Prescription Drugs

CLINICAL PHARMACOLOGY 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. Pharmacodynamics Cardiac Electrophysiology The QTc interval was not affected by therapeutic doses of ERIVEDGE in a thorough QTc trial. Pharmacokinetics Absorption The single dose absolute bioavailability of vismodegib is 31.8%. 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. ERIVEDGE capsule may be taken without regard to meals because the systemic exposure of vismodegib at steady state is 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 greater than 99%. Vismodegib binds to both human serum albumin and alpha-1-acid glycoprotein (AAG) and binding to AAG is saturable. In a pharmacokinetic study, male patients (n=3) had an average concentration of vismodegib in semen on day 8 that was 6.5% of the average steady state concentration (Css) observed in plasma. 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 CYP3A4/5. Elimination 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. The estimated elimination half-life (t½) of vismodegib is 4 days after continuous once-daily dosing and 12 days after a single dose. Specific Populations Hepatic Impairment In a dedicated clinical study, the mean systemic exposure (AUC 0-24hr) of vismodegib was increased by 24% in patients with mild (n=8), 31% in patients with moderate (n=6) and decreased 14% in patients with severe (n=3) hepatic impairment when compared to patients with normal hepatic function (n=9) after 8 days of daily ERIVEDGE administration. The NCI Organ Dysfunction Working Group criteria for hepatic impairment were used in the study. Mild hepatic impairment was defined as normal total bilirubin and aspartate transaminase (AST) > upper limit of normal (ULN) or total bilirubin > 1.0 to 1.5 times ULN, moderate hepatic impairment as total bilirubin > 1.5 to 3.0 times ULN, and severe hepatic impairment as total bilirubin > 3.0 to 10.0 times ULN. Renal Impairment Renal excretion of vismodegib after oral administration of ERIVEDGE is low (<5%). The population pharmacokinetic analysis suggested no clinically relevant effect of renal impairment on the systemic exposure of vismodegib, based on pharmacokinetic data from patients with mild (CLcr 50 to 79 mL/min, n=58), and moderate (CLcr 30 to 49 mL/min, n=16) renal impairment. Weight, Age, And Sex The results of a population pharmacokinetic analysis suggested no clinically relevant effect of weight (range: 41-140 kg), age (range: 26-89 years), and sex on the systemic exposure of vismodegib. Drug Interaction Studies Effect Of Drugs On Vismodegib Coadministration of ERIVEDGE with fluconazole (a moderate CYP2C9 inhibitor and moderate CYP3A4 inhibitor) increased mean AUC0-24hr and steady-state concentrations of vismodegib by 1.3-fold in healthy subjects. A strong inhibitor of CYP3A4 and P-gp (itraconazole) or a proton pump inhibitor (rabeprazole) had no effect on the steady-state systemic exposure of vismodegib when coadministered with ERIVEDGE in healthy subjects. Effects of Vismodegib on Other Drugs: Results of a drug interaction study conducted in cancer patients demonstrated that the systemic exposure of rosiglitazone (a CYP2C8 substrate) or oral contraceptives (ethinyl estradiol and norethindrone) is not altered when either drug is coadministered with vismodegib. In vitro studies suggest that vismodegib is an inhibitor of CYP2C8, CYP2C9, CYP2C19 and the transporter BCRP and that vismodegib is not an inducer of CYP1A2, CYP2B6, or CYP3A. Animal Toxicology Neurologic effects characterized as limb or body tremors or twitching were observed in rats administered oral vismodegib for 4 weeks or longer at ≥ 50 mg/kg/day (approximately ≥ 0.4 times the AUC in patients at the recommended human dose). These observations resolved upon discontinuation of dosing and were not associated with microscopic findings. Clinical Studies A single, international, single-arm, multi-center, open-label, 2-cohort trial 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 150 mg vismodegib per day orally until disease progression or unacceptable toxicity. The major efficacy outcome measure of the trial 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 2 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 a 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 key outcome measures are presented in Table 2, below. Table 2: Objective Response Rate: Efficacy-Evaluable Patients1 mBCC (n = 33) laBCC (n = 63) IRF2-Confirmed ORR, n (%) 10 (30.3) 27 (42.9) (95% CI) (15.6, 48.2) (30.5, 56.0) Complete response3 0 (0.0) 13 (20.6) Partial response 10 (30.3) 14 (22.2) Median Response Duration (months) 7.6 7.6 (95% CI5) (5.6, NE4) (5.7, 9.7) 1Patients who received at least one dose of ERIVEDGE with independent pathologist-confirmed diagnosis of BCC 2IRF = Independent Review Facility 3For laBCC, complete response was defined as objective response with no residual BCC on sampling tumor biopsy. 4NE = Not estimable 5CI = Confidence Interval

Find Lowest Prices on ERIVEDGE® (vismodegib) Capsule for Oral Use WARNING EMBRYO-FETAL TOXICITY ERIVEDGE can cause embryo-fetal death or severe birth defects when administered to a pregnant woman. ERIVEDGE is embryotoxic, fetotoxic, and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations. Verify the pregnancy status of females of reproductive potential within 7 days prior to initiating ERIVEDGE therapy. Advise females of reproductive potential to use effective contraception during and after ERIVEDGE therapy. Advise males of the potential risk of ERIVEDGE exposure through semen and to use condoms with a pregnant partner or a female partner of reproductive potential. Advise pregnant women of the potential risks to a fetus. [See WARNINGS AND PRECAUTIONS, Use In Specific Populations]. DESCRIPTION Vismodegib is an inhibitor of the hedgehog (Hh) signaling pathway, 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 421.30 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. Each ERIVEDGE (vismodegib) capsule for oral administration contains 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.

INDICATIONS ERIVEDGE capsule 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. DOSAGE AND ADMINISTRATION The recommended dose of ERIVEDGE is 150 mg taken orally once daily until disease progression or until unacceptable toxicity [see Clinical Studies]. ERIVEDGE may be taken with or without food. Swallow capsules whole. Do not open or crush capsules. If a dose of ERIVEDGE is missed, do not make up that dose; resume dosing with the next scheduled dose. HOW SUPPLIED Dosage Forms And Strengths ERIVEDGE (vismodegib) capsules, 150 mg. The capsule has a pink opaque body and a grey opaque cap, with “150 mg” printed on the capsule body and “VISMO” printed on the capsule cap in black ink. Storage And Handling Each ERIVEDGE (vismodegib) capsule has a pink opaque body and a 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 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 in order to protect from moisture. Manufactured by: Patheon, Inc., Mississauga, Canada. Distributed by: Genentech USA, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990. Revised: 2017

PATIENT INFORMATION ERIVEDGE® (EH-rih-vej) (vismodegib) Capsule What is the most important information I should know about ERIVEDGE? ERIVEDGE 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 a pregnancy test 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 3 months after your final dose. You should always use a condom, even if you have had a vasectomy, during sex with female partners who are pregnant or who are able to become pregnant, during treatment with ERIVEDGE and for 3 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. Exposure to ERIVEDGE during pregnancy: 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 ERIVEDGE? ERIVEDGE is a prescription medicine used to treat adults with a 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 I tell my healthcare provider before taking ERIVEDGE? Before taking ERIVEDGE, tell your healthcare provider if you: are pregnant or plan to become pregnant. See “What is the most important information I 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 I take ERIVEDGE? 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 one time each day. If you miss a dose, skip the missed dose. Just take your next scheduled dose. What should I avoid while taking ERIVEDGE? Do not donate blood or blood products while you are taking ERIVEDGE and for 24 months after your final dose. Do not donate semen while you are taking ERIVEDGE and for 3 months after your final dose. What are the possible side effects of ERIVEDGE? ERIVEDGE can cause serious side effects, including: See “What is the most important information I should know about ERIVEDGE?” 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 most common side effects of ERIVEDGE are: muscle spasms hair loss change in how things taste or loss of taste weight loss tiredness nausea diarrhea decreased appetite constipation joint pain vomiting ERIVEDGE 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 I store ERIVEDGE? Store ERIVEDGE at room temperature between 68°F to 77°F (20°C to 25°C). 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 a Medication Guide. Do not use ERIVEDGE for a 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 ERIVEDGE? Active ingredient: vismodegib Inactive 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. This Medication Guide has been approved by the U.S. Food and Drug Administration.

OVERDOSE There is no information on overdosage in humans. In clinical trials, ERIVEDGE capsule was administered at 540 mg orally once daily; exposure did not increase between 150 mg and 540 mg daily. CONTRAINDICATIONS None.

SIDE EFFECTS 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. ERIVEDGE capsule was administered as monotherapy at doses ≥ 150 mg orally daily in four open-label, uncontrolled, dose-ranging or fixed single dose clinical trials enrolling a total of 138 patients with advanced basal cell carcinoma (BCC). The median age of these patients was 61 years (range 21 to 101), 100% were White (including Hispanics), and 64% were male. The median duration of treatment was approximately 10 months (305 days; range 0.7 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 Advanced BCC Patients MedDRA Preferred Term2 All aBCC1 Patients (N = 138) All Grades3 (%) Grade 3 (%) Grade 4 (%) Gastrointestinal disorders Nausea 42 (30.4%) 1 (0.7%) - Diarrhea 40 (29.0%) 1 (0.7%) - Constipation 29 (21.0%) - - Vomiting 19 (13.8%) - - General disorders and administration site conditions Fatigue 55 (39.9%) 7 (5.1%) 1 (0.7%) Investigations Weight loss 62 (44.9%) 10 (7.2%) - Metabolism and nutrition disorders Decreased appetite 35 (25.4%) 3 (2.2%) - Musculoskeletal and connective tissue disorders Muscle spasms 99 (71.7%) 5 (3.6%) - Arthralgias 22 (15.9%) 1 (0.7%) Nervous system disorders Dysgeusia 76 (55.1%) - - Ageusia 15 (10.9%) - - Skin and subcutaneous tissue disorders Alopecia 88 (63.8%) - - 1aBCC = Advanced Basal Cell Carcinoma. 2MedDRA = Medical Dictionary for Regulatory Activities. 3Grading according to NCI-CTCAE v3.0. Amenorrhea In clinical trials, a total of 3 of 10 pre-menopausal women developed amenorrhea while receiving ERIVEDGE [see Non-Clinical Toxicology]. Laboratory Abnormalities Treatment-emergent Grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%). 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 CPK reported. Within the subset of patients, 38% had a shift from baseline, and one of the patients had a Grade 3 value. The prevalence of Grade 3/4 CPK elevation across the entire study population with any CPK measurement was 2.4% (11 out of 453 patients). 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. Musculoskeletal And Connective Tissue Disorders Premature fusion of the epiphyses [see WARNINGS AND PRECAUTIONS and Use In Specific Populations]. Investigations blood creatine phosphokinase increased DRUG INTERACTIONS Clinically relevant pharmacokinetic interactions are not expected between vismodegib and a substrate, inducer or inhibitor of cytochrome 450 enzymes or an inhibitor of P-glycoprotein (P-gp) or between vismodegib and gastric pH elevating agents [see CLINICAL PHARMACOLOGY].

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS 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/day. Verify the pregnancy status of females of reproductive potential within 7 days prior to initiating ERIVEDGE therapy. Advise females of reproductive potential to use effective contraception during therapy with ERIVEDGE and for 24 months after the final dose. Advise male patients 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 pregnant women of the potential risk to a fetus [see Use In Specific Populations and CLINICAL PHARMACOLOGY]. Blood Donation Advise patients not to donate blood or blood products while receiving ERIVEDGE and for 24 months after the final dose of ERIVEDGE. Semen Donation Vismodegib is present in semen. It is not known if the amount of vismodegib in semen can cause embryo-fetal harm. Advise male patients not to donate semen during and for 3 months after the final dose of ERIVEDGE [see Use In Specific Populations]. 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 ADVERSE REACTIONS and Use In Specific Populations]. Patient Counseling Information See FDA-approved patient labeling (Medication Guide). Administration Instructions Advise patients to swallow ERIVEDGE capsules whole and not to crush or open the capsules. Embryo-Fetal Toxicity Advise pregnant women of the potential risk to a fetus [see WARNINGS AND PRECAUTIONS and Use In Specific Populations]. Advise females of reproductive potential to use effective contraception during therapy with and for 24 months after the final dose of ERIVEDGE [see WARNINGS AND PRECAUTIONS and Use In Specific Populations]. 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 and for 3 months after the final dose of ERIVEDGE [see WARNINGS AND PRECAUTIONS and Use In Specific Populations]. Advise female patients and female partners of male patients to contact their healthcare provider with a known or suspected pregnancy. Report pregnancies to Genentech at 1-888-835-2555 [see WARNINGS AND PRECAUTIONS and Use In Specific Populations]. Semen Donation Advise males not to donate semen during therapy with and for 3 months after the final dose of ERIVEDGE. Lactation Advise women that breastfeeding is not recommended during therapy with ERIVEDGE and for 24 months after the final dose [see Use In Specific Populations]. Blood Donation Advise patients not to donate blood or blood products while taking ERIVEDGE and for 24 months after the final dose of ERIVEDGE. Premature Fusion Of The Epiphyses Advise patients and caregivers that premature fusion of the epiphyses has been reported in pediatric patients exposed to ERIVEDGE. In some cases, fusion progressed after drug discontinuation. Nonclinical Toxicology Carcinogenesis, 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 steady-state AUC0-24h at the recommended human 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 1.2fold of the steady-state AUC0-24h at the recommended human 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. Use In Specific Populations Pregnancy Risk Summary Based on its mechanism of action and animal reproduction studies, ERIVEDGE can cause fetal harm when administered to a pregnant woman [see CLINICAL PHARMACOLOGY]. In animal reproduction studies, oral administration of vismodegib during organogenesis at doses below the recommended human 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. Report pregnancies to Genentech at 1-888-835-2555. The background risk of major birth defects and miscarriage for the indicated population is unknown. 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 developmental 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 systemic exposure (AUC) in patients at the recommended human dose), which included early resorption of 100% of the fetuses. A dose of 10 mg/kg/day (approximately 0.2 times the AUC in patients at the recommended 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). Lactation No data are available regarding the presence of vismodegib 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 from ERIVEDGE, advise a nursing woman that breastfeeding is not recommended during therapy with ERIVEDGE and for 24 months after the final dose. Females And Males Of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential within 7 days prior to initiating ERIVEDGE therapy. Contraception Females Based on its mechanism of action and animal data, ERIVEDGE can cause fetal harm when administered to a pregnant woman [see Use In Specific Populations]. Advise females of reproductive potential to use effective contraception during therapy and for 24 months after the final dose of ERIVEDGE. Males Vismodegib is present in semen [see CLINICAL PHARMACOLOGY]. It is not known if the amount of vismodegib in semen can cause embryo-fetal harm. Advise male patients to use condoms, even after a vasectomy, to avoid drug exposure to pregnant partners and female partners of reproductive potential during therapy with and for 3 months after the final dose of ERIVEDGE. Advise males of the potential risk to an embryo or fetus if a female partner of reproductive potential is exposed to ERIVEDGE. Advise males not to donate semen during therapy with and for 3 months after the final dose of ERIVEDGE. Infertility Females Amenorrhea can occur in females of reproductive potential. Reversibility of amenorrhea is unknown [see ADVERSE REACTIONS]. Pediatric Use The safety and effectiveness of ERIVEDGE capsule have not been established in pediatric patients. Premature fusion of the epiphyses has been reported in pediatric patients exposed to ERIVEDGE. In some cases, fusion progressed after drug discontinuation. [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS]. 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 systemic exposure (AUC) in patients at the recommended human 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 AUC in patients at the recommended human dose). Geriatric Use Clinical studies of ERIVEDGE capsule did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Hepatic Impairment No dose adjustment is required in patients with hepatic impairment [see CLINICAL PHARMACOLOGY]. Renal Impairment No dose adjustment is required in patients with renal impairment [see CLINICAL PHARMACOLOGY].