An overview of RAVICTI

An overview of RAVICTI^® (glycerol phenylbutyrate) Oral Liquid

Review efficacy data, safety information, mechanism of action, and dosing and administration for 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 and adult patients with urea cycle disorders (UCDs).¹

Adult mean 24-hour venous ammonia levels (post initial dose) — Mean 24-hour area under the curve (AUC_0–24h) 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

^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. 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 AUC_0–24h for ammonia.¹

Adult mean 12-month venous ammonia levels — 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

^b A 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

Pediatric 24h ammonia levels — In patients with UCDs between 2 and 5 years of age (n=11), the ammonia AUC_0–24h 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 (n=11), the ammonia AUC_0–24h 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.²

^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 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 AUC_0–24h 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

Pediatric 12m ammonia levels — 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

^d Long-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

RAVICTI 2 months to under 2 years data — In Study 6 (shown below)(right), mean venous ammonia levels in patients 2 months to less than 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 less than 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 less than 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 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

^e Uncontrolled, 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

^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

RAVICTI under 2 months data — In Study 6 (shown below)(right), mean venous ammonia levels in patients starting treatment at less than 2 months of age (n=16)^j 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,k

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

ⁱ An 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

^j Sixteen, 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

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

Safety profile

The US Food and Drug Administration has approved RAVICTI for use in adult and pediatric patients with UCDs based on its safety and efficacy profiles.¹

Adverse events in adult patients with UCDs^1,l

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

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

Adverse events in pediatric patients 2 to 17 years of age with UCDs^1,m

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

Adverse events in pediatric patients 2 months to less than 2 years of age with UCDs^1,n

Adverse reactions occurring in at least 10% of pediatric patients 2 months to less than 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 less than 2 years of age in 3 open-label studies, 7 patients (41%) reported a total of 11 hyperammonemic crises.¹

Adverse events in pediatric patients less than 2 months of age with UCDs^1,o

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

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 less than 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) and from 96 to 707 μg/mL (mean, 257 μg/mL; median 205 μg/mL) in pediatric patients less than 2 months of age. 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.¹

^l Assessment 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.¹

^m Assessment 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

ⁿ Assessment 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, 0.2‑18 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

^o Assessment of adverse reactions in 1 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, followed by monthly assessment of ammonia control and hyperammonemic crises over a 24-month period.¹

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

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).^1,4,5

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

Absorption of PBA is approximately 70% to 75% slower when administered as RAVICTI vs sodium phenylbutyrate.^1,3

Effective ammonia control that fits into busy lives¹

Help control ammonia with easy-to-administer oral liquid^1,p

Nearly tasteless and odorless liquid^1,10
No pill or powder preparation and minimal dosing steps required¹
Taken with meals or feedings via oral dosing syringe^1,q

^p 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 less than 2 years of age in 3 open-label studies, 7 patients (41%) reported a total of 11 hyperammonemic crises.¹ Of the 16 pediatric patients less than 2 months of age in an uncontrolled, open-label study, 5 patients (31%) reported a total of 7 hyperammonemic crises.¹

^q 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 less than 2 years of age, 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 gastrostomy feeding tube^r

^r 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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Important Safety Information for BUPHENYL® (sodium phenylbutyrate) Tablets and Powder

References: 1. RAVICTI [package insert]. Lake Forest, IL: Horizon Pharma USA, Inc.; 2018. 2. Data on file. Horizon Pharma USA, Inc.; 2015. 3. 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. 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. 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. Ammonia toxicity to the brain. J Inherit Metab Dis. 2013;36(4):595-612. doi:10.1007/s10545-012-9546-2. 8. Mokhtarani M, Diaz GA, Rhead W, et al. Elevated phenylacetic acid levels do not correlate with adverse events in patients with urea cycle disorders or hepatic encephalopathy and can be predicted based on the plasma PAA to PAGN ratio. Mol Genet Metab. 2012;107(3):308-314. doi:10.1016/j.ymgme.2012.08.006. 9. Mokhtarani M, Diaz GA, Rhead W, et al. Urinary phenylacetylglutamine as dosing biomarker for patients with urea cycle disorders. 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. 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.

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