Erivedge · 4.3 Contraindications · 1

HOS-096448 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile 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%). Tabulated list of adverse reactions 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 studies 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 studies 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 studies 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. 8 Table 1 ADRs occurring in patients treated with Erivedge MedDRA SOC Very common Common Frequency not known Endocrine disorders precocious puberty**** Metabolism and decreased appetite dehydration nutrition disorders Nervous system dysgeusia hypogeusia disorder ageusia Gastrointestinal nausea abdominal pain upper disorders diarrhoea abdominal pain constipation vomiting dyspepsia Hepatobiliary hepatic enzymes drug induced liver disorders increased** injury***** Skin and alopecia ma

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HOS-096444 · has-contraindication-information · PDF-Seite 3

 Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  Women who are pregnant or breast-feeding (see sections 4.4 and 4.6).  Women of childbearing potential who do not comply with the Erivedge Pregnancy Prevention Programme (see sections 4.4 and 4.6). Coadministration of St John's wort (Hypericum perforatum) (see section 4.5).

HOS-096443 · has-indication-information · PDF-Seite 2

Erivedge is indicated for the treatment of adult patients with: symptomatic metastatic basal cell carcinoma locally advanced basal cell carcinoma inappropriate for surgery or radiotherapy (see section 5.1).

HOS-096446 · has-interaction-information · PDF-Seite 6

Effects of concomitant medicinal products on vismodegib Clinically significant pharmacokinetic (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 hours 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). Effects of vismodegib on concomitant medicinal products Contraceptive steroids 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. Effects on specific enzymes and transporters 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 nece

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HOS-096447 · has-pregnancy-information · PDF-Seite 7

Women of childbearing potential (WCBP) 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. 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 Erivedge 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 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. 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 Erivedge 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). Pregnancy 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. Breast-feeding 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 fi

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HOS-096445 · has-warning-information · PDF-Seite 3

Embryo-foetal death or severe birth defects 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 (see section 4.3). Criteria for a woman of childbearing potential (WCBP) A WCBP is defined in the Erivedge Pregnancy Prevention Programme as:  a sexually mature female who  has menstruated at any time during the previous 12 consecutive months,  has not undergone a hysterectomy or a bilateral oophorectomy, or who does not have medically-confirmed permanent premature ovarian failure,  does not have a XY genotype, Turner’s syndrome, or uterine agenesis, 3   becomes amenorrhoeic following cancer therapy, including treatment with Erivedge. Counselling For a WCBP Erivedge is contraindicated in a WCBP who does not comply with the Erivedge Pregnancy Prevention Programme. A WCBP must understand that:  Erivedge exposes a teratogenic risk to the unborn child,  She must not take Erivedge if she is pregnant or plans to become pregnant,  She must have a negative pregnancy test, conducted by a health care provider within 7 days before starting Erivedge treatment,  She must have a negative pregnancy test monthly during treatment, even if she has become amenorrhoeic,  She must not become pregnant while taking Erivedge and for 24 months after her final dose,  She must be able to comply with effective contraceptive measures,  She must use 2 methods of recommended contraception (see the ‘Contraception' section below and section 4.6) while she is taking Erivedge, unless she commits to not having sexual intercourse (abstinence),  She must tell her healthcare provider if any of the following occur during treatment and for 24 months after her final dose:  If she becomes pregnant or think for any reason that she may be pregnant,  If she misses her expected menstrual period,  If she stops using contraception unless she commits to not having sexual intercourse (abstinence),

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