An overview of RAVICTI

Review efficacy data, safety information, mechanism of action, and dosing and administration for RAVICTI® (glycerol phenylbutyrate) Oral Liquid

Explore RAVICTI

Effective ammonia control through life’s busy moments1

RAVICTI is the only FDA-approved oral therapy clinically studied over the long term (12 months) in pediatric patients ≥2 months of age and adult patients with urea cycle disorders (UCDs).1

Selected Important Safety Information

Neurotoxicity: Phenylacetate (PAA), the major metabolite of RAVICTI, may be toxic at levels of 500 μg/mL or greater. Reduce RAVICTI dosage if symptoms of neurotoxicity, including vomiting, nausea, headache, somnolence, or confusion, are present in the absence of high ammonia or other intercurrent illnesses.

Adult

  • 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.2

RAVICTI offers effective ammonia control throughout the day and night for adult patients with UCDs1,a

Adult mean 24-hour venous ammonia levels (post initial dose)

a A 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. Fifty-one 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 (n=44).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 long-term ammonia control for adult patients with UCDs1,b

Adult mean 12-month venous ammonia levels

b A long-term (12-month), uncontrolled, open-label study was conducted to assess monthly ammonia control and hyperammonemic crises over a 12-month period. 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

Pediatric Patients with UCDs (2–18 years)

  • In patients with UCDs between 2 and 5 years of age, the ammonia AUC0–24h value was 632 μmol⋅h/L vs 720 μmol⋅h/L on RAVICTI vs NaPBA, respectively.1
  • In patients 6 to 17 years of age, 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 RAVICT2

RAVICTI provides effective 24-hour ammonia control for pediatric patients with UCDs1,c

Pediatric 24h ammonia levels

c The efficacy of RAVICTI in pediatric patients 2 to 17 years of age was evaluated in 2 fixed-sequence, open-label, NaPBA-to-RAVICTI switchover 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 long-term ammonia control for pediatric patients with UCDs1,d

Pediatric 12m ammonia levels

d Long-term (12-month), uncontrolled, open-label studies were conducted to assess monthly ammonia control and hyperammonemic crises over a 12-month period. 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

Pediatric Patients With UCDs (2 Months–<2 Years)

  • In Study 6 (shown below)(right), mean venous ammonia levels in patients 2 months to <2 years of age (n=10)f 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 <2 years of age successfully transitioned to RAVICTI within 7 days.1,g
  • In Studies 4/4E and 5, mean venous ammonia levels in patients 2 months to <2 years of age (n=7)h 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 participating in the open-label trial with RAVICTI, 7 patients (41%) reported a total of 11 hyperammonemic crises.1

RAVICTI provides effective ammonia control for pediatric patients 2 months to <2 years of age with UCDs1,e

RAVICTI under 2 data

e Uncontrolled, open-label studies were conducted to assess monthly ammonia control and hyperammonemic crises with RAVICTI in pediatric patients 2 months to <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 <2 years of age participated in the studies: 6 pediatric patients completed 12 months of treatment (median exposure, 6 months). Ammonia values across different laboratories were normalized to a common normal pediatric range of 28 to 57 μmol/L.1

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

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

h Seven, 6, 6, 6, and 3 patients completed 1, 6, 9, 12, and 18 months of treatment, respectively (mean and median exposure of 15 and 17 months, respectively); ammonia values were collected at 1, 3, 6, 9, and 12 months.1

Safety profile

The US Food and Drug Administration has determined that RAVICTI is safe and effective in adult and pediatric patients (2 months of age and older) with UCDs.1

Selected Important Safety Information

Reduced phenylbutyrate absorption in 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.

RAVICTI is not used for the treatment of acute hyperammonemia in patients with UCDs.

Adverse events in adults1,i

  • Adverse reactions occurring in ≥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

Adverse events during 12 months of treatment: pediatric patients 2 to 18 years of age1,j

  • Adverse reactions occurring in ≥10% of pediatric patients 2 to 17 years of age during 12 months of treatment 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

Adverse events for pediatric patients 2 months to <2 years of age with UCDs1,k

  • Adverse reactions occurring in at least 10% of pediatric patients 2 months to <2 years of age were neutropenia, vomiting, diarrhea, pyrexia, hypophagia, cough, nasal congestion, rhinorrhea, rash, and papule.1
  • Of the 17 pediatric patients 2 months to <2 years of age in 3 open-label studies, 7 patients (41%) reported a total of 11 hyperammonemic crises.1

Phenylacetate (PAA)-associated adverse events

  • The major metabolite of RAVICTI, PAA, is associated with neurotoxicity. In a study of adult patients with cancer who were administered PAA intravenously, 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 of 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 ranging from 1.6 to 178 μg/mL (mean, 39 μg/mL) in adult patients and from 1 to 410 μg/mL (mean, 70 μg/mL; median, 50 μg/mL) in pediatric patients 2 years of age and older. In pediatric patients 2 months to <2 years of age, peak PAA concentrations after dosing with RAVICTI ranged from 1 to 1215 μg/mL (mean, 142 μg/mL; median, 35 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 at the time of neurotoxicity symptoms.1

Postmarketing experience

The following adverse reactions have been identified during postapproval use of RAVICTI1:

  • Abnormal body odor, including from skin, hair, and urine
  • Retching and gagging
  • Dysgeusia or burning sensation in mouth

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

i Assessment of adverse reactions was based on a randomized, double-blind, active-controlled, crossover study in which 45 adult patients (≥18 years of age) were treated with either RAVICTI or NaPBA for 2 weeks.1

j RAVICTI has been evaluated in 77 patients (51 adult and 26 pediatric patients 2 years to 17 years of age) in 2 long-term open-label studies, in which 69 patients completed 12 months of treatment with RAVICTI (median exposure, 51 weeks). There were no deaths during these studies.1

k RAVICTI has been evaluated in 17 patients 2 months to <2 years of age in 3 open-label studies. The median exposure was 6 months (range, 0.2 to 18 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

RAVICTI® (glycerol phenylbutyrate) Oral Liquid has a unique mechanism of action designed for a slow release of phenylbutyrate (PBA)1,3-5

An alternate vehicle for waste nitrogen removal can help control ammonia, which can fluctuate daily above the upper limit of normal in patients with urea cycle disorders (UCDs).1,3,4

Part 1 of informational graphic depicting RAVICTI’s mechanism of action Part 2 of informational graphic depicting RAVICTI’s mechanism of action Part 3 of informational graphic depicting RAVICTI’s mechanism of action Part 4 of informational graphic depicting RAVICTI’s mechanism of action Part 5 of informational graphic depicting RAVICTI’s mechanism of action Part 6 of informational graphic depicting RAVICTI’s mechanism of action Part 7 of informational graphic depicting RAVICTI’s mechanism of action Part 8 of informational graphic depicting RAVICTI’s mechanism of action
Part 1 of informational graphic depicting RAVICTI’s mechanism of action Part 2 of informational graphic depicting RAVICTI’s mechanism of action Part 3 of informational graphic depicting RAVICTI’s mechanism of action

The absorption of phenylbutyrate is approximately 70% to 75% slower when administered as RAVICTI vs sodium phenylbutyrate.1,5

Effective ammonia control that fits into busy lives1

Help control ammonia with easy-to-administer oral liquid1,l

  • Nearly tasteless and odorless liquid1,10

  • No pill or powder preparation and minimal dosing steps required1,10

  • Taken with meals via oral dosing syringe1,m

l Of the 51 adult patients in the 12-month study of RAVICTI, 7 patients (14%) reported a total of 10 hyperammonemic crises. Of the 26 pediatric patients 6 to 17 years of age in both 12-month studies of RAVICTI, 5 patients (19%) reported a total of 5 hyperammonemic crises. Of the 17 pediatric patients 2 months to <2 years of age in 3 open-label studies, 7 patients (41%) reported a total of 11 hyperammonemic crises.1

m For patients who require a volume of less than 1 mL per dose via nasogastric or gastrostomy tube, the delivered dose may be less than anticipated. Closely monitor these patients using ammonia levels.1

Important reminders

  • For patients 2 years of age and older, the total daily dosage is given in 3 equally divided doses, each rounded up to the nearest 0.5 mL.1
  • For patients 2 months of age to less than 2 years, the total daily dosage is given in 3 or more doses, each rounded up to the nearest 0.1 mL.1
  • The maximum total daily dosage is 17.5 mL (19 g).1
  • RAVICTI must be used with dietary protein restriction and, in some cases, dietary supplements (eg, essential amino acids, arginine, citrulline, protein-free calorie supplements).1

Administration

Please refer to the following videos to review administration instructions.

Administering RAVICTI orally

Administering RAVICTI with a nasogastric or gastronomy feeding tuben

n Accommodates patients who require nasogastric or gastrostomy feeding tubes for food and nutrition.1

Ready to select the dosage?

See the Dosage Guide for more information on starting RAVICTI, switching from NaPBA, and optimizing RAVICTI dosing.

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References:  1. RAVICTI [package insert]. Lake Forest, IL: Horizon Pharma USA, Inc.; 2017.  2. Data on file. Horizon Pharma USA, Inc.; 2015.  3. Lee B, Diaz GA, Rhead W, et al. Genet Med. 2015;17(7):561-568. doi:10.1038/gim.2014.148.  4. Lichter-Konecki U, Diaz GA, Merritt JL II, et al. Mol Genet Metab. 2011;103(4):323-329. doi:10.1016/j.ymgme.2011.04.013.  5. Monteleone JPR, Mokhtarani M, Diaz GA, et al. J Clin Pharmacol. 2013;53(7):699-710. doi:10.1002/jcph.92.  6. The Physician’s Guide to Urea Cycle Disorders. National Organization for Rare Disorders website. 2012. http://nordphysicianguides.org/urea-cycle-disorders/. Accessed May 3, 2017.  7. Braissant O, McLin VA, Cudalbu C. Inherit Metab Dis. 2013;36(4):595-612. doi:10.1007/s10545-012-9546-2.  8. Mokhtarani M, Diaz GA, Rhead W, et al. Mol Genet Metab. 2013;110(4):446-453. doi:10.1016/j.ymgme.2013.09.017.  9. Mokhtarani M, Diaz GA, Rhead W, et al. Mol Genet Metab. 2012;107(3):308-314. doi:10.1016/j.ymgme.2012.08.006.  10. Diaz GA, Krivitzky LS, Mokhtarani M, et al. Hepatology. 2013;57(6):2171-2179. doi:10.1002/hep.26058.