Vismodegib

Author: Anoma Ranaweera, Staff Writer, 2012.


Advanced basal cell carcinoma

Basal cell carcinoma (BCC) is usually curable if the lesions are restricted to a small area of the skin. However, in rare cases, the lesions can become disfiguring, invade surrounding tissue, or metastasize. In these instances of advanced BCC, the disease cannot be effectively treated with surgery or radiation — the standard treatments.

What is vismodegib?

On January 30, 2012, the US Food and Drugs Administration (FDA) approved vismodegib (Erivedge®, made by Genentech, Inc. USA) for the treatment of adults with metastatic basal cell carcinoma. It is not currently funded by PHARMAC in New Zealand (Aug 2016).

Vismodegib is intended for use in adult patients with locally advanced basal cell cancer who are not candidates for surgery or radiation and for patients whose cancer has metastasized.

This is the first FDA-approved drug for use in advanced forms of BCC, one of the most common skin cancers.

Advanced basal cell carcinoma

How is vismodegib administered?

  • Vismodegib is supplied as a capsule for oral administration.
  • The recommended initial dose is 150 mg taken orally once daily until disease progression or until unacceptable toxicity.
  • If a dose is missed, do not make up that dose; resume dosing with the next scheduled dose.
  • Vismodegib may be taken with or without food.
  • Patients are advised to swallow capsules whole and not to crush or open the capsules.
  • Capsules should be stored at room temperature between 68°F to 77°F (20°C to 25°C).

How does vismodegib act?

  • Vismodegib is an oral drug that is designed to selectively inhibit abnormal signalling in the Hedgehog (Hh) pathway, which is an underlying molecular driver of BCC.
  • Vismodegib binds to and inhibits Smoothened, a transmembrane protein involved in Hedgehog signal transduction.
  • The Hh pathway promotes cellular development and division in several cell types, both by direct cellular activation and by secondary activation of multiple pathways of tissue generation, including angiogenesis (new blood vessel formation) and tissue growth.
  • The Hh pathway is typically over-activated in BCC through down regulation of Hedgehog signal inhibition.

Link to key clinical-trial evidence about vismodegib

Potential drug interactions with vismodegib

  • Systemic exposure to vismodegib and incidence of adverse events may be increased when the drug is co-administered with clarithromycin, erythromycin or azithromycin, antibiotics that inhibit the efflux transporter P- glycoprotein.
  • Vismodegib does not inhibit or induce CYP450 enzymes.
  • Drugs that alter the pH of the upper gastrointestinal tract (e.g. proton pump inhibitors, H2-receptor antagonists, and antacids) may alter the solubility of vismodegib and reduce its bioavailability.
  • No formal clinical study has been conducted to evaluate the effect of gastric pH altering agents on the efficacy of vismodegib.
  • Vismodegib does not interact with oral contraceptives

Adverse events associated with vismodegib

The most common adverse reactions (incidence of 10% or more) associated with vismodegib are:

  • muscle spasms
  • hair loss / drug-induced alopecia
  • altered taste sensation
  • weight loss
  • fatigue
  • nausea
  • diarrhoea
  • decreased appetite

Use in pregnancy

  • Vismodegib has been approved with a boxed warning stating that use of this drug can result in embryo-fetal death or severe birth defects when administered to a pregnant woman.
  • Vismodegib can cause the baby to die before it is born (be stillborn) or cause the baby to have severe birth defects.
  • Pregnancy status must be verified prior to initiation of treatment with vismodegib.
  • A pregnancy test must be done in women of childbearing potential within 7 days before starting vismodegib.
  • Women of child-bearing potential need to be advised of the need for 2 reliable methods of contraception (including a barrier method) or complete abstinence from sexual intercourse.
  • In order to avoid pregnancy, highly effective birth control is advised before starting vismodegib, during treatment, and for 24 months after the last dose of the drug, due to the potential to cause serious developmental defects in breast-fed infants and children (note: this time was extended from an earlier time of 7 months).
  • All male patients taking vismodegib, even those with prior vasectomy, should use condoms with spermicide, during sexual intercourse with female partners while taking vismodegib and for at least 2 months after the last drug dose.

Use of vismodegib in nursing mothers

  • There is a potential for serious adverse reactions from vismodegib in nursing infants.
  • Female patients on vismodegib must not breastfeed.

Blood donation

  • Patients must not donate blood or blood products while receiving vismodegib and for at least 24 months after the last drug dose.

Paediatric use

  • The safety and effectiveness of vismodegib have not been established in children. Vismodegib is not approved for paediatric use. 
  • Cases of premature fusion of the epiphyses (growth plates) have been reported in children with the use of vismodegib.

Geriatric use

  • Clinical studies of vismodegib did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.

Hepatic impairment

  • The safety and effectiveness of vismodegib have not been established in patients with liver disease.

Renal impairment

  • The safety and effectiveness of vismodegib have not been established in patients with kidney disease.

Cardiac electrophysiology

  • In a study in 60 healthy subjects, therapeutic doses of vismodegib did not have a significant effect on the QTc interval (a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle).

Future considerations for vismodegib

Roche and Genentech are currently evaluating vismodegib in a phase 2 trial for patients with operable forms of BCC.

New Zealand approved datasheets are the official source of information for these prescription medicines, including approved uses and risk information. Check the individual New Zealand datasheet on the Medsafe website.

 

Related Information

References:

  • Lorusso PM, Jimeno A, Dy G, Adjei A, Berlin J, Leichman L, Low JA, Colburn D, Chang I, Cheeti S, Jin JY, Graham RA. Pharmacokinetic dose-scheduling study of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors. Clin Cancer Res 2011 Sep 1; 17(17):5774-82.
  • Wong H, Alicke B, West KA, et al. Pharmacokinetic-pharmacodynamic analysis of vismodegib in preclinical models of mutational and ligand-dependent Hedgehog pathway activation. Clin Cancer Res 2011 Jul 15; 17(14):4682-92.
  • 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 Apr 15; 17(8):2502-11.
  • De Smaele E, Ferretti E, Gulino A. Vismodegib, a small-molecule inhibitor of the hedgehog pathway for the treatment of advanced cancers. Curr Opin Investig Drugs 2010 Jun; 11(6):707-18.
  • Dirix L, Migden MR, Oro AE et al. A pivotal multicenter trial evaluating efficacy and safety of the Hedgehog pathway inhibitor (HPI) vismodegib in patients with advanced basal cell carcinoma (BCC). Presented at the 2011 European Multidisciplinary Cancer Conference. Stockholm, Sweden. September 23-27, 2011. Abstract LBA1.
  • Patricia M. LoRusso, Sarina A. Piha-Paul, Alexander D. Colevas, Vikram Malhi et al. Pharmacokinetic assessment of drug-drug interaction potential when rosiglitazone or combined oral contraceptive is coadministered with vismodegib in patients with locally advanced or metastatic solid tumors. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10 (11 Suppl):Abstract no. B188.

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