GLYCERINE ADULTE

Glycerol phenylbutyrate is a clear, colorless to pale yellow oral liquid.

It is freely soluble in toluene and in acetone, practically insoluble in water.

Glycerol phenylbutyrate is a nitrogen-binding agent.

It is a triglyceride containing 3 molecules of PBA linked to a glycerol backbone, the chemical name of which is benzenebutanoic acid, 1', 1' ' –(1,2,3-propanetriyl) ester with a molecular weight of 530.67.

It has a molecular formula of

C 33 H 38 O 6.

The structural formula is: str.

Used for catch therapy and intestinal discharge.

The safety category during pregnancy: "C": There are currently insufficient studies to confirm the safe use of treatment on the foetus; treatment is used if the therapeutic benefit is greater than the risk to the foetus.

A doctor or pharmacist must be consulted before treatment is taken in case of pregnancy.

It is not known whether the treatment is produced in milk, it must be used with caution and after consultation with a doctor or pharmacist.

UCDs are inherited deficiencies of enzymes or transporters necessary for the synthesis of urea from ammonia (NH 3, NH 4 + ).

Absence of these enzymes or transporters results in the accumulation of toxic levels of ammonia in the blood and brain of affected patients.

Glycerol phenylbutyrate is a triglyceride containing 3 molecules of PBA.

PAA, the major metabolite of PBA, is the active moiety of glycerol phenylbutyrate.

PAA conjugates with glutamine (which contains 2 molecules of nitrogen) via acetylation in the liver and kidneys to form PAGN, which is excreted by the kidneys (Figure 1).

On a molar basis, PAGN, like urea, contains 2 moles of nitrogen and provides an alternate vehicle for waste nitrogen excretion.

Figure 1: Glycerol Phenylbutyrate Mechanism of Action fig 12.2 Pharmacodynamics Pharmacological Effects In clinical studies, total 24-hour area under the plasma concentration-time curve (AUC) of ammonia levels was comparable at steady state during the switchover period between glycerol phenylbutyrate and sodium phenylbutyrate.

The effect of multiple doses of glycerol phenylbutyrate 13.2 g/day and 19.8 g/day (approximately 69% and 104% of the maximum recommended daily dosage) on QTc interval was evaluated in a randomized, placebo.

• and active-controlled (moxifloxacin 400 mg), four-treatment-arm, crossover study in 57 healthy subjects.

The upper bound of the one-sided 95% CI for the largest placebo-adjusted, baseline-corrected QTc, based on individual correction method (QTcI) for glycerol phenylbutyrate, was below 10 ms. 12.3 Pharmacokinetics Absorption Glycerol phenylbutyrate is a pro-drug of PBA.

Upon oral ingestion, PBA is released from the glycerol backbone in the gastrointestinal tract by lipases.

PBA derived from glycerol phenylbutyrate is further converted by β-oxidation to PAA.

In healthy, fasting adult subjects receiving a single oral dose of 2.9 mL/m of glycerol phenylbutyrate, peak plasma levels of PBA, PAA, and PAGN occurred at 2 hours, 4 hours, and 4 hours, respectively.

Upon single-dose administration of glycerol phenylbutyrate, plasma concentrations of PBA were quantifiable in of 22 participants at the first sample time postdose (0.25 hours).

Mean maximum concentration (C max ) for PBA, PAA, and PAGN was 37.0 micrograms/mL, 14.9 micrograms/mL, and 30.2 micrograms/mL, respectively.

In healthy subjects, intact glycerol phenylbutyrate was detected in plasma.

While the study was inconclusive, the incomplete hydrolysis of glycerol phenylbutyrate cannot be ruled out.

In healthy subjects, the systemic exposure to PAA, PBA, and PAGN increased in a dose-dependent manner.

Following 4 mL of glycerol phenylbutyrate 3 times a day for 3 days, the mean C max and AUC were 66 micrograms/mL and 930 micrograms•h/mL for PBA and 28 micrograms/mL and 942 micrograms•h/mL for PAA, respectively.

In the same study, following 6 mL of glycerol phenylbutyrate three times a day for 3 days, mean C max and AUC were 100 micrograms/mL and 1400 micrograms•h/mL for PBA and 65 mcg/mL and 2064 micrograms•h/mL for PAA, respectively.

In adult patients with

UCDs receiving multiple doses of glycerol phenylbutyrate, maximum plasma concentrations at steady state (C max, ss ) of PBA, PAA, and PAGN occurred at 8 hours, 12 hours, and 10 hours, respectively, after the first dose in the day. Intact glycerol phenylbutyrate was not detectable in plasma in patients with UCDs.

In clinical studies of glycerol phenylbutyrate in patients with UCDs, the peak observed PAA concentrations by are shown in Table 2.

Table 2: Peak PAA Concentrations in Patients with UCDs Treated with Glycerol Phenylbutyrate in Clinical Trials Age Range Glycerol Phenylbutyrate Dose Mean Peak PAA Concentration (SD) Median Peak PAA Concentration (Range) Less than 2 months (n=16) 3.1 to 12.7 mL/m 2 /day (3.4 to 14 g/m 2 /day) 257 205 (96 to 707) 2 months to less than 2 years (n=17) 3.3 to 12.3 mL/m 2 /day (3.7 to 13.5 g/m 2 /day) 142 35 (1 to 1215) 2 years to 17 years (n=53) 1.4 to 13.7 mL/m 2 /day (1.5 to 15.1 g/m 2 /day) 70 50 (1 to 410) Adults (n=43) 0.6 to 14 mL/m 2 /day (0.7 to 15.4 g/m 2 /day) 39 25 (1.6 to 178) *micrograms/mL Distribution In vitro, the extent of plasma protein binding for 14 C-labeled metabolites was 81% to 98% for PBA (over to 250 micrograms/mL), and 37% to 66% for PAA (over to 500 micrograms/mL).

The protein binding for

PAGN was 7% to 12% and no concentration effects were noted.

Upon oral administration, pancreatic lipases hydrolyze glycerol phenylbutyrate (i.e., glycerol phenylbutyrate), and release PBA.

PBA undergoes β-oxidation to PAA, which is conjugated with glutamine in the liver and in the kidney through the enzyme phenylacetyl-CoA: L-glutamine-N-acetyltransferase to form PAGN.

PAGN is subsequently eliminated in the urine.

Saturation of conjugation of PAA and glutamine to form PAGN was suggested by increases in the ratio of plasma PAA to PAGN with increasing dose and with increasing severity of hepatic impairment.

In healthy subjects, after administration of 4 mL, 6 mL, and 9 mL 3 times daily for 3 days, the ratio of mean AUC 0-23h of PAA to PAGN was 1, 1.25, and 1.6, respectively.

In a separate study, in patients with hepatic impairment (Child-Pugh B and C), the ratios of mean C max values for PAA to PAGN among all patients dosed with 6 mL and 9 mL twice daily were and 3.7.

In in vitro studies, the specific activity of lipases for glycerol phenylbutyrate was in the following decreasing order: pancreatic triglyceride lipase, carboxyl ester lipase, and pancreatic lipase–related protein 2.

Further, glycerol phenylbutyrate was hydrolyzed in vitro by esterases in human plasma.

In these in vitro studies, a complete disappearance of glycerol phenylbutyrate did not produce molar equivalent PBA, suggesting the formation of mono.

• or bis-ester metabolites.

However, the formation of mono.

• or bis-esters was not studied in humans.

The mean (SD) percentage of administered PBA excreted as PAGN was approximately 69% in adults and 66% in pediatric patients with UCDs at steady state.

PAA and

PBA represented minor urinary metabolites, each accounting for less than 1% of the administered dose of PBA.

Pediatric Population Population pharmacokinetic modeling and dosing simulations suggest body surface area to be the most significant covariate explaining the variability of PAA clearance.

PAA clearance was 10.9 L/h, 16.4 L/h, and 24.4 L/h, respectively, for patients ages to 5, 6 to 11, and to 17 years with UCDs.

In pediatric patients with

UCDs (n = 14) ages 2 months to less than 2 years, PAA clearance was 6.8 L/h.

UCDs (n = 16) ages less than 2 months, PAA clearance was 3.8 L/h.

The mean peak ratio of PAA to PAGN in UCD patients aged birth to less than 2 months was higher (mean: 1.6; range 0.1 to 7.1) than that of UCD patients aged 2 months to less than 2 years (mean 0.5; range 0.1 to 1.2).

In healthy adult subjects, a gender effect was found for all metabolites, with women generally having higher plasma concentrations of all metabolites than men at a given dose level.

In healthy female subjects, mean C max for PAA was and 120% higher than in male volunteers after administration of 4 mL and 6 mL 3 times daily for 3 days, respectively.

The dose normalized mean

AUC 0-23h for PAA was 108% higher in females than in males.

The pharmacokinetics of glycerol phenylbutyrate in patients with impaired renal function, including those with end-stage renal disease (ESRD) or those on hemodialysis, have not been studied.

The effects of hepatic impairment on the pharmacokinetics of glycerol phenylbutyrate were studied in patients with mild, moderate and severe hepatic impairment of (Child-Pugh class A, B, and C, respectively) receiving 100 mg/kg of glycerol phenylbutyrate twice daily for 7 days.

Plasma glycerol phenylbutyrate was not measured in patients with hepatic impairment.

After multiple doses of glycerol phenylbutyrate in patients with hepatic impairment of Child-Pugh A, B, and C, geometric mean AUC t of PBA was 42%, 84%, and 50% higher, respectively, while geometric mean AUC t of PAA was 22%, 53%, and 94% higher, respectively, than in healthy subjects.

In patients with hepatic impairment of Child-Pugh A, B, and C, geometric mean AUC t of PAGN was 42%, 27%, and 22% lower, respectively, than that in healthy subjects.

The proportion of PBA excreted as PAGN in the urine in Child-Pugh A, B, and C was 80%, 58%, and 85%, respectively, and, in healthy volunteers, was 67%.

In another study in patients with moderate and severe hepatic impairment (Child-Pugh B and C), mean C max of PAA was 144 micrograms/mL (range: 14 to 358 micrograms/mL) after daily dosing of 6 mL of glycerol phenylbutyrate twice daily, while mean C max of PAA was 292 micrograms/mL (range: 57 to 655 micrograms/mL) after daily dosing of 9 mL of glycerol phenylbutyrate twice daily.

The ratio of mean C max values for PAA to PAGN among all patients dosed with 6 mL and 9 mL twice daily were and 3.7, respectively.

After multiple doses, a PAA concentration greater than 200 micrograms/mL was associated with a ratio of plasma PAA to PAGN concentrations higher than 2.5.

Drug Interaction Studies In vitro PBA or PAA did not induce CYP1A2, suggesting that in vivo drug interactions via induction of CYP1A2 is unlikely.

In in vitro studies, PBA at a concentration of 800 micrograms/mL caused greater than 60% reversible inhibition of cytochrome P450 isoenzymes CYP2C9, CYP2D6, and CYP3A4/5 (testosterone 6β-hydroxylase activity).

The in vitro study suggested that in vivo drug interactions with substrates of CYP2D6 cannot be ruled out.

The inhibition of

CYP isoenzymes 1A2, 2C8, 2C19, and 2D6 by PAA at the concentration of 2.8 mg/mL was observed in vitro.

Clinical implication of these results is unknown.

Effects of glycerol phenylbutyrate on other drugs Midazolam In healthy subjects, when oral midazolam was administered after multiple doses of glycerol phenylbutyrate (4 mL three times a day for 3 days) under fed conditions, the mean C max and AUC for midazolam were 25% and 32% lower, respectively, compared to administration of midazolam alone.

In addition, the mean C max and AUC for 1-hydroxy midazolam were 28% and 58% higher, respectively, compared to administration of midazolam alone.

Concomitant administration of glycerol phenylbutyrate did not significantly affect the pharmacokinetics of celecoxib, a substrate of CYP2C9.

When 200 mg of celecoxib was orally administered with glycerol phenylbutyrate after multiple doses of glycerol phenylbutyrate (4 mL three times a day for 6 days) under fed conditions (a standard breakfast was consumed 5 minutes after celecoxib administration), the mean C max and AUC for celecoxib were 13% and 8% lower than after administration of celecoxib alone.

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The following clinically significant adverse reactions are described elsewhere in the labeling: Neurotoxicity Pancreatic insufficiency or Intestinal Malabsorption Most common adverse reactions (≥10%) in adults are: diarrhea, flatulence, and headache.

To report SUSPECTED ADVERSE

REACTIONS, contact Aurobindo Pharma USA, Inc.fda.gov/medwatch. 6.1 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 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).

Table 1: Adverse Reactions Reported in 2 or More Adult Patients with UCDs (at least 4% in Either Treatment Arm) in Study 1 Number (%) of Patients in Study 1 Sodium Phenylbutyrate (N = 45) Glycerol Phenylbutyrate (N = 44) Diarrhea 3 7 Headache 4 6 Flatulence 1 6 Abdominal pain 2 3 Vomiting 2 3 Decreased appetite 2 3 Fatigue 1 3 Dyspepsia 3 2 Nausea 3 1 Dizziness 4 0 Abdominal discomfort 3 0 Other Adverse Reactions Glycerol phenylbutyrate has been evaluated in 77 patients with UCDs (51 adult and 26 pediatric patients ages 2 years to 17 years) in 2 open-label long-term studies, in which 69 patients completed 12 months of treatment with glycerol phenylbutyrate (median exposure = 51 weeks).

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.

Glycerol phenylbutyrate has been evaluated in 17 patients with UCDs ages 2 months to less than 2 years in 3 open-label studies.

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.

Glycerol phenylbutyrate has been evaluated in 16 patients with UCDs less than 2 months of age (age range 0.1 to 2 months, median age 0.5 months) in a single, open-label study.

The median exposure was 10 months (range to 20 months).

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. 6.2 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.

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.

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.

Glycerol phenylbutyrate oral liquid should be prescribed by a physician experienced in management of UCDs.

For administration and preparation, see full prescribing information.

Switching From Sodium Phenylbutyrate Tablets or Powder to Glycerol Phenylbutyrate Oral Liquid: Patients should receive the dosage of glycerol phenylbutyrate oral liquid that contains the same amount of phenylbutyric acid, see full prescribing information for conversion.

Initial Dosage in

Phenylbutyrate-Naïve Patients: Recommended dosage range is 4.5 to 11.2 mL/m 2 /day (5 to 12.4 g/m 2 /day).

For patients with some residual enzyme activity not adequately controlled with dietary restriction, the recommended starting dose is 4.5 mL/m 2 /day. Take into account patient's estimated urea synthetic capacity, dietary protein intake, and diet adherence.

Follow plasma ammonia levels to determine the need for dosage titration.

Dosage Modifications in Patients with Hepatic Impairment: Start dosage at lower end of range. 2.1 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). 2.2 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 2.3 Initial Dosage in Phenylbutyrate-Naïve Patients The recommended dosage range, based upon body surface area, in patients naïve to phenylbutyrate (PBA) is 4.5 to 11.2 mL/m 2 /day (5 to 12.4 g/m 2 /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. 2.4 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.

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 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.

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.

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.

The amount of dosage adjustment should factor in the amount of dietary protein that has not been covered, as indicated by the 24-hour U-PAGN output, and the estimated glycerol phenylbutyrate oral liquid dose needed per gram of dietary protein ingested and the maximum total daily dosage (i.e., 17.5 mL).

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. 2.5 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. 2.6 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.

For patients who require a volume of less than 1 mL per dose via nasogastric or gastrostomy tube, the delivered dosage may be less than anticipated due to adherence of glycerol phenylbutyrate oral liquid to the plastic tubing.

Therefore, these patients should be closely monitored using ammonia levels following initiation of glycerol phenylbutyrate oral liquid dosing or dosage adjustments.

Glycerol phenylbutyrate oral liquid 1.1 g/mL is supplied in multi-use, 25-mL glass bottle as follows: NDC 59651-988-25: Single 25-mL bottle per carton Store at 20º to 25ºC (68º to 77ºF), excursions permitted to 15° to 30°C (59° to 86°F) .

Discard bottle 28 days after opening.

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 to 4% and to 20%, respectively.

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 [AUCs] 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.

The dose of 650 mg/kg/day in rats is approximately 5.7 times the dose of 6.87 mL/m 2 /day in adult patients, based on combined AUCs for PBA and PAA.

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.

Patients 2 Years to 17 Years of Age The safety and effectiveness of glycerol phenylbutyrate in patients 2 years to less than 18 years of age have been established in 3 clinical studies: 2 open-label, fixed-sequence, switchover clinical studies from sodium phenylbutyrate to glycerol phenylbutyrate, and 1 long-term, open label safety study.

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.

Pharmacokinetics and pharmacodynamics (plasma ammonia), and safety were studied in 17 patients aged 2 months to less than 2 years of age and in 16 patients less than 2 months of age.

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.

However, fertility (number of pregnant rats) was decreased by up to 25% at 650 mg/kg/day or higher (2.6 times the dose of 6.87 mL/m 2 /day in adult patients, based on combined AUCs for PBA and PAA).

Clinical studies of glycerol phenylbutyrate did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently than younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.