Sodium Phenylbutyrate and Taurursodiol (Monograph)

Brand name: Relyvrio
Drug class: Amyotrophic Lateral Sclerosis (ALS) Agents

Medically reviewed by Drugs.com on Jun 10, 2024. Written by ASHP.

Warning

Sodium phenylbutyrate and taurursodiol will no longer be available for new patients as of 4/4/2024; patients currently on therapy who, in consultation with their physician, wish to continue can be transitioned to a free drug program. See the FDA website (https://www.accessdata.fda.gov/scripts/cder/daf/) for information on drugs that have been discontinued.

Because this drug is no longer available in the U.S. market, the material in this monograph is no longer updated by AHFS DI. If this drug is used in countries other than the U.S., it is essential that the manufacturers’ labeling be consulted for more recently available information.

[Web]

Introduction

Sodium phenylbutyrate and taurursodiol (sodium phenylbutyrate/taurursodiol) is a fixed-combination preparation that contains sodium phenylbutyrate (an ammonia detoxicant) and taurursodiol (a hydrophilic bile acid), also known as tauroursodeoxycholic acid).

Uses for Sodium Phenylbutyrate and Taurursodiol

Amyotrophic Lateral Sclerosis (ALS)

Sodium phenylbutyrate/taurursodiol is used for the treatment of ALS in adults; designated an orphan drug by FDA for use in this condition.
Slows the rate of decline in function associated with ALS progression compared with placebo.

Sodium Phenylbutyrate and Taurursodiol Dosage and Administration

General

Patient Monitoring

Monitor patients with conditions that interfere with bile acid circulation for worsening diarrhea.
Monitor patients with conditions sensitive to salt intake (e.g., heart failure, hypertension, renal impairment) for potential exacerbation of those conditions.
Monitor serum transaminases and bilirubin in patients using sodium phenylbutyrate/taurursodiol concomitantly with strong inhibitors of bile salt export pump (BSEP), such as cyclosporine.

Other General Considerations

Each packet of sodium phenylbutyrate/taurursodiol contains 464 mg of sodium.

Administration

Each packet contains sodium phenylbutyrate 3 g and taurursodiol 1 g powder.

Empty the contents of 1 packet into 240 mL (8 ounces) of room temperature water; stir vigorously to form reconstituted suspension. Suspension is stable up to 1 hour at room temperature; discard unused suspension after 1 hour.

Administer doses orally or via feeding tube before a meal or snack.

Using mint flavored mouth strips/mouth spray before or after doses, eating a snack or honey after doses, or drinking milk after doses may help with bitter aftertaste; drinking fruit juice after doses may worsen aftertaste.

Dosage

Adults

Amyotrophic Lateral Sclerosis

Oral

Dosage of sodium phenylbutyrate is expressed in terms of the salt.

Initial dosage: 1 packet (sodium phenylbutyrate 3 g and taurursodiol 1 g) daily for 3 weeks, then increase to maintenance dosage.

Maintenance dosage: 1 packet twice daily.

Special Populations

Hepatic Impairment

Mild hepatic impairment: Manufacturer states that dosage adjustment is not needed.

Moderate or severe hepatic impairment: Avoid use.

Renal Impairment

Mild renal impairment: Manufacturer states that dosage adjustment is not needed.

Moderate or severe renal impairment: Avoid use.

Geriatric Use

Manufacturer makes no specific dosage recommendations.

Cautions for Sodium Phenylbutyrate and Taurursodiol

Contraindications

None.

Warnings/Precautions

Risk in Patients with Enterohepatic Circulation Disorders, Pancreatic Disorders, or Intestinal Disorders

Taurursodiol is a bile acid and may increase risk of worsening diarrhea in patients with disorders that interfere with bile acid circulation.

Pancreatic insufficiency, intestinal malabsorption, or intestinal diseases may decrease absorption of sodium phenylbutyrate or taurursodiol.

There is no experience for sodium phenylbutyrate/taurursodiol in disorders of enterohepatic circulation, severe pancreatic disorders, and intestinal disorders that may alter concentrations of bile acids; consider consulting a specialist in these disorders if using sodium phenylbutyrate/taurursodiol in these patients.

Use in Patients Sensitive to High Sodium Intake

Sodium phenylbutyrate/taurursodiol has high sodium content; each packet contains 464 mg of sodium resulting in a daily sodium contribution of 928 mg at the maintenance dosage.

Consider clinical consequences of using sodium phenylbutyrate/taurursodiol in patients with conditions sensitive to sodium (e.g., heart failure, hypertension, renal impairment) and monitor appropriately.

Specific Populations

Pregnancy

Insufficient data in humans.

Animal studies showed increased offspring mortality when given to rats throughout pregnancy and lactation at doses less than the maximum recommended dose in humans.

Animal studies showed no adverse effects when given only during organogenesis in rats and mice at doses up to approximately 2-fold the maximum recommended dose in humans.

Lactation

Unknown whether sodium phenylbutyrate/taurursodiol or metabolites distribute into human milk or if the drug has any effect on milk production or the nursing infant; consider risks and benefits of breastfeeding during sodium phenylbutyrate/taurursodiol therapy.

Pediatric Use

Safety and effectiveness in pediatric patients not established.

Geriatric Use

No overall differences in safety or efficacy observed between geriatric and younger patients.

Renal Impairment

No specific safety concerns with mild renal impairment; safety and efficacy with moderate and severe renal impairment not established.

Hepatic Impairment

No specific safety concerns with mild hepatic impairment; safety and efficacy with moderate and severe hepatic impairment not established.

Common Adverse Effects

Most common adverse reactions (≥15% and ≥5% greater than placebo): Diarrhea, abdominal pain, nausea, upper respiratory tract infection.

Drug Interactions

Metabolic pathway not confirmed.

Substrate of organic anion transporting polypeptide 1B3 (OATP1B3), multidrug and toxin extruder 2-K (MATE2-K), organic anion transporter 3 (OAT3), and bile salt export pump (BSEP).

Inhibits CYP2C8, CYP2B6, P-glycoprotein (P-gp), OAT1, and breast cancer resistance protein (BCRP) in vitro; phenylbutyrate inhibits pan-histone deacetylase (HDAC).

Induces CYP1A2, CYP2B6, and CYP3A4 in vitro.

Bile Acid Transporter Inhibitors

Concomitant use with drugs that inhibit canalicular membrane bile acid transporters (e.g., BSEP) may increase accumulation of conjugated bile acids in liver and cause or worsen clinical symptoms. Avoid concomitant use with strong BSEP inhibitors (e.g., cyclosporine); if concomitant use necessary, use caution and monitor serum transaminases and bilirubin.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP2C8 and CYP2B6 Substrates

Inhibits CYP2C8 and CYP2B6 in vitro at clinically relevant concentrations.

Avoid concomitant use if small changes in plasma concentrations of the substrate may lead to serious toxicities or loss of efficacy.

CYP1A2, CYP2B6, and CYP3A4 Substrates

Induces CYP1A2, CYP2B6, and CYP3A4 in vitro at clinically relevant concentrations.

Avoid concomitant use if small changes in plasma concentrations of the substrate may lead to serious toxicities or loss of efficacy.

Drugs Affecting or Affected by Transport Systems

Organic Anion Transporting Polypeptide (OATP) Inhibitors

Substrate of OATP1B3 in vitro; avoid concomitant use with OATP1B3 inhibitors.

Organic Anion Transporter (OAT) Substrates

May increase plasma concentrations of OAT1 substrates; avoid concomitant use if small changes in plasma concentrations of the substrate may lead to serious toxicities or loss of efficacy.

P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) Substrates

Inhibits P-gp and BCRP in vitro.

Avoid concomitant use if small changes in plasma concentrations of the substrate may lead to serious toxicities or loss of efficacy.

pan-Histone Deacetylase (HDAC) Inhibitors

Phenylbutyrate inhibits HDAC; avoid concomitant use with other HDAC inhibitors.

Specific Drugs

Drug	Interaction	Comments
Aluminum-based antacids	Adsorbs taurursodiol interfering with its absorption.	Avoid concomitant use; consider alternative class of acid lowering agents.
Bile acid sequestering agents (e.g., cholesytramine, colestipol, colesevelam)	May interfere with taurursodiol absorption.	Avoid concomitant use; consider alternative cholesterol lowering agents.
Strong bile salt export pump (BSEP) inhibitors (e.g., cyclosporine)	Increase accumulation of conjugated bile salts in liver causing or worsening clinical symptoms.	Avoid concomitant use. If concomitant use necessary, use caution and monitor serum transaminases and bilirubin.
Probenecid	May affect renal excretion of sodium phenylbutyrate metabolites.	Avoid concomitant use.

Sodium Phenylbutyrate and Taurursodiol Pharmacokinetics

Absorption

Plasma Concentrations

Median time to maximum plasma concentrations in healthy subjects:

Sodium phenylbutyrate: 0.5 hour.
Taurursodiol: 4.5 hours.

Food

Administration with high-fat meal:

Sodium phenylbutyrate maximum plasma concentration: decreased 76%.
Sodium phenylbutyrate AUC: decreased 54%.
Taurursodiol maximum plasma concentration: not substantially altered.
Taurursodiol AUC: increased 39%.

Distribution

Plasma Protein Binding

Sodium phenylbutyrate: 82%.

Taurursodiol: 98%.

Elimination

Metabolism

Metabolic pathway and elimination routes not confirmed.

Phenylacetate major metabolite of phenylbutyrate; ursodiol and glyco-ursodiol major metabolites of taurursodiol.

Elimination Route

Sodium phenylbutyrate: 80–100% in urine as phenylacetylglutamine within 24 hours.

Special Populations

The effect of age, gender, racial, or ethnic group, hepatic impairment, or renal impairment on the pharmacokinetics of sodium phenylbutyrate/taurursodiol is not established.

Stability

Storage

Oral

Powder, for suspension

Packets: 20–25°C (excursions permitted to 15–30°C); protect from moisture.

Reconstituted suspension: room temperature for up to 1 hour.

Actions

Sodium phenylbutyrate is an ammonia detoxicant; taurursodiol is a bile acid.
Mechanism of action in ALS is not established; reduces neuronal cell death in ALS animal models.
May decrease endoplasmic reticulum stress and mitochondrial dysfunction.

Advice to Patients

Instruct patients or caregivers to empty the contents of one packet in a cup containing 8 ounces of room temperature water and stir vigorously. Advise that sodium phenylbutyrate/taurursodiol can be taken orally or administered via feeding tube, and to use or discard within 1 hour of preparation. Instruct patients or caregivers to administer sodium phenylbutyrate/taurursodiol before a snack or meal.
Inform patients about the risks and benefits of sodium phenylbutyrate/taurursodiol if they have underlying medical conditions such as enterohepatic circulation, pancreatic, or intestinal disorders and advise them to notify their healthcare provider if they have new or worsening diarrhea.
Inform patients that 2 packets of sodium phenylbutyrate/taurursodiol contain 928 mg sodium (46% of WHO daily recommended intake) and patients who are sensitive to sodium (e.g., those with congestive heart failure, severe renal insufficiency, other conditions associated with sodium retention) should limit their sodium intake.
Inform patients that aluminum-based antacids may interfere with the absorption of sodium phenylbutyrate/taurursodiol, and therefore should not be taken during treatment with sodium phenylbutyrate/taurursodiol.
Advise patient to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant.
Advise patients to notify their healthcare provider if they intend to breastfeed or are breastfeeding an infant.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Sodium phenylbutyrate/taurursodiol is obtained through designated specialty pharmacies. Contact manufacturer or consult the Relyvrio website ([Web]) for specific availability information.