VISMODEGIB: 8,135 Adverse Event Reports & Safety Profile

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

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 ® (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 )

AND ADMINISTRATION 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) ]</span> .

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) <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> . Interrupt ERIVEDGE for severe or intolerable musculoskeletal adverse reactions. Permanently discontinue ERIVEDGE for recurrent, severe or intolerable musculoskeletal adverse reactions <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span> .

None. None.

REACTIONS 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> .

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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) ]</span>.

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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span>. Permanently discontinue ERIVEDGE in patients with these reactions <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span>.

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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.4) ]</span>. ERIVEDGE is not indicated for pediatric patients.