ZELBORAF 240mg tablets medication leaflet

Zelboraf 240 mg film-coated tablets.

Each tablet contains 240 mg of vemurafenib (as a co-precipitate of vemurafenib and hypromelloseacetate succinate).

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Pinkish white to orange white, oval, biconvex film-coated tablets of approximately 19 mm, with‘VEM’ engraved on one side.

Vemurafenib is indicated in monotherapy for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma (see section 5.1).

Treatment with vemurafenib should be initiated and supervised by a qualified physician experiencedin the use of anticancer medicinal products.

Before taking vemurafenib, patients must have BRAF V600 mutation-positive tumour statusconfirmed by a validated test (see sections 4.4 and 5.1).

The recommended dose of vemurafenib is 960 mg (4 tablets of 240 mg) twice daily (equivalent to atotal daily dose of 1,920 mg). Vemurafenib may be taken with or without food, but consistent intake ofboth daily doses on an empty stomach should be avoided (see section 5.2).

Treatment with vemurafenib should continue until disease progression or the development ofunacceptable toxicity (see tables 1 and 2 below).

If a dose is missed, it can be taken up to 4 hours prior to the next dose to maintain the twice dailyregimen. Both doses should not be taken at the same time.

In case of vomiting after vemurafenib administration the patient should not take an additional dose ofthe medicinal product but the treatment should be continued as usual.

Posology adjustments

Management of adverse drug reactions or QTc prolongation may require dose reduction, temporaryinterruption and/or treatment discontinuation (see tables 1 and 2). Posology adjustments resulting in adose below 480 mg twice daily are not recommended.

In the event the patient develops Cutaneous Squamous Cell Carcinoma (cuSCC), it is recommended tocontinue the treatment without modifying the dose of vemurafenib (see sections 4.4 and 4.8).

Table 1: Dose modification schedule based on the grade of any Adverse Events (AEs)

Grade (CTC-AE) (a) Recommended dose modification

Grade 1 or Grade 2 (tolerable) Maintain vemurafenib at a dose of 960 mg twice daily.

Grade 2 (intolerable) or Grade 31st occurrence of any grade 2 or 3 AE Interrupt treatment until grade 0 - 1. Resume dosing at720 mg twice daily (or 480 mg twice daily if the dose hasalready been lowered).

2nd occurrence of any grade 2 or 3 AE Interrupt treatment until grade 0 - 1. Resume dosing ator persistence after treatment 480 mg twice daily (or discontinue permanently if theinterruption dose has already been lowered to 480 mg twice daily).

3rd occurrence of any grade 2 or 3 AE Discontinue permanently.

or persistence after 2nd dose reduction

Grade 41st occurrence of any grade 4 AE Discontinue permanently or interrupt vemurafenibtreatment until grade 0 - 1.

Resume dosing at 480 mg twice daily (or discontinuepermanently if the dose has already been lowered to 480mg twice daily).

2nd occurrence of any grade 4 AE or Discontinue permanently.

persistence of any grade 4 AE after 1stdose reduction(a) The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events v4.0(CTC-AE).

Exposure-dependent QT prolongation was observed in an uncontrolled, open-label phase II study inpreviously treated patients with metastatic melanoma. Management of QTc prolongation may requirespecific monitoring measures (see section 4.4).

Table 2: Dose modification schedule based on prolongation of the QT interval

QTc value Recommended dose modification

QTc>500 ms at baseline Treatment not recommended.

QTc increase meets values of both >500 ms and Discontinue permanently.

>60 ms change from pre-treatment values1st occurrence of QTc>500 ms during treatment Temporarily interrupt treatment until QTcand change from pre-treatment value remains decreases below 500 ms.

<60 ms See monitoring measures in section 4.4.

Resume dosing at 720 mg twice daily (or480 mg twice daily if the dose has already beenlowered).

2nd occurrence of QTc>500 ms during treatment Temporarily interrupt treatment until QTcand change from pre-treatment value remains decreases below 500 ms.

<60 ms See monitoring measures in section 4.4.

Resume dosing at 480 mg twice daily (ordiscontinue permanently if the dose has alreadybeen lowered to 480 mg twice daily).

3rd occurrence of QTc>500 ms during treatment Discontinue permanently.

and change from pre-treatment value remains<60 ms

Special population

No special dose adjustment is required in patients aged > 65 years old.

Limited data are available in patients with renal impairment. A risk for increased exposure in patientswith severe renal impairment cannot be excluded. Patients with severe renal impairment should beclosely monitored (see sections 4.4 and 5.2).

Limited data are available in patients with hepatic impairment. As vemurafenib is cleared by the liver,patients with moderate to severe hepatic impairment may have increased exposure and should beclosely monitored (see sections 4.4 and 5.2).

The safety and efficacy of vemurafenib in children less than 18 years old have not been established.

Currently available data are described in sections 4.8, 5.1, and 5.2, but no recommendation on aposology can be made.

The safety and efficacy of vemurafenib has not been established in non-Caucasian patients. No dataare available.

Vemurafenib is for oral use. The tablets are to be swallowed whole with water. They should not bechewed or crushed.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Before taking vemurafenib, patients must have BRAF V600 mutation-positive tumour statusconfirmed by a validated test. The efficacy and safety of vemurafenib in patients with tumoursexpressing rare BRAF V600 mutations other than V600E and V600K have not been convincinglyestablished (see section 5.1). Vemurafenib should not be used in patients with wild type BRAFmalignant melanoma.

Hypersensitivity reaction

Serious hypersensitivity reactions, including anaphylaxis have been reported in association withvemurafenib (see sections 4.3 and 4.8). Severe hypersensitivity reactions may include

Stevens-Johnson syndrome, generalised rash, erythema or hypotension. In patients who experiencesevere hypersensitivity reactions, vemurafenib treatment should be permanently discontinued.

Severe dermatologic reactions have been reported in patients receiving vemurafenib, including rarecases of Stevens-Johnson syndrome and toxic epidermal necrolysis in the pivotal clinical trial. Drugreaction with eosinophilia and systemic symptoms (DRESS) has been reported in association withvemurafenib in the post-marketing setting (see section 4.8). In patients who experience a severedermatologic reaction, vemurafenib treatment should be permanently discontinued.

Potentiation of radiation toxicity

Cases of radiation recall and radiation sensitization have been reported in patients treated withradiation either prior, during, or subsequent to vemurafenib treatment. Most cases were cutaneous innature but some cases involving visceral organs had fatal outcomes (see sections 4.5 and 4.8).

Vemurafenib should be used with caution when given concomitantly or sequentially with radiationtreatment.

Exposure-dependent QT prolongation was observed in an uncontrolled, open-label phase II study inpreviously treated patients with metastatic melanoma (see section 4.8). QT prolongation may lead toan increased risk of ventricular arrhythmias including Torsade de Pointes. Treatment withvemurafenib is not recommended in patients with uncorrectable electrolyte abnormalities (includingmagnesium), long QT syndrome or who are taking medicinal products known to prolong the QTinterval.

Electrocardiogram (ECG) and electrolytes (including magnesium) must be monitored in all patientsbefore treatment with vemurafenib, after one month of treatment and after dose modification.

Further monitoring is recommended in particular in patients with moderate to severe hepaticimpairment monthly during the first 3 months of treatment followed by every 3 months thereafter ormore often as clinically indicated. Initiation of treatment with vemurafenib is not recommended inpatients with QTc>500 milliseconds (ms). If during treatment the QTc exceeds 500 ms, vemurafenibtreatment should be temporarily interrupted, electrolyte abnormalities (including magnesium) shouldbe corrected, and cardiac risk factors for QT prolongation (e.g. congestive heart failure,bradyarrhythmias) should be controlled. Re-initiation of treatment should occur once the QTcdecreases below 500 ms and at a lower dose as described in table 2. Permanent discontinuation ofvemurafenib treatment is recommended if the QTc increase meets values of both >500 ms and >60 mschange from pre-treatment values.

Ophthalmologic reactions

Serious ophthalmologic reactions, including uveitis, iritis and retinal vein occlusion, have beenreported. Monitor patients routinely for ophthalmologic reactions.

Cutaneous Squamous Cell Carcinoma (cuSCC)

Cases of cuSCC (which include those classified as keratoacanthoma or mixed keratoacanthomasubtype) have been reported in patients treated with vemurafenib (see section 4.8).

It is recommended that all patients receive a dermatologic evaluation prior to initiation of therapy andbe monitored routinely while on therapy. Any suspicious skin lesions should be excised, sent fordermatopathologic evaluation and treated as per local standard of care. The prescriber should examinethe patient monthly during and up to six months after treatment for cuSCC. In patients who developcuSCC, it is recommended to continue the treatment without dose adjustment. Monitoring shouldcontinue for 6 months following discontinuation of vemurafenib or until initiation of anotheranti-neoplastic therapy. Patients should be instructed to inform their physicians upon the occurrence ofany skin changes.

Non-Cutaneous Squamous Cell Carcinoma (non-cuSCC)

Cases of non-cuSCC have been reported in clinical trials where patients received vemurafenib.

Patients should undergo a head and neck examination, consisting of at least a visual inspection of oralmucosa and lymph node palpation prior to initiation of treatment and every 3 months during treatment.

In addition, patients should undergo a chest Computerised Tomography (CT) scan, prior to treatmentand every 6 months during treatment.

Anal examinations and pelvic examinations (for women) are recommended before and at the end oftreatment or when considered clinically indicated.

Following discontinuation of vemurafenib, monitoring for non-cuSCC should continue for up to6 months or until initiation of another anti-neoplastic therapy. Abnormal findings should be managedaccording to clinical practices.

New primary melanomas have been reported in clinical trials. Cases were managed with excision andpatients continued treatment without dose adjustment. Monitoring for skin lesions should occur asoutlined above for cutaneous squamous cell carcinoma.

Other malignancies

Based on mechanism of action, vemurafenib may cause progression of cancers associated with RASmutations (see section 4.8). Carefully consider benefits and risks before administering vemurafenib topatients with a prior or concurrent cancer associated with RAS mutation.

Pancreatitis has been reported in vemurafenib-treated subjects. Unexplained abdominal pain should bepromptly investigated (including measurement of serum amylase and lipase). Patients should beclosely monitored when re-starting vemurafenib after an episode of pancreatitis.

Liver injury

Liver injury, including cases of severe liver injury, has been reported with vemurafenib (see section4.8). Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be measured beforeinitiation of treatment and monitored monthly during treatment, or as clinically indicated. Laboratoryabnormalities should be managed with dose reduction, treatment interruption or with treatmentdiscontinuation (see sections 4.2 and 4.8).

Renal toxicity

Renal toxicity, ranging from serum creatinine elevations to acute interstitial nephritis and acute tubularnecrosis, has been reported with vemurafenib. Serum creatinine should be measured before initiationof treatment and monitored during treatment as clinically indicated (see sections 4.2 and 4.8).

No adjustment to the starting dose is needed for patients with hepatic impairment. Patients with mildhepatic impairment due to liver metastases without hyperbilirubinaemia may be monitored accordingto the general recommendations. There are only very limited data available in patients with moderateto severe hepatic impairment. Patients with moderate to severe hepatic impairment may have increasedexposure (see section 5.2). Thus close monitoring is warranted especially after the first few weeks oftreatment as accumulation may occur over an extended period of time (several weeks). In addition

ECG monitoring every month during the first three months is recommended.

No adjustment to the starting dose is needed for patients with mild or moderate renal impairment.

There are only limited data available in patients with severe renal impairment (see section 5.2).

Vemurafenib should be used with caution in patients with severe renal impairment and patients shouldbe closely monitored.

Mild to severe photosensitivity was reported in patients who received vemurafenib in clinical studies(see section 4.8). All patients should be advised to avoid sun exposure while taking vemurafenib.

While taking the medicinal product, patients should be advised to wear protective clothing and use abroad spectrum Ultraviolet A (UVA)/Ultraviolet B (UVB) sunscreen and lip balm (Sun Protection

Factor ≥ 30) when outdoors to help protect against sunburn.

For photosensitivity grade 2 (intolerable) or greater, dose modifications are recommended (see section4.2).

Dupuytren’s contracture and plantar fascial fibromatosis

Dupuytren’s contracture and plantar fascial fibromatosis have been reported with vemurafenib. Themajority of cases were mild to moderate, but severe, disabling cases of Dupuytren’s contracture havealso been reported (see section 4.8).

Events should be managed with dose reduction with treatment interruption or with treatmentdiscontinuation (see section 4.2).

Effects of vemurafenib on other medicinal products

Vemurafenib may increase the plasma exposure of medicinal products predominantly metabolised by

CYP1A2 and decrease the plasma exposure of medicines predominantly metabolised by CYP3A4.

Concomitant use of vemurafenib with agents metabolized by CYP1A2 and CYP3A4 with narrowtherapeutic windows is not recommended. Dose adjustments for medicinal products predominantlymetabolised via CYP1A2 or CYP3A4 should be considered based on their therapeutic windows beforeconcomitantly treating with vemurafenib (see sections 4.5 and 4.6).

Exercise caution and consider additional INR (International Normalised Ratio) monitoring whenvemurafenib is used concomitantly with warfarin.

Vemurafenib may increase the plasma exposure of medicinal products that are P-gp substrates.

Caution should be exercised when dosing vemurafenib concurrently with P-gp substrates. Dosereduction and/or additional drug level monitoring for P-gp substrate medicinal products with narrowtherapeutic index (NTI) (e.g. digoxin, dabigatran etexilate, aliskiren) may be considered if thesemedicinal products are used concomitantly with vemurafenib (see section 4.5).

Effect of other medicinal products on vemurafenib

Concomitant administration of strong inducers of CYP3A4, P-gp and glucuronidation (e.g. rifampicin,rifabutin, carbamazepine, phenytoin or St John’s Wort [hypericin]) might lead to decreased exposureof vemurafenib and should be avoided when possible (see section 4.5). Alternative treatment with lessinducing potential should be considered to maintain the efficacy of vemurafenib. Caution should beused when administering Vemurafenib with strong CYP3A4/PgP inhibitors. Patients should becarefully monitored for safety and dose modifications applied if clinically indicated (see Table 1 insection 4.2).

Concurrent administration with ipilimumab

In a Phase I trial, asymptomatic grade 3 increases in transaminases (ALT/AST >5 x ULN) andbilirubin (total bilirubin >3x ULN) were reported with concurrent administration of ipilimumab(3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID). Based on these preliminary data, theconcurrent administration of ipilimumab and vemurafenib is not recommended.

Effects of vemurafenib on Drug Metabolizing Enzymes

Results from an in vivo drug-drug interaction study in metastatic melanoma patients demonstrated thatvemurafenib is a moderate CYP1A2 inhibitor and a CYP3A4 inducer.

Concomitant use of vemurafenib with agents metabolized by CYP1A2 with narrow therapeuticwindows (e.g. agomelatine, alosetron, duloxetine, melatonin, ramelteon, tacrine, tizanidine,theophylline) is not recommended. If co-administration cannot be avoided, exercise caution, asvemurafenib may increase plasma exposure of CYP1A2 substrate drugs. Dose reduction of theconcomitant CYP1A2 substrate drug may be considered, if clinically indicated.

Co-administration of vemurafenib increased the plasma exposure (AUC) of caffeine (CYP1A2substrate) 2.6-fold. In another clinical trial, vemurafenib increased Cmax and AUC of a single 2 mgdose of tizanidine (CYP1A2 substrate) approximately 2.2-foldand 4.7-fold, respectively.

Concomitant use of vemurafenib with agents metabolized by CYP3A4 with narrow therapeuticwindows is not recommended. If co-administration cannot be avoided, it needs to be considered thatvemurafenib may decrease plasma concentrations of CYP3A4 substrates and thereby their efficacymay be impaired. On this basis, the efficacy of contraceptive pills metabolized by CYP3A4 usedconcomitantly with vemurafenib might be decreased. Dose adjustments for CYP3A4 substrates withnarrow therapeutic window may be considered, if clinically indicated (see sections 4.4 and 4.6).

In a clinical trial, co-administration of vemurafenib decreased the AUC of midazolam (CYP3A4substrate) by an average 39% (maximum decrease up to 80%).

Mild induction of CYP2B6 by vemurafenib was noted in vitro at a vemurafenib concentration of10 µM. It is currently unknown whether vemurafenib at a plasma level of 100 µM observed in patientsat steady state (approximately 50 µg/ml) may decrease plasma concentrations of concomitantlyadministered CYP2B6 substrates, such as bupropion.

Co-administration of vemurafenib resulted in an 18% increase in AUC of S-warfarin (CYP2C9substrate). Exercise caution and consider additional INR (international normalized ratio) monitoringwhen vemurafenib is used concomitantly with warfarin (see section 4.4).

Vemurafenib moderately inhibited CYP2C8 in vitro. The in vivo relevance of this finding is unknown,but a risk for a clinically relevant effect on concomitantly administered CYP2C8 substrates cannot beexcluded. Concomitant administration of CYP2C8 substrates with a narrow therapeutic windowshould be made with caution since vemurafenib may increase their concentrations.

Due to the long half-life of vemurafenib, the full inhibitory effect of vemurafenib on a concomitantmedicinal product might not be observed before 8 days of vemurafenib treatment.

After cessation of vemurafenib treatment, a washout of 8 days might be necessary to avoid aninteraction with a subsequent treatment.

Radiation treatment

Potentiation of radiation treatment toxicity has been reported in patients receiving vemurafenib (seesections 4.4 and 4.8). In the majority of cases, patients received radiotherapy regimens greater than orequal to 2 Gy/day (hypofractionated regimens).

Effects of vemurafenib on drug transport systems

In vitro studies have demonstrated that vemurafenib is an inhibitor of the efflux transporters

P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).

A clinical drug interaction study demonstrated that multiple oral doses of vemurafenib (960 mg twicedaily) increased the exposure of a single oral dose of the P-gp substrate digoxin, approximately 1.8and 1.5 fold for digoxin AUClast and Cmax, respectively.

Caution should be exercised when dosing vemurafenib concurrently with P-gp substrates (e.g.

aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, lapatinib,maraviroc, nilotinib, posaconazole, ranolazine, sirolimus, sitagliptin, talinolol, topotecan) and dosereduction of the concomitant medicinal product may be considered, if clinically indicated. Consideradditional drug level monitoring for P-gp substrate medicinal products with a narrow therapeutic index(NTI) (e.g. digoxin, dabigatran etexilate, aliskiren) (see section 4.4).

The effects of vemurafenib on medicinal products that are substrates of BCRP are unknown. It cannotbe excluded that vemurafenib may increase the exposure of medicines transported by BCRP (e.g.

methotrexate, mitoxantrone, rosuvastatin).

Many anticancer medicinal products are substrates of BCRP and therefore there is a theoretical riskfor an interaction with vemurafenib.

The possible effect of vemurafenib on other transporters is currently unknown.

Effects of concomitant medicines on vemurafenib

In vitro studies suggest that CYP3A4 metabolism and glucuronidation are responsible for themetabolism of vemurafenib. Biliary excretion appears to be another important elimination pathway. Invitro studies have demonstrated that vemurafenib is a substrate of the efflux transporters P-gp and

BCRP. It is currently unknown whether vemurafenib is a substrate also to other transport proteins.

Concomitant administration of strong CYP3A4 inhibitors or inducers or inhibitors/inducer of transportprotein activity may alter vemurafenib concentrations.

Co-administration of itraconazole, a strong CYP3A4/Pgp inhibitor, increased steady state vemurafenib

AUC by approximately 40%. Vemurafenib should be used with caution in combination with stronginhibitors of CYP3A4, glucuronidation and/or transport proteins (e.g. ritonavir, saquinavir,telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone, atazanavir).

Patients co-treated with such agents should be carefully monitored for safety and dose modificationsapplied if clinically indicated (see Table 1 in section 4.2).

In a clinical study, co-administration of a single dose 960 mg of vemurafenib with rifampicin,significantly decreased the plasma exposure of vemurafenib by approximately 40%.

Concomitant administration of strong inducers of P-gp, glucuronidation, and/or CYP3A4 (e.g.

rifampicin, rifabutin, carbamazepine, phenytoin or St John’s Wort [Hypericum perforatum]) may leadto suboptimal exposure to vemurafenib and should be avoided.

The effects of P-gp and BCRP inhibitors that are not also strong CYP3A4 inhibitors are unknown. Itcannot be excluded that vemurafenib pharmacokinetics could be affected by such medicines throughinfluence on P-gp (e.g. verapamil, cyclosporine, quinidine) or BCRP (e.g. cyclosporine, gefitinib).

Women of childbearing potential have to use effective contraception during treatment and for at least6 months after treatment.

Vemurafenib might decrease the efficacy of hormonal contraceptives (see section 4.5).

There are no data regarding the use of vemurafenib in pregnant women.

Vemurafenib revealed no evidence of teratogenicity in rat or rabbit embryo/foetuses (see section 5.3).

In animal studies, vemurafenib was found to cross the placenta. Based on its mechanism of action,vemurafenib could cause fetal harm when administered to a pregnant woman. Vemurafenib should notbe administered to pregnant women unless the possible benefit to the mother outweighs the possiblerisk to the foetus.

It is not known whether vemurafenib is excreted in human milk. A risk to the newborns/infants cannotbe excluded. A decision must be made whether to discontinue breast-feeding or to discontinuevemurafenib therapy taking into account the benefit of breast-feeding for the child and the benefit oftherapy for the woman.

No specific studies with vemurafenib have been conducted in animals to evaluate the effect onfertility. However, in repeat-dose toxicity studies in rats and dogs, no histopathological findings werenoted in reproductive organs in males and females (see section 5.3).

Vemurafenib has minor influence on the ability to drive and use machines. Patients should be madeaware of the potential fatigue or eye problems that could be a reason for not driving.

The most common adverse drug reactions (ADR) of any grade (> 30%) reported with vemurafenibinclude arthralgia, fatigue, rash, photosensitivity reaction, alopecia, nausea diarrhea, headache,pruritus, vomiting, skin papilloma and hyperkeratosis. The most common (≥ 5%) Grade 3 ADRs werecuSCC, keratoacanthoma, rash, arthralgia and gamma-glutamyltransferase (GGT) increased. CuSCCwas most commonly treated by local excision.

ADRs which were reported in melanoma patients are listed below by MedDRA body system organclass, frequency and grade of severity. The following convention has been used for the classificationof frequency:

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

In this section, ADRs are based on results in 468 patients from a phase III randomised open labelstudy in adult patients with BRAF V600 mutation-positive unresectable or stage IV melanoma, as wellas a phase II single-arm study in patients with BRAF V600 mutation-positive stage IV melanoma whohad previously failed at least one prior systemic therapy (see section 5.1). In addition ADRsoriginating from safety reports across all clinical trials and post-marketing sources are reported. Allterms included are based on the highest percentage observed among phase II and phase III clinicaltrials. Within each frequency grouping, ADRs are presented in order of decreasing severity and werereported using NCI-CTCAE v 4.0 (common toxicity criteria) for assessment of toxicity.

Table 3: ADRs occurring in patients treated with vemurafenib in the phase II or phase IIIstudyand events originating from safety reports across all trials(1) and post-marketingsources(2).

System organ class Very Common Common Uncommon Rare

Infections and Folliculitisinfestations

Neoplasms benign, SCC of the skin(d), Basal cell Non-cuSCC(1)(3) Chronicmalignant and keratoacanthoma, carcinoma, new myelomonocyticunspecified seborrhoeic primary leukaemia(2)(4),(including cysts and keratosis, skin melanoma(3) pancreaticpolyps) papilloma adenocarcinoma(5)

Blood and lymphatic Neutropenia,system disorders thrombocytopenia(6)

Immune System Sarcoidosis(1)(2)(j)

Disorders

Metabolism and Decreased appetitenutrition disorders

Nervous system Headache, 7th nervedisorders dysgeusia, paralysis,dizziness neuropathyperipheral

Eye disorders Uveitis, Retinal veinocclusion,iridocyclitis

Vascular disorders Vasculitis

Respiratory, thoracic Coughand mediastinaldisorders

Gastrointestinal Diarrhoea, Stomatitis Pancreatitis(2)disorders vomiting, nausea,constipation

Hepatobiliary Liver injury(1)(2)(g)disorders

Skin and Photosensitivity Rash papular, Toxic epidermal Drug reactionsubcutaneous tissue reaction, actinic panniculitis necrolysis(e), with eosinophiliadisorders keratosis, rash, (including Stevens-Johnson and systemicrash maculo- erythema syndrome(f) symptoms(1)(2)papular, pruritus, nodosum),hyperkeratosis, keratosis pilariserythema, palmar-plantarerythrodysaesthesia syndrome,alopecia, dry skin,sunburn

System organ class Very Common Common Uncommon Rare

Musculoskeletal and Arthralgia, Arthritis, Plantar fascialconnective tissue myalgia, pain in fibromatosis(1)(2)disorders extremity, Dupuytren’smusculoskeletal contracture(1)(2)pain, back pain

Renal and urinary Acute interstitialdisorders nephritis(1)(2)(h),acute tubularnecrosis(1)(2)(h)

General disorders Fatigue, pyrexia,and administration oedema peripheral,site conditions asthenia

Investigations ALT increased(c),alkalinephosphataseincreased(c), ASTincreased(c),bilirubinincreased(c) GGTincreased(c),weight decreased,electrocardiogram

QT prolonged,blood creatinineincreased(1)(2)(h)

Injury, Poisoning, Potentiation ofand Procedural Radiation toxicity

Complications (1)(2)(i)(1) Events originating from safety reports across all trials(2) Events originating from post-marketing sources.(3) A causal relationship between the medicinal product and the adverse event is at least a reasonable possibility.(4) Progression of pre-existing chronic myelomonocytic leukaemia with NRAS mutation.(5) Progression of pre-existing pancreatic adenocarcinoma with KRAS mutation.(6) Calculated based on phase II and phase III studies.

Hepatic enzyme increase (c)

Liver enzyme abnormalities reported in the phase III clinical study are expressed below as theproportion of patients who experienced a shift from baseline to a grade 3 or 4 liver enzymeabnormalities:

● Very common: GGT● Common: ALT, alkaline phosphatase, bilirubin● Uncommon: AST

There were no increases to Grade 4 ALT, alkaline phosphatase or bilirubin.

Liver injury (g)

Based on the criteria for drug induced liver injury developed by an international expert working groupof clinicians and scientists, liver injury was defined as any one of the following laboratoryabnormalities:

● ≥ 5x ULN ALT● ≥ 2x ULN ALP (without other cause for ALP elevation)● ≥ 3x ULN ALT with simultaneous elevation of bilirubin concentration > 2x ULN

Cutaneous squamous cell carcinoma (d) (cuSCC)

Cases of cuSCC have been reported in patients treated with vemurafenib. The incidence of cuSCC invemurafenib-treated patients across studies was approximately 20%. The majority of the excisedlesions reviewed by an independent central dermatopathology laboratory were classified as SCC-keratoacanthoma subtype or with mixed-keratoacanthoma features (52%). Most lesions classified as“other” (43%) were benign skin lesions (e.g. verruca vulgaris, actinic keratosis, benign keratosis,cyst/benign cyst). CuSCC usually occurred early in the course of treatment with a median time to thefirst appearance of 7 to 8 weeks. Of the patients who experienced cuSCC, approximately 33%experienced > 1 occurrence with median time between occurrences of 6 weeks. Cases of cuSCC weretypically managed with simple excision, and patients generally continued on treatment without dosemodification (see sections 4.2 and 4.4).

Non-cutaneous squamous cell carcinoma (non-cuSCC)

Cases of non-cuSCC have been reported in patients receiving vemurafenib while enrolled in clinicaltrials. Surveillance for non-cuSCC should occur as outlined in section 4.4.

New primary melanomas have been reported in clinical trials. These cases were managed withexcision, and patients continued treatment without dose adjustment. Monitoring for skin lesions shouldoccur as outlined in section 4.4.

Potentiation of radiation toxicity(i)

Cases reported include recall phenomenon, radiation skin injury, radiation pneumonitis, radiationesophagitis, radiation proctitis, radiation hepatitis, cystitis radiation, and radiation necrosis.

In a phase III clinical trial (MO25515, N= 3219), a higher incidence of potentiation of radiationtoxicity was reported when vemurafenib patients received radiation prior to and during vemurafenibtherapy (9.1%) compared to those patients who received radiation and vemurafenib concomitantly (5.2%) or to those whose radiation treatment was prior to vemurafenib (1.5%).

Hypersensitivity reactions (e)

Serious hypersensitivity reactions, including anaphylaxis have been reported in association withvemurafenib. Severe hypersensitivity reactions may include Stevens-Johnson syndrome, generalisedrash, erythema or hypotension. In patients who experience severe hypersensitivity reactions,vemurafenib treatment should be permanently discontinued (see section 4.4).

Dermatologic reactions (f)

Severe dermatologic reactions have been reported in patients receiving vemurafenib, including rarecases of Stevens-Johnson syndrome and toxic epidermal necrolysis in the pivotal clinical trial. Inpatients who experience a severe dermatologic reaction, vemurafenib treatment should be permanentlydiscontinued.

Analysis of centralised ECG data from an open-label uncontrolled phase II QT sub-study in 132patients dosed with vemurafenib 960 mg twice daily (NP22657) showed an exposure-dependent QTcprolongation. The mean QTc effect remained stable between 12-15 ms beyond the first month oftreatment, with the largest mean QTc prolongation (15.1 ms; upper 95% CI: 17.7 ms) observed withinthe first 6 months (n=90 patients). Two patients (1.5%) developed treatment-emergent absolute QTcvalues >500 ms (CTC Grade 3), and only one patient (0.8%) exhibited a QTc change from baseline of>60 ms (see section 4.4).

Acute kidney injury (h)

Cases of renal toxicity have been reported with vemurafenib ranging from creatinine elevations toacute interstitial nephritis and acute tubular necrosis, some observed in the setting of dehydrationevents. Serum creatinine elevations were mostly mild (>1-1.5x ULN) to moderate (>1.5-3x ULN) andobserved to be reversible in nature (see table 4).

Table 4: Creatinine changes from baseline in the phase III study

Vemurafenib (%) Dacarbazine (%)

Change  1 grade from baseline to any grade 27.9 6.1

Change  1 grade from baseline to grade 3 or higher 1.2 1.1

* To grade 3 0.3 0.4

* To grade 4 0.9 0.8

Table 5: Acute kidney injury cases in the phase III study

Vemurafenib (%) Dacarbazine (%)

Acute kidney injury cases* 10.0 1.4

Acute kidney injury cases associated with dehydration5.5 1.0events

Dose modified for acute kidney injury 2.1 0

All percentages are expressed as cases out of total patients exposed to each medicinal product.

* Includes acute kidney injury, renal impairment, and laboratory changes consistent with acute kidney injury.

Sarcoidosis (j)

Cases of sarcoidosis have been reported in patients treated with vemurafenib, mostly involving theskin, lung and eye. In majority of the cases, vemurafenib was maintained and the event of sarcoidosiseither resolved or persisted.

In the phase III study, ninety-four (28%) of 336 patients with unresectable or metastatic melanomatreated with vemurafenib were ≥ 65 years. Older patients (≥ 65 years) may be more likely toexperience adverse reactions, including cuSCC, decreased appetite, and cardiac disorders.

During clinical trials with vemurafenib, grade 3 adverse reactions reported more frequently in femalesthan males were rash, arthralgia and photosensitivity.

The safety of vemurafenib in children and adolescents has not been established. No new safety signalswere observed in a clinical study with six adolescent patients.

Reporting 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.

There is no specific antidote for overdose of vemurafenib. Patients who develop adverse reactionsshould receive appropriate symptomatic treatment. No cases of overdose have been observed withvemurafenib in clinical trials. In case of suspected overdose, vemurafenib should be withheld andsupportive care initiated.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitor, ATC code: L01EC01

Mechanism of action and pharmacodynamic effects

Vemurafenib is an inhibitor of BRAF serine-threonine kinase. Mutations in the BRAF gene result inconstitutive activation of BRAF proteins, which can cause cell proliferation without associated growthfactors.

Preclinical data generated in biochemical assays demonstrated that vemurafenib can potently inhibit

BRAF kinases with activating codon 600 mutations (table 6).

Table 6: Kinase inhibitory activity of vemurafenib against different BRAF kinases

Kinase Anticipated frequency in V600 Inhibitory Concentrationmutation-positive melanoma (t) 50 (nM)

BRAFV600E 87.3% 10

BRAFV600K 7.9% 7

BRAFV600R 1% 9

BRAFV600D <0.2% 7

BRAFV600G <0.1% 8

BRAFV600M <0.1% 7

BRAFV600A <0.1% 14

BRAFWT N/A 39(t) Estimated from 16,403 melanomas with annotated BRAF codon 600 mutations in the public COSMICdatabase, release 71 (November 2014).

This inhibitory effect was confirmed in the ERK phosphorylation and cellular anti-proliferation assaysin available melanoma cell lines expressing V600-mutant BRAF. In cellular anti-proliferation assaysthe inhibitory concentration 50 (IC50) against V600 mutated cell lines (V600E, V600R, V600D and

V600K mutated cell lines) ranged from 0.016 to 1.131 M whereas the IC50 against BRAF wild typecell lines were 12.06 and 14.32 M, respectively.

Before taking vemurafenib, patients must have BRAF V600 mutation-positive tumour statusconfirmed by a validated test. In the phase II and phase III clinical trials, eligible patients wereidentified using a real-time polymerase chain reaction assay (the cobas 4800 BRAF V600 Mutation

Test). This test has CE marking and is used to assess the BRAF mutation status of DNA isolated fromformalin-fixed, paraffin-embedded (FFPE) tumour tissue. It was designed to detect the predominant

BRAF V600E mutation with high sensitivity (down to 5% V600E sequence in a background of wildtype sequence from FFPE-derived DNA). Non-clinical and clinical studies with retrospectivesequencing analyses have shown that the test also detects the less common BRAF V600D mutationsand V600K mutations with lower sensitivity. Of the specimens available from the non-clinical andclinical studies (n=920), that were mutation-positive by the cobas test and additionally analyzed bysequencing, no specimen was identified as being wild type by both Sanger and 454 sequencing.

The efficacy of vemurafenib has been evaluated in 336 patients from a phase III clinical trial(NO25026) and 278 patients from two phase II clinical trials (NP22657 and MO25743). All patientswere required to have advanced melanoma with BRAF V600 mutations according to the cobas 4800

BRAF V600 Mutation Test.

Results from the Phase III study (NO25026) in previously untreated patients

An open-label, multicentre, international, randomised phase III study supports the use of vemurafenibin previously untreated patients with BRAF V600E mutation-positive unresectable or metastaticmelanoma. Patients were randomised to treatment with vemurafenib (960 mg twice daily) ordacarbazine (1000 mg/m2 on day 1 every 3 weeks).

A total of 675 patients were randomised to vemurafenib (n=337) or dacarbazine (n=338). Mostpatients were male (56%) and Caucasian (99%), the median age was 54 years (24% were ≥ 65 years),all patients had ECOG performance status of 0 or 1, and the majority of patients had stage M1cdisease (65%). The co-primary efficacy endpoints of the study were overall survival (OS) andprogression-free survival (PFS).

At the pre-specified interim analysis with a December 30, 2010 data cut-off, significant improvementsin the co-primary endpoints of OS (p<0.0001) and PFS (p<0.0001) (unstratified log-rank test) wereobserved. Upon Data Safety Monitoring Board (DSMB) recommendation, those results were releasedin January 2011 and the study was modified to permit dacarbazine patients to cross over to receivevemurafenib. Post-hoc survival analyses were undertaken thereafter as described in table 7.

Table 7: Overall survival in previously untreated patients with BRAF V600 mutation-positivemelanoma by study cut-off date (N=338 dacarbazine, N=337 vemurafenib)

Cut-off dates Treatment Number of deaths Hazard Ratio Number of cross-(%) (95% CI) over patients (%)

December 30, dacarbazine 75 (22) 0.37 (0.26, 0.55) 0 (not applicable)2010 vemurafenib 43 (13)

March 31, dacarbazine 122 (36) 0.44 (0.33, 0.59) (w) 50 (15%)2011 vemurafenib 78 (23)

October 3, dacarbazine 175 (52) 0.62 (0.49, 0.77) (w) 81 (24%)2011 vemurafenib 159 (47)

February 1, dacarbazine 200 (59) 0.70 (0.57, 0.87) (w) 83 (25%)2012 vemurafenib 199 (59)

December 20, dacarbazine 236 (70) 0.78 (0.64, 0.94) (w) 84 (25%)2012 vemurafenib 242 (72)(w) Censored results at time of cross-over

Non-censored results at time of cross-over: March 31 2011: HR (95% CI) = 0.47 (0.35, 0.62); October 3 2011:

HR (95% CI) = 0.67 (0.54, 0.84); February 1 2012: HR (95% CI) = 0.76 (0.63, 0.93); December 20 2012:

HR (95% CI) = 0.79 (0.66, 0.95)

Figure 1: Kaplan-Meier curves of overall survival - previously untreated patients (December 20,2012 cut-off)

Table 8 shows the treatment effect for all pre-specified stratification variables which are established asprognostic factors.

Table 8: Overall survival in previously untreated patients with BRAF V600 mutation-positivemelanoma by LDH, tumour stage and ECOG status (post hoc analysis, December 20, 2012 cut-off, censored results at time of cross over)

Stratification variable N Hazard Ratio 95% Confidence Interval

LDH normal 391 0.88 0.67; 1.16

LDH >ULN 284 0.57 0.44; 0.76

Stage IIIc/M1A/M1B 234 1.05 0.73; 1.52

Stage MIC 441 0.64 0.51; 0.81

ECOG PS=0 459 0.86 0.67; 1.10

ECOG PS=1 216 0.58 0.42; 0.9

LDH: Lactate Dehydrogenase, ECOG PS: Eastern Cooperative Oncology Group Performance Status

Table 9 shows the overall response rate and progression-free survival in previously untreated patientswith BRAF V600 mutation-positive melanoma.

Table 9: Overall response rate and progression-free survival in previously untreated patientswith BRAF V600 mutation-positive melanomavemurafenib dacarbazine p-value (x)

December 30, 2010 data cut-off date (y)

Overall Response Rate 48.4% 5.5%(95% CI) (41.6%, 55.2%) (2.8%, 9.3%) <0.0001

Progression-freesurvival

Hazard Ratio 0.26(95% CI) (0.20, 0.33) <0.0001

Number of events (%) 104 (38%) 182 (66%)

Median PFS (months) 5.32 1.61(95% CI) (4.86, 6.57) (1.58, 1.74)

February 01, 2012 data cut-off date (z)

Progression-freesurvival

Hazard Ratio 0.38(95% CI) (0.32, 0.46) <0.0001

Number of events (%) 277 (82%) 273 (81%)

Median PFS (months) 6.87 1.64(95% CI) (6.14, 6.97) (1.58, 2.07)(x) Unstratified log-rank test for PFS and Chi-squared test for Overall Response Rate.(y) As of December 30, 2010, a total of 549 patients were evaluable for PFS and 439 patients were evaluable foroverall response rate.(z) As of February 01, 2012, a total of 675 patients were evaluable for the post-hoc analysis update of PFS.

A total of 57 patients out of 673 whose tumours were analysed retrospectively by sequencing werereported to have BRAF V600K mutation-positive melanoma in NO25026. Although limited by thelow number of patients, efficacy analyses among these patients with V600K-positive tumourssuggested similar treatment benefit of vemurafenib in terms of OS, PFS and confirmed best overallresponse. No data are available in patients with melanoma harbouring rare BRAF V600 mutationsother than V600E and V600K.

Results from the phase II study (NP22657) in patients who failed at least one prior therapy

A phase II single-arm, multi-centre, multinational study was conducted in 132 patients who had BRAF

V600E mutation-positive metastatic melanoma according to the cobas 4800 BRAF V600 Mutation

Test and had received at least one prior therapy. The median age was 52 years with 19% of patientsbeing older than 65 years. The majority of patients was male (61%), Caucasian (99%), and had stage

M1c disease (61%). Forty-nine percent of patients failed ≥ 2 prior therapies.

With a median follow-up of 12.9 months (range, 0.6 to 20.1), the primary endpoint of confirmed bestoverall response rate (CR + PR) as assessed by an independent review committee (IRC) was 53%(95% CI: 44%, 62%). Median overall survival was 15.9 months (95% CI: 11.6, 18.3). The overallsurvival rate at 6 months was 77% (95% CI: 70%, 85%) and at 12 months was 58% (95% CI: 49%,67%).

Nine of the 132 patients enrolled into NP22657 had V600K mutation-positive tumours according toretrospective Sanger sequencing. Amongst these patients, 3 had a PR, 3 had SD, 2 had PD and onewas not evaluable.

Results from the phase II study (MO25743) in patients with brain metastases

A single-arm, multicentre study (N = 146) of vemurafenib was conducted in adult patients withhistologically confirmed metastatic melanoma harbouring the BRAF V600 mutation (according to thecobas 4800 BRAF V600 Mutation Test) and with brain metastases. The study included twosimultaneously enrolling cohorts:

- Cohort 1 with previously untreated patients (N = 90): Patients who had not received previoustreatment for brain metastases; prior systemic therapy for metastatic melanoma was allowed,excluding BRAF inhibitors and MEK inhibitors.

- Cohort 2 with previously treated patients (N = 56): Patients who had been previously treated fortheir brain metastases and had progressed following this treatment. For patients treated withstereotactic radiotherapy (SRT) or surgery, a new RECIST-assessable brain lesion must havedeveloped following this prior therapy.

A total of 146 patients were enrolled. The majority of patients were male (61.6%), and Caucasian(92.5%), and the median age was 54 years (range 26 to 83 years), similarly distributed between thetwo cohorts. The median number of brain target lesions at baseline was 2 (range 1 to 5), in bothcohorts.

The primary efficacy objective of the study was best overall response rate (BORR) in the brain ofmetastatic melanoma patients with previously untreated brain metastases, as assessed by anindependent review committee (IRC).

Secondary objectives included an evaluation of the efficacy of vemurafenib using BORR in the brainof previously treated patients, duration of response (DOR), progression-free survival (PFS) and overallsurvival (OS) in patients with melanoma metastatic to the brain (see table 10).

Table 10: Efficacy of vemurafenib in patients with brain metastases

Cohort 1 Cohort 2 Total

No previous Previouslytreatment treatedn = 90 n = 56 n = 146

BORRa in brain

Responders n (%) 16 (17.8%) 10 (17.9%) 26 (17.8%)(95% CI)b (10.5, 27.3) (8.9, 30.4) (12.0, 25.0)

DORc in brain (n) (n = 16) (n = 10) (n = 26)

Median (months) 4.6 6.6 5.0(95% CI)d (2.9, 6.2) (2.8, 10.7) (3.7, 6.6)

BORR extra-cranial n (%)a 26 (32.9%) 9 (22.5%) 35 (29.4%)

PFS - overall

Median (months)e 3.7 3.7 3.7(95% CI)d (3.6, 3.7) (3.6, 5.5) (3.6, 3.7)

PFS - brain only

Median (months)e 3.7 4.0 3.7(95% CI)d (3.6, 4.0) (3.6, 5.5) (3.6, 4.2)

OS

Median (months) 8.9 9.6 9.6(95% CI)d (6.1, 11.5) (6.4, 13.9) (6.9, 11.5)a Best overall confirmed response rate as assessed by independent review committee, number of respondersn (%)b Two-sided 95% Clopper-Pearson Confidence Interval (CI)c Duration of response as assessed by an Independent Review Committeed Kaplan-Meier estimatee Assessed by investigator

Results from the phase I study (NO25390) in paediatric patients

A phase I dose-escalation study evaluating the use of vemurafenib in six adolescent patients with stage

IIIC or IV BRAF V600 mutation positive melanoma was conducted. All patients treated were at least15 years of age and weighed at least 45 kg. Three patients were treated with vemurafenib 720 mgtwice daily, and three patients were treated with vemurafenib 960 mg twice daily. The maximumtolerated dose could not be determined. Although transient tumour regressions were seen, the bestoverall response rate (BORR) was 0% (95% CI: 0%, 46%) based on confirmed responses. The studywas terminated due to low enrollment. See section 4.2 for information on paediatric use.

Vemurafenib is a Class IV substance (low solubility and permeability), using the criteria described inthe Biopharmaceutics Classification System. The pharmacokinetic parameters for vemurafenib weredetermined using non-compartmental analysis in a phase I and phase III studies (20 patients after 15days of dosing at 960 mg twice daily, and 204 patients in steady state day 22) as well as by population

PK analysis using pooled data from 458 patients. Among these patients, 457 were Caucasians.

The bioavailability at steady state ranged between 32 and 115% (mean 64%) relative to an intravenousmicrodose, in a phase I study with uncontrolled food conditions in 4 patients with BRAF V600positive malignancies.

Vemurafenib is absorbed with a median Tmax of approximately 4 hours following a single 960 mgdose (four 240 mg tablets). Vemurafenib exhibits high inter-patient variability. In the phase II study,

AUC0-8h and Cmax at day 1 were 22.1 ± 12.7 µgh/mL and 4.1 ± 2.3 µg/mL. Accumulation occurs uponmultiple twice daily dosing of vemurafenib. In the non-compartmental analysis, after dosing with960 mg vemurafenib twice daily the Day 15/Day 1 ratio ranged from 15- to 17-fold for AUC, and 13-to 14-fold for Cmax, yielding AUC0-8h and Cmax of 380.2 ± 143.6 µgh/mL and 56.7 ± 21.8 µg/mL,respectively, under steady-state conditions.

Food (high fat meal) increases the relative bioavailability of a single 960 mg dose of vemurafenib. Thegeometric mean ratios between the fed and fasted states for Cmax and AUC were 2.5 and 4.6 to 5.1fold, respectively. The median Tmax was increased from 4 to 7.5 hours when a single vemurafenib dosewas taken with food.

The effect of food on steady state vemurafenib exposure is currently unknown. Consistent intake ofvemurafenib on an empty stomach may lead to significantly lower steady state exposure thanconsistent intake of vemurafenib with or a short time after a meal. Occasional intake of vemurafenibon an empty stomach is expected to have limited influence on steady state exposure due to the highaccumulation of vemurafenib at steady state. Safety and efficacy data from pivotal studies werecollected from patients taking vemurafenib with or without food.

Variability in exposure may also occur due to differences in gastro-intestinal fluid content, volumes,pH, motility and transition time and bile composition.

At steady state, the mean vemurafenib exposure in plasma is stable during the 24-hour interval asindicated by the mean ratio of 1.13 between the plasma concentrations before and 2-4 hours after themorning dose. Following oral dosing, the absorption rate constant for the population of metastaticmelanoma patients is estimated to be 0.19 hr-1 (with 101% between patient variability).

The population apparent volume of distribution for vemurafenib in metastatic melanoma patients isestimated to be 91 L (with 64.8% between patient variability). It is highly bound to human plasmaproteins in vitro (>99%).

The relative proportions of vemurafenib and its metabolites were characterised in a human massbalance study with a single dose of 14C-labeled vemurafenib administered orally. CYP3A4 is theprimary enzyme responsible for the metabolism of vemurafenib in vitro. Conjugation metabolites(glucuronidation and glycosylation) were also identified in humans. However, the parent compoundwas the predominant component (95%) in plasma. Although metabolism does not appear to result in arelevant amount of metabolites in plasma, the importance of metabolism for excretion cannot beexcluded.

The population apparent clearance of vemurafenib in patients with metastatic melanoma is estimatedto be 29.3 L/day (with 31.9% between patient variability). The population elimination half-lifeestimated by the population PK analysis for vemurafenib is 51.6 hours (the 5th and 95th percentilerange of the individual half-life estimates is 29.8 - 119.5 hours).

In the human mass balance study with vemurafenib administered orally, on average 95% of the dosewas recovered within 18 days. The majority of vemurafenib-related material (94%) was recovered infaeces, and <1% in urine. Renal elimination does not appear to be of importance for vemurafenibelimiation, whereas biliary excretion of unchanged compound may be an important route ofelimination.. Vemurafenib is a substrate and inhibitor of P-gp in vitro.

Based on the population PK analysis, age has no statistically significant effect on vemurafenibpharmacokinetics.

The population pharmacokinetic analysis indicated a 17% greater apparent clearance (CL/F) and a48% greater apparent volume of distribution (V/F) in males than in females. It is unclear whether thisis a gender or a body size effect. However, the differences in exposure are not large enough to warrantdose adjustment based on body size or gender.

In the population pharmacokinetic analysis using data from clinical trials in patients with metastaticmelanoma, mild and moderate renal impairment did not influence the apparent clearance ofvemurafenib (creatinine clearance >40 ml/min). There are no data in patients with severe renalimpairment (see sections 4.2 and 4.4).

Based on preclinical data and the human mass balance study, major part of vemurafenib is eliminatedvia the liver. In the population pharmacokinetic analysis using data from clinical trials in patients withmetastatic melanoma, increases in AST and ALT up to three times the upper limit of normal did notinfluence the apparent clearance of vemurafenib. Data are insufficient to determine the effect ofmetabolic or excretory hepatic impairment on vemurafenib pharmacokinetics (see sections 4.2 and4.4).

Limited pharmacokinetic data from six adolescent patients aged between 15 and 17 years with stage

IIIC or IV BRAF V600 mutation positive melanoma suggest that vemurafenib pharmacokineticcharacteristics in adolescents are generally similar to those in adults. See section 4.2 for informationon paediatric use.

The preclinical safety profile of vemurafenib was assessed in rats, dogs, and rabbits.

Repeat-dose toxicology studies identified the liver and bone marrow as target organs in the dog.

Reversible toxic effects (hepatocellular necrosis and degeneration) in the liver at exposures below theanticipated clinical exposure (based on AUC comparisons) were noted in the 13-week dog study.

Focal bone marrow necrosis was noted in one dog in a prematurely terminated 39-week BID dog studyat exposures similar to the anticipated clinical exposure (based on AUC comparisons). In an in vitrobone marrow cytotoxicity study, slight cytotoxicity was observed in some lympho-haematopoietic cellpopulations of rat, dog and human at clinically relevant concentrations.

Vemurafenib was shown to be phototoxic, in vitro, on cultured murine fibroblasts after UVAirradiation, but not in vivo in a rat study at doses up to 450 mg/kg/day (at exposures below theanticipated clinical exposure (based on AUC comparison).

No specific studies with vemurafenib have been conducted in animals to evaluate the effect onfertility.

However, in repeat-dose toxicity studies, no histopathological findings were noted on reproductiveorgans in males and females in rats and dogs at doses up to 450 mg/kg/day (at exposures below theanticipated clinical exposure based on AUC comparison). No teratogenicity was observed inembryofoetal development studies in rats and rabbits at doses up to respectively 250 mg/kg/day and450 mg/kg/day leading to exposures below the anticipated clinical exposure (based on AUCcomparison). However, exposures in the embryofoetal development studies were below the clinicalexposure based on AUC comparison, it is therefore difficult to define to what extent these results canbe extrapolated to humans. Therefore an effect of vemurafenib on the foetus cannot be excluded. Nostudies were performed regarding pre- and postnatal development.

No signs of genotoxicity were identified in in vitro assays (bacterial mutation [AMES Assay], humanlymphocyte chromosome aberration) nor in the in vivo rat bone marrow micronucleus test conductedwith vemurafenib.

Carcinogenicity studies have not been conducted with vemurafenib.

Croscarmellose sodium

Colloidal anhydrous silica

Magnesium stearate

Hydroxypropylcellulose

Polyvinyl alcohol

Titanium dioxide (E171)

Macrogol 3350

Talc

Iron oxide red (E172)

Not applicable.

3 years.

Store in the original package in order to protect from moisture.

Aluminium/Aluminium perforated unit dose blisters.

Pack-size: 56 x 1 film-coated tablets (7 blisters of 8 x 1 tablet)

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

EU/1/12/751/001

Date of first authorisation: 17 February 2012

Date of latest renewal: 22 September 2016

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.