Bylvay (Capsules) Instructions for Use

Marketing Authorization Holder

Ipsen Pharma (France)

Manufactured By

Patheon France (France)

Packaging and Quality Control Release

ALMAC PHARMA SERVICES, Limited (United Kingdom)

ATC Code

A05AX05 (Odevixibat)

Active Substance

Odevixibat (Rec.INN registered by WHO)

Dosage Forms

	Bylvay	Capsules 200 mcg: 30 pcs.
		Capsules 400 mcg: 30 pcs.
		Capsules 600 mcg: 30 pcs.
		Capsules 1200 mcg: 30 pcs.

Dosage Form, Packaging, and Composition

Capsules size 0, with a white opaque body and a light yellow opaque cap, printed with the identification code “A200” in black ink, containing white to almost white granules.

Excipients: hypromellose, microcrystalline cellulose; capsule cap: hypromellose, iron oxide yellow (E172), titanium dioxide (E171); capsules: hypromellose, titanium dioxide (E171).

Ink composition shellac, propylene glycol, ammonium hydroxide, isopropyl alcohol, n-butanol, iron oxide black (E172).

30 pcs. – polyethylene bottles (1) – cardboard packs.

Capsules size 3, with a white opaque body and a brownish-orange opaque cap, printed with the identification code “A400” in black ink, containing white to almost white granules.

Excipients: hypromellose, microcrystalline cellulose; capsule cap: hypromellose, iron oxide red (E172), iron oxide yellow (E172), titanium dioxide (E171); capsules: hypromellose, titanium dioxide (E171).

Ink composition shellac, propylene glycol, ammonium hydroxide, isopropyl alcohol, n-butanol, iron oxide black (E172).

30 pcs. – polyethylene bottles (1) – cardboard packs.

Capsules size 0, with a light yellow opaque body and a light yellow opaque cap, printed with the identification code “A600” in black ink, containing white to almost white granules.

Excipients: hypromellose, microcrystalline cellulose; capsule cap: hypromellose, iron oxide yellow (E172), titanium dioxide (E171); capsule body: hypromellose, iron oxide yellow (E172), titanium dioxide (E171).

Ink composition shellac, propylene glycol, ammonium hydroxide, isopropyl alcohol, n-butanol, iron oxide black (E172).

30 pcs. – polyethylene bottles (1) – cardboard packs.

Capsules size 3, with a brownish-orange opaque body and a brownish-orange opaque cap, printed with the identification code “A1200” in black ink, containing white to almost white granules.

Excipients: hypromellose, microcrystalline cellulose; capsule cap: hypromellose, iron oxide red (E172), iron oxide yellow (E172), titanium dioxide (E171); capsules: hypromellose, iron oxide red (E172), iron oxide yellow (E172), titanium dioxide (E171).

Ink composition shellac, propylene glycol, ammonium hydroxide, isopropyl alcohol, n-butanol, iron oxide black (E172).

30 pcs. – polyethylene bottles (1) – cardboard packs.

Clinical-Pharmacological Group

A drug used to treat diseases of the liver and biliary tract

Pharmacotherapeutic Group

Drugs for the treatment of liver and biliary tract diseases; drugs for the treatment of gallbladder diseases; other drugs for the treatment of biliary tract diseases

Pharmacological Action

Odevixibat is a reversible, potent, selective inhibitor of the ileal bile acid transporter (IBAT).

Odevixibat acts locally in the distal ileum, reducing the reabsorption of bile acids and increasing their clearance through the colon, which leads to a decrease in the concentration of bile acids in the blood serum. The degree of reduction in serum bile acid concentration does not correlate with the systemic exposure of odevixibat.

Pharmacokinetics

Odevixibat is minimally absorbed after oral administration; data on absolute bioavailability in humans are lacking, and the estimated relative bioavailability is < 1%. C_max of odevixibat in blood plasma is reached within 1-5 hours. The observed exposure in pediatric patients (age from 1.1 to 15.5 years; body weight from 5.6 to 44 kg) is limited to trough (minimum) concentration (C_trough) values; for a dose of 120 mcg/kg/day, these values were below the limit of quantification for 83% of samples in patients with mild hepatic impairment (Child-Pugh class A) and for 42% of samples in patients with moderate hepatic impairment (Child-Pugh class B). The maximum C_trough values in patients with mild and moderate hepatic impairment (Child-Pugh classes A and B, respectively) were 0.455 and 3.38 ng/ml, respectively. Simulated C_max values in the pediatric population with progressive familial intrahepatic cholestasis (PFIC) for doses of 40 and 120 mcg/kg/day are 0.211 and 0.623 ng/ml, respectively, and AUC values are 2.26 ng×h/ml and 5.99 ng×h/ml, respectively. Simulated C_max and AUC values for a dose of 120 mcg/kg/day in the pediatric population with Alagille syndrome were similar to those in patients with PFIC. Odevixibat shows minimal accumulation with once-daily administration. Plasma protein binding is more than 99%. The mean apparent V_d adjusted for body weight in children receiving odevixibat at a dose of 40 or 120 mcg/kg/day is 40.3 and 43.7 L/kg, respectively. The mean V_d in a patient weighing 70 kg is predicted to be 3388 L. Odevixibat is minimally metabolized in the human body. After a single oral dose of 3000 mcg of radiolabeled odevixibat in healthy adult volunteers, 82.9% of the administered dose was excreted in feces, and less than 0.002% of the administered dose was excreted in urine. Furthermore, 97% of the radioactivity excreted in feces was attributed to unchanged Odevixibat. The mean apparent total plasma clearance normalized for body weight in children receiving odevixibat at a dose of 40 or 120 mcg/kg/day is 26.4 and 23 L/kg/h, respectively. The mean plasma clearance in a patient weighing 70 kg is predicted to be 2970 L/h, and the mean T_1/2 is about 2.5 hours.

Indications

Adults and children aged 6 months or older: for the treatment of progressive familial intrahepatic cholestasis (PFIC); for the treatment of cholestatic pruritus in Alagille syndrome.

ICD codes

Dosage Regimen

Orally.

The recommended dose is 40 mcg/kg once daily.

In some patients, after starting therapy with odevixibat, the reduction in pruritus and the decrease in serum bile acid levels may occur gradually. If an adequate clinical response is not achieved after 3 months of continuous therapy, the dose may be increased to 120 mcg/kg/day.

The maximum daily dose can be 7200 mcg/day.

If tolerance problems occur in the absence of other causes, a dose reduction to 40 mcg/kg/day may be recommended. Once tolerance problems have stabilized, the dose can be increased to 120 mcg/kg/day.

Alternative treatment may be considered for patients for whom a clinical benefit from treatment cannot be established after 6 months of continuous daily treatment with odevixibat.

Adverse Reactions

Gastrointestinal system very common – diarrhea; common – abdominal pain, hemorrhagic diarrhea, stool softening.

Hepatobiliary system common – hepatomegaly, increased liver enzyme activity.

Contraindications

Hypersensitivity to odevixibat; children under 6 months of age; pregnancy, breastfeeding period.

Use in Pregnancy and Lactation

Data on the use of odevixibat in pregnant women are limited or absent. Reproductive toxicity has been observed in animal studies. Contraindicated for use during pregnancy and in women of childbearing potential who are not using reliable methods of contraception.

Data on the passage of odevixibat and/or its metabolites into human breast milk are lacking. Data on the passage of odevixibat into animal breast milk are insufficient. A risk to newborns and breastfed infants cannot be excluded. A decision must be made either to discontinue breastfeeding or to discontinue therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Use in Hepatic Impairment

In patients with mild and moderate hepatic impairment, dose adjustment is not required.

There are no available clinical data on the use of odevixibat in patients with severe hepatic impairment (Child-Pugh class C). In this category of patients, additional monitoring for adverse reactions may be required.

Use in Renal Impairment

In patients with mild and moderate renal impairment, dose adjustment is not required.

There are no available clinical data on the use of odevixibat in patients with moderate and severe renal impairment or end-stage chronic kidney disease requiring hemodialysis.

Pediatric Use

The safety and efficacy of odevixibat in children under 6 months of age have not been established.

Special Precautions

The mechanism of action of odevixibat requires preserved enterohepatic circulation of bile acids and bile salt transport into the bile canaliculi. Diseases, medications, or surgical interventions that impair gastrointestinal motility or the enterohepatic circulation of bile acids, including bile salt transport into the bile canaliculi, may potentially reduce the efficacy of odevixibat. For this reason, for example, patients with PFIC type 2, who completely lack or have a non-functional protein known as the bile salt export pump (BSEP) (i.e., patients with PFIC type 2 and BSEP subtype 3), will not respond to therapy with odevixibat.

Evaluation of liver function tests is recommended before starting treatment with odevixibat, along with monitoring according to standard clinical practice. Odevixibat has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Periodic monitoring of liver function laboratory parameters is recommended in patients with severe hepatic impairment.

Patient condition should be monitored to ensure adequate fluid replacement during episodes of diarrhea.

Before starting therapy with odevixibat, it is recommended to assess the levels of fat-soluble vitamins (vitamins A, D, and E) and INR in all patients and subsequently monitor them according to standard clinical practice.

Therapy with odevixibat may affect the absorption of fat-soluble drugs, including lipophilic oral contraceptives.

Drug Interactions

Odevixibat is a substrate for the efflux transporter P-glycoprotein (P-gp). In healthy adult volunteers, concomitant use of the strong P-gp inhibitor itraconazole led to an increase in the plasma concentration of odevixibat after a single dose of 7200 mcg by approximately 50-60%. This increase is not considered clinically significant.

In vitro studies have shown that Odevixibat is an inhibitor of CYP3A4/5. In healthy adult volunteers, concomitant use of odevixibat led to a 30% decrease in the AUC of orally administered midazolam (a CYP3A4 substrate) and a less than 20% decrease in the plasma concentration of 1-OH-midazolam, which is not considered clinically significant.

In a drug interaction study with a lipophilic combined oral contraceptive containing ethinylestradiol (0.03 mg) and levonorgestrel (0.15 mg) conducted in healthy adult women, concomitant use of odevixibat did not affect the AUC of levonorgestrel and decreased the AUC of ethinylestradiol by 17%, which is not clinically significant. Interaction studies with other lipophilic drugs have not been conducted, so an effect on the absorption of other fat-soluble drugs, including lipophilic oral contraceptives, cannot be excluded.

In clinical studies, some patients taking Odevixibat experienced a decrease in fat-soluble vitamin levels. Fat-soluble vitamin levels should be monitored.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.