Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639, Grenzach-Wyhlen, Germany
Erivedge may cause embryo-foetal death or severe birth defects when administered to a pregnant woman (see section 4.6). Hedgehog pathway inhibitors, (see section 5.1) 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 (see section 5.3). Erivedge must not be used during pregnancy.
A WCBP is defined in the Erivedge Pregnancy Prevention Programme as:
Erivedge is contraindicated in a WCBP who does not comply with the Erivedge Pregnancy Prevention Programme.
A WCBP must understand that:
Vismodegib is present in semen. To avoid potential foetal exposure during pregnancy, a male patient must understand that:
HCPs must educate the patients so they understand and acknowledge all the conditions of the Erivedge Pregnancy Prevention Programme.
Female patients must use two methods of recommended contraception including one highly effective method and a barrier method during Erivedge therapy and for 24 months after the final dose (see section 4.6).
Male patients must always use a condom (with spermicide, if available), even after a vasectomy, when having sex with a female partner while taking Erivedge and for 2 months after the final dose (see section 4.6).
In a WCBP, a medically supervised pregnancy test, conducted by a heath care provider, should be performed within 7 days prior to initiating treatment and monthly during treatment. Pregnancy tests should have a minimum sensitivity of 25 mIU/mL as per local availability. Patients who present with amenorrhoea during treatment with Erivedge should continue monthly pregnancy testing while on treatment.
The initial prescription and dispensing of Erivedge should occur within a maximum of 7 days of a negative pregnancy test (day of pregnancy test = day 1). Prescriptions of Erivedge should be limited to 28 days of treatment and continuation of treatment requires a new prescription.
In order to assist health care providers and patients to avoid embryonic and foetal exposure to Erivedge the Marketing Authorisation Holder will provide educational materials (Erivedge Pregnancy Prevention Programme) to reinforce the potential risks associated with the use of Erivedge.
Premature fusion of the epiphyses and precocious puberty have been reported in paediatric patients exposed to Erivedge. Due to the long drug elimination half-life, these events may occur or progress after drug discontinuation. In animal species, vismodegib has been shown to cause severe irreversible changes in growing teeth (degeneration/necrosis of odontoblasts, formation of fluid-filled cysts in the dental pulp, ossification of the root canal, and haemorrhage) and closure of the epiphyseal growth plate. The findings of premature fusion of the epiphyses indicate a potential risk for short stature and tooth deformities to infants and children (see section 5.3).
Patients should not donate blood while taking Erivedge and for 24 months after the final dose.
Male patients should not donate semen while taking Erivedge and for 2 months after the final dose.
Concomitant treatment with strong CYP inducers (e.g. rifampicin, carbamazepine or phenytoin) should be avoided, as a risk for decreased plasma concentrations and decreased efficacy of vismodegib cannot be excluded (see also section 4.5).
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 (see section 4.8). 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.
Patients with advanced BCC have an increased risk of developing cuSCC. Cases of cuSCC have been reported in advanced BCC patients treated with Erivedge. It has not been determined whether cuSCC is related to Erivedge treatment. Therefore, all patients should be monitored routinely while taking Erivedge, and cuSCC should be treated according to the standard of care.
Patients should be instructed never to give this medicinal product to another person. Any unused capsules at the end of treatment should immediately be disposed of by the patient in accordance with local requirements (if applicable, e.g. by returning the capsules to their pharmacist or physician).
Erivedge capsules contain lactose monohydrate. Patients with a rare hereditary problem of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium free’.
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.
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.
When vismodegib is administered with CYP inducers (rifampicin, carbamazepine, phenytoin, St. John’s wort), exposure to vismodegib may be decreased (see sections 4.3 and 4.4).
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.
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 substrates are not expected. In vitro, CYP2C8 was the most sensitive CYP isoform for vismodegib inhibition. However, results of a drug-drug interaction study conducted in cancer patients demonstrated that the systemic exposure of rosiglitazone (a CYP2C8 substrate) is not altered when co-administered with vismodegib. Thus inhibition of CYP enzymes by vismodegib in vivo may be excluded.
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.
Due to the risk of embryo-foetal death or severe birth defects caused by vismodegib, women taking Erivedge must not be pregnant or become pregnant during treatment and for 24 months after the final dose (see sections 4.3 and 4.4). Erivedge is contraindicated in WCBP who do not comply with the Erivedge 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 Erivedge 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 Erivedge 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 Erivedge 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:
Erivedge may cause embryo-foetal death or severe birth defects when administered to a pregnant woman (see section 4.4). Hedgehog pathway inhibitors (see section 5.1) 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 (see section 5.3). In case of pregnancy in a woman treated with Erivedge, 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 Erivedge and for 24 months after the final dose (see sections 4.3 and 5.3).
Human female fertility may be compromised by treatment with Erivedge (see section 5.3). Reversibility of fertility impairment is unknown. Additionally, amenorrhoea has been observed in clinical trials in WCBP (see section 4.8). Fertility preservation strategies should be discussed with WCBP prior to starting treatment with Erivedge.
Fertility impairment in human males is not expected (see Section 5.3).
Erivedge 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 in table 1 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 Erivedge 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 Erivedge 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.
Table 1. ADRs occurring in patients treated with Erivedge:
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 (see section 4.4).
***** 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.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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