4.1. Therapeutic indications

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).

4.2. Posology and method of administration

Erivedge should only be prescribed by or under the supervision of a specialist physician experienced in the management of the approved indication.

Posology

The recommended dose is one 150 mg capsule taken once daily.

Missed doses

If a dose is missed, patients should be instructed not to take the missed dose but to resume with the next scheduled dose.

Duration of treatment

In clinical studies, treatment with Erivedge was continued until disease progression or until unacceptable toxicity. Treatment interruptions of up to 4 weeks were allowed based on individual tolerability.

Benefit of continued treatment should be regularly assessed, with the optimal duration of therapy varying for each individual patient.

Special populations

Elderly

No dose adjustment is required in patients ≥ 65years of age (see section 5.2). Of a total number of 138 patients in 4 clinical studies of Erivedge in advanced basal cell carcinoma, approximately 40 % of patients were ≥ 65 years old and no overall differences in safety and efficacy were observed between these patients and younger patients.

Renal impairment

Mild and moderate renal impairment is not expected to impact the elimination of vismodegib and no dose adjustment is needed. Very limited data is available in patients with severe renal impairment. Patients with severe renal impairment should be carefully monitored for adverse reactions.

Hepatic impairment

No dose adjustment is required in patients with mild, moderate or severe hepatic impairment defined based on National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG)- criteria for hepatic impairment (see section 5.2):

• mild:total bilirubin (TB) ≤ upper limit of normal (ULN), aspartate aminotransferase (AST)>ULN or ULN<TB≤1.5xULN, AST any

• moderate: 1.5 x ULN < TB < 3 x ULN, AST any

• severe: 3 x ULN < TB < 10 x ULN, AST any

Paediatric population

The safety and efficacy of Erivedge in children and adolescents aged below 18 years have not been established.

Due to safety concerns (see sections 4.4 and 5.3), this medicinal product should not be used in children and adolescents aged below 18 years.

Method of administration

Erivedge is for oral use.The capsules must be swallowed whole with water, with or without food (see section 5.2). The capsules must not be opened, to avoid unintended exposure to patients and health care providers.

4.3. Contraindications

• 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).

4.4. Special warnings and precautions for use

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,

•

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),

•

If she needs to change contraception during treatment,

• She must not breast-feed while taking Erivedge and for 24 months after the final dose.

For men

Vismodegib is present in semen. To avoid potential foetal exposure during pregnancy, a male patient must understand that:

• Erivedge exposes a teratogenic risk to the unborn child if he engages in unprotected sexual activity with a pregnant woman,

• He must always use the recommended contraception (see the 'Contraception' section below and section 4.6),

• He will tell his healthcare provider if his female partner becomes pregnant while he is taking Erivedge or during the 2 months after his final dose.

For health care providers (HCP)

HCPs must educate the patients so they understand and acknowledge all the conditions of the Erivedge Pregnancy Prevention Programme.

Contraception

WCBP

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).

Men

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).

Pregnancy testing

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.

Prescribing and dispensing restrictions for WCBP

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.

Educational material

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.

Effects on post-natal development

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).

Blood donation

Patients should not donate blood while taking Erivedge and for 24 months after the final dose.

Semen donation

Male patients should not donate semen while taking Erivedge and for 2 months after the final dose.

Interactions

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

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.

Excipients

Erivedge capsules contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total 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, that is to say essentially 'sodium free'.

4.5. Interaction with other medicinal products and other forms of interaction

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 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.

4.6. Fertility, pregnancy and lactation

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 final dose (see sections 4.3 and 5.3).

Fertility

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 studies 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).

4.7. Effects on ability to drive and use machines

Erivedge has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

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.

Table 1 ADRs occurring in patients treated with Erivedge

MedDRA SOC

Very common

Common

Frequency not known

Endocrine disorders

precocious puberty****

Metabolism and nutrition disorders

decreased appetite

dehydration

Nervous system disorder

dysgeusia

ageusia

hypogeusia

Gastrointestinal disorders

nausea

diarrhoea

constipation

vomiting

dyspepsia

abdominal pain upper

abdominal pain

Hepatobiliary disorders

hepatic enzymes increased**

drug induced liver injury*****

Skin and subcutaneous tissue disorders

alopecia

pruritus

rash

madarosis

abnormal hair growth

Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP)******

Musculoskeletal and connective tissue disorders

muscle spasms

arthralgia

pain in extremity

back pain

musculoskeletal chest pain

myalgia

flank pain

musculoskeletal pain

blood creatine phosphokinase increased***

epiphyses premature fusion****

Reproductive system and breast disorders

amenorrhoea*

General disorders and administration site conditions

weight decreased

fatigue

pain

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 of suspected adverse reactions

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 (see details below).

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

Erivedge has been administered at doses 3.6 times higher than the recommended 150 mg daily dose. No increases in plasma vismodegib levels or toxicity were observed during these clinical studies.