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Vismodegib

Medically reviewed on Dec 27, 2018

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: 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)

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 adult patients who are not candidates for surgery and not candidates for radiation therapy

Contraindications

There are no contraindications listed in the manufacturer's US 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

Basal cell carcinoma, metastatic or locally advanced: Oral: 150 mg once daily until disease progression or unacceptable toxicity (Sekulic 2012; Sekulic 2017).

Missed doses: If a dose is missed, resume dosing with the next scheduled dose.

Dosing: Adjustment for Toxicity

Intolerable adverse reactions: Withhold vismodegib treatment for up to 8 weeks until improvement or resolution.

Administration

Oral: May be taken with or without food. Swallow capsules whole; do not open or crush.

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). Keep bottle closed tightly to protect from moisture.

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%), increased creatine phosphokinase (38%), arthralgia (16%)

1% to 10%:

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

Genitourinary: Azotemia (grade 3: 2%)

ALERT: U.S. Boxed Warning

Embryofetal toxicity:

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. Advise pregnant women of the potential risks to a fetus. Advise females of reproductive potential to use effective contraception during and after vismodegib. 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.

Warnings/Precautions

Concerns related to adverse effects:

• Gastrointestinal toxicity: Nausea, vomiting, diarrhea, constipation, and decreased appetite may occur (usually grade 1 or 2).

Special populations:

• Pediatrics: Premature fusion of the epiphyses has been reported in pediatric patients exposed to vismodegib; the fusion progressed after vismodegib discontinuation in some cases. Vismodegib is not indicated for use in pediatric patients.

• Pregnancy: [US Boxed Warning]: 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. Advise pregnant women of the potential risks to a fetus. [US Boxed Warning]: Verify pregnancy status of females of reproductive potential within 7 days prior to initiating vismodegib. Advise females of reproductive potential to use effective contraception during and after vismodegib. 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.

Other warnings/precautions:

• Blood donations: Advise patients not to donate blood or blood products during vismodegib treatment and for at least 24 months after the last vismodegib dose.

• 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 male 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 (in females of reproductive potential). Monitor adherence.

Pregnancy Considerations

[US Boxed Warning]: 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. Advise pregnant women of the potential risks to a fetus.

[US Boxed Warning]: Verify pregnancy status of females of reproductive potential within 7 days prior to initiating vismodegib. Advise females of reproductive potential to use effective contraception during and after vismodegib. 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. After a negative pregnancy test, initiate highly effective contraception prior to the first vismodegib dose and continue during treatment and for 24 months after the final vismodegib dose. Amenorrhea may occur in females. Vismodegib is present in semen. During treatment and for 3 months after the last vismodegib dose, male patients should not donate sperm and should use condoms (even after vasectomy) if their partner is of childbearing potential.

Women exposed to vismodegib during pregnancy (directly or via seminal fluid) are encouraged to contact the Pregnancy Exposure Registry (1-888-835-2555).

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.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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