Table 1 ADRs occurring in patients treated with Erivedge in clinical trials

 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, amenorrhea 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.
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).
Ireland
HPRA Pharmacovigilance
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.hpra.ie
e-mail:medsafety@hpra.ie
Malta
ADR Reporting
Website: www.medicinesauthority.gov.mt/adrportal
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
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 trials.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XX43.
Mechanism of action
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.
Clinical efficacy and safety
The pivotal trial, ERIVANCE BCC (SHH4476g), was an international, single-arm, multi-centre, 2-cohort study. Metastatic BCC was defined as BCC that had spread beyond the skin to other parts of the body, including the lymph nodes, lung, bones and/or internal organs. LaBCC patients had cutaneous lesions that were inappropriate for surgery (inoperable, multiply recurrent where curative resection deemed to be unlikely or for whom surgery would result in substantial deformity or morbidity) and for which radiotherapy was unsuccessful or contraindicated or inappropriate. Prior to study enrolment, diagnosis of BCC was confirmed by histology. Patients with Gorlin syndrome who had at least one aBCC lesion and met inclusion criteria were eligible to participate in the study. Patients were treated with oral daily dosing of Erivedge at 150 mg.
The median age of the efficacy eva luable population was 62 years (46 % were at least 65 years old), 61 % male and 100 % White. For the mBCC cohort, 97 % of patients had prior therapy including surgery (97 %), radiotherapy (58 %), and systemic therapies (30 %). For the laBCC cohort (n = 63), 94 % of patients had prior therapies including surgery (89 %), radiotherapy (27 %), and systemic/topical therapies (11 %). The median duration of treatment was 12.9 months (range 0.7 to 47.8 months ).
The primary endpoint was objective response rate (ORR) as assessed by an independent review facility (IRF) as summarised in Table 2. Objective response was defined as a complete or partial response determined on two consecutive assessments separated by at least 4 weeks. In the mBCC cohort, tumour response was assessed according to the Response eva luation Criteria in Solid Tumours (RECIST) version 1.0. In the laBCC cohort, tumour response was assessed based on visual assessment of external tumour and ulceration, tumour imaging (where appropriate), and tumour biopsy. A patient was considered a responder in the laBCC cohort if at least one of the following criteria was met and the patient did not experience progression: (1) ≥ 30 % reduction in lesion size [sum of the longest diameter (SLD)], from baseline in target lesions by radiography; (2) ≥ 30 % reduction in SLD from baseline in externally visible dimension of target lesions; (3) Complete resolution of ulceration in all target lesions. Key data are summarised in Table 2:
Table 2 SHH4476g Erivedge Efficacy Results (IRF 21 months and Investigator assessed 39 months follow-up after last patient enrolled): efficacy-eva luable patients*,† 

NE = not estimable
* Efficacy-eva luable patient population is defined as all enrolled patients who received any amount of Erivedge and for whom the independent pathologist's interpretation of archival tissue or baseline biopsy was consistent with BCC.
† Uneva luable/missing data included 1 mBCC and 4 laBCC patients.
‡ Progression in laBCC cohort is defined as meeting any of the following criteria: (1) ≥ 20 % increase in the sum of the longest dimensions (SLD) from nadir in target lesions (either by radiography or by externally visible dimension), (2) New ulceration of target lesions persisting without evidence of healing for at least 2 weeks, (3) New lesions by radiography or physical examination, (4) Progression of non-target lesions by RECIST.
**54 % of laBCC patients had no histopathologic evidence of BCC at 24 weeks.
As shown in the waterfall plots in figures 1 and 2, which chart maximum reduction in target lesion(s) size for each patient, the majority of patients in both cohorts experienced tumour shrinkage as assessed by the IRF.
Figure 1 SHH4476g Metastatic BCC Cohort

Note: Tumour size is based on sum of longest dimensions of target lesions. PD = progressive disease, SD = stable disease, PR = partial response. 3 patients had a best percent change in tumour size of 0; these are represented by minimal positive bars in the figure. Four patients were excluded from the figure: 3 patients with stable disease were assessed by non-target lesions only and 1 patient was uneva luable.
Figure 2 SHH4476g Locally Advanced BCC Cohort

Note: Tumour size is based on sum of longest dimensions of target lesions. PD = progressive disease, SD = stable disease, R = response, * = complete resolution of ulceration(s). Response assessment was based on a composite endpoint defined as above. Four patients did not have lesion measurements and were not included in the plot.
Time to maximum tumour reduction
Among patients who achieved tumour reduction, the median time to maximum tumour reduction occurred in 5.6 and 5.5 months for laBCC and mBCC patients respectively, based on the IRF assessment. According to investigator assessment, the median time to maximum tumour reduction occurred in 6.7 and 5.5 months for laBCC and mBCC patients respectively.
Cardiac electrophysiology
In a thorough QTc study in 60 healthy subjects, there was no effect of therapeutic doses of Erivedge on the QTc interval.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Erivedge in all subsets of the paediatric population with basal cell carcinoma (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
5.2 Pharmacokinetic properties
Absorption
Erivedge is a highly permeable compound with low aqueous solubility (BCS Class 2). The single dose mean (CV %) absolute bioavailability of Erivedge is 31.8 (14.5) %. Absorption is saturable as evidenced by the lack of dose proportional increase in exposure after a single dose of 270 mg and 540 mg Erivedge. Under clinically relevant conditions (steady state), the PK of vismodegib is not affected by food. Therefore, Erivedge may be taken without regard to meals.
Distribution
The volume of distribution for vismodegib is low, ranging from 16.4 to 26.6 L. In vitro binding of vismodegib to human plasma proteins is high (97 %) at clinically relevant concentrations. Vismodegib binds to both human serum albumin and alpha-1-acid glycoprotein (AAG). In vitro binding to AAG is saturable at clinically relevant concentrations. Ex vivo plasma protein binding in human patients is > 99 %. Vismodegib concentrations are strongly correlated with AAG levels, showing parallel fluctuations of AAG and total vismodegib over time and consistently low unbound vismodegib levels.
Biotransformation
Vismodegib is slowly eliminated by a combination of metabolism and excretion of parent drug substance. Vismodegib is predominant in plasma, with concentrations representing greater than 98 % of the total circulating concentrations (including associated metabolites). Metabolic pathways of vismodegib in humans include oxidation, glucuronidation, and an uncommon pyridine ring cleavage. The two most abundant oxidative metabolites recovered in faeces are produced in vitro by recombinant CYP2C9 and CYP3A4/5. These enzymes may thus be major enzymes involved in the elimination.
Elimination
After oral administration of a radiolabelled dose, vismodegib is absorbed and slowly eliminated by a combination of metabolism and excretion of parent drug substance, the majority of which is recovered in the faeces (82 % of the administered dose), with 4.4 % of the administered dose recovered in urine. Vismodegib and associated metabolic products are eliminated primarily by the hepatic route.
After continuous once-daily dosing, the pharmacokinetics of vismodegib appears to be nonlinear due to saturable absorption and saturable protein binding. After a single oral dose, vismodegib has a terminal half-life of ca. 12 days.
The apparent half-life of vismodegib at steady-state is estimated to be 4 days with continuous daily dosing. Upon continuous daily dosing, there is a 3 fold accumulation of vismodegib total plasma concentrations.
Vismodegib inhibits UGT2B7 in vitro and it may not be excluded that inhibition can take place in vivo in the intestine.
Special populations
Older people
There are limited data in older people. In clinical trials with aBCC, approximately 40 % of patients were of geriatric age (≥ 65 years). Population pharmacokinetic analyses suggest that age did not have a clinically significant impact on steady-state concentration of vismodegib.
Gender
Based on population pharmacokinetic analysis of combined data from 121 males and 104 females, gender did not appear to affect the pharmacokinetics of vismodegib.
Race
There are limited data in non-Caucasian patients. Since the number of subjects who were not Caucasian comprised only < 3% of the total population (6 Black, 219 Caucasian), race was not eva luated as a covariate in the population pharmacokinetic analysis.
Patients with renal impairment
There are currently insufficient data in patients with severe renal impairment. Therefore, an effect of severe renal impairment cannot be excluded. Based on population pharmacokinetic analysis of combined data from 5 clinical studies, renal function (creatinine clearance) did not appear to affect the pharmacokinetics of vismodegib (see section 4.2). Therefore, based on the low urinary excretion of vismodegib, an effect of mild to moderate renal impairment is not expected.
Patients with hepatic impairment
Limited data indicate that exposure of vismodegib is not relevantly increased in patients with mild hepatic impairment. Data in moderate and severe hepatic impairment are too limited to draw conclusions.
Paediatric population
There are insufficient pharmacokinetic data in paediatric patients.
5.3 Preclinical safety data
The preclinical safety profile of Erivedge was assessed in mice, rats, and dogs.
Repeat-dose toxicity
In general, the tolerability of Erivedge in repeat-dose toxicity studies in rats and dogs was limited by nonspecific manifestations of toxicity including decreased body weight gain and food consumption. Additional findings at clinically relevant exposures included faecal changes; skeletal muscle twitching or tremors; alopecia; swelling, follicular hyperkeratosis, and inflammation in paw pads; and increased LDL and HDL cholesterol. Decreased haematocrit or platelet count were observed in some dogs at clinically relevant exposures; however, there was no evidence of a primary effect on bone marrow in affected animals.
Carcinogenicity
Dedicated nonclinical studies to eva luate the carcinogenicity of vismodegib have not been performed. However, pilomatricoma (a benign cutaneous neoplasm) was observed in the 26 week rat toxicity study. Pilomatricoma has not been reported in clinical trials with Erivedge, and the relevance of this finding to humans is therefore uncertain.
Mutagenicity
There was no evidence of genotoxicity in in vitro assays (reverse bacterial mutagenesis [Ames] and human lymphocyte chromosome aberration assays) or in the in vivo rat bone marrow micronucleus assay.
Fertility
Dedicated nonclinical studies to assess the potential of Erivedge to affect fertility have not been performed. However, data from studies in rats and dogs indicate that male and female fertility may be irreversibly compromised by treatment with Erivedge. Germ cell degeneration and hypospermia were observed in the 4 week dog toxicity study but not in longer-duration studies with older dogs. Decreased number of corpora lutea in the ovary and decreased mean percent motile sperm in the 26 week rat toxicity study were not demonstrated to be reversible by the end of the 8 week recovery period.
Teratogenicity
In an embryo-foetal development study in which pregnant rats were administered vismodegib daily during organogenesis, vismodegib crossed the placenta and was severely toxic to the conceptus. Malformations, including craniofacial anomalies, open perineum, and absent and/or fused digits, were observed in foetuses of dams at a dose which corresponded to 20 % of the typical steady-state exposure in patients, and a 100 % incidence of embryolethality was observed at higher doses.
Post-natal development
Dedicated studies to assess the potential of vismodegib to affect post-natal development have not been performed. However, irreversible defects in growing teeth and premature closure of the femoral epiphyseal plate, observed in rat toxicity studies at clinically relevant exposures, represent risks to post-natal development.
6. Pharmaceutical particulars
6.1 List of excipients
Capsule contents
Microcrystalline cellulose
Lactose monohydrate
Sodium lauril sulfate
Povidone
Sodium starch glycolate (Type A)
Talc
Magnesium stearate
Capsule shell
Iron oxide black (E172)
Iron oxide red (E172)
Titanium dioxide (E171)
Gelatine
Printing ink
Shellac glaze
Iron oxide black (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Do not store above 30 °C.
6.5 Nature and contents of container
HDPE bottle with a child-resistant screw cap containing 28 hard capsules. Each pack contains one bottle.
6.6 Special precautions for disposal and other handling
Any unused medicinal product at the end of treatment must immediately be disposed of by the patient in accordance with local requirements (if applicable, e.g. by returning the capsules to the pharmacist or physician).
7. Marketing authorisation holder
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
8. Marketing authorisation number(s)
EU/1/13/848/001
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 12 July 2013
10. Date of revision of the text
18 December 2014
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.