Birth to less than 2 months
  • In Study 6 (right), mean venous ammonia levels in patients starting treatment at less than 2 months of age (n=16)b were less than 100 μmol/L during treatment with RAVICTI for up to 24 months (range, 35-94 μmol/L).1
  • In this study, 16 of 16 (100%) patients less than 2 months of age successfully transitioned to RAVICTI within 7 days (4 days of transition followed by 3 days of observation).1,c
  • Of 16 patients starting treatment at less than 2 months of age in this 24-month study, 5 patients (31%) reported a total of 7 hyperammonemic crises, all of which occurred in patients less than 1 month of age.1

RAVICTI provides ammonia control in pediatric patients less than 2 months of age with UCDs1,a

Graph showing efficacy of RAVICTI ammonia level control in UCD patients less than 2 months old, with mean normalized blood ammonia between 60 and 130 μmol/L at baseline and between 50 and 70 μmol/L at Month 24

Click to enlarge

aAn uncontrolled, open-label study was conducted in 16 children less than 2 months of age to assess transition to RAVICTI over a period of 7 days, followed by monthly assessment of ammonia control and hyperammonemic crises over a 24-month period. Ammonia values across different laboratories were normalized to a common normal pediatric range of 28 to 57 μmol/L.1

bSixteen, 14, 12, 6, and 3 patients completed 1, 3, 6, 12, and 18 months of treatment, respectively (median exposure of 10 months [range, 2 to 20 months]).1

cSuccessful transition was defined as no signs and symptoms of hyperammonemia and a venous ammonia value less than 100 μmol/L.1

2 months to less than 2 years
  • In Study 6 (right), mean venous ammonia levels in patients 2 months to less than 2 years of age (n=10)e were less than 100 μmol/L during treatment with RAVICTI for up to 6 months (range, 53-99 μmol/L).1
  • In Study 6, 9 of 10 (90%) patients 2 months to less than 2 years of age successfully transitioned to RAVICTI within 7 days.1,f
  • In Studies 4/4E and 5, mean venous ammonia levels in patients 2 months to less than 2 years of age (n=7)d were less than 100 μmol/L during treatment with RAVICTI for up to 12 months (range, 31-65 μmol/L).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

RAVICTI provides ammonia control in pediatric patients 2 months to less than 2 years of age with UCDs1,d

Graph showing efficacy of RAVICTI ammonia level control in pediatric patients from 2 months to less than 2 years, with mean normalized blood ammonia between 80 and 130 μmol/L at baseline and between 50 and 70 μmol/L at Month 6 Click to enlarge

dUncontrolled, open-label studies were conducted to assess monthly ammonia control and hyperammonemic crises with RAVICTI in pediatric patients 2 months to less than 2 years of age (study 4/4E, study 5, and study 6). Patients in study 5 previously participated in study 4/4E. A total of 17 pediatric patients with UCDs 2 months to less than 2 years of age participated in the studies. Ammonia values across different laboratories were normalized to a common normal pediatric range of 28 to 57 μmol/L.1

eNine, 7, and 3 patients completed 1, 3, and 6 months of treatment, respectively (mean and median exposure of 4 and 5 months, respectively).1

fSuccessful transition was defined as no signs and symptoms of hyperammonemia and a venous ammonia value less than 100 μmol/L.1

2 to 17 years

RAVICTI provides effective 24-hour ammonia control in pediatric patients with UCDs1,g

Graph showing efficacy of RAVICTI 24 hour ammonia level control in UCD pediatric patients from 2 to 17 compared to sodium phenylbutyrate, with RAVICTI mean normalized blood ammonia between 18 and 26 μmol/L pre-dose and between 15 and 22 μmol/L at Hour 24, lower than sodium phenylbutyrate Click to enlarge

  • In patients with UCDs between 2 and 5 years of age (n=11), the ammonia AUC0–24h value was 632 μmol⋅h/L vs 720 μmol⋅h/L on RAVICTI vs sodium phenylbutyrate (NaPBA), respectively.1
  • In patients 6 to 17 years of age (n=11), the ammonia AUC0–24h value was 604 μmol⋅h/L vs 815 μmol⋅h/L on RAVICTI vs NaPBA, respectively.1
  • Among the 22 patients in these studies, no hyperammonemic crises were reported during treatment with RAVICTI.3

gThe efficacy of RAVICTI in pediatric patients 2 to 17 years of age was evaluated in 2 fixed-sequence, open-label, NaPBA-to-RAVICTI crossover studies (studies 3 and 4). Study 3 was 7 days in duration and study 4 was 10 days in duration. These studies compared blood ammonia levels of patients on RAVICTI with venous ammonia levels of patients on NaPBA in 26 pediatric patients between 2 months and 17 years of age. The AUC0–24h for blood ammonia in 11 pediatric patients 6 to 17 years of age (study 3) and 11 pediatric patients 2 to 5 years of age (study 4) were similar between treatments.1

  • Mean fasting venous ammonia values in pediatric patients (n=26) 6 to 17 years of age were within normal limits (≤35 μmol/L) during long-term treatment with RAVICTI (range, 17–23 μmol/L).1
  • Of the 26 pediatric patients 6 to 17 years of age participating in these 2 trials, 5 patients (19%) reported a total of 5 hyperammonemic crises.1

RAVICTI provides effective ammonia control sustained over 12 months in pediatric patients with UCDs1,h

Graph showing RAVICTI efficacy of sustained ammonia level control over 12 months in pediatric UCD patients, with mean normalized blood ammonia between 18 and 22 μmol/L at baseline and between 15 and 21 μmol/L at Month 12 Click to enlarge

hLong-term (12-month), uncontrolled, open-label studies were conducted to assess monthly ammonia control and hyperammonemic crises. In 2 studies, a total of 26 pediatric patients 6 to 17 years of age were enrolled, and all but 1 had been converted from NaPBA to RAVICTI. Ammonia values across different laboratories were normalized to a common normal range of 9 to 35 μmol/L.1

Adult

RAVICTI provides 24-hour ammonia control for urea cycle disorders in adults1,i

Graph showing efficacy of RAVICTI for 24 hour ammonia level control in adults with Urea Cycle Disorder compared to sodium phenylbutyrate, with RAVICTI mean normalized blood ammonia between 22 and 30 μmol/L pre-dose and at Hour 24, lower than sodium phenylbutyrate Click to enlarge

  • Mean 24-hour area under the curve (AUC0–24h) values during steady-state dosing were 866 μmol⋅h/L and 977 μmol⋅h/L with RAVICTI and NaPBA, respectively (ratio of geometric means, 0.91 [95% CI 0.8, 1.04]).1
  • Among the 44 patients in this short-term study, no hyperammonemic crises were reported during treatment with RAVICTI.3

iA randomized, double-blind, active-controlled, crossover, noninferiority study compared RAVICTI with NaPBA by evaluating venous ammonia levels in patients with UCDs who had been on NaPBA prior to enrollment. Forty-four patients were randomized 1:1 to receive either NaPBA for 2 weeks then RAVICTI for 2 weeks, or RAVICTI for 2 weeks then NaPBA for 2 weeks. RAVICTI was noninferior to NaPBA with respect to the AUC0–24h for ammonia.1

  • Mean fasting venous ammonia values in adults (n=51) were within normal limits (≤35 μmol/L) during long-term treatment with RAVICTI (range, 6–30 μmol/L).1
  • Of the 51 adult patients participating in the 12-month, open-label treatment with RAVICTI, 7 patients (14%) reported a total of 10 hyperammonemic crises.1

RAVICTI provides effective ammonia control sustained over 12 months in adult patients with UCDs1,j

Graph showing efficacy of RAVICTI in ammonia control sustained over 12 months for adults with Urea Cycle Disorders, with mean normalized blood ammonia between 27 and 31 μmol/L at baseline and between 24 and 29 μmol/L at Month 12 Click to enlarge

jA long-term (12-month), uncontrolled, open-label study was conducted to assess monthly ammonia control and hyperammonemic crises. A total of 51 adult patients were in the study and all but 6 had been converted from NaPBA to RAVICTI. Ammonia values across different laboratories were normalized to a common normal range of 9 to 35 μmol/L.1

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References: 1. RAVICTI (glycerol phenylbutyrate) Oral Liquid [prescribing information] Horizon. 2. Berry SA, Longo N, Diaz GA, et al. Safety and efficacy of glycerol phenylbutyrate for management of urea cycle disorders in patients aged 2 months to 2 years. Mol Genet Metab. 2017;122(3):46-53. doi:10.1016/j.ymgme.2017.09.002 3. Longo N, Holt RJ. Glycerol phenylbutyrate for the maintenance treatment of patients with deficiencies in enzymes of the urea cycle. Exp Opin Orphan Drugs. 2017;5(12):999-1010. doi:10.1080/21678707.2017.1405807. 4. 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 5. 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 6. Smith W, Diaz GA, Lichter-Konecki U, et al. Ammonia control in children ages 2 months through 5 years with urea cycle disorders: comparison of sodium phenylbutyrate and glycerol phenylbutyrate. J Pediatr. 2013;162(6):1228-1234.e1. doi:10.1016/j.jpeds.2012.11.084 7. 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 8. 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 9. Data on File. Horizon, April 2017.

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.