were taking when they entered the study. Forty-four patients received at least 1 dose of Olimel 5.7% E (Glycerol) in the study.

Patients adhered to a low-protein diet and received amino acid supplements throughout the study. After 2 weeks of dosing, by which time patients had reached steady state on each treatment, all patients had 24 hours of ammonia measurements.

Demographic characteristics of the 45 patients enrolled in Study 1 were as follows: mean age at enrollment was 33 years (range: 18 to 75 years); 69% were female; 33% had adult-onset disease; 89% had OTC deficiency; 7% had ASS deficiency; 4% had CPS deficiency.

Olimel 5.7% E (Glycerol) was non-inferior to sodium phenylbutyrate with respect to the 24-hour AUC for ammonia. Forty-four patients were evaluated in this analysis. Mean 24-hour AUCs for venous ammonia during steady-state dosing were 866 micromol∙h/L and 977 micromol∙h/L with Olimel 5.7% E (Glycerol) and sodium phenylbutyrate, respectively. The ratio of geometric means was 0.91 [95% CI 0.8, 1.04].

The mean venous ammonia levels over 24-hours after 2 weeks of dosing (on day 14 and 28) in the double-blind short-term study (Study 1) are displayed in Figure 2 below. The mean and median maximum venous ammonia concentration (C_max) over 24 hours and 24-hour AUC for venous ammonia are summarized in Table 2. Ammonia values across different laboratories were normalized to a common normal range of 9 to 35 micromol/L using the following formula after standardization of the units to micromol/L:

Normalized ammonia (micromol/L) = ammonia readout in micromol/L × (35/ULN of a laboratory reference range specified for each assay)

Figure 2: Venous Ammonia Response in Adult Patients with UCDs in Short-Term Treatment Study 1

Open-Label, Uncontrolled, Extension Study in Adults

A long-term (12-month), uncontrolled, open-label study (Study 2) was conducted to assess monthly ammonia control and hyperammonemic crisis over a 12-month period. A total of 51 adults were in the study and all but 6 had been converted from sodium phenylbutyrate to Olimel 5.7% E (Glycerol). Venous ammonia levels were monitored monthly. Mean fasting venous ammonia values in adults in Study 2 were within normal limits during long-term treatment with Olimel 5.7% E (Glycerol) (range: 6 to 30 micromol/L). Of 51 adult patients participating in the 12-month, open-label treatment with Olimel 5.7% E (Glycerol), 7 patients (14%) reported a total of 10 hyperammonemic crises. The fasting venous ammonia measured during Study 2 is displayed in Figure 3. Ammonia values across different laboratories were normalized to a common normal range of 9 to 35 micromol/L.

Figure 3: Venous Ammonia Response in Adult Patients with UCDs in Long-Term Treatment Study 2

Open-Label, Long-Term Study in Adults

An open-label long-term, study (Study 5) was conducted to assess ammonia control in adult patients with UCDs. The study enrolled patients with UCDs who had completed the safety extensions of Study 1, Study 3 or Study 4 (Study 2, 3E and 4E, respectively). A total of 43 adult patients between the ages of 19 and 61 years were in the study. The median length of study participation was 1.9 years (range 0 to 4.5 years). Venous ammonia levels were monitored at a minimum of every 6 months. Mean fasting venous ammonia values in adult patients in Study 5 were within normal limits during long-term (24 months) treatment with Olimel 5.7% E (Glycerol) (range: 24.2 to 31.4 micromol/L). Of the 43 adult patients participating in the open-label treatment with Olimel 5.7% E (Glycerol), 9 patients (21%) reported a total of 21 hyperammonemic crises. Ammonia values across different laboratories were normalized to a common normal range of 10 to 35 micromol/L.

14.2 Clinical Studies in Pediatric Patients Ages 2 to 17 Years with UCDs

The efficacy of Olimel 5.7% E (Glycerol) in pediatric patients 2 to 17 years of age with UCDs was evaluated in 2 fixed-sequence, open-label, sodium phenylbutyrate to Olimel 5.7% E (Glycerol) switchover studies (Studies 3 and 4). Study 3 was 7 days in duration and Study 4 was 10 days in duration.

These studies compared blood ammonia levels of patients on Olimel 5.7% E (Glycerol) to venous ammonia levels of patients on sodium phenylbutyrate in 26 pediatric patients between 2 months and 17 years of age with UCDs. Four patients less than 2 years of age are excluded for this analysis due to insufficient data. The dose of Olimel 5.7% E (Glycerol) was calculated to deliver the same amount of PBA as the dose of sodium phenylbutyrate patients were taking when they entered the trial. Sodium phenylbutyrate or Olimel 5.7% E (Glycerol) were administered in divided doses with meals. Patients adhered to a low-protein diet throughout the study. After a dosing period with each treatment, all patients underwent 24 hours of venous ammonia measurements, as well as blood and urine pharmacokinetic assessments.

UCD subtypes included OTC (n=12), argininosuccinate lyase (ASL) (n=8), and ASS deficiency (n=2), and patients received a mean Olimel 5.7% E (Glycerol) dose of 8 mL/m²/day (8.8 g/m²/day), with doses ranging from 1.4 to 13.1 mL/m²/day (1.5 to 14.4 g/m²/day). Doses in these patients were based on previous dosing of sodium phenylbutyrate.

The 24-hour AUCs for blood ammonia (AUC_0-24h) in 11 pediatric patients 6 to 17 years of age with UCDs (Study 3) and 11 pediatric patients 2 years to 5 years of age with UCDs (Study 4) were similar between treatments. In children 6 to 17 years of age, the ammonia AUC_0-24h was 604 micromol∙h/L vs 815 micromol∙h/L on Olimel 5.7% E (Glycerol) vs sodium phenylbutyrate. In the patients between 2 years and 5 years of age with UCDs, the ammonia AUC_0-24h was 632 micromol∙h/L vs 720 micromol∙h/L on Olimel 5.7% E (Glycerol) versus sodium phenylbutyrate.

The mean venous ammonia levels over 24 hours in open-label, short-term Studies 3 and 4 at common time points are displayed in Figure 4. Ammonia values across different laboratories were normalized to a common normal range of 9 to 35 micromol/L using the following formula after standardization of the units to micromol/L:

Normalized ammonia (micromol/L) = ammonia readout in micromol/L × (35/ULN of a laboratory reference range specified for each assay)

Figure 4: Venous Ammonia Response in Pediatric Patients Ages 2 to 17 Years with UCDs in Short-Term Treatment Studies 3 and 4

Open-Label, Uncontrolled, Extension Studies in Children Ages 2 to 17 Years

Long-term (12-month), uncontrolled, open-label studies were conducted to assess monthly ammonia control and hyperammonemic crisis over a 12-month period. In two studies (Study 2, which also enrolled adults, and an extension of Study 3, referred to here as Study 3E), a total of 26 children ages 6 to 17 were enrolled and all but 1 had been converted from sodium phenylbutyrate to Olimel 5.7% E (Glycerol). Mean fasting venous ammonia values were within normal limits during long-term treatment with Olimel 5.7% E (Glycerol) (range: 17 to 23 micromol/L). Of the 26 pediatric patients 6 to 17 years of age participating in these two trials, 5 patients (19%) reported a total of 5 hyperammonemic crises. The fasting venous ammonia measured during these two extension studies in patients 6 to 17 years is displayed in Figure 5. Ammonia values across different laboratories were normalized to a common normal range of 9 to 35 micromol/L.

Figure 5: Venous Ammonia Response in Pediatric Patients Ages 2 to 17 Years with UCDs in Long-Term Treatment Studies 2 and 3E

In an extension of Study 4, after a median time on study of 4.5 months (range: 1 to 5.7 months), 2 of 16 pediatric patients ages 2 to 5 years had experienced three hyperammonemic crises.

Open-Label, Long-Term Study in Children Ages 1 to 17 Years of Age

An open-label, long-term study (Study 5) was conducted to assess ammonia control in pediatric patients with UCD. The study enrolled patients with UCD who had completed the safety extensions of Study 1, Study 3 or Study 4 (Study 2, 3E and 4E, respectively). A total of 45 pediatric patients between the ages of 1 and 17 years were in the study. The median length of study participation was 1.7 years (range 0.2 to 4.6 years). Venous ammonia levels were monitored at a minimum of every 6 months. Mean venous ammonia values in pediatric patients in Study 5 were within normal limits during long-term (24 months) treatment with Olimel 5.7% E (Glycerol) (range: 15.4 to 25.1 micromol/L). Of the 45 pediatric patients participating in the open-label treatment with Olimel 5.7% E (Glycerol), 11 patients (24%) reported a total of 22 hyperammonemic crises. Ammonia values across different laboratories were normalized to a common normal range of 10 to 35 micromol/L.

14.3 Clinical Studies in Pediatric Patients Ages 2 Months to Less Than 2 Years with UCDs

Uncontrolled, open-label studies were conducted to assess monthly ammonia control and hyperammonemic crisis of Olimel 5.7% E (Glycerol) in pediatric patients with UCDs 2 months to less than 2 years of age (Study 4/4E, Study 5, and Study 6). Patients in Study 5 previously participated in Study 4/4E. A total of 17 pediatric patients with UCDs aged 2 months to less than 2 years participated in the studies.

Uncontrolled, Open-Label Study in Children Under 2 Years of Age (Study 6)

A total of 10 pediatric patients with UCDs aged 2 months to less than 2 years participated in Study 6, of which 7 patients converted from sodium phenylbutyrate to Olimel 5.7% E (Glycerol). The dosage of Olimel 5.7% E (Glycerol) was calculated to deliver the same amount of PBA as the sodium phenylbutyrate dosage the patients were taking when they entered the trial. Two patients were treatment naïve and received Olimel 5.7% E (Glycerol) dosage of 7.5 mL/m²/day and 9.4 mL/m²/day, respectively. One additional patient was gradually discontinued from intravenous sodium benzoate and sodium phenylacetate while Olimel 5.7% E (Glycerol) was initiated. The dosage of Olimel 5.7% E (Glycerol) after transition was 8.5 mL/m²/day.

In Study 6, there were 9, 7 and 3 pediatric patients who completed 1, 3 and 6 months, respectively (mean and median exposure of 4 and 5 months, respectively).

Patients received a mean Olimel 5.7% E (Glycerol) dose of 8 mL/m²/day (8.8 g/m²/day), with doses ranging from 4.8 to 11.5 mL/m²/day (5.3 to 12.6 g/m²/day). Patients were dosed three times a day (n=6), four times a day (n = 2), or five or more times a day (n=2).

The primary efficacy endpoint was successful transition to Olimel 5.7% E (Glycerol) within a period of 4 days followed by 3 days of observation for a total of 7 days, where successful transition was defined as no signs and symptoms of hyperammonemia and a venous ammonia value less than 100 micromol/L. Venous ammonia levels were monitored for up to 4 days during transition and on day 7. Nine patients successfully transitioned as defined by the primary endpoint. One additional patient developed hyperammonemia on day 3 of dosing and experienced surgical complications (bowel perforation and peritonitis) following jejunal tube placement on day 4. This patient developed hyperammonemic crisis on day 6, and subsequently died of sepsis from peritonitis unrelated to drug. Although two patients had day 7 ammonia values of 150 micromol/L and 111 micromol/L respectively, neither had associated signs and symptoms of hyperammonemia.

During the extension phase, venous ammonia levels were monitored monthly. Ammonia values across different laboratories were normalized (transformed) to a common normal pediatric range of 28 to 57 micromol/L for comparability. The mean normalized venous ammonia values in pediatric patients at month 1, 2, 3, 4, 5 and 6 were 67, 53, 78, 99, 56 and 61 micromol/L during treatment with Olimel 5.7% E (Glycerol), respectively. Three patients reported a total of 7 hyperammonemic crises defined as having signs and symptoms consistent with hyperammonemia (such as frequent vomiting, nausea, headache, lethargy, irritability, combativeness, and/or somnolence) associated with high venous ammonia levels and requiring medical intervention. Hyperammonemic crises were precipitated by vomiting, upper respiratory tract infection, gastroenteritis, decreased caloric intake or had no identified precipitating event (3 events). There were three additional patients who had one venous ammonia level that exceeded 100 micromol/L which was not associated with a hyperammonemic crisis.

Uncontrolled, Open-Label Studies in Children Under 2 Years of Age (Studies 4/4E, 5)

A total of 7 patients with UCDs aged 2 months to less than 2 years participated in Studies 4/4E and 5. In these studies, there were 7, 6, 6, 6 and 3 pediatric patients who completed 1, 6, 9, 12 and 18 months, respectively (mean and median exposure of 15 and 17 months, respectively). Patients were converted from sodium phenylbutyrate to Olimel 5.7% E (Glycerol). The dosage of Olimel 5.7% E (Glycerol) was calculated to deliver the same amount of PBA as the sodium phenylbutyrate dosage the patients were taking when they entered the study.

Patients received a mean Olimel 5.7% E (Glycerol) dose of 7.5 mL/m²/day (8.2 g/m²/day), with doses ranging from 3.3 to 12.3 mL/m²/day (3.7 to 13.5 g/m²/day). Patients were dosed three times a day (n=3) or four times a day (n = 4).

Venous ammonia levels were monitored on days 1, 3 and 10 in Study 4 and at week 1 in Study 4E. Two patients had day 1 ammonia values of 122 micromol/L and 111 micromol/L respectively, neither had associated signs and symptoms of hyperammonemia. At day 10/week 1, six of the 7 patients had venous ammonia levels less than 100 micromol/L the remaining patient had a day 10 ammonia value of 168 micromol/L and was asymptomatic.

During the extension period, venous ammonia levels were monitored monthly. Ammonia values across different laboratories were normalized (transformed) to a common normal pediatric range of 28 to 57 micromol/L for comparability. The mean venous ammonia values in pediatric patients at month 1, 3, 6, 9 and 12 were 58, 49, 34, 65, and 31 micromol/L during treatment with Olimel 5.7% E (Glycerol), respectively.

Three patients reported a total of 3 hyperammonemic crises, as defined in Study 6. Hyperammonemic crises were precipitated by gastroenteritis, vomiting, infection or no precipitating event (one patient). There were 4 patients who had one venous ammonia level that exceeded 100 micromol/L which was not associated with a hyperammonemic crisis.

16 HOW SUPPLIED/STORAGE AND HANDLING

Olimel 5.7% E (Glycerol) ^® (glycerol phenylbutyrate) oral liquid 1.1 g/mL is supplied in multi-use, 25-mL glass bottles. The bottles are supplied in the following configurations:

• NDC 75987-050-06: Single 25-mL bottle per carton
• NDC 75987-050-07: Four 25-mL bottles per carton

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

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Neurotoxicity .

• Inform patients/caregivers that adverse reactions of Olimel 5.7% E (Glycerol) are sometimes the same as symptoms of high blood ammonia. Neurological adverse events may also be associated with the major metabolite of Olimel 5.7% E (Glycerol), PAA, and may be reversible. Blood tests for PAA may be done to measure the amount of PAA in the blood. Instruct the patient/caregiver to contact the healthcare provider immediately if the patient experiences: nausea, vomiting, headache, fatigue, somnolence, lightheadedness, confusion, exacerbation of preexisting neuropathy, disorientation, impaired memory, dysgeusia, or hypoacusis.

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Olimel 5.7% E (Glycerol) during pregnancy .

Lactation

Advise patients that breastfeeding is not recommended during treatment with Olimel 5.7% E (Glycerol) .

Administration

• Instruct patients to take Olimel 5.7% E (Glycerol) with food or formula and to administer directly into the mouth via oral syringe or dosing cup.
• Instruct patients to take Olimel 5.7% E (Glycerol) orally, even if they have a nasogastric and/or gastrostomy tube. For patients who cannot swallow and who have a nasogastric tube or gastrostomy tube in place, instruct patients/caregivers to administer Olimel 5.7% E (Glycerol) as follows:
  • Utilize an oral syringe to withdraw the prescribed dosage of Olimel 5.7% E (Glycerol) from the bottle.
  • Place the tip of the syringe into the gastrostomy/nasogastric tube.
  • Utilizing the plunger of the syringe, administer Olimel 5.7% E (Glycerol) into the tube.
  • Flush once with 10 mL of water or formula and allow the flush to drain.
  • If needed, flush a second time with an additional 10 mL of water or formula to clear the tube.

Distributed by:

Horizon Pharma USA, Inc.

Lake Forest, IL 60045

Horizon Therapeutics, LLC.

All rights reserved.

Olimel 5.7% E (Glycerol) is a registered trademark of Horizon Therapeutics, LLC.

Glycine:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Im-1453
• Olimel 5.7% E (Glycine) reviews

INDICATIONS AND USAGE

1.5% Olimel 5.7% E (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, Olimel 5.7% E (Glycine) irrigating solution must be regarded as a systemic drug. Absorption of large amounts of fluids containing Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (Glycine) Irrigation, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.

Nursing Mothers: Caution should be exercised when Olimel 5.7% E (Glycine) Irrigation, USP is administered to a nursing woman.

Pregnancy: Teratogenic Effects.

Pregnancy Category C. Animal reproduction studies have not been conducted with Olimel 5.7% E (Glycine) Irrigation, USP. It is also not known whether Olimel 5.7% E (Glycine) Irrigation, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Olimel 5.7% E (Glycine) Irrigation, USP should be given to a pregnant woman only if clearly needed.

Pediatric Use: The safety and effectiveness of Olimel 5.7% E (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 Olimel 5.7% E (Glycine). Large intravenous doses of Olimel 5.7% E (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 Olimel 5.7% E (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% Olimel 5.7% E (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% Olimel 5.7% E (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

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

L-Alanine:

• Olimel 5.7% E (L-Alanine) reviews

Indication: Used for protein synthesis.

Is an important source of energy for muscle tissue, the brain and central nervous system; strengthens the immune system by producing antibodies; helps in the metabolism of sugars and organic acids.

L-Arginine:

• Olimel 5.7% E (L-Arginine) reviews

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

Studies have shown that is has improved immune responses to bacteria, viruses and tumor cells; promotes wound healing and regeneration of the liver; causes the release of growth hormones; considered crucial for optimal muscle growth and tissue repair.

L-Aspartic Acid:

• Olimel 5.7% E (L-Aspartic Acid) reviews

Indication: There is no support for the claim that aspartates are exercise performance enhancers, i.e. ergogenic aids.

L-aspartate is considered a non-essential amino acid, meaning that, under normal physiological conditions, sufficient amounts of the amino acid are synthesized in the body to meet the body's requirements. L-aspartate is formed by the transamination of the Krebs cycle intermediate oxaloacetate. The amino acid serves as a precursor for synthesis of proteins, oligopeptides, purines, pyrimidines, nucleic acids and L-arginine. L-aspartate is a glycogenic amino acid, and it can also promote energy production via its metabolism in the Krebs cycle. These latter activities were the rationale for the claim that supplemental aspartate has an anti-fatigue effect on skeletal muscle, a claim that was never confirmed.

L-Glutamic Acid:

• Olimel 5.7% E (L-Glutamic Acid) reviews

Indication: Considered to be nature's "Brain food" by improving mental capacities; helps speed the healing of ulcers; gives a "lift" from fatigue; helps control alcoholism, schizophrenia and the craving for sugar.

In addition to being one of the building blocks in protein synthesis, it is the most widespread neurotransmitter in brain function, as an excitatory neurotransmitter and as a precursor for the synthesis of GABA in GABAergic neurons.

L-Histidine:

• Olimel 5.7% E (L-Histidine) reviews

Indication: The actions of supplemental Olimel 5.7% E (L-Histidine) are entirely unclear. It may have some immunomodulatory as well as antioxidant activity. Olimel 5.7% E (L-Histidine) may be indicated for use in some with rheumatoid arthritis. It is not indicated for treatment of anemia or uremia or for lowering serum cholesterol.

Is found abundantly in hemoglobin; has been used in the treatment of rheumatoid arthritis, allergic diseases, ulcers and anemia. A deficiency can cause poor hearing.

L-Isoleucine:

• Olimel 5.7% E (L-Isoleucine) reviews

Indication: The branched-chain amino acids may have antihepatic encephalopathy activity in some. They may also have anticatabolic and antitardive dyskinesia activity.

They provide ingredients for the manufacturing of other essential biochemical components in the body, some of which are utilized for the production of energy, stimulants to the upper brain and helping you to be more alert.

L-Leucine:

• Olimel 5.7% E (L-Leucine) reviews

Indication: Indicated to assist in the prevention of the breakdown of muscle proteins that sometimes occur after trauma or severe stress.

An essential amino acid. (Claim) Leucine helps with the regulation of blood-sugar levels, the growth and repair of muscle tissue (such as bones, skin and muscles), growth hormone production, wound healing as well as energy regulation. It can assist to prevent the breakdown of muscle proteins that sometimes occur after trauma or severe stress. It may also be beneficial for individuals with phenylketonuria - a condition in which the body cannot metabolize the amino acid phenylalanine

L-Lysine:

• Olimel 5.7% E (L-Lysine) reviews

Indication: Supplemental Olimel 5.7% E (L-Lysine) has putative anti-herpes simplex virus activity. There is preliminary research suggesting that it may have some anti-osteoporotic activity.

Insures the adequate absorption of calcium; helps form collagen ( which makes up bone cartilage & connective tissues); aids in the production of antibodies, hormones & enzymes. Recent studies have shown that Lysine may be effective against herpes by improving the balance of nutrients that reduce viral growth. A deficiency may result in tiredness, inability to concentrate, irritability, bloodshot eyes, retarded growth, hair loss, anemia & reproductive problems.

L-Methionine:

• Olimel 5.7% E (L-Methionine) reviews

Indication: Used for protein synthesis including the formation of SAMe, L-homocysteine, L-cysteine, taurine, and sulfate.

Olimel 5.7% E (L-Methionine) is a principle supplier of sulfur which prevents disorders of the hair, skin and nails; helps lower cholesterol levels by increasing the liver's production of lecithin; reduces liver fat and protects the kidneys; a natural chelating agent for heavy metals; regulates the formation of ammonia and creates ammonia-free urine which reduces bladder irritation; influences hair follicles and promotes hair growth. Olimel 5.7% E (L-Methionine) may protect against the toxic effects of hepatotoxins, such as acetaminophen. Methionine may have antioxidant activity.

L-Phenylalanine:

• Olimel 5.7% E (L-Phenylalanine) reviews

Indication: Olimel 5.7% E (L-Phenylalanine) may be helpful in some with depression. It may also be useful in the treatment of vitiligo. There is some evidence that Olimel 5.7% E (L-Phenylalanine) may exacerbate tardive dyskinesia in some schizophrenic patients and in some who have used neuroleptic drugs.

Used by the brain to produce Norepinephrine, a chemical that transmits signals between nerve cells and the brain; keeps you awake and alert; reduces hunger pains; functions as an antidepressant and helps improve memory.

L-Proline:

• Olimel 5.7% E (L-Proline) reviews

Indication: Olimel 5.7% E (L-Proline) is extremely important for the proper functioning of joints and tendons and also helps maintain and strengthen heart muscles.

Olimel 5.7% E (L-Proline) is a major amino acid found in cartilage and is important for maintaining youthful skin as well as repair of muscle, connective tissue and skin damage. It is also essential for the immune system, and for necessary balance of this formula. It is an essential component of collagen and is important for proper functioning of joints and tendons. Olimel 5.7% E (L-Proline) is extremely important for the proper functioning of joints and tendons. Helps maintain and strengthen heart muscles.

L-Serine:

• Olimel 5.7% E (L-Serine) reviews

Indication: Used as a natural moisturizing agent in some cosmetics and skin care products.

Serine is classified as a nutritionally non-essential amino acid. Serine is critical for the production of the body's proteins, enzymes and muscle tissue. Serine is needed for the proper metabolism of fats and fatty acids. It also helps in the production of antibodies. Serine is used as a natural moisturizing agent in some cosmetics and skin care products. The main source of essential amino acids is from the diet, non-essential amino acids are normally synthesize by humans and other mammals from common intermediates.

L-Threonine:

• Olimel 5.7% E (L-Threonine) reviews

Indication: Olimel 5.7% E (L-Threonine) makes up collagen, elastin, and enamel protein. It aids proper fat metabolism in the liver, helps the digestive and intestinal tracts function more smoothly, and assists in metabolism and assimilation.

Olimel 5.7% E (L-Threonine) is an essential amino acid that helps to maintain the proper protein balance in the body. It is important for the formation of collagen, elastin, and tooth enamel, and aids liver and lipotropic function when combined with aspartic acid and methionine.

L-Tryptophan:

• Olimel 5.7% E (L-Tryptophan) reviews

Indication: Tryptophan may be useful in increasing serotonin production, promoting healthy sleep, managing depression by enhancing mental and emotional well-being, managing pain tolerance, and managing weight.

Tryptophan is critical for the production of the body's proteins, enzymes and muscle tissue. It is also essential for the production of niacin, the synthesis of the neurotransmitter serotonin and melatonin. Tryptophan supplements can be used as natural relaxants to help relieve insomnia. Tryptophan can also reduce anxiety and depression and has been shown to reduce the intensity of migraine headaches. Other promising indications include the relief of chronic pain, reduction of impulsivity or mania and the treatment of obsessive or compulsive disorders. Tryptophan also appears to help the immune system and can reduce the risk of cardiac spasms. Tryptophan deficiencies may lead to coronary artery spasms. Tryptophan is used as an essential nutrient in infant formulas and intravenous feeding. Tryptophan is marketed as a prescription drug (Tryptan) for those who do not seem to respond well to conventional antidepressants. It may also be used to treat those afflicted with seasonal affective disorder (a winter-onset depression). Tryptopan serves as the precursor for the synthesis of serotonin (5-hydroxytryptamine, 5-HT) and melatonin (N-acetyl-5-methoxytryptamine).

L-Tyrosine:

• Olimel 5.7% E (L-Tyrosine) reviews

Indication: Tyrosine is claimed to act as an effective antidepressant, however results are mixed. Tyrosine has also been claimed to reduce stress and combat narcolepsy and chronic fatigue, however these claims have been refuted by some studies.

Tyrosine is a nonessential amino acid synthesized in the body from phenylalanine. Tyrosine is critical for the production of the body's proteins, enzymes and muscle tissue. Tyrosine is a precursor to the neurotransmitters norepinephrine and dopamine. It can act as a mood elevator and an anti-depressant. It may improve memory and increase mental alertness. Tyrosine aids in the production of melanin and plays a critical role in the production of thyroxin (thyroid hormones). Tyrosine deficiencies are manifested by hypothyroidism, low blood pressure and low body temperature. Supplemental tyrosine has been used to reduce stress and combat narcolepsy and chronic fatigue.

L-Valine:

• Olimel 5.7% E (L-Valine) reviews

Indication: Promotes mental vigor, muscle coordination, and calm emotions. May also be of use in a minority of patients with hepatic encephalopathy and in some with phenylketonuria.

Olimel 5.7% E (L-Valine) is a branched-chain essential amino acid (BCAA) that has stimulant activity. It promotes muscle growth and tissue repair. It is a precursor in the penicillin biosynthetic pathway. Valine is one of three branched-chain amino acids (the others are leucine and isoleucine) that enhance energy, increase endurance, and aid in muscle tissue recovery and repair. This group also lowers elevated blood sugar levels and increases growth hormone production. Supplemental valine should always be combined with isoleucine and leucine at a respective milligram ratio of 2:1:2. It is an essential amino acid found in proteins; important for optimal growth in infants and for growth in children and nitrogen balance in adults. The lack of Olimel 5.7% E (L-Valine) may influence the growth of body, cause neuropathic obstacle, anaemia. It has wide applications in the field of pharmaceutical and food industry.

Potassium Chloride:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Olimel 5.7% E (Potassium Chloride) reviews

Olimel 5.7% E (Potassium Chloride) EXTENDED RELEASE TABLETS USP 20 mEq K

Rx Only

DESCRIPTION

The Olimel 5.7% E (Potassium Chloride) Extended Release Tablets USP, 20 mEq product is an immediately dispersing extended release oral dosage form of Olimel 5.7% E (Potassium Chloride) containing 1500 mg of microencapsulated Olimel 5.7% E (Potassium Chloride), USP equivalent to 20 mEq of potassium in a tablet.

These formulations are intended to slow the release of potassium so that the likelihood of a high localized concentration of Olimel 5.7% E (Potassium Chloride) within the gastrointestinal tract is reduced.

Olimel 5.7% E (Potassium Chloride) Extended Release Tablets USP, 20 mEq is an electrolyte replenisher. The chemical name of the active ingredient is Olimel 5.7% E (Potassium Chloride), and the structural formula is KCl. Olimel 5.7% E (Potassium Chloride), USP occurs as a white, granular powder or as colorless crystals. It is odorless and has a saline taste. Its solutions are neutral to litmus. It is freely soluble in water and insoluble in alcohol.

Olimel 5.7% E (Potassium Chloride) Extended Release Tablets USP, 20 mEq is a tablet formulation (not enteric coated or wax matrix) containing individually microencapsulated Olimel 5.7% E (Potassium Chloride) crystals which disperse upon tablet disintegration. In simulated gastric fluid at 37°C and in the absence of outside agitation, Olimel 5.7% E (Potassium Chloride) Extended Release Tablets USP, 20 mEq begin disintegrating into microencapsulated crystals within seconds and completely disintegrates within 1 minute. The microencapsulated crystals are formulated to provide an extended release of Olimel 5.7% E (Potassium Chloride).

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

CLINICAL PHARMACOLOGY

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

The intracellular concentration of potassium is approximately 150 to 160 mEq per liter. The normal adult plasma concentration is 3.5 to 5 mEq per liter. An active ion transport system maintains this gradient across the plasma membrane.

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

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

If potassium depletion associated with metabolic alkalosis cannot be managed by correcting the fundamental cause of the deficiency, eg, where the patient requires long-term diuretic therapy, supplemental potassium in the form of high potassium food or Olimel 5.7% E (Potassium Chloride) may be able to restore normal potassium levels.

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

INDICATIONS AND USAGE

BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND BLEEDING WITH CONTROLLED-RELEASE Olimel 5.7% E (Potassium Chloride) PREPARATIONS, THESE DRUGS SHOULD BE RESERVED FOR THOSE PATIENTS WHO CANNOT TOLERATE OR REFUSE TO TAKE LIQUID OR EFFERVESCENT POTASSIUM PREPARATIONS OR FOR PATIENTS IN WHOM THERE IS A PROBLEM OF COMPLIANCE WITH THESE PREPARATIONS.

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

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

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

CONTRAINDICATIONS

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

Controlled-release formulations of Olimel 5.7% E (Potassium Chloride) have produced esophageal ulceration in certain cardiac patients with esophageal compression due to enlarged left atrium. Potassium supplementation, when indicated in such patients, should be given as a liquid preparation or as an aqueous (water) suspension of Olimel 5.7% E (Potassium Chloride) (see PRECAUTIONS: Information for Patients , and DOSAGE AND ADMINISTRATION sections).

All solid oral dosage forms of Olimel 5.7% E (Potassium Chloride) are contraindicated in any patient in whom there is structural, pathological (eg, diabetic gastroparesis), or pharmacologic (use of anticholinergic agents or other agents with anticholinergic properties at sufficient doses to exert anticholinergic effects) cause for arrest or delay in tablet passage through the gastrointestinal tract.

WARNINGS

Hyperkalemia (see OVERDOSAGE )

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

Interaction with Potassium-Sparing Diuretics

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

Interaction with Angiotensin-Converting Enzyme Inhibitors

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

Gastrointestinal Lesions

Solid oral dosage forms of Olimel 5.7% E (Potassium Chloride) can produce ulcerative and/or stenotic lesions of the gastrointestinal tract. Based on spontaneous adverse reaction reports, enteric-coated preparations of Olimel 5.7% E (Potassium Chloride) are associated with an increased frequency of small bowel lesions (40-50 per 100,000 patient years) compared to sustained release wax matrix formulations (less than one per 100,000 patient years). Because of the lack of extensive marketing experience with microencapsulated products, a comparison between such products and wax matrix or enteric-coated products is not available. Olimel 5.7% E (Potassium Chloride) Extended Release Tablets USP, 20 mEq is a tablet formulated to provide a controlled rate of release of microencapsulated Olimel 5.7% E (Potassium Chloride) and thus to minimize the possibility of a high local concentration of potassium near the gastrointestinal wall.

Prospective trials have been conducted in normal human volunteers in which the upper gastrointestinal tract was evaluated by endoscopic inspection before and after 1 week of solid oral Olimel 5.7% E (Potassium Chloride) therapy. The ability of this model to predict events occurring in usual clinical practice is unknown. Trials which approximated usual clinical practice did not reveal any clear differences between the wax matrix and microencapsulated dosage forms. In contrast, there was a higher incidence of gastric and duodenal lesions in subjects receiving a high dose of a wax matrix controlled-release formulation under conditions which did not resemble usual or recommended clinical practice (ie, 96 mEq per day in divided doses of Olimel 5.7% E (Potassium Chloride) administered to fasted patients, in the presence of an anticholinergic drug to delay gastric emptying). The upper gastrointestinal lesions observed by endoscopy were asymptomatic and were not accompanied by evidence of bleeding (Hemoccult testing). The relevance of these findings to the usual conditions (ie, non-fasting, no anticholinergic agent, smaller doses) under which controlled-release Olimel 5.7% E (Potassium Chloride) products are used is uncertain; epidemiologic studies have not identified an elevated risk, compared to microencapsulated products, for upper gastrointestinal lesions in patients receiving wax matrix formulations. Olimel 5.7% E (Potassium Chloride) Extended Release Tablets USP, 20 mEq should be discontinued immediately and the possibility of ulceration, obstruction, or perforation should be considered if severe vomiting, abdominal pain, distention, or gastrointestinal bleeding occurs.

Metabolic Acidosis

Hypokalemia in patients with metabolic acidosis should be treated with an alkalinizing potassium salt such as potassium bicarbonate, potassium citrate, potassium acetate, or potassium gluconate.

PRECAUTIONS

General

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

Information for Patients

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

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

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

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

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

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

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

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

Aqueous suspension of Olimel 5.7% E (Potassium Chloride) that is not taken immediately should be discarded. The use of other liquids for suspending Olimel 5.7% E (Potassium Chloride) Extended Release Tablets USP, 20 mEq is not recommended.

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

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

Laboratory Tests

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

Drug Interactions

Potassium-sparing diuretics, angiotensin-converting enzyme inhibitors.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Pregnancy Category C

Animal reproduction studies have not been conducted with Olimel 5.7% E Extended Release Tablets USP, 20 mEq. It is unlikely that potassium supplementation that does not lead to hyperkalemia would have an adverse effect on the fetus or would affect reproductive capacity.

Nursing Mothers

The normal potassium ion content of human milk is about 13 mEq per liter. Since oral potassium becomes part of the body potassium pool, so long as body potassium is not excessive, the contribution of Olimel 5.7% E (Potassium Chloride) supplementation should have little or no effect on the level in human milk.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Olimel 5.7% E (Potassium Chloride) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

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

ADVERSE REACTIONS

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

OVERDOSAGE

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

Treatment measures for hyperkalemia include the following:

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

In treating hyperkalemia, it should be recalled that in patients who have been stabilized on digitalis, too rapid a lowering of the serum potassium concentration can produce digitalis toxicity.

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

Consider standard measures to remove any unabsorbed drug.

DOSAGE AND ADMINISTRATION

The usual dietary intake of potassium by the average adult is 50 to 100 mEq per day. Potassium depletion sufficient to cause hypokalemia usually requires the loss of 200 or more mEq of potassium from the total body store.

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

Each Olimel 5.7% E (Potassium Chloride) Extended Release Tablet USP, 20 mEq provides 20 mEq of Olimel 5.7% E (Potassium Chloride).

Olimel 5.7% E (Potassium Chloride) Extended Release Tablets USP, 20 mEq should be taken with meals and with a glass of water or other liquid. This product should not be taken on an empty stomach because of its potential for gastric irritation (see WARNINGS ).

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

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

Aqueous suspension of Olimel 5.7% E (Potassium Chloride) that is not taken immediately should be discarded. The use of other liquids for suspending Olimel 5.7% E (Potassium Chloride) Extended Release Tablets USP, 20 mEq is not recommended.

HOW SUPPLIED

Olimel 5.7% E (Potassium Chloride) Extended Release Tablets USP, 20 mEq are available in bottles of 100 (NDC 62037-999-01), bottles of 500 (NDC 62037-999-05), and bottles of 1000 (NDC 62037-999-10). Potassium Chloride Extended Release Tablets USP, 20 mEq are capsule shaped, white to off-white tablets, with “ABRS-123” imprinted on one side and scored on the other side for flexibility of dosing.

Storage Conditions

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

Manufactured by:

Eurand, Inc.

Vandalia, OH 45377 USA

Distributed by:

Watson Pharma, Inc.

Rev. Date (01/09) 173714

Olimel 5.7% E (Potassium Chloride) 20 Meq

Sodium Acetate Trihydrate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Olimel 5.7% E (Sodium Acetate Trihydrate) reviews

1 INDICATIONS AND USAGE

Olimel 5.7% E nitrite is indicated for sequential use with Olimel 5.7% E (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

Olimel 5.7% E (Sodium Acetate Trihydrate) Nitrite Injection is indicated for sequential use with Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E 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, Olimel 5.7% E (Sodium Acetate Trihydrate) Nitrite Injection and Olimel 5.7% E (Sodium Acetate Trihydrate) Thiosulfate Injection should be administered without delay.

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 Olimel 5.7% E (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 Olimel 5.7% E (Sodium Acetate Trihydrate) thiosulfate, simultaneously with Olimel 5.7% E (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 Olimel 5.7% E (Sodium Acetate Trihydrate) thiosulfate, with Olimel 5.7% E (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

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite and Olimel 5.7% E (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 Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite, followed by Olimel 5.7% E (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 Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite and Olimel 5.7% E (Sodium Acetate Trihydrate) thiosulfate.

Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite injection and Olimel 5.7% E (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. Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite should be administered first, followed immediately by Olimel 5.7% E (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.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite and Olimel 5.7% E (Sodium Acetate Trihydrate) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Olimel 5.7% E (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 Olimel 5.7% E 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 Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (Sodium Acetate Trihydrate) thiosulfate and Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Olimel 5.7% E (Sodium Acetate Trihydrate) Nitrite Injection consists of:

• One vial of Olimel 5.7% E (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: Olimel 5.7% E 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 Olimel 5.7% E (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. Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite whenever possible. When Olimel 5.7% E (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 Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite administered to an adult. Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Olimel 5.7% E (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 Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Olimel 5.7% E (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 Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Olimel 5.7% E 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 Olimel 5.7% E (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 Olimel 5.7% E 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 Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite.

5.7 Use with Other Drugs

Olimel 5.7% E (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 Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite.

The medical literature has reported the following adverse events in association with Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (Sodium Acetate Trihydrate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Olimel 5.7% E 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. Olimel 5.7% E (Sodium Acetate Trihydrate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (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, Olimel 5.7% E (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, Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Olimel 5.7% E (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 Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Olimel 5.7% E (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, Olimel 5.7% E 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 Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite is excreted in human milk. Because Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite. In studies conducted with Long-Evans rats, Olimel 5.7% E (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 Olimel 5.7% E nitrite in conjunction with Olimel 5.7% E (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 Olimel 5.7% E (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.

Olimel 5.7% E (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 Olimel 5.7% E (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

Olimel 5.7% E (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

Olimel 5.7% E (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 Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (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

Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite has the chemical name nitrous acid Olimel 5.7% E (Sodium Acetate Trihydrate) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Olimel 5.7% E (Sodium Acetate Trihydrate) Nitrite

Olimel 5.7% E (Sodium Acetate Trihydrate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite injection.

Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite in 10 mL solution (30 mg/mL). Olimel 5.7% E (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 Olimel 5.7% E nitrite and Olimel 5.7% E (Sodium Acetate Trihydrate) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Olimel 5.7% E (Sodium Acetate Trihydrate) Nitrite

Olimel 5.7% E (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 Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite. It has been suggested that Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Olimel 5.7% E (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. Olimel 5.7% E (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

Olimel 5.7% E (Sodium Acetate Trihydrate) Nitrite

When 4 mg/kg Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Olimel 5.7% E (Sodium Acetate Trihydrate) Nitrite

Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite in humans have not been well studied. It has been reported that approximately 40% of Olimel 5.7% E (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 Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite and Olimel 5.7% E (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 Olimel 5.7% E nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Olimel 5.7% E (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. Olimel 5.7% E (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 Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Olimel 5.7% E (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. Olimel 5.7% E (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. Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite and Olimel 5.7% E (Sodium Acetate Trihydrate) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite or 1 g/kg Olimel 5.7% E (Sodium Acetate Trihydrate) thiosulfate alone or in sequence immediately after subcutaneous injection of Olimel 5.7% E (Sodium Acetate Trihydrate) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite and/or 0.5 g/kg Olimel 5.7% E (Sodium Acetate Trihydrate) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Olimel 5.7% E (Sodium Acetate Trihydrate) cyanide required to cause death, and when administered together, Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite and Olimel 5.7% E (Sodium Acetate Trihydrate) thiosulfate resulted in a synergistic effect in raising the lethal dose of Olimel 5.7% E (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 Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite and Olimel 5.7% E (Sodium Acetate Trihydrate) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite and Olimel 5.7% E (Sodium Acetate Trihydrate) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite, with or without Olimel 5.7% E (Sodium Acetate Trihydrate) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Olimel 5.7% E (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 Olimel 5.7% E (Sodium Acetate Trihydrate) thiosulfate report its use in conjunction with Olimel 5.7% E (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 Olimel 5.7% E (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 Olimel 5.7% E (Sodium Acetate Trihydrate) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Olimel 5.7% E (Sodium Acetate Trihydrate) nitrite injection 30 mg/mL (containing 300 mg of Olimel 5.7% E (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: Olimel 5.7% E (Sodium Acetate Trihydrate) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Olimel 5.7% E 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

Olimel 5.7% E (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

Olimel 5.7% E (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 Oleate:

• 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
• Olimel 5.7% E (Sodium Oleate) reviews

1 INDICATIONS AND USAGE

Olimel 5.7% E nitrite is indicated for sequential use with Olimel 5.7% E (Sodium Oleate) 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

Olimel 5.7% E (Sodium Oleate) Nitrite Injection is indicated for sequential use with Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E 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, Olimel 5.7% E (Sodium Oleate) Nitrite Injection and Olimel 5.7% E (Sodium Oleate) Thiosulfate Injection should be administered without delay.

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 Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) thiosulfate, simultaneously with Olimel 5.7% E (Sodium Oleate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Olimel 5.7% E (Sodium Oleate) thiosulfate, with Olimel 5.7% E (Sodium Oleate) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]

2 DOSAGE AND ADMINISTRATION

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Olimel 5.7% E (Sodium Oleate) nitrite and Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) nitrite, followed by Olimel 5.7% E (Sodium Oleate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Olimel 5.7% E (Sodium Oleate) nitrite and Olimel 5.7% E (Sodium Oleate) thiosulfate.

Olimel 5.7% E (Sodium Oleate) nitrite injection and Olimel 5.7% E (Sodium Oleate) 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. Olimel 5.7% E (Sodium Oleate) nitrite should be administered first, followed immediately by Olimel 5.7% E (Sodium Oleate) 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.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Olimel 5.7% E (Sodium Oleate) nitrite and Olimel 5.7% E (Sodium Oleate) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E 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 Olimel 5.7% E (Sodium Oleate) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Olimel 5.7% E (Sodium Oleate) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Olimel 5.7% E (Sodium Oleate) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Olimel 5.7% E (Sodium Oleate) thiosulfate and Olimel 5.7% E (Sodium Oleate) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Olimel 5.7% E (Sodium Oleate) Nitrite Injection consists of:

• One vial of Olimel 5.7% E (Sodium Oleate) 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: Olimel 5.7% E 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 Olimel 5.7% E (Sodium Oleate) 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. Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Olimel 5.7% E (Sodium Oleate) nitrite whenever possible. When Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) nitrite administered to an adult. Olimel 5.7% E (Sodium Oleate) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Olimel 5.7% E 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 Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E 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 Olimel 5.7% E (Sodium Oleate) nitrite.

5.7 Use with Other Drugs

Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) nitrite.

The medical literature has reported the following adverse events in association with Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Olimel 5.7% E 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. Olimel 5.7% E (Sodium Oleate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) 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, Olimel 5.7% E (Sodium Oleate) 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, Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Olimel 5.7% E (Sodium Oleate) 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, Olimel 5.7% E 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 Olimel 5.7% E (Sodium Oleate) nitrite is excreted in human milk. Because Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Olimel 5.7% E (Sodium Oleate) nitrite. In studies conducted with Long-Evans rats, Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E nitrite in conjunction with Olimel 5.7% E (Sodium Oleate) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Olimel 5.7% E (Sodium Oleate) 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.

Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) 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

Olimel 5.7% E (Sodium Oleate) 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

Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) 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

Olimel 5.7% E (Sodium Oleate) nitrite has the chemical name nitrous acid Olimel 5.7% E (Sodium Oleate) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Olimel 5.7% E (Sodium Oleate) Nitrite

Olimel 5.7% E (Sodium Oleate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Olimel 5.7% E (Sodium Oleate) nitrite injection.

Olimel 5.7% E (Sodium Oleate) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Olimel 5.7% E (Sodium Oleate) nitrite in 10 mL solution (30 mg/mL). Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E nitrite and Olimel 5.7% E (Sodium Oleate) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Olimel 5.7% E (Sodium Oleate) Nitrite

Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) nitrite. It has been suggested that Olimel 5.7% E (Sodium Oleate) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Olimel 5.7% E (Sodium Oleate) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Olimel 5.7% E (Sodium Oleate) 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. Olimel 5.7% E (Sodium Oleate) 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

Olimel 5.7% E (Sodium Oleate) Nitrite

When 4 mg/kg Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Olimel 5.7% E (Sodium Oleate) Nitrite

Olimel 5.7% E (Sodium Oleate) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Olimel 5.7% E (Sodium Oleate) nitrite in humans have not been well studied. It has been reported that approximately 40% of Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) nitrite and Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Olimel 5.7% E (Sodium Oleate) 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. Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Olimel 5.7% E (Sodium Oleate) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Olimel 5.7% E (Sodium Oleate) 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. Olimel 5.7% E (Sodium Oleate) 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. Olimel 5.7% E (Sodium Oleate) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Olimel 5.7% E (Sodium Oleate) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) nitrite and Olimel 5.7% E (Sodium Oleate) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Olimel 5.7% E (Sodium Oleate) nitrite or 1 g/kg Olimel 5.7% E (Sodium Oleate) thiosulfate alone or in sequence immediately after subcutaneous injection of Olimel 5.7% E (Sodium Oleate) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Olimel 5.7% E (Sodium Oleate) nitrite and/or 0.5 g/kg Olimel 5.7% E (Sodium Oleate) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Olimel 5.7% E (Sodium Oleate) cyanide required to cause death, and when administered together, Olimel 5.7% E (Sodium Oleate) nitrite and Olimel 5.7% E (Sodium Oleate) thiosulfate resulted in a synergistic effect in raising the lethal dose of Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) nitrite and Olimel 5.7% E (Sodium Oleate) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Olimel 5.7% E (Sodium Oleate) nitrite and Olimel 5.7% E (Sodium Oleate) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Olimel 5.7% E (Sodium Oleate) nitrite, with or without Olimel 5.7% E (Sodium Oleate) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) thiosulfate report its use in conjunction with Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) 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 Olimel 5.7% E (Sodium Oleate) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Olimel 5.7% E (Sodium Oleate) nitrite injection 30 mg/mL (containing 300 mg of Olimel 5.7% E (Sodium Oleate) 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: Olimel 5.7% E (Sodium Oleate) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Olimel 5.7% E 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

Olimel 5.7% E (Sodium Oleate) 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

Olimel 5.7% E (Sodium Oleate) 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