ERIVEDGE

Vismodegib is an

Oral active small molecule that inhibits the hedgehog signaling pathway by binding to and inhibiting the transmembrane protein smoothened homologue (SMO). 4, 5, 6 It was discovered by high-throughput screening of a library of small-molecule compounds and subsequent optimization through medicinal chemistry.

Since it targets the hedgehog signaling pathway, vismodegib has anti-tumor activity in basal-cell carcinoma.

Hedgehog signaling pathway plays an important role in the development of organs and tissues during embryogenesis.

Afterwards, it is silenced in all cells and tissues, except for hair, skin and stem cells.

However, dysregulated or aberrant Hedgehog signaling has been associated with basal cell carcinoma pathogenesis. 3, 6 In January 2012, vismodegib was approved by the FDA for the treatment of adult basal cell carcinoma.

In July 2013, it was approved by the EMA, and since then, it has been approved by several other countries. 2, 5, 6.

Vismodegib 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.

Vismodegib selectively binds to and inhibits the transmembrane protein smoothened homologue (SMO) to inhibit the Hedgehog signalling pathway.

Following 7 days of 150 mg once-daily dosing, the use of vismodegib was not associated with a clinically significant QT interval prolongation.

Vismodegib can cause embryo-fetal death or severe birth defects, as well as severe cutaneous adverse reactions and musculoskeletal adverse reactions.

In pediatric patients given vismodegib, premature fusion of the epiphyses has been reported.

Vismodegib appears to have a nonlinear pharmacokinetic profile following daily oral dosing, and steady state is achieved within 7 days.

A dose increase from 150 mg to 540 mg (1-3.6 times the recommended dose) does not lead to an increase in steady-state plasma concentrations.

With a once-daily dose of 150 mg, the average plasma concentration of vismodegib at steady state is approximately 23 µM. The absolute bioavailability of a single dose of vismodegib is 31.8%.

Absorption is saturable and is not affected by food.

The volume of distribution of vismodegib ranges between 16.4 and 26.6 L.

Vismodegib is mainly metabolized by

CYP2C9 and CYP3A4 in the liver; however, more than 98% of total systemic vismodegib is not metabolized.

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.

Hover over products below to view reaction partners Vismodegib Vismodegib M1 metabolite Vismodegib M4 metabolite Vismodegib M3 metabolite Vismodegib M5 metabolite Vismodegib M14 metabolite.

Vismodegib is excreted mostly unchanged.

Vismodegib and its metabolites are mainly eliminated through feces.

Approximately 82% and 4.4% of the administered dose are recovered in feces and urine, respectively.

The half-life of vismodegib after a single dose is 12 days, and after continuous daily dosing is 4 days.

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information regarding vismodegib is not readily available.

Patients experiencing an overdose are at an increased risk of severe adverse effects such as severe cutaneous adverse reactions and musculoskeletal adverse reactions.

Symptomatic and supportive measures are recommended.

Patients treated with vismodegib have an increased risk of embryo-fetal death and significant birth defects.

Common adverse event include muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia.

Based on the results of in vitro and in vivo studies, vismodegib is not mutagenic.

No evidence of carcinogenicity was found in mice and rats given vismodegib.

A 26-week rat fertility study found that at doses of 100 mg/kg/day, vismodegib has no effects on male reproductive organs or fertility.

In female rats, the administration of vismodegib was associated with decreased implantations, increased percent preimplantation loss, and decreased numbers of dams with viable embryos.

The recommended dosage is 150 mg orally once daily. 2.1 Important Safety Information Verify pregnancy status of females of reproductive potential within 7 days prior to initiating ERIVEDGE. 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) .

ERIVEDGE for severe or intolerable musculoskeletal adverse reactions.

ERIVEDGE for recurrent, severe or intolerable musculoskeletal adverse reactions.

capsules have 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) .

Keep the bottle tightly closed to protect from moisture.

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) .

Keep the bottle tightly closed to protect from moisture.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ERIVEDGE during pregnancy.

Report pregnancies to

Genentech at 1-888-835-2555.

Based on its mechanism of action and findings from animal reproduction studies, ERIVEDGE can cause fetal harm when administered to a pregnant woman.

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.

There are no human data on the use of ERIVEDGE in pregnant women.

Advise pregnant women of the potential risk to a 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.

In 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.

• and post-implantation loss were increased at doses of ≥ 60 mg/kg/day [approximately 2 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.

A 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).

The safety and effectiveness of

ERIVEDGE have not been established in pediatric patients.

Premature fusion of the epiphyses and precocious puberty have been reported in pediatric patients exposed to ERIVEDGE.

In some cases, epiphyseal fusion progressed after drug discontinuation.

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).

Clinical studies of

ERIVEDGE did not include sufficient numbers of patients aged and over to determine whether they respond differently from younger patients.