Odomzo sonidegib 200 mg Capsule, 30-count — NDC 47335-303-15 (Billing 47335-0303-15)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Sonidegib is an inhibitor of the Hh pathway. Sonidegib binds to and inhibits Smoothened, a transmembrane protein involved in Hh signal transduction.

12.2Pharmacodynamics Cardiac Electrophysiology At a dose of 800 mg once daily, sonidegib does not prolong the QTc interval.

12.3Pharmacokinetics Sonidegib exhibited dose-proportional increases in the area under the curve (AUC) and the maximal concentration (C max ) 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 C max is 1030 ng/mL, AUC 0-24h is 22 μg*h/mL and minimal concentration (C min ) 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 (T max ) 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 AUC inf and C max ) by 7.4- to 7.8-fold [see Dosage and Administration (2.1) ] .

Distribution The estimated apparent steady-state volume of distribution (V ss /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 (t 1/2 ) 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 AUC inf 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 AUC 0-10d increased by 2.2-fold and the C max 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 AUC 0-24h 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 AUC 0-24h 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 AUC 0-10d decreased by 72% and the C max 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 AUC 0-24h would decrease 56% in cancer patients taking ODOMZO 200 mg once daily when coadministered with a moderate CYP3A inducer (efavirenz) for 14 days and w… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Sonidegib is an inhibitor of the Hh pathway. Sonidegib binds to and inhibits Smoothened, a transmembrane protein involved in Hh signal transduction.

12.3Pharmacokinetics Sonidegib exhibited dose-proportional increases in the area under the curve (AUC) and the maximal concentration (C max ) 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 C max is 1030 ng/mL, AUC 0-24h is 22 μg*h/mL and minimal concentration (C min ) 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 (T max ) 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 AUC inf and C max ) by 7.4- to 7.8-fold [see Dosage and Administration (2.1) ] .

Distribution The estimated apparent steady-state volume of distribution (V ss /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 (t 1/2 ) 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 AUC inf 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 AUC 0-10d increased by 2.2-fold and the C max 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 AUC 0-24h 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 AUC 0-24h 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 AUC 0-10d decreased by 72% and the C max 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 AUC 0-24h 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 acti… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Cardiac Electrophysiology At a dose of 800 mg once daily, sonidegib does not prolong the QTc interval.

14 CLINICAL STUDIES The safety and effectiveness of ODOMZO were evaluated in a single, multicenter, double-blind, multiple cohort clinical trial conducted in patients with locally advanced basal cell carcinoma (laBCC) (n=194) or metastatic basal cell carcinoma (mBCC) (n=36) (BOLT, NCT01327053). Patients were randomized (2:1) to receive either ODOMZO 800 mg or 200 mg orally, once daily, until disease progression or intolerable toxicity. Randomization was stratified by stage of disease (locally advanced or metastatic), laBCC disease histology (aggressive vs. non-aggressive), and geographic region.

Patients with laBCC were required to have lesions for which radiotherapy was contraindicated or inappropriate (e.g., Gorlin syndrome or limitations because of location of tumor), that had recurred after radiotherapy, that were unresectable or for which surgical resection would result in substantial deformity, or that had recurred after prior surgical resection. The major efficacy outcome measure of the trial was objective response rate (ORR) as determined by blinded central review according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) for patients with laBCC or RECIST version 1.1 for patients with mBCC.

Duration of response (DoR), determined by blinded central review, was a key secondary outcome measure. For patients with laBCC, the evaluation of tumor response was based on a composite assessment that integrated tumor measurements obtained by radiographic assessments of target lesions (per RECIST 1.1), digital clinical photography, and histopathology assessments (via punch biopsies). All modalities used must have demonstrated absence of tumor to achieve a composite assessment of complete response (CR).

Response by digital clinical photography was evaluated by World Health Organization (WHO) adapted criteria [partial response (PR): ≥50% decrease in the sum of the product of perpendicular diameters (SPD) of the lesions, CR: disappearance of all lesions, progressive disease (PD): ≥25% increase in the SPD of the lesions]. Multiple punch biopsies of target lesions were performed to confirm a CR or when a response assessment was confounded by presence of lesion ulceration, cyst, and or scarring/fibrosis. A total of 66 patients randomized to ODOMZO 200 mg daily had laBCC.

Three of these patients had a diagnosis of Gorlin Syndrome. The demographic characteristics of the 66 patients with laBCC were: median age of 67 years (range: 25 to 92 years; 58% were ≥65 years); 58% male, 89% white, and ECOG performance status of 0 (67%). Seventy-six percent of patients had prior therapy for treatment of BCC; this included surgery (73%), radiotherapy (18%), and topical/photodynamic therapies (21%).

Approximately half of these patients (56%) had aggressive histology. Patients with laBCC randomized to receive ODOMZO 200 mg daily were followed for at least 30 months unless discontinued earlier. The ORR was 56% (95% confidence interval: 43, 68), consisting of 3 (5%) complete responses and 34 (52%) partial responses.

A pre-specified sensitivity analysis using an alternative definition for complete response, defined as at least a PR according to MRI and/or photography and no evidence of tumor on biopsy of the residual lesion, yielded a CR rate of 21%. The median duration of response was 26.1 months (95% CI:10.1, not reached). A total of 128 patients randomized to ODOMZO 800 mg daily had laBCC.

Twelve of these patients had a diagnosis of Gorlin Syndrome. There was no evidence of better antitumor activity (ORR) among patients with laBCC randomized to receive ODOMZO 800 mg daily and followed for at least 30 months unless discontinued earlier.

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies were performed in mice and rats. No carcinogenic potential was identified in either species. 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.

13.2Animal 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).