Odevixibat is an ileal bile acid transporter (IBAT) inhibitor indicated for the treatment of pruritus in patients 3 months and older with progressive familial intrahepatic cholestasis (PFIC) and patients 1 year and older with Alagille syndrome (ALGS). PFIC and ALGS are rare, inherited childhood disorders associated with cholestasis, pruritus, and potentially fatal liver disease. The most prominent and problematic manifestation of these conditions is pruritis, which can lead to physical abrasions and scarring, as well as functional impacts (e.g., sleep and mood disorders) and deterioration in quality of life. Prior to IBAT inhibitors, treatment relied on supportive pharmacologic therapy for symptomatic relief (e.g., ursodeoxycholic acid, cholestyramine, antihistamines) or surgical intervention (e.g., surgical biliary diversion, liver transplantation). In clinical trials for PFIC (n = 62) and ALGS (n = 52), pediatric patients treated with odevixibat demonstrated greater improvement in pruritus compared to placebo, based on caregiver-reported outcome. Monitor hepatic function and fat-soluble vitamin concentrations at baseline and periodically throughout treatment.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Administer once daily in the morning with a meal.
Oral Solid Formulations
Capsules
-Swallow capsule whole with a glass of water. Do NOT crush or chew capsules.
-Alternatively, open the capsule and mix with a small amount of soft food or with an age appropriate liquid as per the instructions for oral pellets.
Oral Pellets Administered with Soft Food
-Do NOT swallow the shell containing oral pellets whole.
-Place a small amount of soft food (up to 30 mL [2 tablespoons] of apple sauce, oatmeal, banana or carrot puree, chocolate or rice pudding) in a bowl. Keep food at or below room temperature.
-Open the shell and empty the pellets into the bowl of soft food. Gently tap the shell to ensure all contents have been dispersed.
-Gently mix until well dispersed and administer the entire dose immediately.
-Follow the dose with breast milk, infant formula, or other age-appropriate liquid.
-Storage: Do not store the mixture for future use.
Oral Pellets Administered with Liquid (Using an Oral Dosing Syringe)
-Do NOT swallow the shell containing oral pellets whole.
-Do not administer by bottle or sippy cup; oral pellets will not dissolve in the liquid and will not pass through the opening.
-Open the shell and empty the pellets into a small mixing cup. Gently tap the shell to ensure all contents have been dispersed.
-Add 5 mL (1 teaspoon) of an age-appropriate liquid (breast milk, infant formula, or water) to mixing cup.
-Let the pellets sit in the liquid for approximately 5 minutes. The oral pellets will not dissolve in the liquid.
-After 5 minutes, place the tip of the oral syringe completely into the mixing cup and withdraw the liquid/pellet mixture by pulling the plunger of the syringe slowly. Gently expel the mixture back into the mixing cup and repeat this process 2 to 3 times to ensure complete mixture of pellets into the liquid.
-Withdraw the entire contents of mixture into oral syringe.
-Place the tip of the oral syringe into the front of the patients mouth, between the tongue and the side of the mouth, and administer entire contents of mixture as well as any remaining mixture in mixing cup. Do not administer into the back of the patient's throat.
-Follow the dose with breast milk, infant formula, or other age-appropriate liquid.
Treatment-emergent elevated hepatic enzymes were observed during odevixibat clinical trials. Monitor hepatic enzymes and INR at baseline and during treatment. Interrupt treatment if new onset abnormalities occur or symptoms consistent with clinical hepatitis develop. Once hepatic enzymes return to baseline or stabilize at a new baseline, consider restarting odevixibat at 40 mcg/kg/day and increase as tolerated. Consider treatment discontinuation for persistent or recurrent hepatic enzyme abnormalities. Permanently discontinue treatment if a patient progresses to portal hypertension or experiences a hepatic decompensation event (e.g., variceal hemorrhage, ascites, hepatic encephalopathy). During clinical trials, elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 150 units/L or more over baseline were reported in 11% to 37% of patients receiving odevixibat 120 mcg/kg/day (n = 54) compared with 4% to 9% of patients receiving odevixibat 40 mcg/kg/day (n = 23). Hyperbilirubinemia, presenting as total bilirubin elevations (2 mg/dL or more over baseline) and direct bilirubin elevations (1 mg/dL or more over baseline), occurred in 5% to 17% and 11% to 22% of odevixibat-treated patients, respectively. During clinical trials, treatment interruption for elevated hepatic enzymes ranged from 3 to 124 days; no patients permanently discontinued treatment. Splenomegaly (11%), and cholelithiasis (5%) were also reported in patients receiving odevixibat 120 mcg/kg/day in clinical trials (n = 19); no patients receiving odevixibat 40 mcg/kg/day reported these adverse reactions.
Diarrhea was reported in 21% to 39% of odevixibat-treated patients during clinicals trials. Dehydration was reported in 1 patient. If diarrhea occurs, monitor for dehydration and treat promptly. Interrupt treatment for persistent diarrhea. Once diarrhea has resolved, restart odevixibat at 40 mcg/kg/day and increase the dose as tolerated. Discontinue odevixibat if diarrhea persists and no alternative etiology is identified. During clinical trials, treatment interruption days due to diarrhea ranged from 3 to 7 days. One patient withdrew due to persistent diarrhea. Other gastrointestinal-related adverse reactions reported in odevixibat-treated patients in clinical trials include abdominal pain (13% to 16%), vomiting (16% to 17%), and weight loss (6%).
Odevixibat may affect the absorption of fat-soluble vitamins (A, D, E, and K) resulting in vitamin A deficiency, vitamin D deficiency, vitamin E deficiency, and vitamin K deficiency. Obtain serum fat-soluble vitamin concentrations and INR (to monitor for vitamin K) at baseline and periodically during treatment. Supplement with fat-soluble vitamins if a deficiency is diagnosed. Discontinue odevixibat if the deficiency persists or worsens despite supplementation. In clinical trials, new onset or worsening fat-soluble vitamin deficiency was reported in 8.6% to 16% of patients receiving odevixibat 120 mcg/kg/day (n = 54); these deficiencies were not observed in those receiving odevixibat 40 mcg/kg/day (n = 23).
Fracture (bone fractures) was reported in 4% of odevixibat-treated patients in clinical trials (n = 23).
Hematoma was reported in 9% of odevixibat-treated patients in clinical trials (n = 35).
Patients with progressive familial intrahepatic cholestasis (PFIC) or Alagille Syndrome (ALGS) may have hepatic impairment at baseline. Establish a baseline pattern of hepatic function variability prior to odevixibat initiation so that potential signs of liver injury can be identified. Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, direct bilirubin, and INR during treatment. Interrupt treatment if new onset hepatic function abnormalities occur or symptoms consistent with clinical hepatitis develop. Once hepatic function returns to baseline or stabilizes at a new baseline, consider restarting odevixibat at the recommended indication-specific dose and increase as tolerated. Consider treatment discontinuation for persistent or recurrent hepatic function abnormalities. Permanently discontinue treatment if a patient progresses to portal hypertension or experiences a hepatic decompensation event (e.g., variceal hemorrhage, ascites, hepatic encephalopathy). Safety and efficacy of odevixibat have not been established in patients with clinically significant portal hypertension or decompensated biliary cirrhosis.
Odevixibat may affect the absorption of fat-soluble vitamins (A, D, E, and K). Obtain serum fat-soluble vitamin concentrations and INR (to monitor for vitamin K) at baseline and periodically during treatment. Supplement with fat-soluble vitamins if vitamin A deficiency, vitamin D deficiency, vitamin E deficiency, or vitamin K deficiency is diagnosed. Discontinue odevixibat if the deficiency persists or worsens despite supplementation.
There are no data on odevixibat use in human pregnancy to establish a drug-associated risk of major birth defects, miscarriage, or adverse developmental outcomes. Animal reproduction studies suggest odevixibat may cause cardiac malformations in the exposed fetus. In pregnant rabbits receiving odevixibat during organogenesis, an increase in cardiovascular malformations (e.g., 5-chambered heart, small ventricle, large atrium, ventricular septal defect, misshapen aortic valve, dilated aortic arch, right sided and retroesophageal aortic arch, fusion of aortic arch and pulmonary trunk, ductus arteriosus atresia, absence of subclavian artery) occurred at all doses. At the lowest dose, maternal systemic exposure was 2.1 times the maximum recommended human dose (MRHD). There is a pregnancy registry study that monitors pregnancy outcomes in women exposed to odevixibat during pregnancy. Pregnant women exposed to odevixibat, or their health care providers, should report odevixibat exposure by calling 1-855-252-4736.
Breast-feeding is not expected to result in exposure of the infant to odevixibat at recommended doses; odevixibat has low absorption after oral administration. However, there are no data on the presence of odevixibat in human milk, the effects on the breast-fed infant, or the effects on milk production. Odevixibat may reduce the absorption of fat-soluble vitamins. Monitor fat-soluble vitamin concentrations and increase intake if deficiency is observed during lactation. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
For the treatment of progressive familial intrahepatic cholestasis-associated pruritus:
NOTE: Odevixibat may not be effective in progressive familial intrahepatic cholestasis (PFIC) type 2 patients with ABCB11 variants resulting in nonfunctional or complete absence of bile salt export pump protein (BSEP-3).
Oral dosage (capsules):
Adults: 40 mcg/kg/dose PO once daily in the morning; round to appropriate capsule strength. If no improvement after 3 months, may increase dose in 40 mcg/kg increments up to 120 mcg/kg/day (Max: 6 mg/day).
Children and Adolescents weighing 19.5 kg or more: 40 mcg/kg/dose PO once daily in the morning; round to appropriate capsule strength. If no improvement after 3 months, may increase dose in 40 mcg/kg increments up to 120 mcg/kg/day (Max: 6 mg/day).
Oral dosage (oral pellets/granules):
Infants 3 to 11 months and Children weighing less than 19.5 kg: 40 mcg/kg/dose PO once daily in the morning; round to appropriate oral pellet strength. If no improvement after 3 months, may increase dose in 40 mcg/kg increments up to 120 mcg/kg/day.
For the treatment of Alagille syndrome-associated cholestatic pruritus:
Oral dosage (capsules):
Adults: 120 mcg/kg/dose PO once daily in the morning; round to appropriate capsule strength. May decrease dose to 40 mcg/kg/dose PO once daily for adverse reactions; once tolerability issues stabilize, increase to 120 mcg/kg/day (Max: 7.2 mg/day).
Children and Adolescents weighing 19.5 kg or more: 120 mcg/kg/dose PO once daily in the morning; round to appropriate capsule strength. May decrease dose to 40 mcg/kg/dose PO once daily for adverse reactions; once tolerability issues stabilize, increase to 120 mcg/kg/day (Max: 7.2 mg/day).
Oral dosage (oral pellets/granules):
Children weighing less than 19.5 kg: 120 mcg/kg/dose PO once daily in the morning; round to appropriate oral pellet strength. May decrease dose to 40 mcg/kg/dose PO once daily for adverse reactions; once tolerability issues stabilize, increase to 120 mcg/kg/day.
Maximum Dosage Limits:
-Adults
120 mcg/kg/day (Max: 7.2 mg/day) PO.
-Geriatric
Safety and efficacy have not been established. PFIC and ALGS are largely diseases of pediatric and young adults. Clinical studies did not include patients 65 years of age and older.
-Adolescents
120 mcg/kg/day (Max: 7.2 mg/day) PO.
-Children
120 mcg/kg/day (Max: 7.2 mg/day) PO.
-Infants
3 to 11 months: 120 mcg/kg/day PO.
1 to 2 months: Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Interrupt treatment if new onset liver test abnormalities occur or symptoms consistent with clinical hepatitis are observed. Once hepatic function returns to baseline or stabilizes at a new baseline, consider restarting odevixibat at the recommended indication-specific dose and increase as tolerated. Consider permanent discontinuation for persistent or recurrent hepatic function abnormalities. Permanently discontinue treatment if a patient progresses to portal hypertension or experiences a hepatic decompensation event (e.g., variceal hemorrhage, ascites, hepatic encephalopathy).
Patients with Renal Impairment Dosing
No dosage adjustments are needed; less than 0.002% of a dose is excreted in the urine.
*non-FDA-approved indication
Acetaminophen; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with odevixibat is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If odevixibat is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Odevixibat is a weak CYP3A inducer. Concomitant use with odevixibat can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Acetaminophen; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with odevixibat is necessary; consider increasing the dose of hydrocodone as needed. If odevixibat is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A substrate and odevixibat is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Acetaminophen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with odevixibat is necessary; consider increasing the dose of oxycodone as needed. If odevixibat is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A substrate and odevixibat is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Alfentanil: (Moderate) Consider an increased dose of alfentanil and monitor for evidence of opioid withdrawal if coadministration with odevixibat is necessary. If odevixibat is discontinued, consider reducing the alfentanil dosage and monitor for evidence of respiratory depression. Coadministration of a weak CYP3A inducer like odevixibat with alfentanil, a CYP3A substrate, may decrease exposure to alfentanil resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to alfentanil. Alfentanil plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with odevixibat is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If odevixibat is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Odevixibat is a weak CYP3A inducer. Concomitant use with odevixibat can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Aspirin, ASA; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with odevixibat is necessary; consider increasing the dose of oxycodone as needed. If odevixibat is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A substrate and odevixibat is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Atogepant: (Major) Avoid use of atogepant and odevixibat when atogepant is used for chronic migraine. Use an atogepant dose of 30 or 60 mg PO once daily for episodic migraine if coadministered with odevixibat. Concurrent use may decrease atogepant exposure and reduce efficacy. Atogepant is a CYP3A substrate and odevixibat is a weak CYP3A inducer. Coadministration with a weak CYP3A inducer resulted in a 25% reduction in atogepant overall exposure and a 24% reduction in atogepant peak concentration.
Avanafil: (Major) Coadministration of avanafil with odevixibat is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and odevixibat is a weak CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated, plasma concentrations may decrease.
Benzhydrocodone; Acetaminophen: (Moderate) Monitor for reduced efficacy of benzhydrocodone and signs of opioid withdrawal if coadministration with odevixibat is necessary; consider increasing the dose of benzhydrocodone as needed. If odevixibat is discontinued, consider a dose reduction of benzhydrocodone and frequently monitor for signs of respiratory depression and sedation. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a CYP3A substrate and odevixibat is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Bile acid sequestrants: (Moderate) Take odevixibat at least 4 hours before or 4 hours after taking a bile acid sequestrant. Bile acid sequestrants may bind odevixibat in the gut, which may reduce its efficacy.
Buprenorphine: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with odevixibat is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If odevixibat is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A substrate and odevixibat is a weak CYP3A inducer.
Buprenorphine; Naloxone: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with odevixibat is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If odevixibat is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A substrate and odevixibat is a weak CYP3A inducer.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with odevixibat is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If odevixibat is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Odevixibat is a weak CYP3A inducer. Concomitant use with odevixibat can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with odevixibat is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If odevixibat is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Odevixibat is a weak CYP3A inducer. Concomitant use with odevixibat can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Carbamazepine: (Moderate) Monitor carbamazepine concentrations closely during coadministration of odevixibat; carbamazepine dose adjustments may be needed. Concomitant use may decrease carbamazepine concentrations. Carbamazepine is a CYP3A substrate and odevixibat is a weak CYP3A inducer.
Cariprazine: (Major) Coadministration of cariprazine with odevixibat is not recommended as the net effect of CYP3A induction on cariprazine and its metabolites is unclear. Cariprazine is a CYP3A substrate and odevixibat is a weak CYP3A inducer. Coadministration of cariprazine with CYP3A inducers has not been evaluated.
Celecoxib; Tramadol: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with odevixibat is necessary; consider increasing the dose of tramadol as needed. If odevixibat is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and odevixibat is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Chlorpheniramine; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with odevixibat is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If odevixibat is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Odevixibat is a weak CYP3A inducer. Concomitant use with odevixibat can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Chlorpheniramine; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with odevixibat is necessary; consider increasing the dose of hydrocodone as needed. If odevixibat is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A substrate and odevixibat is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Cholestyramine: (Moderate) Take odevixibat at least 4 hours before or 4 hours after taking a bile acid sequestrant. Bile acid sequestrants may bind odevixibat in the gut, which may reduce its efficacy.
Clozapine: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with odevixibat. Consideration should be given to increasing the clozapine dose if necessary. When odevixibat is discontinued, reduce the clozapine dose based on clinical response. Odevixibat is a weak inducer of CYP3A, one of the isoenzymes responsible for the metabolism of clozapine.
Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with odevixibat is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If odevixibat is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Odevixibat is a weak CYP3A inducer. Concomitant use with odevixibat can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Codeine; Guaifenesin: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with odevixibat is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If odevixibat is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Odevixibat is a weak CYP3A inducer. Concomitant use with odevixibat can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with odevixibat is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If odevixibat is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Odevixibat is a weak CYP3A inducer. Concomitant use with odevixibat can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Codeine; Phenylephrine; Promethazine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with odevixibat is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If odevixibat is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Odevixibat is a weak CYP3A inducer. Concomitant use with odevixibat can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Codeine; Promethazine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with odevixibat is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If odevixibat is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Odevixibat is a weak CYP3A inducer. Concomitant use with odevixibat can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Colesevelam: (Moderate) Take odevixibat at least 4 hours before or 4 hours after taking a bile acid sequestrant. Bile acid sequestrants may bind odevixibat in the gut, which may reduce its efficacy.
Colestipol: (Moderate) Take odevixibat at least 4 hours before or 4 hours after taking a bile acid sequestrant. Bile acid sequestrants may bind odevixibat in the gut, which may reduce its efficacy.
Cyclosporine: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with odevixibat is necessary. Concurrent use may decrease cyclosporine exposure resulting in decreased efficacy. Cyclosporine is extensively metabolized by CYP3A and has a narrow therapeutic index; odevixibat is a weak CYP3A inducer.
Diazepam: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with odevixibat is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A substrate and odevixibat is a weak CYP3A inducer.
Doravirine: (Moderate) Concurrent administration of doravirine and odevixibat may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A substrate; odevixibat is a weak CYP3A inducer.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Concurrent administration of doravirine and odevixibat may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A substrate; odevixibat is a weak CYP3A inducer.
Fentanyl: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of odevixibat is necessary. If odevixibat is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a weak CYP3A inducer like odevixibat with fentanyl, a CYP3A substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Homatropine; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with odevixibat is necessary; consider increasing the dose of hydrocodone as needed. If odevixibat is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A substrate and odevixibat is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with odevixibat is necessary; consider increasing the dose of hydrocodone as needed. If odevixibat is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A substrate and odevixibat is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Hydrocodone; Ibuprofen: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with odevixibat is necessary; consider increasing the dose of hydrocodone as needed. If odevixibat is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A substrate and odevixibat is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Ibuprofen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with odevixibat is necessary; consider increasing the dose of oxycodone as needed. If odevixibat is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A substrate and odevixibat is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Isradipine: (Minor) Monitor for decreased efficacy of isradipine if coadministration with odevixibat is necessary. Concomitant use may decrease isradipine exposure. Isradipine is a CYP3A substrate and odevixibat is a weak CYP3A inducer.
Lopinavir; Ritonavir: (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with odevixibat. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and odevixibat is a weak CYP3A inducer.
Lumateperone: (Major) Avoid coadministration of lumateperone and odevixibat as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A substrate; odevixibat is a weak CYP3A inducer.
Mefloquine: (Moderate) Use mefloquine with caution if coadministration with odevixibat is necessary as concurrent use may decrease mefloquine exposure and efficacy. Mefloquine is a CYP3A substrate and odevixibat is a weak CYP3A inducer.
Meperidine: (Moderate) Monitor for reduced efficacy of meperidine and signs of opioid withdrawal if coadministration with odevixibat is necessary. Consider increasing the dose of meperidine as needed. If odevixibat is discontinued, consider a dose reduction of meperidine and frequently monitor for signs of respiratory depression and sedation. Meperidine is a substrate of CYP3A; odevixibat is a weak CYP3A inducer. Concomitant use can decrease meperidine exposure resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Methadone: (Moderate) Monitor for reduced efficacy of methadone and signs of opioid withdrawal if coadministration with odevixibat is necessary. Consider increasing the dose of methadone as needed. If odevixibat is discontinued, consider a dose reduction of methadone and frequently monitor for signs of respiratory depression and sedation. Methadone is a substrate of CYP3A, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; odevixibat is a weak CYP3A inducer. Concomitant use can decrease methadone exposure resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for decreased efficacy of nab-paclitaxel if coadministration with odevixibat is necessary due to the risk of decreased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A substrate and odevixibat is a weak CYP3A inducer.
Nanoparticle Albumin-Bound Sirolimus: (Moderate) Monitor for reduced sirolimus efficacy if sirolimus is coadministered with odevixibat. Concomitant use may decrease sirolimus exposure. Sirolimus is a CYP3A substrate and odevixibat is a weak CYP3A inducer.
Nimodipine: (Moderate) Monitor for decreased efficacy of nimodipine if coadministration with odevixibat is necessary as concomitant use may decrease plasma concentrations of nimodipine. Nimodipine is a CYP3A substrate and odevixibat is a weak CYP3A inducer.
Nirmatrelvir; Ritonavir: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of odevixibat is necessary. Concomitant use of nirmatrelvir and odevixibat may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and odevixibat is a weak CYP3A inducer. (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with odevixibat. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and odevixibat is a weak CYP3A inducer.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with odevixibat as concurrent use may decrease nisoldipine exposure and efficacy. Alternative antihypertensive therapy should be considered. Nisoldipine is a CYP3A substrate and odevixibat is a CYP3A inducer. Coadministration with a strong CYP3A inducer lowered nisoldipine plasma concentrations to undetectable levels.
Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with odevixibat is necessary; consider increasing the dose of oxycodone as needed. If odevixibat is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A substrate and odevixibat is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Paclitaxel: (Moderate) Monitor for decreased efficacy of paclitaxel if coadministration with odevixibat is necessary due to the risk of decreased plasma concentrations of paclitaxel. Paclitaxel is a CYP3A substrate and odevixibat is a weak CYP3A inducer.
Ritonavir: (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with odevixibat. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and odevixibat is a weak CYP3A inducer.
Sildenafil: (Moderate) Monitor for decreased efficacy of sildenafil if coadministration with odevixibat is necessary as concurrent use may decrease sildenafil exposure. Sildenafil is a sensitive CYP3A substrate and odevixibat is a weak CYP3A inducer. Population pharmacokinetic analysis indicates an approximately 3-fold increase in sildenafil clearance with concomitant use of weak CYP3A inducers.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of odevixibat. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and odevixibat is a weak CYP3A inducer.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if odevixibat must be administered. Monitor for reduced efficacy of sufentanil injection and signs of opioid withdrawal if coadministration with odevixibat is necessary; consider increasing the dose of sufentanil injection as needed. If odevixibat is discontinued, consider a dose reduction of sufentanil injection and frequently monitor for signs of respiratory depression and sedation. Sufentanil is a CYP3A substrate and odevixibat is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease sufentanil concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Tacrolimus: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with odevixibat is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; odevixibat is a weak CYP3A inducer.
Tramadol: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with odevixibat is necessary; consider increasing the dose of tramadol as needed. If odevixibat is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and odevixibat is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Tramadol; Acetaminophen: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with odevixibat is necessary; consider increasing the dose of tramadol as needed. If odevixibat is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and odevixibat is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Ubrogepant: (Major) Increase the initial and second dose of ubrogepant to 100 mg if coadministered with odevixibat as concurrent use may decrease ubrogepant exposure and reduce its efficacy. Ubrogepant is a CYP3A substrate; odevixibat is a weak CYP3A inducer.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with odevixibat is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. The R-enantiomer of warfarin is a CYP3A substrate and odevixibat is a weak CYP3A inducer. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Odevixibat is a reversible inhibitor of the ileal bile acid transporter (IBAT). The mechanism by which odevixibat improves pruritus in patients with progressive familial intrahepatic cholestasis or Alagille syndrome is not known; however, it may involve inhibition of the IBAT. Inhibition of the IBAT blocks the reabsorption of bile acids (primarily in the salt form) from the terminal ileum, interrupting enterohepatic circulation by shunting the bile acids away from the liver and towards fecal excretion which reduces the bile acid pool. Intrahepatic accumulation of bile acids can damage hepatic tissue and spill over into the systemic circulation.
Odevixibat is administered orally. It is more than 99% protein bound and is metabolized via mono-hydroxylation. After a single dose, odevixibat is primarily eliminated in the feces (83%, with 97% unchanged). Following a single dose of 7.2 mg odevixibat in healthy adults, the mean half-life was 2.4 hours.
Affected cytochrome P450 isoenzymes and drug transporters: P-gp
Odevixibat is a substrate of P-gp; however, clinically significant drug interactions are not expected.
-Route-Specific Pharmacokinetics
Oral Route
Odevixibat is minimally absorbed after oral administration. Following a single dose of odevixibat 7.2 mg in healthy adults, odevixibat Cmax is reached between 1 and 5 hours. Following a single oral dose of 7.2 mg odevixibat in healthy adults, the mean Cmax and AUC were 0.47 ng/mL and 2.2 ng x hour/mL, respectively. No accumulation of odevixibat was observed following once-daily dosing. The effect of food or sprinkling on soft food is not clinically significant. After sprinkling on applesauce, Cmax and AUC decreased 39% and 35%, respectively. Concomitant administration with a high-fat meal decreased Cmax and AUC 72% and 62%, respectively. Both administration techniques delayed Tmax from 3 hours to 4.5 hours compared to fasted conditions.
-Special Populations
Pediatrics
In pediatric patients with progressive familial intrahepatic cholestasis (PFIC), measurable odevixibat concentrations ranged from 0.06 to 0.72 ng/mL; in the majority of plasma samples, odevixibat concentrations were below the limit of quantification (0.05 ng/mL). In pediatric patients with Alagille syndrome (ALGS), measurable odevixibat concentrations ranged from 0.05 to 3.4 ng/mL.
In clinical trials in patients with PFIC, serum bile acid concentrations decreased within 4 to 8 weeks of treatment. These decreased concentrations fluctuated over time but were generally maintained over 24 weeks. The extent of decrease was similar between 40 and 120 mcg/kg doses. In clinical trials in patients with ALGS, serum bile acid concentrations were decreased as early as week 4 of treatment and the reduction was generally maintained over 24 weeks.