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Vismodegib

Pronunciation

(vis moe DEG ib)

Index Terms

  • GDC-0449
  • Hedgehog Antagonist GDC-0449

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Erivedge: 150 mg

Brand Names: U.S.

  • Erivedge

Pharmacologic Category

  • Antineoplastic Agent, Hedgehog Pathway Inhibitor

Pharmacology

Basal cell cancer is associated with mutations in Hedgehog pathway components. Hedgehog regulates cell growth and differentiation in embryogenesis; while generally not active in adult tissue, Hedgehog mutations associated with basal cell cancer can activate the pathway resulting in unrestricted proliferation of skin basal cells. Vismodegib is a selective Hedgehog pathway inhibitor which binds to and inhibits Smoothened homologue (SMO), the transmembrane protein involved in Hedgehog signal transduction.

Distribution

Vd: 16.4 to 26.6 L

Males: In a small pharmacokinetic study, the average vismodegib concentration in semen was 6.5% of the average steady state plasma concentration on day 8

Metabolism

Metabolized by oxidation, glucuronidation, and pyridine ring cleavage, although >98% of circulating components are as the parent drug

Excretion

Feces (82%); urine (4%)

Time to Peak

~2.4 days (Graham, 2011)

Half-Life Elimination

Continuous daily dosing: ~4 days; Single dose: ~12 days

Protein Binding

>99%; primarily to serum albumin and alpha1 acid glycoprotein (AAG)

Special Populations: Hepatic Function Impairment

In patients with mild hepatic impairment (normal total bilirubin and AST >ULN or total bilirubin >1 to 1.5 times ULN), the mean systemic vismodegib exposure was increased 24% as compared to patients with normal hepatic function. Systemic exposure was increased 31% in patients with moderate impairment (total bilirubin >1.5 to 3 times ULN) and decreased 14% in patients with severe impairment (total bilirubin >3 to 10 times ULN), respectively, compared to patients with normal hepatic function.

Use: Labeled Indications

Basal cell carcinoma, metastatic or locally advanced: Treatment of metastatic basal cell carcinoma, or locally-advanced basal cell carcinoma that has recurred following surgery or in patients who are not candidates for surgery, and not candidates for radiation therapy

Contraindications

US labeling: There are no contraindications listed in the manufacturer’s labeling.

Canadian labeling: Hypersensitivity to vismodegib or any component of the formulation; pregnancy or females at risk of becoming pregnant; breast-feeding; male patients or female patients of childbearing potential who do not comply with the Erivedge Pregnancy Prevention Program; children and adolescents <18 years of age.

Dosing: Adult

Note: Vismodegib is associated with a moderate emetic potential; antiemetics may be needed to prevent nausea and vomiting.

Basal cell carcinoma, metastatic or locally advanced: Oral: 150 mg once daily until disease progression or unacceptable toxicity.

Missed doses: If a dose is missed, do not make up; resume dosing with the next scheduled dose.

Dosing: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

No dosage adjustment necessary.

Dosing: Adjustment for Toxicity

In clinical trials, no dosage reductions were allowed for toxicities, however, treatment interruptions up to 4 to 8 weeks were allowed for toxicity recovery (Basset-Seguin 2015; Sekulik 2012).

Administration

Oral: May be taken with or without food. Swallow capsules whole; do not open or crush. Vismodegib is associated with a moderate emetic potential; antiemetics may be needed to prevent nausea and vomiting. Hazardous agent; use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

There are no known significant interactions.

Adverse Reactions

>10%:

Central nervous system: Fatigue (40%)

Dermatologic: Alopecia (64%)

Endocrine & metabolic: Amenorrhea (30%)

Gastrointestinal: Dysgeusia (55%), weight loss (45%), nausea (30%), diarrhea (29%), decreased appetite (25%), constipation (21%), vomiting (14%), ageusia (11%)

Neuromuscular & skeletal: Muscle spasm (72%), arthralgia (16%)

1% to 10%:

Endocrine & metabolic: Hyponatremia (grade 3: 4%), hypokalemia (grade 3: 1%)

Renal: Azotemia (grade 3: 2%)

<1% (Limited to important or life-threatening): Cholestasis, hepatic injury, hepatitis, rhabdomyolysis

ALERT: U.S. Boxed Warning

Embryofetal death and severe birth defects:

Vismodegib can cause embryofetal death or severe birth defects when administered to a pregnant woman. Vismodegib 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 vismodegib therapy. Advise females of reproductive potential to use effective contraception during and after vismodegib therapy. Advise males of the potential risk of vismodegib 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.

Warnings/Precautions

Concerns related to adverse effects:

• Amenorrhea: Amenorrhea was observed in women of reproductive potential; it is unknown if this is reversible.

• Cardiac events: Cardiac events (eg, cardiac failure, atrial fibrillation, left ventricular dysfunction, restrictive cardiomyopathy, myocardial infarction) have been observed during treatment. All events ≥ grade 3 occurred in patients with a history of significant cardiac disease.

• Cutaneous squamous cell cancer (cuSCC): Cases of cuSCC have been reported. Patients with advanced basal cell carcinoma are at risk for developing cuSCC; monitor during treatment.

• Gastrointestinal toxicity: Vismodegib is associated with a moderate emetic potential; antiemetics may be needed to prevent nausea and vomiting. Diarrhea, constipation, abdominal pain, and decreased appetite may also occur.

Disease-related concerns:

• Hepatic impairment: Vismodegib metabolism is primarily hepatic. Elevated liver function tests (ALT, AST, total bilirubin, and alkaline phosphatase) have been observed; cases of cholestasis, hepatitis, and hepatocellular injury have also been reported. Monitor liver function tests; may require treatment interruption or discontinuation (Erivedge Canadian product monograph, 2015).

• Renal impairment: Population pharmacokinetic analyses demonstrate that creatinine clearance (range: 30 to 80 mL/minute) does not have a clinically meaningful effect on systemic exposure; urinary excretion is <5%.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pregnancy: [US Boxed Warnings]: May result in severe birth defects or embryo-fetal death. Teratogenic effects (severe midline defects, missing digits, and other irreversible malformations), embryotoxic, and fetotoxic events were observed in animal reproduction studies. Verify pregnancy status (in females of reproductive potential) within 7 days prior to initiating treatment and advise patients (female and male) of the risk of birth defects, the need for contraception and risk of exposure through semen and to use condoms with a pregnant partner or a female partner of childbearing potential.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

Other warnings/precautions:

• Blood donations: Advise patients not to donate blood or blood products during vismodegib treatment and for at least 7 months after the last vismodegib dose. The Canadian labeling recommends patients not donate blood or blood products during treatment (including treatment interruptions) and for 24 months after discontinuation.

• Semen donations: Vismodegib is present in semen, although the amount of drug in semen that may cause embryotoxicity and/or fetotoxicity is not known. Advise patients not to donate sperm during vismodegib treatment and for 3 months after the last vismodegib dose.

• Toxicity duration: In a study of vismodegib in patients with basal cell nevus syndrome (not an approved use), with discontinuation of vismodegib treatment, taste alteration and muscle cramps abated within 1 month, and scalp and body hair began to regrow within 3 months (Tang 2012).

Monitoring Parameters

Pregnancy test within 1 week prior to treatment initiation.

Canadian labeling: Pregnancy testing (minimum sensitivity of 25 milliunits/mL) within 1 week prior to treatment initiation, monthly during treatment (including during treatment interruptions), and for 24 months after discontinuation; CBC with differential and comprehensive metabolic panel at baseline and every 4 weeks thereafter; liver function tests; skin examination routinely during therapy.

Pregnancy Considerations

[US Boxed Warning]: May result in severe birth defects or embryo-fetal death. Teratogenic effects (severe midline defects, missing digits, and other irreversible malformations), embryotoxic, and fetotoxic events were observed in animal reproduction studies when administered in doses less than the normal human dose. Based on its mechanism of action adverse effects on pregnancy would be expected. [US Boxed Warning]: Verify pregnancy status (in females of reproductive potential) within 7 days prior to initiating treatment and advise patients (female and male) of the risk of birth defects, the need for contraception and risk of exposure through semen and to use condoms with a pregnant partner or a female partner of childbearing potential. In females of childbearing potential, obtain pregnancy test within 7 days prior to treatment initiation; after the negative pregnancy test, initiate highly effective contraception prior to the first vismodegib dose and continue during and for 7 months after treatment. During treatment (including treatment interruptions) and for 3 months after treatment, male patients should not donate sperm and should use condoms with spermicide (even after vasectomy) if their partner is of childbearing potential.

Women exposed to vismodegib during pregnancy (directly or via seminal fluid) are encouraged to participate in the Erivedge Pregnancy Pharmacovigilance program by contacting the Genentech Adverse Event Line (1-888-835-2555). Pregnancies occurring during or within 7 months after treatment should be reported to the Genentech Adverse Event Line.

The Canadian labeling recommends that females of childbearing potential use 2 simultaneous forms of effective contraception beginning at least 4 weeks prior to treatment initiation, during treatment (including treatment interruptions), and for 24 months after discontinuation. Pregnancy testing should be performed within 7 days prior to treatment initiation, monthly during treatment (including treatment interruptions) and for 24 months after discontinuation. For females of child bearing potential, a new prescription is required each month to allow for monthly pregnancy testing. Any suspected exposure (directly or via seminal fluid) during pregnancy should be immediately reported to the Erivedge Pregnancy Prevention Program (EPPP) at 1-888-748-8926.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, alopecia, constipation, lack of appetite, loss of strength and energy, weight loss, diarrhea, muscle pain, joint pain, or change in taste (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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