Graphic of Urea Cycle Disorder pathophsiology showing elevated levels of ammonia and amino acids circulating in the liver Graphic of Urea Cycle Disorder pathophsiology showing elevated levels of ammonia and amino acids circulating in the liver Graphic of Urea Cycle Disorder pathophsiology 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 urea cycle disorder (UCD) is a rare genetic condition caused by an enzyme or transporter in the urea cycle that is missing or defective.

Metabolic stressors can occur anytime, anywhere

  • Decreased level of consciousness
  • Dizziness
  • Infection
  • Nausea and vomiting
  • Abdominal pain
  • Fever
  • Weight loss3

UCDs affect every patient and their family

UCDs result in a considerable long-term psychosocial impact (i.e., anxiety, guilt, helplessness, etc.) on patients and their caregivers and may impact the consideration for liver transplantation vs medical treatment.4,5 UCDs also impact patients and their families due to requirements for low-protein meal planning and other disruptions in family routines.4

Rapid and accurate diagnosis of UCDs is challenging

Symptoms of elevated ammonia in patients with partial OTCD 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 sudden trigger results in hyperammonemic crisis.6,7

Triggers of HA and UCDs include high-protein intake, pregnancy/labor and delivery, illness, surgical interventions, circumstantial life occurrences (i.e., stress), and some medications such as steroids.3,7

Ammonia elevations: it’s not a matter of if, but when

The inherited risk of UCDs can result in elevated ammonia levels (greater than or equal to 35 μmol/L) for a prolonged period of time, leading to serious medical consequences.8,9

Despite UCD treatment, adherence may affect ammonia control

67% of physicians reported poor adherence to treatment to be a barrier or unmet need in the care of patients with UCDs.8

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

Unique mechanism of action designed for slow release of phenylbutyrate (PBA)

Absorption of PBA is slower when administered as RAVICTI vs sodium phenylbutyrate, resulting in more sustained levels of active downstream metabolites.10,11

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

Long-term safety data exist for patients on RAVICTI and RAVICTI is the only 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.9,10

Easy administration and convenient dosing

RAVICTI is nearly tasteless and odorless with no pills or powder to prepare.10,12

RAVICTI is contraindicated in patients with known hypersensitivity to phenylbutrate.10

aThe safety and efficacy of RAVICTI for the treatment of NAGS deficiency have not been established.10

Stay informed about RAVICTI® (glycerol phenylbutyrate) Oral Liquid

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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. 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:S72-S80. 5. Comparative effectiveness of therapy in rare diseases: Liver transplantation vs. conservative management of urea cycle disorders. Website. Accessed April 21, 2022. https://www.rarediseasesnetwork.org/cms/ucdc/Get-Involved/Studies/5117 6. 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. 7. 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. doi:10.1186/1750-1172-7-32 8. 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. doi:10.1016/j.ymgme.2019.07.009 9. 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. doi:10.1016/j.ymgme.2019.07.004 10. RAVICTI (glycerol phenylbutyrate) Oral Liquid [prescribing information] Horizon. 11. 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. doi:10.1002/jcph.92 12. 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. doi:10.1002/hep.26058

INDICATION and IMPORTANT SAFETY INFORMATION

INDICATION

RAVICTI is indicated for the chronic management of patients with UCDs who cannot be managed by diet and supplementation alone. It must be used with dietary protein restriction. RAVICTI is not indicated for the treatment of acute hyperammonemia or for NAGS deficiency.1

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

INDICATION

RAVICTI is indicated for the chronic management of patients with UCDs who cannot be managed by diet and supplementation alone. It must be used with dietary protein restriction. RAVICTI is not indicated for the treatment of acute hyperammonemia or for NAGS deficiency.1

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.