BIRTH TO LESS THAN 2 MONTHS

Adverse reactions in pediatric patients less than 2 months of age with UCDsa

Adverse reactions occurring in at least 10% of pediatric patients less than 2 months of age were vomiting, rash, gastroesophageal reflux, increased hepatic enzymes, feeding disorder (decreased appetite, hypophagia), anemia, cough, dehydration, metabolic acidosis, thrombocytosis, thrombocytopenia, neutropenia, lymphocytosis, diarrhea, flatulence, constipation, pyrexia, lethargy, and irritability/agitation.1

Of the 16 pediatric patients less than 2 months of age in an open-label study, 5 patients (31%) reported a total of 7 hyperammonemic crises, all of which occurred in patients less than 1 month of age.1

aAssessment of adverse reactions in a single open-label study of 16 patients with UCDs who began treatment at less than 2 months of age (median exposure, 10 months [range, 2-20 months]) to assess transition to RAVICTI over a period of 7 days. During the safety extension phase (months 1 to 24), ammonia levels were monitored monthly for the first 6 months of treatment then every 3 months thereafter until patient termination or completion of the study.1

2 MONTHS TO LESS THAN 2 YEARS

Adverse Reactions in pediatric patients 2 months to less than 2 years of age with UCDsb

Adverse reactions occurring in at least 10% of pediatric patients 2 months to less than 2 years of age were neutropenia, vomiting, constipation, diarrhea, pyrexia, hypophagia, cough, nasal congestion, rhinorrhea, rash, and papule.1

Of the 17 pediatric patients 2 months to less than 2 years of age in 3 open-label studies, 7 patients (41%) reported a total of 11 hyperammonemic crises.1

bAssessment of adverse reactions in 3 open-label studies of 17 patients with UCDs 2 months to less than 2 years of age (median exposure, 6 months [range, 0.2‑20 months]). One patient developed hyperammonemia during dosing and experienced surgical complications (bowel perforation and peritonitis) following jejunal tube placement; this patient developed hyperammonemic crisis, and subsequently died of sepsis from peritonitis unrelated to drug.1

2 TO 17 YEARS

Adverse Reactions in pediatric patients 2 to 17 years of age with UCDsc

Adverse reactions occurring in at least 10% of pediatric patients 2 to 17 years of age during 12 months of treatment with RAVICTI were upper abdominal pain, rash, nausea, vomiting, diarrhea, decreased appetite, and headache.1

Of the 26 pediatric patients 6 to 17 years of age, 5 patients (19%) reported a total of 5 hyperammonemic crises.1

cAssessment of adverse reactions in 2 open-label studies of 26 patients with UCDs 2 to 17 years of age being treated with RAVICTI for 12 months. There were no deaths during these studies.1

ADULT

Adverse reactions in adult patients with UCDsd

Adverse reactions reported in 2 or more adult patients with UCDs in a short-term clinical trial.1

Chart showing reported adverse reactions for RAVICTI in adult Urea Cycle Disorder patients in short-term clinical trials, including abdominal discomfort, abdominal pain, diarrhea, dyspepsia, flatulence, nausea, vomiting, fatigue, decreased appetite, dizziness, and headacheChart showing reported adverse reactions for RAVICTI in adult Urea Cycle Disorder patients in short-term clinical trials, including abdominal discomfort, abdominal pain, diarrhea, dyspepsia, flatulence, nausea, vomiting, fatigue, decreased appetite, dizziness, and headache Click to enlarge Tap to enlarge

Adverse reactions occurring in at least 10% of adult patients during 12 months of treatment were nausea, vomiting, diarrhea, decreased appetite, dizziness, headache, and fatigue.1

Of the 51 adult patients, 7 patients (14%) reported a total of 10 hyperammonemic crises.1

dAssessment of adverse reactions in a randomized, double-blind, active-controlled, crossover study in which 45 adult patients (at least 18 years of age) with UCDs were treated with either RAVICTI or NaPBA for 2 weeks then switched to NaPBA or RAVICTI, respectively, for 2 weeks.1

Phenylacetate (PAA)-associated adverse reactions

The major metabolite of RAVICTI, PAA, may be associated with neurotoxicity. In a study of adult patients with cancer who were administered PAA intravenously, signs and symptoms of potential PAA neurotoxicity, including somnolence, fatigue, lightheadedness, headache, dysgeusia, hypoacusis, disorientation, impaired memory, and exacerbation of preexisting neuropathy were observed at plasma PAA concentrations above 500 μg/mL. In this study, adverse reactions were reversible.1

In clinical trials, patients with UCDs who had been on NaPBA prior to administration of RAVICTI had peak PAA concentrations after dosing with RAVICTI in the following ranges1:

  • Adult patients: 1.6 to 178 μg/mL (mean, 39 μg/mL; median, 25 μg/mL)
  • Pediatric patients 2 years to 17 years of age: 1 to 410 μg/mL (mean, 70 μg/mL; median, 50 μg/mL)
  • Pediatric patients 2 months to less than 2 years of age: 1 to 1215 μg/mL (mean, 142 μg/mL; median, 35 μg/mL)
  • Pediatric patients less than 2 months of age: 96 to 707 μg/mL (mean, 257 μg/mL; median 205 μg/mL)

Some patients with UCDs experienced headache, fatigue, symptoms of peripheral neuropathy, seizures, tremors, and/or dizziness. No correlation between PAA levels and neurotoxicity symptoms was identified, but PAA levels were generally not measured consistently at the time of neurotoxicity symptoms.1

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Reference: 1. RAVICTI (glycerol phenylbutyrate) Oral Liquid [prescribing information] Horizon.

INDICATION and IMPORTANT SAFETY INFORMATION

true

INDICATION

RAVICTI (glycerol phenylbutyrate) Oral Liquid is indicated for use as a nitrogen-binding agent for chronic management of patients with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or supplementation alone. RAVICTI 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
  • 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.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS
  • Patients with known hypersensitivity to phenylbutyrate: Reactions include wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash.
WARNINGS AND PRECAUTIONS
  • Neurotoxicity: Phenylacetate (PAA), the major metabolite of RAVICTI, may be toxic at levels of 500 micrograms/mL or greater. 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: 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.
ADVERSE REACTIONS

The most common adverse reactions reported in clinical trials (at least 10% of patients) were:

  • Adult patients: diarrhea, flatulence, and headache occurred during 4-week treatment (n=45) with RAVICTI; nausea, vomiting, diarrhea, decreased appetite, dizziness, headache, and fatigue occurred during 12-month treatment (n=51) with RAVICTI.
  • Pediatric patients ages 2 to 17 years: upper abdominal pain, rash, nausea, vomiting, diarrhea, decreased appetite, and headache occurred during 12-month treatment (n=26) with RAVICTI.
  • Pediatric patients ages 2 months to less than 2 years: neutropenia, vomiting, constipation, diarrhea, pyrexia, hypophagia, cough, nasal congestion, rhinorrhea, rash, and papule occurred during 12-month treatment (n=17) with RAVICTI.
  • Pediatric patients less than 2 months of age: vomiting, rash, gastroesophageal reflux, increased hepatic enzymes, feeding disorder (decreased appetite, hypophagia), anemia, cough, dehydration, metabolic acidosis, thrombocytosis, thrombocytopenia, neutropenia, lymphocytosis, diarrhea, flatulence, constipation, pyrexia, lethargy, and irritability/agitation occurred during 24-month treatment (n=16) with RAVICTI.
DRUG INTERACTIONS
  • Corticosteroids, valproic acid, or haloperidol may increase plasma ammonia level. Monitor ammonia levels closely.
  • Probenecid may affect renal excretion of metabolites of RAVICTI, including phenylacetylglutamine (PAGN) and PAA.
  • CYP3A4 substrates with narrow therapeutic index (eg, alfentanil, quinidine, cyclosporine): RAVICTI may decrease exposure to the concomitant drug.
  • Midazolam: Use of RAVICTI decreased exposure of midazolam with concomitant use.
USE IN SPECIFIC POPULATIONS
  • Pregnancy: RAVICTI should be used with caution in patients who are pregnant or planning to become pregnant. Based on animal data, RAVICTI may cause fetal harm. Report pregnancies to Horizon at 1‐866‐479‐6742.
  • Lactation: breastfeeding is not recommended during treatment with RAVICTI. There are no data on the presence of RAVICTI in human milk, the effects on the breastfed infant, nor the effects on milk production.

Please see Full Prescribing Information.

INDICATION and IMPORTANT SAFETY INFORMATION

true

INDICATION

RAVICTI (glycerol phenylbutyrate) Oral Liquid is indicated for use as a nitrogen-binding agent for chronic management of patients with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or supplementation alone. RAVICTI 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
  • 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.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS
  • Patients with known hypersensitivity to phenylbutyrate: Reactions include wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash.
WARNINGS AND PRECAUTIONS
  • Neurotoxicity: Phenylacetate (PAA), the major metabolite of RAVICTI, may be toxic at levels of 500 micrograms/mL or greater. 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: 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.
ADVERSE REACTIONS

The most common adverse reactions reported in clinical trials (at least 10% of patients) were:

  • Adult patients: diarrhea, flatulence, and headache occurred during 4-week treatment (n=45) with RAVICTI; nausea, vomiting, diarrhea, decreased appetite, dizziness, headache, and fatigue occurred during 12-month treatment (n=51) with RAVICTI.
  • Pediatric patients ages 2 to 17 years: upper abdominal pain, rash, nausea, vomiting, diarrhea, decreased appetite, and headache occurred during 12-month treatment (n=26) with RAVICTI.
  • Pediatric patients ages 2 months to less than 2 years: neutropenia, vomiting, constipation, diarrhea, pyrexia, hypophagia, cough, nasal congestion, rhinorrhea, rash, and papule occurred during 12-month treatment (n=17) with RAVICTI.
  • Pediatric patients less than 2 months of age: vomiting, rash, gastroesophageal reflux, increased hepatic enzymes, feeding disorder (decreased appetite, hypophagia), anemia, cough, dehydration, metabolic acidosis, thrombocytosis, thrombocytopenia, neutropenia, lymphocytosis, diarrhea, flatulence, constipation, pyrexia, lethargy, and irritability/agitation occurred during 24-month treatment (n=16) with RAVICTI.
DRUG INTERACTIONS
  • Corticosteroids, valproic acid, or haloperidol may increase plasma ammonia level. Monitor ammonia levels closely.
  • Probenecid may affect renal excretion of metabolites of RAVICTI, including phenylacetylglutamine (PAGN) and PAA.
  • CYP3A4 substrates with narrow therapeutic index (eg, alfentanil, quinidine, cyclosporine): RAVICTI may decrease exposure to the concomitant drug.
  • Midazolam: Use of RAVICTI decreased exposure of midazolam with concomitant use.
USE IN SPECIFIC POPULATIONS
  • Pregnancy: RAVICTI should be used with caution in patients who are pregnant or planning to become pregnant. Based on animal data, RAVICTI may cause fetal harm. Report pregnancies to Horizon at 1‐866‐479‐6742.
  • Lactation: breastfeeding is not recommended during treatment with RAVICTI. There are no data on the presence of RAVICTI in human milk, the effects on the breastfed infant, nor the effects on milk production.

Please see Full Prescribing Information.