Erivedge targets Hedgehog pathway signaling, a known driver of BCC 3,4

The mechanism of action of Erivedge is primarily based on preclinical models.

More than 90% of all BCCs have abnormal Hedgehog pathway signaling. 3

 

Hedgehog Pathway Signaling

The Hedgehog pathway plays a crucial role during embryonic development, but normally has limited activity in most adult tissues. 15

  1. Patched (PTCH): A Hedgehog receptor that inhibits SMO in the absence of ligands. 15
  2. Smoothened (SMO): A signaling receptor that transmits Hedgehog signaling upon activation. 12

Abnormal Hedgehog Pathway Signaling

Mutations in key receptor proteins Patched (PTCH) and Smoothened (SMO) result in abnormal activation of the Hedgehog pathway in adults. 12

Smoothened (SMO): Signaling receptor

Glioma-associated oncogene (GLI): Transcription factor

  1. Mutations in PTCH or SMO release SMO from the inhibitory effect of PTCH. Once activated, SMO moves to the cell surface and activates GLI. 12
  2. GLI travels to the cell nucleus and initiates the transcription of multiple target genes. 12
  3. These target genes regulate cell proliferation and survival. 12

Erivedge Is a Hedgehog Pathway Inhibitor

Erivedge works systemically to inhibit Hedgehog pathway signaling. 4,13 Research in preclinical models has shown that this may lead to inhibition of BCC proliferation. Erivedge capsule can cause fetal harm when administered to a pregnant woman based on its mechanism of action.

Smoothened (SMO): Signaling receptor

Glioma-associated oncogene (GLI): Transcription factor
  1. Erivedge is a small-molecule inhibitor that binds to and helps inhibit SMO function. 4,16
  2. Inhibition of SMO by Erivedge helps prevent the activation of GLI and its translocation to the nucleus. 12
  3. Transcription of Hedgehog pathway genes is blocked. Preclinical models have shown that blocking Hedgehog pathway activity can inhibit basal cell proliferation. 7,11,12,16
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BOXED 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 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

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INDICATION

Erivedge® (vismodegib) 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.

BOXED WARNING AND ADDITIONAL IMPORTANT SAFETY INFORMATION

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 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
  • 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 (888) 835‑2555

Female Patients

  • Advise females of reproductive potential to use effective contraception during therapy with Erivedge and for 24 months after the final dose

Male Patients

  • Advise males of the potential risk to an embryo or fetus if a female partner of reproductive potential is exposed to Erivedge. Advise male patients to use condoms with a pregnant partner or a female partner of reproductive potential, even after a vasectomy, during therapy and for 3 months after the final dose of Erivedge

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

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

Adverse Reactions

  • The most common adverse reactions (≥10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia
  • Amenorrhea can occur in females of reproductive potential. Reversibility of amenorrhea is unknown. In clinical trials, a total of 3 of 10 pre-menopausal women developed amenorrhea while receiving Erivedge
  • 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)

Use in Specific Populations

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

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555.

Please see full Prescribing Information, including the BOXED WARNING and the Medication Guide, for a complete discussion of the risks associated with Erivedge.