odevixibat (Rx)

>10%

PFIC

• Diarrhea (21-39%)
• AST/ALT increased (13-21%)
• Vomiting (15-17%)
• Abdominal pain (13-16%)
• FSV deficiency (16%)
• Blood bilirubin increased (11-13%)
• Splenomegaly (11%)

ALGS

• Diarrhea (29%)
• Abdominal pain (14%)

1-10%

PFIC

• Cholelithiasis (5%)
• Dehydration (5%)
• Fracture (4%)

ALGS

• Hematoma (9%)
• Weight decreased (6%)

Contraindications

None

Cautions

Liver test abnormalities

• Patients enrolled in clinical trial had abnormal LFTs at baseline, including elevated AST, ALT, TB, and DB
• Treatment interruption days ranged from 3-124 days
• Obtain baseline LFTs and monitor during treatment
• Dose reduction or treatment interruption maybe required if abnormalities occur; for persistent or recurrent liver test abnormalities, consider treatment discontinuation
• Closely monitor for liver test abnormalities; permanently discontinue therapy if a patient progresses to portal hypertension orexperiences a hepatic decompensation event

Diarrhea

• Diarrhea reported
• If diarrhea occurs, monitor for dehydration and treat promptly
• Interrupt dosing if diarrhea persists
• Restart at 40 mcg/kg/day once resolved; may increase dose as tolerated if appropriate
• If diarrhea persists and no alternate etiology identified, stop treatment

Fat-soluble vitamin (FSV) deficiency

• Fat-soluble vitamins (FSV) include vitamin A, D, E, and K (measured using INR levels)
• Patients with PFIC or ALGS can have FSV deficiency at baseline
• Therapy may affect absorption of FSVs
• Obtain serum FSV levels at baseline and monitor during treatment, along with any clinical manifestations
• If FSV deficiency diagnosed, supplement with FSVs
• Discontinue if FSV deficiency persists or worsens despite adequate supplementation

Drug interaction overview

• Substrate of P-gp; strong P-gp inhibitors are not expected to have a clinically significant effect on odevixibat

• Bile acid–binding resins

  • Separate administration of bile acid–binding resins (eg, cholestyramine, colesevelam, colestipol) at least 4 hr before or after odevixibat
  • Bile acid–binding resins may bind odevixibat in the gut, resulting in reduced efficacy

Pregnancy

There is a pregnancy safety study that monitors pregnancy outcomes in women exposed during pregnancy; pregnant women exposed to therapy, or their healthcare providers, should report exposure by calling 1-855-252-4736

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

Animal data

• May cause cardiac malformations in fetus if exposed during pregnancy
• In pregnant rabbits treated orally with odevixibat during organogenesis, an increased incidence of malformations in fetal heart, great blood vessels, and other vascular sites occurred at all doses; maternal systemic exposure at the lowest dose was 2.1x the maximum recommended dose

Lactation

Odevixibat has low absorption following oral administration, and breastfeeding is not expected to result in exposure of infant

No data are available on its presence in human milk, effects on breastfed infants, or effects on milk production

May reduce absorption of FSVs

Monitor FSV levels and increase FSV intake, if FSV deficiency occurs during lactation

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

Ileal bile acid transport inhibitor (IBATi); acts locally in the distal ileum to decrease reuptake of bile acids and increase clearance of bile acids through the colon, thereby, reducing bile acid serum concentration

Although mechanism of action in PFIC patients is unknown, it may involve inhibition of the IBAT, which results in decreased reuptake of bile salts, as observed by a decrease in serum bile acids

Absorption

Plasma concentration: 0.06-0.72 ng/mL (aged 6 months to 17 years)

No accumulation of odevixibat was observed following once-daily dosing

Peak plasma concentration: 0.47 ng/mL (single 7.2-mg dose in healthy adults)

AUC: 2.19 ng·hr/mL (single 7.2-mg dose in healthy adults)

Peak plasma time: 1-5 hr (single 7.2-mg dose in healthy adults)

Effect of food

• Sprinkle on applesauce (9.6 mg-dose): Decreased peak plasma concentration by 39% and AUC by 35%
• High-fat meal (800-100 calories with ~50% of total caloric content of meal from fat): Decreased peak plasma concentration by 72% and AUC by 62%; delayed peak plasma time by 3-4.5 hr
• Effect of food on systemic exposures to odevixibat is not clinically significant

Distribution

Protein bound: >99%

Metabolism

Metabolized via mono-hydroxylation

Elimination

Half-life: 2.36 hr

Excretion: Feces (97% unchanged); urine (0.002%)

Oral Preparation (oral pellets only)

Mix the contents of shell containing oral pellets into soft food or liquid

Do not let child swallow unopened shell containing pellets

Soft food

• Place small amount of soft food (up to 30 mL [2 tablespoons] of applesauce, oatmeal, banana or carrot puree, chocolate, or rice pudding) in a bowl
• Keep food at or below room temperature
• Open shell containing oral pellets and empty contents into bowl of soft food
• Gently tap shell to ensure all contents have been dispersed
• If dose requires >1 shell of oral pellets, repeat above steps
• Gently mix until well dispersed

Liquids (using oral dosing syringe)

• Open shell containing oral pellets and empty contents into small mixing cup
• Gently tap shell to ensure all contents have been emptied into cup
• If dose requires >1 shell of oral pellets, repeat above steps
• Add 1 teaspoon (5 mL) of an age-appropriate liquid (eg, breast milk, infant formula, water)
• Let pellets sit in liquid for ~5 minutes to allow complete wetting
• NOTE: Oral pellets will not dissolve in liquid
• After 5 minutes, place tip of oral syringe completely into mixing cup; pull syringe plunger up slowly to withdraw liquid/pellet mixture into syringe
• Gently push plunger down again to expel liquid/pellet mixture back into mixing cup; do this 2-3 times to ensure complete mixing of pellets into liquid
• Withdraw entire contents into oral syringe and place syringe tip into front of patient’s mouth between tongue and side of mouth; then, gently push plunger down to squirt liquid/pellet mixture between child's tongue and side of mouth
• Do not squirt liquid/pellet mixture in back of child's throat because this could cause gagging or choking
• Do not administer via a bottle or “sippy cup” because the oral pellets will not pass through the opening; oral pellets will not dissolve in liquid
• Follow dose with breast milk, infant formula, or other age-appropriate liquid
• If any pellet/liquid mixture remains in mixing cup, repeat above administration steps until entire dose has been administered
• Check child's mouth to make sure all liquid/pellet mixture has been swallowed

Oral Administration

Administer in morning with a meal

For patients taking bile acid–binding resins, take at least 4 hr before or after taking a bile acid–binding resin

Oral pellets

• Administer entire dose immediately after mixture is prepared; follow dose with water or age appropriate liquid
• Do not store mixture for future use
• Do not use in patients who are exclusively on liquid food

Capsules

Swallow capsules whole with glass of water; do not crush or chew

• Unable to swallow capsules

  • Capsules may be opened, and sprinkled and mixed with small amount of soft food or liquid
  • Follow directions above for oral pellets to prepare and administer

Patients taking bile acid binding resins

• Separate odevixibat dose by at least 4 hr before or after bile acid binding resin dose

Storage

Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)