Leaflet ERIVEDGE 150mg capsules
Indicated for: cancer
Route of administration: oral
Substance: vismodegib (antineoplastic agent)
ATC: L01XX43 (Antineoplastic and immunomodulating agents | Other antineoplastic agents)
This medicine may affect fertility.
Dose adjustment may be needed in liver disease.
Handle with special care.
Effective contraception is required during treatment.
Do not use this medicine while breastfeeding.
Do not use this medicine during pregnancy.
This medicine may affect the liver.
This medicine may have important interactions with other medicines.
This medicine may lower blood cell counts.
This medicine is subject to additional monitoring.
Periodic laboratory tests may be required during treatment.
Stop taking the medicine and seek urgent medical help if a severe rash occurs.
Vismodegib is a medication used for the treatment of advanced basal cell carcinoma, a type of skin cancer that cannot be treated with surgery or radiation therapy. It is a Hedgehog pathway inhibitor, which plays a critical role in the growth and survival of tumor cells. By blocking this pathway, vismodegib halts the proliferation of cancer cells.
The medication is administered orally, usually once daily, and the duration of treatment depends on the patient's response and tolerability. It is indicated for patients with locally advanced basal cell carcinoma as well as those with metastases.
Common side effects include nausea, fatigue, loss of appetite, muscle cramps, and hair loss. In rare cases, severe adverse reactions such as liver function impairment or allergic reactions may occur.
Patients receiving vismodegib should be regularly monitored for signs of toxicity and treatment efficacy. The medication represents an important therapeutic option for patients with advanced basal cell carcinoma, offering a chance to control disease progression.
General data about ERIVEDGE 150mg
- Substance: vismodegib
- Date of latest medicines list: 01-06-2026
- Product code: W64376001
- Concentration: 150mg
- Pharmaceutical form: capsules
- Quantity: 28
- Product type: Original
- Price: 15788.57 RON
- Prescription status: P-RF - Medicines dispensed with a medical prescription that is retained by the pharmacy and cannot be renewed.
Leaflet ERIVEDGE 150mg
Contents of the package leaflet for the medicine ERIVEDGE 150mg capsules
1. NAME OF THE MEDICINAL PRODUCT
Erivedge 150 mg hard capsules
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each hard capsule contains 150 mg of vismodegib.
Excipient with known effectEach hard capsule contains 71.5 mg lactose monohydrate.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Hard capsule (capsule).
Pink coloured opaque body marked “150 mg” and a grey opaque cap marked “VISMO” with blackink. The size of the capsule is ‘Size 1’ (dimensions 19.0 x 6.6 mm).
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Erivedge is indicated for the treatment of adult patients with:symptomatic metastatic basal cell carcinomalocally 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 experiencedin the management of the approved indication.
PosologyThe recommended dose is one 150 mg capsule taken once daily.
Missed dosesIf a dose is missed, patients should be instructed not to take the missed dose but to resume with thenext scheduled dose.
Duration of treatmentIn clinical studies, treatment with Erivedge was continued until disease progression or untilunacceptable toxicity. Treatment interruptions of up to 4 weeks were allowed based on individualtolerability.
Benefit of continued treatment should be regularly assessed, with the optimal duration of therapyvarying for each individual patient.
Special populationsElderly
No dose adjustment is required in patients ≥ 65years of age (see section 5.2). Of a total number of138 patients in 4 clinical studies of Erivedge in advanced basal cell carcinoma, approximately 40 % ofpatients were ≥ 65 years old and no overall differences in safety and efficacy were observed betweenthese patients and younger patients.
Renal impairmentMild and moderate renal impairment is not expected to impact the elimination of vismodegib and nodose 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 impairmentNo dose adjustment is required in patients with mild, moderate or severe hepatic impairment definedbased on National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG)- criteria forhepatic 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 anysevere: 3 x ULN < TB < 10 x ULN, AST any
Paediatric populationThe safety and efficacy of Erivedge in children and adolescents aged below 18 years have not beenestablished.
Due to safety concerns (see sections 4.4 and 5.3), this medicinal product should not be used in childrenand adolescents aged below 18 years.
Method of administrationErivedge 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 andhealth 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
Erivedge may cause embryo-foetal death or severe birth defects when administered to a pregnantwoman (see section 4.6). Hedgehog pathway inhibitors, (see section 5.1) such as vismodegib, havebeen demonstrated to be embryotoxic and/or teratogenic in multiple animal species and can causesevere 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 havemedically-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.
CounsellingFor 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 daysbefore starting Erivedge treatment,
- She must have a negative pregnancy test monthly during treatment, even if she has becomeamenorrhoeic,
- 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 belowand section 4.6) while she is taking Erivedge, unless she commits to not having sexualintercourse (abstinence),
- She must tell her healthcare provider if any of the following occur during treatment and for24 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 menVismodegib is present in semen. To avoid potential foetal exposure during pregnancy, a male patientmust understand that:
- Erivedge exposes a teratogenic risk to the unborn child if he engages in unprotected sexualactivity with a pregnant woman,
- He must always use the recommended contraception (see the ‘Contraception' section below andsection 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.
ContraceptionWCBP
Female patients must use two methods of recommended contraception including one highly effectivemethod and a barrier method during Erivedge therapy and for 24 months after the final dose(see section 4.6).
MenMale patients must always use a condom (with spermicide, if available), even after a vasectomy, whenhaving sex with a female partner, while taking Erivedge and for 2 months after the final dose(see section 4.6).
Pregnancy testingIn a WCBP, a medically supervised pregnancy test, conducted by a heath care provider, should beperformed within 7 days prior to initiating treatment and monthly during treatment. Pregnancy testsshould have a minimum sensitivity of 25 mIU/mL as per local availability. Patients who present withamenorrhoea during treatment with Erivedge should continue monthly pregnancy testing while ontreatment.
Prescribing and dispensing restrictions for WCBPThe initial prescription and dispensing of Erivedge should occur within a maximum of 7 days of anegative pregnancy test (day of pregnancy test = day 1). Prescriptions of Erivedge should be limitedto 28 days of treatment and continuation of treatment requires a new prescription.
Educational materialIn 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 developmentPremature fusion of the epiphyses and precocious puberty have been reported in paediatric patientsexposed to Erivedge. Due to the long drug elimination half-life, these events may occur or progressafter drug discontinuation. In animal species, vismodegib has been shown to cause severe irreversiblechanges in growing teeth (degeneration/necrosis of odontoblasts, formation of fluid-filled cysts in thedental pulp, ossification of the root canal, and haemorrhage) and closure of the epiphyseal growthplate. The findings of premature fusion of the epiphyses indicate a potential risk for short stature andtooth deformities to infants and children (see section 5.3).
Blood donationPatients should not donate blood while taking Erivedge and for 24 months after the final dose.
Semen donationMale patients should not donate semen while taking Erivedge and for 2 months after the final dose.
InteractionsConcomitant 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 vismodegibcannot be excluded (see also section 4.5).
Severe cutaneous adverse reactionsSevere cutaneous adverse reactions (SCARs) including cases of Stevens-Johnson syndrome/Toxicepidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS)and acute generalised exanthematous pustulosis (AGEP), which can be life-threatening, have beenreported during post-marketing use (see section 4.8). If the patient has developed any of thesereactions with the use of vismodegib, treatment with vismodegib must not be restarted in this patient atany time.
ExcipientsErivedge capsules contain lactose monohydrate. Patients with rare hereditary problems of galactoseintolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinalproduct.
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
Clinically significant pharmacokinetic (PK) interactions between vismodegib and pH elevating agentsare not expected. Results from a clinical study demonstrated a 33% decrease in vismodegib unbounddrug concentrations after 7 days co-treatment with 20 mg rabeprazole (a proton pump inhibitor) given2 hours before each vismodegib administration. This interaction is not expected to be clinicallysignificant.
Clinically significant PK interactions between vismodegib and CYP450 inhibitors are not expected.
Results from a clinical study demonstrated a 57% increase in vismodegib unbound drugconcentrations 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 CYP3A4inhibitor) 200 mg daily did not influence vismodegib AUC0-24h after 7 days co-treament in healthyvolunteers.
Clinically significant PK interactions between vismodegib and P-gp inhibitors are not expected.
Results from a clinical study demonstrated no clinically significant PK interaction betweenvismodegib 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 productsContraceptive steroids
Results of a drug-drug interaction study conducted in cancer patients demonstrated that the systemicexposure 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 vismodegibupon longer treatment is an inducer of enzymes which metabolise contraceptive steroids. Inductioncould lead to decreases in systemic exposure of the contraceptive steroids and thereby reducedcontraceptive efficacy.
Effects on specific enzymes and transportersIn vitro studies indicate that vismodegib has the potential to act as an inhibitor of breast cancerresistance protein (BCRP). In vivo interaction data is not available. It may not be excluded thatvismodegib may give rise to increased exposure of medicinal products transported by this protein,such as rosuvastatin, topotecan, and sulfasalazin. Concomitant administration should be performedwith caution and a dose adjustment may be necessary.
Clinically significant PK interactions between vismodegib and CYP450 substrates are not expected. Invitro, CYP2C8 was the most sensitive CYP isoform for vismodegib inhibition. However, results of adrug-drug interaction study conducted in cancer patients demonstrated that the systemic exposure ofrosiglitazone (a CYP2C8 substrate) is not altered when co-administered with vismodegib. Thusinhibition 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 increasethe exposure to substrates of OATP1B1, e.g. bosentan, ezetimibe, glibenclamide, repaglinide,valsartan and statins. In particular, caution should be exercised if vismodegib is administered incombination with any statin.
4.6 Fertility, pregnancy and lactation
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 finaldose (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 periodsIf the patient does become pregnant, misses a menstrual period, or suspects for any reason that shemay be pregnant, she must notify her treating physician immediately.
Persistent lack of menses during treatment with Erivedge should be assumed to indicate pregnancyuntil medical evaluation and confirmation.
Contraception in males and femalesWomen of childbearing potential (WCBP)
WCBP must be able to comply with effective contraceptive measures. She must use two methods ofrecommended 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 orstopped, must follow all the advice on effective contraception.
MenVismodegib is present in semen. To avoid potential foetal exposure during pregnancy, male patientsmust always use a condom (with spermicide, if available), even after a vasectomy, when having sexwith 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).
PregnancyErivedge may cause embryo-foetal death or severe birth defects when administered to a pregnantwoman (see section 4.4). Hedgehog pathway inhibitors (see section 5.1) such as vismodegib, havebeen demonstrated to be embryotoxic and/or teratogenic in multiple animal species and can causesevere 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 stoppedimmediately.
Breast-feedingThe extent to which vismodegib is excreted in breast milk is not known. Due to its potential to causeserious developmental defects women must not breast-feed while taking Erivedge and for 24 monthsafter the final dose (see sections 4.3 and 5.3).
FertilityHuman female fertility may be compromised by treatment with Erivedge (see section 5.3).
Reversibility of fertility impairment is unknown. Additionally, amenorrhoea has been observed inclinical 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
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 reactionsADRs 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 advancedbasal 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 onedose of Erivedge monotherapy at doses 150 mg. Doses > 150 mg did not result in higher plasmaconcentrations 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 evaluablefor safety and treated with 150 mg. In general the safety profile observed was consistent in bothmBCC 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 decreased appetite dehydrationnutrition disorders
Nervous system dysgeusia hypogeusiadisorder ageusia
Gastrointestinal nausea abdominal pain upperdisorders diarrhoea abdominal painconstipationvomitingdyspepsia
Hepatobiliary hepatic enzymes drug induced liverdisorders increased** injury*****
Skin and alopecia madarosis Stevens-Johnson syndromesubcutaneous tissue pruritus abnormal hair growth (SJS)/toxic epidermaldisorders rash necrolysis (TEN), drugreaction with eosinophiliaand systemic symptoms(DRESS) and acutegeneralised exanthematouspustulosis (AGEP)******
Musculoskeletal and muscle spasms back pain epiphyses prematureconnective tissue arthralgia musculoskeletal chest fusion****disorders pain in extremity painmyalgiaflank painmusculoskeletal painblood creatinephosphokinaseincreased***
Reproductive system amenorrhoea*and breast disorders
General disorders weight decreased astheniaand administration fatiguesite conditions pain
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 in3 patients (30 %).
MedDRA Medical Dictionary for Regulatory Activities.
**Includes preferred terms: liver function test abnormal, blood bilirubin increased, gamma-glutamyl transferaseincreased, 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 section4.4)
***** 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 reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.
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.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents,
ATC code: L01XJ01
Mechanism of actionVismodegib is an orally available small-molecule inhibitor of the Hedgehog pathway. Hedgehogpathway signalling through the Smoothened transmembrane protein (SMO) leads to the activation andnuclear localisation of Glioma-Associated Oncogene (GLI) transcription factors and induction of
Hedgehog target genes. Many of these genes are involved in proliferation, survival, anddifferentiation. Vismodegib binds to and inhibits the SMO protein thereby blocking Hedgehog signaltransduction.
Clinical efficacy and safetyThe 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 ofthe body, including the lymph nodes, lung, bones and/or internal organs. LaBCC patients hadcutaneous lesions that were inappropriate for surgery (inoperable, multiply recurrent where curativeresection deemed to be unlikely or for whom surgery would result in substantial deformity ormorbidity) and for which radiotherapy was unsuccessful or contraindicated or inappropriate. Prior tostudy enrolment, diagnosis of BCC was confirmed by histology. Patients with Gorlin syndrome whohad 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 evaluable 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 includingsurgery (97 %), radiotherapy (58 %), and systemic therapies (30 %). For the laBCC cohort (n = 63),94 % of patients had prior therapies including surgery (89 %), radiotherapy (27 %), andsystemic/topical therapies (11 %). The median duration of treatment was 12.9 months (range 0.7 to47.8 months).
The primary endpoint was objective response rate (ORR) as assessed by an independent reviewfacility (IRF) as summarised in Table 2. Objective response was defined as a complete or partialresponse determined on two consecutive assessments separated by at least 4 weeks. In the mBCCcohort, tumour response was assessed according to the Response Evaluation Criteria in Solid Tumours(RECIST) version 1.0. In the laBCC cohort, tumour response was assessed based on visual assessmentof external tumour and ulceration, tumour imaging (where appropriate), and tumour biopsy. A patientwas considered a responder in the laBCC cohort if at least one of the following criteria was met andthe patient did not experience progression: (1) ≥ 30 % reduction in lesion size [sum of the longestdiameter (SLD)], from baseline in target lesions by radiography; (2) ≥ 30 % reduction in SLD frombaseline in externally visible dimension of target lesions; (3) Complete resolution of ulceration in alltarget lesions. Key data are summarised in Table 2:
Table 2 SHH4476g Erivedge Efficacy Results (IRF 21 months and Investigator assessed39 months follow-up after last patient enrolled): efficacy-evaluable patients*, †
IRF-Assessed Investigator-AssessedmBCC laBCC** mBCC laBCC**(n 33) (n 63) (n 33) (n 63)
Responders 11 (33.3 %) 30 (47.6 %) 16 (48.5 %) 38 (60.3 %)95 % CI for overall (19.2 %, 51.8 %) (35.5 %, 60.6 %) (30.8%, 66.2 %) (47.2 %, 71.7 %)response
Complete Response 0 14 (22.2 %) 0 20 (31.7 %)
Partial Response 11 (33.3 %) 16 (25.4 %) 16 (48.5 %) 18 (28.6 %)
Stable disease 20 22 14 15
Progressive disease ‡ 1 8 2 6
Median Duration of 7.6 9.5 14.8 26.2
Response (months)(95 % CI) (5.5, 9.4) (7.4, 21.4) (5.6, 17.0) (9.0, 37.6)
Median Progression 9.5 9.5 9.3 12.9
Free survival (months)(95 % CI) (7.4,11.1) (7.4, 14.8) (7.4, 16.6) (10.2, 28.0)
Median OS, 33.4 NE(months) (18.1, NE) (NE, NE)(95 % CI)1-year survival 78.7 % 93.2 %rate (64.7, 92.7) (86.8, 99.6)(95 % CI)
NE not estimable
* Efficacy-evaluable patient population is defined as all enrolled patients who received any amount of Erivedge andfor whom the independent pathologist’s interpretation of archival tissue or baseline biopsy was consistent with BCC.† Unevaluable/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 ofthe 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 byradiography 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 assessedby 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 inthe figure. Four patients were excluded from the figure: 3 patients with stable disease were assessed by non-target lesionsonly and 1 patient was unevaluable.
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 asabove. Four patients did not have lesion measurements and were not included in the plot.
Time to maximum tumour reductionAmong patients who achieved tumour reduction, the median time to maximum tumour reductionoccurred in 5.6 and 5.5 months for laBCC and mBCC patients respectively, based on the IRFassessment. According to investigator assessment, the median time to maximum tumour reductionoccurred in 6.7 and 5.5 months for laBCC and mBCC patients respectively.
Cardiac electrophysiologyIn a thorough QTc study in 60 healthy subjects, there was no effect of therapeutic doses of Erivedgeon the QTc interval.
Post approval study resultsA post-approval, open-label, non-comparative, multicenter, phase II clinical trial (MO25616) wasconducted in 1232 patients with advanced BCC, of whom 1215 patients were evaluable for efficacyand safety with laBCC (n = 1119) or mBCC (n = 96). LaBCC was defined as cutaneous lesions thatwere 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 ashistologically confirmed distant metastasis. Prior to study enrollment, diagnosis of BCC wasconfirmed 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% hadmBCC whereas 92% had laBCC. For the metastatic cohort, the majority of patients had priortherapies, including surgery (91%), radiotherapy (62%) and systemic therapy (16%). For the locallyadvanced 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 confirmeddisease, 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 and33.4% in the laBCC cohort. Partial response was achieved in 32.1% patients in the mBCC cohort and35.1% in the laBCC cohort.
Paediatric populationThe 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 forinformation on paediatric use).
5.2 Pharmacokinetic properties
Erivedge is a highly permeable compound with low aqueous solubility (BCS Class 2). The single dosemean (CV %) absolute bioavailability of Erivedge is 31.8 (14.5) %. Absorption is saturable asevidenced by the lack of dose proportional increase in exposure after a single dose of 270 mg and540 mg Erivedge. Under clinically relevant conditions (steady state), the PK of vismodegib is notaffected by food. Therefore, Erivedge may be taken without regard to meals.
DistributionThe volume of distribution for vismodegib is low, ranging from 16.4 to 26.6 L. In vitro binding ofvismodegib to human plasma proteins is high (97 %) at clinically relevant concentrations. Vismodegibbinds to both human serum albumin and alpha-1-acid glycoprotein (AAG). In vitro binding to AAG issaturable at clinically relevant concentrations. Ex vivo plasma protein binding in human patients is> 99 %. Vismodegib concentrations are strongly correlated with AAG levels, showing parallelfluctuations of AAG and total vismodegib over time and consistently low unbound vismodegib levels.
BiotransformationVismodegib is slowly eliminated by a combination of metabolism and excretion of parent drugsubstance. Vismodegib is predominant in plasma, with concentrations representing greater than 98 %of the total circulating concentrations (including associated metabolites). Metabolic pathways ofvismodegib in humans include oxidation, glucuronidation, and an uncommon pyridine ring cleavage.
CYP2C9 appears to contribute in part to vismodegib metabolism in vivo.
EliminationAfter oral administration of a radiolabelled dose, vismodegib is absorbed and slowly eliminated by acombination of metabolism and excretion of parent drug substance, the majority of which is recoveredin 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 dueto saturable absorption and saturable protein binding. After a single oral dose, vismodegib has aterminal half-life of ca. 12 days.
The apparent half-life of vismodegib at steady-state is estimated to be 4 days with continuous dailydosing. Upon continuous daily dosing, there is a 3 fold accumulation of vismodegib total plasmaconcentrations.
Vismodegib inhibits UGT2B7 in vitro and it may not be excluded that inhibition can take place in vivoin the intestine.
Special populationsElderly
There are limited data in older people. In clinical trials with aBCC, approximately 40 % of patientswere of geriatric age (≥ 65 years). Population pharmacokinetic analyses suggest that age did not have aclinically significant impact on steady-state concentration of vismodegib.
GenderBased on population pharmacokinetic analysis of combined data from 121 males and 104 females,gender did not appear to affect the pharmacokinetics of vismodegib.
RaceThere 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 notevaluated as a covariate in the population pharmacokinetic analysis.
Renal impairmentRenal excretion of orally administered vismodegib is low. Therefore, mild and moderate renalimpairment 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 moderateimpaired 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.
Hepatic impairmentThe major elimination pathways of vismodegib involve hepatic metabolism and biliary/intestinalsecretion. In a clinical study in patients with hepatic impairment (degree of impairment based onsubject’s AST and total bilirubin levels) following multiple doses of vismodegib, it was shown that inpatients with mild (NCI-ODWG criteria, n=8), moderate (NCI-ODWG criteria, n=6), and severe(NCI-ODWG criteria, n=3) hepatic impairment, the pharmacokinetic profile of vismodegib wascomparable to that of subjects with normal hepatic function (n=9) (see section 4.2).
Paediatric populationThere 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 toxicityIn general, the tolerability of Erivedge in repeat-dose toxicity studies in rats and dogs was limited bynonspecific manifestations of toxicity including decreased body weight gain and food consumption.
Additional findings at clinically relevant exposures included faecal changes; skeletal muscle twitchingor 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 atclinically relevant exposures; however, there was no evidence of a primary effect on bone marrow inaffected animals.
CarcinogenicityCarcinogenicity studies were performed in mice and rats. Carcinogenic potential was identified in ratsonly and was limited to benign hair follicle tumors, including pilomatricomas and keratoacanthomasrespectively at ≥ 0.1-fold and ≥0.6-fold of the steady-state AUC(0-24h) of the recommended humandose. No malignant tumors were identified in either species tested. Benign hair follicle tumors havenot been reported in clinical studies with Erivedge, and the relevance of this finding to humans isuncertain.
MutagenicityThere was no evidence of genotoxicity in in vitro assays (reverse bacterial mutagenesis [Ames] andhuman lymphocyte chromosome aberration assays) or in the in vivo rat bone marrow micronucleusassay.
FertilityIn the dedicated 26-week vismodegib rat fertility study, significantly increased absolute weights ofseminal vesicles and reduced absolute weights of prostate were observed. In addition, the ratio oforgan 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 malereproductive 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 thesteady-state AUC0-24h at the recommended human dose). In addition, in the vismodegib generaltoxicity studies up to 26-week in sexually mature rats and dogs, no effects on male reproductiveorgans were observed. Increased number of degenerating germ cells and hypospermia in sexuallyimmature dogs observed at ≥ 50 mg/kg/day in the 4-week general toxicity study was of undeterminedrelationship to vismodegib.
In the dedicated 26-week vismodegib rat fertility study, vismodegib-related effects on femalereproductive organs were observed at 100 mg/kg/day immediately after treatment discontinuation,including decreased implantations, increased percent preimplantation loss, and decreased number ofdams with viable embryos. Similar findings were not observed after a 16 week recovery period. Nocorrelative histopathologic changes were observed. The exposure in female rats at 100 mg/kgcorresponds 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 at100 mg/kg/day; the effect was not reversed by the end of an 8 week recovery period.
TeratogenicityIn an embryo-foetal development study in which pregnant rats were administered vismodegib dailyduring organogenesis, vismodegib crossed the placenta and was severely toxic to the conceptus.
Malformations, including craniofacial anomalies, open perineum, and absent and/or fused digits, wereobserved in foetuses of dams at a dose which corresponded to 20 % of the typical steady-stateexposure in patients, and a 100 % incidence of embryolethality was observed at higher doses.
Post-natal developmentDedicated studies to assess the potential of vismodegib to affect post-natal development have not beenperformed. However, irreversible defects in growing teeth and premature closure of the femoralepiphyseal plate, observed in rat toxicity studies at clinically relevant exposures, represent risks topost-natal development.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Microcrystalline cellulose
Lactose monohydrate
Sodium lauril sulfate
Povidone (K29/32)
Sodium starch glycolate (Type A)
Talc
Magnesium stearate
Capsule shellIron oxide black (E172)
Iron oxide red (E172)
Titanium dioxide (E171)
Gelatine
Printing inkShellac glaze
Iron oxide black (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
4 years.
6.4 Special precautions for storage
Do not store above 30 °C.
Keep the bottle tightly closed in order to protect from moisture.
6.5 Nature and contents of container
HDPE bottle with a child-resistant closure containing 28 hard capsules. The bottle cap material ispolypropylene. The cap liner is aluminum foil-lined waxed pulp board.
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 patientin accordance with local requirements (if applicable, e.g. by returning the capsules to the pharmacist orphysician).
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.