Odevixibat (Monograph)

Brand name: Bylvay
Drug class: Cholelitholytic Agents

Medically reviewed by Drugs.com on Apr 10, 2024. 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 subgroup of patients with PFIC type 2 with specificABCB11 variants resulting in non-functional or complete absence of the 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.

Alagille Syndrome

Treatment of cholestatic pruritus in patients ≥12 months of age with Alagille syndrome (ALGS). Designated an orphan drug by FDA for use in this condition.

ALGS is an autosomal dominant, multisystem disorder caused by various mutations affecting the Notch signaling pathway. The syndrome, which is usually diagnosed in infancy, mainly affects the liver and is associated with significant cholestasis. Patients often suffer from intractable pruritus. Some drugs have been used for symptomatic treatment (e.g., ursodiol, cholestyramine, rifampin, colesevelam, antihistamines). Odevixibat may provide an additional 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. Oral pellets are intended for patients weighing <19.5 kg and capsules are intended for patients weighing ≥19.5 kg.

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

Oral Pellets

Oral pellets are supplied enclosed in size 0 capsule shells. Open shell and mix oral pellet contents into soft food or a liquid as described below and give with the first morning meal. Discard the empty shells. Do not let the child swallow unopened shells containing oral pellets.

For patients capable of swallowing food:

• Open the shell containing oral pellets and empty contents into a bowl containing a small amount (approximately 2 tablespoons) of soft food (e.g., apple sauce, oatmeal, banana or carrot puree, chocolate or rice pudding). Keep the soft food at or cooler than room temperature. Gently tap the oral pellet shell to ensure that all contents have been dispersed. If the dose requires more than one shell, repeat this process.

• Gently mix and administer the entire dose immediately; give breast milk, infant formula, or other age-appropriate liquid after the dose is taken. Do notstore the mixture for future use.

For administration with liquids with an oral dosing syringe:

• Open the shell containing oral pellets and empty contents into a small mixing cup. Gently tap the shell containing oral pellets to ensure that all contents have been emptied into the mixing cup. If the dose requires more than one shell, repeat this process. Add one teaspoonful of an age-appropriate liquid (e.g., breast milk, infant formula, water) and let the pellets sit in the liquid for approximately 5 minutes to allow complete wetting of the pellets; the oral pellets will not dissolve in the liquid.

• After 5 minutes, place the tip of the oral syringe completely into the mixing cup. Pull the plunger of the syringe up slowly to withdraw the liquid and pellet mixture into the syringe. Gently push the plunger down again to expel the liquid and pellet mixture back into the mixing cup. Repeat this 2 to 3 times to ensure complete mixing of the pellets into the liquid. Withdraw the entire contents into the oral syringe by pulling the plunger on the end of the syringe.

• Place the tip of the syringe into the front of the patient's mouth between the tongue and the side of the mouth, and then gently push the plunger down to squirt the liquid and pellet mixture between the child's tongue and the side of the mouth. Do not squirt liquid and pellet mixture in the back of the child's throat because this could cause gagging or choking. If any pellet and liquid mixture remains in the mixing cup, withdraw the remaining mixture and repeat the administration process. Do not administer via a bottle or "sippy cup" because the oral pellets will not pass through the opening. Follow the dose with breast milk, infant formula, or other age-appropriate liquid. Check the child's mouth to make sure all of the liquid and pellet mixture has been swallowed.

Capsules

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 a small amount (approximately 2 tablespoons) of soft food (e.g., apple sauce, oatmeal, banana or carrot puree, chocolate or rice pudding) or mix with an age-appropriate liquid; follow directions for oral pellets to prepare and administer such a mixture.

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

Alagille Syndrome

Oral

Pediatric patients ≥12 months of age: Recommended dosage is 120 mcg/kg taken orally once daily in the morning with a meal.

Weight-based once daily dosages based on the recommended dosage of 120 mcg/kg once daily are described in Table 2.

Adults

Pruritus Due to Progressive Familial Intrahepatic Cholestasis

Oral

Recommended initial dosage: 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 once daily dosage based on an initial dosage of 40 mcg/kg once daily are described in Table 1.

Alagille Syndrome

Oral

Recommended dosage: 120 mcg/kg taken orally once daily in the morning with a meal.

Weight-based once daily dosages based on the recommended dosage of 120 mcg/kg once daily are described in Table 2.

Dosage Modification for Toxicity

Adverse Reactions

Consider dose reduction to 40 mcg/kg/day (see Table 1) if tolerability issues occur in the absence of other causes. Once tolerability issues stabilize, increase to 120 mcg/kg/day.

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 recommended dosage. 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.

Special Populations

Hepatic Impairment

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

Interruption of odevixibat therapy may be necessary based on the degree of change in hepatic function from baseline or presence of clinical symptoms.

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) or Alagille syndrome (ALGS) 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.

Report odevixibat exposure during pregnancy by calling 1-855-252-4736.

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 for this use.

Safety and efficacy established in pediatric patients 12 months to 17 years of age for the treatment of pruritus due to ALGS. Safety and efficacy not established in pediatric patients <12 months of age for this use.

Geriatric Use

The manufacturer states that PFIC and ALGS are largely diseases of pediatric and young adult patients. Clinical studies with odevixibat did not include patients ≥65 years of age.

Hepatic Impairment

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

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

Common Adverse Effects

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

Most common adverse reactions (>5%) in patients with ALGS: Diarrhea, abdominal pain, hematoma, weight loss.

Drug Interactions

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 in the majority of plasma samples.

No accumulation observed following once daily administration.

Following a single oral dose in healthy adults, time to peak plasma concentration was 1–5 hours.

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 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 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).

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 and ALGS 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 or 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 (e.g., cholestyramine, colesevelam, or colestipol), 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.

• Advise patients or their caregiver(s) that there is a pregnancy safety study that collects outcome data in women taking odevixibat duringpregnancy. Pregnant women exposed to odevixibat, or their healthcare providers, should report odevixibat exposure by calling 1-855-252-4736.

• 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.

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