Glycerol Phenylbutyrate Drug Information
Generic name: GLYCEROL PHENYLBUTYRATE
Uses of Glycerol Phenylbutyrate
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 amino acid supplementation alone. Glycerol phenylbutyrate oral liquid 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: Glycerol phenylbutyrate oral liquid 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 glycerol phenylbutyrate oral liquid for the treatment of N -acetylglutamate synthase (NAGS) deficiency has not been established.
Dosage & Administration of Glycerol Phenylbutyrate
Important Administration Instructions
Glycerol phenylbutyrate oral liquid should be prescribed by a physician experienced in the management of UCDs. Instruct patients to take glycerol phenylbutyrate oral liquid with food or formula and to administer directly into the mouth via oral syringe. Instruct patients to use the glycerol phenylbutyrate oral liquid bottle and oral syringe as follows: Use a new reclosable bottle cap adapter with each new bottle that is opened.
Open the glycerol phenylbutyrate oral liquid bottle and twist on the new reclosable bottle cap adapter. Use a new and dry oral syringe to withdraw each prescribed dose of glycerol phenylbutyrate oral liquid. Discard the oral syringe after each dose.
Tightly close the tethered tab on the reclosable bottle cap adapter after each use. Do not rinse the reclosable bottle cap adapter. Discard bottle and any remaining contents 28 days after opening.
If water or moisture enters the glycerol phenylbutyrate oral liquid bottle, the contents will become cloudy in appearance. If the contents of the bottle appear cloudy at any time, do not use the remaining glycerol phenylbutyrate oral liquid in the bottle and return it to the pharmacy to be discarded. Instruct that glycerol phenylbutyrate oral liquid should be administered just prior to breastfeeding in infants who are breastfeeding.
For patients who cannot swallow, see the instructions on administration of glycerol phenylbutyrate oral liquid by nasogastric tube or gastrostomy tube. 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.
The recommended dosages for patients switching from sodium phenylbutyrate to glycerol phenylbutyrate oral liquid and patients naïve to phenylbutyric acid are different. For both subpopulations: Patients 2 years of age and older: Give glycerol phenylbutyrate oral liquid in 3 equally divided dosages, each rounded up to the nearest 0.5 mL Patients less than 2 years: Give glycerol phenylbutyrate oral liquid in 3 or more equally divided dosages, each rounded up to the nearest 0.1 mL. The maximum total daily dosage is 17.5 mL (19 g).
Glycerol phenylbutyrate oral liquid must be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements).
Switching From Sodium Phenylbutyrate to Glycerol Phenylbutyrate Oral Liquid Patients switching from sodium phenylbutyrate to glycerol phenylbutyrate oral liquid should receive the dosage of glycerol phenylbutyrate oral liquid that contains the same amount of phenylbutyric acid. The conversion is as follows: Total daily dosage of glycerol phenylbutyrate oral liquid (mL) = total daily dosage of sodium phenylbutyrate tablets (g) x 0.86 Total daily dosage of glycerol phenylbutyrate oral liquid (mL) = total daily dosage of sodium phenylbutyrate powder (g) x 0.81
Initial Dosage in Phenylbutyrate-Naïve Patients
The recommended dosage range, based upon body surface area, in patients naïve to phenylbutyrate (PBA) is /day. For patients with some residual enzyme activity who are not adequately controlled with protein restriction, the recommended starting dosage is 4.5 mL/m 2 /day. In determining the starting dosage of glycerol phenylbutyrate oral liquid in treatment-naïve patients, consider the patient’s residual urea synthetic capacity, dietary protein requirements, and diet adherence.
Dietary protein is approximately 16% nitrogen by weight. Given that approximately 47% of dietary nitrogen is excreted as waste and approximately 70% of an administered PBA dose will be converted to urinary phenylacetylglutamine (U-PAGN), an initial estimated glycerol phenylbutyrate oral liquid dose for a 24-hour period is 0.6 mL glycerol phenylbutyrate oral liquid per gram of dietary protein ingested per 24-hour period. The total daily dosage should not exceed 17.5 mL.
Dosage Adjustment and Monitoring
During treatment with glycerol phenylbutyrate oral liquid, patients should be followed clinically and with plasma ammonia levels to determine the need for dosage titration. Closely monitor plasma ammonia levels during treatment with glycerol phenylbutyrate oral liquid and when changing the dosage of glycerol phenylbutyrate oral liquid. The methods used for measuring plasma ammonia levels vary among individual laboratories and values obtained using different assay methods may not be interchangeable.
Normal ranges and therapeutic target levels for plasma ammonia depend upon the assay method used by the individual laboratory. During treatment with glycerol phenylbutyrate oral liquid, refer to the assay-specific normal ranges and to the therapeutic target ranges for plasma ammonia. Normal Plasma Ammonia In patients treated with glycerol phenylbutyrate oral liquid who experience neurologic symptoms (e.g. nausea, vomiting, headache, somnolence or confusion) in the absence of high plasma ammonia or other intercurrent illness to explain these symptoms, consider reducing the glycerol phenylbutyrate oral liquid dosage and clinically monitor patients for potential neurotoxicity from high phenylacetate (PAA) concentrations.
If available, obtain measurements of plasma PAA concentrations and plasma phenylacetylglutamine (PAGN) to calculate the ratio of plasma PAA to PAGN which may help to guide glycerol phenylbutyrate oral liquid dosing. The PAA to PAGN ratio has generally been less than 1 in patients with UCDs who did not have significant plasma PAA accumulation. In general, a high PAA to PAGN ratio may indicate a slower or less efficient conjugation reaction to form PAGN, which may lead to increases in PAA without further conversion to PAGN.
Elevated Plasma Ammonia In patients 6 years and older, when plasma ammonia is elevated, increase the glycerol phenylbutyrate oral liquid dosage to maintain fasting plasma ammonia to less than half the upper limit of normal (ULN). In infants and pediatric patients below 6 years of age, if obtaining fasting ammonia is problematic due to frequent feedings, adjust the glycerol phenylbutyrate oral liquid dosage to keep the first ammonia of the morning below the ULN for age. If available, the ratio of PAA to PAGN in the same plasma sample may provide additional information to assist in dosage adjustment decisions.
Dietary Protein Intake If available, urinary phenylacetylglutamine (U-PAGN) measurements may be used to help guide glycerol phenylbutyrate oral liquid dosage adjustment. Each gram of U-PAGN excreted over 24 hours covers waste nitrogen generated from 1.4 grams of dietary protein. If U-PAGN excretion is insufficient to cover daily dietary protein intake and the fasting ammonia is greater than half the ULN, the glycerol phenylbutyrate oral liquid dosage should be increased.
Consider a patient’s use of concomitant medications, such as probenecid, when making dosage adjustment decisions based on U-PAGN. Probenecid may result in a decrease of the urinary excretion of PAGN.
Dosage Modifications in Patients with Hepatic Impairment
For patients with moderate to severe hepatic impairment, the recommended starting dosage is at the lower end of the recommended dosing range (4.5 mL/m 2 /day) and the dosage should be kept at the lowest necessary to control the patient’s plasma ammonia.
Preparation for Nasogastric Tube or Gastrostomy Tube Administration It is recommended that all patients who can swallow take glycerol phenylbutyrate oral liquid orally, even those with nasogastric and/or gastrostomy tubes. For patients who cannot swallow, a nasogastric tube or gastrostomy tube may be used to administer glycerol phenylbutyrate oral liquid as follows: Utilize a new dry oral syringe to withdraw each prescribed dosage of glycerol phenylbutyrate oral liquid from the bottle. Place the tip of the syringe into the nasogastric/gastrostomy tube.
Utilizing the plunger of the syringe, administer glycerol phenylbutyrate oral liquid into the tube. Use a separate syringe to flush the nasogastric/gastrostomy tube. Flush once with 10 mL of water or formula and allow the flush to drain.
If needed, flush a second time with an additional 10 mL of water or formula to clear the tube. Therefore, these patients should be closely monitored using ammonia levels following initiation of glycerol phenylbutyrate oral liquid dosing or dosage adjustments.
Side Effects of Glycerol Phenylbutyrate
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Assessment of adverse reactions was based on exposure of 45 adult patients (31 female and 14 male) with UCD subtype deficiencies of ornithine transcarbamylase (OTC, n=40), carbamoyl phosphate synthetase (CPS, n=2), and argininosuccinate synthetase (ASS, n=1) in a randomized, double-blind, active-controlled (glycerol phenylbutyrate vs sodium phenylbutyrate), crossover, 4-week study (Study 1) that enrolled patients 18 years of age and older. One of the 45 patients received only sodium phenylbutyrate prior to withdrawing on day 1 of the study due to an adverse reaction.
The most common adverse reactions (occurring in at least 10% of patients) reported during short-term treatment with glycerol phenylbutyrate were diarrhea, flatulence, and headache. Table 1 summarizes adverse reactions occurring in 2 or more patients treated with glycerol phenylbutyrate or sodium phenylbutyrate (incidence of at least 4% in either treatment arm). During these studies there were no deaths.
Adverse reactions reported in at least 10% of adult patients were nausea, vomiting, diarrhea, decreased appetite, dizziness, headache, and fatigue. Adverse reactions reported in at least 10% of pediatric patients ages 2 years to 17 years were upper abdominal pain, rash, nausea, vomiting, diarrhea, decreased appetite, and headache. The median exposure was 6 months (range 0.2 to 20 months).
Adverse reactions reported in at least 10% of pediatric patients aged 2 months to less than 2 years were neutropenia, vomiting, constipation, diarrhea, pyrexia, hypophagia, cough, nasal congestion, rhinorrhea, rash, and papule. Adverse reactions reported in at least 10% of pediatric patients aged less than 2 months 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.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of glycerol phenylbutyrate. 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: Abnormal body odor, including from skin, hair and urine Retching and gagging Dysgeusia or burning sensation in mouth
| Number (%) of Patients in Study 1 | ||
|---|---|---|
| Sodium Phenylbutyrate (N = 45) | Glycerol Phenylbutyrate (N = 44) | |
| Diarrhea | 3 (7) | 7 (16) |
| Headache | 4 (9) | 6 (14) |
| Flatulence | 1 (2) | 6 (14) |
| Abdominal pain | 2 (4) | 3 (7) |
| Vomiting | 2 (4) | 3 (7) |
| Decreased appetite | 2 (4) | 3 (7) |
| Fatigue | 1 (2) | 3 (7) |
| Dyspepsia | 3 (7) | 2 (5) |
| Nausea | 3 (7) | 1 (2) |
| Dizziness | 4 (9) | 0 |
| Abdominal discomfort | 3 (7) | 0 |
Warnings & Cautions for Glycerol Phenylbutyrate
Neurotoxicity
Increased exposure to PAA, the major metabolite of glycerol phenylbutyrate, may be associated with neurotoxicity in patients with UCDs. In a study of adult cancer patients, subjects received sodium phenylacetate administered as a 1-hour infusion twice daily at two dose levels of 125 and 150 mg/kg for a 2-week period. Of 18 subjects enrolled, 7 had a history of primary central nervous system tumor.
Signs and symptoms of potential PAA neurotoxicity, which were reversible, were reported at plasma PAA concentrations above 500 micrograms/mL and included somnolence, fatigue, lightheadedness, headache, dysgeusia, hypoacusis, disorientation, impaired memory, and exacerbation of preexisting neuropathy. PAA concentrations were not measured when symptoms resolved. In clinical trials in patients with UCDs who had been on sodium phenylbutyrate prior to administration of glycerol phenylbutyrate, adverse reactions of headache, fatigue, symptoms of peripheral neuropathy, seizures, tremor and/or dizziness were reported.
No correlation between plasma PAA concentration and neurologic symptoms was identified but plasma PAA concentrations were generally not consistently measured at the time of neurologic symptom occurrence. 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 glycerol phenylbutyrate dosage.
Pancreatic Insufficiency or Intestinal Malabsorption
Exocrine pancreatic enzymes hydrolyze glycerol phenylbutyrate in the small intestine, separating the active moiety, phenylbutyrate, from glycerol. This process allows phenylbutyrate to be absorbed into the circulation. Low or absent pancreatic enzymes or intestinal disease resulting in fat malabsorption may result in reduced or absent digestion of glycerol phenylbutyrate and/or absorption of phenylbutyrate and reduced control of plasma ammonia.
Monitor ammonia levels closely in patients with pancreatic insufficiency or intestinal malabsorption.
Drug Interactions with Glycerol Phenylbutyrate
Potential for Other Drugs to Affect Ammonia Corticosteroids Use of corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels. Monitor ammonia levels closely when corticosteroids and glycerol phenylbutyrate are used concomitantly. Valproic Acid and Haloperidol Hyperammonemia may be induced by haloperidol and by valproic acid.
Monitor ammonia levels closely when use of valproic acid or haloperidol is necessary in patients with UCDs.
Potential for Other Drugs to Affect Glycerol Phenylbutyrate Probenecid Probenecid may inhibit the renal excretion of metabolites of glycerol phenylbutyrate including PAGN and PAA.
Potential for Glycerol Phenylbutyrate to Affect Other Drugs Drugs with narrow therapeutic index that are substrates of CYP3A4 Glycerol phenylbutyrate is a weak inducer of CYP3A4 in humans. Concomitant use of glycerol phenylbutyrate may decrease the systemic exposure to drugs that are substrates of CYP3A4. Monitor for decreased efficacy of drugs with narrow therapeutic index (e.g., alfentanil, quinidine, cyclosporine).
Midazolam Concomitant use of glycerol phenylbutyrate decreased the systemic exposure of midazolam. Monitor for suboptimal effect of midazolam in patients who are being treated with glycerol phenylbutyrate.
Pregnancy Safety for Glycerol Phenylbutyrate
Pregnancy Risk Summary Limited available data with glycerol phenylbutyrate use in pregnant women are insufficient to inform a drug-associated risk of major birth defects and miscarriage. In an animal reproduction study, administration of oral glycerol phenylbutyrate to pregnant rabbits during organogenesis at doses up to 2.7–times the dose of 6.87 mL/m 2 /day in adult patients resulted in maternal toxicity, but had no effects on embryo-fetal development. In addition, there were no adverse developmental effects with administration of oral glycerol phenylbutyrate to pregnant rats during organogenesis at 1.9 times the dose of 6.87 mL/m 2 /day in adult patients; however, maternal toxicity, reduced fetal weights, and variations in skeletal development were observed in pregnant rats administered oral glycerol phenylbutyrate during organogenesis at doses greater than or equal to 5.7 times the dose of 6.87 mL/m 2 /day in adult patients.
Report pregnancies to Aurobindo Pharma USA, Inc.at 1-866-850-2876. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Data Animal Data Oral administration of glycerol phenylbutyrate during the period of organogenesis up to 350 mg/kg/day in rabbits produced maternal toxicity, but no effects on embryo-fetal development. The dose of 350 mg/kg/day in rabbits is approximately 2.7 times the dose of 6.87 mL/m 2 /day in adult patients, based on combined area under the plasma concentration-time curve for PBA and PAA.
In rats, at an oral dose of 300 mg/kg/day of glycerol phenylbutyrate (1.9 times the dose of 6.87 mL/m 2 /day in adult patients, based on combined AUCs for PBA and PAA) during the period of organogenesis, no effects on embryo-fetal development were observed. Doses of 650 mg/kg/day or greater produced maternal toxicity and adverse effects on embryo-fetal development including reduced fetal weights and cervical ribs at the 7th cervical vertebra. No developmental abnormalities, effects on growth, or effects on learning and memory were observed through maturation of offspring following oral administration in pregnant rats with up to 900 mg/kg/day of glycerol phenylbutyrate (8.5 times the dose of 6.87 mL/m 2 /day in adult patients, based on combined AUCs for PBA and PAA) during organogenesis and lactation.
Pediatric Use of Glycerol Phenylbutyrate
Patients Less Than 2 Years of Age The safety and effectiveness of glycerol phenylbutyrate in patients with UCDs less than 2 years of age have been established in 3 open-label studies. Juvenile Animal Toxicity Data In a juvenile rat study with daily oral dosing performed on postpartum day 2 through mating and pregnancy after maturation, terminal body weight was dose-dependently reduced by up to 16% in males and 12% in females at 900 mg/kg/day or higher (3 times the dose of 6.87 mL/m 2 /day in adult patients, based on combined AUCs for PBA and PAA). Learning, memory, and motor activity endpoints were not affected.
Contraindications for Glycerol Phenylbutyrate
Glycerol phenylbutyrate oral liquid is contraindicated in patients with known hypersensitivity to phenylbutyrate. Signs of hypersensitivity include wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash. Known hypersensitivity to phenylbutyrate.
Overdosage Information for Glycerol Phenylbutyrate
While there is no experience with overdosage in human clinical trials, PAA, a toxic metabolite of glycerol phenylbutyrate, can accumulate in patients who receive an overdose. If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.
Clinical Studies of Glycerol Phenylbutyrate
Clinical Studies in Adult Patients with UCDs Active-Controlled, 4-Week, Noninferiority Study (Study 1) A randomized, double-blind, active-controlled, crossover, noninferiority study (Study 1) compared glycerol phenylbutyrate to sodium phenylbutyrate by evaluating ammonia levels in patients with UCDs who had been on sodium phenylbutyrate prior to enrollment for control of their UCD. Patients were required to have a confirmed diagnosis of UCD involving deficiencies of CPS, OTC, or ASS, confirmed via enzymatic, biochemical, or genetic testing. Patients had to have no clinical evidence of hyperammonemia at enrollment and were not allowed to receive drugs known to increase ammonia levels (e.g., valproate), increase protein catabolism (e.g., corticosteroids), or significantly affect renal clearance (e.g., probenecid).
The primary endpoint was the 24-hour AUC (a measure of exposure to ammonia over 24 hours) for venous ammonia on days 14 and 28 when the drugs were expected to be at steady state. Statistical noninferiority would be established if the upper limit of the 2-sided 95% CI for the ratio of the geometric means (glycerol phenylbutyrate/sodium phenylbutyrate) for the endpoint was 1.25 or less. Sodium phenylbutyrate or glycerol phenylbutyrate were administered three times daily with meals.
The dose of glycerol phenylbutyrate was calculated to deliver the same amount of PBA as the sodium phenylbutyrate dose the patients were taking when they entered the study. Forty-four patients received at least 1 dose of glycerol phenylbutyrate in the study. Patients adhered to a low-protein diet and received amino acid supplements throughout the study.
After 2 weeks of dosing, by which time patients had reached steady state on each treatment, all patients had 24 hours of ammonia measurements. Glycerol phenylbutyrate was non-inferior to sodium phenylbutyrate with respect to the 24-hour AUC for ammonia. Forty-four patients were evaluated in this analysis.
Mean 24-hour AUCs for ammonia during steady-state dosing were 866 micromol•h/L and 977 micromol•h/L with glycerol phenylbutyrate and sodium phenylbutyrate, respectively. The ratio of geometric means was 0.91. The mean and median maximum ammonia levels (C max ) over 24 hours and 24-hour AUC for ammonia are summarized in Table 3.
Ammonia values across different laboratories were normalized to a common normal range of 9 to 35 micromol/L using the following formula after standardization of the units to micromol/L: Normalized ammonia (micromol/L) = ammonia readout in micromol/L x (35/ULN of a laboratory reference range specified for each assay) Figure 2: Ammonia Levels in Adult Patients with UCDs in Short-Term Treatment Study 1 Table 3: Ammonia Levels in Adult Patients with UCDs in Short-Term Treatment Study 1 977 653 Open-Label, Uncontrolled, Extension Study in Adults A long-term (12-month), uncontrolled, open-label study (Study 2) was conducted to assess monthly ammonia control and hyperammonemic crisis over a 12-month period. A total of 51 adults were in the study and all but 6 had been converted from sodium phenylbutyrate to glycerol phenylbutyrate. Venous ammonia levels were monitored monthly.
Mean fasting ammonia values in adults in Study 2 were within normal limits during long-term treatment with glycerol phenylbutyrate (range: 6 to 30 micromol/L). The fasting ammonia measured during Study 2 is displayed in Figure 3. A total of 43 adult patients between the ages of 19 and 61 years were in the study.
The median length of study participation was 1.9 years (range 0 to 4.5 years). Venous ammonia levels were monitored at a minimum of every 6 months. These studies compared ammonia levels of patients on glycerol phenylbutyrate to ammonia levels of patients on sodium phenylbutyrate in 26 pediatric patients between 2 months and 17 years of age with UCDs.
Four patients less than 2 years of age were excluded from this analysis due to insufficient data. Sodium phenylbutyrate or glycerol phenylbutyrate were administered in divided doses with meals. After a dosing period with each treatment, all patients underwent 24 hours of venous ammonia measurements, as well as blood and urine pharmacokinetic assessments.
UCD subtypes included OTC (n=12), ASL (n=8), and ASS deficiency (n=2), and patients received a mean glycerol phenylbutyrate dose of /day, with doses ranging from /day. Doses in these patients were based on previous dosing of sodium phenylbutyrate. Ammonia values across different laboratories were normalized to a common normal range of 9 to 35 micromol/L using the following formula after standardization of the units to micromol/L: Normalized ammonia (micromol/L) = ammonia readout in micromol/L x (35/ULN of a laboratory reference range specified for each assay) Figure 4: Ammonia Levels in Pediatric Patients 2 Years to 17 Years of Age with UCDs in Short-Term Treatment Studies 3 and 4 Open-Label, Uncontrolled, Extension Studies in Pediatric Patients 2 Years to 17 Years of Age Long-term (12-month), uncontrolled, open-label studies were conducted to assess monthly ammonia control and hyperammonemic crises over a 12-month period.
Mean fasting venous ammonia levels were within normal limits (range 17 to 23 micromol/L) during long-term treatment with glycerol phenylbutyrate. The fasting ammonia levels measured during these two extension studies in patients 6 years to 17 years are displayed in Figure 5. Open-Label, Long-Term Study in Pediatric Patients 1 Year to 17 Years of Age An open-label, long-term study (Study 5) was conducted to assess ammonia levels in pediatric patients with UCD.
The study enrolled patients with UCDs who had completed Studies 2, 3E and 4E. A total of 45 pediatric patients ages 1 year to 17 years were included in the study. The median length of treatment was 1.7 years (range 0.2 to 4.6 years).
Clinical Studies in Pediatric Patients Less Than 2 Years of Age with UCDs The efficacy of glycerol phenylbutyrate in pediatric patients less than 2 years of age with UCDs was evaluated in uncontrolled, open label studies (Studies 4/4E, 5 and 6). Study 6 enrolled 16 pediatric patients less than 2 months of age. In these studies, there were pediatric patients who completed months, respectively (mean and median exposure of 15 and 17 months, respectively).
Patients were converted from sodium phenylbutyrate to glycerol phenylbutyrate. Patients were dosed three times per day (n=3) or four times per day (n = 4). Two patients had elevated ammonia values on day 1 of treatment (122 micromol/L and 111 micromol/L respectively) and neither had associated signs and symptoms of hyperammonemia.
During the extension period, venous ammonia levels were monitored monthly. Ammonia values across different laboratories were normalized (transformed) to a common normal pediatric range of 28 to 57 micromol/L for comparability. The mean ammonia levels in pediatric patients at month micromol/L during treatment with glycerol phenylbutyrate, respectively.
Three patients reported a total of 3 hyperammonemic crises defined as having signs and symptoms consistent with hyperammonemia (such as frequent vomiting, nausea, headache, lethargy, irritability, combativeness, and/or somnolence) associated with high ammonia levels (greater than 100 micromol/L) and requiring medical intervention. Hyperammonemic crises were precipitated by gastroenteritis, vomiting, infection or no precipitating event (one patient). There were 4 patients who had one ammonia level that exceeded 100 micromol/L which was not associated with a hyperammonemic crisis.
The primary efficacy endpoint was successful transition to glycerol phenylbutyrate within a period of 4 days followed by 3 days of observation for a total of 7 days, where successful transition was defined as no signs and symptoms of hyperammonemia and a venous ammonia level less than 100 micromol/L. Ammonia levels were monitored for up to 4 days during transition and on day 7. One additional patient was gradually discontinued from intravenous sodium benzoate and sodium phenylacetate while glycerol phenylbutyrate was initiated.
The dosage of glycerol phenylbutyrate after transition was 8.5 mL/m 2 /day. Patients were dosed three times a day (n=6), four times a day (n = 2), or five or more times a day (n=2). Nine patients successfully transitioned as defined by the primary endpoint.
One additional patient developed hyperammonemia on day 3 of dosing and experienced surgical complications (bowel perforation and peritonitis) following jejunal tube placement on day 4. This patient developed hyperammonemic crisis on day 6, and subsequently died of sepsis from peritonitis unrelated to drug. Although two patients had day 7 ammonia values of 150 micromol/L and 111 micromol/L respectively, neither had associated signs and symptoms of hyperammonemia.
Three patients reported a total of 7 hyperammonemic crises as defined in Study 4/4E and 5. Hyperammonemic crises were precipitated by vomiting, upper respiratory tract infection, gastroenteritis, decreased caloric intake or had no identified precipitating event (3 events). Median age at enrollment was 0.5 months (range: 0.1 to 2 months).
Eight patients had OTC deficiency, 7 patients had ASS deficiency, and 1 patient had ASL deficiency. Ten of the 16 patients transitioned from sodium phenylbutyrate to glycerol phenylbutyrate within 3 days of treatment and their initial dosage of glycerol phenylbutyrate was calculated to deliver the same amount of phenylbutyrate as the sodium phenylbutyrate dosage administered prior to glycerol phenylbutyrate dosing. Three of the 16 patients were treatment-naïve and started glycerol phenylbutyrate at dosages of /day.
The remaining 3 of the 16 patients transitioned from intravenous sodium benzoate and sodium phenylacetate to glycerol phenylbutyrate within 3 days of treatment and their initial dosages of glycerol phenylbutyrate were /day. Of the 16 patients, patients were treated for months, respectively. After the initial 7-day transition period, patients received a mean glycerol phenylbutyrate dosage of /day, with doses ranging from /day.
The frequency of dosing varied throughout the study. The majority of patients were dosed three times per day with feeding. No patients discontinued during the 7-day transition phase.
During the safety extension phase, 1 patient discontinued from the study due to an adverse event (increased hepatic enzymes), 2 patients were withdrawn from the study by their parent/guardian, and 4 patients discontinued from the study early to undergo a liver transplant (protocol-defined discontinuation criterion). The normalized ammonia levels in pediatric patients with available values (which varied by month of treatment) in Study 6 in patients less than 2 months of age are shown in Table 4. Table 4: Ammonia* Levels in Pediatric Patients Less than *normalized ammonia (micromol/L) = ammonia readout in micromol/L x (35/ULN of a laboratory reference range specified for each assay) *normal range: 28 to 57 micromol/L.
Five patients (all less than 1 month of age) experienced a total of 7 hyperammonemic crises defined as in Study 4/4E and 5. Hyperammonemic crises were precipitated by upper respiratory tract infection (2 events), change in diet (1 event), or had no identified precipitating event (4 events).
| Timepoint | Ammonia (n=44) | |
|---|---|---|
| Mean (SD) | Median (min, max) | |
| Daily C max (micromol/L) | ||
| Glycerol Phenylbutyrate | 61 (46) | 51 (12, 245) |
| Sodium phenylbutyrate | 71 (67) | 46 (14, 303) |
| 24-Hour AUC (micromol•h/L) | ||
| Glycerol Phenylbutyrate | 866 (661) | 673 (206, 3351) |
| Sodium phenylbutyrate | 977 (865) | 653 (302, 4666) |
| Month | N (patients with available ammonia level) | Normalized Ammonia (micromol/L) | |
|---|---|---|---|
| Mean (SD) | Median (Min, Max) | ||
| 1 | 15 | 71 (52) | 60 (18, 227) |
| 2 | 11 | 58 (40) | 50 (16, 168) |
| 3 | 14 | 53 (34) | 46 (11, 122) |
| 4 | 11 | 94 (106) | 64 (35, 407) |
| 5 | 10 | 52 (18) | 57 (27, 86) |
| 6 | 9 | 49 (24) | 42 (22, 91) |
| 9 | 8 | 56 (34) | 45 (22, 122) |
| 12 | 6 | 35 (17) | 36 (11, 60) |
| 15 | 4 | 52 (12) | 52 (39, 67) |
| 18 | 3 | 64 (14) | 63 (50, 78) |
| 24 | 9 | 63 (29) | 72 (23, 106) |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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