glycerol phenylbutyrate (Rx)

Brand and Other Names:Ravicti
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

oral liquid

  • 1.1 g/mL

Urea Cycle Disorders

Nitrogen-binding agent for chronic management of adults with urea cycle disorders who cannot be managed by dietary protein restriction and/or amino acid supplementation alone

Administer PO in 3 equally divided dosages, each rounded up to nearest 0.5 mL

Not to exceed 17.5 mL/day

Also see Administration section

Switching from sodium phenylbutyrate to glycerol phenylbutyrate

  • Total daily dose of Ravicti (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.86
  • Total daily dose of Ravicti (mL) = total daily dosage of sodium phenylbutyrate powder (g) x 0.81

Phenylbutyrate-naïve

  • 4.5-11.2 mL/m²/day (5-12.4 g/m²/day)
  • Determine starting dose by patient’s residual urea synthetic capacity, dietary protein requirements, and diet adherence
  • Dietary protein is ~15% nitrogen by weight
  • ~47% of dietary nitrogen is excreted as waste and ~70% of phenylbutyrate dose is converted to urinary phenylacetylglutamine (U-PAGN), so an initial estimated dose is 0.6 mL/g dietary protein ingested per day

Dosage Modifications

Adjustment based on plasma ammonia: Adjust dose to produce fasting plasma ammonia level less than half ULN according to age

Adjustment based on urinary phenylacetylglutamine

  • Each gram of U-PAGN excreted over 24 hr 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, adjusted dosage upward
  • The amount of dose adjustment should factor in the amount of dietary protein that has not been covered (not to exceed 17.5 mL/day)
  • Also consider concomitant medications (eg, probenecid) that may decrease urinary excretion of PAGN

Adjustment based on plasma phenylacetate (PPA)

  • PAA levels may be useful to guide dosing if symptoms of vomiting, nausea, headache, somnolence, confusion, or sleepiness are present in the absence of high ammonia or intercurrent illness
  • Ammonia levels must be monitored closely when changing the dose
  • If a high PAA to PAGN ratio exists, a further dosage increase may not increase PAGN formation, even if plasma PAA concentrations are increased, due to saturation of the conjugation reaction
  • The PAA to PAGN ratio has been observed to be generally <1 in patients without significant PAA accumulation

Hepatic impairment

  • Moderate-to-severe hepatic impairment: Use starting dose at lower end of dosage range
  • Conversion of PAA to PAGN occurs in the liver, hepatic impairment may reduce conversion capability and result in higher plasma PAA and PAA to PAGN ratio

Renal impairment

  • Efficacy and safety unknown in patients with renal impairment
  • Monitor ammonia levels closely when initiating in patients with impaired renal function

Dosing Considerations

Must be used with dietary protein restriction and, in some cases, dietary supplements (eg, essential amino acids, arginine, citrulline, protein-free calorie supplements)

Monitor plasma ammonia levels

Limitations of use

  • Not indicated for treatment of acute hyperammonemia in patients with UCDs because more rapidly acting interventions are essential to reduce plasma ammonia levels
  • Safety and efficacy for N-acetylglutamate synthase (NAGS) deficiency not established

Dosage Forms & Strengths

oral liquid

  • 1.1 g/mL

Urea Cycle Disorders

Nitrogen-binding agent for chronic management of adults and children (including newborns) with urea cycle disorders who cannot be managed by dietary protein restriction and/or amino acid supplementation alone

<2 years: Give PO in 3 or more equally divided dosages, each rounded up to nearest 0.1 mL

≥2 years: Give PO in 3 equally divided dosages, each rounded up to nearest 0.5 mL

Not to exceed 17.5 mL/day

Also see Administration section

Switching from sodium phenylbutyrate to glycerol phenylbutyrate

  • Total daily dose of Ravicti (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.86
  • Total daily dose of Ravicti (mL) = total daily dosage of sodium phenylbutyrate powder (g) x 0.81

Phenylbutyrate-naïve

  • 4.5-11.2 mL/m²/day (5-12.4 g/m²/day)
  • Determine starting dose by patient’s residual urea synthetic capacity, dietary protein requirements, and diet adherence
  • Dietary protein is ~15% nitrogen by weight
  • ~47% of dietary nitrogen is excreted as waste and ~70% of phenylbutyrate dose is converted to urinary phenylacetylglutamine (U-PAGN), so an initial estimated dose is 0.6 mL/g dietary protein ingested per day

Dosage Modifications

Adjustment based on plasma ammonia: Adjust dose to produce fasting plasma ammonia level less than half ULN according to age

Adjustment based on urinary phenylacetylglutamine

  • Each gram of U-PAGN excreted over 24 hr 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, adjusted dosage upward
  • The amount of dose adjustment should factor in the amount of dietary protein that has not been covered (not to exceed 17.5 mL/day)
  • Also consider concomitant medications (eg, probenecid) that may decrease urinary excretion of PAGN

Adjustment based on plasma phenylacetate (PPA)

  • PAA levels may be useful to guide dosing if symptoms of vomiting, nausea, headache, somnolence, confusion, or sleepiness are present in the absence of high ammonia or intercurrent illness
  • Ammonia levels must be monitored closely when changing the dose
  • If a high PAA to PAGN ratio exists, a further dosage increase may not increase PAGN formation, even if plasma PAA concentrations are increased, due to saturation of the conjugation reaction
  • The PAA to PAGN ratio has been observed to be generally <1 in patients without significant PAA accumulation

Hepatic impairment

  • Moderate-to-severe hepatic impairment: Use starting dose at lower end of dosage range
  • Conversion of PAA to PAGN occurs in the liver, hepatic impairment may reduce conversion capability and result in higher plasma PAA and PAA to PAGN ratio

Renal impairment

  • Efficacy and safety unknown in patients with renal impairment
  • Monitor ammonia levels closely when initiating in patients with impaired renal function

Dosing Considerations

Must be used with dietary protein restriction and, in some cases, dietary supplements (eg, essential amino acids, arginine, citrulline, protein-free calorie supplements)

Monitor plasma ammonia levels

Limitations of use

  • Not indicated for treatment of acute hyperammonemia in patients with UCDs because more rapidly acting interventions are essential to reduce plasma ammonia levels
  • Safety and efficacy for N-acetylglutamate synthase (NAGS) deficiency not established
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Interactions

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                • alfentanil

                  glycerol phenylbutyrate will decrease the level or effect of alfentanil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of CYP3A4 substrates that have a narrow therapeutic index.

                • betamethasone

                  betamethasone decreases effects of glycerol phenylbutyrate by Other (see comment). Use Caution/Monitor. Comment: Corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels; monitor ammonia levels closely when glycerol phenylbutyrate is coadministered with corticosteroids.

                • carbamazepine

                  glycerol phenylbutyrate will decrease the level or effect of carbamazepine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of CYP3A4 substrates that have a narrow therapeutic index.

                • clonidine

                  glycerol phenylbutyrate will decrease the level or effect of clonidine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of CYP3A4 substrates that have a narrow therapeutic index.

                • colchicine

                  glycerol phenylbutyrate will decrease the level or effect of colchicine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of CYP3A4 substrates that have a narrow therapeutic index.

                • cortisone

                  cortisone decreases effects of glycerol phenylbutyrate by Other (see comment). Use Caution/Monitor. Comment: Corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels; monitor ammonia levels closely when glycerol phenylbutyrate is coadministered with corticosteroids.

                • cyclosporine

                  glycerol phenylbutyrate will decrease the level or effect of cyclosporine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of CYP3A4 substrates that have a narrow therapeutic index.

                • dexamethasone

                  dexamethasone decreases effects of glycerol phenylbutyrate by Other (see comment). Use Caution/Monitor. Comment: Corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels; monitor ammonia levels closely when glycerol phenylbutyrate is coadministered with corticosteroids.

                • dihydroergotamine

                  glycerol phenylbutyrate will decrease the level or effect of dihydroergotamine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of CYP3A4 substrates that have a narrow therapeutic index.

                • disopyramide

                  glycerol phenylbutyrate will decrease the level or effect of disopyramide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of CYP3A4 substrates that have a narrow therapeutic index.

                • ergotamine

                  glycerol phenylbutyrate will decrease the level or effect of ergotamine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of CYP3A4 substrates that have a narrow therapeutic index.

                • ethosuximide

                  glycerol phenylbutyrate will decrease the level or effect of ethosuximide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of CYP3A4 substrates that have a narrow therapeutic index.

                • everolimus

                  glycerol phenylbutyrate will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of CYP3A4 substrates that have a narrow therapeutic index.

                • fentanyl

                  glycerol phenylbutyrate will decrease the level or effect of fentanyl by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of CYP3A4 substrates that have a narrow therapeutic index.

                • fludrocortisone

                  fludrocortisone decreases effects of glycerol phenylbutyrate by Other (see comment). Use Caution/Monitor. Comment: Corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels; monitor ammonia levels closely when glycerol phenylbutyrate is coadministered with corticosteroids.

                • haloperidol

                  haloperidol decreases effects of glycerol phenylbutyrate by Other (see comment). Use Caution/Monitor. Comment: Haloperidol may induce hyperammonemia; monitor ammonia levels closely when coadministered with glycerol phenylbutyrate.

                • hydrocortisone

                  hydrocortisone decreases effects of glycerol phenylbutyrate by Other (see comment). Use Caution/Monitor. Comment: Corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels; monitor ammonia levels closely when glycerol phenylbutyrate is coadministered with corticosteroids.

                • methylprednisolone

                  methylprednisolone decreases effects of glycerol phenylbutyrate by Other (see comment). Use Caution/Monitor. Comment: Corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels; monitor ammonia levels closely when glycerol phenylbutyrate is coadministered with corticosteroids.

                • midazolam

                  glycerol phenylbutyrate will decrease the level or effect of midazolam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of CYP3A4 substrates that have a narrow therapeutic index. Cmax and AUC were 25% and 32% lower for a single dose of midazolam after multiple doses of glycerol phenylbutyrate.

                • pimozide

                  glycerol phenylbutyrate will decrease the level or effect of pimozide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of CYP3A4 substrates that have a narrow therapeutic index.

                • prednisolone

                  prednisolone decreases effects of glycerol phenylbutyrate by Other (see comment). Use Caution/Monitor. Comment: Corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels; monitor ammonia levels closely when glycerol phenylbutyrate is coadministered with corticosteroids.

                • prednisone

                  prednisone decreases effects of glycerol phenylbutyrate by Other (see comment). Use Caution/Monitor. Comment: Corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels; monitor ammonia levels closely when glycerol phenylbutyrate is coadministered with corticosteroids.

                • probenecid

                  probenecid, glycerol phenylbutyrate. decreasing renal clearance. Use Caution/Monitor. Probenecid may inhibit the renal excretion glycerol phenylbutyrate metabolites PAA and PAGN; caution when adjusting doses based on these metabolite levels.

                • quinidine

                  glycerol phenylbutyrate will decrease the level or effect of quinidine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of CYP3A4 substrates that have a narrow therapeutic index.

                • quinine

                  glycerol phenylbutyrate will decrease the level or effect of quinine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of CYP3A4 substrates that have a narrow therapeutic index.

                • sirolimus

                  glycerol phenylbutyrate will decrease the level or effect of sirolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of CYP3A4 substrates that have a narrow therapeutic index.

                • tacrolimus

                  glycerol phenylbutyrate will decrease the level or effect of tacrolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of CYP3A4 substrates that have a narrow therapeutic index.

                • triamcinolone acetonide injectable suspension

                  triamcinolone acetonide injectable suspension decreases effects of glycerol phenylbutyrate by Other (see comment). Use Caution/Monitor. Comment: Corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels; monitor ammonia levels closely when glycerol phenylbutyrate is coadministered with corticosteroids.

                • triazolam

                  glycerol phenylbutyrate will decrease the level or effect of triazolam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of CYP3A4 substrates that have a narrow therapeutic index.

                • valproic acid

                  valproic acid decreases effects of glycerol phenylbutyrate by Other (see comment). Use Caution/Monitor. Comment: Valproic acid may induce hyperammonemia; monitor ammonia levels closely when coadministered with glycerol phenylbutyrate.

                Minor (1)

                • celecoxib

                  glycerol phenylbutyrate decreases levels of celecoxib by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown. Glycerol phenylbutyrate does not significantly affect the pharmacokinetics of celecoxib, a substrate of CYP2C9. Cmax and AUC for celecoxib were 13% and 8% lower than after administration of celecoxib alone.

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                Adverse Effects

                >10%

                Diarrhea (16%)

                Flatulence (14%)

                Headache (14%)

                Children

                • Neutropenia
                • Vomiting
                • Constipation
                • Diarrhea
                • Pyrexia
                • Hypophagia
                • Cough, nasal congestion
                • Rhinorrhea
                • Rash
                • Papule
                • Gastroesophageal reflux
                • Increased hepatic enzymes
                • Feeding disorder (decreased appetite, hypophagia)
                • Anemia
                • Cough
                • Dehydration
                • Metabolic acidosis
                • Thrombocytosis
                • Thrombocytopenia
                • Lymphocytosis
                • Flatulence
                • Lethargy
                • Irritability/agitation

                1-10%

                Abdominal pain (7%)

                Vomiting (7%)

                Decreased appetite (7%)

                Fatigue (7%)

                Ammonia increased (5%)

                Dyspepsia (5%)

                Nausea (2%)

                Postmarketing Reports

                Abnormal body odor, including from skin, hair, and urine

                Retching and gagging

                Dysgeusia or burning sensation in mouth

                Neutropenia

                Pyrexia

                Hypophagia

                Cough

                Nasal congestion

                Rhinorrhea

                Rash and papule

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                Warnings

                Contraindications

                Hypersensitivity to phenylbutyrate (eg, wheezing, dyspnea, coughing, hypotension, flushing, nausea, rash)

                Cautions

                Safety and efficacy not established for N-acetylglutamate synthase (NAGS) deficiency

                Increased exposure to phenylacetate (PAA), the major metabolite, associated with neurotoxicity; if symptoms of vomiting, nausea, headache, somnolence, or confusion occur without high ammonia or other intercurrent illness which explains these symptoms, consider the potential for PAA neurotoxicity

                Low or absent pancreatic enzymes or intestinal disease resulting in fat malabsorption may result in reduced or absent digestion/absorption of glycerol phenylbutyrate

                Drug interaction overview

                • Probenecid may inhibit renal excretion of glycerol phenylbutyrate metabolites including PAGN and PAA
                • Drugs that may affect plasma ammonia levels
                  • Corticosteroids may cause breakdown of protein and increase plasma ammonia levels
                  • Hyperammonemia may be induced by haloperidol or valproic acid
                • Potential for glycerol phenylbutyrate to affect other drugs
                  • Glycerol phenylbutyrate is a weak inducer of CYP3A4
                  • Coadministration may decrease systemic exposure to CYP3A4 substrates
                  • Monitor for decreased efficacy of drugs with narrow therapeutic index (eg, alfentanil, quinidine, cyclosporine, midazolam)
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                Pregnancy & Lactation

                Pregnancy

                Limited available data to inform a drug-associated risk of major birth defects and miscarriage

                Report pregnancies to Horizon at 1-866-479-6742

                Animal data

                • Administration to pregnant rabbits during organogenesis at ≥2.7 x the dose of 6.87 mL/m²/day resulted in maternal toxicity, but had no effects on embryo-fetal development
                • Administration to pregnant rats during organogenesis at ≥5.7 x the dose of 6.87 mL/m²/day resulted in maternal toxicity, reduced fetal weights, and variations in skeletal development; no adverse developmental effects were seen at 1.9 x the dose of 6.87 mL/m²/day

                Lactation

                Unknown if distributed in human breast milk; because of the potential for serious adverse reactions, including neurotoxicity and tumorigenicity in a breastfed infant, advise patients that breastfeeding is not recommended

                Pregnancy Categories

                A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

                B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

                C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

                D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

                X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

                NA: Information not available.

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                Pharmacology

                Mechanism of Action

                Decreases elevated plasma ammonia glutamine levels

                Pre-prodrug that is metabolized by ester hydrolysis and pancreatic lipases to phenylbutyrate (PBA) and then by beta oxidation to phenylacetate (PAA); glutamine is conjugated with phenylacetate to form phenylacetylglutamine (PAGN), a nitrogen waste product that is excreted renally

                The phenylacetylglutamine conjugate provides an alternate vehicle to urea for waste nitrogen excretion; for each gram of sodium phenylbutyrate administered, it is estimated that between 0.12–0.15 grams of phenylacetylglutamine nitrogen are produced

                Absorption

                Peak plasma time: 2 hr (PBA), 4 hr (PAA), 4 hr (PAGN)

                Peak plasma concentration: 37 mcg/mL (PBA), 14.9 mcg/mL (PAA), 30.2 mcg/mL (PAGN)

                AUC: 930-1400 mcg•h/mL (PBA); 942-2064 mcg•h/mL (PAA)

                Distribution

                Protein Bound: 80.6-98% (PBA), 37.1-65.6% (PAA), 7-12% (PAGN)

                Metabolism

                Glycerol phenylbutyrate metabolized by hydrolyzed by pancreatic lipases and release phenylbutyric acid (PBA); PBA undergoes beta-oxidation to phenylacetic acid (PAA)

                PAA is conjugated with glutamine in the liver and kidney through the enzyme phenylacetyl-CoA: L-glutamine-N-acetyltransferase to form PAGN

                Elimination

                Excretion: 66.4-68.9% in urine as PAGN

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                Administration

                Oral Administration

                Take with food or formula

                Administer directly into the mouth via oral syringe or dosing cup

                Nasogastric or gastrostomy tube

                • For patients unable to swallow, may be administered via nasogastric tube (NG tube) or gastrostomy (G-tube); flush tube once with 30 mL of water and allow the flush to drain, and then repeat flush to clear the tube
                • For patients who require a volume of <1 mL per dose via NG tube or G-tube, the delivered dose may be less than anticipated; closely monitor these patients using ammonia levels
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                Patient Handout

                Patient Education
                glycerol phenylbutyrate oral

                GLYCEROL PHENYLBUTYRATE - ORAL

                (GLIS-er-ol FEN-il-BUE-ti-rate)

                COMMON BRAND NAME(S): Ravicti

                USES: This medication is used along with diet changes for long-term treatment of a certain inherited disorder (urea cycle disorder). It helps remove a certain chemical (ammonia) from the body. Too much ammonia in the body can cause brain damage and sometimes death.This medication should not be used to treat sudden, severely high levels of ammonia in the body. Get medical help right away if you have sudden symptoms of too much ammonia, such as trouble thinking, vomiting, irritability, trouble speaking, trouble walking, fainting.

                HOW TO USE: Read the Medication Guide provided by your pharmacist before you start taking glycerol phenylbutyrate and each time you get a refill. Learn all preparation and usage instructions. If you have any questions, ask your doctor or pharmacist.Take this medication by mouth exactly as directed by your doctor. The dosage is based on your body size, medical condition, and response to treatment. The total daily dose should be divided into equal amounts and taken with each meal or feeding (such as 3 to 6 times daily). Do not increase or decrease your dose without your doctor's approval.Carefully measure the dose using an oral syringe. Do not use a household spoon because you may not get the correct dose.If you are giving this medication through a tube into the stomach (nasogastric or gastric tube), ask your health care professional for detailed instructions on how to properly give it.Use this medication regularly to get the most benefit from it. To help you remember, take it at the same times each day.

                SIDE EFFECTS: Loss of appetite, diarrhea, or gas may occur. If any of these effects last or get worse, tell your doctor or pharmacist promptly.Remember that this medication has been prescribed because your doctor has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.Tell your doctor right away if you have any serious side effects, including: nausea, vomiting, headache, drowsiness/lightheadedness, mental/mood changes (such as confusion), tiredness, decreased hearing.A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.In the US -Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

                PRECAUTIONS: Before taking this medication, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.Before using this medication, tell your doctor or pharmacist your medical history, especially of: disease of the pancreas, difficulty absorbing fat from food (malabsorption), kidney disease, liver disease.Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.It is unknown if this medication passes into breast milk. Consult your doctor before breast-feeding.

                DRUG INTERACTIONS: Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.

                OVERDOSE: If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center.

                NOTES: Do not share this medication with others.Lab and/or medical tests (such as ammonia/amino acid levels, urine tests, drug levels) should be done while you are taking this medication. Keep all medical and lab appointments. Consult your doctor for more details.

                MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose. Take your next dose at the regular time. Do not double the dose to catch up. It is very important to take the full amount prescribed for each 24-hour period.

                STORAGE: Store in a tightly closed container at room temperature away from light and moisture. Do not store in the bathroom. Different brands of this medication may have different storage needs. Check the product package for instructions on how to store your brand, or ask your pharmacist. Keep all medications away from children and pets.Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

                Information last revised September 2021. Copyright(c) 2021 First Databank, Inc.

                IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

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                Formulary

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                Tier Description
                1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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                Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.