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  • CLASSES

    Other Antineoplastic Agents

    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.

    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

    COMMON BRAND NAMES

    ODOMZO

    HOW SUPPLIED

    ODOMZO Oral Cap: 200mg

    DOSAGE & 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%.

    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.

    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.

    ADMINISTRATION

    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.

    STORAGE

    ODOMZO:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Rhabdomyolysis

    Musculoskeletal adverse reactions (e.g., muscle spasm, musculoskeletal pain, and myalgia) have been reported with sonidegib therapy in patients with basal cell carcinoma in a noncomparative, 2-cohort, phase II trial. Elevated serum creatine kinase (CK) levels frequently preceded symptoms; the median time to onset of grade 2 or higher serum CK levels was 12.9 weeks (range, 2 to 39 weeks) and the median time to resolution (grade 1 or less) was 12 days (95% CI, 8 to 14 days). Rhabdomyolysis has been reported rarely. Obtain baseline serum CK and serum creatinine(SCr) levels prior to starting sonidegib therapy, periodically during treatment, and as clinically indicated; monitor serum CK and SCr levels at least weekly in patients with musculoskeletal adverse reactions and an elevated CK level greater than 2.5 times upper limit of normal until clinical signs and symptoms resolve. Therapy interruption or discontinuation may be necessary in patients who develop musculoskeletal adverse reactions or elevated serum CK levels. Medical management of musculoskeletal toxicity has included IV hydration, magnesium supplementation, muscle relaxants, and analgesics or narcotics.

    Blood donation

    Blood donation during sonidegib therapy or up to 20 months after the last sonidegib dose is not recommended due to the risk of giving blood or blood products to women of reproductive potential.

    Geriatric

    There was a higher incidence of grade 3 and 4 adverse events and of adverse events requiring therapy interruption or discontinuation in geriatric patients aged 65 years or older compared with younger patients in a clinical study that evaluated the use of sonidegib 200 mg/day or 800 mg/day for the treatment of advanced basal cell carcinoma. In this study, 54% of patients were aged 65 years and older and 28% of patients were aged 75 years and older.

    Children, infants, neonates

    The safety and effectiveness of sonidegib have not been established in adolescents, children, infants, or neonates. Bone, teeth, reproductive tissue, and nerve abnormalities were observed in juvenile rats that received sonidegib doses approximately 1.2 times the recommended human dose in a 5-week study.

    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.

    Breast-feeding

    Due to a potential for serious adverse reactions in breast fed infants, nursing women should not breast feed during sonidegib therapy or up to 20 months after the last sonidegib dose. The effects of sonidegib on breast fed infants or on milk production are unknown. 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.

    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

    Moderate

    anemia / Delayed / 32.0-32.0

    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

    DRUG INTERACTIONS

    Alogliptin; Pioglitazone: (Moderate) Use caution with the concomitant use of sonidegib and pioglitazone; sonidegib levels may be decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and pioglitazone 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.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid concomitant use of sonidegib and clarithromycin as alterations in sonidegib plasma levels and/or exposure are expected. Clarithromycin is a strong CYP3A4 inhibitor and may significantly increase the level of the CYP3A4 substrate, sonidegib, resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. The sonidegib geometric mean Cmax and AUC (0-10 days) values were increased 2.2-fold and 1.5-fold, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 14 days of a strong CYP3A4 inhibitor. Physiologic-based pharmacokinetics simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would be increased to a similar extent in cancer patients who received 14 days of sonidegib 200 mg/day with a strong CYP3A inhibitor.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concomitant use of sonidegib and clarithromycin as alterations in sonidegib plasma levels and/or exposure are expected. Clarithromycin is a strong CYP3A4 inhibitor and may significantly increase the level of the CYP3A4 substrate, sonidegib, resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. The sonidegib geometric mean Cmax and AUC (0-10 days) values were increased 2.2-fold and 1.5-fold, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 14 days of a strong CYP3A4 inhibitor. Physiologic-based pharmacokinetics simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would be increased to a similar extent in cancer patients who received 14 days of sonidegib 200 mg/day with a strong CYP3A inhibitor.
    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. 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 and inducer and may increase plasma concentrations of solifenacin. 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. Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 1.8-fold in cancer patients who received 14 days of sonidegib 200 mg/day and a moderate CYP3A inhibitor. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 2.8-fold in cancer patients who received sonidegib 200 mg/day and a moderate CYP3A inhibitor for 4 months. The AUC of a single dose of another CYP3A4 substrate, midazolam, increased by 2.3-fold and 3.3-fold on days 1 and 5, respectively, when coadministered with a 5-day oral aprepitant regimen. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    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 the concomitant use of sonidegib and atazanavir; sonidegib exposure may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and atazanavir is a moderate CYP3A4 inhibitor. If concomitant use cannot be avoided, administer the moderate CYP3A inhibitor for less than 14 days; monitor patients closely for adverse reactions (e.g., elevated serum creatine kinase and serum creatinine levels). Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 1.8-fold in cancer patients who received 14 days of sonidegib 200 mg/day and a moderate CYP3A4 inhibitor. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 2.8-fold in cancer patients who received sonidegib 200 mg/day and a moderate CYP3A4 inhibitor for 4 months.
    Atazanavir; Cobicistat: (Major) Avoid the concomitant use of sonidegib and atazanavir; sonidegib exposure may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and atazanavir is a moderate CYP3A4 inhibitor. If concomitant use cannot be avoided, administer the moderate CYP3A inhibitor for less than 14 days; monitor patients closely for adverse reactions (e.g., elevated serum creatine kinase and serum creatinine levels). Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 1.8-fold in cancer patients who received 14 days of sonidegib 200 mg/day and a moderate CYP3A4 inhibitor. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 2.8-fold in cancer patients who received sonidegib 200 mg/day and a moderate CYP3A4 inhibitor for 4 months.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid the concomitant use of sonidegib and phenobarbital; sonidegib exposure may be significantly decreased and its efficacy reduced. Increased phenobarbital levels may also occur if these agents are taken together. Sonidegib is a CYP3A4 substrate and a CYP2C9 inhibitor in vitro and phenobarbital is a strong CYP3A4 inducer and a CYP2C9 substrate. The sonidegib geometric mean Cmax and AUC (0-10 days) values were decreased by 54% and 72%, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 5 days of a strong CYP3A4 inducer.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid the concomitant use of sonidegib and phenobarbital; sonidegib exposure may be significantly decreased and its efficacy reduced. Increased phenobarbital levels may also occur if these agents are taken together. Sonidegib is a CYP3A4 substrate and a CYP2C9 inhibitor in vitro and phenobarbital is a strong CYP3A4 inducer and a CYP2C9 substrate. The sonidegib geometric mean Cmax and AUC (0-10 days) values were decreased by 54% and 72%, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 5 days of a strong CYP3A4 inducer.
    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 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.
    Boceprevir: (Major) Avoid the concomitant use of sonidegib and boceprevir; sonidegib levels may be significantly increased resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and boceprevir is a strong CYP3A4 inhibitor. The sonidegib geometric mean Cmax and AUC (0-10 days) values were increased 2.2-fold and 1.5-fold, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 14 days of a strong CYP3A4 inhibitor. Physiologic-based pharmacokinetics simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would be increased to a similar extent in cancer patients who received 14 days of sonidegib 200 mg/day with a strong CYP3A inhibitor.
    Bosentan: (Major) Avoid the concomitant use of sonidegib and bosentan; sonidegib levels may be decreased and its efficacy reduced. Increased bosentan levels may also occur if these agents are taken together. Sonidegib is a CYP3A4 substrate and a CYP2C9 inhibitor in vitro and bosentan is an inducer and substrate of both CYP3A4 and CYP2C9. 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.
    Brigatinib: (Major) Avoid coadministration of brigatinib with sonidegib due to decreased plasma exposure to sonidegib which may result in decreased efficacy. Sonidegib is a CYP3A4 substrate and brigatinib is a CYP3A4 inducer in vitro. The geometric mean AUC and Cmax of sonidegib decreased by 72% and 54%, respectively, when coadministered with a strong CYP3A4 inducer. The geometric mean steady-state AUC decreased by 56% in cancer patients taking sonidegib with a moderate CYP3A inducer for 14 days, and decreased by 69% when coadministered with a moderate CYP3A inducer for 4 months. Brigatinib may also decrease sonidegib exposure.
    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. The sonidegib geometric mean Cmax and AUC (0-10 days) values were decreased by 54% and 72%, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 5 days of a strong CYP3A4 inducer.
    Ceritinib: (Major) Avoid coadministration of ceritinib with sonidegib due to increased sonidegib exposure. Ceritinib is a CYP3A4 inhibitor and sonidegib is primarily metabolized by CYP3A4. Because the strength of ceritinib inhibition of CYP3A4 is unknown, a specific recommendation for the safe use of ceritinib and sonidegib cannot be provided. The manufacturer of sonidegib provides the following recommendations for coadministration of strong and moderate CYP3A4 inhibitors: avoid coadministration of strong and moderate CYP3A4 inhibitors; if a moderate CYP3A4 must be used, limit the moderate inhibitor to 14 days and monitor closely for adverse reactions particularly musculoskeletal adverse reactions.
    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%.
    Clarithromycin: (Major) Avoid concomitant use of sonidegib and clarithromycin as alterations in sonidegib plasma levels and/or exposure are expected. Clarithromycin is a strong CYP3A4 inhibitor and may significantly increase the level of the CYP3A4 substrate, sonidegib, resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. The sonidegib geometric mean Cmax and AUC (0-10 days) values were increased 2.2-fold and 1.5-fold, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 14 days of a strong CYP3A4 inhibitor. Physiologic-based pharmacokinetics simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would be increased to a similar extent in cancer patients who received 14 days of sonidegib 200 mg/day with a strong CYP3A inhibitor.
    Clobazam: (Moderate) Use caution with the concomitant use of sonidegib and clobazam; sonidegib levels may be decreased and its efficacy reduced. Increased clobazam levels may also occur if these agents are taken together. Sonidegib is a CYP3A4 substrate and a CYP2B6 inhibitor in vitro and clobazam is a weak CYP3A4 inducer and CYP2B6 substrate. 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.
    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 CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor for 14 days increased the sonidegib AUC by 1.8-fold; coadministration for 4 months increased the AUC of sonidegib AUC by 2.8-fold.
    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 in vitro. 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.
    Darunavir: (Major) Avoid the concomitant use of sonidegib and darunavir; sonidegib levels may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and darunavir is a moderate CYP3A4 inhibitor. If concomitant use cannot be avoided, administer the moderate CYP3A inhibitor for less than 14 days; monitor patients closely for adverse reactions (e.g., elevated serum creatine kinase and serum creatinine levels). Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 1.8-fold in cancer patients who received 14 days of sonidegib 200 mg/day and a moderate CYP3A inhibitor. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 2.8-fold in cancer patients who received sonidegib 200 mg/day and a moderate CYP3A inhibitor for 4 months.
    Darunavir; Cobicistat: (Major) Avoid the concomitant use of sonidegib and darunavir; sonidegib levels may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and darunavir is a moderate CYP3A4 inhibitor. If concomitant use cannot be avoided, administer the moderate CYP3A inhibitor for less than 14 days; monitor patients closely for adverse reactions (e.g., elevated serum creatine kinase and serum creatinine levels). Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 1.8-fold in cancer patients who received 14 days of sonidegib 200 mg/day and a moderate CYP3A inhibitor. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 2.8-fold in cancer patients who received sonidegib 200 mg/day and a moderate CYP3A inhibitor for 4 months.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid the concomitant use of sonidegib and ritonavir or lopinavir; ritonavir as sonidegib levels may be significantly increased resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. The sonidegib geometric mean Cmax and AUC (0-10 days) values were increased 2.2-fold and 1.5-fold, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 14 days of a strong CYP3A4 inhibitor. Physiologic-based pharmacokinetics simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would be increased to a similar extent in cancer patients who received 14 days of sonidegib 200 mg/day with a strong CYP3A inhibitor.
    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.
    Dexamethasone: (Major) Avoid the concomitant use of sonidegib and dexamethasone; sonidegib levels may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and dexamethasone is a moderate 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.
    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. If concomitant use cannot be avoided, administer the moderate CYP3A inhibitor for less than 14 days; monitor patients closely for adverse reactions (e.g., elevated serum creatine kinase and serum creatinine levels). Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 1.8-fold in cancer patients who received 14 days of sonidegib 200 mg/day and a moderate CYP3A4 inhibitor. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 2.8-fold in cancer patients who received sonidegib 200 mg/day and a moderate CYP3A4 inhibitor for 4 months.
    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. If concomitant use cannot be avoided, administer the moderate CYP3A inhibitor for less than 14 days; monitor patients closely for adverse reactions (e.g., elevated serum creatine kinase and serum creatinine levels). Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 1.8-fold in cancer patients who received 14 days of sonidegib 200 mg/day and a moderate CYP3A inhibitor. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 2.8-fold in cancer patients who received sonidegib 200 mg/day and a moderate CYP3A inhibitor for 4 months.
    Efavirenz: (Major) Avoid the concomitant use of sonidegib and efavirenz; sonidegib exposure may be significantly decreased and its efficacy reduced. Increased efavirenz levels may also occur if these agents are taken together. Sonidegib is a CYP3A4 substrate and a CYP2B6 inhibitor in vitro and efavirenz is a CYP3A4 inducer and CYP2B6 substrate. 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 (i.e., efavirenz). 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 (i.e., efavirenz) for 4 months.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Avoid the concomitant use of sonidegib and efavirenz; sonidegib exposure may be significantly decreased and its efficacy reduced. Increased efavirenz levels may also occur if these agents are taken together. Sonidegib is a CYP3A4 substrate and a CYP2B6 inhibitor in vitro and efavirenz is a CYP3A4 inducer and CYP2B6 substrate. 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 (i.e., efavirenz). 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 (i.e., efavirenz) for 4 months.
    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.
    Enzalutamide: (Major) Avoid coadministration of sonidegib with enzalutamide due to decreased plasma concentrations of sonidegib. Sonidegib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased sonidegib exposure by 72%.
    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. Sonidegib is a CYP3A substrate and erythromycin is a moderate CYP3A4 inhibitor. If concomitant use cannot be avoided, administer the moderate CYP3A inhibitor for less than 14 days; monitor patients closely for adverse reactions (e.g., elevated serum creatine kinase and serum creatinine levels). Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 1.8-fold in cancer patients who received 14 days of sonidegib 200 mg/day and a moderate CYP3A4 inhibitor (i.e., erythromycin). Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 2.8-fold in cancer patients who received sonidegib 200 mg/day and a moderate CYP3A4 inhibitor (i.e., erythromycin) for 4 months.
    Erythromycin; Sulfisoxazole: (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. Sonidegib is a CYP3A substrate and erythromycin is a moderate CYP3A4 inhibitor. If concomitant use cannot be avoided, administer the moderate CYP3A inhibitor for less than 14 days; monitor patients closely for adverse reactions (e.g., elevated serum creatine kinase and serum creatinine levels). Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 1.8-fold in cancer patients who received 14 days of sonidegib 200 mg/day and a moderate CYP3A4 inhibitor (i.e., erythromycin). Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 2.8-fold in cancer patients who received sonidegib 200 mg/day and a moderate CYP3A4 inhibitor (i.e., erythromycin) for 4 months.
    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 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.
    Etravirine: (Major) Avoid the concomitant use of sonidegib and etravirine; sonidegib levels may be decreased and its efficacy reduced. Increased etravirine levels may also occur if these agents are taken together. Sonidegib is a CYP3A4 substrate and a CYP2C9 inhibitor in vitro and etravirine is a CYP3A4 inducer and substrate and a CYP2C9 substrate. 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.
    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%.
    Famotidine; Ibuprofen: (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%.
    Felbamate: (Major) Avoid the concomitant use of sonidegib and felbamate; sonidegib levels may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and felbamate is a CYP3A4 inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24hours) 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.
    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. Sonidegib is a CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor. If concomitant use cannot be avoided, administer the moderate CYP3A inhibitor for less than 14 days; monitor patients closely for adverse reactions (e.g., elevated serum creatine kinase and serum creatinine levels). Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 1.8-fold in cancer patients who received 14 days of sonidegib 200 mg/day and a moderate CYP3A inhibitor. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 2.8-fold in cancer patients who received sonidegib 200 mg/day and a moderate CYP3A inhibitor for 4 months.
    Fosamprenavir: (Major) Avoid the concomitant use of sonidegib and fosamprenavir; sonidegib levels may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Increased fosamprenavir levels may also occur if these agents are taken together. Sonidegib is a CYP3A4 substrate and a CYP2C9 inhibitor in vitro and fosamprenavir is a moderate CYP3A4 inhibitor and a CYP2C9 substrate. If concomitant use cannot be avoided, administer the moderate CYP3A inhibitor for less than 14 days; monitor patients closely for adverse reactions (e.g., elevated serum creatine kinase and serum creatinine levels). Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 1.8-fold in cancer patients who received 14 days of sonidegib 200 mg/day and a moderate CYP3A inhibitor. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 2.8-fold in cancer patients who received sonidegib 200 mg/day and a moderate CYP3A inhibitor for 4 months.
    Fosphenytoin: (Major) Avoid the concomitant use of sonidegib and phenytoin or fosphenytoin; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A substrate and phenytoin is a strong CYP3A4 inducer. The sonidegib geometric mean Cmax and AUC (0-10 days) values were decreased by 54% and 72%, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 5 days of a strong CYP3A4 inducer.
    Glimepiride; Pioglitazone: (Moderate) Use caution with the concomitant use of sonidegib and pioglitazone; sonidegib levels may be decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and pioglitazone 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.
    Grapefruit juice: (Major) Avoid concomitant use of sonidegib and grapefruit juice 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 moderate CYP3A4 inhibitor.
    Griseofulvin: (Major) Avoid the concomitant use of sonidegib and griseofulvin; sonidegib levels may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and griseofulvin is a CYP3A4 inducer in vitro. 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.
    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. Increased imatinib levels may also occur if these agents are taken together. Sonidegib is a CYP3A4 substrate and a CYP2C9 inhibitor in vitro and imatinib is a moderate CYP3A4 inhibitor and a CYP2C9 substrate. If concomitant use cannot be avoided, administer the moderate CYP3A inhibitor for less than 14 days; monitor patients closely for adverse reactions (e.g., elevated serum creatine kinase and serum creatinine levels). Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 1.8-fold in cancer patients who received 14 days of sonidegib 200 mg/day and a moderate CYP3A inhibitor. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 2.8-fold in cancer patients who received sonidegib 200 mg/day and a moderate CYP3A inhibitor for 4 months.
    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. The sonidegib geometric mean Cmax and AUC (0-10 days) values were increased 2.2-fold and 1.5-fold, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 14 days of a strong CYP3A4 inhibitor. Physiologic-based pharmacokinetics simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would be increased to a similar extent in cancer patients who received 14 days of sonidegib 200 mg/day with a strong CYP3A inhibitor.
    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. Sonidegib is a CYP3A4 substrate and isavuconazonium is a moderate CYP3A4 inhibitor. If concomitant use cannot be avoided, administer the moderate CYP3A inhibitor for less than 14 days; monitor patients closely for adverse reactions (e.g., elevated serum creatine kinase and serum creatinine levels). Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 1.8-fold in cancer patients who received 14 days of sonidegib 200 mg/day and a moderate CYP3A inhibitor. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 2.8-fold in cancer patients who received sonidegib 200 mg/day and a moderate CYP3A inhibitor for 4 months.
    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 (0-10 days) values were decreased by 54% and 72%, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 14 days of rifampin 600 mg daily (n = 16) compared with healthy subjects who received a single dose of sonidegib only (n = 16).
    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 (0-10 days) values were decreased by 54% and 72%, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 14 days of rifampin 600 mg daily (n = 16) compared with healthy subjects who received a single dose of sonidegib only (n = 16).
    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. The sonidegib geometric mean Cmax and AUC (0-10 days) values were increased 2.2-fold and 1.5-fold, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 14 days of a strong CYP3A inhibitor. Physiologic-based pharmacokinetics simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would be increased to a similar extent in cancer patients who received 14 days of sonidegib 200 mg/day with a strong CYP3A4 inhibitor.
    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. The sonidegib geometric mean Cmax and AUC (0-10 days) values were increased 2.2-fold and 1.5-fold, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 14 days of ketoconazole 200 mg twice daily (n = 15) compared with healthy subjects who received a single dose of sonidegib only (n = 16). Physiologic-based pharmacokinetics simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would be increased to a similar extent in cancer patients who received 14 days of sonidegib 200 mg/day with a strong CYP3A4 inhibitor.
    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.
    Lopinavir; Ritonavir: (Major) Avoid the concomitant use of sonidegib and ritonavir or lopinavir; ritonavir as sonidegib levels may be significantly increased resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. The sonidegib geometric mean Cmax and AUC (0-10 days) values were increased 2.2-fold and 1.5-fold, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 14 days of a strong CYP3A4 inhibitor. Physiologic-based pharmacokinetics simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would be increased to a similar extent in cancer patients who received 14 days of sonidegib 200 mg/day with a strong CYP3A inhibitor. (Major) Avoid the concomitant use of sonidegib and ritonavir or lopinavir; ritonavir as sonidegib levels may be significantly increased resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. The sonidegib geometric mean Cmax and AUC (0-10 days) values were increased 2.2-fold and 1.5-fold, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 14 days of a strong CYP3A4 inhibitor. Physiologic-based pharmacokinetics simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would be increased to a similar extent in cancer patients who received 14 days of sonidegib 200 mg/day with a strong CYP3A inhibitor.
    Metformin; Pioglitazone: (Moderate) Use caution with the concomitant use of sonidegib and pioglitazone; sonidegib levels may be decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and pioglitazone 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.
    Metyrapone: (Major) Avoid the concomitant use of sonidegib and metyrapone; sonidegib levels may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and metyrapone 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.
    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. The sonidegib geometric mean Cmax and AUC (0-10 days) values were decreased by 54% and 72%, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 14 days of another strong CYP3A inducer (rifampin 600 mg daily) (n = 16) compared with healthy subjects who received a single dose of sonidegib only (n = 16).
    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 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.
    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 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 (0-24hours) would decrease by 69% in cancer patients who received sonidegib 200 mg/day with a moderate CYP3A inducer for 4 months.
    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. The sonidegib geometric mean Cmax and AUC (0-10 days) values were increased 2.2-fold and 1.5-fold, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 14 days of a strong CYP3A4 inhibitor. Physiologic-based pharmacokinetics simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would be increased to a similar extent in cancer patients who received 14 days of sonidegib 200 mg/day with a strong CYP3A4 inhibitor.
    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. The sonidegib geometric mean Cmax and AUC (0-10 days) values were increased 2.2-fold and 1.5-fold, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 14 days of a strong CYP3A4 inhibitor. Physiologic-based pharmacokinetics simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would be increased to a similar extent in cancer patients who received 14 days of sonidegib 200 mg/day with a strong CYP3A inhibitor.
    Netupitant; 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. Sonidegib is a CYP3A4 substrate and netupitant; palonosetron is a moderate CYP3A4 inhibitor. If concomitant use cannot be avoided, administer the moderate CYP3A inhibitor for less than 14 days; monitor patients closely for adverse reactions (e.g., elevated serum creatine kinase and serum creatinine levels). Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 1.8-fold in cancer patients who received 14 days of sonidegib 200 mg/day and a moderate CYP3A inhibitor. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 2.8-fold in cancer patients who received sonidegib 200 mg/day and a moderate CYP3A inhibitor for 4 months.
    Nevirapine: (Major) Avoid the concomitant use of sonidegib and nevirapine; sonidegib levels may be decreased and its efficacy reduced. Increased nevirapine levels may also occur if these agents are taken together. Sonidegib is a CYP3A4 substrate and a CYP2B6 inhibitor in vitro and nevirapine is a CYP3A4 inducer and CYP2B6 substrate. 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.
    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%.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid the concomitant use of sonidegib and ritonavir or lopinavir; ritonavir as sonidegib levels may be significantly increased resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. The sonidegib geometric mean Cmax and AUC (0-10 days) values were increased 2.2-fold and 1.5-fold, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 14 days of a strong CYP3A4 inhibitor. Physiologic-based pharmacokinetics simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would be increased to a similar extent in cancer patients who received 14 days of sonidegib 200 mg/day with a strong CYP3A inhibitor.
    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.
    Oxcarbazepine: (Major) Avoid the concomitant use of sonidegib and oxcarbazepine; sonidegib levels may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and oxcarbazepine 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.
    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. Sonidegib is a CYP3A4 substrate and netupitant; palonosetron is a moderate CYP3A4 inhibitor. If concomitant use cannot be avoided, administer the moderate CYP3A inhibitor for less than 14 days; monitor patients closely for adverse reactions (e.g., elevated serum creatine kinase and serum creatinine levels). Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 1.8-fold in cancer patients who received 14 days of sonidegib 200 mg/day and a moderate CYP3A inhibitor. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 2.8-fold in cancer patients who received sonidegib 200 mg/day and a moderate CYP3A inhibitor for 4 months.
    Phenobarbital: (Major) Avoid the concomitant use of sonidegib and phenobarbital; sonidegib exposure may be significantly decreased and its efficacy reduced. Increased phenobarbital levels may also occur if these agents are taken together. Sonidegib is a CYP3A4 substrate and a CYP2C9 inhibitor in vitro and phenobarbital is a strong CYP3A4 inducer and a CYP2C9 substrate. The sonidegib geometric mean Cmax and AUC (0-10 days) values were decreased by 54% and 72%, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 5 days of a strong CYP3A4 inducer.
    Phenytoin: (Major) Avoid the concomitant use of sonidegib and phenytoin or fosphenytoin; sonidegib exposure may be significantly decreased and its efficacy reduced. Increased phenytoin levels may also occur if these agents are taken together. Sonidegib is a CYP3A4 substrate and a CYP2C9 inhibitor in vitro and phenytoin is a strong CYP3A4 inducer and a CYP2C9 substrate. The sonidegib geometric mean Cmax and AUC (0-10 days) values were decreased by 54% and 72%, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 5 days of a strong CYP3A4 inducer.
    Pioglitazone: (Moderate) Use caution with the concomitant use of sonidegib and pioglitazone; sonidegib levels may be decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and pioglitazone 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.
    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. The sonidegib geometric mean Cmax and AUC (0-10 days) values were increased 2.2-fold and 1.5-fold, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 14 days of a strong CYP3A4 inhibitor. Physiologic-based pharmacokinetics simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would be increased to a similar extent in cancer patients who received 14 days of sonidegib 200 mg/day with a strong CYP3A4 inhibitor.
    Primidone: (Major) Avoid the concomitant use of sonidegib and primidone; sonidegib levels may be decreased and its efficacy reduced. Increased primidone levels may also occur if these agents are taken together. Sonidegib is a CYP3A4 substrate and a CYP2C9 inhibitor in vitro and primidone is a CYP3A4 inducer and CYP2C9 substrate. Up to 25% of primidone is metabolized to phenobarbital, a strong CYP3A4 inducer. The sonidegib geometric mean Cmax and AUC (0-10 days) values were decreased by 54% and 72%, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 5 days of a strong CYP3A4 inducer.
    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 the concomitant use of sonidegib and ribociclib; sonidegib exposure may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Ribociclib is a CYP3A4 inhibitor in vitro at clinically relevant concentrations and sonidegib is a CYP3A4 substrate. Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC would increase 1.8-fold in cancer patients who received 14 days of sonidegib in combination with a moderate CYP3A inhibitor. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC would increase 2.8-fold in cancer patients who received sonidegib in combination with a moderate CYP3A inhibitor for 4 months.
    Ribociclib; Letrozole: (Major) Avoid the concomitant use of sonidegib and ribociclib; sonidegib exposure may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Ribociclib is a CYP3A4 inhibitor in vitro at clinically relevant concentrations and sonidegib is a CYP3A4 substrate. Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC would increase 1.8-fold in cancer patients who received 14 days of sonidegib in combination with a moderate CYP3A inhibitor. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC would increase 2.8-fold in cancer patients who received sonidegib in combination with a moderate CYP3A inhibitor for 4 months.
    Rifabutin: (Major) Avoid the concomitant use of sonidegib and rifabutin; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A substrate and rifabutin is a strong CYP3A4 inducer. The sonidegib geometric mean Cmax and AUC (0-10 days) values were decreased by 54% and 72%, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 14 days of a strong CYP3A4 inducer.
    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 (0-10 days) values were decreased by 54% and 72%, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 14 days of rifampin 600 mg daily (n = 16) compared with healthy subjects who received a single dose of sonidegib only (n = 16).
    Rifapentine: (Major) Avoid the concomitant use of sonidegib and rifapentine; sonidegib levels may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. The sonidegib geometric mean Cmax and AUC (0-10 days) values were decreased by 54% and 72%, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 5 days of a strong CYP3A4 inducer.
    Rifaximin: (Major) Avoid the concomitant use of sonidegib and rifaximin; sonidegib levels may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and rifaximin is a CYP3A4 inducer in vitro. When given at the recommended dosage, rifaximin is not expected to induce the CYP3A4 isoenzyme in patients with normal liver function; however, it is not known whether rifaximin may induce metabolism of CYP3A4 substrates in patients with reduced hepatic function who may have elevated rifaximin concentrations. Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24hours) 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.
    Ritonavir: (Major) Avoid the concomitant use of sonidegib and ritonavir or lopinavir; ritonavir as sonidegib levels may be significantly increased resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. The sonidegib geometric mean Cmax and AUC (0-10 days) values were increased 2.2-fold and 1.5-fold, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 14 days of a strong CYP3A4 inhibitor. Physiologic-based pharmacokinetics simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would be increased to a similar extent in cancer patients who received 14 days of sonidegib 200 mg/day with a strong CYP3A inhibitor.
    Saquinavir: (Major) Avoid the concomitant use of sonidegib and saquinavir; sonidegib exposure may be significantly increased resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and saquinavir is a strong CYP3A4 inhibitor. The sonidegib geometric mean Cmax and AUC (0-10 days) values were increased 2.2-fold and 1.5-fold, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 14 days of a strong CYP3A4 inhibitor. Physiologic-based pharmacokinetics simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would be increased to a similar extent in cancer patients who received 14 days of sonidegib 200 mg/day with a strong CYP3A4 inhibitor.
    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. The sonidegib geometric mean Cmax and AUC (0-10 days) values were decreased by 54% and 72%, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 5 days of a strong CYP3A4 inducer.
    Telaprevir: (Major) Avoid the concomitant use of sonidegib and telaprevir; sonidegib levels may be significantly increased resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and telaprevir is a strong CYP3A4 inhibitor. The sonidegib geometric mean Cmax and AUC (0-10 days) values were increased 2.2-fold and 1.5-fold, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 14 days of a strong CYP3A4 inhibitor. Physiologic-based pharmacokinetics simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would be increased to a similar extent in cancer patients who received 14 days of sonidegib 200 mg/day with a strong CYP3A inhibitor.
    Telithromycin: (Major) Avoid the concomitant use of sonidegib and telithromycin; sonidegib exposure may be significantly increased resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and telithromycin is a strong CYP3A4 inhibitor. The sonidegib geometric mean Cmax and AUC (0-10 days) values were increased 2.2-fold and 1.5-fold, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 14 days of a strong CYP3A4 inhibitor. Physiologic-based pharmacokinetics simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would be increased to a similar extent in cancer patients who received 14 days of sonidegib 200 mg/day with a strong CYP3A4 inhibitor.
    Telotristat Ethyl: (Major) Avoid coadministration of telotristat ethyl with sonidegib, as the systemic exposure of sonidegib may be decreased resulting in reduced efficacy. Sonidegib is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when co-administered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. Exposure to sonidegib (AUC) decreased by 56% in cancer patients when coadministered with a moderate CYP3A inducer for 14 days, and by 69% when coadministered with a moderate CYP3A inducer for 4 months.
    Trandolapril; Verapamil: (Major) Avoid the concomitant use of sonidegib and verapamil or trandolapril; verapamil as sonidegib levels may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Increased verapamil levels may also occur if these agents are taken together. Sonidegib is a CYP3A4 substrate and a CYP2C9 inhibitor in vitro and verapamil is a moderate CYP3A4 inhibitor and a CYP2C9 substrate. If concomitant use cannot be avoided, administer the moderate CYP3A inhibitor for less than 14 days; monitor patients closely for adverse reactions (e.g., elevated serum creatine kinase and serum creatinine levels). Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 1.8-fold in cancer patients who received 14 days of sonidegib 200 mg/day and a moderate CYP3A inhibitor. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 2.8-fold in cancer patients who received sonidegib 200 mg/day and a moderate CYP3A inhibitor for 4 months.
    Verapamil: (Major) Avoid the concomitant use of sonidegib and verapamil or trandolapril; verapamil as sonidegib levels may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Increased verapamil levels may also occur if these agents are taken together. Sonidegib is a CYP3A4 substrate and a CYP2C9 inhibitor in vitro and verapamil is a moderate CYP3A4 inhibitor and a CYP2C9 substrate. If concomitant use cannot be avoided, administer the moderate CYP3A inhibitor for less than 14 days; monitor patients closely for adverse reactions (e.g., elevated serum creatine kinase and serum creatinine levels). Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 1.8-fold in cancer patients who received 14 days of sonidegib 200 mg/day and a moderate CYP3A inhibitor. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 2.8-fold in cancer patients who received sonidegib 200 mg/day and a moderate CYP3A inhibitor for 4 months.
    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. Increased voriconazole levels may also occur if these agents are taken together. Sonidegib is a CYP3A4 substrate and a CYP2C9 inhibitor in vitro and voriconazole is a strong CYP3A4 inhibitor and a CYP2C9 substrate. The sonidegib geometric mean Cmax and AUC (0-10 days) values were increased 2.2-fold and 1.5-fold, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 14 days of a strong CYP3A4 inhibitor. Physiologic-based pharmacokinetics simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would be increased to a similar extent in cancer patients who received 14 days of sonidegib 200 mg/day with a strong CYP3A4 inhibitor.

    PREGNANCY AND LACTATION

    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.

    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.