Odevixibat (Monograph)

Brand name: Bylvay
Drug class: GI Drugs, Miscellaneous
Chemical name: (2S)-2-[[(2R)-2-[[2-[(3,3-dibutyl-7-methylsulfanyl-1,1-dioxo-5-phenyl-2,4-dihydro-1lambda6,2,5-benzothiadiazepin-8-yl)oxy]acetyl]amino]-2-(4-hydroxyphenyl)acetyl]amino]butanoic acid
Molecular formula: C₃₇H₄₈N₄O₈S₂
CAS number: 501692-44-0

Medically reviewed by Drugs.com on Aug 30, 2022. Written by ASHP.

Introduction

Ileal bile acid transporter (IBAT) inhibitor.

Uses for Odevixibat

Pruritus Due to Progressive Familial Intrahepatic Cholestasis

Treatment of pruritus in patients ≥3 months of age with progressive familial intrahepatic cholestasis (PFIC). Designated an orphan drug by FDA for use in this condition.

May not be effective in patients with PFIC type 2 with ABCB11 variants resulting in non-functional or complete absence of bile salt export pump protein (BSEP-3).

PFIC is a rare, autosomal recessive liver disorder that typically presents during infancy or early childhood. Severe pruritus is a characteristic clinical manifestation of PFIC type 1 and type 2. Some therapies have been used for symptomatic treatment (e.g., ursodiol, cholestyramine, rifampin) with limited efficacy. Odevixibat may provide an additional therapeutic option.

Odevixibat Dosage and Administration

General

Pretreatment Screening

• Assess baseline liver function tests (e.g., ALT, AST, bilirubin).

• Obtain fat-soluble vitamin (e.g., vitamins A, D, E, and K [measured using INR levels]) serum levels at baseline; initiate vitamin supplementation if a deficiency is diagnosed.

Patient Monitoring

• Monitor liver function tests (e.g., ALT, AST, bilirubin) during therapy.

• Monitor for fat-soluble vitamin deficiency (e.g., vitamins A, D, E, and K [measured using INR levels]) during therapy; initiate vitamin supplementation if a deficiency is diagnosed.

• Monitor for diarrhea during therapy.

Administration

Oral Administration

Administer orally once daily in the morning with a meal.

Commercially available as capsules and oral pellets.

Odevixibat should be administered at least 4 hours before or after administration of bile acid sequestrants.

Oral Pellets

Oral pellets are intended for patients weighing <19.5 kg.

Open the shell containing oral pellets and empty the contents into approximately 2 tablespoons of soft food (e.g., apple sauce, oatmeal, banana or carrot puree, chocolate or rice pudding); gently tap the oral pellet shell to ensure that all contents have been dispersed.

Gently mix and administer the entire dose immediately. Give water after the dose is taken.

Do not mix with liquids. Patients who are exclusively on a liquid diet should not use odevixibat.

Do not store the mixture for future use.

Do not swallow the shell containing the oral pellets whole.

Capsules

Capsules are intended for patients weighing ≥19.5 kg.

Swallow capsules whole with a glass of water. Do not crush or chew the capsules.

If a patient is unable to swallow the capsules whole, open capsule and sprinkle contents onto approximately 2 tablespoons of soft food (e.g., apple sauce, oatmeal, banana or carrot puree, chocolate or rice pudding); follow directions for oral pellets to prepare and administer the mixture.

Do not mix with liquids. Patients who are exclusively on a liquid diet should not use odevixibat.

Dosage

Commercially available as odevixibat sesquihydrate; dosage expressed in terms of odevixibat.

Pediatric Patients

Pruritus Due to Progressive Familial Intrahepatic Cholestasis

Oral

Pediatric patients ≥3 months of age: Recommended initial dosage is 40 mcg/kg orally once daily in the morning with a meal.

If no improvement in pruritus is observed after 3 months, increase dosage in 40 mcg/kg increments up to 120 mcg/kg once daily (not to exceed total daily dose of 6 mg).

Weight-based total daily dosage based on an initial dosage of 40 mcg/kg once daily are described in Table 1.

Dosage Modification for Toxicity

Hepatotoxicity

If new onset liver test abnormalities or symptoms consistent with clinical hepatitis occur, interrupt odevixibat therapy. When laboratory values stabilize or return to baseline, consider restarting odevixibat at the lowest dose of 40 mcg/kg, and then increase the dosage as tolerated, if appropriate. If liver function abnormalities recur, consider permanently discontinuing therapy.

If a hepatic decompensation event (e.g., variceal hemorrhage, ascites, hepatic encephalopathy) or portal hypertension occurs, permanently discontinue therapy.

Prescribing Limits

Pediatric Patients

Pruritus Due to Progressive Familial Intrahepatic Cholestasis

Oral

Do not exceed total daily dose of 6 mg.

Adults

Pruritus Due to Progressive Familial Intrahepatic Cholestasis

Oral

Do not exceed total daily dose of 6 mg.

Special Populations

Hepatic Impairment

No specific dosage recommendations for patients with hepatic impairment at baseline.

Clinical studies included patients with hepatic impairment at baseline. Dosage reduction of odevixibat or temporary reduction of therapy may be necessary based on the degree of change in hepatic function from baseline.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Cautions for Odevixibat

Contraindications

• None.

Warnings/Precautions

Liver Test Abnormalities

New or worsening elevations of liver function tests observed during therapy. Most common abnormalities included elevations in ALT, AST, or total bilirubin/direct bilirubin.

Obtain liver function values at baseline and during therapy. Consider dosage reduction or treatment interruption if abnormalities occur. For persistent or recurrent liver function abnormalities, consider discontinuing odevixibat therapy.

Not evaluated in patients with progressive familial intrahepatic cholestasis (PFIC) and concomitant cirrhosis. Closely monitor these patients for liver test abnormalities. Permanently discontinue odevixibat if the patient progresses to portal hypertension or experiences a hepatic decompensation event.

Diarrhea

Diarrhea reported.

If diarrhea occurs, monitor patients for dehydration and treat promptly.

If diarrhea persists, temporarily withhold therapy; when diarrhea resolves, restart odevixibat at a dosage of 40 mcg/kg daily and increase dosage as tolerated, if appropriate.

If diarrhea persists and no alternate etiology is identified, discontinue therapy.

Fat-soluble Vitamin Deficiency

Assess fat-soluble vitamin levels (e.g., vitamins A, D, E, and K [measured using INR]) prior to initiation and during therapy; supplement with vitamins if deficiency is diagnosed.

Discontinue odevixibat if vitamin deficiency persists or worsens despite adequate supplementation.

Specific Populations

Pregnancy

No available data on use of odevixibat in pregnant women.

Cardiac malformations reported in animal studies.

Lactation

Breast-feeding is not expected to result in exposure to the infant. Not known whether odevixibat is distributed into human milk. Effects of the drug on breast-fed infants or on milk production also not known.

Consider developmental and health benefits of breast-feeding along with the mother's need for odevixibat and any potential adverse effects on the breast-fed child from the drug or underlying maternal condition.

Monitor fat-soluble vitamin levels and provide supplementation if a deficiency is diagnosed during lactation.

Pediatric Use

Safety and efficacy established in pediatric patients 3 months to 17 years of age for the treatment of pruritus due to PFIC.

Safety and efficacy not established in pediatric patients <3 months of age with pruritus due to PFIC.

Geriatric Use

Safety and efficacy not established in adults, including patients ≥65 years of age.

Hepatic Impairment

Clinical studies included patients with PFIC and hepatic impairment at baseline.

Safety and efficacy not established in patients with PFIC and clinically significant portal hypertension or decompensated cirrhosis.

Common Adverse Effects

Most common adverse reactions (>2%): Liver test abnormalities, diarrhea, abdominal pain, vomiting, fat-soluble vitamin deficiency.

Interactions for Odevixibat

Does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6, or induce CYP isoenzymes 1A2, 2B6, or 3A4.

Substrate of P-glycoprotein (P-gp), but not a substrate of breast cancer resistance protein (BCRP).

In vitro, not an inhibitor of P-gp, BCRP, organic anion transporter polypeptide (OATP)1B1 or OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter 2 (OCT2), or multidrug and toxin extrusion exporter 1 and 2K (MATE1 and MATE2K).

Specific Drugs

Odevixibat Pharmacokinetics

Absorption

Bioavailability

Systemic exposure is minimal. Following oral administration, plasma concentrations are below the limit of quantification.

No accumulation observed following once daily administration.

Time to peak plasma concentration was 1–5 hours following a single oral dose.

Food

When odevixibat pellets were opened and sprinkled on applesauce, peak plasma concentration and AUC decreased by 39% and 35%, respectively, and median time to peak plasma concentration was delayed by 1.5 hours (from 3 hours to 4.5 hours) compared to administration under fasting conditions; these changes are not considered clinically important.

When administered with a high-fat meal, peak plasma concentration and AUC decreased by 72% and 62%, respectively, and median time to peak plasma concentration was delayed by 1.5 hours (from 3 hours to 4.5 hours) compared to administration under fasting conditions; these changes are not considered clinically important.

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

99%.

Elimination

Metabolism

Metabolized in vitro by mono-hydroxylation.

Elimination Route

Following a single oral dose of radiolabeled odevixibat, 82.9% of the dose was recovered in feces (97% as unchanged drug), and <0.002% was recovered in the urine (no unchanged drug).

Half-life

Approximately 2.36 hours in healthy adults.

Stability

Storage

Oral

Capsules

20–25°C (excursions permitted to 15–30°C).

Oral Pellets

20–25°C (excursions permitted to 15–30°C).

Actions

• Reversible inhibitor of the ileal bile acid transporter (IBAT).

• Decreases reabsorption of bile acids (primarily the salt forms) from terminal ileum.

• Mechanism of action in patients with pruritus associated with PFIC not fully elucidated, but may involve inhibition of IBAT.

• Inhibition of IBAT decreases reuptake of bile salts.

Advice to Patients

• Abdominal pain, vomiting, diarrhea, and dehydration have been reported with the use of odevixibat. Advise patients to contact their healthcare provider if they experience new onset or worsening of diarrhea.

• Elevations in liver function tests (e.g., AST, ALT, total bilirubin) have been observed with use of odevixibat. Advise patients that their healthcare provider will obtain liver function tests before starting odevixibat and periodically during treatment. Advise patients to report any symptoms of liver problems (e.g., nausea, vomiting, yellow discoloration in skin or the whites of eyes, dark or brown urine, pain on the right side of the abdomen, loss of appetite).

• Odevixibat may impair absorption of fat-soluble vitamins, including vitamins A, D, E, and K (vitamin K is assessed by measuring INR). Advise patients that their healthcare provider will obtain serum levels of vitamins A, D, E, and INR (for vitamin K) at baseline and periodically during treatment to assess for worsening of fat-soluble vitamin deficiency.

• Take odevixibat in the morning with a meal.

• Odevixibat oral pellets: Do not swallow the capsule shell containing the oral pellets. The oral pellets are intended to be opened and the contents mixed into soft food. Do not mix the oral pellets with liquids.

• Odevixibat capsules: For patients unable to swallow the capsules whole, follow stepwise administration instructions for oral pellets.

• For patients taking bile acid binding resins, take odevixibat at least 4 hours before or 4 hours after taking the bile acid binding resin.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

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.

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