PHARMACODYNAMICS SECTION.

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

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)] Premature Fusion of the Epiphyses [see Warnings and Precautions (5.3)] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)] Premature Fusion of the Epiphyses [see Warnings and Precautions (5.3)] 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.. 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. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 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 CarcinomaAdverse ReactionERIVEDGE(N 138)All GradesGrading according to National Cancer Institute-Common Terminology Criteria for Adverse Events version 3.0. (%)Grade (%)Grade (%)Gastrointestinal Nausea30%0.7%- Diarrhea29%0.7%- Constipation21%-- Vomiting14%--General Fatigue40%5%0.7%Investigations Weight loss45%7%-Metabolism and nutrition Decreased appetite25%2.2%-Musculoskeletal and connective tissue Muscle spasms72%3.6%- Arthralgias16%0.7%Nervous system Dysgeusia55%-- Ageusia11%--Skin and subcutaneous tissue Alopecia64%--. 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 AbnormalitiesGrade laboratory abnormalities observed in clinical trials were hyponatremia (4%), azotemia (2%) and hypokalemia (1%).Additionally, in post-approval clinical trial conducted in 1232 patients with locally advanced or metastatic BCC treated with ERIVEDGE, subset of 29 patients had baseline values for blood creatine phosphokinase (CPK) reported. Within this subset of patients, 38% had shift from baseline, including Grade (3%) increased CPK. Grade or increased CPK occurred in 2.4% of the 453 patients across the entire study population with any CPK measurement. 6.2Postmarketing Experience. The following adverse reactions have been identified during post-approval use of ERIVEDGE. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Hepatobiliary disorders: Drug-induced liver injurySkin and subcutaneous tissue disorders: Stevens-Johnson syndrome/toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms [see Warnings and Precautions (5.2)].

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2Animal Toxicology and/or Pharmacology. Neurologic effects characterized as limb or body tremors or twitching were observed in rats administered oral vismodegib for weeks or longer at >= 50 mg/kg/day (approximately >= 0.4 times the human exposure (AUC) at the 150 mg clinical dose). These observations resolved upon discontinuation of dosing and were not associated with microscopic findings.

BOXED WARNING SECTION.

WARNING: EMBRYO-FETAL TOXICITY. ERIVEDGE can cause embryo-fetal death or severe birth defects when administered to pregnant woman. ERIVEDGE is embryotoxic, fetotoxic, and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations [see Warnings and Precautions (5.1), Use in Specific Populations (8.1)]. Verify the pregnancy status of females of reproductive potential within days prior to initiating ERIVEDGE. Advise pregnant women of the potential risks to fetus. Advise females of reproductive potential to use effective contraception during and after ERIVEDGE [see Dosage and Administration (2.1), Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3)]. Advise males of the potential risk of ERIVEDGE exposure through semen and to use condoms with pregnant partner or female partner of reproductive potential [see Warnings and Precautions (5.1), Use in Specific Populations (8.3)].. ERIVEDGE can cause embryo-fetal death or severe birth defects when administered to pregnant woman. ERIVEDGE is embryotoxic, fetotoxic, and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations [see Warnings and Precautions (5.1), Use in Specific Populations (8.1)]. Verify the pregnancy status of females of reproductive potential within days prior to initiating ERIVEDGE. Advise pregnant women of the potential risks to fetus. Advise females of reproductive potential to use effective contraception during and after ERIVEDGE [see Dosage and Administration (2.1), Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3)]. Advise males of the potential risk of ERIVEDGE exposure through semen and to use condoms with pregnant partner or female partner of reproductive potential [see Warnings and Precautions (5.1), Use in Specific Populations (8.3)].. WARNING: EMBRYO-FETAL TOXICITYSee full prescribing information for complete boxed warning.ERIVEDGE can cause embryo-fetal death or severe birth defects when administered to pregnant woman. ERIVEDGE is embryotoxic, fetotoxic, and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations. (5.1, 8.1)Verify the pregnancy status of females of reproductive potential within days prior to initiating ERIVEDGE. Advise pregnant women of the potential risks to fetus. Advise females of reproductive potential to use effective contraception during and after ERIVEDGE. (2.1, 5.1, 8.1, 8.3)Advise males of the potential risk of ERIVEDGE exposure through semen and to use condoms with pregnant partner or female partner of reproductive potential. (5.1, 8.3). ERIVEDGE can cause embryo-fetal death or severe birth defects when administered to pregnant woman. ERIVEDGE is embryotoxic, fetotoxic, and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations. (5.1, 8.1). Verify the pregnancy status of females of reproductive potential within days prior to initiating ERIVEDGE. Advise pregnant women of the potential risks to fetus. Advise females of reproductive potential to use effective contraception during and after ERIVEDGE. (2.1, 5.1, 8.1, 8.3). Advise males of the potential risk of ERIVEDGE exposure through semen and to use condoms with pregnant partner or female partner of reproductive potential. (5.1, 8.3).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1Carcinogenesis, 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 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 AUC0-24hr) at the 150 mg clinical dose] either at the end of dosing or following 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 female fertility study, treatment of rats with vismodegib at 100 mg/kg/day [approximately 1.2-times the human exposure (steady state AUC0-24hr) 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 16-week recovery period. In 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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Vismodegib is an inhibitor of the Hedgehog pathway. Vismodegib binds to and inhibits Smoothened, transmembrane protein involved in Hedgehog signal transduction. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyERIVEDGE did not prolong the QT interval to any clinically relevant extent following 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 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 (Css,avg) is ~23 uM following 150 mg once daily dose.. AbsorptionThe single dose absolute bioavailability of vismodegib is 32%. Absorption is saturable as evidenced by the lack of dose proportional increase in exposure after single dose of 270 mg or 540 mg vismodegib. Effect of FoodCmax and AUC0-24hr of vismodegib at steady state are not affected by food.. DistributionThe 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 that was 6.5% of the average steady state concentration (Css) observed in plasma.. EliminationThe estimated elimination half-life (t1/2) of vismodegib is days after continuous once-daily dosing and 12 days after single dose.. MetabolismGreater 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.. ExcretionVismodegib 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 PopulationsWeight (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 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 StudiesNo 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 StudiesVismodegib is an inhibitor of the transporter BCRP and is not an inducer of CYP1A2, CYP2B6, or CYP3A.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. single, international, single-arm, multi-center, open-label, 2-cohort trial [SHH4476g (NCT00833417)] was conducted in 104 patients with either metastatic basal cell carcinoma (mBCC) (n 33) or locally advanced BCC (laBCC) (n 71). Patients with laBCC were required to have lesions that had recurred after radiotherapy, unless radiotherapy was contraindicated or inappropriate (e.g. Gorlin syndrome; limitations because of location of tumor or cumulative prior radiotherapy dose), and where the lesions were either unresectable or surgical resection would result in substantial deformity. Patients were to receive ERIVEDGE 150 mg orally once daily until disease progression or unacceptable toxicity.The major efficacy outcome measure was objective response rate (ORR) as assessed by an independent review facility (IRF). In the mBCC cohort, tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. In the laBCC cohort, tumor response evaluation included measurement of externally assessable tumor (including scar) and assessment for ulceration in photographs, radiographic assessment of target lesions (if appropriate), and tumor biopsy. An objective response in laBCC required at least one of the following criteria and absence of any criterion for disease progression: (1) >= 30% reduction in lesion size [sum of the longest diameter (SLD)] from baseline in target lesions by radiographic assessment; (2) >= 30% reduction in SLD from baseline in externally visible dimension of target lesions; (3) complete resolution of ulceration in all target lesions. Complete response was defined as objective response (as defined above) with no residual BCC on sampling tumor biopsy. Disease progression was defined as any of the following: (1) >= 20% increase in the SLD from nadir in target lesions (either by radiography or by externally visible dimension); (2) new ulceration of target lesions persisting without evidence of healing for at least weeks; (3) new lesions by radiographic assessment or physical examination; (4) progression of non-target lesions by RECIST.Of the 104 patients enrolled, 96 patients were evaluable for ORR. Twenty-one percent of patients carried diagnosis of Gorlin syndrome. The median age of the efficacy evaluable population was 62 years (46% were at least 65 years old), 61% male and 100% White. For the mBCC cohort (n 33), 97% of patients had prior therapy including surgery (97%), radiotherapy (58%), and systemic therapies (30%). For the laBCC cohort (n 63), 94% of patients had prior therapies including surgery (89%), radiotherapy (27%), and systemic/topical therapies (11%). The median duration of treatment was 10.2 months (range 0.7 to 18.7 months).The efficacy results are presented in Table 2.Table 2:Efficacy Results for Evaluable Patients in Study SHH4476gPatients who received at least one dose of ERIVEDGE with independent pathologist-confirmed diagnosis of BCC mBCC(n 33)laBCC(n 63)IRFIRF Independent Review Facility-Confirmed ORR, (%)10 (30.3)27 (42.9) (95% CI) (15.6, 48.2)(30.5, 56.0) Complete responseFor laBCC, complete response was defined as objective response with no residual BCC on sampling tumor biopsy. (0.0)13 (20.6) Partial response10 (30.3)14 (22.2)Median Response Duration (months)7.67.6 (95% CICI Confidence Interval) (5.6, NENE Not estimable)(5.7, 9.7).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None.

DESCRIPTION SECTION.

11 DESCRIPTION. Vismodegib is 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 C19H14Cl2N2O3S. The molecular weight is 421.3 g/mol and the structural formula is:Vismodegib is crystalline free base with pKa (pyridinium cation) of 3.8, appearing as white to tan powder. The solubility of vismodegib is pH dependent with 0.1 ug/mL at pH 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.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended dosage is 150 mg orally once daily. (2). 2.1Important Safety Information. Verify pregnancy status of females of reproductive potential within days prior to initiating ERIVEDGE [see Use in Specific Populations (8.1, 8.3)].. 2.2Recommended 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 dose of ERIVEDGE is missed, resume dosing with the next scheduled dose.. 2.3Dosage Modifications for Adverse Reactions Withhold ERIVEDGE for up to weeks for intolerable adverse reactions until improvement or resolution. Treatment durations shorter than 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)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. 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).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify the pregnancy status of females of reproductive potential within days prior to initiating ERIVEDGE.. ContraceptionBased on its mechanism of action and animal data, ERIVEDGE can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. FemalesAdvise females of reproductive potential to use effective contraception during therapy with ERIVEDGE and for 24 months after the final dose.. MalesVismodegib is present in semen [see Clinical Pharmacology (12.3)]. It is not known if the amount of vismodegib in semen can cause embryo-fetal harm. Advise male patients to use condoms, even after vasectomy, to avoid drug exposure to pregnant partners and female partners of reproductive potential during therapy with and for months after the final dose of ERIVEDGE. Advise males of the potential risk to an embryo or fetus if female partner of reproductive potential is exposed to ERIVEDGE. Advise males not to donate semen during therapy with ERIVEDGE and for months after the final dose.. Infertility. FemalesAmenorrhea can occur in females of reproductive potential. Reversibility of amenorrhea is unknown [see Adverse Reactions (6.1)].

GERIATRIC USE SECTION.

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

HEPATIC IMPAIRMENT SUBSECTION.

8.6Hepatic Impairment. No dose adjustment is required in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. ERIVEDGE capsules have pink opaque body and grey opaque cap with 150 mg printed on the capsule body and VISMO printed on the capsule cap in black ink.ERIVEDGE capsules are available in bottles of 28 capsules (NDC 50242-140-01).. Store at room temperature 20C to 25C (68F to 77F); excursions permitted between 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].Keep the bottle tightly closed to protect from moisture.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. 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(R) (vismodegib) is 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).

INFORMATION FOR PATIENTS SECTION.

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 PotentialAdvise women of the potential risk to fetus. Advise female patients and female partners of male patients to contact their healthcare provider with known or suspected pregnancy.Inform females there is 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.. Advise women of the potential risk to fetus. Advise female patients and female partners of male patients to contact their healthcare provider with known or suspected pregnancy.. Inform females there is 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.. MalesAdvise 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 months after the final dose.Advise males not to donate semen during therapy with ERIVEDGE and for months after the final dose. 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 months after the final dose.. Advise males not to donate semen during therapy with ERIVEDGE and for months after the final dose. Blood DonationAdvise patients not to donate blood or blood products during therapy with ERIVEDGE and for 24 months after the final dose.. 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)].. 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 ReactionsInform 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)].. 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)].

LACTATION SECTION.

8.2 Lactation. No data are available regarding the presence of vismodegib in human milk, the effects of the drug on the breastfed child, or the effects of the drug on milk production. Because of the potential for serious adverse reactions in breastfed infants from ERIVEDGE, advise women that breastfeeding is not recommended during therapy with ERIVEDGE and for 24 months after the final dose.

MECHANISM OF ACTION SECTION.

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

NONCLINICAL TOXICOLOGY SECTION.

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. 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 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 AUC0-24hr) at the 150 mg clinical dose] either at the end of dosing or following 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 female fertility study, treatment of rats with vismodegib at 100 mg/kg/day [approximately 1.2-times the human exposure (steady state AUC0-24hr) 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 16-week recovery period. In 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.. 13.2Animal Toxicology and/or Pharmacology. Neurologic effects characterized as limb or body tremors or twitching were observed in rats administered oral vismodegib for weeks or longer at >= 50 mg/kg/day (approximately >= 0.4 times the human exposure (AUC) at the 150 mg clinical dose). These observations resolved upon discontinuation of dosing and were not associated with microscopic findings.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 150 mg Capsule Bottle Carton. NDC 50242-140-01Erivedge(R) (vismodegib)capsules150 mgEach capsule contains 150 mg of vismodegibAttention Pharmacist: Dispense the accompanying Medication Guide to each patient.28 capsulesRx onlyGenentech10181780. PRINCIPAL DISPLAY PANEL 150 mg Capsule Bottle Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. 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).

PHARMACOKINETICS SECTION.

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 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 (Css,avg) is ~23 uM following 150 mg once daily dose.. AbsorptionThe single dose absolute bioavailability of vismodegib is 32%. Absorption is saturable as evidenced by the lack of dose proportional increase in exposure after single dose of 270 mg or 540 mg vismodegib. Effect of FoodCmax and AUC0-24hr of vismodegib at steady state are not affected by food.. DistributionThe 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 that was 6.5% of the average steady state concentration (Css) observed in plasma.. EliminationThe estimated elimination half-life (t1/2) of vismodegib is days after continuous once-daily dosing and 12 days after single dose.. MetabolismGreater 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.. ExcretionVismodegib 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 PopulationsWeight (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 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 StudiesNo 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 StudiesVismodegib is an inhibitor of the transporter BCRP and is not an inducer of CYP1A2, CYP2B6, or CYP3A.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ERIVEDGE during pregnancy. Report pregnancies to Genentech at 1-888-835-2555.. Risk SummaryBased on its mechanism of action and findings from animal reproduction studies, ERIVEDGE can cause fetal harm when administered to 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 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 DataIn 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 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. 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).

RECENT MAJOR CHANGES SECTION.

Dosage and Administration (2.3)07/2020Warnings and Precautions (5.2)07/2020.

RENAL IMPAIRMENT SUBSECTION.

8.7Renal Impairment. No dose adjustment is required in patients with renal impairment [see Clinical Pharmacology (12.3)].

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: July 2020MEDICATION GUIDEERIVEDGE(R) (EH-rih-vej) (vismodegib)capsuleWhat is the most important information should know about ERIVEDGEERIVEDGE can cause your baby to die before it is born (be stillborn) or cause your baby to have severe birth defects.For females who can become pregnant:You should talk with your healthcare provider about the risks of ERIVEDGE to your unborn child.Your healthcare provider will do pregnancy test within days before you start taking ERIVEDGE.In order to avoid pregnancy, you should use birth control during treatment and for 24 months after your final dose of ERIVEDGE. Talk with your healthcare provider about what birth control method is right for you during this time.Talk to your healthcare provider right away if you have unprotected sex or if you think that your birth control has failed.Tell your healthcare provider right away if you become pregnant or think that you may be pregnant.For males:ERIVEDGE is present in semen. Do not donate semen while you are taking ERIVEDGE and for months after your final dose.You should always use condom, even if you have had vasectomy, during sex with female partners who are pregnant or who are able to become pregnant, during treatment with ERIVEDGE and for months after your final dose to protect your female partner from being exposed to ERIVEDGE.Tell your healthcare provider right away if your partner becomes pregnant or thinks she is pregnant while you are taking ERIVEDGE.Pregnancy Exposure Registry:There is Pregnancy Exposure Registry for females taking ERIVEDGE who become pregnant. The purpose of this registry is to monitor the health of you and your unborn baby. If you think that you or your female partner may have been exposed to ERIVEDGE during pregnancy, talk to your healthcare provider right away. If you become pregnant during treatment with ERIVEDGE, you or your healthcare provider should report your pregnancy to Genentech at 1-888-835-2555.What is ERIVEDGEERIVEDGE is prescription medicine used to treat adults with type of skin cancer, called basal cell carcinoma, that has spread to other parts of the body, or that has come back after surgery or that your healthcare provider decides cannot be treated with surgery or radiation.It is not known if ERIVEDGE is safe and effective in children. What should tell my healthcare provider before taking ERIVEDGEBefore taking ERIVEDGE, tell your healthcare provider if you:are pregnant or plan to become pregnant. See What is the most important information should know about ERIVEDGE are breastfeeding or plan to breastfeed. It is not known if ERIVEDGE passes into your breast milk. You should not breastfeed during treatment and for 24 months after your final dose of ERIVEDGE. Talk to your healthcare provider about the best way to feed your baby during this time.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How should take ERIVEDGETake ERIVEDGE exactly as your healthcare provider tells you.You can take ERIVEDGE with or without food.Swallow ERIVEDGE capsules whole. Do not open or crush the capsules.Take ERIVEDGE time each day.If you miss dose, skip the missed dose. Just take your next scheduled dose.What should avoid while taking ERIVEDGEDo not donate blood or blood products while you are taking ERIVEDGE and for 24 months after your final dose. For Males: Do not donate semen while you are taking ERIVEDGE and for months after your final dose.What are the possible side effects of ERIVEDGEERIVEDGE can cause serious side effects, including:See What is the most important information should know about ERIVEDGE Severe skin reactions. Severe skin reactions have happened in some people taking ERIVEDGE. You may need to be treated in hospital because these severe skin reactions can be life-threatening or lead to death. Tell your healthcare provider right away if you develop any of the following signs or symptoms of severe skin reaction, including:blisters or peeling of your skinblisters on your lip, or around your mouth or eyesmouth sores or genital soreshigh fever or flu-like symptomsenlarged lymph nodesskin pain and burning Your healthcare provider may permanently stop ERIVEDGE if you develop severe skin reaction.Bone growth problems. Bone growth problems have happened in children who have been exposed to ERIVEDGE. These problems may continue even after stopping treatment with ERIVEDGE.The common side effects of ERIVEDGE are:muscle spasmshair losschange in how things taste or loss of tasteweight losstirednessnauseadiarrheadecreased appetiteconstipationjoint painvomitingERIVEDGE can cause absence of menstrual periods (amenorrhea) in females who are able to become pregnant. It is not known if amenorrhea is permanent. Talk to your healthcare provider if you have concerns about fertility.These are not all the possible side effects of ERIVEDGE.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.You may also report side effects to Genentech, Inc. at 1-888-835-2555.How should store ERIVEDGEStore ERIVEDGE at room temperature between 68F to 77F (20C to 25C).Keep the bottle tightly closed to protect ERIVEDGE from moisture.Keep ERIVEDGE and all medicines out of the reach of children.General information about the safe and effective use of ERIVEDGE.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use ERIVEDGE for condition for which it was not prescribed. Do not give ERIVEDGE to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ERIVEDGE that is written for health professionals.What are the ingredients in ERIVEDGEActive ingredient: vismodegibInactive ingredients: microcrystalline cellulose, lactose monohydrate, sodium lauryl sulfate, povidone, sodium starch glycolate, talc, 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.Manufactured by: Patheon, Inc. Mississauga, CanadaDistributed by: Genentech USA, Inc. Member of the Roche Group DNA Way South San Francisco, CA 94080-4990ERIVEDGE is registered trademark of Genentech, Inc.(C)2020 Genentech, Inc.For more information, call 1-855-737-4833 or go to www.erivedge.com. You should talk with your healthcare provider about the risks of ERIVEDGE to your unborn child.. Your healthcare provider will do pregnancy test within days before you start taking ERIVEDGE.. In order to avoid pregnancy, you should use birth control during treatment and for 24 months after your final dose of ERIVEDGE. Talk with your healthcare provider about what birth control method is right for you during this time.. Talk to your healthcare provider right away if you have unprotected sex or if you think that your birth control has failed.. Tell your healthcare provider right away if you become pregnant or think that you may be pregnant.. ERIVEDGE is present in semen. Do not donate semen while you are taking ERIVEDGE and for months after your final dose.. You should always use condom, even if you have had vasectomy, during sex with female partners who are pregnant or who are able to become pregnant, during treatment with ERIVEDGE and for months after your final dose to protect your female partner from being exposed to ERIVEDGE.. Tell your healthcare provider right away if your partner becomes pregnant or thinks she is pregnant while you are taking ERIVEDGE.. are pregnant or plan to become pregnant. See What is the most important information should know about ERIVEDGE are breastfeeding or plan to breastfeed. It is not known if ERIVEDGE passes into your breast milk. You should not breastfeed during treatment and for 24 months after your final dose of ERIVEDGE. Talk to your healthcare provider about the best way to feed your baby during this time.. Take ERIVEDGE exactly as your healthcare provider tells you.. You can take ERIVEDGE with or without food.. Swallow ERIVEDGE capsules whole. Do not open or crush the capsules.. Take ERIVEDGE time each day.. If you miss dose, skip the missed dose. Just take your next scheduled dose.. Do not donate blood or blood products while you are taking ERIVEDGE and for 24 months after your final dose. For Males: Do not donate semen while you are taking ERIVEDGE and for months after your final dose.. See What is the most important information should know about ERIVEDGE Severe skin reactions. Severe skin reactions have happened in some people taking ERIVEDGE. You may need to be treated in hospital because these severe skin reactions can be life-threatening or lead to death. Tell your healthcare provider right away if you develop any of the following signs or symptoms of severe skin reaction, including:. blisters or peeling of your skin. blisters on your lip, or around your mouth or eyes. mouth sores or genital sores. high fever or flu-like symptoms. enlarged lymph nodes. skin pain and burning. Your healthcare provider may permanently stop ERIVEDGE if you develop severe skin reaction.. Bone growth problems. Bone growth problems have happened in children who have been exposed to ERIVEDGE. These problems may continue even after stopping treatment with ERIVEDGE.. muscle spasms. hair loss. change in how things taste or loss of taste. weight loss. tiredness. nausea. diarrhea. decreased appetite. constipation. joint pain. vomiting. Store ERIVEDGE at room temperature between 68F to 77F (20C to 25C).. Keep the bottle tightly closed to protect ERIVEDGE from moisture.

SPL UNCLASSIFIED SECTION.

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

STORAGE AND HANDLING SECTION.

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

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Breastfeeding not recommended. (8.2)Females and Males of Reproductive Potential: May cause amenorrhea in females. (8.3). Lactation: Breastfeeding not recommended. (8.2). Females and Males of Reproductive Potential: May cause amenorrhea in females. (8.3). 8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ERIVEDGE during pregnancy. Report pregnancies to Genentech at 1-888-835-2555.. Risk SummaryBased on its mechanism of action and findings from animal reproduction studies, ERIVEDGE can cause fetal harm when administered to 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 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 DataIn 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 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. 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).. 8.2 Lactation. No data are available regarding the presence of vismodegib in human milk, the effects of the drug on the breastfed child, or the effects of the drug on milk production. Because of the potential for serious adverse reactions in breastfed infants from ERIVEDGE, advise women that breastfeeding is not recommended during therapy with ERIVEDGE and for 24 months after the final dose. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify the pregnancy status of females of reproductive potential within days prior to initiating ERIVEDGE.. ContraceptionBased on its mechanism of action and animal data, ERIVEDGE can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. FemalesAdvise females of reproductive potential to use effective contraception during therapy with ERIVEDGE and for 24 months after the final dose.. MalesVismodegib is present in semen [see Clinical Pharmacology (12.3)]. It is not known if the amount of vismodegib in semen can cause embryo-fetal harm. Advise male patients to use condoms, even after vasectomy, to avoid drug exposure to pregnant partners and female partners of reproductive potential during therapy with and for months after the final dose of ERIVEDGE. Advise males of the potential risk to an embryo or fetus if female partner of reproductive potential is exposed to ERIVEDGE. Advise males not to donate semen during therapy with ERIVEDGE and for months after the final dose.. Infertility. FemalesAmenorrhea can occur in females of reproductive potential. Reversibility of amenorrhea is unknown [see Adverse Reactions (6.1)].. 8.4 Pediatric Use. 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).. 8.5 Geriatric Use. Clinical studies of ERIVEDGE did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 8.6Hepatic Impairment. No dose adjustment is required in patients with hepatic impairment [see Clinical Pharmacology (12.3)].. 8.7Renal Impairment. No dose adjustment is required in patients with renal impairment [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

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 months after therapy (5.1, 8.3) Severe Cutaneous Adverse Reactions: Permanently discontinue ERIVEDGE in patients with these reactions (5.2)Premature fusion of the epiphyses (5.3, 8.4). 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 months after therapy (5.1, 8.3) 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 months after therapy (5.1, 8.3). Severe Cutaneous Adverse Reactions: Permanently discontinue ERIVEDGE in patients with these reactions (5.2). Premature fusion of the epiphyses (5.3, 8.4). 5.1Embryo-Fetal Toxicity. Based on its mechanism of action, ERIVEDGE can cause embryo-fetal death or severe birth defects when administered to 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 PotentialVerify the pregnancy status of females of reproductive potential within days prior to initiating ERIVEDGE. Advise pregnant women of the potential risk to 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)]. MalesVismodegib 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 vasectomy, to avoid potential drug exposure in pregnant partners and female partners of reproductive potential during therapy and for months after the final dose of ERIVEDGE. Advise male patients not to donate semen during and for months after the final dose of ERIVEDGE [see Use in Specific Populations (8.3)]. Blood DonationAdvise 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 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.