sodium phenylbutyrate/taurursodiol (Rx)

>10%

Diarrhea (25%)

Abdominal pain (21%)

Nausea (18%)

Upper respiratory tract infection (18%)

Fatigue (12%)

Salivary hypersecretion (11%)

1-10%

Dizziness (10%)

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

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.

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])

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