Vismodegib

Registered South African indications:

• Basal cell carcinoma

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding
• Women of childbearing potential who do not comply with a pregnancy prevention programme  
• Coadministration with St John's wort

Cautions

• Severe renal impairment
• Women of childbearing potential
• Blood donation (during vismodegib treatment and for 24 months after final dose)
• Semen donation (during vismodegib treatment and for 2 months after final dose)
• Advanced basal cell carcinoma
• Galactose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption

Forms avail. in SA and covered in this monograph: cap

Used for the treatment of

• Symptomatic metastatic basal cell carcinoma
• Locally advanced basal cell carcinoma
  - Inappropriate for surgery or radiotherapy

Consult specialist for dosages and regimens

Not established for use in children below 18 years

Pregnancy

• Contraindicated
• Vismodegib may cause embryo-foetal death or severe birth defects when administered to a pregnant woman. Hedgehog pathway inhibitors such as vismodegib, have been demonstrated to be embryotoxic and/or teratogenic in multiple animal species and can cause severe malformations, including craniofacial anomalies, midline defects and limb defects. In case of pregnancy in a woman treated with vismodegib, treatment must be stopped immediately
• Women of childbearing potential: see additional prescribing points
• Contraception in males and females: see additional prescribing points

Breastfeeding

• Contraindicated
• The extent to which vismodegib is excreted in breast milk is not known. Due to its potential to cause serious developmental defects, women must not breastfeed while taking vismodegib and for 24 months after the final dose 

Fertility

• Human fertility may be compromised by treatment with vismodegib. Reversibility of fertility impairment is unknown. Additionally, amenorrhoea has been observed in clinical trials
• Fertility preservation strategies should be discussed in women of childbearing potential prior to starting treatment with vismodegib
• Fertility impairment in human males is not expected

Renal Impairment

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no dose adjustment recommended
  Very limited data is available for severe renal impairment. Monitor closely for adverse reactions

Hepatic Impairment

• No dose adjustment recommended

Elderly

• No dose adjustment recommended

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Fatigue

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Constipation
• Dyspepsia
• Abdominal pain

Hepatobiliary Disorders

• Increased hepatic enzymes
  - Abnormal liver function test
  - Increased bilirubin
  - Increased gamma-glutamyl transferase
  - Increased aspartate aminotransferase
  - Increased alkaline phosphatase
• Drug induced liver injury

Genitourinary Disorders

• Amenorrhoea

Endocrine and Metabolic Disorders

• Decreased appetite
• Dehydration
• Decreased weight
• Precocious puberty

Musculoskeletal Disorders

• Muscle spasms
• Arthralgia
• Pain in extremity
• Back pain
• Musculoskeletal pain (including chest pain)
• Myalgia
• Flank pain
• Increased blood creatine phosphokinase
• Epiphyses premature fusion

Skin and Subcutaneous Tissue Disorders

• Alopecia
• Pruritus
• Rash
• Madarosis
• Abnormal hair growth
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Drug reaction with eosinophilia and systemic symptoms (DRESS)
• Acute generalised exanthematous pustulosis

Sensory Disorders

• Dysgeusia
• Ageusia
• Hypogeusia

Other

• Pain

• CYP inducers
• Rifampicin
• Carbamazepine
• Phenytoin
• St John's wort
• Contraceptive steroids
• Ethinyl estradiol
• Norethindrone
• Breast cancer resistance protein (BCRP) substrates
• Rosuvastatin
• Topotecan
• Sulfasalazine
• OATP1B1 substrates
• Bosentan
• Ezetimibe
• Glibenclamide
• Repaglinide
• Valsartan
• Statins

None routine. Specific cases may require:

• Pregnancy test

Women of childbearing potential (WCBP) 

• Due to the risk of embryo-foetal death or severe birth defects caused by vismodegib, women taking vismodegib must not be pregnant or become pregnant during treatment and for 24 months after the final dose
• In case of pregnancy or missed menstrual periods: If the patient does become pregnant, misses a menstrual period, or suspects for any reason that she may be pregnant, she must notify her treating physician immediately. Persistent lack of menses during treatment with vismodegib should be assumed to indicate pregnancy until medical evaluation and confirmation

Contraception in males and females 

• Women of childbearing potential (WCBP):
  WCBP must be able to comply with effective contraceptive measures. She must use two methods of recommended contraception including one highly effective method and a barrier method during vismodegib therapy and for 24 months after the final dose. WCBP, whose periods are irregular or stopped, must follow all the advice on effective contraception
• Men: 
  Vismodegib is present in semen. To avoid potential foetal exposure during pregnancy, male patients must always use a condom (with spermicide, if available), even after a vasectomy, when having sex with a female partner while taking vismodegib and for 2 months after the final dose
• The following are recommended forms of highly effective methods:
  - Hormonal depot injection,
  - Tubal sterilisation,
  - Vasectomy,
  - Intrauterine device (IUD)
• The following are recommended forms of barrier methods:
  - Any male condom (with spermicide, if available),
  - Diaphragm (with spermicide, if available)

Vismodegib is an orally available small-molecule inhibitor of the Hedgehog pathway. Hedgehog pathway signalling through the smoothened transmembrane protein (SMO) leads to the activation and nuclear localisation of glioma-associated oncogene (GLI) transcription factors and induction of Hedgehog target genes. Many of these genes are involved in proliferation, survival, and differentiation. Vismodegib binds to and inhibits the SMO protein thereby blocking Hedgehog signal transduction.

Capsule 150mg

• Erivedge (Roche) originator