sodium phenylbutyrate/taurursodiol (Rx)

Brand and Other Names:Relyvrio
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

sodium phenylbutyrate/taurursodiol

powder for oral suspension

  • (3g/1g)/single-dose packet

Amyotrophic Lateral Sclerosis

Indicated for treatment of amyotrophic lateral sclerosis

Initial: 1 packet (3 g sodium phenylbutyrate/ 1 g taurursodiol) PO qDay for first 3 weeks

Maintenance: 1 packet PO BID

Dosage Modifications

Renal impairment

  • Pharmacokinetics not studied
  • Mild: No dosage adjustment necessary; no reports of safety issues in clinical trials
  • Moderate-to-severe: Avoid use

Hepatic impairment

  • Pharmacokinetics not studied
  • Mild: No dosage adjustment necessary; no reports of safety issues in clinical trials
  • Moderate-to-severe: Avoid use

Safety and efficacy not established

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Interactions

Interaction Checker

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                    Adverse Effects

                    >10%

                    Diarrhea (25%)

                    Abdominal pain (21%)

                    Nausea (18%)

                    Upper respiratory tract infection (18%)

                    Fatigue (12%)

                    Salivary hypersecretion (11%)

                    1-10%

                    Dizziness (10%)

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                    Warnings

                    Contraindications

                    None

                    Cautions

                    Each initial daily dosage of 1 packet contains 464 mg of sodium; each maintenance dosage of 2 packets daily contains 928 mg of sodium; consider the daily sodium intake in patients sensitive to salt intake (eg, those with heart failure, hypertension, or renal impairment) and monitor appropriately

                    Risk with enterohepatic circulation disorders, pancreatic disorders, or intestinal disorders

                    • Taurursodiol is a bile acid
                    • May increase risk of worsening diarrhea in patients with disorders that interfere with bile acid circulation; monitor appropriately
                    • Pancreatic insufficiency, intestinal malabsorption, or intestinal diseases may alter bile acid concentration and may lead to decreased absorption of sodium phenylbutyrate/taurursodiol
                    • Owing to different enterohepatic circulation, pancreatic and intestinal disorders have varying degrees of severity; consider consulting with specialist
                    • Enterohepatic circulation disorders (eg,, biliary infection, active cholecystitis), severe pancreatic disorders (eg, pancreatitis), and intestinal disorders that may alter bile acid concentrations (eg, ileal resection, regional ileitis) were not studied; inform patients with such conditions about risks and benefits with use and advise to notify their healthcare provider if new or worsening diarrhea occurs

                    Drug interaction overview

                    • In in vitro studies show sodium phenylbutyrate/taurursodiol
                    • Induces CYP1A2, CYP2B6, and CYP3A4 at clinically relevant concentrations
                    • Inhibits CYP2C8 and CYP2B6 at clinically relevant concentrations
                    • Inhibits OAT1, P-gP, and BCRP at clinically relevant concentrations
                    • Substrate of OATP1B3, MATE2-K, OAT3, and BSEP
                    • Bile acid sequestering agents
                      • Avoid use; consider alternative cholesterol lowering agents
                      • Bile acid sequestering agents (eg, cholestyramine, colestipol, colesevelam) may interfere with taurursodiol absorption
                    • Bile acid transport inhibitors
                      • Avoid use of strong bile salt export pump (BSEP) inhibitors (eg, cyclosporine)
                      • If coadministration is necessary, exercise caution and monitor serum ALT/AST and bilirubin
                      • Medications that inhibit canalicular membrane bile acid transporters such as BSEP may exacerbate accumulation of conjugated bile salts in liver and result in clinical symptoms
                    • Aluminum-based antacids
                      • Avoid use and consider alternants
                      • Aluminum-based antacids have been shown to adsorb bile acids in vitro and may interfere with taurursodiol absorption
                    • Probenecid
                      • Avoid use
                      • Probenecid may affect renal excretion of sodium phenylbutyrate metabolites
                    • Pan-histone deacetylase (HDAC) inhibitors
                      • Avoid coadministration with other HDAC inhibitors
                    • OATP1B3 inhibitors
                      • Avoid use
                      • OATP1B3 inhibitors may increase sodium phenylbutyrate/taurursodiol
                    • Sensitive OAT1 substrates
                      • Avoid coadministration with sensitive OAT1 substrates
                      • Sodium phenylbutyrate/taurursodiol may increase plasma concentrations of OAT1 substrates
                    • Sensitive P-glycoprotein (P-gP) and Breast Cancer Resistance Protein (BCRP) substrates
                      • Avoid coadministration with sensitive P-gP and BCRP substrates
                      • Sodium phenylbutyrate/taurursodiol may increase plasma concentrations of P-gP and BCRP substrates
                    • CYP2C8, CYP1A2, CYP2B6, and CYP3A4 substrates
                      • Avoid coadministration of sensitive substrates of CYP2C8, CYP1A2, CYP2B6, and CYP3A4
                      • Sodium phenylbutyrate/taurursodiol may change plasma concentrations of substrates for these enzymes
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                    Pregnancy & Lactation

                    Pregnancy

                    No data are available for use in pregnant females to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes

                    Animal data

                    • Administration to rats during pregnancy and lactation exhibited increased offspring mortality at all doses tested, which were less than or like clinical doses

                    Lactation

                    There are no data on presence of sodium phenylbutyrate or taurursodiol in human milk, effects on breastfed infants, or effects on milk production

                    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

                    Sodium phenylbutyrate: Histone deacetylase inhibitor shown to upregulate heat shock proteins and act as a small molecular chaperone, thereby ameliorating toxicity from endoplasmic reticulum stress

                    Taurursodiol: Recovers mitochondrial bioenergetics deficits through several mechanisms, including by preventing translocation of the Bax protein into the mitochondrial membrane, thus reducing mitochondrial permeability and increasing the cell’s apoptotic threshold

                    Mechanism of action in patients with ALS is unknown

                    Absorption

                    Peak plasma time

                    • Sodium phenylbutyrate: 0.5 hr
                    • Taurursodiol: 4.5 hr

                    Effects of food

                    • High-fat meal: Slows absorption (reduced peak plasma concentration by 76%) and lowers overall exposure (reduced AUC by 54%) of sodium phenylbutyrate
                    • A high-fat meal did not significantly affect the Cmax for taurursodiol, but AUC was increased by 39%

                    Distribution

                    Protein bound

                    • Sodium phenylbutyrate: 82%
                    • Taurursodiol: 95%

                    Metabolism

                    • No mass balance studies conducted in humans to confirm metabolic pathways and elimination routes
                    • Sodium phenylbutyrate: Phenylacetate (major metabolite)
                    • Taurursodiol: Ursodiol and glyco-ursodiol (major metabolite)

                    Elimination

                    Excretion: ~80-100% (urine as phenylacetylglutamine [conjugated product])

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                    Administration

                    Oral Suspension Preparation

                    Empty contents of 1 packet into 8 ounces of room temperature water and stir vigorously

                    Oral Administration

                    Administer before a snack or meal

                    Take orally or administer via feeding tube within 1 hr of preparation

                    Discard any unused suspension after 1 hr

                    Inform patients that 2 packets contain 928 mg sodium; advise patients who are sensitive to sodium (eg, those with congestive heart failure, severe renal insufficiency, or other conditions associated with sodium retention) to limit their sodium intake

                    Inform patients that aluminum-based antacids should not be taken during treatment

                    Storage

                    Unopened packets

                    • Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)
                    • Protect from moisture

                    Reconstituted suspension

                    • Store for up to 1 hr at room temperature after reconstituted
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                    Patient Handout

                    A Patient Handout is not currently available for this monograph.
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                    Formulary

                    FormularyPatient Discounts

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                    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.
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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.