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Vismodegib

Medically reviewed by Drugs.com. Last updated on May 28, 2020.

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 (in adults) 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

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.

Severe cutaneous adverse reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms: Permanently discontinue vismodegib.

Administration

Oral: May be administered 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%:

Cardiovascular: Increased serum creatine phosphokinase (38%)

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%)

Genitourinary: Azotemia (grade 3: 2%)

<1%, postmarketing, and/or case reports: Hepatic injury

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:

• Dermatologic toxicity: Severe cutaneous adverse reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms, have been reported with vismodegib; may be life-threatening or fatal. Permanently discontinue vismodegib if severe cutaneous adverse reactions occur.

• GI 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. 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.

• 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 for signs/symptoms of cutaneous adverse reactions. Monitor adherence.

Reproductive Considerations

[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. 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.

[US Boxed Warning]: 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. It is not known if the presence of vismodegib in semen can cause embryotoxicity and/or fetotoxicity.

Male patients should not donate sperm during vismodegib treatment and for 3 months after the last vismodegib dose.

Male patients with female partners of childbearing potential should use condoms (even after vasectomy) during vismodegib treatment and for 3 months after the last vismodegib dose.

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.

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

What is this drug used for?

• It is used to treat skin cancer.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Constipation, diarrhea, upset stomach, throwing up, or feeling less hungry

• Hair loss

• Feeling tired or weak

• Weight loss

• Muscle spasm

• Joint pain

• Change in taste

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Flu-like signs

• Swollen gland

• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

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