glycerol phenylbutyrate (Rx)

Brand and Other Names:Ravicti
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

oral liquid

  • 1.1 g/mL
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Urea Cycle Disorders

Nitrogen-binding agent for chronic management of adults and children aged ≥2 months with urea cycle disorders who cannot be managed by dietary protein restriction and/or amino acid supplementation alone

Adults: 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

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

Dosage Forms & Strengths

oral liquid

  • 1.1 g/mL
more...

Urea Cycle Disorders

Nitrogen-binding agent for chronic management of adults and children aged ≥2 months with urea cycle disorders who cannot be managed by dietary protein restriction and/or amino acid supplementation alone

<2 months: Safety and efficacy not established

2 months to <2 years: Give PO in 3 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

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Interactions

Interaction Checker

and glycerol phenylbutyrate

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            Adverse Effects

            >10%

            Diarrhea (16%)

            Flatulence (14%)

            Headache (14%)

            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

            Age <2 months; may have immature pancreatic exocrine function, which could impair hydrolysis of glycerol phenylbutyrate and lead to impaired absorption of phenylbutyrate and hyperammonemia

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

            Cautions

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

            The major metabolite, phenylacetate (PAA), is associated with neurotoxicity

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

            A registry has been established by Hyperion Therapeutics in order to better assess long-term outcomes in patients with UCDs taking glycerol phenylbutyrate, including growth and neurocognitive outcomes and the outcome of pregnancy for women with UCDs who become pregnant 1-855-823-2495

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            Pregnancy & Lactation

            Pregnancy

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

            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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            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

            To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

            Adding plans allows you to:

            • View the formulary and any restrictions for each plan.
            • Manage and view all your plans together – even plans in different states.
            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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