TAFINLAR 75mg capsules medication leaflet

Tafinlar 50 mg hard capsules

Tafinlar 75 mg hard capsules

Tafinlar 50 mg hard capsules

Each hard capsule contains dabrafenib mesilate equivalent to 50 mg of dabrafenib.

Tafinlar 75 mg hard capsules

Each hard capsule contains dabrafenib mesilate equivalent to 75 mg of dabrafenib.

For the full list of excipients, see section 6.1.

Hard capsule (capsule).

Tafinlar 50 mg hard capsules

Opaque dark red capsules, approximately 18 mm long, with capsule shell imprinted with “GS TEW”and “50 mg”.

Tafinlar 75 mg hard capsules

Opaque dark pink capsules, approximately 19 mm long, with capsule shell imprinted with “GS LHF”and “75 mg”.

Dabrafenib as monotherapy or in combination with trametinib is indicated for the treatment of adultpatients with unresectable or metastatic melanoma with a BRAF V600 mutation (see sections 4.4and 5.1).

Dabrafenib in combination with trametinib is indicated for the adjuvant treatment of adult patientswith Stage III melanoma with a BRAF V600 mutation, following complete resection.

Dabrafenib in combination with trametinib is indicated for the treatment of adult patients withadvanced non-small cell lung cancer with a BRAF V600 mutation.

Treatment with dabrafenib should be initiated and supervised by a qualified physician experienced inthe use of anti-cancer medicinal products.

Before taking dabrafenib, patients must have confirmation of tumour BRAF V600 mutation using avalidated test.

The efficacy and safety of dabrafenib have not been established in patients with wild-type BRAFmelanoma or wild-type BRAF NSCLC. Dabrafenib should therefore not be used in patients with wild-type BRAF melanoma or wild-type BRAF NSCLC (see sections 4.4 and 5.1).

The recommended dose of dabrafenib, either used as monotherapy or in combination with trametinib,is 150 mg (two 75 mg capsules) twice daily (corresponding to a total daily dose of 300 mg). Therecommended dose of trametinib, when used in combination with dabrafenib, is 2 mg once daily.

Treatment should continue until the patient no longer derives benefit or the development ofunacceptable toxicity (see Table 2). In the adjuvant melanoma setting, patients should be treated for aperiod of 12 months unless there is disease recurrence or unacceptable toxicity.

If a dose of dabrafenib is missed, it should not be taken if it is less than 6 hours until the nextscheduled dose.

If a dose of trametinib is missed, when dabrafenib is given in combination with trametinib, the dose oftrametinib should only be taken if it is more than 12 hours until the next scheduled dose.

Two dabrafenib capsule strengths, 50 mg and 75 mg, are available to effectively manage dosemodification requirements.

The management of adverse reactions may require treatment interruption, dose reduction, or treatmentdiscontinuation (see Tables 1 and 2).

Dose modifications or interruptions are not recommended for adverse reactions of cutaneoussquamous cell carcinoma (cuSCC) or new primary melanoma (see section 4.4).

No dose modifications are required for uveitis as long as effective local therapies can control ocularinflammation. If uveitis does not respond to local ocular therapy, withhold dabrafenib until resolutionof ocular inflammation and then restart dabrafenib reduced by one dose level (see section 4.4).

Recommended dose level reductions and recommendations for dose modifications are provided in

Tables 1 and 2, respectively.

Table 1 Recommended dose level reductions

Dose level Dabrafenib dose Trametinib dose*

Used as monotherapy or in Only when used in combination withcombination with trametinib dabrafenib

Starting dose 150 mg twice daily 2 mg once daily1st dose reduction 100 mg twice daily 1.5 mg once daily2nd dose reduction 75 mg twice daily 1 mg once daily50 mg twice daily 1 mg once daily3rd dose reduction

Dose adjustment for dabrafenib below 50 mg twice daily is not recommended, whether used as monotherapyor in combination with trametinib. Dose adjustment for trametinib below 1 mg once daily is notrecommended, when used in combination with dabrafenib.

*For dosing instructions for treatment with trametinib monotherapy, see trametinib SmPC, Posology and

Table 2 Dose modification schedule based on the grade of any adverse reactions (excludingpyrexia)

Grade (CTCAE)* Recommended dabrafenib dose modifications

Used as monotherapy or in combination with trametinib

Grade 1 or Grade 2 Continue treatment and monitor as clinically indicated.

(Tolerable)

Grade 2 (Intolerable) or Interrupt therapy until toxicity is Grade 0 to 1 and reduce by one dose

Grade 3 level when resuming therapy.

Grade 4 Discontinue permanently, or interrupt therapy until Grade 0 to 1 andreduce by one dose level when resuming therapy.

* The intensity of clinical adverse reactions graded by the Common Terminology Criteria for Adverse Events(CTCAE)

When an individual’s adverse reactions are under effective management, dose re-escalation followingthe same dosing steps as de-escalation may be considered. The dabrafenib dose should not exceed150 mg twice daily.

If a patient’s temperature is ≥38oC, therapy should be interrupted (dabrafenib when used asmonotherapy, and both dabrafenib and trametinib when used in combination). In case of recurrence,therapy can also be interrupted at the first symptom of pyrexia. Treatment with anti-pyretics such asibuprofen or acetaminophen/paracetamol should be initiated. The use of oral corticosteroids should beconsidered in those instances in which anti-pyretics are insufficient. Patients should be evaluated forsigns and symptoms of infection and, if necessary, treated in line with local practice (see section 4.4).

Dabrafenib, or both dabrafenib and trametinib when used in combination, should be restarted if thepatient is symptom-free for at least 24 hours either (1) at the same dose level, or (2) reduced by onedose level if the pyrexia is recurrent and/or was accompanied by other severe symptoms includingdehydration, hypotension or renal failure.

If treatment-related toxicities occur when dabrafenib is used in combination with trametinib, then bothtreatments should be simultaneously dose reduced, interrupted or discontinued. Exceptions where dosemodifications are necessary for only one of the two treatments are detailed below for uveitis, RASmutation-positive non-cutaneous malignancies (primarily related to dabrafenib), left ventricularejection fraction (LVEF) reduction, retinal vein occlusion (RVO), retinal pigment epithelialdetachment (RPED) and interstitial lung disease (ILD)/pneumonitis (primarily related to trametinib).

Dose modification exceptions (where only one of the two therapies is dose reduced) for selectedadverse reactions

No dose modifications are required for uveitis as long as effective local therapies can control ocularinflammation. If uveitis does not respond to local ocular therapy, dabrafenib should be withheld untilresolution of ocular inflammation, and then dabrafenib should be restarted reduced by one dose level.

No dose modification of trametinib is required when taken in combination with dabrafenib (seesection 4.4).

RAS mutation-positive non-cutaneous malignancies

The benefits and risks should be considered before continuing treatment with dabrafenib in patientswith a non-cutaneous malignancy that has a RAS mutation. No dose modification of trametinib isrequired when taken in combination with dabrafenib.

If dabrafenib is being used in combination with trametinib and an asymptomatic, absolute decrease of>10% in LVEF compared to baseline occurs, and the ejection fraction is below the institution’s lowerlimit of normal (LLN), please refer to the trametinib SmPC (see section 4.2) for dose modificationinstructions for trametinib. No dose modification of dabrafenib is required when taken in combinationwith trametinib.

If patients report new visual disturbances such as diminished central vision, blurred vision or loss ofvision at any time while on combination therapy with dabrafenib and trametinib, please refer to thetrametinib SmPC (see section 4.2) for dose modification instructions for trametinib. No dosemodification of dabrafenib is required when taken in combination with trametinib for confirmed casesof RVO or RPED.

In patients treated with dabrafenib in combination with trametinib with suspected ILD or pneumonitis,including patients presenting with new or progressive pulmonary symptoms and findings includingcough, dyspnoea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations, please referto the trametinib SmPC (see section 4.2) for dose modification instructions for trametinib. No dosemodification of dabrafenib is required when taken in combination with trametinib for cases of ILD orpneumonitis.

No dose adjustment is required for patients with mild or moderate renal impairment. There are noclinical data in subjects with severe renal impairment and the potential need for dose adjustmentcannot be determined (see section 5.2). Dabrafenib should be used with caution in patients with severerenal impairment when administered as monotherapy or in combination with trametinib.

No dose adjustment is required for patients with mild hepatic impairment. There are no clinical data insubjects with moderate to severe hepatic impairment and the potential need for dose adjustment cannotbe determined (see section 5.2). Hepatic metabolism and biliary secretion are the primary routes ofelimination of dabrafenib and its metabolites and patients with moderate to severe hepatic impairmentmay have increased exposure. Dabrafenib should be used with caution in patients with moderate orsevere hepatic impairment when administered as monotherapy or in combination with trametinib.

Limited safety and efficacy data have been collected on dabrafenib in non-Caucasian patients. Thepopulation pharmacokinetic analysis showed no significant differences in the pharmacokinetics ofdabrafenib between Asian and Caucasian patients. No dabrafenib dose adjustment is needed in Asianpatients.

No adjustment of the initial dose is required in patients >65 years of age.

The safety and efficacy of dabrafenib capsules in children and adolescents (<18 years) have not yetbeen established. No clinical data are available. Studies in juvenile animals have shown adverseeffects of dabrafenib which had not been observed in adult animals (see section 5.3).

Tafinlar is for oral use. The capsules are to be swallowed whole with water. They should not bechewed or opened and should not be mixed with food or liquids due to chemical instability ofdabrafenib.

It is recommended that the doses of dabrafenib be taken at similar times every day, leaving an intervalof approximately 12 hours between doses. When dabrafenib and trametinib are taken in combination,the once-daily dose of trametinib should be taken at the same time each day with either the morningdose or the evening dose of dabrafenib.

Dabrafenib should be taken at least one hour before, or at least 2 hours after a meal.

If a patient vomits after taking dabrafenib, the patient should not retake the dose and should take thenext scheduled dose.

Please refer to trametinib SmPC for information on method of administration when given incombination with dabrafenib.

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

When dabrafenib is given in combination with trametinib, the SmPC of trametinib must be consultedprior to intiation of combination treatment. For additional information on warnings and precautionsassociated with trametinib treatment, please refer to the trametinib SmPC.

The efficacy and safety of dabrafenib have not been established in patients with wild-type BRAFmelanoma or wild-type BRAF NSCLC therefore dabrafenib should not be used in patients with wild-type BRAF melanoma or wild-type BRAF NSCLC (see sections 4.2 and 5.1).

Dabrafenib in combination with trametinib in patients with melanoma who have progressed on a

BRAF inhibitor

There are limited data in patients taking the combination of dabrafenib with trametinib who haveprogressed on a prior BRAF inhibitor. These data show that the efficacy of the combination will belower in these patients (see section 5.1). Therefore, other treatment options should be consideredbefore treatment with the combination in this prior BRAF inhibitor treated population. The sequencingof treatments following progression on a BRAF inhibitor therapy has not been established.

New malignancies, cutaneous and non-cutaneous, can occur when dabrafenib is used as monotherapyor in combination with trametinib.

Cases of cuSCC (including keratoacanthoma) have been reported in patients treated with dabrafenibalone and in combination with trametinib (see section 4.8). In the Phase III clinical trials MEK115306and MEK116513 in patients with unresectable or metastatic melanoma, cuSCC occurred in 10%(22/211) of patients receiving dabrafenib as a monotherapy and in 18% (63/349) of patients receivingvemurafenib as a monotherapy, respectively. In the integrated safety population of patients withmelanoma and advanced NSCLC, cuSCC occurred in 2% (19/1 076) of patients receiving dabrafenibin combination with trametinib. The median time to diagnosis of the first occurrence of cuSCC instudy MEK115306 was 223 days (range 56 to 510 days) in the combination therapy arm and 60 days(range 9 to 653 days) in the dabrafenib monotherapy arm. In the Phase III study BRF115532(COMBI-AD) in the adjuvant treatment of melanoma, 1% (6/435) of patients receiving dabrafenib incombination with trametinib as compared to 1% (5/432) of patients receiving placebo had developedcuSCC at the time of the primary analysis. During the long-term (up to 10 years) off-treatmentfollow-up, 2 additional patients reported cuSCC in each treatment arm. Overall, the median time toonset of the first occurrence of cuSCC in the combination arm of the adjuvant treatment study wasapproximately 21 weeks and was 34 weeks in the placebo arm.

It is recommended that skin examination be performed prior to initiation of therapy with dabrafeniband monthly throughout treatment and for up to six months after treatment for cuSCC. Monitoringshould continue for 6 months following discontinuation of dabrafenib or until initiation of anotheranti-neoplastic therapy.

Cases of cuSCC should be managed by dermatological excision and dabrafenib treatment or, if takenin combination, dabrafenib and trametinib should be continued without any dose adjustment. Patientsshould be instructed to immediately inform their physician if new lesions develop.

New primary melanomas have been reported in clinical trials in patients treated with dabrafenib. Inclinical trials in unresectable or metastatic melanoma,these cases were identified within the first5 months of dabrafenib as monotherapy. Cases of new primary melanoma can be managed withexcision and do not require treatment modification. Monitoring for skin lesions should occur asdescribed for cuSCC.

In vitro experiments have demonstrated paradoxical activation of mitogen-activated protein kinase(MAP kinase) signalling in BRAF wild-type cells with RAS mutations when exposed to BRAFinhibitors. This may lead to increased risk of non-cutaneous malignancies with dabrafenib exposure(see section 4.8) when RAS mutations are present. RAS-associated malignancies have been reportedin clinical trials, both with another BRAF inhibitor (chronic myelomonocytic leukaemia and non-cutaneous SCC of the head and neck) as well as with dabrafenib monotherapy (pancreaticadenocarcinoma, bile duct adenocarcinoma) and with dabrafenib in combination with the MEKinhibitor, trametinib (colorectal cancer, pancreatic cancer).

Prior to initiation of treatment patients should undergo a head and neck examination with minimallyvisual inspection of oral mucosa and lymph node palpation, as well as chest/abdomen computerisedtomography (CT) scan. During treatment patients should be monitored as clinically appropriate whichmay include a head and neck examination every 3 months and a chest/abdomen CT scan every6 months. Anal examinations and pelvic examinations are recommended before and at the end oftreatment or when considered clinically indicated. Complete blood cell counts and blood chemistryshould be performed as clinically indicated.

The benefits and risks should be considered before administering dabrafenib in patients with a prior orconcurrent cancer associated with RAS mutations. No dose modification of trametinib is requiredwhen taken in combination with dabrafenib.

Following discontinuation of dabrafenib, monitoring for non-cutaneous secondary/recurrentmalignancies should continue for up to 6 months or until initiation of another anti-neoplastic therapy.

Abnormal findings should be managed according to clinical practices.

Haemorrhagic events, including major haemorrhagic and fatal haemorrhages, have occurred inpatients taking the combination of dabrafenib with trametinib (see section 4.8). Please refer to thetrametinib SmPC (see section 4.4) for additional information.

Visual impairment

In clinical trials ophthalmologic reactions, including uveitis, iridocyclitis and iritis, have been reportedin patients treated with dabrafenib as monotherapy and in combination with trametinib. Patients shouldbe routinely monitored for visual signs and symptoms (such as change in vision, photophobia and eyepain) while on therapy.

No dose modifications are required as long as effective local therapies can control ocularinflammation. If uveitis does not respond to local ocular therapy, withhold dabrafenib until resolutionof ocular inflammation and then restart dabrafenib reduced by one dose level. No dose modification oftrametinib is required when taken in combination with dabrafenib following diagnosis of uveitis.

Cases of biocular panuveitis or biocular iridocyclitis suggestive of Vogt-Koyanagi-Harada syndromehave been reported in patients treated with dabrafenib in combination with trametinib. Withholddabrafenib until resolution of ocular inflammation and consider consulting an ophthalmologist.

Systemic corticosteroid treatment may be necessary.

RPED and RVO may occur with dabrafenib in combination with trametinib. Please refer to thetrametinib SmPC (see section 4.4). No dose modification of dabrafenib is required when taken incombination with trametinib following diagnosis of RVO or RPED.

Fever has been reported in clinical trials with dabrafenib as monotherapy and in combination withtrametinib (see section 4.8). In 1% of patients in clinical trials with dabrafenib monotherapy, seriousnon-infectious febrile events were identified (defined as fever accompanied by severe rigors,dehydration, hypotension and/or acute renal insufficiency of pre-renal origin in patients with normalbaseline renal function) (see section 4.8). The onset of these serious non-infectious febrile events wastypically within the first month of dabrafenib as monotherapy. Patients with serious non-infectiousfebrile events responded well to dose interruption and/or dose reduction and supportive care.

The incidence and severity of pyrexia are increased with combination therapy. In the combinationtherapy arm of study MEK115306 in patients with unresectable or metastatic melanoma, pyrexia wasreported in 57% (119/209) of patients with 7% Grade 3, as compared to the dabrafenib monotherapyarm with 33% (69/211) of patients reporting pyrexia, 2% Grade 3. In the Phase II study BRF113928 inpatients with advanced NSCLC the incidence and severity of pyrexia were increased slightly whendabrafenib was used in combination with trametinib (48%, 3% Grade 3) as compared to dabrafenibmonotherapy (39%, 2% Grade 3). In the Phase III study BRF115532 in the adjuvant treatment ofmelanoma, the incidence and severity of pyrexia were higher in the dabrafenib in combination withtrametinib arm (67%; 6% Grade 3/4) as compared to the placebo arm (15%; <1% Grade 3).

For patients with unresectable or metastatic melanoma who received dabrafenib in combination withtrametinib and developed pyrexia, approximately half of the first occurrences of pyrexia happenedwithin the first month of therapy and approximately one-third of the patients had 3 or more events.

Therapy (dabrafenib when used as monotherapy, and both dabrafenib and trametinib when used incombination) should be interrupted if the patient’s temperature is ≥38ºC (see section 5.1). In case ofrecurrence, therapy can also be interrupted at the first symptom of pyrexia. Treatment with anti-pyretics such as ibuprofen or acetaminophen/paracetamol should be initiated. The use of oralcorticosteroids should be considered in those instances in which anti-pyretics are insufficient. Patientsshould be evaluated for signs and symptoms of infection. Therapy can be restarted once the feverresolves. If fever is associated with other severe signs or symptoms, therapy should be restarted at areduced dose once fever resolves and as clinically appropriate (see section 4.2).

Dabrafenib in combination with trametinib has been reported to decrease LVEF (see section 4.8).

Please refer to the trametinib SmPC for additional information (see section 4.4). No dose modificationof dabrafenib is required when taken in combination with trametinib.

Renal failure has been identified in <1% of patients treated with dabrafenib alone and in ≤1% ofpatients treated with dabrafenib in combination with trametinib. Observed cases were generallyassociated with pyrexia and dehydration and responded well to dose interruption and generalsupportive measures. Granulomatous nephritis has been reported (see section 4.8). Patients should beroutinely monitored for serum creatinine while on therapy. If creatinine increases, dabrafenib mayneed to be interrupted as clinically appropriate. Dabrafenib has not been studied in patients with renalinsufficiency (defined as creatinine >1.5 x ULN) therefore caution should be used in this setting (seesection 5.2).

Hepatic adverse events have been reported in clinical trials with dabrafenib in combination withtrametinib (see section 4.8). It is recommended that patients receiving treatment with dabrafenib incombination with trametinib have liver function monitored every four weeks for 6 months aftertreatment initiation with trametinib. Liver monitoring may be continued thereafter as clinicallyindicated. Please refer to the trametinib SmPC for additional information.

Elevations in blood pressure have been reported in association with dabrafenib in combination withtrametinib, in patients with or without pre-existing hypertension (see section 4.8). Please refer to thetrametinib SmPC for additional information.

Cases of pneumonitis or ILD have been reported in clinical trials with dabrafenib in combination withtrametinib. Please refer to the trametinib SmPC section 4.4 for additional information. If dabrafenib isbeing used in combination with trametinib then therapy with dabrafenib may be continued at the samedose.

Rash has been observed in about 24% of patients in clinical trials when dabrafenib is used incombination with trametinib (see section 4.8). The majority of these cases were Grade 1 or 2 and didnot require any dose interruptions or dose reductions. Please refer to the trametinib SmPC section 4.4for additional information.

Rhabdomyolysis has been reported in patients taking dabrafenib in combination with trametinib (seesection 4.8). Please refer to the trametinib SmPC section 4.4 for additional information.

Pancreatitis has been reported in <1% of patients treated with dabrafenib as monotherapy and incombination with trametinib in unresectable or metastatic melanoma clinical trials and about 4% ofpatients treated with dabrafenib in combination with trametinib in the NSCLC clinical trial. One of theevents occurred on the first day of dabrafenib dosing of a metastatic melanoma patient and recurredfollowing re-challenge at a reduced dose. In the adjuvant treatment of melanoma trial, pancreatitis wasreported in <1% (1/435) of patients receiving dabrafenib in combination with trametinib, and nopatients receiving placebo. Unexplained abdominal pain should be promptly investigated to includemeasurement of serum amylase and lipase. Patients should be closely monitored when restartingdabrafenib after an episode of pancreatitis.

Deep vein thrombosis/Pulmonary embolism

Pulmonary embolism or deep vein thrombosis can occur when dabrafenib is used in combination withtrametinib. If patients develop symptoms of pulmonary embolism or deep vein thrombosis such asshortness of breath, chest pain, or arm or leg swelling, they should immediately seek medical care.

Permanently discontinue trametinib and dabrafenib for life-threatening pulmonary embolism.

Cases of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome, and drugreaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal,have been reported during treatment with dabrafenib/trametinib combination therapy. Before initiatingtreatment, patients should be advised of the signs and symptoms and monitored closely for skinreactions. If signs and symptoms suggestive of SCARs appear, dabrafenib and trametinib should bewithdrawn.

Colitis and gastrointestinal perforation, including fatal outcome, have been reported in patients takingdabrafenib in combination with trametinib (see section 4.8). Please refer to the trametinib SmPC foradditional information (see section 4.4).

Cases of sarcoidosis have been reported in patients treated with dabrafenib in combination withtrametinib, mostly involving the skin, lung, eye and lymph nodes. In the majority of the cases,treatment with dabrafenib and trametinib was maintained. In case of a diagnosis of sarcoidosis,relevant treatment should be considered. It is important not to misinterpret sarcoidosis as diseaseprogression.

Haemophagocytic lymphohistiocytosis

In post-marketing experience, haemophagocytic lymphohistiocytosis (HLH) has been observed inpatients treated with dabrafenib in combination with trametinib. Caution should be taken whendabrafenib is administered in combination with trametinib. If HLH is confirmed, administration ofdabrafenib and trametinib should be discontinued and treatment for HLH initiated.

The occurrence of TLS, which may be fatal, has been associated with the use of dabrafenib incombination with trametinib (see section 4.8). Risk factors for TLS include high tumour burden,pre-existing chronic renal insufficiency, oliguria, dehydration, hypotension and acidic urine. Patientswith risk factors for TLS should be closely monitored and prophylactic hydration should beconsidered. TLS should be treated promptly, as clinically indicated.

Effects of other medicinal products on dabrafenib

Dabrafenib is a substrate of CYP2C8 and CYP3A4. Potent inducers of these enzymes should beavoided when possible as these agents may decrease the efficacy of dabrafenib (see section 4.5).

Effects of dabrafenib on other medicinal products

Dabrafenib is an inducer of metabolising enzymes which may lead to loss of efficacy of manycommonly used medicinal products (see examples in section 4.5). A drug utilisation review (DUR) istherefore essential when initiating dabrafenib treatment. Concomitant use of dabrafenib with medicinalproducts that are sensitive substrates of certain metabolising enzymes or transporters (see section 4.5)should generally be avoided if monitoring for efficacy and dose adjustment is not possible.

Concomitant administration of dabrafenib with warfarin results in decreased warfarin exposure.

Caution should be exercised and additional International Normalised Ratio (INR) monitoring isrecommended when dabrafenib is used concomitantly with warfarin and at discontinuation ofdabrafenib (see section 4.5).

Concomitant administration of dabrafenib with digoxin may result in decreased digoxin exposure.

Caution should be exercised and additional monitoring of digoxin is recommended when digoxin (atransporter substrate) is used concomitantly with dabrafenib and at discontinuation of dabrafenib (seesection 4.5).

Effect of other medicinal products on dabrafenib

Dabrafenib is a substrate for the metabolising enzymes CYP2C8 and CYP3A4, while the activemetabolites hydroxy-dabrafenib and desmethyl-dabrafenib are CYP3A4 substrates. Medicinalproducts that are strong inhibitors or inducers of CYP2C8 or CYP3A4 are therefore likely to increaseor decrease, respectively, dabrafenib concentrations. Alternative agents should be considered duringadministration with dabrafenib when possible. Dabrafenib should be used with caution if stronginhibitors (e.g. ketoconazole, gemfibrozil, nefazodone, clarithromycin, ritonavir, saquinavir,telithromycin, itraconazole, voriconazole, posaconazole, atazanavir) are co-administered withdabrafenib. Co-administration of dabrafenib with potent inducers (e.g. rifampicin, phenytoin,carbamazepine, phenobarbital, or St John’s wort (Hypericum perforatum)) of CYP2C8 or CYP3A4should be avoided.

Administration of ketoconazole (a CYP3A4 inhibitor) 400 mg once daily, with dabrafenib 75 mgtwice daily, resulted in a 71% increase in dabrafenib AUC and a 33% increase in dabrafenib Cmaxrelative to administration of dabrafenib 75 mg twice daily alone. Co-administration resulted inincreases in hydroxy- and desmethyl-dabrafenib AUC (increases of 82% and 68%, respectively). Adecrease of 16% in AUC was noted for carboxy-dabrafenib.

Administration of gemfibrozil (a CYP2C8 inhibitor) 600 mg twice daily, with dabrafenib 75 mg twicedaily, resulted in a 47% increase in dabrafenib AUC but did not alter dabrafenib Cmax relative toadministration of dabrafenib 75 mg twice daily alone. Gemfibrozil had no clinically relevant effect onthe systemic exposure to dabrafenib metabolites (≤13%).

Administration of rifampin (a CYP3A4/CYP2C8 inducer) 600 mg once daily, with dabrafenib 150 mgtwice daily, resulted in a decrease in repeat-dose dabrafenib Cmax (27%) and AUC (34%). No relevantchange in AUC was noted for hydroxy-dabrafenib. There was an increase in AUC of 73% forcarboxy-dabrafenib and a decrease in AUC of 30% for desmethyl-dabrafenib.

Co-administration of repeat doses of dabrafenib 150 mg twice daily and the pH-elevating agentrabeprazole 40 mg once daily resulted in a 3% increase in AUC and a 12% decrease in dabrafenib

Cmax. These changes in dabrafenib AUC and Cmax are considered not clinically meaningful. Medicinalproducts that alter the pH of the upper gastrointestinal (GI) tract (e.g. proton pump inhibitors, H2-receptor antagonists, antacids) are not expected to reduce the bioavailability of dabrafenib.

Effect of dabrafenib on other medicinal products

Dabrafenib is an enzyme inducer and increases the synthesis of drug-metabolising enzymes including

CYP3A4, CYP2Cs and CYP2B6 and may increase the synthesis of transporters. This results inreduced plasma levels of medicinal products metabolised by these enzymes and may affect sometransported medicinal products. The reduction in plasma concentrations can lead to lost or reducedclinical effect of these medicinal products. There is also a risk of increased formation of activemetabolites of these medicinal products. Enzymes that may be induced include CYP3A in the liverand gut, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and UGTs (glucuronide conjugating enzymes). Thetransport protein P-gp may also be induced as well as other transporters, e.g. MRP-2. Induction of

OATP1B1/1B3 and BCRP is not likely based on the observations from a clinical study withrosuvastatin.

In vitro, dabrafenib produced dose-dependent increases in CYP2B6 and CYP3A4. In a clinical druginteraction study, Cmax and AUC of oral midazolam (a CYP3A4 substrate) decreased by 47% and 65%,respectively with co-administration of repeat-dose dabrafenib.

Administration of dabrafenib 150 mg twice daily and warfarin resulted in a decrease in AUC of S- and

R- warfarin of 37% and 33%, respectively, compared to administration of warfarin alone. Cmax of S-and R-warfarin increased 18% and 19%.

Interactions with many medicinal products eliminated through metabolism or active transport isexpected. If their therapeutic effect is of large importance to the patient, and dose adjustments are noteasily performed based on monitoring of efficacy or plasma concentrations, these medicinal productsare to be avoided or used with caution. The risk for liver injury after paracetamol administration issuspected to be higher in patients concomitantly treated with enzyme inducers.

The number of affected medicinal products is expected to be large, although the magnitude of theinteraction will vary. Groups of medicinal products that can be affected include, but are not limited to:

* Analgesics (e.g. fentanyl, methadone)

* Antibiotics (e.g. clarithromycin, doxycycline)

* Anti-cancer agents (e.g. cabazitaxel)

* Anticoagulants (e.g. acenocoumarol, warfarin, see section 4.4)

* Antiepileptics (e.g. carbamazepine, phenytoin, primidone, valproic acid)

* Antipsychotics (e.g. haloperidol)

* Calcium channel blockers (e.g. diltiazem, felodipine, nicardipine, nifedipine, verapamil)

* Cardiac glycosides (e.g. digoxin, see section 4.4)

* Corticosteroids (e.g. dexamethasone, methylprednisolone)

* HIV antivirals (e.g. amprenavir, atazanavir, darunavir, delavirdine, efavirenz, fosamprenavir,indinavir, lopinavir, nelfinavir, saquinavir, tipranavir)

* Hormonal contraceptives (see section 4.6)

* Hypnotics (e.g. diazepam, midazolam, zolpidem)

* Immunosuppressants (e.g. cyclosporin, tacrolimus, sirolimus)

* Statins metabolised by CYP3A4 (e.g. atorvastatin, simvastatin)

Onset of induction is likely to occur after 3 days of repeat dosing with dabrafenib. Upondiscontinuation of dabrafenib offset of induction is gradual, concentrations of sensitive CYP3A4,

CYP2B6, CYP2C8, CYP2C9 and CYP2C19, UDP glucuronosyl transferase (UGT) and transportersubstrates (e.g. P-gp or MRP-2) may increase and patients should be monitored for toxicity and doseof these agents may need to be adjusted.

In vitro, dabrafenib is a mechanism based inhibitor of CYP3A4. Therefore, transient inhibition of

CYP3A4 may be observed during the first few days of treatment.

Effects of dabrafenib on substance transport systems

Dabrafenib is an in vitro inhibitor of human organic anion transporting polypeptide (OATP) 1B1(OATP1B1), OATP1B3 and BCRP. Following co-administration of a single dose of rosuvastatin(OATP1B1, OATP1B3 and BCRP substrate) with repeat-dose dabrafenib 150 mg twice daily in16 patients, Cmax of rosuvastatin increased 2.6-fold whereas the AUC was only minimally changed(7% increase). The increased Cmax of rosuvastatin is unlikely to have clinical relevance.

Combination with trametinib

Co-administration of repeat dosing of trametinib 2 mg once daily and dabrafenib 150 mg twice dailyresulted in no clinically meaningful changes in trametinib or dabrafenib Cmax and AUC with increasesof 16 and 23%, respectively, in dabrafenib Cmax and AUC. A small decrease in trametinibbioavailability, corresponding to a decrease in AUC of 12%, was estimated when trametinib isadministered in combination with dabrafenib, a CYP3A4 inducer, using a population pharmacokineticanalysis.

When dabrafenib is used in combination with trametinib refer to the guidance for medicinal productinteractions found in sections 4.4 and 4.5 of dabrafenib and trametinib SmPC.

Effect of food on dabrafenib

Patients should take dabrafenib as monotherapy or in combination with trametinib at least one hourprior to or two hours after a meal due to the effect of food on dabrafenib absorption (see section 5.2).

Interaction studies have only been performed in adults.

Women of childbearing potential must use effective methods of contraception during therapy and for2 weeks following discontinuation of dabrafenib and 16 weeks following the last dose of trametinibwhen given in combination with dabrafenib. Dabrafenib may decrease the efficacy of oral or anysystemic hormonal contraceptives and an effective alternative method of contraception should be used(see section 4.5).

There are no data from the use of dabrafenib in pregnant women. Animal studies have shownreproductive toxicity and embryo-foetal developmental toxicities, including teratogenic effects (seesection 5.3). Dabrafenib should not be administered to pregnant women unless the potential benefit tothe mother outweighs the possible risk to the foetus. If the patient becomes pregnant while takingdabrafenib, the patient should be informed of the potential hazard to the foetus. Please see trametinib

SmPC (see section 4.6) when used in combination with trametinib.

It is not known whether dabrafenib is excreted in human milk. Because many medicinal products areexcreted in human milk, a risk to the breast-feeding child cannot be excluded. A decision should bemade whether to discontinue breast-feeding or discontinue dabrafenib, taking into account the benefitof breast-feeding for the child and the benefit of therapy for the woman.

There are no data in humans for dabrafenib as monotherapy or in combination with trametinib.

Dabrafenib may impair male and female fertility as adverse effects on male and female reproductiveorgans have been seen in animals (see section 5.3). Male patients taking dabrafenib as monotherapy orin combination with trametinib should be informed of the potential risk for impaired spermatogenesis,which may be irreversible. Please see trametinib SmPC (see section 4.6) when used in combinationwith trametinib.

Dabrafenib has minor influence on the ability to drive and use machines. The clinical status of thepatient and the adverse reaction profile of dabrafenib should be borne in mind when considering thepatient's ability to perform tasks that require judgement, motor or cognitive skills. Patients should bemade aware of the potential for fatigue and eye problems to affect these activities.

The safety of dabrafenib monotherapy is based on the integrated safety population from five clinicaltrials, BRF113683 (BREAK-3), BRF113929 (BREAK-MB), BRF113710 (BREAK-2), BRF113220,and BRF112680, which included 578 patients with BRAF V600 mutant unresectable or metastaticmelanoma treated with dabrafenib 150 mg twice daily. The most common adverse reactions (incidence15%) reported with dabrafenib were hyperkeratosis, headache, pyrexia, arthralgia, fatigue, nausea,papilloma, alopecia, rash, and vomiting.

The safety of dabrafenib in combination with trametinib has been evaluated in the integrated safetypopulation of 1 076 patients with BRAF V600 mutant unresectable or metastatic melanoma, Stage III

BRAF V600 mutant melanoma following complete resection (adjuvant treatment) and advanced

NSCLC treated with dabrafenib 150 mg twice daily and trametinib 2 mg once daily. Of these patients,559 were treated with the combination for BRAF V600 mutant melanoma in two randomised Phase IIIclinical trials, MEK115306 (COMBI-d) and MEK116513 (COMBI-v), 435 were treated with thecombination in the adjuvant treatment of Stage III BRAF V600 mutant melanoma after completeresection in a randomised Phase III study BRF115532 (COMBI-AD) and 82 were treated with thecombination for BRAF V600 mutant NSCLC in a multi-cohort, non-randomised Phase II study

BRF113928 (see section 5.1).

The most common adverse reactions (incidence 20%) for dabrafenib in combination with trametinibwere: pyrexia, fatigue, nausea, chills, headache, diarrhoea, vomiting, arthralgia and rash.

Adverse reactions associated with dabrafenib obtained from clinical studies and post-marketingsurveillance are tabulated below for dabrafenib monotherapy (Table 3) and dabrafenib in combinationwith trametinib (Table 4). Adverse reactions are listed below by MedDRA system organ class andranked by frequency using the following convention: 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) and notknown (cannot be estimated from the available data). Within each frequency grouping, adversereactions are presented in order of decreasing seriousness.

Table 3 Adverse reactions with dabrafenib monotherapy

System organ class Frequency (all grades) Adverse reactions

Very common Papilloma

Neoplasms benign, malignant

Seborrhoeic keratosisand unspecified (incl cysts and Common

Acrochordon (skin tags)polyps)

Basal cell carcinoma

Uncommon New primary melanoma

Immune system disorders Uncommon Hypersensitivity

Very common Decreased appetite

Metabolism and nutrition

Hypophosphataemiadisorders Common

Very common Headache

Nervous system disorders Peripheral neuropathy (including

Commonsensory and motor neuropathy)

Eye disorders Uncommon Uveitis

Respiratory, thoracic and

Very common Coughmediastinal disorders

Nausea

Very common Vomiting

Gastrointestinal disorders Diarrhoea

Common Constipation

Uncommon Pancreatitis

Hyperkeratosis

Alopecia

Very common Rash

Palmar-plantar erythrodysaesthesiasyndrome

Dry skin

Skin and subcutaneous tissue

Pruritusdisorders

Actinic keratosis

Common

Skin lesion

Erythema

Acute febrile neutrophilic dermatosis

Uncommon

Panniculitis

Arthralgia

Musculoskeletal and

Very common Myalgiaconnective tissue disorders

Pain in extremity

Renal failure, acute renal failure

Renal and urinary disorders Uncommon

Nephritis

General disorders and Very common

Chillsadministration site conditions

Asthenia

Common Influenza-like illness

Table 4 Adverse reactions with dabrafenib in combination with trametinib

System organ class Frequency (all grades) Adverse reactions

Very common Nasopharyngitis

Cellulitis

Common Folliculitis

Paronychia

Rash pustular

Cutaneous squamous cell carcinomaab

Neoplasms benign, Common Papillomamalignant and unspecified Seborrhoeic keratosis(incl cysts and polyps) New primary melanomac

Uncommon

Acrochordon (skin tags)

Blood and lymphatic system Anaemia

Commondisorders Thrombocytopenia

Leukopenia

Hypersensitivityd

Uncommon

Immune system disorders Sarcoidosis

Rare Haemophagocytic lymphohistiocytosis

Very common Decreased appetite

Metabolism and nutrition Hyponatraemia

Commondisorders Hypophosphataemia

Not known Tumour lysis syndrome

Very common

Dizziness

Peripheral neuropathy (including

Commonsensory and motor neuropathy)

Vision blurred

Common Visual impairment

Uveitise

Chorioretinopathy

Uncommon Retinal detachment

Periorbital oedema

Ejection fraction decreased

Common

Atrioventricular blockf

Uncommon Bradycardia

Not known Myocarditis

Very common

Haemorrhageg

Common

Lymphoedema

Very common Cough

Respiratory, thoracic and

Common Dyspnoeamediastinal disorders

Uncommon Pneumonitis

Abdominal painh

Very common Diarrhoea

Nausea

Dry mouth

Common

Stomatitis

Uncommon

Rare Gastrointestinal perforation

Dry skin

Pruritus

Very common

Erythemai

Actinic keratosis

Night sweats

Hyperkeratosis

Alopecia

Palmar-plantar erythrodysaesthesia

Skin and subcutaneous tissue Commonsyndromedisorders

Skin lesion

Hyperhidrosis

Panniculitis

Skin fissures

Uncommon Acute febrile neutrophilic dermatosis

Stevens-Johnson syndrome

Drug reaction with eosinophilia and

Not knownsystemic symptoms

Dermatitis exfoliative generalised

Arthralgia

Musculoskeletal and Myalgia

Very commonconnective tissue disorders Pain in extremity

Muscle spasmsj

Renal and urinary disorders Uncommon

Nephritis

Chills

Asthenia

General disorders and Very common

Oedema peripheraladministration site

Pyrexiaconditions

Influenza-like illness

Mucosal inflammation

Common

Face oedema

Alanine aminotransferase increased

Very common

Aspartate aminotransferase increased

Blood alkaline phosphatase increased

Gamma-glutamyltransferase increased

Common

Blood creatine phosphokinaseincreased

The safety profile from MEK116513 is generally similar to that of MEK115306 with the following exceptions:

1) The following adverse reactions have a higher frequency category as compared to MEK115306: muscle spasm(very common); renal failure and lymphoedema (common); acute renal failure (uncommon); 2) The followingadverse reactions have occurred in MEK116513 but not in MEK115306: cardiac failure, left ventricular dysfunction,interstitial lung disease (uncommon); 3) The following adverse reaction has occurred in MEK116513 and

BRF115532 but not in MEK115306 and BRF113928: rhabdomyolysis (uncommon).a Cutaneous squamous cell carcinoma (cu SCC): SCC, SCC of the skin, SCC in situ (Bowen’s disease) andkeratoacanthomab Papilloma, skin papillomac Malignant melanoma, metastatic malignant melanoma, and superficial spreading melanoma stage IIId Includes drug hypersensitivitye Includes cases of biocular panuveitis or biocular iridocyclitis suggestive of Vogt-Koyanagi-Harada syndromef Atrioventricular block, atrioventricular block first degree, atrioventricular block second degree, atrioventricularblock completeg Bleeding from various sites, including intracranial bleeding and fatal bleedingh Abdominal pain upper and abdominal pain loweri Erythema, generalised erythemaj Muscle spasms, musculoskeletal stiffness

For dabrafenib monotherapy in study MEK115306, cutaneous squamous cell carcinomas (includingthose classified as keratoacanthoma or mixed keratoacanthoma subtype) occurred in 10% of patientsand approximately 70% of the events occurred within the first 12 weeks of treatment with a mediantime to onset of 8 weeks. In the integrated safety population for dabrafenib in combination withtrametinib, 2% of patients developed cuSCC and the events occurred later than with dabrafenibmonotherapy with a median time to onset of 18-31 weeks. All patients receiving dabrafenib asmonotherapy or in combination with trametinib who developed cuSCC continued on treatment withoutdose modification.

New primary melanomas have been reported in clinical trials with dabrafenib as monotherapy and incombination with trametinib in melanoma studies. Cases were managed with excision and did notrequire treatment modification (see section 4.4). No new primary melanoma was reported from the

Phase II NSCLC study (BRF113928).

Non-cutaneous malignancy

Activation of MAP kinase signalling in BRAF wild-type cells which are exposed to BRAF inhibitorsmay lead to increased risk of non-cutaneous malignancies, including those with RAS mutations (seesection 4.4). Non-cutaneous malignancies were reported in 1% (6/586) of patients in the integratedsafety population of dabrafenib monotherapy, and <1% (8/1 076) of patients in the integrated safetypopulation of dabrafenib in combination with trametinib. In the Phase III study BRF115532(COMBI-AD) in the adjuvant treatment of melanoma, 1% (5/435) of patients receiving dabrafenib incombination with trametinib as compared to <1% (3/432) of patients receiving placebo developednon-cutaneous malignancies. During the long-term (up to 10 years) off-treatment follow-up, 9additional patients reported non-cutaneous malignancies in the combination arm and 4 in in theplacebo arm. Cases of RAS-driven malignancies have been seen with dabrafenib as monotherapy andin combination with trametinib. Patients should be monitored as clinically appropriate.

Haemorrhagic events, including major haemorrhagic events and fatal haemorrhages, have occurred inpatients taking dabrafenib in combination with trametinib. Please refer to the trametinib SmPC.

Decreased LVEF has been reported in 6% (65/1 076) of patients in the integrated safety population ofdabrafenib in combination with trametinib. Most cases were asymptomatic and reversible. Patientswith LVEF lower than the institutional lower limit of normal were not included in clinical trials withdabrafenib. Dabrafenib in combination with trametinib should be used with caution in patients withconditions that could impair left ventricular function. Please refer to the trametinib SmPC.

Fever has been reported in clinical trials with dabrafenib as monotherapy and in combination withtrametinib; the incidence and severity of pyrexia are increased with the combination therapy (seesection 4.4). For patients who received dabrafenib in combination with trametinib and developedpyrexia, approximately half of the first occurrences of pyrexia happened within the first month oftherapy and approximately one-third of the patients had 3 or more events. In 1% of patients receivingdabrafenib as monotherapy in the integrated safety population, serious non-infectious febrile eventswere identified as fever accompanied by severe rigors, dehydration, hypotension and/or acute renalinsufficiency or pre-renal origin in subjects with normal baseline renal function. The onset of theseserious non-infectious febrile events was typically within the first month of therapy. Patients withserious non-infectious febrile events responded well to dose interruption and/or dose reduction andsupportive care (see sections 4.2 and 4.4).

Hepatic adverse events have been reported in clinical trials with dabrafenib in combination withtrametinib. Please refer to the trametinib SmPC.

Elevations in blood pressure have been reported in association with dabrafenib in combination withtrametinib, in patients with or without pre-existing hypertension. Blood pressure should be measuredat baseline and monitored during treatment, with control of hypertension by standard therapy asappropriate.

Arthralgia

Arthralgia was reported very commonly in the integrated safety population of dabrafenib monotherapy(25%) and dabrafenib in combination with trametinib (25%) although these were mainly Grade 1 and2 in severity with Grade 3 occurring uncommonly (<1%) and no Grade 4 occurrences being reported.

Hypophosphataemia

Hypophosphataemia has been reported commonly in the integrated safety population of dabrafenibmonotherapy (7%) and of dabrafenib in combination with trametinib (4%). It should be noted thatapproximately half of these occurrences with dabrafenib monotherapy (4%) and 1% with dabrafenib incombination with trametinib were Grade 3 in severity.

Pancreatitis has been reported in dabrafenib monotherapy and in combination with trametinib.

Unexplained abdominal pain should be promptly investigated to include measurement of serumamylase and lipase. Patients should be closely monitored when re-starting dabrafenib after an episodeof pancreatitis (see section 4.4).

Renal failure due to pyrexia-associated pre-renal azotaemia or granulomatous nephritis wasuncommon; however, dabrafenib has not been studied in patients with renal insufficiency (defined ascreatinine >1.5 x ULN). Caution should be used in this setting (see section 4.4).

Of the total number of patients in the integrated safety population of dabrafenib monotherapy (n=578),22% were 65 years of age and older, and 6% were 75 years of age and older. Compared with youngersubjects (<65), more subjects 65 years old had adverse reactions that led to study drug dosereductions (22% versus 12%) or interruptions (39% versus 27%). In addition, older patientsexperienced more serious adverse reactions compared to younger patients (41% versus 22%). Nooverall differences in efficacy were observed between these subjects and younger subjects.

In the integrated safety population of dabrafenib in combination with trametinib (n=1 076),265 patients (25%) were ≥65 years of age, 62 patients (6%) were ≥75 years of age. The proportion ofpatients experiencing AEs was similar in those aged <65 years and those aged ≥65 years in all clinicaltrials. Patients ≥65 years were more likely to experience SAEs and AEs leading to permanentdiscontinuation of medicinal product, dose reduction and dose interruption than those <65 years.

Dabrafenib in combination with trametinib in patients with brain metastases

The safety and efficacy of the combination of dabrafenib and trametinib have been evaluated in amulti-cohort, open-label, Phase II study in patients with BRAF V600 mutant melanoma with brainmetastases. The safety profile observed in these patients appears to be consistent with the integratedsafety profile of the combination.

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 treatment for an overdose of dabrafenib. If overdose occurs, the patient should betreated supportively with appropriate monitoring as necessary.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, B-Raf serine-threoninekinase (BRAF) inhibitors, ATC code: L01EC02

Dabrafenib is an inhibitor of RAF kinases. Oncogenic mutations in BRAF lead to constitutiveactivation of the RAS/RAF/MEK/ERK pathway. BRAF mutations have been identified at a highfrequency in specific cancers, including approximately 50% of melanoma. The most commonlyobserved BRAF mutation is V600E which accounts for approximately 90% of the BRAF mutationsthat are seen in melanoma.

Preclinical data generated in biochemical assays demonstrated that dabrafenib inhibits BRAF kinaseswith activating codon 600 mutations (Table 5).

Table 5 Kinase inhibitory activity of dabrafenib against RAF kinases

Kinase Inhibitory concentration 50 (nM)

BRAF V600E 0.65

BRAF V600K 0.50

BRAF V600D 1.8

BRAF WT 3.2

CRAF WT 5.0

Dabrafenib demonstrated suppression of a downstream pharmacodynamic biomarker (phosphorylated

ERK) and inhibited cell growth of BRAF V600 mutant melanoma cell lines, in vitro and in animalmodels.

In subjects with BRAF V600 mutation-positive melanoma, administration of dabrafenib resulted ininhibition of tumour phosphorylated ERK relative to baseline.

Combination with trametinib

Trametinib is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellularsignal regulated kinase 1 (MEK1) and MEK2 activation and kinase activity. MEK proteins arecomponents of the extracellular signal-related kinase (ERK) pathway.

Thus, trametinib and dabrafenib inhibit two kinases in this pathway, MEK and RAF, and therefore thecombination provides concomitant inhibition of the pathway. The combination of dabrafenib withtrametinib has shown anti-tumour activity in BRAF V600 mutation-positive melanoma cell lines invitro and delays the emergence of resistance in vivo in BRAF V600 mutation-positive melanomaxenografts.

Before taking dabrafenib or combination with trametinib, patients must have BRAF V600 mutation-positive tumour status confirmed by a validated test. In the Phase II and III clinical trials, screening foreligibility required central testing for BRAF V600 mutation using a BRAF mutation assay conductedon the most recent tumour sample available. Primary tumour or tumour from a metastatic site wastested with an investigational use only assay (IUO). The IUO is an allele-specific polymerase chainreaction (PCR) assay performed on DNA extracted from formalin-fixed paraffin-embedded (FFPE)tumour tissue. The assay was specifically designed to differentiate between the V600E and V600Kmutations. Only subjects with BRAF V600E or V600K mutation-positive tumours were eligible forstudy participation.

Subsequently, all patient samples were re-tested using the bioMerieux (bMx) THxID BRAF validatedassay, which has CE marking. The bMx THxID BRAF assay is an allele-specific PCR performed on

DNA extracted from FFPE tumour tissue. The assay was designed to detect the BRAF V600E and

V600K mutations with high sensitivity (down to 5% V600E and V600K sequence in a background ofwild-type sequence using DNA extracted from FFPE tissue). Non-clinical and clinical trials withretrospective bi-directional Sanger sequencing analyses have shown that the test also detects the lesscommon BRAF V600D mutation and V600E/K601E mutation with lower sensitivity. Of thespecimens from the non-clinical and clinical trials (n=876) that were mutation-positive by the THxID

BRAF assay and subsequently were sequenced using the reference method, the specificity of the assaywas 94%.

* Dabrafenib in combination with trametinib

The efficacy and safety of the recommended dose of trametinib (2 mg once daily) in combination withdabrafenib (150 mg twice daily) for the treatment of adult patients with unresectable or metastaticmelanoma with a BRAF V600 mutation was studied in two Phase III trials and one supportive

Phase I/II study.

MEK115306 was a Phase III, randomised, double-blinded study comparing the combination ofdabrafenib and trametinib to dabrafenib and placebo in first-line therapy for subjects with unresectable(Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous melanoma. Theprimary endpoint of the study was progression-free survival (PFS), with a key secondary endpoint ofoverall survival (OS). Subjects were stratified by lactate dehydrogenase (LDH) level (> the upper limitof normal (ULN) versus ≤ULN) and BRAF mutation (V600E versus V600K).

A total of 423 subjects were randomised 1:1 to either combination (N=211) or dabrafenib (N=212).

Most subjects were Caucasian (>99%) and male (53%), with a median age of 56 years (28% were≥65 years). The majority of subjects had Stage IVM1c disease (67%). Most subjects had LDH ≤ULN(65%), Eastern Cooperative Oncology Group (ECOG) performance status of 0 (72%), and visceraldisease (73%) at baseline. The majority of subjects had a BRAF V600E mutation (85%). Subjects withbrain metastases were not included in the trial.

Median OS and estimated 1-year, 2-year, 3-year, 4 year and 5-year survival rates are presented in

Table 6. From an OS analysis at 5 years, the median OS for the combination arm was approximately7 months longer than for dabrafenib monotherapy (25.8 months versus 18.7 months) with 5-yearsurvival rates of 32% for the combination versus 27% for dabrafenib monotherapy (Table 6, Figure 1).

The Kaplan-Meier OS curve appears to stabilise from 3 to 5 years (see Figure 1). The 5-year overallsurvival rate was 40% (95% CI: 31.2, 48.4) in the combination arm versus 33% (95% CI: 25.0, 41.0)in the dabrafenib monotherapy arm for patients who had a normal lactate dehydrogenase level atbaseline, and 16% (95% CI: 8.4, 26.0) in the combination arm versus 14% (95% CI: 6.8, 23.1) in thedabrafenib monotherapy arm for patients with an elevated lactate dehydrogenase level at baseline.

Table 6 Overall Survival results for Study MEK115306 (COMBI-d)

OS analysis 5-year OS analysis(data cut-off: 12-Jan-2015) (data cut-off: 10-Dec-2018)

Dabrafenib + Dabrafenib + Dabrafenib + Dabrafenib +

Trametinib Placebo Trametinib Placebo(n=211) (n=212) (n=211) (n=212)

Number of patients

Died (event), n99 (47) 123 (58) 135 (64) 151 (71)(%)

Estimates of OS (months)25.1 18.7 25.8 18.7

Median (95% CI)(19.2, NR) (15.2, 23.7) (19.2, 38.2) (15.2, 23.1)

Hazard ratio 0.71 0.80(95% CI) (0.55, 0.92) (0.63, 1.01)p-value 0.011 NA

Overall survival

Dabrafenib + Trametinib Dabrafenib + Placeboestimate, % (95%(n=211) (n=212)

CI)

At 1 year 74 (66.8, 79.0) 68 (60.8, 73.5)

At 2 years 52 (44.7, 58.6) 42 (35.4, 48.9)

At 3 years 43 (36.2, 50.1) 31 (25.1, 37.9)

At 4 years 35 (28.2, 41.8) 29 (22.7, 35.2)

At 5 years 32 (25.1, 38.3) 27 (20.7, 33.0)

NR = Not reached, NA = Not applicable

Figure 1 Kaplan-Meier overall survival curves for Study MEK115306 (ITT population)1.0

Dabrafenib + Trametinib

Dabrafenib + Placebo0.80.60.40.20.00 6 12 18 24 30 36 42 48 54 60 66 72 78

Time since Randomisation (Months)

Subjects at Risk:

Dabrafenib + Trametinib 211 188 145 113 98 86 79 71 63 60 57 54 12 0

Dabrafenib + Placebo 212 175 137 104 84 69 60 56 54 51 50 46 10 0

Improvements for the primary endpoint of PFS were sustained over a 5 year timeframe in thecombination arm compared to dabrafenib monotherapy. Improvements were also observed for overallresponse rate (ORR) and a longer duration of response (DoR) was observed in the combination armcompared to dabrafenib monotherapy (Table 7).

Estimated Survival Function

Table 7 Efficacy results for Study MEK115306 (COMBI-d)

Primary analysis (data Updated analysis (data 5-year analysis (data cut-cut-off: 26-Aug-2013) cut-off: 12-Jan-2015) off: 10-Dec-2018)

Endpoint Dabrafenib Dabrafenib Dabrafenib Dabrafenib Dabrafenib Dabrafenib+ + + + + +

Trametinib Placebo Trametinib Placebo Trametinib Placebo(n=211) (n=212) (n=211) (n=212) (n=211) (n=212)

PFSa

Progressive 102 (48) 109 (51) 139 (66) 162 (76) 160 (76) 166 (78)disease or death, n(%)

Median PFS 9.3 8.8 11.0 8.8 10.2 8.8(months) (95% (7.7, 11.1) (5.9, 10.9) (8.0, 13.9) (5.9, 9.3) (8.1, 12.8) (5.9, 9.3)

CI)

Hazard Ratio 0.75 0.67 0.73(95% CI) (0.57, 0.99) (0.53, 0.84) (0.59, 0.91)

P value 0.035 <0.001f NA

ORRb 67 51 69 53 69 54% (95% CI) (59.9, 73.0) (44.5, 58.4) (61.8, 74.8) (46.3, 60.2) (62.5, 75.4) (46.8, 60.6)

ORR difference 15e 15e NA(95% CI) (5.9, 24.5) (6.0, 24.5)

P value 0.0015 0.0014f NA

DoRc (months)

Median 9.2d 10.2d 12.9 10.6 12.9 10.2(95% CI) (7.4, NR) (7.5, NR) (9.4,19.5) (9.1, 13.8) (9.3, 18.4) (8.3, 13.8)a Progression-free survival (investigator assessed)b Overall Response Rate = Complete Response + Partial Responsec Duration of responsed At the time of the reporting the majority (≥59%) of investigator-assessed responses were still ongoinge ORR difference calculated based on the ORR result not roundedf Updated analysis was not pre-planned and the p-value was not adjusted for multiple testing

NR = Not reached

NA = Not applicable

Study MEK116513 was a 2-arm, randomised, open-label, Phase III study comparing dabrafenib andtrametinib combination therapy with vemurafenib monotherapy in BRAF V600 mutation-positiveunresectable or metastatic melanoma. The primary endpoint of the study was OS with a key secondaryendpoint of PFS. Subjects were stratified by lactate dehydrogenase (LDH) level (> the upper limit ofnormal (ULN) versus ≤ULN) and BRAF mutation (V600E versus V600K).

A total of 704 subjects were randomised 1:1 to either combination or vemurafenib. Most subjects were

Caucasian (>96%) and male (55%), with a median age of 55 years (24% were ≥65 years). Themajority of subjects had Stage IV M1c disease (61% overall). Most subjects had LDH ≤ULN (67%),

ECOG performance status of 0 (70%), and visceral disease (78%) at Baseline. Overall, 54% ofsubjects had <3 disease sites at baseline. The majority of subjects had BRAF V600E mutation-positivemelanoma (89%). Subjects with brain metastases were not included in the trial.

Median OS and estimated 1-year, 2-year, 3-year, 4-year and 5-year survival rates are presented in

Table 8. From an OS analysis at 5 years, the median OS for the combination arm was approximately8 months longer than the median OS for vemurafenib monotherapy (26.0 months versus 17.8 months)with 5-year survival rates of 36% for the combination versus 23% for vemurafenib monotherapy(Table 8, Figure 2). The Kaplan-Meier OS curve appears to stabilise from 3 to 5 years (see Figure 2).

The 5-year overall survival rate was 46% (95% CI: 38.8, 52.0) in the combination arm versus 28%(95% CI: 22.5, 34.6) in the vemurafenib monotherapy arm for patients who had a normal lactatedehydrogenase level at baseline, and 16% (95% CI: 9.3, 23.3) in the combination arm versus 10%(95% CI: 5.1, 17.4) in the vemurafenib monotherapy arm for patients with an elevated lactatedehydrogenase level at baseline.

Table 8 Overall Survival results for Study MEK116513 (COMBI-v)

OS analysis 5-year OS analysisdata cut-off: 13-Mar-2015) (data cut-off: 08-Oct-2018)

Dabrafenib + Dabrafenib +

Vemurafenib Vemurafenib

Trametinib Trametinib(n=352) (n=352)(n=352) (n=352)

Number of patients

Died (event), n155 (44) 194 (55) 216 (61) 246 (70)(%)

Estimates of OS (months)

Median (95% CI)25.6 18.0 26.0 17.8(22.6, NR) (15.6, 20.7) (22.1, 33.8) (15.6, 20.7)

Adjusted hazard 0.66 0.70ratio (95% CI) (0.53, 0.81) (0.58, 0.84)p-value <0.001 NA

Overall survival

Dabrafenib + Trametinib Vemurafenibestimate, % (95%(n=352) (n=352)

CI)

At 1 year 72 (67, 77) 65 (59, 70)

At 2 years 53 (47.1, 57.8) 39 (33.8, 44.5)

At 3 years 44 (38.8, 49.4) 31 (25.9, 36.2)

At 4 years 39 (33.4, 44.0) 26 (21.3, 31.0)

At 5 years 36 (30.5, 40.9) 23 (18.1, 27.4)

NR = Not reached, NA = Not applicable

Figure 2 Kaplan-Meier overall survival curves for Study MEK1165131.0

Dabrafenib + Trametinib

Vemurafenib0.80.60.40.20.00 6 12 18 24 30 36 42 48 5 4 6 0 66 72 78

Time since Randomisation (Months)

Subjects at Risk:

Dabrafenib + Trametinib 352 311 246 201 171 151 140 130 118 109 104 49 4 0

Vemurafenib 352 287 201 154 120 104 94 86 78 72 65 30 1 0

Estimated Survival Function

Improvements for the secondary endpoint of PFS were sustained over a 5 year timeframe in thecombination arm compared to vemurafenib monotherapy. Improvements were also observed for ORRand a longer DoR was observed in the combination arm compared to vemurafenib monotherapy(Table 9).

Table 9 Efficacy results for Study MEK116513 (COMBI-v)

Primary analysis (Data cut-off: 17- 5-year analysis (Data cut-off: 08-

Apr-2014) Oct-2018)

Endpoint Dabrafenib + Vemurafenib Dabrafenib + Vemurafenib

Trametinib (n=352) Trametinib (n=352)(n=352) (n=352)

PFSa

Progressive 166 (47) 217 (62) 257 (73) 259 (74)disease or death,n (%)

Median PFS 11.4 7.3 12.1 7.3(months) (9.9, 14.9) (5.8, 7.8) (9.7, 14.7) (6.0, 8.1)(95% CI)

Hazard Ratio 0.56 0.62(95% CI) (0.46, 0.69) (0.52, 0.74)

P value <0.001 NA

ORRb 64 51 67 53% (95% CI) (59.1, 69.4) (46.1, 56.8) (62.2, 72.2) (47.2, 57.9)

ORR difference 13 NA(95% CI) (5.7, 20.2)

P value 0.0005 NA

DoRc (months)

Median 13.8d 7.5d 13.8 8.5(95% CI) (11.0, NR) (7.3, 9.3) (11.3, 18.6) (7.4, 9.3)a Progression-free survival (investigator assessed)b Overall Response Rate = Complete Response + Partial Responsec Duration of responsed At the time of the reporting the majority (59% of dabrafenib+trametinib and 42% of vemurafenib) ofinvestigator-assessed responses were still ongoing

NR = Not reached

NA = Not applicable

There are limited data in patients taking the combination of dabrafenib with trametinib who haveprogressed on a prior BRAF inhibitor.

Part B of study BRF113220 included a cohort of 26 patients that had progressed on a BRAF inhibitor.

The trametinib 2 mg once daily and dabrafenib 150 mg twice daily combination demonstrated limitedclinical activity in patients who had progressed on a BRAF inhibitor. The investigator-assessedconfirmed response rate was 15% (95% CI: 4.4, 34.9) and the median PFS was 3.6 months (95% CI:

1.9, pct. 5.2). Similar results were seen in the 45 patients who crossed over from dabrafenib monotherapyto the trametinib 2 mg once daily and dabrafenib 150 mg twice daily combination in Part C of thisstudy. In these patients a 13% (95 CI: 5.0, 27.0) confirmed response rate was observed with a median

PFS of 3.6 months (95% CI: 2, 4).

The efficacy and safety of dabrafenib in combination with trametinib in patients with BRAF mutation-positive melanoma that has metastasised to the brain was studied in a non-randomised, open-label,multicentre, Phase II study (COMBI-MB study). A total of 125 patients were enrolled into fourcohorts:

* Cohort A: patients with BRAF V600E mutant melanoma with asymptomatic brain metastaseswithout prior local brain-directed therapy and ECOG performance status of 0 or 1.

* Cohort B: patients with BRAF V600E mutant melanoma with asymptomatic brain metastaseswith prior local brain-directed therapy and ECOG performance status of 0 or1.

* Cohort C: patients with BRAF V600D/K/R mutant melanoma with asymptomatic brainmetastases, with or without prior local brain-directed therapy and ECOG performance status of0 or 1.

* Cohort D: patients with BRAF V600D/E/K/R mutant melanoma with symptomatic brainmetastases, with or without prior local brain-directed therapy and ECOG performance status of0 or 1 or 2.

The primary endpoint of the study was intracranial response in Cohort A, defined as the percentage ofpatients with a confirmed intracranial response assessed by the investigator using modified Response

Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Intracranial response assessed by theinvestigator in Cohorts B, C and D were secondary endpoints of the study. Due to small sample sizereflected by wide 95% CIs, the results in Cohorts B, C, and D should be interpreted with caution.

Efficacy results are summarised in Table 10.

Table 10 Efficacy data by investigator assessment from COMBI-MB study

All treated patients population

Endpoints/ Cohort A Cohort B Cohort C Cohort Dassessment N=76 N=16 N=16 N=17

Intracranial response rate, % (95 % CI)59% 56% 44% 59%(47.3, 70.4) (29.9, 80.2) (19.8, 70.1) (32.9, 81.6)

Duration of intracranial response, median, months (95% CI)6.5 7.3 8.3 4.5(4.9, 8.6) (3.6, 12.6) (1.3, 15.0) (2.8, 5.9)

Overall response rate, % (95% CI)59% 56% 44% 65%(47.3, 70.4) (29.9, 80.2) (19.8, 70.1) (38.3, 85.8)

Progression-free survival, median, months (95% CI)5.7 7.2 3.7 5.5(5.3, 7.3) (4.7, 14.6) (1.7, 6.5) (3.7, 11.6)

Overall survival, median, months (95% CI)10.8 24.3 10.1 11.5(8.7, 17.9) (7.9, NR) (4.6, 17.6) (6.8, 22.4)

CI = Confidence interval, NR = Not reached

* Dabrafenib monotherapy

The efficacy of dabrafenib in the treatment of adult patients with BRAF V600 mutation-positiveunresectable or metastatic melanoma has been evaluated in 3 clinical trials (BRF113683 [BREAK-3],

BRF113929 [BREAK-MB], and BRF113710 [BREAK-2]) including patients with BRAF V600Eand/or V600K mutations.

Included in these clinical trials were in total 402 subjects with BRAF V600E and 49 subjects with

BRAF V600K mutation. Patients with melanoma driven by BRAF mutations other than V600E wereexcluded from the confirmatory trial and with respect to patients with the V600K mutation in singlearm clinical trials the activity appears lower than in V600E tumours.

No data is available in patients with melanoma harbouring BRAF V600 mutations others than V600Eand V600K. Efficacy of dabrafenib in subjects previously treated with a protein kinase inhibitor hasnot been investigated.

Previously untreated patients (results from the Phase III study [BREAK-3])

The efficacy and safety of dabrafenib were evaluated in a Phase III randomised, open-label study[BREAK 3] comparing dabrafenib to dacarbazine (DTIC) in previously untreated patients with BRAF

V600E mutation-positive advanced (unresectable Stage III) or metastatic (Stage IV) melanoma.

Patients with melanoma driven by BRAF mutations other than V600E were excluded.

The primary objective for this study was to evaluate the efficacy of dabrafenib compared to DTIC withrespect to PFS per investigator assessment. Patients on the DTIC arm were allowed to cross over todabrafenib after independent radiographic confirmation of initial progression. Baseline characteristicswere balanced between treatment groups. Sixty percent of patients were male and 99.6% were

Caucasian; the median age was 52 years with 21% of patients being ≥65 years, 98.4% had ECOGstatus of 0 or 1, and 97% of patients had metastatic disease.

At the pre-specified analysis with a 19 December 2011 data cut, a significant improvement in theprimary endpoint of PFS (HR=0.30; 95% Cl 0.18, 0.51; p < 0.0001) was achieved. Efficacy resultsfrom the primary analysis and a post-hoc analysis with 6-months additional follow up are summarisedin Table 11. OS data from a further post-hoc analysis based on a 18 December 2012 data cut areshown in Figure 3.

Table 11 Efficacy in previously untreated patients (BREAK-3 Study, 25 June 2012)

Data as of Data as of

December 19, 2011 June 25, 2012

Dabrafenib DTIC Dabrafenib DTIC

N=187 N=63 N=187 N=63

Progression-free survival

Median, months 5.1 (4.9, 6.9) 2.7 (1.5, 3.2) 6.9 (5.2,9.0) 2.7 (1.5,3.2)(95% CI)

HR (95% CI) 0.30 (0.18, 0.51) 0.37 (0.24, 0.58)

P < 0.0001 P < 0.0001

Overall responsea% (95% CI) 53 (45.5, 60.3) 19 (10.2, 30.9) 59 (51.4, 66.0) 24 (14, 36.2)

Duration of response

Median, months N=99 N=12 N=110 N=15(95% CI) 5.6 (4.8, NR) NR (5.0, NR) 8.0 (6.6, 11.5) 7.6 (5.0, 9.7)

Abbreviations: CI: confidence interval; DTIC: dacarbazine; HR: hazard ratio; NR: not reacheda Defined as confirmed complete + partial response.

As of 25 June 2012 cut-off, thirty five subjects (55.6%) of the 63 randomised to DTIC had crossedover to dabrafenib and 63% of subjects randomised to dabrafenib and 79% of subjects randomised to

DTIC had progressed or died. Median PFS after cross-over was 4.4 months.

Table 12 Survival data from the primary analysis and post-hoc analyses

Cut-off date Treatment Number of Hazard ratio (95% CI)deaths (%)

December 19, 2011 DTIC 9 (14%) 0.61 (0.25, 1.48) (a)dabrafenib 21 (11%)

June 25, 2012 DTIC 21 (33%) 0.75 (0.44, 1.29) (a)dabrafenib 55 (29%)

December 18, 2012 DTIC 28 (44%)0.76 (0.48, 1.21) (a)dabrafenib 78 (42%)(a) Patients were not censored at the time of cross-over

OS data from a further post-hoc analysis based on the 18 December 2012 data cut demonstrated a 12-month OS rate of 63% and 70% for DTIC and dabrafenib treatments, respectively.

Figure 3 Kaplan-Meier curves of overall survival (BREAK-3) (18 December 2012)

Patients with brain metastases (results from the Phase II study (BREAK-MB)

BREAK-MB was a multicentre, open-label, two-cohort, Phase II study designed to evaluate theintracranial response of dabrafenib in subjects with histologically confirmed (Stage IV) BRAFmutation-positive (V600E or V600K) melanoma metastatic to the brain. Subjects were enrolled into

Cohort A (subjects with no prior local therapy for brain metastasis) or Cohort B (subjects whoreceived prior local therapy for brain metastasis).

The primary endpoint of the study was overall intracranial response rate (OIRR) in the V600E patientpopulation, as assessed by investigators. The confirmed OIRR and other efficacy results perinvestigator assessment are presented in Table 13.

Table 13 Efficacy data in patients with brain metastases (BREAK-MB Study)

All Treated Subjects Population

BRAF V600E (Primary) BRAF V600K

Cohort A Cohort B Cohort A Cohort B

N=74 N=65 N=15 N=18

Overall intracranial response rate,% (95% CI)a39% (28.0, 51.2) 31% (19.9, 43.4) 7% (0.2, 31.9) 22% (6.4, 47.6)

P < 0.001b P < 0.001b

Duration of intracranial response, median, months (95% CI)

N=29 N=20 N=1 N=44.6 (2.8, NR) 6.5 (4.6, 6.5) 2.9 (NR, NR) 3.8 (NR, NR)

Overall response,% (95% CI)a38% (26.8, 49.9) 31% (19.9, 43.4) 0 (0, 21.8) 28% (9.7, 53.5)

Duration of response, median, months (95% CI)

N=28 N=20 NA N=55.1 (3.7, NR) 4.6 (4.6, 6.5) 3.1 (2.8, NR)

Progression-free survival, median, months (95% CI)3.7 (3.6, 5.0) 3.8 (3.6, 5.5) 1.9 (0.7, 3.7) 3.6 (1.8, pct. 5.2)

Overall survival, median, months (95% CI)

Median, months 7.6 (5.9, NR) 7.2 (5.9, NR) 3.7 (1.6, pct. 5.2) 5.0 (3.5, NR)

Abbreviations: CI: confidence interval; NR: not reached; NA: not applicablea Confirmed response.b This study was designed to support or reject the null hypothesis of OIRR ≤10% (based on historical results)in favour of the alternative hypothesis of OIRR ≥ 30% in BRAF V600E mutation-positive subjects.

Patients who were previously untreated or failed at least one prior systemic therapy (results from the

Phase II [BREAK-2])

BRF113710 (BREAK-2) was a multicentre, single-arm study that enrolled 92 subjects with metastaticmelanoma (Stage IV) with confirmed BRAF V600E or V600K mutation-positive melanoma.

The investigator assessed confirmed response rate in patients with BRAF V600E metastatic melanoma(n=76) was 59% (95% CI: 48.2, 70.3) and the median DoR was 5.2 months (95% CI: 3.9, notcalculable) based on a median follow-up time of 6.5 months. In patients with BRAF V600K mutation-positive metastatic melanoma (n=16) the response rate was 13% (95% CI: 0.0, 28.7) with a median

DoR of 5.3 months (95% CI: 3.7, 6.8). Although limited by the low number of patients, median OSappeared consistent with data in patients with BRAF V600E mutation-positive tumours.

The efficacy and safety of dabrafenib in combination with trametinib were studied in a Phase III,multicentre, randomised, double-blind, placebo-controlled study in patients with Stage III (Stage IIIA[lymph node metastasis >1 mm], IIIB, or IIIC) cutaneous melanoma with a BRAF V600 E/Kmutation, following complete resection.

Patients were randomised 1:1 to receive either combination therapy (dabrafenib 150 mg twice dailyand trametinib 2 mg once daily) or two placebos for a period of 12 months. Enrollment requiredcomplete resection of melanoma with complete lymphadenectomy within 12 weeks prior torandomisation. Any prior systemic anti-cancer treatment, including radiotherapy, was not allowed.

Patients with a history of prior malignancy, if disease-free for at least 5 years, were eligible. Patientspresenting with malignancies with confirmed activating RAS mutations were not eligible. Patientswere stratified by BRAF mutation status (V600E versus V600K) and stage of disease prior to surgeryusing the American Joint Committee on Cancer (AJCC) 7th edition Melanoma Staging System (by

Stage III sub-stage, indicating different levels of lymph node involvement and primary tumour sizeand ulceration). The primary endpoint was investigator-assessed relapse-free survival (RFS), definedas the time from randomisation to disease recurrence or death from any cause. Radiological tumourassessment was conducted every 3 months for the first two years and every 6 months thereafter, untilfirst relapse was observed. Secondary endpoints include overall survival (OS; key secondaryendpoint), freedom from relapse (FFR) and distant metastasis-free survival (DMFS).

A total of 870 patients were randomised to the combination therapy (n=438) and placebo (n=432)arms. Most patients were Caucasian (99%) and male (55%), with a median age of 51 years (18% were≥65 years). The study included patients with all sub-stages of Stage III disease prior to resection; 18%of these patients had lymph node involvement only identifiable by microscope and no primary tumourulceration. The majority of patients had a BRAF V600E mutation (91%).

The median duration of follow-up at the time of the primary analysis was 2.83 years in the dabrafeniband trametinib combination arm and 2.75 years in the placebo arm.

Results for the primary analysis of RFS are presented in Table 14. The study showed a statisticallysignificant difference for the primary outcome of investigator-assessed RFS between treatment arms,with a median RFS of 16.6 months for the placebo arm and not yet reached for the combination arm(HR: 0.47; 95% confidence interval: (0.39, 0.58); p=1.53×10-14). The observed RFS benefit wasconsistently demonstrated across subgroups of patients including age, sex and race. Results were alsoconsistent across stratification factors for disease stage and BRAF V600 mutation type.

Table 14 Investigator-assessed RFS results for Study BRF115532 (COMBI-AD primaryanalysis)

Dabrafenib + Trametinib Placebo

RFS parameter N=438 N=432

Number of events, n (%) 166 (38%) 248 (57%)

Recurrence 163 (37%) 247 (57%)

Relapsed with distant metastasis 103 (24%) 133 (31%)

Death 3 (<1%) 1 (<1%)

Median (months) NE 16.6(95% CI) (44.5, NE) (12.7, 22.1)

Hazard ratio[1] 0.47(95% CI) (0.39, 0.58)p-value[2] 1.53×10-141-year rate (95% CI) 0.88 (0.85, 0.91) 0.56 (0.51, 0.61)2-year rate (95% CI) 0.67 (0.63, 0.72) 0.44 (0.40, 0.49)3-year rate (95% CI) 0.58 (0.54, 0.64) 0.39 (0.35, 0.44)[1] Hazard ratio is obtained from the stratified Pike model.[2] P-value is obtained from the two-sided stratified log-rank test (stratification factors were disease stage - IIIAvs. IIIB vs. IIIC - and BRAF V600 mutation type - V600E vs. V600K)

NE = not estimable

Based on updated data with an additional 29 months of follow-up compared to the primary analysis(minimum follow-up of 59 months), the RFS benefit was maintained with an estimated HR of 0.51(95% CI: 0.42, 0.61) (Figure 4). The 5-year RFS rate was 52% (95% CI: 48, 58) in the combinationarm compared to 36% (95% CI: 32, 41) in the placebo arm.

Figure 4 Kaplan-Meier RFS curves for Study BRF115532 (ITT population, updated results)1.00.90.80.70.60.50.40.30.2 Group N Events Median, months (95% CI)

Dabrafenib + t rametinib 438 190 NA (47.9, NA)0.1 Placebo 432 262 16.6 (12.7, 22.1)

HR for recurrence = 0.510.0 95% CI (0.42, 0.61)0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80

Time from randomisation (months)

Subjects at risk

Dabrafenib+ T rametinib 438 413 405 391 381 372 354 335 324 298 281 275 262 256 249 242 236 233 229 228 221 217 213 210 204 202 199 195 176 156 133 109 92 80 45 38 17 8 6 2 0

Placebo 432 387 322 280 263 243 219 204 199 185 178 175 168 166 164 158 157 151 147 146 143 140 139 137 136 133 133 132 121 115 99 80 69 56 35 26 13 1 1 2 0

At the time of the final OS analysis, the median duration of follow-up was 8.3 years in thecombination arm and 6.9 years in the placebo arm. The observed difference in OS was not statisticallysignificant (HR: 0.80; 95% CI: 0.62, 1.01) with 125 events (29%) in the combination arm and136 events (31%) in the placebo arm. Estimated 5-year OS rates were 79% in the combination arm and70% in the placebo arm, and estimated 10-year OS rates were 66% in the combination arm and 63% inthe placebo arm.

The efficacy and safety of dabrafenib in combination with trametinib was studied in a Phase II, three-cohort, multicentre, non-randomised and open-label study in which patients with stage IV BRAF

V600E mutant NSCLC were enrolled. The primary endpoint was ORR using the RECIST 1.1 assessedby the investigator. Secondary endpoints included DoR, PFS, OS, safety and populationpharmacokinetics. ORR, DoR and PFS were also assessed by an Independent Review Committee(IRC) as a sensitivity analysis.

Cohorts were enrolled sequentially:

* Cohort A: Monotherapy (dabrafenib 150 mg twice daily), 84 patients enrolled. 78 patients hadprevious systemic treatment for their metastatic disease.

* Cohort B: Combination therapy (dabrafenib 150 mg twice daily and trametinib 2 mg oncedaily), 59 patients enrolled. 57 patients had 1-3 lines of previous systemic treatment for theirmetastatic disease. 2 patients had no previous systemic treatment and were included in theanalysis for patients enrolled in Cohort C.

* Cohort C: Combination therapy (dabrafenib 150 mg twice daily and trametinib 2 mg oncedaily), 34 patients. All patients received study medicinal product as first-line treatment formetastatic disease.

Proportion alive and relapse free

Among the total of 93 patients who were enrolled in the combination therapy cohorts B and C, mostpatients were Caucasian (>90%), and similar female versus male (54% versus 46%), with a medianage of 64 years in second line or higher patients and 68 years in the first line patients. Most patients(94%) enrolled in the combination therapy treated cohorts had an ECOG performance status of 0 or 1.

26 (28%) had never smoked. The majority of patients had a non-squamous histology. In the previouslytreated population, 38 patients (67%) had one line of systemic anti-cancer therapy for metastaticdisease.

At the time of the primary analysis, the primary endpoint of investigator-assessed ORR in the first linepopulation was 61.1% (95% CI, 43.5%, 76.9%), and in the previously treated population was 66.7%(95% CI, 52.9%, 78.6%). These met the statistical significance to reject the null hypothesis that the

ORR of dabrafenib in combination with trametinib for this NSCLC population was less than or equalto 30%. The ORR results assessed by IRC were consistent with the investigator assessment. Theefficacy of the combination with trametinib was superior when indirectly compared to dabrafenibmonotherapy in Cohort A. The final analysis of efficacy performed 5 years after last subject first doseis presented in Table 15.

Table 15 Summary of efficacy in the combination treatment cohorts based on investigatorand independent radiology review

Endpoint Analysis Combination 1st line Combination 2nd line plus

N=361 N=571

Overall confirmed By Investigator 23 (63.9%) 39 (68.4%)response n (%) (46.2, 79.2) (54.8, 80.1)(95% CI) By IRC 23 (63.9%) 36 (63.2%)(46.2, 79.2) (49.3, 75.6)

Median DoR By Investigator 10.2 (8.3, 15.2) 9.8 (6.9, 18.3)

Months (95% CI) By IRC 15.2 (7.8, 23.5) 12.6 (5.8, 26.2)

Median PFS By Investigator 10.8 (7.0, 14.5) 10.2 (6.9, 16.7)

Months (95% CI) By IRC 14.6 (7.0, 22.1) 8.6 (5.2, 16.8)

Median OS - 17.3 (12.3, 40.2) 18.2 (14.3, 28.6)

Months (95% CI)1 Data cut-off: 7 January 2021

Worst-case QTc prolongation of >60 millisecond (msec) was observed in 3% of dabrafenib-treatedsubjects (one >500 msec in the integrated safety population). In the Phase III study MEK115306 nopatients treated with trametinib in combination with dabrafenib had worst-case QTcB prolongation to>500 msec; QTcB was increased more than 60 msec from baseline in 1% (3/209) of patients. In the

Phase III study MEK116513 four patients (1%) treated with trametinib in combination with dabrafenibhad a QTcB Grade 3 increase (>500 msec). Two of these patients had a QTcB Grade 3 increase(>500 msec) that was also an increase >60 msec from baseline.

The potential effect of dabrafenib on QT prolongation was assessed in a dedicated multiple dose QTstudy. A supratherapeutic dose of 300 mg dabrafenib twice daily was administered in 32 subjects with

BRAF V600 mutation-positive tumours. No clinically relevant effect of dabrafenib or its metaboliteson the QTc interval was observed.

Pyrexia is observed in patients treated with dabrafenib and trametinib combination therapy. The initialregistration studies for the combination therapy in the unresectable or metastatic melanoma setting(COMBI-d and COMBI-v; total N=559) and in the adjuvant melanoma setting (COMBI-AD, N=435)recommended to interrupt only dabrafenib in case of pyrexia (fever ≥38.5°C). In two subsequentstudies in unresectable or metastatic melanoma (COMBI-i control arm, N=264) and in the adjuvantmelanoma setting (COMBI-Aplus, N=552), interruption of both medicinal products when patient’stemperature is ≥38oC (COMBI-Aplus), or at the first symptom of pyrexia (COMBI-i; COMBI-Aplusfor recurrent pyrexia) was advised. In COMBI-i and COMBI-Aplus there was a lower incidence ofgrade 3/4 pyrexia, complicated pyrexia, hospitalisation due to serious pyrexia adverse events ofspecial interest (AESIs), the time spent in pyrexia AESIs, and permanent discontinuations from bothmedicinal products due to pyrexia AESIs (the latter in the adjuvant setting only) compared to COMBI-d, COMBI-v and COMBI-AD. The COMBI-Aplus study met its primary endpoint with a compositerate of 8.0% (95% CI: 5.9, 10.6) for grade 3/4 pyrexia, hospitalisation due to pyrexia, or permanenttreatment discontinuation due to pyrexia compared to 20.0% (95% CI: 16.3, 24.1) for the historicalcontrol (COMBI-AD).

The European Medicines Agency has deferred the obligation to submit the results of studies withdabrafenib in one or more subsets of the paediatric population in melanoma and solid malignanttumours (see section 4.2 for information on paediatric use).

Dabrafenib is absorbed orally with median time to achieve peak plasma concentration of 2 hours post-dose. Mean absolute bioavailability of oral dabrafenib is 95% (90% CI: 81, 110%). Dabrafenibexposure (Cmax and AUC) increased in a dose proportional manner between 12 and 300 mg followingsingle-dose administration, but the increase was less than dose-proportional after repeat twice dailydosing. A decrease in exposure was observed with repeat dosing, likely due to induction of its ownmetabolism. Mean accumulation AUC Day 18/Day 1 ratios was 0.73. Following administration of150 mg twice daily, geometric mean Cmax, AUC(0-) and predose concentration (C) were1 478 ng/ml, 4 341 ng*hr/ml and 26 ng/ml, respectively.

Administration of dabrafenib with food reduced the bioavailability (Cmax and AUC decreased by 51%and 31% respectively) and delayed absorption of dabrafenib capsules when compared to the fastedstate.

Dabrafenib binds to human plasma protein and is 99.7% bound. The steady-state volume ofdistribution following intravenous microdose administration is 46 L.

The metabolism of dabrafenib is primarily mediated by CYP2C8 and CYP3A4 to form hydroxy-dabrafenib, which is further oxidised via CYP3A4 to form carboxy-dabrafenib. Carboxy-dabrafenibcan be decarboxylated via a non-enzymatic process to form desmethyl-dabrafenib. Carboxy-dabrafenib is excreted in bile and urine. Desmethyl-dabrafenib may also be formed in the gut andreabsorbed. Desmethyl-dabrafenib is metabolised by CYP3A4 to oxidative metabolites. Hydroxy-dabrafenib terminal half-life parallels that of parent with a half-life of 10 hrs while the carboxy- anddesmethyl-metabolites exhibited longer half-lives (21-22 hours). Mean metabolite-to-parent AUCratios following repeat-dose administration were 0.9, 11 and 0.7 for hydroxy-, carboxy-, anddesmethyl-dabrafenib, respectively. Based on exposure, relative potency, and pharmacokineticproperties, both hydroxy- and desmethyl-dabrafenib are likely to contribute to the clinical activity ofdabrafenib while the activity of carboxy-dabrafenib is not likely to be significant.

Effects of other medicinal products on dabrafenib

Dabrafenib is a substrate of human P-glycoprotein (P-gp) and human BCRP in vitro. However, thesetransporters have minimal impact on dabrafenib oral bioavailability and elimination and the risk forclinically relevant drug-drug interactions with inhibitors of P-gp or BCRP is low. Neither dabrafenibnor its 3 main metabolites were demonstrated to be inhibitors of P-gp in vitro.

Effects of dabrafenib on other medicinial products

Although dabrafenib and its metabolites, hydroxy-dabrafenib, carboxy-dabrafenib and desmethyl-dabrafenib, were inhibitors of human organic anion transporter (OAT) 1 and OAT3 in vitro, anddabrafenib and its desmethyl metabolite were found to be inhibitors of organic cation transporter 2(OCT2) in vitro, the risk of a drug-drug interaction at these transporters is minimal based on clinicalexposure of dabrafenib and its metabolites.

Terminal half-life of dabrafenib following an intravenous single microdose is 2.6 hours. Dabrafenibterminal half-life after a single oral dose is 8 hours due to absorption-limited elimination after oraladministration (flip-flop pharmacokinetics). IV plasma clearance is 12 l/hr.

After an oral dose, the major route of elimination of dabrafenib is metabolism, mediated via CYP3A4and CYP2C8. Dabrafenib related material is excreted primarily in faeces, with 71% of an oral doserecovered in faeces; 23% of the dose was recovered in urine in the form of metabolites only.

A population pharmacokinetic analysis indicates that mildly elevated bilirubin and/or AST levels(based on National Cancer Institute [NCI] classification) do not significantly affect dabrafenib oralclearance. In addition, mild hepatic impairment as defined by bilirubin and AST did not have asignificant effect on dabrafenib metabolite plasma concentrations. No data are available in patientswith moderate to severe hepatic impairment. As hepatic metabolism and biliary secretion are theprimary routes of elimination of dabrafenib and its metabolites, administration of dabrafenib should beundertaken with caution in patients with moderate to severe hepatic impairment (see section 4.2).

A population pharmacokinetic analysis suggests that mild renal impairment does not affect oralclearance of dabrafenib. Although data in moderate renal impairment are limited these data mayindicate no clinically relevant effect. No data are available in subjects with severe renal impairment(see section 4.2).

Based on the population pharmacokinetic analysis, age had no significant effect on dabrafenibpharmacokinetics. Age greater than 75 years was a significant predictor of carboxy- and desmethyl-dabrafenib plasma concentrations with a 40% greater exposure in subjects ≥75 years of age, relative tosubjects <75 years old.

Based on the population pharmacokinetic analysis, gender and weight were found to influencedabrafenib oral clearance; weight also impacted oral volume of distribution and distributionalclearance. These pharmacokinetic differences were not considered clinically relevant.

The population pharmacokinetic analysis showed no significant differences in the pharmacokinetics ofdabrafenib between Asian and Caucasian patients. There are insufficient data to evaluate the potentialeffect of other races on dabrafenib pharmacokinetics.

The pharmacokinetic exposures of dabrafenib at a weight-adjusted dosage in adolescent patients werewithin range of those observed in adults.

Carcinogenicity studies with dabrafenib have not been conducted. Dabrafenib was not mutagenic orclastogenic using in vitro tests in bacteria and cultured mammalian cells, and an in vivo rodentmicronucleus assay.

In combined female fertility, early embryonic and embryo-foetal development studies in rats numbersof ovarian corpora lutea were reduced in pregnant females at 300 mg/kg/day (approximately 3 timeshuman clinical exposure based on AUC), but there were no effects on oestrous cycle, mating orfertility indices. Developmental toxicity including embryo-lethality and ventricular septal defects andvariation in thymic shape were seen at 300 mg/kg/day, and delayed skeletal development and reducedfoetal body weight at ≥20 mg/kg/day (≥0.5 times human clinical exposure based on AUC).

Male fertility studies with dabrafenib have not been conducted. However, in repeat dose studies,testicular degeneration/depletion was seen in rats and dogs (≥0.2 times the human clinical exposurebased on AUC). Testicular changes in rat and dog were still present following a 4-week recoveryperiod (see section 4.6).

Cardiovascular effects, including coronary arterial degeneration/necrosis and/or haemorrhage, cardiacatrioventricular valve hypertrophy/haemorrhage and atrial fibrovascular proliferation were seen indogs (≥2 times human clinical exposure based on AUC). Focal arterial/perivascular inflammation invarious tissues was observed in mice and an increased incidence of hepatic arterial degeneration andspontaneous cardiomyocyte degeneration with inflammation (spontaneous cardiomyopathy) wasobserved in rats (≥0.5 and 0.6 times human clinical exposure for rats and mice, respectively). Hepaticeffects, including hepatocellular necrosis and inflammation, were observed in mice (≥0.6 times humanclinical exposure). Bronchoalveolar inflammation of the lungs was observed in several dogs at ≥20mg/kg/day (≥9 times human clinical exposure based on AUC) and was associated with shallow and/orlaboured breathing.

Reversible haematological effects have been observed in dogs and rats given dabrafenib. In studies ofup to 13 weeks, decreases in reticulocyte counts and/or red cell mass were observed in dogs and rats(≥10 and 1.4 times human clinical exposure, respectively).

In juvenile toxicity studies in rats, effects on growth (shorter long bone length), renal toxicity (tubulardeposits, increased incidence of cortical cysts and tubular basophilia and reversible increases in ureaand/or creatinine concentrations) and testicular toxicity (degeneration and tubular dilation) wereobserved (≥0.2 times human clinical exposure based on AUC).

Dabrafenib was phototoxic in an in vitro mouse fibroblast 3T3 Neutral Red Uptake (NRU) assay andin vivo at doses ≥100 mg/kg (>44 times human clinical exposure based on Cmax) in an oralphototoxicity study in hairless mice.

Combination with trametinib

In a study in dogs in which trametinib and dabrafenib were given in combination for 4 weeks, signs ofgastrointestinal toxicity and decreased lymphoid cellularity of the thymus were observed at lowerexposures than in dogs given trametinib alone. Otherwise, similar toxicities were observed as incomparable monotherapy studies.

Microcrystalline cellulose

Magnesium stearate

Colloidal silicone dioxide

Red iron oxide (E172)

Titanium dioxide (E171)

Hypromellose (E464)

Black iron oxide (E172)

Shellac

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Opaque white high-density polyethylene (HDPE) bottle with polypropylene screw cap and a silica geldesiccant.

Each bottle contains either 28 or 120 hard capsules.

Not all pack sizes may be marketed.

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

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

Tafinlar 50 mg hard capsules

EU/1/13/865/001

EU/1/13/865/002

Tafinlar 75 mg hard capsules

EU/1/13/865/003

EU/1/13/865/004

Date of first authorisation: 26 August 2013

Date of latest renewal: 08 May 2018

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

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