RAVICTI® (glycerol phenylbutyrate) oral liquid

RAVICTI® (glycerol phenylbutyrate) oral liquid

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RAVICTI® (glycerol phenylbutyrate) oral liquid

RAVICTI (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.

Glycerol phenylbutyrate is a nitrogen-binding agent. It is a triglyceride containing 3 molecules of PBA linked to a 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.

Indications and usage

RAVICTI is a nitrogen-binding agent indicated for chronic management of patients with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. RAVICTI must be used with dietary protein restriction and, in some cases, dietary supplements.

Limitations of Use:

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

Mechanism of Action

UCDs are inherited deficiencies of enzymes or transporters necessary for the synthesis of urea from ammonia (NH3, NH4 + ). Absence of these enzymes or transporters results in the accumulation of toxic levels of ammonia in the blood and brain of affected patients. RAVICTI is a triglyceride containing 3 molecules of PBA. PAA, the major metabolite of PBA, is the active moiety of RAVICTI. 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. On a molar basis, PAGN, like urea, contains 2 moles of nitrogen and provides an alternate vehicle for waste nitrogen excretion.

Dosage and administration

RAVICTI should be prescribed by a physician experienced in management of UCDs. For administration and preparation, see full prescribing information.

Switching From Sodium Phenylbutyrate Tablets or Powder to RAVICTI:

  • Patients should receive the dosage of RAVICTI that contains the same amount of phenylbutyric acid, see full prescribing information for conversion

Initial Dosage in Phenylbutyrate-Naïve Patients:

  • 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.

Contraindications

RAVICTI is contraindicated in patients with known hypersensitivity to phenylbutyrate. Signs of hypersensitivity include wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash.

Warnings and precautions

Neurotoxicity: Increased exposure to PAA, the major metabolite of RAVICTI, may be associated with neurotoxicity in patients with UCDs.

If symptoms of vomiting, nausea, headache, somnolence or confusion are present in the absence of high ammonia or other intercurrent illness which explains these symptoms, consider the potential for PAA neurotoxicity which may need reduction in the RAVICTI dosage

Pancreatic Insufficiency or Intestinal Malabsorption: Exocrine pancreatic enzymes hydrolyze RAVICTI in the small intestine, separating the active moiety, phenylbutyrate, from 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 RAVICTI and/or absorption of phenylbutyrate and reduced control of plasma ammonia. Monitor ammonia levels closely in patients with pancreatic insufficiency or intestinal malabsorption.

Adverse reactions

Most common adverse reactions (≥10%) in adults are: diarrhea, flatulence, and headache.

Drug interactions

Corticosteroids: Use of corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels. Monitor ammonia levels closely when corticosteroids and RAVICTI are used concomitantly.

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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.

Probenecid: Probenecid may inhibit the renal excretion of metabolites of RAVICTI including PAGN and PAA.

Drugs with narrow therapeutic index that are substrates of CYP3A4: RAVICTI is a weak inducer of CYP3A4 in humans. Concomitant use of RAVICTI 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 RAVICTI decreased the systemic exposure of midazolam. Monitor for suboptimal effect of midazolam in patients who are being treated with RAVICTI.

Use in specific populations

Pregnancy: Limited available data with RAVICTI use in pregnant women are insufficient to inform a drug-associated risk of major birth defects and miscarriage.

Lactation: There are no data on the presence of RAVICTI 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 RAVICTI.

Patients 2 Years to 17 Years of Age: The safety and effectiveness of RAVICTI in patients 2 years to less than 18 years of age have been established in 3 clinical studies: 2 open-label, fixed-sequence, switchover clinical studies from sodium phenylbutyrate to RAVICTI, and 1 long-term, open label safety study.

Patients Less Than 2 Years of Age: The safety and effectiveness of RAVICTI in patients with UCDs less than 2 years of age have been established in 3 open-label studies. Pharmacokinetics and pharmacodynamics (plasma ammonia), and safety were studied in 17 patients aged 2 months to less than 2 years of age and in 16 patients less than 2 months of age

Geriatric Use: Clinical studies of RAVICTI 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.

Renal Impairment: The efficacy and safety of RAVICTI in patients with renal impairment are unknown. Monitor ammonia levels closely when starting patients with impaired renal function on RAVICTI.

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

Overdosage

While there is no experience with overdosage in human clinical trials, PAA, a toxic metabolite of RAVICTI, 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.

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