AHFS Class:

• Amyotrophic Lateral Sclerosis (ALS) Agents 28:44

Generic Name(s):

• Sodium Phenylbutyrate

• Taurursodiol

Sodium phenylbutyrate and taurursodiol (sodium phenylbutyrate/taurursodiol) is a fixed combination of sodium phenylbutyrate (an ammonia detoxicant) and taurursodiol (a hydrophilic bile acid), also known as tauroursodeoxycholic acid.1,2,3 The mechanism of action of sodium phenylbutyrate and taurursodiol together in the treatment of amyotrophic lateral sclerosis (ALS) is unknown.1 The combination may block cell stress signals and confer neuroprotective effects.3

Amyotrophic Lateral Sclerosis (ALS)

Sodium phenylbutyrate/taurursodiol is used for the treatment of amyotrophic lateral sclerosis (ALS) in adults.1 Sodium phenylbutyrate/taurursodiol has been designated an orphan drug by the FDA for use in this condition.9

The efficacy of sodium phenylbutyrate/taurursodiol for treatment of ALS in adults is based principally on results from a randomized, double-blind, placebo-controlled trial (CENTAUR) that showed sodium phenylbutyrate/taurursodiol was more effective than placebo in slowing the decline in function associated with ALS progression.1,4,5 The trial included 137 patients with ALS, determined using revised El Escorial criteria, who were within 18 months of the onset of symptoms.1,4 Patients were randomized 2:1 to sodium phenylbutyrate/taurursodiol or placebo for 24 weeks.1,4 Each packet (sachet) of active treatment contained sodium phenylbutyrate 3 g and taurursodiol 1 g for oral or feeding tube administration.4 Patients took 1 packet per day for the first 3 weeks, then 1 packet twice daily thereafter if tolerated.1,4 Use of riluzole was only permitted if it was used at a stable dose for at least 30 days prior to screening; edaravone was also permitted.4 The median age of enrollees was 57.7 years and approximately 68% of patients were male.1 The baseline Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score was 36 points and the baseline ALSFRS-R slope was 0.94.4 This scale measures 12 items in 4 domains of function, with each item scored from 0 to 4 and higher scores indicating better function.1,4 The slope of the score was defined as the rate of decline in total score from symptom onset to trial entry.4 The baseline Accurate Test of Limb Isometric Strength (ATLIS) score was approximately 55.8% of predicted normal value.4 This score was standardized to the percentage of the predicted normal value based on age, height, sex, and weight.4 The average time since ALS symptom onset was approximately 13.5 months and the average time since ALS diagnosis was 6 months.1,4 More patients were using edaravone in the placebo group than in the treatment group at trial entry (50% versus 25%).4 More patients in the treatment group had bulbar-onset ALS compared with the placebo group (30% versus 21%).1,4

The primary efficacy outcome was the slope in ALSFRS-R from trial baseline through week 24.4 The sodium phenylbutyrate/taurursodiol group had a smaller slope of -1.24 points per month compared with the placebo group at -1.66 points per month showing a slower rate of decline in function associated with sodium phenylbutyrate/taurursodiol.4 The study included a sensitivity analysis to adjust for the unbalanced edaravone use, which found a less robust between-group difference in the same direction.4 The mean ALSFRS-R total score at week 24 was markedly larger in the treatment group compared with the placebo group at 29.06 and 26.73 points, respectively.1,4 There were no differences between groups in secondary outcomes, including ATLIS scores, and the time to death, tracheostomy, permanent ventilation, or hospitalization.4

Study participants who completed the 24-week trial could enter an open-label extension to receive sodium phenylbutyrate/taurursodiol for up to 30 months.5 The exploratory survival analysis compared time to all-cause mortality between patients originally randomized to active treatment and those originally randomized to placebo.1,5 Median survival was 25 months in the group originally randomized to sodium phenylbutyrate/taurursodiol and 18.5 months in the group originally randomized to placebo.5 The suggested survival benefit was consistent independent of baseline riluzole or edaravone use.5

General

Patient Monitoring

• Monitor patients with conditions that interfere with bile acid circulation for worsening diarrhea.1
• Monitor patients with conditions sensitive to salt intake (e.g., heart failure, hypertension, renal impairment) for potential exacerbation of those conditions.1
• Monitor serum transaminases and bilirubin in patients using sodium phenylbutyrate/taurursodiol concomitantly with strong inhibitors of bile salt export pump (BSEP), such as cyclosporine.1

Other General Considerations

• Each packet of sodium phenylbutyrate/taurursodiol contains 464 mg of sodium.1

Administration

Oral

Each packet contains a powder with sodium phenylbutyrate 3 g and taurursodiol 1 g.1 Each packet should be emptied into a cup with 240 mL (8 ounces) of room temperature water and vigorously stirred to form a reconstituted suspension.1

Doses may be given orally or via feeding tube.1 Administer doses before a snack or meal.1

Sodium phenylbutyrate/taurursodiol doses may result in a bitter aftertaste.6 Using mint-flavored mouth strips or mouth spray immediately before or after doses, eating a small snack or honey after doses, or drinking milk after doses may help lessen or remove the bitter aftertaste.6 Consuming fruit juice immediately after doses can worsen the bitter aftertaste.6

Store packets at 20-25°C (excursions permitted to 15-30°C).1 Protect product from moisture.1

Dosage

Amyotrophic Lateral Sclerosis

Adult Dosage

Dosage of sodium phenylbutyrate is expressed in terms of the salt.1 The recommended initial dosage for the treatment of ALS in adults is 1 packet, containing sodium phenylbutyrate 3 g and taurursodiol 1 g, daily.1 After 3 weeks, increase to the recommended maintenance dosage of 1 packet twice daily.1

Special Populations

Hepatic Impairment

The manufacturer states that dosage adjustment is not needed in patients with mild hepatic impairment.1 The manufacturer recommends avoiding use in patients with moderate or severe hepatic impairment.1

Renal Impairment

The manufacturer states that dosage adjustment is not needed in patients with mild renal impairment.1 The manufacturer recommends avoiding use in patients with moderate or severe renal impairment.1

Geriatric Use

The manufacturer does not have specific dosage recommendations for geriatric patients.1

Contraindications

• None.1

Warnings/Precautions

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

Taurursodiol is a bile acid.1 Taurursodiol may increase the risk for worsening diarrhea in patients with disorders that interfere with bile acid circulation.1

Because pancreatic insufficiency, intestinal malabsorption, and intestinal diseases may alter the concentration of bile acids, these conditions may decrease the absorption of sodium phenylbutyrate or taurursodiol.1 Consider consulting with a specialist in enterohepatic, pancreatic, and intestinal disorders when using sodium phenylbutyrate/taurursodiol in patients with these conditions.1 There is no clinical experience for sodium phenylbutyrate/taurursodiol in patients with disorders of enterohepatic circulation (e.g., active cholecystitis), severe pancreatic disorders (e.g., pancreatitis), or intestinal disorders that may alter concentrations of bile acids (e.g., ileal resection).1

Use in Patients Sensitive to High Sodium Intake

Sodium phenylbutyrate/taurursodiol has a high sodium content.1 Each packet of medication contains 464 mg of sodium resulting in a daily sodium contribution of 928 mg at the maintenance dosage.1 Consider the potential clinical consequences of using sodium phenylbutyrate/taurursodiol in patients with conditions sensitive to sodium intake (e.g., heart failure, hypertension, renal impairment) and monitor appropriately.1

Specific Populations

Pregnancy

There are insufficient data in humans to evaluate for risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes associated with sodium phenylbutyrate/taurursodiol.1 Animal data show that sodium phenylbutyrate/taurursodiol was associated with increased offspring mortality when given to rats throughout pregnancy and lactation at doses less than the maximum recommended dose in humans (i.e., sodium phenylbutyrate 6 g and taurursodiol 2 g per day).1 Administration of sodium phenylbutyrate/taurursodiol only during the period of organogenesis was not associated with adverse effects in rats or mice at doses similar to and up to approximately 2-fold the maximum recommended dose in humans.1

Lactation

It is not known whether sodium phenylbutyrate or taurursodiol distribute into human milk or if the drugs have any effect on milk production or the nursing infant.1 The risks and benefits of breastfeeding during sodium phenylbutyrate/taurursodiol therapy should be considered.1

Pediatric Use

The safety and efficacy of sodium phenylbutyrate/taurursodiol in pediatric patients have not been established.1

Geriatric Use

The principal efficacy study included 25 patients (28%) 65 years of age or older and 4 patients (4.5%) 75 years of age or older.1 There were no overall differences in safety or efficacy observed between geriatric and younger patients.1

Hepatic Impairment

There were no reports of safety concerns in patients with mild hepatic impairment in the principal efficacy study.1 The safety and efficacy of sodium phenylbutyrate/taurursodiol in patients with moderate and severe hepatic impairment have not been established.1

Renal Impairment

There were no reports of safety concerns in patients with mild renal impairment in the principal efficacy study.1 The safety and efficacy of sodium phenylbutyrate/taurursodiol in patients with moderate and severe renal impairment have not been established.1

Common Adverse Effects

Amyotrophic Lateral Sclerosis

Adverse effects reported in at least 15% of patients receiving sodium phenylbutyrate/taurursodiol (and reported at least 5% more commonly than in patients receiving placebo) included diarrhea, abdominal pain, nausea, and upper respiratory tract infection.1 Gastrointestinal-related adverse reactions occurred throughout the principal efficacy trial, but were more frequent during the first 3 weeks of treatment.1

The metabolic pathway of sodium phenylbutyrate and taurursodiol has not been confirmed.1 It is a 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).1

Sodium phenylbutyrate/taurursodiol inhibits cytochrome P-450 (CYP) isoenzymes CYP2C8 and CYP2B6, and transporters P-glycoprotein (P-gp), OAT1, and breast cancer resistance protein (BCRP) in vitro at clinically relevant concentrations.1 It induces CYP1A2, CYP2B6, and CYP3A4 in vitro at clinically relevant concentrations.1 Phenylbutyrate inhibits pan-histone deacetylase (HDAC).1

Aluminum-Based Antacids

Aluminum-based antacids adsorb bile acids in vitro.1 This class of antacids may interfere with the absorption of taurursodiol, a bile acid.1 Avoid concomitant use of aluminum-based antacids with sodium phenylbutyrate/taurursodiol; consider alternative acid lowering agents.1

Bile Acid Sequestering Agents

Taurursodiol is a bile acid.1 Bile acid sequestering agents (e.g., cholestyramine, colestipol, colesevelam) may interfere with the absorption of taurursodiol.1 Avoid concomitant use of bile acid sequestering agents with sodium phenylbutyrate/taurursodiol; consider alternative cholesterol lowering agents.1

Bile Acid Transporter Inhibitors

Concomitant use of sodium phenylbutyrate/taurursodiol with drugs that inhibit canalicular membrane bile acid transporters, including BSEP, may increase accumulation of conjugated bile salts in the liver and cause or worsen clinical symptoms.1 Avoid concomitant use of strong BSEP inhibitors (e.g., cyclosporine) with sodium phenylbutyrate/taurursodiol.1 If concomitant use is necessary, use caution and monitor serum transaminases and bilirubin.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP2C8 and CYP2B6 Substrates

Sodium phenylbutyrate/taurursodiol inhibits CYP2C8 and CYP2B6 in vitro at clinically relevant concentrations.1 Concomitant use with substrates of these isoenzymes may alter plasma concentrations of the substrates.1 Avoid concomitant use if small changes in plasma concentrations of the substrate may lead to serious toxicities or loss of efficacy.1

CYP1A2, CYP2B6, and CYP3A4 Substrates

Sodium phenylbutyrate/taurursodiol induces CYP1A2, CYP2B6, and CYP3A4 in vitro at clinically relevant concentrations.1 Concomitant use with substrates of these isoenzymes may alter plasma concentrations of the substrates.1 Avoid concomitant use if small changes in plasma concentrations of the substrate may lead to serious toxicities or loss of efficacy.1

Drugs Affecting or Affected by Transport Systems

Organic Anion Transporting Polypeptide (OATP) Inhibitors

Sodium phenylbutyrate/taurursodiol is a substrate of OATP1B3 in vitro.1 Avoid concomitant use with OATP1B3 inhibitors.1

Organic Anion Transporter (OAT) Substrates

Concomitant use of sodium phenylbutyrate/taurursodiol with OAT1 substrates may increase plasma concentrations of the substrates.1 Avoid concomitant use if small changes in plasma concentrations of the OAT1 substrate may lead to serious toxicities or loss of efficacy.1

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

Sodium phenylbutyrate/taurursodiol inhibits P-gp and BCRP in vitro at clinically relevant concentrations.1 Concomitant use with P-gp or BCRP substrates may increase plasma concentrations of the substrates.1 Avoid concomitant use if small changes in plasma concentrations of the P-gp or BCRP substrates may lead to serious toxicities or loss of efficacy.1

pan-Histone Deacetylase (HDAC) Inhibitors

Phenylbutyrate inhibits pan-histone deacetylase (HDAC).1 Avoid concomitant use with other HDAC inhibitors.1

Probenecid

Probenecid may affect the renal excretion of sodium phenylbutyrate metabolites; avoid concomitant use.1

Description

Sodium phenylbutyrate and taurursodiol are both active ingredients in the fixed combination product.1 Sodium phenylbutyrate is traditionally considered an ammonia detoxicant.7 Taurursodiol, the taurine conjugate of ursodiol, is a bile acid also called tauroursodeoxycholic acid.1 The mechanism of action of sodium phenylbutyrate/taurursodiol in ALS is not established.1 The combination may decrease endoplasmic reticulum stress and mitochondrial dysfunction.2 Both substances reduce neuronal cell death in ALS animal models.2 The manufacturer has no description of the pharmacodynamics of sodium phenylbutyrate/taurursodiol since its mechanism of action is not established.1 It does not prolong the QT interval to a clinically relevant extent at the maximum recommended doses.1

The median time to maximum plasma concentrations is 0.5 hour for sodium phenylbutyrate and 4.5 hours for taurursodiol when given under fasting conditions in healthy subjects.1 Administration with a high-fat meal substantially slows absorption and decreases exposure of sodium phenylbutyrate with maximum plasma concentrations decreasing by 76% and AUC decreasing by 54%.1 The maximum plasma concentrations of taurursodiol are not substantially altered by administration with a high-fat meal, but the AUC increases by 39%.1 Sodium phenylbutyrate and taurursodiol bind to human plasma proteins at 82% and 98%, respectively.1 The metabolic pathways and elimination routes of sodium phenylbutyrate and taurursodiol have not been confirmed.1 Phenylacetate is a major metabolite of phenylbutyrate.1 Ursodiol and glyco-ursodiol are major metabolites of taurursodiol.1 Sodium phenylbutyrate is primarily (80-100%) excreted in the urine within 24 hours as phenylacetylglutamine.1 The effect of age, gender, racial or ethnic group, hepatic impairment, or renal impairment on the pharmacokinetics of sodium phenylbutyrate/taurursodiol is not established.1

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.1 Advise that sodium phenylbutyrate/taurursodiol can be taken orally or administered via feeding tube, and to use or discard within 1 hour of preparation.1 Instruct patients or caregivers to administer sodium phenylbutyrate/taurursodiol before a snack or meal.1
• 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.1
• 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.1
• 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.1
• 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.1
• Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant .1
• Advise patients to notify their healthcare provider if they intend to breastfeed or are breastfeeding an infant.1
• Inform patients of other important precautionary information.1

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.

1. Amylyx Pharmaceuticals, Inc. Relyvrio^TM(sodium phenylbutyrate/taurursodiol) for oral suspension prescribing information. Cambridge, MA; 2022 Sep.

2. Johnson SA, Fang T, De Marchi F, et al. Pharmacotherapy for Amyotrophic Lateral Sclerosis: A Review of Approved and Upcoming Agents. Drugs. 2022;82(13):1367-1388. doi:10.1007/s40265-022-01769-1

3. Ketabforoush A, Chegini R, Barati S, et al. Masitinib: The promising actor in the next season of the Amyotrophic Lateral Sclerosis treatment series. Biomed Pharmacother. 2023;160:114378. doi:10.1016/j.biopha.2023.114378

4. Paganoni S, Macklin EA, Hendrix S, et al. Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis. N Engl J Med. 2020;383(10):919-930. doi:10.1056/NEJMoa1916945

5. Paganoni S, Hendrix S, Dickson SP, et al. Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis. Muscle Nerve. 2021;63(1):31-39. doi:10.1002/mus.27091

6. Amylyx Pharmaceuticals. Relyvrio Dosing & Admin. From Relyvrio healthcare professionals website.

7. AHFS Drug Information. AHFS Clinical Drug Information. Sodium Phenylbutyrate. Bethesda, MD: American Society of Health-System Pharmacists; UpdatedJan 1, 2009. Accessed Jun 21, 2023

8. Amylyx Pharmaceuticals. Relyvrio Support & Resources. From Relyvrio healthcare professionals website.

9. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. Accessed 2023 Jul 31.