Glycerolyte 57 Solution

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
• Glycerolyte 57 Solution (Glycerol) reviews

Glycerolyte 57 Solution (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. Glycerolyte 57 Solution (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:

• Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol) for the treatment of N-acetylglutamate synthase (NAGS) deficiency has not been established.

Glycerolyte 57 Solution (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. Glycerolyte 57 Solution (Glycerol) must be used with dietary protein restriction and, in some cases, dietary supplements. (1)

Limitations of Use:

• Glycerolyte 57 Solution (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

• Glycerolyte 57 Solution 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 Glycerolyte 57 Solution (Glycerol):

• Patients should receive the dosage of Glycerolyte 57 Solution (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

Glycerolyte 57 Solution (Glycerol) should be prescribed by a physician experienced in the management of UCDs.

• Instruct patients to take Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol) and patients naïve to phenylbutyric acid are different . For both subpopulations:
  • Patients 2 years of age and older: Give Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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).
  • Glycerolyte 57 Solution (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 Glycerolyte 57 Solution

Patients switching from sodium phenylbutyrate to Glycerolyte 57 Solution (Glycerol) should receive the dosage of Glycerolyte 57 Solution (Glycerol) that contains the same amount of phenylbutyric acid. The conversion is as follows:

Total daily dosage of Glycerolyte 57 Solution (Glycerol) (mL) = total daily dosage of sodium phenylbutyrate tablets (g) × 0.86

Total daily dosage of Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol) dose for a 24-hour period is 0.6 mL Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol) as follows:

• Utilize an oral syringe to withdraw the prescribed dosage of Glycerolyte 57 Solution (Glycerol) from the bottle.
• Place the tip of the syringe into the nasogastric/gastrostomy tube.
• Utilizing the plunger of the syringe, administer Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol) to the plastic tubing. Therefore, these patients should be closely monitored using ammonia levels following initiation of Glycerolyte 57 Solution (Glycerol) dosing or dosage adjustments.

3 DOSAGE FORMS AND STRENGTHS

Oral liquid: colorless to pale yellow, 1.1 g/mL of Glycerolyte 57 Solution (Glycerol) phenylbutyrate (delivers 1.02 g/mL of phenylbutyrate).

Oral liquid: 1.1 g/mL. (3)

4 CONTRAINDICATIONS

Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol), peak PAA concentrations after dosing with Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol) dosage .

5.2 Reduced Phenylbutyrate Absorption in Pancreatic Insufficiency or Intestinal Malabsorption

Exocrine pancreatic enzymes hydrolyze Glycerolyte 57 Solution (Glycerol) in the small intestine, separating the active moiety, phenylbutyrate, from Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol) were diarrhea, flatulence, and headache. Table 1 summarizes adverse reactions occurring in 2 or more patients treated with Glycerolyte 57 Solution (Glycerol) or sodium phenylbutyrate (incidence of at least 4% in either treatment arm).

Other Adverse Reactions

Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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.

Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol), including phenylacetylglutamine (PAGN) and PAA. (7.2)
• CYP3A4 Substrates with narrow therapeutic index (e.g., alfentanil, quinidine, cyclosporine): Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution

Probenecid

Probenecid may inhibit the renal excretion of metabolites of Glycerolyte 57 Solution (Glycerol) including PAGN and PAA.

7.3 Potential for Glycerolyte 57 Solution to Affect Other Drugs

Drugs with narrow therapeutic index that are substrates of CYP3A4

Glycerolyte 57 Solution (Glycerol) is a weak inducer of CYP3A4 in humans. Concomitant use of Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol) decreased the systemic exposure of midazolam. Monitor for suboptimal effect of midazolam in patients who are being treated with Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol) during pregnancy. Healthcare providers are encouraged to report any prenatal exposure to Glycerolyte 57 Solution (Glycerol) by calling the Pregnancy Registry at 1-855-823-2595 or visiting www.ucdregistry.com.

Risk Summary

Limited available data with Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution 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 Glycerolyte 57 Solution (Glycerol).

8.4 Pediatric Use

Safety and efficacy of Glycerolyte 57 Solution (Glycerol) have been established in pediatric patients 2 months of age and older with UCDs.

Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol) in patients 2 years to less than 18 years of age were established in 2 open-label, sodium phenylbutyrate to Glycerolyte 57 Solution (Glycerol), fixed-sequence, switchover clinical studies .

Patients 2 Months to Less Than 2 Years of Age

The safety and efficacy of Glycerolyte 57 Solution (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

Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol). Pancreatic lipases may be necessary for intestinal hydrolysis of Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol). If there is inadequate intestinal hydrolysis of Glycerolyte 57 Solution (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 Glycerolyte 57 Solution 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 Glycerolyte 57 Solution (Glycerol) in patients with renal impairment are unknown. Monitor ammonia levels closely when starting patients with impaired renal function on Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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

Glycerolyte 57 Solution (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.

Glycerolyte 57 Solution (Glycerol) phenylbutyrate is a nitrogen-binding agent. It is a triglyceride containing 3 molecules of PBA linked to a Glycerolyte 57 Solution (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. Glycerolyte 57 Solution (Glycerol) is a triglyceride containing 3 molecules of phenylbutyrate (PBA). PAA, the major metabolite of PBA, is the active moiety of Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol) and sodium phenylbutyrate .

Cardiac Electrophysiology

The effect of multiple doses of Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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

Glycerolyte 57 Solution (Glycerol) is a pro-drug of PBA. Upon oral ingestion, PBA is released from the Glycerolyte 57 Solution (Glycerol) backbone in the gastrointestinal tract by lipases. PBA derived from Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol), peak plasma levels of PBA, PAA, and PAGN occurred at 2 hours, 4 hours, and 4 hours, respectively. Upon single-dose administration of Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol) phenylbutyrate was detected in plasma. While the study was inconclusive, the incomplete hydrolysis of Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol) (i.e., Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol) phenylbutyrate was in the following decreasing order: pancreatic triglyceride lipase, carboxyl ester lipase, and pancreatic lipase–related protein 2. Further, Glycerolyte 57 Solution (Glycerol) phenylbutyrate was hydrolyzed in vitro by esterases in human plasma. In these in vitro studies, a complete disappearance of Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol) twice daily for 7 days.

Plasma Glycerolyte 57 Solution (Glycerol) phenylbutyrate was not measured in patients with hepatic impairment.

After multiple doses of Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol) on other drugs

Midazolam

In healthy subjects, when oral midazolam was administered after multiple doses of Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol) did not significantly affect the pharmacokinetics of celecoxib, a substrate of CYP2C9. When 200 mg of celecoxib was orally administered with Glycerolyte 57 Solution (Glycerol) after multiple doses of Glycerolyte 57 Solution (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, Glycerolyte 57 Solution (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, Glycerolyte 57 Solution (Glycerol) phenylbutyrate was not tumorigenic at doses up to 1000 mg/kg/day.

Mutagenesis

Glycerolyte 57 Solution (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

Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 → Glycerolyte 57 Solution (Glycerol) for 2 weeks; or
• Glycerolyte 57 Solution (Glycerol) for 2 weeks → sodium phenylbutyrate for 2 weeks.

Sodium phenylbutyrate or Glycerolyte 57 Solution (Glycerol) were administered three times daily with meals. The dose of Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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.

Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol) (range: 6 to 30 micromol/L). Of 51 adult patients participating in the 12-month, open-label treatment with Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol) (range: 24.2 to 31.4 micromol/L). Of the 43 adult patients participating in the open-label treatment with Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol) in pediatric patients 2 to 17 years of age with UCDs was evaluated in 2 fixed-sequence, open-label, sodium phenylbutyrate to Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol). Mean fasting venous ammonia values were within normal limits during long-term treatment with Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol) (range: 15.4 to 25.1 micromol/L). Of the 45 pediatric patients participating in the open-label treatment with Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol). The dosage of Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol) was initiated. The dosage of Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol). The dosage of Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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

Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol) are sometimes the same as symptoms of high blood ammonia. Neurological adverse events may also be associated with the major metabolite of Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol) during pregnancy .

Lactation

Advise patients that breastfeeding is not recommended during treatment with Glycerolyte 57 Solution (Glycerol) .

Administration

• Instruct patients to take Glycerolyte 57 Solution (Glycerol) with food or formula and to administer directly into the mouth via oral syringe or dosing cup.
• Instruct patients to take Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Glycerol) as follows:
  • Utilize an oral syringe to withdraw the prescribed dosage of Glycerolyte 57 Solution (Glycerol) from the bottle.
  • Place the tip of the syringe into the gastrostomy/nasogastric tube.
  • Utilizing the plunger of the syringe, administer Glycerolyte 57 Solution (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.

Glycerolyte 57 Solution (Glycerol) is a registered trademark of Horizon Therapeutics, LLC.

Potassium Chloride:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Glycerolyte 57 Solution (Potassium Chloride) reviews

Glycerolyte 57 Solution (Potassium Chloride) EXTENDED RELEASE TABLETS USP 20 mEq K

Rx Only

DESCRIPTION

The Glycerolyte 57 Solution (Potassium Chloride) Extended Release Tablets USP, 20 mEq product is an immediately dispersing extended release oral dosage form of Glycerolyte 57 Solution (Potassium Chloride) containing 1500 mg of microencapsulated Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Potassium Chloride) within the gastrointestinal tract is reduced.

Glycerolyte 57 Solution (Potassium Chloride) Extended Release Tablets USP, 20 mEq is an electrolyte replenisher. The chemical name of the active ingredient is Glycerolyte 57 Solution (Potassium Chloride), and the structural formula is KCl. Glycerolyte 57 Solution (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.

Glycerolyte 57 Solution (Potassium Chloride) Extended Release Tablets USP, 20 mEq is a tablet formulation (not enteric coated or wax matrix) containing individually microencapsulated Glycerolyte 57 Solution (Potassium Chloride) crystals which disperse upon tablet disintegration. In simulated gastric fluid at 37°C and in the absence of outside agitation, Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Potassium Chloride) (see PRECAUTIONS: Information for Patients , and DOSAGE AND ADMINISTRATION sections).

All solid oral dosage forms of Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Potassium Chloride) can produce ulcerative and/or stenotic lesions of the gastrointestinal tract. Based on spontaneous adverse reaction reports, enteric-coated preparations of Glycerolyte 57 Solution (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. Glycerolyte 57 Solution (Potassium Chloride) Extended Release Tablets USP, 20 mEq is a tablet formulated to provide a controlled rate of release of microencapsulated Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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. Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Potassium Chloride) that is not taken immediately should be discarded. The use of other liquids for suspending Glycerolyte 57 Solution (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 Glycerolyte 57 Solution 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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Potassium Chloride) Extended Release Tablet USP, 20 mEq provides 20 mEq of Glycerolyte 57 Solution (Potassium Chloride).

Glycerolyte 57 Solution (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 Glycerolyte 57 Solution (Potassium Chloride) that is not taken immediately should be discarded. The use of other liquids for suspending Glycerolyte 57 Solution (Potassium Chloride) Extended Release Tablets USP, 20 mEq is not recommended.

HOW SUPPLIED

Glycerolyte 57 Solution (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

Glycerolyte 57 Solution (Potassium Chloride) 20 Meq

Sodium Lactate:

• 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
• Glycerolyte 57 Solution (Sodium Lactate) reviews

1 INDICATIONS AND USAGE

Glycerolyte 57 Solution nitrite is indicated for sequential use with Glycerolyte 57 Solution (Sodium Lactate) 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

Glycerolyte 57 Solution (Sodium Lactate) Nitrite Injection is indicated for sequential use with Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution 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, Glycerolyte 57 Solution (Sodium Lactate) Nitrite Injection and Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) thiosulfate, simultaneously with Glycerolyte 57 Solution (Sodium Lactate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Glycerolyte 57 Solution (Sodium Lactate) thiosulfate, with Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) nitrite and Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) nitrite, followed by Glycerolyte 57 Solution (Sodium Lactate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Glycerolyte 57 Solution (Sodium Lactate) nitrite and Glycerolyte 57 Solution (Sodium Lactate) thiosulfate.

Glycerolyte 57 Solution (Sodium Lactate) nitrite injection and Glycerolyte 57 Solution (Sodium Lactate) 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. Glycerolyte 57 Solution (Sodium Lactate) nitrite should be administered first, followed immediately by Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) nitrite and Glycerolyte 57 Solution (Sodium Lactate) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution 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 Glycerolyte 57 Solution (Sodium Lactate) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Glycerolyte 57 Solution (Sodium Lactate) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Glycerolyte 57 Solution (Sodium Lactate) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Glycerolyte 57 Solution (Sodium Lactate) thiosulfate and Glycerolyte 57 Solution (Sodium Lactate) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Glycerolyte 57 Solution (Sodium Lactate) Nitrite Injection consists of:

• One vial of Glycerolyte 57 Solution (Sodium Lactate) 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: Glycerolyte 57 Solution 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 Glycerolyte 57 Solution (Sodium Lactate) 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. Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Glycerolyte 57 Solution (Sodium Lactate) nitrite whenever possible. When Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) nitrite administered to an adult. Glycerolyte 57 Solution (Sodium Lactate) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Glycerolyte 57 Solution 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 Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution 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 Glycerolyte 57 Solution (Sodium Lactate) nitrite.

5.7 Use with Other Drugs

Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) nitrite.

The medical literature has reported the following adverse events in association with Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Glycerolyte 57 Solution 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. Glycerolyte 57 Solution (Sodium Lactate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) 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, Glycerolyte 57 Solution (Sodium Lactate) 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, Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Glycerolyte 57 Solution (Sodium Lactate) 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, Glycerolyte 57 Solution 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 Glycerolyte 57 Solution (Sodium Lactate) nitrite is excreted in human milk. Because Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Glycerolyte 57 Solution (Sodium Lactate) nitrite. In studies conducted with Long-Evans rats, Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution nitrite in conjunction with Glycerolyte 57 Solution (Sodium Lactate) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Glycerolyte 57 Solution (Sodium Lactate) 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.

Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) 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

Glycerolyte 57 Solution (Sodium Lactate) 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

Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) 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

Glycerolyte 57 Solution (Sodium Lactate) nitrite has the chemical name nitrous acid Glycerolyte 57 Solution (Sodium Lactate) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Glycerolyte 57 Solution (Sodium Lactate) Nitrite

Glycerolyte 57 Solution (Sodium Lactate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Glycerolyte 57 Solution (Sodium Lactate) nitrite injection.

Glycerolyte 57 Solution (Sodium Lactate) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Glycerolyte 57 Solution (Sodium Lactate) nitrite in 10 mL solution (30 mg/mL). Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution nitrite and Glycerolyte 57 Solution (Sodium Lactate) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Glycerolyte 57 Solution (Sodium Lactate) Nitrite

Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) nitrite. It has been suggested that Glycerolyte 57 Solution (Sodium Lactate) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Glycerolyte 57 Solution (Sodium Lactate) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Glycerolyte 57 Solution (Sodium Lactate) 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. Glycerolyte 57 Solution (Sodium Lactate) 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

Glycerolyte 57 Solution (Sodium Lactate) Nitrite

When 4 mg/kg Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Glycerolyte 57 Solution (Sodium Lactate) Nitrite

Glycerolyte 57 Solution (Sodium Lactate) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Glycerolyte 57 Solution (Sodium Lactate) nitrite in humans have not been well studied. It has been reported that approximately 40% of Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) nitrite and Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Glycerolyte 57 Solution (Sodium Lactate) 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. Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Glycerolyte 57 Solution (Sodium Lactate) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Glycerolyte 57 Solution (Sodium Lactate) 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. Glycerolyte 57 Solution (Sodium Lactate) 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. Glycerolyte 57 Solution (Sodium Lactate) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Glycerolyte 57 Solution (Sodium Lactate) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) nitrite and Glycerolyte 57 Solution (Sodium Lactate) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Glycerolyte 57 Solution (Sodium Lactate) nitrite or 1 g/kg Glycerolyte 57 Solution (Sodium Lactate) thiosulfate alone or in sequence immediately after subcutaneous injection of Glycerolyte 57 Solution (Sodium Lactate) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Glycerolyte 57 Solution (Sodium Lactate) nitrite and/or 0.5 g/kg Glycerolyte 57 Solution (Sodium Lactate) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Glycerolyte 57 Solution (Sodium Lactate) cyanide required to cause death, and when administered together, Glycerolyte 57 Solution (Sodium Lactate) nitrite and Glycerolyte 57 Solution (Sodium Lactate) thiosulfate resulted in a synergistic effect in raising the lethal dose of Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) nitrite and Glycerolyte 57 Solution (Sodium Lactate) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Glycerolyte 57 Solution (Sodium Lactate) nitrite and Glycerolyte 57 Solution (Sodium Lactate) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Glycerolyte 57 Solution (Sodium Lactate) nitrite, with or without Glycerolyte 57 Solution (Sodium Lactate) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) thiosulfate report its use in conjunction with Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) 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 Glycerolyte 57 Solution (Sodium Lactate) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Glycerolyte 57 Solution (Sodium Lactate) nitrite injection 30 mg/mL (containing 300 mg of Glycerolyte 57 Solution (Sodium Lactate) 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: Glycerolyte 57 Solution (Sodium Lactate) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Glycerolyte 57 Solution 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

Glycerolyte 57 Solution (Sodium Lactate) 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

Glycerolyte 57 Solution (Sodium Lactate) 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