Graphic of Urea Cycle Disorder pathophysiology showing elevated levels of ammonia and amino acids circulating in the liver

About Urea Cycle Disorders (UCDs)

The lifelong, chronic nature of UCDs means patients are constantly living on the edge1,2

Graphic of Urea Cycle Disorder pathophsiology showing elevated levels of ammonia and amino acids circulating in the liver

A UCD is a rare genetic condition caused by an enzyme or transporter in the urea cycle that is missing or defective. The resulting dysfunction of the urea cycle may cause a buildup of ammonia in the blood.1,2

Metabolic stressors can occur anytime, anywhere3
  • Infection
  • Nausea and vomiting4
  • Abdominal pain4
  • Fever5
  • Weight loss5

Rapid and accurate diagnosis of UCDs is challenging

Elevated ammonia levels (greater than or equal to 35 μmol/L), whether acute or chronic, may lead to serious medical consequences.6,7

Symptoms of elevated ammonia in patients with partial ornithine transcarbamylase deficiency (OTC-D) or those with mild or late-onset disease may be underappreciated or undertreated by patients and first-responding clinicians and go unrecognized for many years until a trigger results in a hyperammonemic crisis.8,9

Triggers of hyperammonemic crises include high-protein intake, pregnancy/labor and delivery, illness, surgical interventions, circumstantial life occurrences (i.e., stress), and some medications such as steroids.3,9

Despite UCD treatment, adherence may affect ammonia control

Poor adherence to treatment was reported by 67% of physicians to be a barrier or unmet need in the care of patients with UCD.6

UCDs affect every patient and their family

UCDs result in a considerable long-term psychosocial impact (ie, anxiety, guilt, helplessness, etc) on patients and their caregivers and may impact the consideration for liver transplantation versus medical treatment.10,11 UCDs also impact patients and their families due to requirements for low-protein meal planning and other disruptions in family routines.10

One moment can change everything for patients with UCDsa—now is the time to consider RAVICTI

Formulation designed for slow release of phenylbutyrate (PBA)*

Absorption of PBA is slower when administered as RAVICTI versus sodium phenylbutyrate because it “trickles” the metabolites into systemic circulation compared to a bolus-like effect following sodium phenylbutyrate treatment.12,13

Established long-term ammonia control and safety profile for patients of all ages

Long-term safety data exist for patients on RAVICTI. RAVICTI is a UCD treatment that has been shown to provide ammonia control in both the short-term (2 or 4 weeks) and long-term (at least 12 months) in clinical studies.12,14

Help control ammonia with an oral liquid therapy

RAVICTI is a nearly odorless and nearly tasteless liquid with no pills or powder to prepare.12,14

RAVICTI is contraindicated in patients with known hypersensitivity to phenylbutyrate.12

aThe safety and efficacy of RAVICTI for the treatment of NAGS deficiency have not been established.12

*Please see the PI for full information on the function of PBA in the body.

About RAVICTI

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and pediatric patients

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Prescribing RAVICTI

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References:
1. Lichter-Konecki U, Diaz GA, Merritt JL II, et al. Ammonia control in children with urea cycle disorders (UCDs); phase 2 comparison of sodium phenylbutyrate and glycerol phenylbutyrate. Mol Genet Metab. 2011;103(4):323-329. doi:10.1016/j.ymgme.2011.04.013 2. Lee B, Diaz GA, Rhead W, et al. Blood ammonia and glutamine as predictors of hyperammonemic crises in patients with urea cycle disorder. Genet Med. 2015;17(7):561-568. doi:10.1038/gim.2014.148. 3. Summar ML, Dobbelaere D, Brusilow S, Lee B. Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21-year, multicentre study of acute hyperammonaemic episodes. Acta Paediatr. 2008;97(10):1420-1425. doi:10.1111/j.1651-2227.2008.00952.x 4. Häberle J, Burlina A, Chakrapani A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision. J Inherit Metab Dis. 2019;42(6):1192-1230. 5. Stepien KM, Geberhiwot T, Hendriksz CJ, Treacy EP. Challenges in diagnosing and managing adult patients with urea cycle disorders. J Inherit Metab Dis. 2019;42(6):1136. 6. Enns GM, Porter MH, Francis-Sedlak M, Burdett A, Vockley J. Perspectives on urea cycle disorder management: results of a clinician survey. Mol Genet Metab. 2019;128(1-2):102-108. 7. Diaz GA, Schulze A, Longo N, et al. Long-term safety and efficacy of glycerol phenylbutyrate for the management of urea cycle disorder patients. Mol Genet Metab. 2019;127(4):336-345. 8. Ah Mew N, Simpson KL, Gropman AL, Lanpher BC, Chapman KA, Summar ML. Urea Cycle Disorders Overview. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; April 29, 2003. 9. Häberle J, Boddaert N, Burlina A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012;7:32. 10. Cederbaum JA, LeMons C, Rosen M, Ahrens M, Vonachen S, Cederbaum SD. Psychosocial issues and coping strategies in families affected by urea cycle disorders. J. Pediatr. 2001;138(suppl 1):S72-S80. 11. Comparative effectiveness of therapy in rare diseases: liver transplantation vs. conservative management of urea cycle disorders. Accessed April 21, 2022. https://www.rarediseasesnetwork.org/cms/ucdc/Get-Involved/Studies/5117 12. RAVICTI (glycerol phenylbutyrate) Oral Liquid [prescribing information] Horizon. 13. Monteleone JPR, Mokhtarani M, Diaz GA, et al. Population pharmacokinetic modeling and dosing simulations of nitrogen-scavenging compounds: disposition of glycerol phenylbutyrate and sodium phenylbutyrate in adult and pediatric patients with urea cycle disorders. J Clin Pharmacol. 2013;53(7):699-710. 14. Diaz GA, Krivitzky LS, Mokhtarani M, et al. Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate. Hepatology. 2013;57(6):2171-2179.

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.