Vismodegib, a hedgehog signaling pathway inhibitor, is an antineoplastic agent.1, 3
Vismodegib is used for the treatment of metastatic basal cell carcinoma.1, 3, 7, 9 The drug also is used for the treatment of locally advanced basal cell carcinoma in patients whose disease has recurred following surgery, and in patients who are not candidates for surgery or radiation therapy.1, 3, 7, 9
In an open-label, multicenter, noncomparative study in 104 adults with basal cell carcinoma treated with vismodegib for a median duration of 10.2 months, objective response was observed in 30.3 or 42.9% of patients with metastatic or locally advanced disease, respectively.1, 7 While a complete response was not observed in patients with metastatic disease, 20.6% of those with locally advanced disease achieved a complete response.1, 7 Both cohorts had a median response duration of 7.6 months.1, 7 Tumor response was evaluated in patients with metastatic disease using the Response Evaluation Criteria in Solid Tumors (RECIST)7, 8 and in patients with locally advanced disease by measurement of externally assessable tumor (including scar), assessment of ulceration, radiographic assessment of target lesions (if appropriate), and tumor biopsy.1, 7 Objective response in locally advanced disease was defined as lack of disease progression and at least one of the following: 30% or greater reduction in lesion size (i.e., sum of the longest diameter from baseline in target lesions as assessed by radiograph), 30% or greater reduction from baseline in the sum of the longest diameter in externally visible dimension of target lesions, or complete resolution of ulceration in all target lesions.1, 7 Patients with such an objective response and no residual basal cell carcinoma (as determined by tumor biopsy) were considered to have a complete response.1, 7 Disease progression was defined as a 20% or greater increase from nadir in the sum of the longest diameter in target lesions (as assessed by radiograph or external visualization), a new ulceration of target lesions persisting for at least 2 weeks without evidence of healing, new lesions (identified by radiograph or physical examination), or progression of nontarget lesions using RECIST.1, 7
Administer vismodegib orally once daily without regard to meals.1 Swallow capsules whole; do not open or crush capsules.1 In the event of a missed dose, resume therapy with the next scheduled dose and do not replace the missed dose.1
The recommended adult dosage for the treatment of metastatic or locally advanced basal cell carcinoma is 150 mg once daily until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity
If intolerable adverse reactions occur, withhold vismodegib therapy for up to 8 weeks until improvement or resolution.1 Treatment durations of <8 weeks prior to interruptions have not been studied.1
Permanently discontinue vismodegib if patients experience severe cutaneous reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms (DRESS).1
Interrupt therapy for severe or intolerable musculokeletal adverse effects.1 Permanently discontinue therapy for recurrent, severe or intolerable musculoskeletal adverse effects.1
No dosage adjustment is required in patients with hepatic impairment.1
No dosage adjustment is required in patients with renal impairment.1
Fetal/Neonatal Morbidity and Mortality
Vismodegib may cause fetal harm, including death or severe birth defects, based on its mechanism of action and animal data.1 A boxed warning regarding this risk is included in the prescribing information for the drug.1 Teratogenicity, embryotoxicity, and fetotoxicity have been demonstrated in animals at exposures lower than those achieved in humans at the recommended daily dosage.1 Fetal malformations in animals have included severe midline defects, craniofacial anomalies, open perineum, absent or fused digits, and other irreversible malformations.1 Fetal retardations and variations also have been observed.1
Advise male and female patients of the risk of embryofetal death and severe birth defects.1 Counsel all patients regarding pregnancy prevention and planning, including the need for effective contraception during and after therapy.1
Verify pregnancy status in female patients of reproductive potential within 7 days prior to initiation of vismodegib therapy.1 In patients with a negative pregnancy test, initiate effective contraception prior to the first dose of vismodegib and continue such contraception during therapy and for 24 months following the last dose of the drug.1
Advise male patients of the potential to expose female sexual partners to vismodegib through semen.1 Male patients, including those with a history of vasectomy, should use condoms during sexual intercourse with female partners of reproductive potential or who are pregnant while receiving vismodegib and for 3 months following the last dose of the drug.1
If pregnancy occurs or is suspected during or following completion of vismodegib therapy, or if female sexual partners of male patients are exposed to the drug during pregnancy, apprise the patient of the potential fetal hazard.1
Severe cutaneous reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported in patients receiving vismodegib.1 Permanently discontinue vismodegib in patients who experience severe cutaneous reactions.1
Musculoskeletal Adverse Reactions
Musculoskeletal adverse reactions, which may include increases in serum creatine phosphokinase (CPK), have been reported with vismodegib and other drugs that inhibit the hedgehog pathway.1 In clinical trials, musculoskeletal and connective tissue adverse reactions occurred in 78% of patients; 7% of reactions were reported as grade 3.1 The most frequently reported reactions (all grades) included muscle spasms (72%) and arthralgias (16%).1 In a post-approval trial, grade 3 or 4 elevations in serum CPK values occurred in 2.4% of 453 patients with any CPK measurement.1
Obtain baseline CPK and creatinine levels, and as clinically indicated.1 Depending on symptom severity, interruption or discontinuation of therapy may be required.1
Premature Fusion of the Epiphyses
Premature fusion of the epiphyses has been reported in pediatric patients exposed to vismodegib.1 In some cases, fusion progressed after discontinuance of the drug.1
Vismodegib is not indicated for use in pediatric patients.1
Patients should not donate blood or blood components while receiving vismodegib and for at least 24 months following the final dose of the drug.1
Vismodegib may cause fetal harm, including death or severe birth defects.1 Teratogenicity and embryo-fetal toxicity have been demonstrated in animals at exposures lower than those achieved in humans at the recommended daily dosage.1 There are no human data on the use of vismodegib in pregnant women.1
Advise patients of the potential risk to a fetus.1 A pregnancy registry has been established to monitor pregnancy outcomes in females exposed to vismodegib during pregnancy.1 Report pregnancies to Genentech at 1-888-835-2555.1
It is not known whether vismodegib is distributed into milk; potential effects on the breast-fed infant or on milk production also are not known.1 Because of the potential for serious adverse reactions to vismodegib in nursing infants, breast-feeding is not recommended during therapy with vismodegib and for 24 months after the final dose.1
Males and Females of Reproductive Potential
Verify pregnancy status in females of reproductive potential within 7 days prior to initiating vismodegib.1 Females of reproductive potential must use effective contraception during therapy with vismodegib and for 24 months after the final dose.1
Vismodegib is present in semen; however, it is not known whether the amount detected can cause embryofetal harm.1 Advise male patients of the potential risk to an embryo or fetus if a female partner of reproductive potential is exposed to vismodegib.1 Advise such patients to use condoms, even after a vasectomy, during therapy and for 3 months after the final dose of vismodegib to avoid drug exposure to pregnant partners and female partners of reproductive potential.1 Advise males not to donate semen during therapy with vismodegib and for 3 months after the final dose.1
Amenorrhea may occur in females receiving vismodegib; the reversibility of this adverse effect is unknown.1
Safety and efficacy of vismodegib have not been established in pediatric patients.1
There is insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1
Mild hepatic impairment (normal total bilirubin and AST > upper limit of normal [ULN] or total bilirubin >1 to 1.5 times ULN), moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN), or severe hepatic impairment (total bilirubin >3 to 10 times ULN) has no clinically relevant effects on systemic exposure of vismodegib.1 Dosage adjustment is not required in patients with hepatic impairment.1
Mild to moderate renal impairment (creatinine clearance of 30-79 mL/minute) has no clinically relevant effects on systemic exposure of vismodegib.1 The effects of severe renal impairment on the pharmacokinetics of vismodegib is not known.1 Dosage adjustment is not required in patients with renal impairment.1
Adverse effects reported in ≥10% of patients receiving vismodegib include muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgia, vomiting, and ageusia.1, 7
Vismodegib is minimally metabolized by cytochrome P-450 (CYP) isoenzymes 2C9 and 3A.1 Vismodegib does not induce CYP isoenzymes 1A2, 2B6, or 3A.1
In vitro data indicate that vismodegib is an inhibitor of breast cancer resistance protein (BCRP).1
Steady-state plasma vismodegib concentrations were not affected when administered concomitantly with fluconazole (a moderate CYP2C9 and CYP3A4 inhibitor).1
Concomitant use of vismodegib and an oral contraceptive containing ethinyl estradiol and norethindrone did not alter systemic exposure to the oral contraceptive components.1
No clinically important effects on vismodegib pharmacokinetics were observed when used concomitantly with itraconazole (a strong CYP3A4 inhibitor and P-gp inhibitor).1
No clinically important effects on vismodegib pharmacokinetics were observed when used concomitantly with rabeprazole.1
Concomitant use of rosiglitazone (a CYP2C8 substrate) and vismodegib did not alter the pharmacokinetics of rosiglitazone.1
Vismodegib is an antineoplastic agent that inhibits the hedgehog pathway by binding to and inhibiting smoothened, a transmembrane protein involved in hedgehog signal transduction.1 The hedgehog signaling pathway is a key regulator of cell growth during development that is generally inactive in adult tissues.3, 5, 6 Genetic mutations that allow for activation of the hedgehog pathway are often observed in patients with basal cell carcinoma.3, 4, 6 In patients with metastatic or locally advanced basal cell carcinoma, vismodegib therapy has been associated with tumor regression, stable disease, and down-regulation of glioma-associated protein 1 (GLI1) in normal skin and hair follicles.1, 3, 5, 6
Vismodegib is orally bioavailable (32%) with saturable absorption that is not affected by food.1, 3 Increased steady-state exposure has not been observed with doses exceeding 150 mg.1, 3, 5 The drug is more than 99% bound to plasma proteins, particularly α1-acid glycoprotein, but also albumin.1, 4 Binding to α1-acid glycoprotein is saturable and total plasma vismodegib concentrations correlate with plasma α1-acid glycoprotein concentrations.1, 4, 5 While vismodegib is metabolized by cytochrome P-450 (CYP) isoenzymes 2C9 and 3A4/5, it is primarily excreted unchanged in the feces (82%) and to a lesser extent in the urine (4.4%).1
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 [Web].
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.10 Consult manufacturer's website for specific availability information.10
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions March 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Genentech USA, Inc. Erivedge® (vismodegib) capsules prescribing information. South San Francisco, CA. 2023 Mar. [Web]
2. Genentech USA, Inc. Erivedge® (vismodegib) capsules medication guide. South San Francisco, CA. 2023 Mar.
3. Von Hoff DD, LoRusso PM, Rudin CM et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med . 2009; 361:1164-72. [PubMed 19726763]
4. Graham RA, Lum BL, Cheeti S et al. Pharmacokinetics of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors: the role of alpha-1-acid glycoprotein binding. Clin Cancer Res . 2011; 17:2512-20. [PubMed 21300760]
5. LoRusso PM, Rudin CM, Reddy JC et al. Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. Clin Cancer Res . 2011; 17:2502-11. [PubMed 21300762]
6. Dierks C. GDC-0449--targeting the hedgehog signaling pathway. Recent Results Cancer Res . 2010; 184:235-8. [PubMed 20072843]
7. Sekulic A, Migden MR, Oro AE et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012; 366:2171-9. [PubMed 22670903]
8. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst . 2000; 92:205-16. [PubMed 10655437]
9. Genentech, Inc., South San Francisco, CA. Personal Communication.
10. Genentech USA, Inc. Erivedge Access Solutions. South San Francisco, CA. Accessed 2022 Mar 28. [Web]
11. Huang SM, Strong JM, Zhang L et al. New era in drug interaction evaluation: US Food and Drug Administration update on CYP enzymes, transporters, and the guidance process. J Clin Pharmacol . 2008; 48:662-70. [PubMed 18378963]