The 2012 edition of The Skin Cancer Foundation Journal features medically reviewed, reader-friendly articles such as tanning, the increasing incidence of skin cancer diagnoses among young women, & the prevalence of melanoma among white males over 50.
Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients (cont)
All aBCC1 MedDRA Preferred Term2
ERIVEDGE (vismodegib) capsule Initial U.S. Approval: 2012
This is a brief summary of information about ERIVEDGE. Before prescribing, please see full prescribing information.
WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS
ERIVEDGE (vismodegib) capsule can result in embryo-fetal death or severe birth defects. ERIVEDGE is embryotoxic and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations.
Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of these risks. Advise female patients of the need for contraception and advise male patients of the potential risk of ERIVEDGE exposure through semen [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.6)].
1 INDICATIONS AND USAGE
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.
2 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 (14)].
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.
4 CONTRAINDICATIONS
None. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Death and Severe Birth Defects
ERIVEDGE capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vismodegib is teratogenic, embryotoxic, and fetotoxic in rats at maternal exposures lower than the human exposures at the recommended dose of 150 mg/day.
In rats, malformations included craniofacial
anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed.
Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of the risks of embryo-fetal death and severe birth defects and the need for contraception during and after treatment.
Advise patients to contact their healthcare provider
immediately if they suspect they (or, for males, their female partner) may be pregnant. Female and male patients of reproductive potential
should be counseled regarding pregnancy prevention
and planning. If ERIVEDGE is used during pregnancy or if a patient becomes pregnant while taking (or for a male patient, if his female partner is exposed to) ERIVEDGE, the patient should be apprised of the potential hazard to the fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Use in Specific Populations (8.1, 8.6)].
5.2 Blood Donation
Advise patients not to donate blood or blood products while receiving ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. 6 ADVERSE REACTIONS 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.
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
All aBCC1 MedDRA Preferred Term2
Gastrointestinal disorders Nausea Diarrhea
Constipation Vomiting
General disorders and administration site conditions
Fatigue
Investigations Weight loss
55 (39.9%) 7 (5.1%) 1 (0.7%) 62 (44.9%) 10 (7.2%) -
All Grades3 (%)
Patients (N = 138)
Grade 3 (%)
42 (30.4%) 1 (0.7%) 40 (29.0%) 1 (0.7%) 29 (21.0%) 19 (13.8%)
- -
Grade 4 (%)
- - - -
Metabolism and nutrition disorders
Decreased appetite
Musculoskeletal and connective tissue disorders
Muscle spasms Arthralgias
Nervous system disorders Dysgeusia Ageusia
Skin and subcutaneous tissue disorders
Alopecia 88 (63.8%) 1aBCC = Advanced Basal Cell Carcinoma.
2MedDRA = Medical Dictionary for Regulatory Activities. 3
Grading 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 (13.1)]. 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%).
7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Vismodegib Drugs that Inhibit or Induce Drug Metabolizing Enzymes Vismodegib elimination involves multiple pathways.
- -
99 (71.7%) 5 (3.6%) 22 (15.9%) 1 (0.7%)
76 (55.1%) 15 (10.9%)
- -
-
- -
35 (25.4%) 3 (2.2%) -
All Grades3 (%)
Patients (N = 138)
Grade 3 (%)
Grade 4 (%)
of the potential for serious adverse reactions in nursing infants from ERIVEDGE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use The safety and effectiveness of ERIVEDGE capsule have not been established in pediatric patients.
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).
8.5 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.
8.6 Females of Reproductive Potential and Males
ERIVEDGE capsule can cause harm to the embryo or fetus when administered during pregnancy.
regarding pregnancy prevention and planning. Female patients Vismodegib is
predominantly excreted as an unchanged drug. Several minor metabolites are produced by multiple CYP enzymes. Although vismodegib is a substrate of CYP2C9 and CYP3A4 in vitro, CYP inhibition is not predicted to alter vismodegib systemic exposure since similar steady-state plasma vismodegib concentrations were observed in patients in clinical trials concomitantly treated with CYP3A4 inducers (i.e., carbamazepine, modafinil, phenobarbital) and those concomitantly treated with CYP3A4 inhibitors (i.e., erythromycin, fluconazole).
Drugs that Inhibit Drug Transport Systems
In vitro studies indicate that vismodegib is a substrate of the efflux transporter P-glycoprotein (P-gp). When ERIVEDGE is coadministered with
drugs that inhibit P-gp Drugs that Affect Gastric pH
Drugs that alter the pH of the upper GI tract (e.g. proton pump inhibitors, H2
-receptor antagonists, and antacids) may alter the solubility of
exposure of vismodegib may be decreased and the effect on efficacy of ERIVEDGE is unknown.
7.2 Effects of Vismodegib on Other Drugs
Results of a drug-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 co-administered with vismodegib.
In vitro studies indicate that vismodegib is an inhibitor of CYP2C8, CYP2C9, CYP2C19 and the transporter BCRP. Vismodegib does not induce CYP1A2, CYP2B6, or CYP3A4/5 in human hepatocytes.
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy
Pregnancy Category D ERIVEDGE capsule can cause fetal harm when administered to a pregnant female based on its mechanism of action.
Vismodegib
craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. Vismodegib is embryolethal in rats at exposures within the range achieved at the recommended human dose. If ERIVEDGE is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the embryo or fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555.
is teratogenic in rats at doses corresponding to an exposure of 20% of the exposure at the recommended human dose (estimated AUC0-24hr
Encourage
women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Warnings and Precautions (5.1)].
In an embryo-fetal developmental toxicity study, pregnant rats were administered oral vismodegib 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).
8.3 Nursing Mothers
It is not known whether vismodegib is excreted in human breast milk. Because many drugs are excreted in human milk and because
steady-state exposure). In rats, malformations included
vismodegib and reduce its bioavailability. However, no formal clinical study has been conducted to evaluate the effect of gastric pH altering agents on the systemic exposure of vismodegib. Increasing the dose of ERIVEDGE when coadministered with such agents is not likely to compensate for the loss of exposure. When ERIVEDGE is coadministered with a proton pump inhibitor, H2
-receptor antagonist or antacid, systemic (e.g. clarithromycin, erythromycin,
azithromycin), systemic exposure of vismodegib and incidence of adverse events of ERIVEDGE may be increased.
Determine pregnancy status within 7 days prior to initiation of treatment in females of reproductive potential. For females with a negative pregnancy test, initiate a highly effective form of contraception (failure rate of less than 1%) prior to the first dose. Continue highly effective contraception during therapy and for 7 months after the last dose of ERIVEDGE. If a patient becomes pregnant while taking ERIVEDGE, or during the 7 months after the last dose of treatment, report the pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage pregnant females to participate in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. Counsel pregnant females about the teratogenic risk to the fetus.
Amenorrhea has been observed in clinical trials in females of reproductive potential. Reversibility of amenorrhea is unknown [see Adverse Reactions (6), Nonclinical Toxicology (13.1)].
Male patients
Male patients should use condoms with spermicide, even after a vasectomy, during sexual intercourse with female partners while being treated with ERIVEDGE capsule and for 2 months after the last dose to avoid exposing an embryo or fetus to vismodegib.
8.7 Hepatic Impairment
The safety and effectiveness of ERIVEDGE capsule have not been established in patients with hepatic
impairment
Pharmacology (12.3)]. 8.8 Renal Impairment
The safety and effectiveness of ERIVEDGE capsule have not been established in patients with renal impairment
Pharmacology (12.3)]. 10
OVERDOSAGE 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.
17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). D /?4<0 :,=408=< =3,= # '
cause embryo-fetal death or severe birth defects.
D 8<=;>.= 107,60 :,=408=< 91 ;0:;9/>.=4?0 :9=08=4,6 =9 ><0 , 34236B effective form of contraception (failure rate of less than 1%) while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE.
D 8<=;>.= ,66 7,60 :,=408=< 0?08 =39<0 @4=3 :;49; ?,<0.=97B =9 ><0 condoms with spermicide, during sexual intercourse with female partners while taking ERIVEDGE and for at least 2 months after the last dose of ERIVEDGE.
D 8<=;>.= :,=408=< =9 4770/4,=06B .98=,.= =304; 30,6=3.,;0 :;9?4/0; if they (or, for males, their female partner) become pregnant or if pregnancy is suspected following exposure to ERIVEDGE.
D 8<=;>.= :,=408=< =9 4770/4,=06B ;0:9;= ,8B :;028,8.B 0A:9<>;0 =9 ERIVEDGE and encourage participation in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555.
D 819;7 107,60 :,=408=< 91 =30 :9=08=4,6 19; <0;49>< ,/?0;<0 reactions in nursing infants from ERIVEDGE, taking into account the importance of the drug to the mother.
D /?4<0 :,=408=< 89= =9 /98,=0 -699/ 9; -699/ :;9/>.=< @3460 =,5482 ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE.
D /?4<0 :,=408=< =9 <@,669@ # ' crush or open the capsules.
.,:<>60< @3960 ,8/ 89= =9 0A:9<>;0 />;482 :;028,8.B .,8 [see Clinical [see Clinical
Counsel female and male patients Advise patients to
contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant [see Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.1)]
ERIVEDGE™ [vismodegib] capsule
Manufactured by: Patheon, Inc. Mississauga, Canada
Distributed by: Genentech USA, Inc.
A Member of the Roche Group 1 DNA Way
ERIVEDGE is a registered trademark of Genentech,
©2012 Genentech,
South San Francisco, CA 94080-4990 HED0000832300
Inc. Inc.
10135493