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The major metabolite of RAVICTI, 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 ≥ 500 μg/mL in a study of cancer patients who were administered IV PAA. In this study, adverse events were reversible.
In healthy subjects, after administration of 4 mL and 6 mL RAVICTI 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 < 100 μg/mL.
In clinical trials in UCD patients who had been on sodium phenylbutyrate prior to administration of RAVICTI, peak PAA concentrations after dosing with RAVICTI ranged from 1.6 to 178 μg/mL (mean: 39 μg/mL) in adult patients and from 7 to 480 μg/mL (mean: 90 μg/mL) in pediatric patients. Some UCD patients 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, confusion, or sleepiness are present in the absence of high ammonia or other intercurrent illnesses, reduce the RAVICTI dosage.
Reduced Phenylbutyrate Absorption In 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.
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide).
Instruct patients or their caregivers on the following information necessary for patients to use the drug safely and effectively:
Instruct patients that the risks associated with RAVICTI include the following:
Common adverse reactions of RAVICTI include diarrhea, gas, and headache. Adverse reactions of RAVICTI are sometimes the same as symptoms of high blood ammonia. Headache, feeling tired, lightheadedness, and confusion are possible adverse reactions of RAVICTI. If the patient experiences these symptoms, instruct the patient to call their doctor right away. The major metabolite of RAVICTI, PAA, is associated with neurological toxicity manifested by somnolence, fatigue, lightheadedness, headache, dysgeusia, hypoacusis, disorientation, and impaired memory. These symptoms of neurological toxicity may be reversible. Instruct the patient to call their doctor if exhibiting these symptoms. Blood tests may be done to measure the amount of PAA in the blood.
Patients and their caregivers should be informed that a registry for UCD patients has been established by Horizon Therapeutics in order to better assess long-term outcomes in patients with UCDs, including growth and neurocognitive outcomes and the outcome of pregnancy for women with UCDs who become pregnant. Patients and their caregivers are encouraged to participate in the registry and advised that their participation is voluntary. For more information regarding the registry program, call 1-855-823-2595.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In a 2-year study in Sprague-Dawley rats, 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 6.87 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 6.87 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 7.45 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 7.45 mL/m²/day in pediatric patients, based on combined AUCs for PBA and PAA. In a 26-week study in transgenic (Tg.rasH2) mice, glycerol phenylbutyrate was not tumorigenic at doses up to 1000 mg/kg/day.
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
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 6.87 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.
Use In Specific Populations
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.
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. In rabbits given glycerol phenylbutyrate at doses up to 2.7 times the dose of 6.87 mL/m²/day in adult patients (based on combined area under the curve [AUCs] for PBA and PAA) during the period of organogenesis, maternal toxicity, but no effects on embryo-fetal development, was observed. In rats given glycerol phenylbutyrate at 1.9 times the dose of 6.87 mL/m²/day in adult patients (based on combined AUCs for PBA and PAA), no adverse embryo-fetal effects were observed. Maternal toxicity, reduced fetal weights, and variations in skeletal development were observed in rats at doses greater than or equal to 5.7 times the dose of 6.87 mL/m²/day in adult patients (based on combined AUCs for PBA and PAA). RAVICTI should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Oral administration of 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 AUCs for PBA and PAA. In rats, at an oral dose of 300 mg/kg/day of 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 ≥ 650 mg/kg/day 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 in rats through day 92 postpartum following oral administration in pregnant rats with up to 900 mg/kg/day of 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.
Breastfeeding is not recommended with maternal use of RAVICTI. It is not known whether RAVICTI or its metabolites are present in breast milk. Because many drugs are present in breast milk and because of the potential for tumorigencity of glycerol phenylbutyrate identified in animal studies, as well as the potential for serious adverse reactions in nursing infants from RAVICTI , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into consideration the importance of the drug to the health of the mother [see Use in Specific Populations and Nonclinical Toxicology].
Patients Between 2 and < 18 Years of Age
The safety and efficacy of RAVICTI in patients 2 to < 18 years of age were established in 2 open-label, sodium phenylbutyrate to RAVICTI, fixed-sequence, switchover clinical trials [see ADVERSE REACTIONS and Clinical Studies].
Patients ≥ 2 Months and < 2 Years of Age
The safety and efficacy of RAVICTI in patients 2 months to < 2 years of age has not been established. PK and ammonia control were studied in only 4 patients between 2 months and < 2 years of age, providing insufficient data to establish a safe and effective dose in this age range.
Patients < 2 Months of Age
RAVICTI is contraindicated in patients < 2 months of age [see CONTRAINDICATIONS]. Children < 2 months of age may have immature pancreatic exocrine function, which could impair hydrolysis of RAVICTI. Pancreatic lipases may be necessary for intestinal hydrolysis of RAVICTI, 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 RAVICTI. If there is inadequate intestinal hydrolysis of RAVICTI, impaired absorption of phenylbutyrate and hyperammonemia could occur.
Juvenile Animal Study
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. 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 (2.6 times the dose of 6.87 mL/m²/day in adult patients, based on combined AUCs for PBA and PAA). Embryo toxicity (increased resorptions) occurred at 650 mg/kg/day (2.6 times the dose of 6.87 mL/m²/day in adult patients, based on combined AUCs for PBA and PAA) and litter size was reduced at 900 mg/kg/day (3 times the dose of 6.87 mL/m²/day in adult patients, based on combined AUCs for PBA and PAA).
Clinical studies of RAVICTI did not include sufficient numbers of subjects ≥ 65 years of age 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.
No studies were conducted in UCD patients with 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 [see CLINICAL PHARMACOLOGY].
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.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 1/26/2016
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