ODOMZO

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ODOMZO

Classes

Small Molecule Antineoplastic Hedgehog Pathway Inhibitors

Administration

Hazardous Drugs Classification
NIOSH (Draft) 2020 List: Table 2
Approved by FDA after NIOSH 2016 list published. The manufacturer recommends this drug be handled as a hazardous drug.
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
Emetic Risk
Minimal/Low
Administer prn antiemetics as necessary.

Oral Administration Oral Solid Formulations

Sonidegib should be taken on an empty stomach at least 1 hour before or 2 hours after a meal.
Swallow whole; do not crush or cut capsules.
If a dose is missed, skip the dose and take the dose the next day at the scheduled time.

Adverse Reactions
Severe

fatigue / Early / 4.0-4.0
elevated hepatic enzymes / Delayed / 4.0-4.0
hyperglycemia / Delayed / 4.0-4.0
muscle cramps / Delayed / 3.0-3.0
weight loss / Delayed / 3.0-3.0
lymphopenia / Delayed / 3.0-3.0
musculoskeletal pain / Early / 1.0-1.0
headache / Early / 1.0-1.0
anorexia / Delayed / 1.0-1.0
nausea / Early / 1.0-1.0
vomiting / Early / 1.0-1.0
diarrhea / Early / 1.0-1.0
hyperamylasemia / Delayed / 1.0-1.0
fetal death / Delayed / Incidence not known
teratogenesis / Delayed / Incidence not known

Moderate

anemia / Delayed / 32.0-32.0
growth inhibition / Delayed / Incidence not known

Mild

alopecia / Delayed / 53.0-53.0
dysgeusia / Early / 46.0-46.0
myalgia / Early / 19.0-19.0
abdominal pain / Early / 18.0-18.0
pruritus / Rapid / 10.0-10.0

Boxed Warning
Intrauterine fetal death, pregnancy

Advise pregnant women of the potential risk to a fetus. Report pregnancy to Sun Pharmaceutical Industries, Inc. at 1-800-406-7984. Based on its mechanism of action and data from animal studies, sonidegib can cause embryo/intrauterine fetal death or severe birth defects when administered to pregnant women; there are no available data on the use of sonidegib in pregnant women. In animal reproduction studies, sonidegib was embryotoxic, fetotoxic, and teratogenic at maternal exposures below the recommended human dose of 200 mg. Administration of sonidegib to pregnant rabbits resulted in abortion, complete resorption, or severe malformations (including midline defects, missing digits, vertebral, distal limb and digit malformations, severe craniofacial malformations, and other defects) at doses approximately 0.05-times the recommended human dose based on AUC. Skeletal variations were observed when maternal exposure to sonidegib was below the limit of detection.

Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

Counsel patients about the reproductive risk and contraception requirements during sonidegib treatment. Females should avoid pregnancy and use effective contraception during and for at least 20 months after treatment with sonidegib. Due to male-mediated teratogenicity, men with female partners should use condoms, even after a vasectomy, during treatment and for at least 8 months after the last dose; men should also not donate sperm for 8 months after the last dose of sonidegib. Females of reproductive potential should undergo pregnancy testing prior to initiation of sonidegib. Women who become pregnant while receiving sonidegib should be apprised of the potential hazard to the fetus. Sonidegib may cause infertility in female patients; amenorrhea was reported in pre-menopausal women in a clinical study that evaluated the use of sonidegib for the treatment of advanced basal cell carcinoma. In a study in female rats, sonidegib resulted in a reduced number of pregnancies, an increased number of early resorptions, and a decrease in the number of viable fetuses at exposures approximately 0.12 times the recommended human dose. Uterine and ovarian atrophy were observed in female rats at exposures >= 2 times the recommended human dose. No adverse effects on fertility were noted in male rats at exposures >= 4 times the recommended human dose.

Common Brand Names

ODOMZO

Dea Class

Rx

Description

Oral hedgehog pathway inhibitor
Approved for the treatment of locally advanced basal cell carcinoma that has recurred following surgery or radiation therapy or in patients who are not candidates for surgery or radiation
May cause embryo-fetal death or severe birth defects when administered to pregnant women; verify pregnancy status prior to starting therapy and advise male and female patients to use contraception during and after therapy

Dosage And Indications
For the treatment of locally advanced basal cell carcinoma that has recurred following surgery or radiation therapy or in patients who are not candidates for surgery or radiation therapy. Oral dosage Adults

200 mg orally once daily until disease progression or unacceptable toxicity. Take on an empty stomach at least 1 hour before or 2 hours after a meal. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy interruption or discontinuation may be necessary in patients who develop severe musculoskeletal toxicity. At a median follow-up of 38.2 months, the objective response rate (ORR), assessed by independent central review, was 56.1% in patients with locally advanced basal cell carcinoma (BCC) not amenable to radiotherapy or curative surgery (n = 66) and 7.7% in patients with metastatic BCC (n = 13) who received sonidegib 200 mg/day in a randomized, double-blind, phase II trial (the BOLT trial). This trial evaluated 2 sonidegib dosages: the approved dosage of 200 mg/day (n = 79) and 800 mg/day (n = 151); response and survival data are reported for patients who received sonidegib 200 mg/day. The durations of response in the locally advanced BCC and metastatic BCC arms were 26.1 months and 24 months, respectively. In patients with locally advanced BCC, the median progression-free survival (PFS) time was 22.1 months, the median overall survival (OS) time had not been reached, and the estimated 2-year OS rate was 93.2%. In patients with metastatic BCC, the median PFS time was 13.1 months, the median OS time had not been reached, and the estimated 2-year OS rate was 69.3%.

Dosing Considerations
Hepatic Impairment

A sonidegib dose adjustment is not necessary in patients with baseline mild hepatic impairment (total bilirubin level <= the upper limit of normal (ULN) and AST level > the ULN OR total bilirubin level of 1 to 1.5 times the ULN. Sonidegib has not been evaluated in patients with moderate or severe hepatic impairment.

Renal Impairment

A sonidegib dose adjustment is not necessary in patients with baseline renal impairment.

Drug Interactions

Adagrasib: (Major) Avoid coadministration of sonidegib with adagrasib due to increased plasma concentrations of sonidegib which may increase the risk of treatment-related adverse reactions. Sonidegib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased sonidegib exposure by 2.2-fold.
Amiodarone: (Major) Avoid the concomitant use of sonidegib and amiodarone; sonidegib exposure may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and amiodarone is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than14 days.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid the concomitant use of sonidegib and clarithromycin; sonidegib exposure may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Clarithromycin is a strong CYP3A4 inhibitor; sonidegib is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Apalutamide: (Major) Avoid the concomitant use of sonidegib and apalutamide; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the geometric mean Cmax and AUC of sonidegib by 54% and 72%, respectively.
Aprepitant, Fosaprepitant: (Major) Avoid the concomitant use of sonidegib and multi-day regimens of oral aprepitant; sonidegib levels may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. If concomitant use cannot be avoided, the manufacturer of sonidegib recommends administering the moderate CYP3A inhibitor for less than 14 days and monitoring patients closely for adverse reactions (e.g., elevated serum creatine kinase and serum creatinine levels). Because aprepitant is used intermittently, the significance of this model is unknown. Sonidegib is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor. When administered as a single oral or single intravenous dose, the inhibitory effect of aprepitant on CYP3A4 is weak and did not result in a clinically significant increase in the AUC of a sensitive substrate. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Armodafinil: (Major) Avoid the concomitant use of sonidegib and armodafinil; sonidegib levels may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and armodafinil is a CYP3A4 inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would decrease by 56% in cancer patients who received 14 days of sonidegib 200 mg/day with a moderate CYP3A inducer. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would decrease by 69% in cancer patients who received sonidegib 200 mg/day with a moderate CYP3A inducer for 4 months.
Atazanavir: (Major) Avoid concomitant use of sonidegib and atazanavir as increased sonidegib plasma are expected, resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Atazanavir is a strong CYP3A4 inhibitor and may significantly increase the level of the CYP3A4 substrate, sonidegib. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Atazanavir; Cobicistat: (Major) Avoid concomitant use of sonidegib and atazanavir as increased sonidegib plasma are expected, resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Atazanavir is a strong CYP3A4 inhibitor and may significantly increase the level of the CYP3A4 substrate, sonidegib. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively. (Major) Avoid concomitant use of sonidegib and cobicistat as increased sonidegib plasma are expected, resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Cobicistat is a strong CYP3A4 inhibitor and may significantly increase the level of the CYP3A4 substrate, sonidegib. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Berotralstat: (Major) Avoid the concomitant use of sonidegib and berotralstat as concurrent use may increase sonidegib exposure. If concomitant use is necessary, administer berotralstat for less than 14 days and monitor for an increased risk of sonidegib-related adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Bexarotene: (Major) Avoid the concomitant use of sonidegib and bexarotene; sonidegib levels may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and bexarotene is a CYP3A4 inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that a moderate CYP3A4 inducer would decrease the sonidegib AUC by 56% if administered for 14 days and by 69% if the moderate CYP3A inducer is administered for more than 14 days.
Bosentan: (Major) Avoid the concomitant use of sonidegib and bosentan; sonidegib levels may be decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that a moderate CYP3A4 inducer would decrease the sonidegib AUC by 56% if administered for 14 days and by 69% if the moderate CYP3A inducer is administered for more than 14 days.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Moderate) Based on population PK analysis, the concomitant administration of a histamine-2-receptor antagonist such as famotidine decreases the geometric mean sonidegib steady-state AUC (0-24 hours) value by 34%.
Carbamazepine: (Major) Avoid the concomitant use of sonidegib and carbamazepine; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the geometric mean Cmax and AUC of sonidegib by 54% and 72%, respectively.
Cenobamate: (Major) Avoid the concomitant use of sonidegib and cenobamate; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer for 14 days decreased the geometric mean AUC of sonidegib by 56%; coadministration with a moderate CYP3A4 inducer for 4 months decreased the sonidegib AUC by 69%.
Ceritinib: (Major) Avoid coadministration of sonidegib with ceritinib due to increased plasma concentrations of sonidegib which may increase the risk of treatment-related adverse reactions. Sonidegib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased sonidegib exposure by 2.2-fold.
Chloramphenicol: (Major) Avoid concomitant use of sonidegib and chloramphenicol as increased sonidegib plasma are expected, resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Chloramphenicol is a strong CYP3A4 inhibitor and may significantly increase the level of the CYP3A4 substrate, sonidegib. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Cimetidine: (Moderate) Use sonidegib and cimetidine together with caution; sonidegib levels and/or exposure may be altered. Cimetidine is a weak CYP3A4 inhibitor and may increase the level of the CYP3A4 substrate, sonidegib, resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Based on population PK analysis, the concomitant administration of a histamine-2-receptor antagonist such as cimetidine decreases the geometric mean sonidegib steady-state AUC (0-24 hours) value by 34%.
Ciprofloxacin: (Major) Avoid the concomitant use of sonidegib and ciprofloxacin; sonidegib exposure may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. If concomitant use cannot be avoided, administer ciprofloxacin for less than 14 days; monitor patients closely for adverse reactions (e.g., elevated serum creatine kinase and serum creatinine levels). Sonidegib is a CYP3A substrate and ciprofloxacin is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Clarithromycin: (Major) Avoid the concomitant use of sonidegib and clarithromycin; sonidegib exposure may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Clarithromycin is a strong CYP3A4 inhibitor; sonidegib is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Cobicistat: (Major) Avoid concomitant use of sonidegib and cobicistat as increased sonidegib plasma are expected, resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Cobicistat is a strong CYP3A4 inhibitor and may significantly increase the level of the CYP3A4 substrate, sonidegib. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Conivaptan: (Major) Avoid the concomitant use of sonidegib and conivaptan as concurrent use may increase sonidegib exposure. If concomitant use is necessary, administer conivaptan for less than 14 days and monitor for an increased risk of sonidegib-related adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A inhibitor would increase sonidegib overall exposure by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Crizotinib: (Major) Avoid coadministration of sonidegib with crizotinib due to increased plasma concentrations of sonidegib, with may result in increased adverse reactions including musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Cyclosporine: (Major) Avoid the concomitant use of sonidegib and cyclosporine; sonidegib exposure may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and cyclosporine is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Dabrafenib: (Major) Avoid the concomitant use of sonidegib and dabrafenib; sonidegib levels may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and dabrafenib is a moderate CYP3A4 inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that a moderate CYP3A4 inducer would decrease the sonidegib AUC by 56% if administered for 14 days and by 69% if the moderate CYP3A inducer is administered for more than 14 days.
Darunavir: (Major) Avoid concomitant use of sonidegib and darunavir as increased sonidegib plasma are expected, resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Darunavir is a strong CYP3A4 inhibitor and may significantly increase the level of the CYP3A4 substrate, sonidegib. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Darunavir; Cobicistat: (Major) Avoid concomitant use of sonidegib and cobicistat as increased sonidegib plasma are expected, resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Cobicistat is a strong CYP3A4 inhibitor and may significantly increase the level of the CYP3A4 substrate, sonidegib. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively. (Major) Avoid concomitant use of sonidegib and darunavir as increased sonidegib plasma are expected, resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Darunavir is a strong CYP3A4 inhibitor and may significantly increase the level of the CYP3A4 substrate, sonidegib. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid concomitant use of sonidegib and cobicistat as increased sonidegib plasma are expected, resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Cobicistat is a strong CYP3A4 inhibitor and may significantly increase the level of the CYP3A4 substrate, sonidegib. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively. (Major) Avoid concomitant use of sonidegib and darunavir as increased sonidegib plasma are expected, resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Darunavir is a strong CYP3A4 inhibitor and may significantly increase the level of the CYP3A4 substrate, sonidegib. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Deferasirox: (Major) Avoid the concomitant use of sonidegib and deferasirox; sonidegib levels may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate deferasirox is a CYP3A4 inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would decrease by 56% in cancer patients who received 14 days of sonidegib 200 mg/day with a moderate CYP3A inducer. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would decrease by 69% in cancer patients who received sonidegib 200 mg/day with a moderate CYP3A inducer for 4 months.
Delavirdine: (Major) Avoid concomitant use of sonidegib and delavirdine as increased sonidegib plasma are expected, resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Delavirdine is a strong CYP3A4 inhibitor and may significantly increase the level of the CYP3A4 substrate, sonidegib. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Diltiazem: (Major) Avoid the concomitant use of sonidegib and diltiazem; sonidegib exposure may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and diltiazem is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Dronedarone: (Major) Avoid the concomitant use of sonidegib and dronedarone; sonidegib levels may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and dronedarone is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Duvelisib: (Major) Avoid coadministration of sonidegib with duvelisib due to increased plasma concentrations of sonidegib, with may result in increased adverse reactions including musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and duvelisib is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Efavirenz: (Major) Avoid the concomitant use of sonidegib and efavirenz; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and efavirenz is a CYP3A4 inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that a moderate CYP3A4 inducer would decrease the sonidegib AUC by 56% if administered for 14 days and by 69% if the moderate CYP3A inducer is administered for more than 14 days.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid the concomitant use of sonidegib and efavirenz; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and efavirenz is a CYP3A4 inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that a moderate CYP3A4 inducer would decrease the sonidegib AUC by 56% if administered for 14 days and by 69% if the moderate CYP3A inducer is administered for more than 14 days.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid the concomitant use of sonidegib and efavirenz; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and efavirenz is a CYP3A4 inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that a moderate CYP3A4 inducer would decrease the sonidegib AUC by 56% if administered for 14 days and by 69% if the moderate CYP3A inducer is administered for more than 14 days.
Elagolix: (Major) Avoid the concomitant use of sonidegib and elagolix; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A substrate and elagolix is a moderate CYP3A inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that a moderate CYP3A inducer would decrease the sonidegib AUC by 56% if administered for 14 days and by 69% if the moderate CYP3A inducer is administered for more than 14 days.
Elagolix; Estradiol; Norethindrone acetate: (Major) Avoid the concomitant use of sonidegib and elagolix; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A substrate and elagolix is a moderate CYP3A inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that a moderate CYP3A inducer would decrease the sonidegib AUC by 56% if administered for 14 days and by 69% if the moderate CYP3A inducer is administered for more than 14 days.
Elbasvir; Grazoprevir: (Moderate) Administering sonidegib with elbasvir; grazoprevir may result in elevated sonidegib plasma concentrations. Sonidegib is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concomitant use of sonidegib and cobicistat as increased sonidegib plasma are expected, resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Cobicistat is a strong CYP3A4 inhibitor and may significantly increase the level of the CYP3A4 substrate, sonidegib. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of sonidegib and cobicistat as increased sonidegib plasma are expected, resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Cobicistat is a strong CYP3A4 inhibitor and may significantly increase the level of the CYP3A4 substrate, sonidegib. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Enzalutamide: (Major) Avoid the concomitant use of sonidegib and enzalutamide; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the geometric mean Cmax and AUC of sonidegib by 54% and 72%, respectively.
Erythromycin: (Major) Avoid the concomitant use of sonidegib and erythromycin; sonidegib exposure may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. If concomitant use cannot be avoided, administer erythromycin for less than 14 days; monitor patients closely for adverse reactions (e.g., elevated serum creatine kinase and serum creatinine levels). Sonidegib is a CYP3A substrate and erythromycin is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Eslicarbazepine: (Major) Avoid the concomitant use of sonidegib and eslicarbazepine; sonidegib levels may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and eslicarbazepine is a CYP3A4 inducer in vitro. Physiologic-based pharmacokinetics (PBPK) simulations indicate that a moderate CYP3A4 inducer would decrease the sonidegib AUC by 56% if administered for 14 days and by 69% if the moderate CYP3A inducer is administered for more than 14 days.
Etravirine: (Major) Avoid the concomitant use of sonidegib and etravirine; sonidegib levels may be decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and etravirine is a CYP3A4 inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that a moderate CYP3A4 inducer would decrease the sonidegib AUC by 56% if administered for 14 days and by 69% if the moderate CYP3A inducer is administered for more than 14 days.
Famotidine: (Moderate) Based on population PK analysis, the concomitant administration of a histamine-2-receptor antagonist such as famotidine decreases the geometric mean sonidegib steady-state AUC (0-24 hours) value by 34%.
Fedratinib: (Major) Avoid the concomitant use of sonidegib and fedratinib; sonidegib levels may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Fluconazole: (Major) Avoid the concomitant use of sonidegib and fluconazole; sonidegib exposure may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. If concomitant use cannot be avoided, administer fluconazole for less than 14 days; monitor patients closely for adverse reactions (e.g., elevated serum creatine kinase and serum creatinine levels). Sonidegib is a CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Fluvoxamine: (Major) Avoid the concomitant use of sonidegib and fluvoxamine; sonidegib exposure may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and fluvoxamine is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Fosamprenavir: (Major) Avoid the concomitant use of sonidegib and fosamprenavir as concurrent use may increase sonidegib exposure. Sonidegib is a CYP3A substrate and fosamprenavir is a moderate CYP3A inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Fosphenytoin: (Major) Avoid the concomitant use of sonidegib and fosphenytoin; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A substrate and phenytoin is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the geometric mean Cmax and AUC of sonidegib by 54% and 72%, respectively.
Grapefruit juice: (Major) Advise patients to avoid consuming grapefruit or grapefruit juice while receiving sonidegib as sonidegib levels may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and grapefruit juice is a strong CYP3A4 inhibitor.
Ibuprofen; Famotidine: (Moderate) Based on population PK analysis, the concomitant administration of a histamine-2-receptor antagonist such as famotidine decreases the geometric mean sonidegib steady-state AUC (0-24 hours) value by 34%.
Idelalisib: (Major) Avoid concomitant use of sonidegib and idelalisib as increased sonidegib plasma are expected, resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Idelalisib is a strong CYP3A4 inhibitor and may significantly increase the level of the CYP3A4 substrate, sonidegib. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Imatinib: (Major) Avoid the concomitant use of sonidegib and imatinib, STI-571; sonidegib levels may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and imatinib is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Indinavir: (Major) Avoid the concomitant use of sonidegib and indinavir; sonidegib levels may be significantly increased resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and indinavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Isavuconazonium: (Major) Avoid the concomitant use of sonidegib and isavuconazonium; sonidegib levels may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. If concomitant use cannot be avoided, administer isavuconazonium for less than 14 days; monitor patients closely for adverse reactions (e.g., elevated serum creatine kinase and serum creatinine levels). Sonidegib is a CYP3A4 substrate and isavuconazonium is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid the concomitant use of sonidegib and rifampin; sonidegib exposure was significantly decreased in healthy subjects who received rifampin and sonidegib compared with sonidegib only. Therefore, the efficacy of sonidegib may be reduced if these agents are administered together. Sonidegib is a CYP3A substrate and rifampin is a strong CYP3A4 inducer. The sonidegib geometric mean Cmax and AUC were decreased by 54% and 72%, respectively when coadministered with rifampin in a drug interaction study.
Isoniazid, INH; Rifampin: (Major) Avoid the concomitant use of sonidegib and rifampin; sonidegib exposure was significantly decreased in healthy subjects who received rifampin and sonidegib compared with sonidegib only. Therefore, the efficacy of sonidegib may be reduced if these agents are administered together. Sonidegib is a CYP3A substrate and rifampin is a strong CYP3A4 inducer. The sonidegib geometric mean Cmax and AUC were decreased by 54% and 72%, respectively when coadministered with rifampin in a drug interaction study.
Itraconazole: (Major) Avoid the concomitant use of sonidegib and itraconazole; sonidegib exposure may be significantly increased resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Ketoconazole: (Major) Avoid the concomitant use of sonidegib and ketoconazole; sonidegib exposure was significantly increased in healthy subjects who received ketoconazole and sonidegib compared with sonidegib only. This interaction may result in an increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid the concomitant use of sonidegib and clarithromycin; sonidegib exposure may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Clarithromycin is a strong CYP3A4 inhibitor; sonidegib is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Lefamulin: (Major) Avoid the concomitant use of sonidegib and oral lefamulin; sonidegib levels may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Lenacapavir: (Major) Avoid the concomitant use of sonidegib and lenacapavir as concurrent use may increase sonidegib exposure. If concomitant use is necessary, administer lenacapavir for less than 14 days and monitor for an increased risk of sonidegib-related adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and lenacapavir is a moderate CYP3A inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of sonidegib; monitor for potential reduction in efficacy. Sonidegib is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of sonidegib; monitor for potential reduction in efficacy. Sonidegib is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
Letermovir: (Major) Avoid concurrent use of sonidegib with letermovir, as taking these drugs together may increase sonidegib concentration and risk for adverse events. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Sonidegib is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days. Coadministration of a strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Levoketoconazole: (Major) Avoid the concomitant use of sonidegib and ketoconazole; sonidegib exposure was significantly increased in healthy subjects who received ketoconazole and sonidegib compared with sonidegib only. This interaction may result in an increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Lonafarnib: (Major) Avoid coadministration of sonidegib with lonafarnib due to increased plasma concentrations of sonidegib which may increase the risk of treatment-related adverse reactions. Sonidegib is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased sonidegib exposure by 2.2-fold.
Lopinavir; Ritonavir: (Major) Avoid coadministration of sonidegib with ritonavir due to increased plasma concentrations of sonidegib which may increase the risk of treatment-related adverse reactions. Sonidegib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased sonidegib exposure by 2.2-fold.
Lorlatinib: (Major) Avoid the concomitant use of sonidegib and lorlatinib; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer for 14 days decreased the geometric mean AUC of sonidegib by 56%; coadministration with a moderate CYP3A4 inducer for 4 months decreased the sonidegib AUC by 69%.
Lumacaftor; Ivacaftor: (Major) Avoid the concomitant use of sonidegib and lumacaftor; ivacaftor; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the geometric mean Cmax and AUC of sonidegib by 54% and 72%, respectively.
Lumacaftor; Ivacaftor: (Major) Avoid the concomitant use of sonidegib and lumacaftor; ivacaftor; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the geometric mean Cmax and AUC of sonidegib by 54% and 72%, respectively.
Mavacamten: (Major) Avoid the concomitant use of sonidegib and mavacamten; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A substrate and mavacamten is a moderate CYP3A inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that a moderate CYP3A inducer would decrease the sonidegib AUC by 56% if administered for 14 days and by 69% if the moderate CYP3A inducer is administered for more than 14 days.
Mifepristone: (Major) Avoid concomitant use of sonidegib and chronic use of mifepristone as increased sonidegib plasma are expected, resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown. Mifepristone is a strong CYP3A4 inhibitor and may significantly increase the level of the CYP3A4 substrate, sonidegib. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Mitotane: (Major) Avoid the concomitant use of mitotane with sonidegib due to decreased sonidegib exposure and possible decreases in efficacy. Mitotane is a strong CYP3A4 inducer and sonidegib is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of sonidegib. Coadministration of a strong CYP3A4 inducer decreased the geometric mean Cmax and AUC of sonidegib by 54% and 72%, respectively.
Modafinil: (Major) Avoid the concomitant use of sonidegib and modafinil; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that the coadministration of a moderate CYP3A4 inducer for 14 days would decrease the sonidegib AUC by 56% and by 69% if the moderate CYP3A inducer is coadministered for 4 months.
Nafcillin: (Major) Avoid the concomitant use of sonidegib and nafcillin; sonidegib levels may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer in vitro. Physiologic-based pharmacokinetics (PBPK) simulations indicate that a moderate CYP3A4 inducer would decrease the sonidegib AUC by 56% if administered for 14 days and by 69% if the moderate CYP3A inducer is administered for more than 14 days.
Nefazodone: (Major) Avoid the concomitant use of sonidegib and nefazodone; sonidegib exposure may be significantly increased resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Nelfinavir: (Major) Avoid the concomitant use of sonidegib and nelfinavir; sonidegib levels may be significantly increased resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and nelfinavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Netupitant, Fosnetupitant; Palonosetron: (Major) Avoid the concomitant use of sonidegib and netupitant; palonosetron as sonidegib levels may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. If concomitant use cannot be avoided, administer netupitant; palonosetron for less than 14 days; monitor patients closely for adverse reactions (e.g., elevated serum creatine kinase and serum creatinine levels). Sonidegib is a CYP3A4 substrate and netupitant is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Nilotinib: (Major) Avoid the concomitant use of sonidegib and nilotinib; sonidegib exposure may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and nilotinib is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Nirmatrelvir; Ritonavir: (Major) Avoid coadministration of sonidegib with ritonavir due to increased plasma concentrations of sonidegib which may increase the risk of treatment-related adverse reactions. Sonidegib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased sonidegib exposure by 2.2-fold.
Nizatidine: (Moderate) Based on population PK analysis, the concomitant administration of a histamine-2-receptor antagonist such as nizatidine decreases the geometric mean sonidegib steady-state AUC (0-24 hours) value by 34%.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid the concomitant use of sonidegib and rifabutin; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that a moderate CYP3A4 inducer would decrease the sonidegib AUC by 56% if administered for 14 days and by 69% if the moderate CYP3A inducer is administered for more than 14 days.
Oritavancin: (Moderate) Use caution with the concomitant use of sonidegib and oritavancin; sonidegib levels may be decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and oritavancin is a weak CYP3A4 inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would decrease by 56% in cancer patients who received 14 days of sonidegib 200 mg/day with a moderate CYP3A inducer. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would decrease by 69% in cancer patients who received sonidegib 200 mg/day with a moderate CYP3A inducer for 4 months.
Pexidartinib: (Major) Avoid the concomitant use of sonidegib and pexidartinib; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and pexidartinib is a moderate CYP3A4 inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that a moderate CYP3A4 inducer would decrease the sonidegib AUC by 56% if administered for 14 days and by 69% if the moderate CYP3A inducer is administered for more than 14 days.
Phenobarbital: (Major) Avoid the concomitant use of sonidegib and phenobarbital; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the geometric mean Cmax and AUC of sonidegib by 54% and 72%, respectively.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid the concomitant use of sonidegib and phenobarbital; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the geometric mean Cmax and AUC of sonidegib by 54% and 72%, respectively.
Phenytoin: (Major) Avoid the concomitant use of sonidegib and phenytoin; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the geometric mean Cmax and AUC of sonidegib by 54% and 72%, respectively.
Posaconazole: (Major) Avoid the concomitant use of sonidegib and posaconazole; sonidegib exposure may be significantly increased resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and posaconazole is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Primidone: (Major) Avoid the concomitant use of sonidegib and primidone; sonidegib levels may be decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and primidone is a CYP3A4 inducer. Primidone is metabolized to phenobarbital, a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the geometric mean Cmax and AUC of sonidegib by 54% and 72%, respectively.
Quinine: (Major) Avoid the concomitant use of sonidegib and quinine; sonidegib exposure may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. If concomitant use cannot be avoided, administer quinine for less than 14 days; monitor patients closely for adverse reactions (e.g., elevated serum creatine kinase and serum creatinine levels). Sonidegib is a CYP3A substrate and quinine is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Ranitidine: (Moderate) Based on population PK analysis, the concomitant administration of a histamine-2-receptor antagonist such as ranitidine decreases the geometric mean sonidegib steady-state AUC (0-24 hours) value by 34%.
Ribociclib: (Major) Avoid coadministration of sonidegib with ribociclib due to increased plasma concentrations of sonidegib which may increase the risk of treatment-related adverse reactions. Sonidegib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased sonidegib exposure by 2.2-fold.
Ribociclib; Letrozole: (Major) Avoid coadministration of sonidegib with ribociclib due to increased plasma concentrations of sonidegib which may increase the risk of treatment-related adverse reactions. Sonidegib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased sonidegib exposure by 2.2-fold.
Rifabutin: (Major) Avoid the concomitant use of sonidegib and rifabutin; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that a moderate CYP3A4 inducer would decrease the sonidegib AUC by 56% if administered for 14 days and by 69% if the moderate CYP3A inducer is administered for more than 14 days.
Rifampin: (Major) Avoid the concomitant use of sonidegib and rifampin; sonidegib exposure was significantly decreased in healthy subjects who received rifampin and sonidegib compared with sonidegib only. Therefore, the efficacy of sonidegib may be reduced if these agents are administered together. Sonidegib is a CYP3A substrate and rifampin is a strong CYP3A4 inducer. The sonidegib geometric mean Cmax and AUC were decreased by 54% and 72%, respectively when coadministered with rifampin in a drug interaction study.
Rifapentine: (Major) Avoid the concomitant use of sonidegib and rifapentine; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A substrate and rifapentine is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the geometric mean Cmax and AUC of sonidegib by 54% and 72%, respectively.
Ritlecitinib: (Major) Avoid the concomitant use of sonidegib and ritlecitinib as concurrent use may increase sonidegib exposure. If concomitant use is necessary, administer ritlecitinib for less than 14 days and monitor for an increased risk of sonidegib-related adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and ritlecitinib is a moderate CYP3A inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Ritonavir: (Major) Avoid coadministration of sonidegib with ritonavir due to increased plasma concentrations of sonidegib which may increase the risk of treatment-related adverse reactions. Sonidegib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased sonidegib exposure by 2.2-fold.
Saquinavir: (Major) Avoid coadministration of sonidegib with saquinavir due to increased plasma concentrations of sonidegib which may increase the risk of treatment-related adverse reactions. Sonidegib is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased sonidegib exposure by 2.2-fold.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Sotorasib: (Major) Avoid the concomitant use of sonidegib and sotorasib; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that a moderate CYP3A4 inducer would decrease the sonidegib AUC by 56% if administered for 14 days and by 69% if the moderate CYP3A inducer is administered for more than 14 days.
St. John's Wort, Hypericum perforatum: (Major) Avoid the concomitant use of sonidegib and St. John's Wort; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the geometric mean Cmax and AUC of sonidegib by 54% and 72%, respectively.
Tipranavir: (Major) Avoid concomitant use of sonidegib and tipranavir as increased sonidegib plasma are expected, resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Tipranavir is a strong CYP3A4 inhibitor and may significantly increase the level of the CYP3A4 substrate, sonidegib. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Trandolapril; Verapamil: (Major) Avoid the concomitant use of sonidegib and verapamil as sonidegib levels may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Tucatinib: (Major) Avoid coadministration of sonidegib with tucatinib due to increased plasma concentrations of sonidegib which may increase the risk of treatment-related adverse reactions. Sonidegib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased sonidegib exposure by 2.2-fold.
Verapamil: (Major) Avoid the concomitant use of sonidegib and verapamil as sonidegib levels may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid the concomitant use of sonidegib and clarithromycin; sonidegib exposure may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Clarithromycin is a strong CYP3A4 inhibitor; sonidegib is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Voriconazole: (Major) Avoid the concomitant use of sonidegib and voriconazole; sonidegib exposure may be significantly increased resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Voxelotor: (Major) Avoid the concomitant use of sonidegib and voxelotor as concurrent use may increase sonidegib exposure. If concomitant use is necessary, administer voxelotor for less than 14 days and monitor for an increased risk of sonidegib-related adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.

How Supplied

ODOMZO Oral Cap: 200mg

Maximum Dosage
Adults

200 mg/day PO.

Geriatric

200 mg/day PO.

Adolescents

Safety and efficacy not established.

Children

Safety and efficacy not established.

Infants

Safety and efficacy not established.

Neonates

Safety and efficacy not established.

Mechanism Of Action

Sonidegib is an inhibitor of smoothened (SMO), a transmembrane protein involved in Hedgehog (Hh) signal transduction, which is important in normal embryogenic growth and development, and becomes less active in adults. SMO is normally inhibited by another transmembrane protein, patched (PTCH1). Abnormal Hh signaling plays an important role in basal cell carcinoma.

Pharmacokinetics

Sonidegib is administered orally. It has an apparent volume of distribution of 9,166 liters and is highly bound to plasma protein (> 97%); it exhibits concentration independent protein binding. Sonidegib is primarily metabolized in the liver by the CYP450 isoenzyme, CYP3A; 36% of the total circulating components are the parent drug. The primary route of elimination for sonidegib and its metabolites is hepatic with about 70% and 30% of the absorbed dose recovered in the feces and urine, respectively. No unchanged sonidegib was detected in urine. The estimated elimination half-life is 28 days based on population pharmacokinetic modeling.
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A
Sonidegib is a CYP3A substrate. The concomitant use with strong or moderate CYP3A inhibitors or inducers should be avoided. In vitro, sonidegib inhibits CYP2B6 and CYP2C9 and is not an inducer of CYP1A2, CYP2B6 or CYP3A. Sonidegib inhibits the breast cancer resistance protein (BCRP) transporter in vitro; it does not inhibit P-glycoprotein, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT1 or OCT2.

Oral Route

Sonidegib has low oral bioavailablity; less than 10% of the oral dose is absorbed. Following a single sonidegib oral dose of 100 mg to 3,000 mg (under fasted conditions), the median time to peak plasma concentration (Tmax) was 2 to 4 hours in a pharmacokinetic analysis in patients with cancer. The mean steady-state Cmax was 1,030 nanograms (ng)/mL, Cmin was 890 ng/mL, and AUC(0-24hours) value was 22,000 ng x hour/mL following sonidegib 200 mg/day orally. At a dose range of 100 mg to 400 mg, dose-proportional increases in the Cmax and AUC were observed; however, less than dose-proportional increases occurred at sonidegib doses greater than 400 mg. After starting sonidegib therapy, steady-state levels are achieved at about 4 months; the estimated steady-state accumulation is 19-fold.
 
Effects of food: When sonidegib was administered with a high-fat meal (i.e., 1,000 calories with 50% of calories from fat), the geometric mean Cmax and AUC(0-inf) values were increased by 7.8- and 7.4-fold, respectively, compared with sonidegib given under fasting conditions. Therefore, sonidegib should be administered on an empty stomach.

Pregnancy And Lactation
Pregnancy

Counsel patients about the reproductive risk and contraception requirements during sonidegib treatment. Females should avoid pregnancy and use effective contraception during and for at least 20 months after treatment with sonidegib. Due to male-mediated teratogenicity, men with female partners should use condoms, even after a vasectomy, during treatment and for at least 8 months after the last dose; men should also not donate sperm for 8 months after the last dose of sonidegib. Females of reproductive potential should undergo pregnancy testing prior to initiation of sonidegib. Women who become pregnant while receiving sonidegib should be apprised of the potential hazard to the fetus. Sonidegib may cause infertility in female patients; amenorrhea was reported in pre-menopausal women in a clinical study that evaluated the use of sonidegib for the treatment of advanced basal cell carcinoma. In a study in female rats, sonidegib resulted in a reduced number of pregnancies, an increased number of early resorptions, and a decrease in the number of viable fetuses at exposures approximately 0.12 times the recommended human dose. Uterine and ovarian atrophy were observed in female rats at exposures >= 2 times the recommended human dose. No adverse effects on fertility were noted in male rats at exposures >= 4 times the recommended human dose.