Erivedge 150 mg Hard Capsules

RMP V14.1

Updated in line with RMP V14.1

Updated in line with RMP V14.1

ERIVEDGE, EMEA/H/C/PSUSA/00010140/201901

Changes to SmPC recommended following PSUR assessment: addition of text in Section 4.8 (skin and subcutaneous tissue disorders).

II/0039/G Safety update to add precocious puberty. SmPC, section 4.4 and 4.8 and PIL sections 2 and 4 have been updated

7.         MARKETING AUTHORISATION HOLDER

Roche Registration GmbH

Emil-Barell-Strasse 1

79639 Grenzach-Wyhlen

Germany

Roche Registration Limited

6 Falcon Way

Shire Park

Welwyn Garden City

AL7 1TW

United Kingdom

10.       DATE OF REVISION OF THE TEXT

15 March 2018

Underlined text has been added, text with strike-through deleted:

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 evaluate the carcinogenicity of vismodegib have not been performed. Carcinogenicity studies were performed in mice and rats. However, pilomatricoma (a benign cutaneous neoplasm) was observed in the 26 week rat toxicity study. Carcinogenic potential was identified in rats only and was limited to benign hair follicle tumors, including pilomatricomas and keratoacanthomas respectively at ≥ 0.1-fold and ≥0.6-fold of the steady-state AUC(0-24h) of the recommended human dose. No malignant tumors were identified in either species tested. Pilomatricoma Benign hair follicle tumors have has not been reported in clinical trials with Erivedge, and the relevance of this finding to humans is therefore uncertain.

​​

[...]

10.       DATE OF REVISION OF THE TEXT

21 April 2017

4.4       Special warnings and precautions for use

[…]

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.

[…]

4.8       Undesirable effects

[…]

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 ³ 150 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 in clinical trials

[…]

5.1       Pharmacodynamic properties

[…]

Post approval study results

A post-approval, open-label, non-comparative, multicenter, phase II clinical trial (MO25616) was conducted in 1232 patients with advanced BCC, of whom 1215 patients were evaluable for efficacy and safety with laBCC (n = 1119) or mBCC (n = 96). LaBCC was defined as cutaneous lesions that were inappropriate for surgery (inoperable, or for whom surgery would result in substantial deformity) and for which radiotherapy was unsuccessful or contraindicated. Metastatic BCC was defined as histologically confirmed distant metastasis. Prior to study enrollment, diagnosis of BCC was confirmed by histology. Patients were treated with oral daily dosing of Erivedge at 150mg.

The median age for all patients was 72 years. The majority of patients were male (57%); 8% had mBCC whereas 92% had laBCC. For the metastatic cohort, the majority of patients had prior therapies, including surgery (91%), radiotherapy (62%) and systemic therapy (16%). For the locally advanced cohort, the majority of patients had prior therapies, including surgery (85%), radiotherapy (28%) and systemic therapy (7%). The median duration of treatment for all patients was 8.6 months (range 0 to 44.1).

Among patients in the efficacy-evaluable population with measurable and histologically confirmed disease, 68.5% and 36.9% responded to treatment in the laBCC and mBCC cohorts, respectively, by RECIST v1.1. Of patients who had a confirmed response (partial or complete), the median Duration of Response was 23.0 months (95% CI:  20.4, 26.7) in the laBCC cohort and 13.9 months (95% CI:  9.2, NE) in the mBCC cohort. Complete response was achieved in 4.8% patients in the mBCC cohort and 33.4% in the laBCC cohort. Partial response was achieved in 32.1% patients in the mBCC cohort and 35.1% in the laBCC cohort.

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.

10.       DATE OF REVISION OF THE TEXT

14 November 2016

6.3       Shelf life

3 4 years

10.       DATE OF REVISION OF THE TEXT

11 November 2016

Underlined text has been added, text with strike-through deleted:

4.2          Posology and method of administration

[…]

Paediatric population

The safety and efficacy of Erivedge in children and adolescents aged below 18 years have not been established. No data are available.

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.

[…]

4.4          Special warnings and precautions for use

[…]

Effects on post-natal development

Premature fusion of the epiphyses has been reported in patients exposed to Erivedge. Due to the long drug elimination half-life, fusion 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. These findings indicate a potential risk for short stature and tooth deformities to infants and children (see section 5.3).

[…]

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 ( ³ 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.

[…]

[…]

5.2          Pharmacokinetic properties

[…]

Hepatic impairment

The major elimination pathways of vismodegib involve hepatic metabolism and biliary/intestinal secretion. In a clinical study in patients with hepatic impairment (degree of impairment based on subject’s AST and total bilirubin levels) following multiple doses of vismodegib, it was shown that in patients with mild (NCI-ODWG criteria, n=8), moderate (NCI-ODWG criteria, n=86), and severe (NCI-ODWG criteria, n=3) hepatic impairment, the pharmacokinetic profile of vismodegib was comparable to that of subjects with normal hepatic function (n=9) (see section 4.2).

[…]

10.          DATE OF REVISION OF THE TEXT

15 September 2016

6.4       Special precautions for storage

Do not store above 30 °C.

Keep the bottle tightly closed in order to protect from moisture.

10.       DATE OF REVISION OF THE TEXT

14 June 2016

4.2       Posology and method of administration

[....]

Special populations

Elderly people
No dose adjustment is required in patients ≥ 65years of age (see section 5.2). Of a total number of 138 patients in 4 clinical trials 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.

RPatients with 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.

Patients with hHepatic 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:

4.6       Fertility, pregnancy and lactation

Fertility

Dedicated 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 Human female fertility may be irreversibly 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).

5.2       Pharmacokinetic properties

Special populations

Elderly 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 evaluated as a covariate in the population pharmacokinetic analysis.

Patients with rRenal impairment

Renal excretion of orally administered vismodegib is low. Therefore, mild and moderate renal impairment is unlikely to have a clinically significant effect on the pharmacokinetics of vismodegib. Based on a population PK analysis in patients with mild (BSA-indexed CrCl 50 to 80 mL/min, n=58) and  moderate (BSA-indexed CrCl 30 to 50 mL/min, n=16) renal impairment, mild and moderate impaired renal function had no clinically significant effect on the pharmacokinetics of vismodegib (see section 4.2). Very limited data is available in patients with severe renal impairments.

Patients with hHepatic impairment

The major elimination pathways of vismodegib involve hepatic metabolism and biliary/intestinal secretion. In a clinical study in patients with hepatic impairment (degree of impairment based on subject’s AST and total bilirubin levels) following multiple doses of vismodegib, it was shown that in patients with mild (NCI-ODWG criteria, n=8), moderate (NCI-ODWG criteria, n=8), and severe (NCI-ODWG criteria, n=3) hepatic impairment, the pharmacokinetic profile of vismodegib was comparable to that of subjects with normal hepatic function (n=9) (see section 4.2).

5.3       Preclinical safety data

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.

In the dedicated 26-week vismodegib rat fertility study, significantly increased absolute weights of seminal vesicles and reduced absolute weights of prostate were observed. In addition, the ratio of organ weight to terminal body weight was significantly increased for epididymis, cauda epididymis, testes and seminal vesicles.  In the same study there were no histopathological findings in male reproductive organs and no effects on male fertility endpoints, including percent motile sperm, observed at 100 mg/kg/day at the end of dosing or recovery phase (corresponding to 1.3-fold of the steady-state AUC0-24h at the recommended human dose).  In addition, in the vismodegib general toxicity studies up to 26-week in sexually mature rats and dogs, no effects on male reproductive organs were observed. Increased number of degenerating germ cells and hypospermia in sexually immature dogs observed at ≥ 50 mg/kg/day in the 4-week general toxicity study was of undetermined relationship to vismodegib. 

In the dedicated 26-week vismodegib rat fertility study, vismodegib-related effects on female reproductive organs were observed at 100 mg/kg/day immediately after treatment discontinuation, including decreased implantations, increased percent preimplantation loss, and decreased number of dams with viable embryos. Similar findings were not observed after a 16 week recovery period.  No correlative histopathologic changes were observed.  The exposure in female rats at 100 mg/kg corresponds to 1.2-fold of the steady-state AUC0-24h at the recommended human dose.  In addition, in the vismodegib general 26-week toxicity study, decreased number of corpora lutea was observed at 100 mg/kg/day; the effect was not reversed by the end of an 8 week recovery period.   

10.       DATE OF REVISION OF THE TEXT

05 February 2016

This version includes the changes from II015G and the renewal R/0016).

Underlined text has been added, text with strike-through deleted:

4.2          Posology and method of administration

[…]

Special populations

ElderlyOlder people
No dose adjustment is required in patients ≥ 65years of age (see section 5.2). Of a total number of 138 patients in 4 clinical trials 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.

Patients with renal and hepatic impairment

The safetyMild and efficacy of Erivedge havemoderate renal impairment is not been studiedexpected to impact the elimination of vismodegib and no dose adjustment is needed. Very limited data is available in patients with impaired renal and hepatic function (see section 5.2). No specific dose recommendations for these patient populations are available.severe renal impairment. Patients with severe renal impairment or moderate to severe hepatic impairment should be carefully monitored for adverse reactions.

Patients with hepatic impairment

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

·      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

(see section 5.2)

4.5          Interaction with other medicinal products and other forms of interaction

Effects of concomitant medicinal products on vismodegib

Medicinal products that alter the pH of the upper gastrointestinal (GI) tract (e.g., proton pump inhibitors, H₂‑receptor antagonists, and antacids) may alter the solubility of vismodegib and reduce its bioavailability. However, no formal clinical trial has been conducted to evaluate the effect of gastric pH altering agents on the systemic exposure of vismodegib. Increasing the dose of vismodegib when co-administered with such agents is not likely to compensate for the loss of exposure. When vismodegib is co-administered with a proton pump inhibitor, H₂‑receptor antagonist, or antacid, systemic exposure of vismodegib may be decreased, and the effect on efficacy of vismodegib is unknown. Patients with achlorhydria would be subject to the same potential effect.

In vitro studies indicate that vismodegib is a substrate of the efflux transporter P‑glycoprotein (P‑gp) and the drug metabolising enzymes CYP2C9 and CYP3A4. When vismodegib is co-administered with medicinal products that inhibit P‑gp (e.g. clarithromycin, erythromycin, azithromycin, verapamil, cyclosporin), CYP2C9 (amiodarone, fluconazole or miconazole), or CYP3A4 (boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, or voriconazole), systemic exposure of vismodegib and incidence of adverse events of vismodegib may be increased.

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 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.

[…]

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.., such as atorvastatin, fluvastatin, pravastatin, rosuvastatin and simvastatin.

[…]

5.2          Pharmacokinetic properties

[…]

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 eliminationCYP2C9 appears to contribute in part to vismodegib metabolism in vivo, but other responsible enzymes and transporters are not identified.

[…]

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.

Renal excretion of orally administered vismodegib is low. Therefore, mild and moderate renal impairment is unlikely to have a clinically significant effect on the pharmacokinetics of vismodegib. Based on a population PK analysis in patients with mild (BSA-indexed CrCl 50 to 80 mL/min, n=58) and  moderate (BSA-indexed CrCl 30 to 50 mL/min, n=16) renal impairment, mild and moderate impaired renal function had no clinically significant effect on the pharmacokinetics of vismodegib (see section 4.2). Very limited data is available in patients with severe renal impairments.

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.

The major elimination pathways of vismodegib involve hepatic metabolism and biliary/intestinal secretion. In a clinical study in patients with hepatic impairment (degree of impairment based on subject’s AST and total bilirubin levels) following multiple doses of vismodegib, it was shown that in patients with mild (NCI-ODWG criteria, n=8), moderate (NCI-ODWG criteria, n=8), and severe (NCI-ODWG criteria, n=3) hepatic impairment, the pharmacokinetic profile of vismodegib was comparable to that of subjects with normal hepatic function (n=9) (see section 4.2).

Paediatric population

There are insufficient pharmacokinetic data in paediatric patients.

10.          DATE OF REVISION OF THE TEXT

27 May 2015

Underlined text has been added, text with strike through deleted:

4.2          Posology and method of administration

[…]

Special populations

Older people
No dose adjustment is required in patients ≥ 65years of age (see section 5.2). Of a total number of 138 patients in 4 clinical trials 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.

Patients with renal and hepatic impairment

The safetyMild and efficacy of Erivedge havemoderate renal impairment is not been studiedexpected to impact the elimination of vismodegib and no dose adjustment is needed. Very limited data is available in patients with impaired renal and hepatic function (see section 5.2). No specific dose recommendations for these patient populations are available.severe renal impairment. Patients with severe renal impairment or moderate to severe hepatic impairment should be carefully monitored for adverse reactions.

Patients with hepatic impairment

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

·      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

(see section 5.2)

[…]

4.4          Special warnings and precautions for use

[…]

For men

Vismodegib is containedpresent 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.

[…]

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 amenorrheaamenorrhoea during treatment with Erivedge should continue monthly pregnancy testing while on treatment.

[…]

4.5          Interaction with other medicinal products and other forms of interaction

Effects of concomitant medicinal products on vismodegib

Medicinal products that alter the pH of the upper gastrointestinal (GI) tract (e.g., proton pump inhibitors, H₂‑receptor antagonists, and antacids) may alter the solubility of vismodegib and reduce its bioavailability. However, no formal clinical trial has been conducted to evaluate the effect of gastric pH altering agents on the systemic exposure of vismodegib. Increasing the dose of vismodegib when co-administered with such agents is not likely to compensate for the loss of exposure. When vismodegib is co-administered with a proton pump inhibitor, H₂‑receptor antagonist, or antacid, systemic exposure of vismodegib may be decreased, and the effect on efficacy of vismodegib is unknown. Patients with achlorhydria would be subject to the same potential effect.

In vitro studies indicate that vismodegib is a substrate of the efflux transporter P‑glycoprotein (P‑gp) and the drug metabolising enzymes CYP2C9 and CYP3A4. When vismodegib is co-administered with medicinal products that inhibit P‑gp (e.g. clarithromycin, erythromycin, azithromycin, verapamil, cyclosporin), CYP2C9 (amiodarone, fluconazole or miconazole), or CYP3A4 (boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, or voriconazole), systemic exposure of vismodegib and incidence of adverse events of vismodegib may be increased.

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.

[…]

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.., such as atorvastatin, fluvastatin, pravastatin, rosuvastatin and simvastatin.

4.6          Fertility, pregnancy and lactation

[…]

Men

Vismodegib is containedpresent 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.

[…]

Fertility

Dedicated 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 (see section 5.3). Additionally, amenorrheaamenorrhoea 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.

4.8          Undesirable effects

[…]

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

5.2          Pharmacokinetic properties

[…]

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 eliminationCYP2C9 appears to contribute in part to vismodegib metabolism in vivo, but other responsible enzymes and transporters are not identified.

[…]

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.

Renal excretion of orally administered vismodegib is low. Therefore, mild and moderate renal impairment is unlikely to have a clinically significant effect on the pharmacokinetics of vismodegib. Based on a population PK analysis in patients with mild (BSA-indexed CrCl 50 to 80 mL/min, n=58) and  moderate (BSA-indexed CrCl 30 to 50 mL/min, n=16) renal impairment, mild and moderate impaired renal function had no clinically significant effect on the pharmacokinetics of vismodegib (see section 4.2). Very limited data is available in patients with severe renal impairments.

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.

The major elimination pathways of vismodegib involve hepatic metabolism and biliary/intestinal secretion. In a clinical study in patients with hepatic impairment (degree of impairment based on subject’s AST and total bilirubin levels) following multiple doses of vismodegib, it was shown that in patients with mild (NCI-ODWG criteria, n=8), moderate (NCI-ODWG criteria, n=8), and severe (NCI-ODWG criteria, n=3) hepatic impairment, the pharmacokinetic profile of vismodegib was comparable to that of subjects with normal hepatic function (n=9) (see section 4.2).

9.            DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 12 July 2013

10.          DATE OF REVISION OF THE TEXT

5 May 2015

Underlined text has been added, text with strike through deleted:

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%65.2%), dysgeusia (58.7%57.2%), weight decreased (50.0%48.6%), fatigue (47.1%44.9%), nausea (34.8 %),. and diarrhea (33.3%).

[…]

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

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

IMB HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.iewww.hpra.ie

e-mail: imbpharmacovigilance@imb.iemedsafety@hpra.ie

Malta

ADR Reporting

The Medicines Authority

Post-Licensing Directorate

203 Level 3, Rue D'Argens

GŻR-1368 Gżira

Website: www.medicinesauthority.gov.mt/adrportal

e-mail: postlicensing.medicinesauthority@gov.mt

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

5.1          Pharmacodynamic properties

[…]

Table 2                                 SHH4476g Erivedge Efficacy Results (IRF 21 months and Investigator assessed 39 months follow-up after last patient enrolled): efficacy‑evaluable patients*^,†

[…]

4.5       Interaction with other medicinal products and other forms of interaction

[…]

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, glibenclamide, repaglinide, valsartan and statins. In particular, caution should be exercised if vismodegib is administered in combination with any statin.

10.       DATE OF REVISION OF THE TEXT

22^nd May 2014