Chemical formula: C₁₉H₁₄Cl₂N₂O₃S Molecular mass: 421.297 g/mol PubChem compound: 24776445
Vismodegib interacts in the following cases:
In vitro, vismodegib is an inhibitor of OATP1B1. It cannot be excluded that vismodegib may increase the exposure to substrates of OATP1B1, e.g. bosentan, ezetimibe, glibenclamide, repaglinide, valsartan and statins. In particular, caution should be exercised if vismodegib is administered in combination with any statin.
In vitro studies indicate that vismodegib has the potential to act as an inhibitor of breast cancer resistance protein (BCRP). In vivo interaction data is not available. It may not be excluded that vismodegib may give rise to increased exposure of medicinal products transported by this protein, such as rosuvastatin, topotecan, and sulfasalazin. Concomitant administration should be performed with caution and a dose adjustment may be necessary.
Clinically significant PK interactions between vismodegib and CYP450 inhibitors are not expected. Results from a clinical study demonstrated a 57% increase in vismodegib unbound drug concentrations on day 7 after co-treatment with 400 mg fluconazole (a moderate CYP2C9 inhibitor) daily, but this interaction is not expected to be clinically significant. Itraconazole (a strong CYP3A4 inhibitor) 200 mg daily did not influence vismodegib AUC0-24h after 7 days co-treament in healthy volunteers.
Clinically significant PK interactions between vismodegib and P-gp inhibitors are not expected. Results from a clinical study demonstrated no clinically significant PK interaction between vismodegib and itraconazole (a strong P-glycoprotein inhibitor) in healthy volunteers.
Very limited data is available in patients with severe renal impairment. Patients with severe renal impairment should be carefully monitored for adverse reactions.
Clinically significant PK interactions between vismodegib and pH elevating agents are not expected. Results from a clinical study demonstrated a 33% decrease in vismodegib unbound drug concentrations after 7 days co-treatment with 20 mg rabeprazole (a proton pump inhibitor) given 2 h before each vismodegib administration. This interaction is not expected to be clinically significant.
Results of a drug-drug interaction study conducted in cancer patients demonstrated that the systemic exposure of ethinyl estradiol and norethindrone is not altered when co-administered with vismodegib. However, the interaction study was of only 7 days duration and it cannot be excluded that vismodegib upon longer treatment is an inducer of enzymes which metabolise contraceptive steroids. Induction could lead to decreases in systemic exposure of the contraceptive steroids and thereby reduced contraceptive efficacy.
Human female fertility may be compromised by treatment with vismodegib. Reversibility of fertility impairment is unknown. Additionally, amenorrhoea has been observed in clinical trials in WCBP. Fertility preservation strategies should be discussed with WCBP prior to starting treatment with vismodegib.
Fertility impairment in human males is not expected.
When vismodegib is administered with CYP inducers (rifampicin, carbamazepine, phenytoin, St. John’s wort), exposure to vismodegib may be decreased.
Severe cutaneous adverse reactions (SCARs) including cases of Stevens-Johnson syndrome/Toxic epidermal necrolysis (SJS/TEN), Drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP), which can be life-threatening, have been reported during post-marketing use. If the patient has developed any of these reactions with the use of vismodegib, treatment with vismodegib must not be restarted in this patient at any time.
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.
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 breast-feed while taking vismodegib and for 24 months after the final dose.
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. Vismodegib is contraindicated in WCBP who do not comply with the vismodegib Pregnancy Prevention Programme.
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.
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.
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:
The following are recommended forms of barrier methods:
Human female fertility may be compromised by treatment with vismodegib. Reversibility of fertility impairment is unknown. Additionally, amenorrhoea has been observed in clinical trials in WCBP. Fertility preservation strategies should be discussed with WCBP prior to starting treatment with vismodegib.
Fertility impairment in human males is not expected.
Vismodegib has no or negligible influence on the ability to drive and use machines.
The most common adverse drug reactions (ADR) occurring in ≥30% of patients, were muscle spasms (74.6%), alopecia (65.9%), dysgeusia (58.7%), weight decreased (50.0%), fatigue (47.1%), nausea (34.8%) and diarrhea (33.3%).
ADRs are presented below by system organ class (SOC) and absolute frequency. Frequencies are defined as: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000), Not known (cannot be estimated from the available data). Within each frequency grouping, ADRs are presented in the order of decreasing seriousness.
The safety of vismodegib has been evaluated in clinical trials with 138 patients treated for advanced basal cell carcinoma (aBCC), which includes both metastatic BCC (mBCC) and locally advanced BCC (laBCC). In four open label phase 1 and 2 clinical trials patients were treated with at least one dose of vismodegib monotherapy at doses ≥150 mg. Doses >150 mg did not result in higher plasma concentrations in clinical trials and patients on doses >150 mg have been included in the analysis. Additionally, safety was assessed in a post approval study that included 1215 aBCC patients evaluable for safety and treated with 150 mg. In general the safety profile observed was consistent in both mBCC and laBCC patients and across studies as described below.
Very common: Decreased appetite
Common: Dehydration
Very common: Dysgeusia, Ageusia
Common: Hypogeusia
Very common: Nausea, Diarrhoea, Constipation, Vomiting, Dyspepsia
Common: Abdominal pain upper, Abdominal pain
Common: Hepatic enzymes increased**
Frequency not known: Drug induced liver injury*****
Very common: Alopecia, Pruritus, Rash
Common: Madarosis, Abnormal hair growth
Frequency not known: Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Acute Generalised Exanthematous Pustulosis (AGEP)******
Very common: Muscle spasms, Arthralgia, Pain in extremity
Common: Back pain, Musculoskeletal chest pain, Myalgia, Flank pain, Musculoskeletal pain, Blood creatine phosphokinase increased***
Frequency not known: Epiphyses premature fusion****
Frequency not known: Precocious puberty****
Very common: Amenorrhoea*
Very common: Weight decreased, Fatigue, Pain
Common: Asthenia
All reporting is based on ADRs of all grades using National Cancer Institute – Common Terminology Criteria for Adverse Events v 3.0 except where noted.
* Of the 138 patients with advanced BCC, 10 were WCBP. Amongst these women, amenorrhoea was observed in 3 patients (30%).
MedDRA = Medical Dictionary for Regulatory Activities.
** Includes preferred terms: liver function test abnormal, blood bilirubin increased, gamma-glutamyl transferase increased, aspartate aminotransferase increased, alkaline phosphatase increased, liver hepatic enzyme increased.
*** Observed in patients during a post-approval study with 1215 safety evaluable patients.
**** Individual cases have been reported in patients with medulloblastoma during post-marketing use.
***** Cases of drug induced liver injury have been reported in patients during post-marketing use.
****** Cases of SCAR (including SJS/TEN, DRESS and AGEP) have been reported in patients during post-marketing use.
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