Vismodegib

ERIVEDGE is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery and who are not candidates for radiation. ERIVEDGE ® (vismodegib) is a hedgehog pathway inhibitor indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery and who are not candidates for radiation. ( 1 )

The recommended dosage is 150 mg orally once daily. ( 2 )

2.1 Important Safety Information Verify pregnancy status of females of reproductive potential within 7 days prior to initiating ERIVEDGE [see Use in Specific Populations (8.1 , 8.3) ] .

2.2 Recommended Dosage The recommended dosage of ERIVEDGE is 150 mg taken orally once daily, with or without food, until disease progression or until unacceptable toxicity . Swallow capsules whole. Do not open or crush capsules . If a dose of ERIVEDGE is missed, resume dosing with the next scheduled dose.

2.3 Dosage Modifications for Adverse Reactions Withhold ERIVEDGE for up to 8 weeks for intolerable adverse reactions until improvement or resolution. Treatment durations shorter than 8 weeks prior to interruptions have not been studied. Permanently discontinue ERIVEDGE if patients experience severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug reaction with eosinophilia and systemic symptoms (DRESS) [see Warnings and Precautions (5.2) ] . Interrupt ERIVEDGE for severe or intolerable musculoskeletal adverse reactions. Permanently discontinue ERIVEDGE for recurrent, severe or intolerable musculoskeletal adverse reactions [see Warnings and Precautions (5.3) ] .

Capsules: 150 mg with "150 mg" printed on pink opaque body and "VISMO" printed on grey opaque cap in black ink. 150 mg capsules. ( 3 )

None. None.

5 WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity: Advise patients not to donate blood or blood products while receiving ERIVEDGE and for 24 months after the final dose of ERIVEDGE ( 5.1 ) Advise males not to donate semen during and for 3 months after therapy ( 5.1 , 8.3 ) Severe Cutaneous Adverse Reactions: Permanently discontinue ERIVEDGE in patients with these reactions ( 5.2 ) Musculoskeletal Adverse Reactions: Temporary dose interruption or discontinuation may be required for these reactions ( 5.3 ) Premature fusion of the epiphyses ( 5.4 , 8.4 )

5.1 Embryo-Fetal Toxicity Based on its mechanism of action, ERIVEDGE can cause embryo-fetal death or severe birth defects when administered to a pregnant woman. In animal reproduction studies, vismodegib was embryotoxic, fetotoxic, and teratogenic at maternal exposures lower than the human exposures at the recommended dose of 150 mg once daily [see Use in Specific Populations (8.1) ] . Females of Reproductive Potential Verify the pregnancy status of females of reproductive potential within 7 days prior to initiating ERIVEDGE. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during therapy with ERIVEDGE and for 24 months after the final dose [see Use in Specific Populations (8.1 , 8.3) ]. Males Vismodegib is present in semen. It is not known if the amount of vismodegib in semen can cause embryo-fetal harm. Advise males to use condoms, even after a vasectomy, to avoid potential drug exposure in pregnant partners and female partners of reproductive potential during therapy and for 3 months after the final dose of ERIVEDGE. Advise male patients not to donate semen during and for 3 months after the final dose of ERIVEDGE [see Use in Specific Populations (8.3) ]. Blood Donation Advise patients not to donate blood or blood products while receiving ERIVEDGE and for 24 months after the final dose of ERIVEDGE.

5.2 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with ERIVEDGE [see Adverse Reactions (6.2) ]. Permanently discontinue ERIVEDGE in patients with these reactions [see Dosage and Administration (2.3) ].

5.3 Musculoskeletal Adverse Reactions Musculoskeletal adverse reactions, which may be accompanied by serum creatine phosphokinase (CPK) elevations, have occurred with ERIVEDGE and other drugs which inhibit the hedgehog (Hh) pathway. In the pooled safety population in clinical trials of ERIVEDGE, musculoskeletal and connective tissue adverse reactions occurred in 78% of patients treated, with 7% (9/138) reported as Grade 3. The most frequent manifestations of musculoskeletal and connective tissue adverse reactions (all grades) reported were muscle spasms (72%) and arthralgias (16%). In a post-approval clinical trial of 1232 patients, Grade 3 or 4 elevations in serum CPK laboratory values occurred in 2.4% of the 453 patients who had any CPK measurement [see Adverse Reactions (6.1) ] . Obtain baseline serum creatine phosphokinase (CPK) and creatinine levels and as clinically indicated (e.g., if muscle symptoms are reported). Depending on the severity of symptoms, temporary dose interruption or discontinuation may be required for musculoskeletal adverse reactions or serum CPK elevation [see Dosage and Administration (2.3) ] .

5.4 Premature Fusion of the Epiphyses Premature fusion of the epiphyses has been reported in pediatric patients exposed to ERIVEDGE. In some cases, fusion progressed after drug discontinuation [see Use in Specific Populations (8.4) ]. ERIVEDGE is not indicated for pediatric patients.

The following clinically significant adverse reactions are described elsewhere in the labeling: Embryo-Fetal Toxicity [see Warnings and Precautions (5.1) ] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2) ] Musculoskeletal Adverse Reactions [see Warnings and Precautions (5.3) ] Premature Fusion of the Epiphyses [see Warnings and Precautions (5.4) ] The most common adverse reactions (incidence of ≥ 10%) are muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia. To report SUSPECTED ADVERSE REACTIONS, contact Genentech, Inc. at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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 data described below reflect exposure to ERIVEDGE in 138 patients with advanced basal cell carcinoma (BCC) who received ERIVEDGE at doses ≥ 150 mg orally daily in four open-label, uncontrolled, dose-ranging or fixed single dose clinical trials [Study SHH3925g, SHH4437g, SHH4476g and SHH4610g]. The median age of these patients was 61 years (range 21 to 101 years), 100% were White (including Hispanics), and 64% were male. The median duration of treatment was approximately 10 months (range 21 days to 36 months); 111 patients received ERIVEDGE for 6 months or longer. The most common adverse reactions (≥ 10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia ( Table 1 ). Table 1: Adverse Reactions Occurring in ≥ 10% of Patients with Advanced Basal Cell Carcinoma Adverse Reaction ERIVEDGE (N = 138) All Grades Grading according to National Cancer Institute-Common Terminology Criteria for Adverse Events version 3.0. (%) Grade 3 (%) Grade 4 (%) Gastrointestinal Nausea 30% 0.7% - Diarrhea 29% 0.7% - Constipation 21% - - Vomiting 14% - - General Fatigue 40% 5% 0.7% Investigations Weight loss 45% 7% - Metabolism and nutrition Decreased appetite 25% 2.2% - Musculoskeletal and connective tissue Muscle spasms 72% 3.6% - Arthralgias 16% 0.7% Nervous system Dysgeusia 55% - - Ageusia 11% - - Skin and subcutaneous tissue Alopecia 64% - - Amenorrhea Among patients from the clinical trials included in the pooled safety data analysis, 30% of 10 pre-menopausal women developed amenorrhea while receiving ERIVEDGE. Laboratory Abnormalities Grade 3 laboratory abnormalities observed in clinical trials were hyponatremia (4%), azotemia (2%) and hypokalemia (1%). Additionally, in a post-approval clinical trial conducted in 1232 patients with locally advanced or metastatic BCC treated with ERIVEDGE, a subset of 29 patients had baseline values for blood creatine phosphokinase (CPK) reported. Within this subset of patients, 38% had a shift from baseline, including Grade 3 (3%) increased CPK. Grade 3 or 4 increased CPK occurred in 2.4% of the 453 patients across the entire study population with any CPK measurement.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ERIVEDGE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hepatobiliary disorders: Drug-induced liver injury Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome/toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms [see Warnings and Precautions (5.2) ] .

Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ERIVEDGE during pregnancy. Report pregnancies to Genentech at 1-888-835-2555. Risk Summary Based on its mechanism of action and findings from animal reproduction studies, ERIVEDGE can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . In animal reproduction studies, oral administration of vismodegib during organogenesis at doses below the 150 mg clinical dose resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats (see Data ) . There are no human data on the use of ERIVEDGE in pregnant women. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In an embryo-fetal toxicity study, pregnant rats were administered vismodegib orally at doses of 10, 60, or 300 mg/kg/day during the period of organogenesis. Pre- and post-implantation loss were increased at doses of ≥ 60 mg/kg/day [approximately 2 times the human exposure at the 150 mg clinical dose based on area under the curve (AUC)], which included early resorption of 100% of the fetuses. A dose of 10 mg/kg/day [approximately 0.2 times the human exposure (AUC) at the recommended 150 mg clinical dose] resulted in malformations (including missing and/or fused digits, open perineum and craniofacial anomalies) and retardations or variations (including dilated renal pelvis, dilated ureter, and incompletely or unossified sternal elements, centra of vertebrae, or proximal phalanges and claws).

The safety and effectiveness of ERIVEDGE have not been established in pediatric patients. Premature fusion of the epiphyses [see Warnings and Precautions (5.3) ] and precocious puberty have been reported in pediatric patients exposed to ERIVEDGE. In some cases, epiphyseal fusion progressed after drug discontinuation . Juvenile Animal Toxicity Data In repeat-dose toxicology studies in rats, administration of oral vismodegib resulted in toxicities in bone and teeth. Effects on bone consisted of closure of the epiphyseal growth plate when oral vismodegib was administered for 26 weeks at ≥ 50 mg/kg/day (approximately ≥ 0.4 times the human exposure (AUC) at the 150 mg clinical dose). Abnormalities in growing incisor teeth (including degeneration/necrosis of odontoblasts, formation of fluid-filled cysts in the dental pulp, ossification of the root canal, and hemorrhage resulting in breakage or loss of teeth) were observed after administration of oral vismodegib at ≥ 15 mg/kg/day (approximately ≥ 0.2 times the human exposure (AUC) at the 150 mg clinical dose).

Clinical studies of ERIVEDGE did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

Vismodegib is a hedgehog (Hh) pathway inhibitor, which is described chemically as 2-Chloro- N -(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide. The molecular formula is C 19 H 14 Cl 2 N 2 O 3 S. The molecular weight is 421.3 g/mol and the structural formula is: Vismodegib is a crystalline free base with a pKa (pyridinium cation) of 3.8, appearing as a white to tan powder. The solubility of vismodegib is pH dependent with 0.1 µg/mL at pH 7 and 0.99 mg/mL at pH 1. The partition coefficient (log P) is 2.7. ERIVEDGE (vismodegib) for oral administration is supplied in capsules containing 150 mg vismodegib and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, sodium lauryl sulfate, povidone, sodium starch glycolate, talc, and magnesium stearate (non-bovine). The capsule shell contains gelatin, titanium dioxide, red iron oxide, and black iron oxide. The black printing ink contains shellac and black iron oxide. Chemical Structure

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

12.2 Pharmacodynamics Cardiac Electrophysiology ERIVEDGE did not prolong the QT interval to any clinically relevant extent following 7 days of 150 mg once-daily dosing (at steady state) .

12.3 Pharmacokinetics The pharmacokinetics of vismodegib were studied in healthy subjects and patients. Following daily oral dosing, the pharmacokinetics of vismodegib appear to be nonlinear with steady state achieved within 7 days. Increasing the dose from 150 mg to 540 mg (1 to 3.6 times the recommended dose) does not result in higher steady state plasma concentrations. Average plasma concentration of vismodegib at steady state (C ss,avg ) is ~23 µM following 150 mg once daily dose. Absorption The single dose absolute bioavailability of vismodegib is 32%. Absorption is saturable as evidenced by the lack of dose proportional increase in exposure after a single dose of 270 mg or 540 mg vismodegib. Effect of Food C max and AUC 0-24hr of vismodegib at steady state are not affected by food. Distribution The volume of distribution of vismodegib ranges from 16.4 to 26.6 L. Vismodegib plasma protein binding in patients is > 99%. Vismodegib binds to both human serum albumin and alpha-1-acid glycoprotein (AAG) and binding to AAG is saturable. Male patients had an average concentration of vismodegib in semen on day 8 that was 6.5% of the average steady state concentration (C ss ) observed in plasma. Elimination The estimated elimination half-life (t 1/2 ) of vismodegib is 4 days after continuous once-daily dosing and 12 days after a single dose. Metabolism Greater than 98% of the total circulating drug-related components are the parent drug. Metabolic pathways of vismodegib in humans include oxidation, glucuronidation, and pyridine ring cleavage. The two most abundant oxidative metabolites recovered in feces are produced in vitro by recombinant CYP2C9 and CYP3A. Excretion Vismodegib and its metabolites are eliminated primarily by the hepatic route with 82% of the administered dose recovered in the feces and 4.4% recovered in urine. Specific Populations Weight (41-140 kg), age (26-89 years), sex, mild to moderate renal impairment (creatinine clearance of 30 to 79 mL/min), mild hepatic impairment (normal total bilirubin and aspartate transaminase (AST) > upper limit of normal (ULN) or total bilirubin > 1 to 1.5 times ULN), moderate hepatic impairment (total bilirubin > 1.5 to 3 times ULN), or severe hepatic impairment (total bilirubin > 3 to 10 times ULN) had no clinically relevant effects on the systemic exposure of vismodegib. The impact of severe renal impairment on the pharmacokinetics of vismodegib is unknown. Drug Interaction Studies Clinical Studies No clinically significant differences in vismodegib pharmacokinetics were observed when used concomitantly with fluconazole (moderate CYP2C9 and CYP3A4 inhibitor), itraconazole (strong CYP3A4 inhibitor and P-gp inhibitor) and rabeprazole (gastric acid reducing agent, proton pump inhibitor). No clinically significant differences in the pharmacokinetics of the following drugs were observed when used concomitantly with vismodegib: rosiglitazone (a CYP2C8 substrate) or ethinyl estradiol and norethindrone (oral contraceptive). In Vitro Studies Vismodegib is an inhibitor of the transporter BCRP and is not an inducer of CYP1A2, CYP2B6, or CYP3A.

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

Cardiac Electrophysiology ERIVEDGE did not prolong the QT interval to any clinically relevant extent following 7 days of 150 mg once-daily dosing (at steady state) .

The pharmacokinetics of vismodegib were studied in healthy subjects and patients. Following daily oral dosing, the pharmacokinetics of vismodegib appear to be nonlinear with steady state achieved within 7 days. Increasing the dose from 150 mg to 540 mg (1 to 3.6 times the recommended dose) does not result in higher steady state plasma concentrations. Average plasma concentration of vismodegib at steady state (C ss,avg ) is ~23 µM following 150 mg once daily dose. Absorption The single dose absolute bioavailability of vismodegib is 32%. Absorption is saturable as evidenced by the lack of dose proportional increase in exposure after a single dose of 270 mg or 540 mg vismodegib. Effect of Food C max and AUC 0-24hr of vismodegib at steady state are not affected by food. Distribution The volume of distribution of vismodegib ranges from 16.4 to 26.6 L. Vismodegib plasma protein binding in patients is > 99%. Vismodegib binds to both human serum albumin and alpha-1-acid glycoprotein (AAG) and binding to AAG is saturable. Male patients had an average concentration of vismodegib in semen on day 8 that was 6.5% of the average steady state concentration (C ss ) observed in plasma. Elimination The estimated elimination half-life (t 1/2 ) of vismodegib is 4 days after continuous once-daily dosing and 12 days after a single dose. Metabolism Greater than 98% of the total circulating drug-related components are the parent drug. Metabolic pathways of vismodegib in humans include oxidation, glucuronidation, and pyridine ring cleavage. The two most abundant oxidative metabolites recovered in feces are produced in vitro by recombinant CYP2C9 and CYP3A. Excretion Vismodegib and its metabolites are eliminated primarily by the hepatic route with 82% of the administered dose recovered in the feces and 4.4% recovered in urine. Specific Populations Weight (41-140 kg), age (26-89 years), sex, mild to moderate renal impairment (creatinine clearance of 30 to 79 mL/min), mild hepatic impairment (normal total bilirubin and aspartate transaminase (AST) > upper limit of normal (ULN) or total bilirubin > 1 to 1.5 times ULN), moderate hepatic impairment (total bilirubin > 1.5 to 3 times ULN), or severe hepatic impairment (total bilirubin > 3 to 10 times ULN) had no clinically relevant effects on the systemic exposure of vismodegib. The impact of severe renal impairment on the pharmacokinetics of vismodegib is unknown. Drug Interaction Studies Clinical Studies No clinically significant differences in vismodegib pharmacokinetics were observed when used concomitantly with fluconazole (moderate CYP2C9 and CYP3A4 inhibitor), itraconazole (strong CYP3A4 inhibitor and P-gp inhibitor) and rabeprazole (gastric acid reducing agent, proton pump inhibitor). No clinically significant differences in the pharmacokinetics of the following drugs were observed when used concomitantly with vismodegib: rosiglitazone (a CYP2C8 substrate) or ethinyl estradiol and norethindrone (oral contraceptive). In Vitro Studies Vismodegib is an inhibitor of the transporter BCRP and is not an inducer of CYP1A2, CYP2B6, or CYP3A.

, Mutagenesis, Impairment of Fertility Carcinogenicity studies were performed in mice and rats. No carcinogenic potential was identified in either species. Vismodegib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro human chromosomal aberration assay in human peripheral blood lymphocytes or in the in vivo rat bone marrow micronucleus assay. In a dedicated 26-week rat fertility study, no effects on male reproductive organs or fertility endpoints were observed at vismodegib doses of 100 mg/kg/day [approximately 1.3 times the human exposure (steady state AUC 0-24hr ) at the 150 mg clinical dose] either at the end of dosing or following a 16-week recovery phase. While there were increased numbers of degenerating germ cells and hypospermia in sexually immature dogs observed at ≥ 50 mg/kg/day in the 4-week general toxicity study, there were no effects on male reproductive organs in sexually mature rats and dogs, in the vismodegib general toxicity studies of up to 26-weeks. In a female fertility study, treatment of rats with vismodegib at 100 mg/kg/day [approximately 1.2-times the human exposure (steady state AUC 0-24hr ) at the 150 mg clinical dose] for 26-weeks prior to mating resulted in decreased implantations, increased percent preimplantation loss, and decreased numbers of dams with viable embryos. No vismodegib-related changes in fertility were observed following a 16-week recovery period. In a 26-week general toxicity study in rats, decreased numbers of corpora lutea were observed at 100 mg/kg/day; the effect was not reversed by the end of an 8-week recovery period.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). Embryo-Fetal Toxicity [see Warnings and Precautions (5.1) , Use in Specific Populations (8.1 , 8.3) ] Females of Reproductive Potential Advise women of the potential risk to a fetus. Advise female patients and female partners of male patients to contact their healthcare provider with a known or suspected pregnancy. Inform females there is a Pregnancy Exposure Registry that monitors pregnancy outcomes in females exposed to ERIVEDGE during pregnancy and that they can contact the Pregnancy Exposure Registry by calling 1-888-835-2555. Advise females of reproductive potential to use effective contraception during therapy with ERIVEDGE and for 24 months after the final dose. Males Advise males, even those with prior vasectomy, to use condoms to avoid potential drug exposure in both pregnant partners and female partners of reproductive potential during therapy with ERIVEDGE and for 3 months after the final dose. Advise males not to donate semen during therapy with ERIVEDGE and for 3 months after the final dose. Blood Donation Advise patients not to donate blood or blood products during therapy with ERIVEDGE and for 24 months after the final dose. Lactation Advise women not to breastfeed during therapy with ERIVEDGE and for 24 months after the final dose [see Use in Specific Populations (8.2) ] . Severe Cutaneous Reactions Inform patients of the signs and symptoms of severe cutaneous reactions. Advise patients to contact their healthcare provider immediately for signs and symptoms of severe cutaneous reactions [see Warnings and Precautions (5.2) ] . Muscle-related adverse reactions Advise patients starting therapy with ERIVEDGE of the risk of muscle-related adverse reactions. Advise patients to contact their healthcare provider immediately for any new unexplained muscle pain, tenderness, or weakness occurring during treatment or that persists after discontinuing ERIVEDGE [see Warnings and Precautions (5.3) ]

Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep the bottle tightly closed to protect from moisture.