Vismodegib (Monograph)

Brand name: Erivedge
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Mar 10, 2024. Written by ASHP.

Warning

May cause embryofetal death or severe birth defects.
Embryotoxic, fetotoxic, and teratogenic effects observed in animals; teratogenic effects include severe midline defects, missing digits, and other irreversible malformations.
Verify pregnancy status in females of reproductive potential within 7 days prior to initiating vismodegib. Advise male and female patients of risks to the fetus, including need for contraception during and after vismodegib therapy and potential for drug exposure through semen. Advise males to use condoms with partners who are pregnant or with female partners of reproductive potential.

Introduction

Antineoplastic agent; hedgehog signaling pathway inhibitor.

Uses for Vismodegib

Basal Cell Carcinoma

Treatment of metastatic basal cell carcinoma.

Treatment of locally advanced basal cell carcinoma that has recurred following surgery or in those who are not candidates for surgery or radiation.

Vismodegib Dosage and Administration

General

Pretreatment Screening

Verify pregnancy status in females of reproductive potential within 7 days prior to initiating vismodegib.
Obtain a baseline serum creatine phosphokinase (CPK) and creatinine level.

Patient Monitoring

Monitor patients for signs and symptoms of severe cutaneous reactions.
Monitor CPK and creatinine levels as clinically indicated during therapy.

Administration

Oral Administration

Administer orally once daily without regard to meals.

Swallow capsules whole; do not open or crush capsules.

If a dose is missed, do not replace missed dose; resume therapy with next scheduled dose.

Dosage

Adults

Basal Cell Carcinoma

Metastatic or Locally Advanced Disease

Oral

150 mg once daily until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Withhold vismodegib for up to 8 weeks if intolerable adverse reactions occur until improvement or resolution. Treatment durations shorter than 8 weeks prior to interruptions have not been studied.

Permanently discontinue vismodegib if patients experience severe cutaneous reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms [DRESS]).

Interrupt therapy for severe or intolerable musculokeletal adverse effects. Permanently discontinue therapy for recurrent, severe or intolerable musculoskeletal adverse effects.

Special Populations

Hepatic Impairment

No dosage adjustment is required in patients with hepatic impairment.

Renal Impairment

No dosage adjustment is required in patients with renal impairment.

Cautions for Vismodegib

Contraindications

None.

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on mechanism of action and animal data. (See Boxed Warning.)

If pregnancy occurs or is suspected in female patients, or female sexual partners of male patients are exposed to the drug during pregnancy, apprise patient of potential fetal hazard.

Other Warnings/Precautions

Severe Cutaneous Reactions

Severe cutaneous reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS, which can be life-threatening or fatal, reported.

Permanently discontinue vismodegib in patients who experience severe cutaneous reactions.

Musculoskeletal Adverse Reactions

Musculoskeletal adverse reactions, which may include increases in serum creatine phosphokinase (CPK), reported.

Obtain baseline CPK and creatinine levels, and as clinically indicated. Depending on symptom severity, interrupt or discontinue therapy.

Premature Fusion of the Epiphyses

Premature fusion of the epiphyses has been reported in pediatric patients exposed to vismodegib. In some cases, fusion progressed after discontinuance of the drug.

Vismodegib is not indicated for use in pediatric patients.

Blood Donation

Patients should not donate blood or blood components while receiving vismodegib and for at least 24 months following final dose of drug.

Specific Populations

Pregnancy

May cause fetal harm, including death or severe birth defects. Teratogenicity, embryotoxicity, and fetotoxicity demonstrated in animals. No human data on use of vismodegib in pregnant women.

Pregnancy planning and prevention necessary, including use of effective contraception. Advise patients of potential risk to a fetus.

Pregnancy registry has been established to monitor pregnancy outcomes. Report pregnancies to Genentech at 1-888-835-2555.

Lactation

Not known whether vismodegib is distributed into milk; potential effects on milk production or on breast-fed infants also not known. Breast-feeding is not recommended during therapy with vismodegib and for 24 months after the final dose.

Females and Males of Reproductive Potential

Verify pregnancy status in females of reproductive potential within 7 days prior to initiating vismodegib. Females of reproductive potential must use effective contraception during therapy with vismodegib and for 24 months after the final dose.

Vismodegib is present in semen; it is not known if the amount detected can cause embryofetal harm. Male patients should use condoms, even after a vasectomy, during vismodegib therapy and for 3 months after the final dose to avoid drug exposure to pregnant partners and female partners of reproductive potential.

Advise males not to donate semen during therapy with vismodegib and for 3 months after the final dose.

Amenorrhea may occur in females receiving vismodegib; the reversibility of this adverse effect is unknown.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.

Hepatic Impairment

Mild hepatic impairment (normal total bilirubin and AST > upper limit of normal [ULN] or total bilirubin >1 to 1.5 times ULN): no clinically relevant effects on systemic exposure of vismodegib.

Moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN): no clinically relevant effects on systemic exposure of vismodegib.

Severe hepatic impairment (total bilirubin >3 to 10 times ULN): no clinically relevant effects on systemic exposure of vismodegib.

Dosage adjustment not necessary in patients with hepatic impairment.

Renal Impairment

Mild to moderate renal impairment (Cl_cr of 30–79 mL/minute): no clinically relevant effects on systemic exposure of vismodegib.

Severe renal impairment: not studied.

Dosage adjustment not necessary in patients with renal impairment.

Common Adverse Effects

Adverse effects (reported in ≥10% of patients): Muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgia, vomiting, ageusia.

Drug Interactions

Minimally metabolized by CYP2C9 and 3A.

Does not induce CYP1A2, 2B6, or 3A.

Inhibitor of breast cancer resistance protein (BCRP).

Specific Drugs

Drug	Interaction	Comments
Fluconazole	No clinically important effects on vismodegib pharmacokinetics observed
Hormonal contraceptives	Ethinyl estradiol and norethindrone: Clinically important changes in pharmacokinetics of contraceptive components not observed
Itraconazole	No clinically important effects on vismodegib pharmacokinetics observed
Rabeprazole	No clinically important effects on vismodegib pharmacokinetics observed
Rosiglitazone	Clinically important changes in rosiglitazone pharmacokinetics not observed

Vismodegib Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability: 32%.

Saturable absorption; increase in exposure not observed with doses >150 mg.

Food

Steady-state exposure not affected by food.

Special Populations

Pharmacokinetics not studied in severe renal impairment.

Weight (41–140 kg), age (26–89 years), Cl_cr (30–79 mL/min), mild to severe hepatic impairment, and gender do not have clinically meaningful effects on systemic exposure.

Distribution

Extent

Not known if distributed into milk.

In male patients, average concentration of vismodegib in semen on day 8 of dosing was 6.5% of the average steady state concentration observed in plasma.

Plasma Protein Binding

>99%; binds to albumin and α₁-acid glycoprotein (saturable).

Elimination

Metabolism

Undergoes oxidation, glucuronidation, and pyridine ring cleavage; oxidative metabolites produced by CYP2C9 and 3A.

Elimination Route

Excreted unchanged and as metabolites primarily in feces (82%) and to a lesser extent in urine (4.4%).

Half-life

4 days following continuous once-daily dosing.

12 days following a single dose.

Stability

Storage

Oral

Capsules

20–25°C (excursions permitted between 15–30°C). Store in tightly closed container to protect from moisture.

Actions

Inhibits the hedgehog pathway by binding to and inhibiting smoothened, a transmembrane protein involved in hedgehog signal transduction.
In patients with metastatic or locally advanced basal cell carcinoma, therapy associated with tumor regression, stable disease, and down-regulation of glioma-associated protein 1 (GLI1) in normal skin and hair follicles.

Advice to Patients

Inform patients to read the manufacturer's medication guide.
Importance of females informing their clinician if they are or plan to become pregnant. Advise female patients and female partners of male patients to contact their clinician immediately if pregnancy is confirmed or suspected; advise patients of the potential risk to a fetus.
Importance of both females and males using effective contraception during therapy. Advise females of reproductive potential to avoid pregnancy during and for at least 24 months after therapy with the drug. Advise males (including those with prior vasectomy) to use condoms to avoid potential drug exposure in both pregnant partners and female partners of reproductive potential during therapy with vismodegib and for 3 months after the final dose.
Inform patients of the existence of a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to vismodegib during pregnancy; contact 1-888-835-2555 to register.
Advise males not to donate semen during therapy with vismodegib and for 3 months after the final dose.
Importance of women informing clinicians immediately if they are breast-feeding or plan to breast-feed. Advise women not to breast-feed during therapy and for 24 months after the final dose.
Importance of patients not donating blood or blood components while receiving vismodegib and for at least 24 months after the drug is discontinued.
Advise patients to swallow capsules whole and not to crush or open capsules.
Advise patients not to replace any missed doses and to resume regular dosing schedule after a missed dose.
Advise patients to contact their clinician immediately if signs or symptoms of severe cutaneous reactions (e.g., blisters or peeling of skin, blisters on lips or around mouth or eyes, sores on mouth or genitals, high fever or flu-like symptoms, enlarged lymph nodes, skin pain or burning) occur.
Advise patients to contact their clinician immediately if any new unexplained muscle pain, tenderness, or weakness occurs during treatment or persists after discontinuing therapy.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Importance of informing patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at https://www.ahfsdruginformation.com.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Vismodegib can only be obtained through designated specialty distributors and specialty pharmacies. Consult manufacturer's website for specific availability information.