DRUG INTERACTIONS- summary

1. Bile Acid Binding Resins-                                                                                            Administer bile acid binding resins (e.g., cholestyramine, colesevelam, or colestipol) at least 4 hours before or 4 hours after administration of BYLVAY.                                                  Bile acid binding resins may bind odevixibat in the gut, which may reduce BYLVAY efficacy.

BRIEF SUMMARY

ODEVIXIBAT- (July 2021)

Indn-  To treat pruritus

Comp-    Oral Pellets: 200 mcg, 600 mcg) -Capsules: 400 mcg, 1200 mcg                The recommended dosage is 40 mcg/kg once daily in the morning with a meal.             

 • If there is no improvement in pruritus after 3 months, the dosage may be increased in 40 mcg/kg increments up to 120 mcg/kg once daily not to exceed a total daily dose of 6 mg.

ADR- Most common adverse reactions are liver test abnormalities, diarrhea, abdominal pain, vomiting, and fat-soluble vitamin deficiency.

CI- None

WARNINGS -

­ • Liver Test Abnormalities: Obtain baseline liver tests and monitor during treatment. Dose reduction or treatment interruption may be required if abnormalities occur. For persistent or recurrent liver test abnormalities, consider treatment discontinuation.

 • Diarrhea: Treat dehydration. Treatment interruption or discontinuation may be required for persistent diarrhea.

Pat Inform-

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

• Elevations in liver tests (for example, AST, ALT, TB) have been observed with use of . Advise patients that their healthcare provider will obtain liver tests before starting  and periodically during treatment .

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U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 32

Name of the Drug-    BYLVAY

Active Ingredient -   Odevixibat

Pharmacological Classification- To treat pruritus                                                               

                                                                                                                                                Date of Approval-          7/20/2021                                                                                                                                           

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                            BYLVAY safely and effectively.                                                                                          See full prescribing information for BYLVAY. BYLVAY (odevixibat) capsules, for oral use BYLVAY (odevixibat) oral pellets

Initial U.S. Approval: 2021

INDICATIONS AND USAGE-

­ BYLVAY is an ileal bile acid transporter (IBAT) inhibitor indicated for the treatment of pruritus in patients 3 months of age and older with progressive familial intrahepatic cholestasis (PFIC).

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

ADVERSE REACTIONS-

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

CONTRAINDICATIONS-                                                                                               ­ None

WARNINGS -

­ • Liver Test Abnormalities: Obtain baseline liver tests and monitor during treatment. Dose reduction or treatment interruption may be required if abnormalities occur. For persistent or recurrent liver test abnormalities, consider treatment discontinuation.

 • Diarrhea: Treat dehydration. Treatment interruption or discontinuation may be required for persistent diarrhea.

 • Fat-Soluble Vitamin (FSV) Deficiency: Obtain baseline levels and monitor during treatment. Supplement if deficiency is observed. If FSV deficiency persists or worsens despite FSV supplementation, discontinue treatment. 

DOSAGE AND ADMINISTRATION-

­ • The recommended dosage is 40 mcg/kg once daily in the morning with a meal.             • If there is no improvement in pruritus after 3 months, the dosage may be increased in 40 mcg/kg increments up to 120 mcg/kg once daily not to exceed a total daily dose of 6 mg.

Administration:                                                                                                                       • Administer BYLVAY in the morning with a meal.                                                                   • Do not crush or chew capsules.                                                                                             • See prescribing information for administration instructions.

DOSAGE FORMS AND STRENGTHS-                                                                                    Oral Pellets: 200 mcg, 600 mcg) -Capsules: 400 mcg, 1200 mcg 

PATIENT COUNSELING INFORMATION-

Inform the patients and their caretakers of the following BYLVAY risks and oral administration procedures:

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

• Elevations in liver tests (for example, AST, ALT, TB) have been observed with use of BYLVAY. Advise patients that their healthcare provider will obtain liver tests before starting BYLVAY and periodically during treatment with BYLVAY.

Advise patients to report any symptoms of liver problems (for example, nausea, vomiting, skin or the whites of eyes turn yellow, dark or brown urine, pain on the right side of the abdomen, loss of appetite).

• BYLVAY may impair absorption of fat-soluble vitamins (FSV), which include 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 FSV deficiency.

Administration • Do not mix BYLVAY with liquids.                                                              • Do not swallow the 200 mcg or 600 mcg capsule(s) containing Oral Pellets whole. These are intended to be opened and the contents mixed into soft food.

Take BYLVAY in the morning with a meal.                                                                            • Follow stepwise administration Instructions [see Dosage and Administration (2.2)] for Oral Pellets and Capsules for patients unable to swallow the capsules whole.

• For patients taking bile acid binding resins, take BYLVAY at least 4 hours before or 4 hours after taking a bile acid binding resin 

Manufactured for: Albireo Pharma, Inc. 10 Post Office Square Boston, MA 02109

CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                     Odevixibat is a reversible inhibitor of the ileal bile acid transporter (IBAT). It decreases the reabsorption of bile acids (primarily the salt forms) from the terminal ileum.

2. Pharmacodynamics-                                                                                               Odevixibat reduces serum bile acids in patients with PFIC. In Trial 1, a 24-week, randomized, doubleblind, placebo-controlled trial conducted in 62 patients with a confirmed diagnosis of PFIC type 1 or type 2, the majority of patients (88.7%) had elevated serum bile acids above 100 µmol/L at baseline .

Absorption-                                                                                                         Odevixibat is minimally absorbed following oral administration. Following a single administration of odevixibat 7.2 mg in healthy adults, odevixibat Cmax is reached between 1 to 5 hours.

Effect of food- Concomitant administration of a high-fat meal (800-1000 calories with approximately 50% of total caloric content of the meal from fat) with a single dose of odevixibat 9.6 mg delayed median Tmax from 3 hours to 4.5 hours and resulted in decreases of 72% and 62% in Cmax and AUC0-24h, respectively, compared to administration under fasted conditions in healthy adults.

Distribution-                                                                                                                    Human plasma protein binding of odevixibat is greater than 99% in vitro.

Elimination-                                                                                                             Following a single oral dose of 7.2 mg odevixibat in healthy adults, the mean half-life (t1/2) was 2.36 hours.

Metabolism-                                                                                                                       In vitro, odevixibat was metabolized via mono-hydroxylation. 

Excretion-                                                                                                                Following a single radiolabeled odevixibat 3 mg oral dose in healthy adults, 82.9% of the dose was recovered in feces (97% unchanged) and less than 0.002% in the urine.

Drug Interaction Studies-                                                                                           Effect of Other Drugs on Odevixibat Odevixibat is a substrate of P-glycoprotein (P-gp) but not a substrate of breast cancer resistance protein (BCRP).

Coadministration of itraconazole (a strong P-gp inhibitor) with a single dose of BYLVAY 7.2 mg increased odevixibat AUC0-24h by 66% and Cmax by 52%, which is not expected to have a clinically significant effect.

Effect of Odevixibat on Other Drugs- In in vitro studies, odevixibat was not an inhibitor of CYP isoforms 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 nor an inducer of CYP isoforms 1A2, 2B6, or 3A4.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary- 

There are no human data on BYLVAY use in pregnant persons to establish a drug-associated risk of major birth defects, miscarriage, or adverse developmental outcomes.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

2. Lactation Risk Summary-

Odevixibat has low absorption following oral administration, and breastfeeding is not expected to result in exposure of the infant to BYLVAY at the recommended doses 

There are no data on the presence of odevixibat in human milk, the effects on the breastfed , or the effects on milk production. BYLVAY may reduce absorption of fat-soluble vitamins 

3. Pediatric Use-                                                                                                            The safety and effectiveness of BYLVAY have been established in pediatric patients 3 months to 17 years of age for the treatment of pruritus in PFIC.

4.Geriatric Use-                                                                                                              The safety and effectiveness of BYLVAY for the treatment of pruritus in PFIC in adult patients, including those 65 years of age and older, have not been established.

5. Hepatic Impairment-                                                                                           Patients with PFIC may have impaired hepatic function at baseline. The efficacy and safety in PFIC patients with clinically significant portal hypertension and in patients with decompensated cirrhosis have not been established