GLYCERINE ADULTE

A trihydroxy sugar alcohol that is an intermediate in carbohydrate and lipid metabolism.

It is used as a solvent, emollient, pharmaceutical agent, and sweetening agent.

Glycerin is commonly classified as an osmotic laxative but may act additionally or alternatively through its local irritant effects; it may also have lubricating and fecal softening actions.

Glycerin suppositories usually work within 15-30 minutes.

Well absorbed

Oral, poorly absorbed rectally.

Studies in humans and animals indicate glycerol is rapidly absorbed in the intestine and the stomach.

Glycerin is distributed throughout the blood.

Although glycerin generally does not appear in ocular fluids, it may enter the orbital sac when the eye is inflamed, with a consequent decrease in osmotic effect.

Glycerin is a substrate for synthesis of triacylglycerols and of phospholipids in the liver and adipose tissue.

When fat metabolized as a source of energy, glycerol and fatty acids are released into the bloodstream.

Circulating glycerin does not glycate proteins and does not lead to the formation of advanced glycation endproducts (AGEs).

In some organisms, the glycerin component can enter the glycolysis pathway directly to provide a substrate for energy or glucose production.

Glycerol must be converted to their intermediate glyceraldehyde 3-phosphate before being used in glycolysis or gluconeogenesis.

Glycerol metabolism is regulated by the enzymes glycerol kinase, (cytosolic) NAD+-dependent G3P dehydrogenase and (mitochondrial) FAD-linked G3P dehydrogenase.

Approx 7-14% of dose is excreted unchanged in the urine within 2.5 hr.

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Glycerol has very low toxicity when ingested.

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.

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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.