2.1 Important Safety Information

Verify the pregnancy status of females of reproductive potential prior to initiating ODOMZO [see Use in Specific Populations (8.1, 8.3)].

2.2 Recommended Dosage

The recommended dosage of ODOMZO is 200 mg taken orally once daily on an empty stomach, at least 1 hour before or 2 hours after a meal, administered until disease progression or unacceptable toxicity [see Clinical Pharmacology (12.3)].

Obtain serum creatine kinase (CK) levels and renal function tests prior to initiating ODOMZO in all patients [see Dosage and Administration (2.2) and Warnings and Precautions (5.2)].

If a dose of ODOMZO is missed, resume dosing with the next scheduled dose.

2.3 Dosage Modifications for Adverse Reactions

Interrupt ODOMZO for

• Severe or intolerable musculoskeletal adverse reactions.
• First occurrence of serum CK elevation between 2.5 and 10 times upper limit of normal (ULN).
• Recurrent serum CK elevation between 2.5 and 5 times ULN.

Resume ODOMZO at 200 mg daily upon resolution of clinical signs and symptoms.

Permanently discontinue ODOMZO for

• Serum CK elevation greater than 2.5 times ULN with worsening renal function.
• Serum CK elevation greater than 10 times ULN.
• Recurrent serum CK elevation greater than 5 times ULN.
• Recurrent severe or intolerable musculoskeletal adverse reactions.

5.1 Embryo-Fetal Toxicity

ODOMZO can cause embryo-fetal death or severe birth defects when administered to a pregnant woman. In animal reproduction studies, sonidegib was embryotoxic, fetotoxic, and teratogenic at maternal exposures below the recommended human dose of 200 mg [see Use in Specific Populations (8.1)].

Females of Reproductive Potential

Verify pregnancy status of females of reproductive potential prior to initiating ODOMZO treatment. Advise pregnant women of the potential risk to a fetus. Advise females to use effective contraception during treatment with ODOMZO and for at least 20 months after the last dose [see Use in Specific Populations (8.3)].

Males

Advise male patients with female partners to use condoms, even after a vasectomy, during treatment with ODOMZO and for at least 8 months after the last dose to avoid potential drug exposure in pregnant females or females of reproductive potential [see Use in Specific Populations (8.3)].

Blood Donation

Advise patients not to donate blood or blood products while taking ODOMZO and for at least 20 months after the last dose of ODOMZO, because their blood or blood products might be given to a female of reproductive potential.

5.2 Musculoskeletal Adverse Reactions

Musculoskeletal adverse reactions, which may be accompanied by serum creatine kinase (CK) elevations, occur with ODOMZO and other drugs which inhibit the hedgehog (Hh) pathway.

In a pooled safety analysis of 12 clinical studies involving 571 patients with various advanced cancers treated with ODOMZO at doses ranging from 100 mg to 3000 mg, rhabdomyolysis (defined as serum CK increase of more than ten times the baseline value with a concurrent 1.5-fold or greater increase in serum creatinine above baseline value) occurred in one patient (0.2%) treated with ODOMZO 800 mg.

In the BOLT study, musculoskeletal adverse reactions occurred in 68% (54/79) of patients treated with ODOMZO 200 mg daily with 9% (7/79) reported as Grade 3 or 4. The most frequent manifestations of musculoskeletal adverse reactions reported as an adverse event were muscle spasms (54%), musculoskeletal pain (32%), and myalgia (19%). Increased serum CK laboratory values occurred in 61% (48/79) of patients with 8% (6/79) of patients having Grade 3 or 4 serum CK elevations. Musculoskeletal pain and myalgia usually preceded serum CK elevation. Among patients with Grade 2 or higher CK elevations, the median time to onset was 12.9 weeks (range: 2 to 39 weeks) and the median time to resolution (to ≤ Grade 1) was 12 days (95% CI: 8 to 14 days). ODOMZO was temporarily interrupted in 8% of patients or permanently discontinued in 8% of patients for musculoskeletal adverse reactions. The incidence of musculoskeletal adverse reactions requiring medical intervention (magnesium supplementation, muscle relaxants, and analgesics or narcotics) was 29%, including four patients (5%) who received intravenous hydration or were hospitalized.

Obtain baseline serum CK and creatinine levels prior to initiating ODOMZO, periodically during treatment, and as clinically indicated (e.g., if muscle symptoms are reported). Obtain serum creatinine and CK levels at least weekly in patients with musculoskeletal adverse reactions with concurrent serum CK elevation greater than 2.5 times ULN until resolution of clinical signs and symptoms. Depending on the severity of symptoms, temporary dose interruption or discontinuation may be required for musculoskeletal adverse reactions or serum CK elevation [see Dosage and Administration (2.2)]. Advise patients starting therapy with ODOMZO of the risk of muscle-related adverse reactions. Advise patients to report promptly any new unexplained muscle pain, tenderness or weakness occurring during treatment or that persists after discontinuing ODOMZO.

5.3 Premature Fusion of the Epiphyses

Premature fusion of the epiphyses has been reported in pediatric patients exposed to ODOMZO and other Hh pathway inhibitors. Despite discontinuation of drug, cases of progressive of epiphyseal fusion have been reported in pediatric patients receiving other Hh pathway inhibitors. ODOMZO is not indicated for use in pediatric patients.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of ODOMZO was evaluated in BOLT, a randomized, double-blind, multiple cohort trial in which 229 patients received ODOMZO at either 200 mg (n=79) or 800 mg (n=150) daily. The frequency of common adverse reactions including muscle spasms, alopecia, dysgeusia, fatigue, nausea, decreased weight, decreased appetite, myalgia, pain, and vomiting was greater in patients treated with ODOMZO 800 mg as compared to 200 mg.

The data described below reflect exposure to ODOMZO 200 mg daily in 79 patients with locally advanced BCC (laBCC; n=66) or metastatic BCC (mBCC; n=13) enrolled in BOLT. Patients were followed for at least 18 months unless discontinued earlier. The median duration of treatment with ODOMZO was 11.0 months (range 1.3 to 33.5 months).

The study population characteristics were: median age of 67 years (range 25 to 92; 59% were ≥65 years), 61% male, and 90% white. The majority of patients had prior surgery (75%), radiotherapy (24%), systemic chemotherapy (4%), or topical or photodynamic therapies (18%) for treatment of BCC. No patient had prior exposure to a Hh pathway inhibitor.

ODOMZO was permanently discontinued in 34% of patients or temporarily interrupted in 20% of patients for adverse reactions. Adverse reactions reported in at least two patients that led to discontinuation of the drug were: muscle spasms, and dysgeusia (each 5%), asthenia, increased lipase, and nausea (each 4%), fatigue, decreased appetite, alopecia, and decreased weight (each 3%). Serious adverse reactions occurred in 18% of patients.

The most common adverse reactions occurring in ≥10% of patients treated with ODOMZO 200 mg were muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, and pruritus (Table 1).

The key laboratory abnormalities are described in Table 2.

Table 1: Adverse Reactions Occurring in ≥10% of Patients in BOLT

Table 2: Key Laboratory Abnormalitiesa in BOLT

Amenorrhea

Amenorrhea lasting for at least 18 months occurred in two of 14 pre-menopausal women treated with ODOMZO 200 mg or 800 mg once daily.

7.1 Effects of Other Drugs on ODOMZO

Strong and Moderate CYP3A Inhibitors

Avoid concomitant administration of ODOMZO with strong CYP3A inhibitors [see Clinical Pharmacology (12.3)].

Avoid concomitant administration of ODOMZO with moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, administer the moderate CYP3A inhibitor for less than 14 days and monitor closely for adverse reactions particularly musculoskeletal adverse reactions [see Clinical Pharmacology (12.3)].

Strong and Moderate CYP3A Inducers

Avoid concomitant administration of ODOMZO with strong and moderate CYP3A inducers [see Clinical Pharmacology (12.3)].

8.1 Pregnancy

Risk Summary

Based on its mechanism of action and data from animal reproduction studies, ODOMZO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of ODOMZO in pregnant women. In animal reproduction studies, oral administration of sonidegib during organogenesis at doses below the recommended human dose of 200 mg resulted in embryotoxicity, fetotoxicity, and teratogenicity in rabbits (see Data). Teratogenic effects observed included severe midline defects, missing digits, and other irreversible malformations. Advise pregnant women of the potential risk to a fetus. Report pregnancies to Sun Pharmaceutical Industries, Inc. at 1-800-406-7984.

In the U.S. general population, the estimated background risk of major birth defects is 2-4% and of miscarriage in clinically recognized pregnancies is 15-20%.

Data

Animal Data

Daily oral administration of sonidegib to pregnant rabbits resulted in abortion, complete resorption of fetuses, or severe malformations at ≥ 5 mg/kg/day (approximately 0.05 times the recommended human dose based on AUC). Teratogenic effects included vertebral, distal limb and digit malformations, severe craniofacial malformations, and other severe midline defects. Skeletal variations were observed when maternal exposure to sonidegib was below the limit of detection.

8.2 Lactation

No data are available regarding the presence of sonidegib in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with ODOMZO and for 20 months after the last dose.

8.3 Females and Males of Reproductive Potential

Based on its mechanism of action and animal data, ODOMZO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating ODOMZO treatment.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with ODOMZO and for at least 20 months after the last dose.

Males

It is not known if sonidegib is present in semen. Advise male patients to use condoms, even after a vasectomy, to avoid potential drug exposure to pregnant partners and female partners of reproductive potential during treatment with ODOMZO and for at least 8 months after the last dose.

Advise males not to donate semen during treatment with ODOMZO and for at least 8 months after the last dose.

Infertility

Based on findings from animal studies, female fertility may be compromised with ODOMZO [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of ODOMZO have not been established in pediatric patients.

Epiphyseal disorders, including premature fusion of the epiphyses, have been reported in pediatric patients exposed to ODOMZO in a clinical trial. In some cases, pediatric patients treated with other Hh pathway inhibitors have experienced progression of epiphyseal fusion despite discontinuation of the Hh pathway inhibitor.

Juvenile Animal Data

In a 5-week juvenile rat toxicology study, effects of sonidegib were observed in bone, teeth, reproductive tissues, and nerves at doses ≥10 mg/kg/day (approximately 1.2 times the recommended human dose based on AUC). Bone findings included thinning/closure of bone growth plate, decreased bone length and width, and hyperostosis. Findings in teeth included missing or fractured teeth, and atrophy. Reproductive tissue toxicity was evidenced by atrophy of testes, ovaries, and uterus, partial development of the prostate gland and seminal vesicles, and inflammation and aspermia of the epididymis. Nerve degeneration was also noted.

8.5 Geriatric Use

Of the 229 patients who received ODOMZO (79 patients receiving 200 mg daily and 150 patients receiving 800 mg daily) in BOLT, 54% were 65 years and older, while 28% were 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients. There was a higher incidence of serious adverse reactions, Grade 3 and 4 adverse reactions, and adverse reactions requiring dose interruption or discontinuation in patients ≥65 years compared with younger patients; this was not attributable to an increase in any specific adverse event.

12.1 Mechanism of Action

Sonidegib is an inhibitor of the Hh pathway. Sonidegib binds to and inhibits Smoothened, a transmembrane protein involved in Hh signal transduction.

12.2 Pharmacodynamics

Cardiac Electrophysiology

At a dose of 800 mg once daily, sonidegib does not prolong the QTc interval.

12.3 Pharmacokinetics

Sonidegib exhibited dose-proportional increases in the area under the curve (AUC) and the maximal concentration (Cmax) over the dose range of 100 mg to 400 mg, but less than dose-proportional increases at doses greater than 400 mg. Steady-state was reached approximately 4 months after starting ODOMZO and the estimated accumulation at steady-state was 19-fold. Following a dose of 200 mg once daily, the estimated mean steady-state Cmax is 1030 ng/mL, AUC0-24h is 22 μg*h/mL and minimal concentration (Cmin) is 890 ng/mL.

Absorption

Less than 10% of an oral dose of ODOMZO is absorbed. Following the administration of a single ODOMZO dose (100 mg to 3000 mg) under fasted conditions in patients with cancer, the median time-to-peak concentration (Tmax) was 2 to 4 hours.

Effect of Food

A high-fat meal (approximately 1000 calories with 50% of calories from fat) increased exposure to sonidegib (geometric mean AUCinf and Cmax) by 7.4- to 7.8-fold [see Dosage and Administration (2.1)].

Distribution

The estimated apparent steady-state volume of distribution (Vss/F) was 9,166 L. Sonidegib was greater than 97% bound to human plasma proteins in vitro and the binding was concentration independent. In vitro studies suggested that sonidegib is not a substrate of P-glycoprotein, MRP2 or BCRP.

Elimination

The elimination half-life (t1/2) of sonidegib estimated from population pharmacokinetic (PK) modeling was approximately 28 days.

Metabolism

Sonidegib is primarily metabolized by CYP3A. The main circulating compound was unchanged sonidegib (36% of circulating radioactivity).

Excretion

Sonidegib and its metabolites are eliminated primarily by the hepatic route. Of the absorbed dose, approximately 70% was eliminated in the feces and 30% was eliminated in the urine. Unchanged sonidegib was not detectable in the urine.

Specific Populations

Age, body weight, hepatic impairment (Child-Pugh A, B and C), mild to moderate renal impairment (creatinine clearance 30 to 89 mL/min) and sex had no clinically meaningful effect on sonidegib steady-state exposure.

Racial or Ethnic Groups

A cross study comparison suggests that geometric mean AUCinf of sonidegib is 1.7-fold higher in Japanese healthy subjects compared to Western healthy subjects (Whites and Blacks) following a single 200 mg dose of ODOMZO.

Drug Interaction Studies

Effects of CYP3A Inhibitors on Sonidegib

Strong CYP3A inhibitor: The geometric mean sonidegib AUC0-10d increased by 2.2-fold and the Cmax increased by 1.5-fold when ODOMZO at a dose of 800 mg was taken with ketoconazole compared to ODOMZO alone [see Drug Interactions (7.1)]. The geometric mean sonidegib steady-state AUC0-24h would similarly increase in cancer patients taking ODOMZO 200 mg once daily when coadministered with a strong CYP3A inhibitor for 14 days.

Moderate CYP3A inhibitor: The geometric mean sonidegib steady-state AUC0-24h would increase 1.8-fold when ODOMZO 200 mg once daily is coadministered with a moderate CYP3A inhibitor (erythromycin) for 14 days and would increase 2.8-fold when ODOMZO 200 mg once daily is coadministered with a moderate CYP3A inhibitor (erythromycin) for 4 months.

Effects of CYP3A Inducers on Sonidegib

Strong CYP3A inducer: The geometric mean sonidegib AUC0-10d decreased by 72% and the Cmax decreased by 54% when ODOMZO at a dose of 800 mg was taken with rifampicin compared to ODOMZO alone [see Drug Interactions (7.1)].

Moderate CYP3A inducer: The geometric mean sonidegib steady-state AUC0-24h would decrease 56% in cancer patients taking ODOMZO 200 mg once daily when coadministered with a moderate CYP3A inducer (efavirenz) for 14 days and would decrease 69% when coadministered with a moderate CYP3A inducer (efavirenz) for 4 months [see Drug Interactions (7.1)].

Effect of Sonidegib on Cytochrome P450 Enzymes and Transporters

In vitro studies suggested that sonidegib inhibits CYP2B6 and CYP2C9 and it does not induce CYP1A2, CYP2B6 or CYP3A expression or activity.

In vitro studies suggested that sonidegib inhibits BCRP, but not P-glycoprotein, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT1 or OCT2.

Effects of Acid Reducing Agents on Sonidegib

No clinically meaningful effect on sonidegib exposure was observed when ODOMZO at dose of 200 mg was coadministered with esomeprazole, a proton pump inhibitor.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with sonidegib have not been performed.

Sonidegib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay and was not clastogenic or aneugenic in the in vitro human chromosome aberration assay or in vivo rat bone marrow micronucleus assay.

Sonidegib resulted in a lack of fertility when administered to female rats at ≥20 mg/kg/day (approximately 1.3 times the recommended human dose based on body surface area (BSA). A reduction of the number of pregnant females, an increase in the number of early resorptions, and a decrease in the number of viable fetuses was also noted at 2 mg/kg/day (approximately 0.12 times the recommended human dose based on BSA). In addition, in a 6 month repeat-dose toxicology study in rats, effects on female reproductive organs included atrophy of the uterus and ovaries at doses of 10 mg/kg (approximately ≥2 times the exposure in humans at the recommended dose of 200 mg based on AUC). No adverse effects on fertility were noted when male rats were administered sonidegib at doses up to 20 mg/kg/day, the highest dose tested.

13.2 Animal Toxicology and/or Pharmacology

Body tremors along with significant increases in creatine kinase were observed in rats administered oral sonidegib for 13 weeks or longer at ≥10 mg/kg/day (approximately ≥2 times the recommended human dose based on AUC).