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Hyperion Therapeutics, Inc. is a commercial-stage biopharmaceutical company committed to advancing science and developing treatments for orphan and hepatic diseases. RAVICTI™ is our first approved product for the treatment of urea cycle disorders (UCDs) and is being developed for a second orphan indication, hepatic encephalopathy.
FDA-approved and now available.
RAVICTI INDICATIONS AND USAGE
RAVICTI is indicated for use as a nitrogen-binding agent for chronic management of adult and pediatric patients ≥2 years of age 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 (eg, essential amino acids, arginine, citrulline, or protein-free calorie supplements).
LIMITATIONS OF USE:
- RAVICTI 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 RAVICTI for the treatment of N-acetylglutamate synthase (NAGS) deficiency has not been established.
- The use of RAVICTI in patients <2 months of age is contraindicated.
RAVICTI IMPORTANT SAFETY INFORMATION
- Patients less than 2 months of age. Children <2 months of age may have immature pancreatic exocrine function, which could impair hydrolysis of RAVICTI, 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.
WARNINGS AND PRECAUTIONS:
- Neurotoxcity: Phenylacetate (PAA), the major metabolite of RAVICTI, may be toxic at levels ≥500 μg/mL. Reduce RAVICTI dosage if symptoms of neurotoxicity, including vomiting, nausea, headache, somnolence, confusion, or sleepiness, are present in the absence of high ammonia or other intercurrent illnesses.
- Reduced Phenylbutyrate Absorption in Pancreatic Insufficiency or Intestinal Malabsorption: Monitor ammonia levels closely. 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.
- Adverse reactions occurring in ≥10% of adult patients during short-term treatment (4 weeks) with RAVICTI were diarrhea, flatulence, and headache (n=44). Adverse reactions occurring in ≥10% of adult patients during long-term treatment (12 months [median exposure=51 weeks]) with RAVICTI were nausea, vomiting, diarrhea, decreased appetite, hyperammonemia, dizziness, headache, and fatigue (n=51).
- Adverse events occurring in ≥10% of pediatric patients during long-term treatment (12 months [median exposure=51 weeks]) with RAVICTI were upper abdominal pain, rash, nausea, vomiting, diarrhea, decreased appetite, hyperammonemia, and headache (n=26).
- Corticosteroids, valproic acid, or haloperidol: May increase plasma ammonia level. Monitor ammonia levels closely.
- Probenecid: May affect renal excretion of metabolites of RAVICTI, including PAGN and PAA.
- Pregnancy: Based on animal data, may cause fetal harm. A voluntary patient registry will include evaluation of pregnancy outcomes in patients with UCDs. For more information regarding the registry program, visit www.ucdregistry.com or call 1-855-823-2595.
- Nursing Mothers: Discontinue nursing or discontinue the drug.
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BUPHENYL INDICATIONS AND USAGE
BUPHENYL® (sodium phenylbutyrate) Tablets for oral administration and BUPHENYL® (sodium phenylbutyrate) Powder for oral, nasogastric, or gastrostomy tube administration are indicated as adjunctive therapy in the chronic management of patients with urea cycle disorders (UCDs) involving deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC), or argininosuccinic acid synthetase (AS).
BUPHENYL is indicated in all patients with neonatal-onset deficiency (complete enzymatic deficiency, presenting within the first 28 days of life). It is also indicated in patients with late-onset disease (partial enzymatic deficiency, presenting after the first month of life) who have a history of hyperammonemic encephalopathy. It is important that the diagnosis be made early and treatment initiated immediately to improve survival.
BUPHENYL must be combined with dietary protein restriction and, in some cases, essential amino acid supplementation.
Any episode of acute hyperammonemia should be treated as a life-threatening emergency.
BUPHENYL IMPORTANT SAFETY INFORMATION
- BUPHENYL should not be used to manage acute hyperammonemia, which is a medical emergency.
WARNINGS AND PRECAUTIONS:
- Use with great care, if at all, in patients with congestive heart failure or severe renal insufficiency, and in clinical states in which there is sodium retention with edema.
- Use caution when administering BUPHENYL to patients with hepatic or renal insufficiency or inborn errors of beta oxidation.
- Probenecid may affect renal excretion of the conjugated product of BUPHENYL as well as its metabolite.
- Use of corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels.
- BUPHENYL should not be administered to patients with known hypersensitivity to sodium phenylbutyrate or any component of this preparation.
- There have been published reports of hyperammonemia being induced by haloperidol and by valproic acid.
The assessment of clinical adverse events came from 206 patients treated with sodium phenylbutyrate. Adverse events (both clinical and laboratory) were not collected systematically in these patients, but were obtained from patient-visit reports by the 65 co-investigators.
- In female patients, the most common clinical adverse event reported was amenorrhea/menstrual dysfunction (occurring in 23% of the menstruating patients).
- Decreased appetite, body odor (probably caused by the metabolite PAA), and bad taste or taste aversion were each reported in 4%, 3%, and 3% of patients, respectively.
- Neurotoxicity was reported in cancer patients receiving intravenous phenylacetate. Manifestations were predominately somnolence, fatigue, and lightheadedness; with less frequent headache, dysgeusia, hypoacusis, disorientation, impaired memory, and exacerbation of a pre-existing neuropathy.
- Laboratory adverse events occurring in >2% of UCD patients by body system were:
- Metabolic: acidosis, alkalosis, hyperchloremia, and hypophosphatemia
- Nutritional: hypoalbuminemia and decreased total protein
- Hepatic: increased alkaline phosphatase and increased liver transaminases
- Hematologic: anemia, leukopenia, leukocytosis, and thrombocytopenia
USE IN SPECIAL POPULATIONS:
- Pregnancy Category C: It is not known whether BUPHENYL can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. BUPHENYL should be given to a pregnant woman only if clearly needed. A voluntary patient registry will include evaluation of pregnancy outcomes in patients with UCDs. For more information regarding the registry program, visit www.ucdregistry.com or call 1-855-823-2595.
- Nursing mothers: It is not known whether BUPHENYL is excreted in human milk. Caution should be exercised when BUPHENYL is administered to a nursing woman.
- Pediatric use: The use of tablets for neonates, infants, and children to the weight of 20 kg is not recommended.
Please review full Prescribing Information and Patient Package Insert.