TAFINLAR 50 MG HARD CAPSULES - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Tafinlar® 50 mg hard capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Tafinlar 50 mg hard capsules

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

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

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”.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Melanoma

Dabrafenib as monotherapy or in combination with trametinib is indicated for the treatment of adult patients with unresectable or metastatic melanoma with

a BRAF V600 mutation (see sections 4.4 and 5.1).

Adjuvant treatment of melanoma

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

Non-small cell lung cancer (NSCLC)

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

4.2 Posology and method of administration

Treatment with dabrafenib should be initiated and supervised by a qualified physician experienced in the use of anticancer medicinal products.

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

The efficacy and safety of dabrafenib have not been established in patients with wild-type BRAF melanoma 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).

Posology

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). The recommended dose of trametinib, when used in combination with dabrafenib, is 2 mg once daily.

Duration of treatment

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

Missed doses

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

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

Dose modification

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

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

Dose modifications or interruptions are not recommended for adverse reactions of cutaneous squamous 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 ocular inflammation. If uveitis does not respond to local ocular therapy, withhold dabrafenib until resolution of 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

For dosing instructions for treatment with trametinib monotherapy, see trametinib SmPC, Posology and Method of administration.

Table 2 Dose modification schedule based on the grade of any adverse events (AE) (excluding pyrexia)

* The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events (CTC-AE) v4.0

When an individual’s ad­verse reactions are under effective management, dose re-escalation following the same dosing steps as de-escalation may be considered. The dabrafenib dose should not exceed 150 mg twice daily.

Pyrexia

If a patient’s tem­perature is >38oC therapy should be interrupted (dabrafenib when used as monotherapy, 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 as ibuprofen or acetaminophen/pa­racetamol should be initiated. The use of oral corticosteroids should be considered in those instances in which anti-pyretics are insufficient. Patients should be evaluated for signs 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 the patient is symptom free for at least 24 hours, either 1) at the same dose level, or 2) reduced by one dose level if the pyrexia is recurrent and/or was accompanied by other severe symptoms including dehydration, hypotension or renal failure.

If treatment-related toxicities occur when dabrafenib is used in combination with trametinib, then both treatments should be simultaneously dose reduced, interrupted or discontinued. Exceptions where dose modifications are necessary for only one of the two treatments are detailed below for uveitis, RAS mutation positive non-cutaneous malignancies (primarily related to dabrafenib), left ventricular ejection fraction (LVEF) reduction, retinal vein occlusion (RVO), retinal pigment epithelial detachment (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 selected adverse reactions

Uveitis

No dose modifications are required for uveitis as long as effective local therapies can control ocular inflammation. If uveitis does not respond to local ocular therapy, dabrafenib should be withheld until resolution 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 (see section 4.4).

RAS-mutation-positive non-cutaneous malignancies

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

Left ventricular ejection fraction (LVEF) reduction/Left ventricular dysfunction If dabrafenib is being used in combination with trametinib and absolute decrease of >10% in LVEF compared to baseline and the ejection fraction is below the institution’s lower limit of normal (LLN), please refer to the trametinib SmPC (see section 4.2) for dose modification instructions for trametinib. No dose modification of dabrafenib is required when taken in combination with trametinib.

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

Interstitial lung disease (ILD)/Pneumonitis

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 including cough, dyspnoea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations, please refer to the trametinib SmPC (see section 4.2) for dose modification instructions for trametinib. No dose modification of dabrafenib is required when taken in combination with trametinib for cases of ILD or pneumonitis.

Renal impairment

No dose adjustment is required for patients with mild or moderate renal impairment. There are no clinical data in subjects with severe renal impairment and the potential need for dose adjustment cannot be determined (see section 5.2). Dabrafenib should be used with caution in patients with severe renal impairment when administered as monotherapy or in combination with trametinib.

Hepatic impairment

No dose adjustment is required for patients with mild hepatic impairment. There are no clinical data in subjects with moderate to severe hepatic impairment and the potential need for dose adjustment cannot be determined (see section 5.2). Hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites and patients with moderate to severe hepatic impairment may have increased exposure. Dabrafenib should be used with caution in patients with moderate or severe hepatic impairment when administered as monotherapy or in combination with trametinib.

Special populations

Non-Caucasian patients

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

Elderly

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

Paediatric population

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

Method of administration

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

It is recommended that the doses of dabrafenib be taken at similar times every day, leaving an interval of 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 morning dose 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 the next scheduled dose.

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

4.3 Contraindications

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

4.4 Special warnings and precautions for use

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

BRAF V600 testing

The efficacy and safety of dabrafenib have not been established in patients with wild-type BRAF melanoma 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 have progressed on a prior BRAF inhibitor. These data show that the efficacy of the combination will be lower in these patients (see section 5.1).

Therefore, other treatment options should be considered before treatment with the combination in this prior BRAF inhibitor treated population. The sequencing of treatments following progression on a BRAF inhibitor therapy has not been established.

New malignancies

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

Cutaneous malignancies

Cutaneous squamous cell carcinoma (cuSCC)

Cases of cuSCC (including keratoacanthoma) have been reported in patients treated with dabrafenib alone and in combination with trametinib (see section 4.8). In the Phase III clinical trials MEK115306 and 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 receiving vemurafenib as a monotherapy, respectively. In the integrated safety population of patients with melanoma and advanced NSCLC, cuSCC occurred in 2% (19/1076) of patients receiving dabrafenib in combination with trametinib. The median time to diagnosis of the first occurrence of cuSCC in study 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 in combination with trametinib as compared to 1% (5/432) of patients receiving placebo developed cuSCC. The median time to onset of the first occurrence of cuSCC in the combination arm of the adjuvant treatment study was approximately 18 weeks and was 33 weeks in the placebo arm.

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

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

New primary melanoma

New primary melanomas have been reported in clinical trials in patients treated with dabrafenib. In clinical trials in unresectable or metastatic melanoma,these cases were identified within the first 5 months of dabrafenib as monotherapy. Cases of new primary melanoma can be managed with excision and do not require treatment modification. Monitoring for skin lesions should occur as described for cuSCC.

Non-cutaneous malignancies

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 BRAF inhibitors. 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 reported in 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 (pancreatic adenocarcinoma, bile duct adenocarcinoma) and with dabrafenib in combination with the MEK inhibitor, trametinib (colorectal cancer, pancreatic cancer).

Prior to initiation of treatment patients should undergo a head and neck examination with minimally visual inspection of oral mucosa and lymph node palpation, as well as chest/abdomen computerised tomography (CT) scan. During treatment patients should be monitored as clinically appropriate which may include a head and neck examination every 3 months and a chest/abdomen CT scan every 6 months. Anal examinations and pelvic examinations are recommended before and at the end of treatment or when considered clinically indicated. Complete blood cell counts and blood chemistry should be performed as clinically indicated.

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

Following discontinuation of dabrafenib, monitoring for non-cutaneous secondary/recurrent malignancies should continue for up to 6 months or until initiation of another anti-neoplastic therapy. Abnormal findings should be managed according to clinical practices.

Haemorrhage

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

Visual impairment

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

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

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

Pyrexia

Fever has been reported in clinical trials with dabrafenib as monotherapy and in combination with trametinib (see section 4.8). In 1% of patients in clinical trials with dabrafenib monotherapy, serious non-infectious febrile events were identified defined as fever accompanied by severe rigors, dehydration, hypotension and/or acute renal insufficiency of pre-renal origin in subjects with normal baseline renal function (see section 4.8). The onset of these serious non-infectious febrile events was typically within the first month of dabrafenib as monotherapy. Patients with serious non-infectious febrile 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 combination therapy arm of study MEK115306 in patients with unresectable or metastatic melanoma, pyrexia was reported in 57% (119/209) of patients with 7% Grade 3, as compared to the dabrafenib monotherapy arm with 33% (69/211) of patients reporting pyrexia, 2% Grade 3. In the Phase II study BRF113928 in patients with advanced NSCLC the incidence and severity of pyrexia were increased slightly when dabrafenib was used in combination with trametinib (48%, 3% Grade 3) as compared to dabrafenib monotherapy (39%, 2% Grade 3). In the Phase III study BRF115532 in the adjuvant treatment of melanoma, the incidence and severity of pyrexia were higher in the dabrafenib in combination with trametinib 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 with trametinib and developed pyrexia, approximately half of the first occurrences of pyrexia happened within 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 in combination) should be interrupted if the patient’s tem­perature is >38°C (see section 5.1). In case of recurrence, 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 oral corticosteroids should be considered in those instances in which anti-pyretics are insufficient. Patients should be evaluated for signs and symptoms of infection. Therapy can be restarted once the fever resolves. If fever is associated with other severe signs or symptoms, therapy should be restarted at a reduced dose once fever resolves and as clinically appropriate (see section 4.2).

LVEF reduction/Left ventricular dysfunction

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 modification of dabrafenib is required when taken in combination with trametinib.

Renal failure

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

Hepatic events

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

Hypertension

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

Interstitial lung disease (ILD)/Pneumonitis

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

Rash

Rash has been observed in about 24% of patients in clinical trials when dabrafenib is used in combination with trametinib (see section 4.8). The majority of these cases were Grade 1 or 2 and did not require any dose interruptions or dose reductions. Please refer to the trametinib SmPC section 4.4 for additional information.

Rhabdomyolysis

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

Pancreatitis

Pancreatitis has been reported in <1% of patients treated with dabrafenib as monotherapy and in combination with trametinib in unresectable or metastatic melanoma clinical trials and about 4% of patients treated with dabrafenib in combination with trametinib in the NSCLC clinical trial. One of the events occurred on the first day of dabrafenib dosing of a metastatic melanoma patient and recurred following re-challenge at a reduced dose. In the adjuvant treatment of melanoma trial, pancreatitis was reported in <1% (1/435) of patients receiving dabrafenib in combination with trametinib, and no patients receiving placebo. Unexplained abdominal pain should be promptly investigated to include measurement of serum amylase and lipase. Patients should be closely monitored when re-starting dabrafenib after an episode of pancreatitis.

Deep vein thrombosis/Pul­monary embolism

Pulmonary embolism or deep vein thrombosis can occur when dabrafenib is used in combination with trametinib. If patients develop symptoms of pulmonary embolism or deep vein thrombosis such as shortness 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.

Severe cutaneous adverse reactions

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

Gastrointestinal disorders

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

Sarcoidosis

Cases of sarcoidosis have been reported in patients treated with dabrafenib in combination with trametinib, 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 disease progression.

Effects of other medicinal products on dabrafenib

Dabrafenib is a substrate of CYP2C8 and CYP3A4. Potent inducers of these enzymes should be avoided 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 many commonly used medicinal products (see examples in section 4.5). A drug utilisation review (DUR) is therefore essential when initiating dabrafenib treatment. Concomitant use of dabrafenib with medicinal products 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 is recommended when dabrafenib is used concomitantly with warfarin and at discontinuation of dabrafenib (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 (a transporter substrate) is used concomitantly with dabrafenib and at discontinuation of dabrafenib (see section 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on dabrafenib

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

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

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

Administration of rifampin (a CYP3A4/CYP2C8 inducer) 600 mg once daily with dabrafenib 150 mg twice daily resulted in a decrease in repeat dose dabrafenib Cmax (27%) and AUC (34%). No relevant change in AUC was noted for hydroxy-dabrafenib. There was an increase in AUC of 73% for carboxy-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 agent rabeprazole 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. Medicinal products 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 in reduced plasma levels of medicinal products metabolised by these enzymes, and may affect some transported medicinal products. The reduction in plasma concentrations can lead to lost or reduced clinical effect of these medicinal products. There is also a risk of increased formation of active metabolites of these medicinal products. Enzymes that may be induced include CYP3A in the liver and gut, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and UGTs (glucuronide conjugating enzymes). The transport protein Pgp 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 with rosuvastatin.

In vitro, dabrafenib produced dose-dependent increases in CYP2B6 and CYP3A4. In a clinical drug interaction 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 is expected. If their therapeutic effect is of large importance to the patient, and dose adjustments are not easily performed based on monitoring of efficacy or plasma concentrations, these medicinal products are to be avoided or used with caution. The risk for liver injury after paracetamol administration is suspected 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 the interaction 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)

Anticancer agents (e.g. cabazitaxel)

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

Antiepileptic (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. Upon discontinuation of dabrafenib offset of induction is gradual, concentrations of sensitive CYP3A4, CYP2B6, CYP2C8, CYP2C9 and CYP2C19, UDP glucuronosyl transferase (UGT) and transporter substrates (e.g. Pgp or MRP-2) may increase and patients should be monitored for toxicity and dose of 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 in

16 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 daily resulted in no clinically meaningful changes in trametinib or dabrafenib Cmax and AUC with increases of 16 and 23%, respectively, in dabrafenib Cmax and AUC. A small decrease in trametinib bioavailability, corresponding to a decrease in AUC of 12%, was estimated when trametinib is administered in combination with dabrafenib, a CYP3A4 inducer, using a population pharmacokinetic analysis.

When dabrafenib is used in combination with trametinib refer to the guidance for medicinal product interactions 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 hour prior to or two hours after a meal due to the effect of food on dabrafenib absorption (see section 5.2).

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/Con­traception in females

Women of childbearing potential must use effective methods of contraception during therapy and for 2 weeks following discontinuation of dabrafenib and 16 weeks following the last dose of trametinib when given in combination with dabrafenib. Dabrafenib may decrease the efficacy of oral or any systemic hormonal contraceptives and an effective alternative method of contraception should be used (see section 4.5).

Pregnancy

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

Breast-feeding

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

Fertility

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 reproductive organs have been seen in animals (see section 5.3). Male patients taking dabrafenib as monotherapy or in 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 combination with trametinib.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

The safety of dabrafenib monotherapy is based on the integrated safety population from five clinical trials, BRF113683 (BREAK-3), BRF113929 (BREAK-MB), BRF113710 (BREAK-2), BRF113220, and BRF112680, which included 578 patients with BRAF V600 mutant unresectable or metastatic melanoma 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 safety population of 1076 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 III clinical trials, MEK115306 (COMBI-d) and MEK116513 (COMBI-v), 435 were treated with the combination in the adjuvant treatment of Stage III BRAF V600 mutant melanoma after complete resection in a randomised Phase III study BRF115532 (COMBI-AD) and 82 were treated with the combination 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 trametinib were: pyrexia, fatigue, nausea, chills, headache, diarrhoea, vomiting, arthralgia and rash.

Tabulated list of adverse reactions

Adverse drug reactions are listed below by MedDRA system organ class ranked 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 not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 3 Adverse reactions reported in the integrated safety population of dabrafenib monotherapy in the studies BRF113683 (BREAK-3), BRF113929 (BREAK-MB), BRF113710 (BREAK-2), BRF113220, and BRF112680 (n=578)

Table 4 Adverse reactions reported in the integrated safety population of dabrafenib in combination with trametinib in the studies MEK115306, MEK116513a, BRF113928, and BRF115532 (n=1076)

a 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 following adverse 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) b Cutaneous squamous cell carcinoma (cu SCC): SCC, SCC of the skin, SCC in situ (Bowen’s disease) and keratoacanthoma

c Papilloma, skin papilloma

d Malignant melanoma, metastatic malignant melanoma, and superficial spreading melanoma stage III

e Includes drug hypersensitivity

f Bleeding from various sites, including intracranial bleeding and fatal bleeding

g Abdominal pain upper and abdominal pain lower h Erythema, generalised erythema

i Muscle spasms, musculoskeletal stiffness

Description of selected adverse reactions

Cutaneous squamous cell carcinoma

For dabrafenib monotherapy in study MEK115306, cutaneous squamous cell carcinomas (including those classified as keratoacanthoma or mixed keratoacanthoma subtype) occurred in 10% of patients and approximately 70% of the events occurred within the first 12 weeks of treatment with a median time to onset of 8 weeks. In the integrated safety population for dabrafenib in combination with trametinib, 2% of patients developed cuSCC and the events occurred later than with dabrafenib monotherapy with a median time to onset of 18–31 weeks. All patients receiving dabrafenib as monotherapy or in combination with trametinib who developed cuSCC continued on treatment without dose modification.

New primary melanoma

New primary melanomas have been reported in clinical trials with dabrafenib as monotherapy and in combination with trametinib in melanoma studies. Cases were managed with excision and did not require 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 inhibitors may lead to increased risk of non-cutaneous malignancies, including those with RAS mutations (see section 4.4). Non-cutaneous malignancies were reported in 1% (6/586) of patients in the integrated safety population of dabrafenib monotherapy, and <1% (8/1076) of patients in the integrated safety population of dabrafenib in combination with trametinib. Cases of RAS-driven malignancies have been seen with dabrafenib as monotherapy and in combination with trametinib. Patients should be monitored as clinically appropriate.

Haemorrhage

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

LVEF reduction/Left ventricular dysfunction

Decreased LVEF has been reported in 6% (65/1076) of patients in the integrated safety population of dabrafenib in combination with trametinib. Most cases were asymptomatic and reversible. Patients with LVEF lower than the institutional lower limit of normal were not included in clinical trials with dabrafenib. Dabrafenib in combination with trametinib should be used with caution in patients with conditions that could impair left ventricular function. Please refer to the trametinib SmPC.

Pyrexia

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

Hepatic events

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

Hypertension

Elevations in blood pressure have been reported in association with dabrafenib in combination with trametinib, in patients with or without pre-existing

hypertension. Blood pressure should be measured at baseline and monitored during treatment, with control of hypertension by standard therapy as appropriate.

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 and 2 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 dabrafenib monotherapy (7%) and of dabrafenib in combination with trametinib (4%). It should be noted that approximately half of these occurrences with dabrafenib monotherapy (4%) and 1% with dabrafenib in combination with trametinib were Grade 3 in severity.

Pancreatitis

Pancreatitis has been reported in dabrafenib monotherapy and in combination with trametinib. Unexplained abdominal pain should be promptly investigated to include measurement of serum amylase and lipase. Patients should be closely monitored when re-starting dabrafenib after an episode of pancreatitis (see section 4.4).

Renal  failure

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

Special populations

Elderly

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 younger subjects (<65), more subjects >65 years old had adverse reactions that led to study drug dose reductions (22% versus 12%) or interruptions (39% versus 27%). In addition, older patients experienced more serious adverse reactions compared to younger patients (41% versus 22%). No overall differences in efficacy were observed between these subjects and younger subjects.

In the integrated safety population of dabrafenib in combination with trametinib (n=1076), 265 patients (25%) were >65 years of age, 62 patients (6%) were >75 years of age. The proportion of patients experiencing AEs was similar in those aged <65 years and those aged >65 years in all clinical trials. Patients >65 years were more likely to experience SAEs and AEs leading to permanent discontinuation 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 a multi-cohort, open-label, Phase II study in patients with BRAF V600 mutant melanoma with brain metastases. The safety profile observed in these patients appears to be consistent with the integrated safety profile of the combination.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

There is no specific treatment for an overdose of dabrafenib. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

Mechanism of action

Dabrafenib is an inhibitor of RAF kinases. Oncogenic mutations in BRAF lead to constitutive activation of the RAS/RAF/MEK/ERK pathway. BRAF mutations have been identified at a high frequency in specific cancers, including approximately 50% of melanoma. The most commonly observed BRAF mutation is V600E which accounts for approximately 90% of the BRAF mutations that are seen in melanoma.

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

Table 5 Kinase inhibitory activity of dabrafenib against RAF kinases

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 animal models.

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

Combination with trametinib

Trametinib is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and kinase activity. MEK proteins are components of the extracellular signal-related kinase (ERK) pathway. Thus, trametinib and dabrafenib inhibit two kinases in this pathway, MEK and RAF, and therefore the combination provides concomitant inhibition of the pathway. The combination of dabrafenib with trametinib has shown anti-tumour activity in BRAF V600 mutation positive melanoma cell lines in vitro and delays the emergence of resistance in vivo in BRAF V600 mutation positive melanoma xenografts.

Determination of BRAF mutation status

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 for eligibility required central testing for BRAF V600 mutation using a BRAF mutation assay conducted on the most recent tumour sample available. Primary tumour or tumour from a metastatic site was tested with an investigational use only assay (IUO). The IUO is an allele-specific polymerase chain reaction (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 V600K mutations. Only subjects with BRAF V600E or V600K mutation positive tumours were eligible for study participation.

Subsequently, all patient samples were re-tested using the bioMerieux (bMx) THxID BRAF validated assay, 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 of wild-type sequence using DNA extracted from FFPE tissue). Non-clinical and clinical trials with retrospective bi-directional Sanger sequencing analyses have shown that the test also detects the less common BRAF V600D mutation and V600E/K601E mutation with lower sensitivity. Of the specimens 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 assay was 94%.

Clinical efficacy and safety

Unresectable or metastatic melanoma

Dabrafenib in combination with trametinib Treatment-naive patients

The efficacy and safety of the recommended dose of trametinib (2 mg once daily) in combination with dabrafenib (150 mg twice daily) for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation was studied in two Phase III trials and one supportive Phase I/II study.

MEK115306 (COMBI-d):

MEK115306 was a Phase III, randomised, double-blinded study comparing the combination of dabrafenib 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. The primary endpoint of the study was progression-free survival (PFS), with a key secondary endpoint of overall survival (OS). Subjects were stratified by lactate dehydrogenase (LDH) level (> the upper limit of 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 visceral disease (73%) at baseline. The majority of subjects had a BRAF V600E mutation (85%). 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 6. From an OS analysis at 5 years, the median OS for the combination arm was approximately 7 months longer than for dabrafenib monotherapy (25.8 months versus 18.7 months) with 5-year survival 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 overall survival 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 at baseline, and 16% (95% CI: 8.4, 26.0) in the combination arm versus 14% (95% CI: 6.8, 23.1) in the dabrafenib monotherapy arm for patients with an elevated lactate dehydrogenase level at baseline.

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

NR = Not reached, NA = Not applicable

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

Dabrafenib + Placebo

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

a – Progression-free survival (investigator assessed)

b – Overall Response Rate = Complete Response + Partial Response

c – Duration of response

d – At the time of the reporting the majority (>59%) of investigator-assessed responses were still ongoing

e – ORR difference calculated based on the ORR result not rounded

f – Updated analysis was not pre-planned and the p-value was not adjusted for multiple testing NR = Not reached

NA = Not applicable

MEK116513 (COMBI-v):

Study MEK116513 was a 2-arm, randomised, open-label, Phase III study comparing dabrafenib and trametinib combination therapy with vemurafenib monotherapy in BRAF V600 mutation-positive unresectable or metastatic melanoma. The primary endpoint of the study was OS with a key secondary endpoint of PFS. Subjects were stratified by lactate dehydrogenase (LDH) level (> the upper limit of normal (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). The majority 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% of subjects had <3 disease sites at baseline. The majority of subjects had BRAF V600E mutation-positive melanoma (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 approximately 8 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 lactate dehydrogenase 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 lactate dehydrogenase level at baseline.

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

NR = Not reached, NA = Not applicable

Figure 2 Kaplan-Meier overall survival curves for Study MEK116513

Time since Randomisation (Months)

Subjects at Risk:

Improvements for the secondary endpoint of PFS were sustained over a 5 year timeframe in the combination arm compared to vemurafenib monotherapy.

Improvements were also observed for ORR and a longer DoR was observed in the combination arm compared to vemurafenib monotherapy (Table 9).

a – Progression-free survival (investigator assessed)

b – Overall Response Rate = Complete Response + Partial Response c – Duration of response

d – At the time of the reporting the majority (59% of dabrafenib+tra­metinib and 42% of vemurafenib) of investigator-assessed responses were still ongoing

NR = Not reached

NA = Not applicable

Prior BRAF inhibitor therapy

There are limited data in patients taking the combination of dabrafenib with trametinib who have progressed 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 limited clinical activity in patients who had progressed on a BRAF inhibitor. The investigator-assessed confirmed response rate was 15% (95% CI: 4.4, 34.9) and the median PFS was 3.6 months (95% CI: 1.9, 5.2). Similar results were seen in the 45 patients who crossed over from dabrafenib monotherapy to the trametinib 2 mg once daily and dabrafenib 150 mg twice daily combination in Part C of this study. 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).

Patients with brain metastases

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

Cohort A: patients with BRAFV600E mutant melanoma with asymptomatic brain metastases without prior local brain-directed therapy and ECOG performance status of 0 or 1.

Cohort B: patients with BRAFV600E mutant melanoma with asymptomatic brain metastases with prior local brain-directed therapy and ECOG performance status of 0 or1.

Cohort C: patients with BRAFV600D/K/R mutant melanoma with asymptomatic brain

metastases, with or without prior local brain-directed therapy and ECOG performance status of 0 or 1.

Cohort D: patients with BRAFV600D/E/K/R mutant melanoma with symptomatic brain metastases, with or without prior local brain-directed therapy and ECOG performance status of 0 or 1 or 2.

The primary endpoint of the study was intracranial response in Cohort A, defined as the percentage of patients 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 the investigator in Cohorts B, C and D were secondary endpoints of the study. Due to small sample size reflected 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

CI = Confidence Interval NR = Not reached

Dabrafenib monotherapy

The efficacy of dabrafenib in the treatment of adult patients with BRAF V600 mutation positive unresectable or metastatic melanoma has been evaluated in 3 clinical trials (BRF113683 [BREAK-3], BRF113929 [BREAK-MB], and BRF113710 [BREAK-2]) including patients with BRAF V600E and/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 were excluded from the confirmatory trial and with respect to patients with the V600K mutation in single arm clinical trials the activity appears lower than in V600E tumours.

No data is available in patients with melanoma harbouring BRAF V600 mutations others than V600E and V600K. Efficacy of dabrafenib in subjects previously treated with a protein kinase inhibitor has not 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 with respect to PFS per investigator assessment. Patients on the DTIC arm were allowed to cross over to dabrafenib after independent radiographic confirmation of initial progression. Baseline characteristics were 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 ECOG status 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 the primary endpoint of PFS (HR=0.30; 95% Cl 0.18, 0.51;

p < 0.0001) was achieved. Efficacy results from the primary analysis and a post-hoc analysis with 6-months additional follow up are summarised in Table 11. OS data from a further post-hoc analysis based on a 18 December 2012 data cut are shown in Figure 3.

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

Abbreviations: CI: confidence interval; DTIC: dacarbazine; HR: hazard ratio; NR: not reached

a Defined as confirmed complete + partial response.

As of 25June 2012 cut-off, thirty five subjects (55.6%) of the 63 randomised to DTIC had crossed over 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

(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 the intracranial response of dabrafenib in subjects with histologically confirmed (Stage IV) BRAF-mutation 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 who received prior local therapy for brain metastasis).

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

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

Abbreviations: CI: confidence interval; NR: not reached; NA: not applicable

a 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 metastatic melanoma (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, not calculable) 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 OS appeared consistent with data in patients with BRAF V600E positive tumours.

Adjuvant treatment of Stage III melanoma

BRF115532 (COMBI-AD)

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/K mutation, following complete resection.

Patients were randomised 1:1 to receive either combination therapy (dabrafenib 150 mg twice daily and trametinib 2 mg once daily) or two placebos for a period of 12 months. Enrollment required complete resection of melanoma with complete lymphadenectomy within 12 weeks prior to randomisation. 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. Patients presenting with malignancies with confirmed activating RAS mutations were not eligible. Patients were stratified by BRAF mutation status (V600E versus V600K) and stage of disease prior to surgery using 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 size and ulceration). The primary endpoint was investigator-assessed relapse-free survival (RFS), defined as the time from randomisation to disease recurrence or death from any cause. Radiological tumour assessment was conducted every 3 months for the first two years and every 6 months thereafter, until first relapse was observed. Secondary endpoints include overall survival (OS; key secondary endpoint), 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 tumour ulceration. The majority of patients had a BRAF V600E mutation (91%). At the time of the primary analysis, the median duration of follow-up (time from randomisation to last contact or death) was 2.83 years in the dabrafenib and 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 statistically significant difference for the primary outcome of 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 was consistently demonstrated across subgroups of patients including age, sex and race. Results were also consistent across stratification factors for disease stage and BRAF V600 mutation type.

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

[1] Hazard ratio is obtained from the stratified Pike model.

[2] P-value is obtained from the two-sided stratified logrank test (stratification factors were disease stage – IIIA vs. 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 combination arm compared to 36% (95% CI: 32, 41) in the placebo arm.

Figure 4 Kaplan-Meier RFS curves for Study BRF115532 (ITT population, updated results)

Time from randomisation (months)

Subjects at risk

Dabrafenib+ Trametinib 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

Based on 153 events (60 [14%] in the combination arm and 93 [22%] in the placebo arm) corresponding to a 26% information fraction of the total target of 597 OS events, the estimated hazard ratio for OS was 0.57 (95% CI: 0.42, 0.79; p=0.0006). These results did not meet the pre-specified boundary to claim statistical significance at this first OS interim analysis (HR=0.50; p=0.000019). Survival estimates at 1 and 2 years from randomisation were 97% and 91% in the combination arm and 94% and 83% in the placebo arm, respectively).

Non-small cell lung cancer

Study BRF113928

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 assessed by the investigator. Secondary endpoints included DoR, PFS, OS, safety and population pharmacokinetics. 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 had previous systemic treatment for their metastatic disease.

Cohort B: Combination therapy (dabrafenib 150 mg twice daily and trametinib 2 mg once daily), 59 patients enrolled. 57 patients had 1–3 lines of previous systemic treatment for their metastatic disease. 2 patients had no previous systemic treatment and were included in the analysis for patients enrolled in Cohort C.

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

Among the total of 93 patients who were enrolled in the combination therapy cohorts B and C, most patients were Caucasian (>90%), and similar female versus male (54% versus 46%), with a median age 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 previously treated population, 38 patients (67%) had one line of systemic anti-cancer therapy for metastatic disease.

For the primary endpoint of investigator-assessed ORR, the ORR in the first line population 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 equal to 30%. The ORR results assessed by IRC were consistent with the investigator assessment. The response was durable with median DoR in the previously treated population reaching 9.8 months (95% CI, 6.9, 16.0) by investigator assessment. In the first line population, 68% of patients had not progressed after 9 months. The median DoR and PFS were not yet estimable (Table 15). The efficacy of the combination with trametinib was superior when indirectly compared to dabrafenib monotherapy in Cohort A.

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

1 Data cut-off: 8t August 2016

2 NE: Not Evaluable

3 Median PFS currently not estimable

4 Event rate for OS calculation was 28% and hence the defined median value still needs to mature

QT prolongation

Worst-case QTc prolongation of >60 millisecond (msec) was observed in 3% of dabrafenib-treated subjects (one >500 msec in the integrated safety population). In the Phase III study MEK115306 no patients 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 dabrafenib had 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 QT study. 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 metabolites on the QTc interval was observed.

Other studies – pyrexia management analysis

Study CPDR001F2301 (COMBI-i) and Study CDRB436F2410 (COMBI-Aplus) Pyrexia is observed in patients treated with dabrafenib and trametinib combination therapy. The initial registration 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 subsequent studies in unresectable or metastatic melanoma (COMBI-i control arm, N=264) and in the adjuvant melanoma setting (COMBI-Aplus, N=552), interruption of both medicinal products when patient’s tem­perature is >38oC (COMBI-Aplus), or at the first symptom of pyrexia (COMBI-i; COMBI-Aplus for recurrent pyrexia) was advised. In COMBI-i and COMBI-Aplus there was a lower incidence of grade 3/4 pyrexia, complicated pyrexia, hospitalisation due to serious pyrexia adverse events of special interest (AESIs), the time spent in pyrexia AESIs, and permanent discontinuations from both medicinal 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 composite rate of 8.0% (95% CI: 5.9, 10.6) for grade 3/4 pyrexia, hospitalisation due to pyrexia, or permanent treatment discontinuation due to pyrexia compared to 20.0% (95% CI: 16.3, 24.1) for the historical control (COMBI-AD).

Paediatric population

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

5.2 Pharmacokinetic properties

Absorption

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%). Dabrafenib exposure (Cmax and AUC) increased in a dose proportional manner between 12 and 300 mg following single-dose administration, but the increase was less than dose-proportional after repeat twice daily dosing. A decrease in exposure was observed with repeat dosing, likely due to induction of its own metabolism. Mean accumulation AUC Day 18/Day 1 ratios was 0.73. Following administration of 150 mg twice daily, geometric mean Cmax, AUC(0-t) and predose concentration (Ct) were 1478 ng/ml, 4341 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 fasted state.

Distribution

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

Biotransformation

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-dabrafenib can 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 and reabsorbed. 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- and desmethyl-metabolites exhibited longer half-lives (21–22 hours). Mean metabolite to parent AUC ratios following repeat-dose administration were 0.9, 11 and 0.7 for hydroxy-, carboxy-, and desmethyl-dabrafenib, respectively. Based on exposure, relative potency, and pharmacokinetic properties, both hydroxy- and desmethyl-dabrafenib are likely to contribute to the clinical activity of dabrafenib while the activity of carboxy-dabrafenib is not likely to be significant.

In vitro evaluation of drug-drug interaction potential

Dabrafenib is a substrate of human P-glycoprotein (Pgp) and human BCRP in vitro. However, these transporters have minimal impact on dabrafenib oral bioavailability and elimination and the risk for clinically relevant drug-drug interactions with inhibitors of Pgp or BCRP is low. Neither dabrafenib nor its 3 main metabolites were demonstrated to be inhibitors of Pgp in vitro.

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, and dabrafenib 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 clinical exposure of dabrafenib and its metabolites.

Elimination

Terminal half-life of dabrafenib following an intravenous single microdose is 2.6 hours. Dabrafenib terminal half-life after a single oral dose is 8 hours due to absorption-limited elimination after oral administration (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 CYP3A4 and CYP2C8. Dabrafenib related material is excreted primarily in faeces, with 71% of an oral dose recovered in faeces; 23% of the dose was recovered in urine in the form of metabolites only.

Special patient populations

Hepatic impairment

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 oral clearance. In addition, mild hepatic impairment as defined by bilirubin and AST did not have a significant effect on dabrafenib metabolite plasma concentrations. No data are available in patients with moderate to severe hepatic impairment. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, administration of dabrafenib should be undertaken with caution in patients with moderate to severe hepatic impairment (see section 4.2).

Renal impairment

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

Elderly

Based on the population pharmacokinetic analysis, age had no significant effect on dabrafenib pharmacokinetics. 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 to subjects <75 years old.

Body weight and gender

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

Race

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

Paediatric , population

No studies have been conducted to investigate the pharmacokinetics of dabrafenib in paediatric patients.

5.3 Preclinical safety data

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

In combined female fertility, early embryonic and embryo-foetal development studies in rats numbers of ovarian corpora lutea were reduced in pregnant females at 300 mg/kg/day (approximately 3 times human clinical exposure based on AUC), but there were no effects on oestrous cycle, mating or fertility indices. Developmental toxicity including embryo-lethality and ventricular septal defects and variation in thymic shape were seen at 300 mg/kg/day, and delayed skeletal development and reduced foetal 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 exposure based on AUC). Testicular changes in rat and dog were still present following a 4-week recovery period (see section 4.6).

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

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

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

Dabrafenib was phototoxic in an in vitro mouse fibroblast 3T3 Neutral Red Uptake (NRU) assay and in vivo at doses >100 mg/kg (>44 times clinical exposure based on Cmax) in an oral phototoxicity 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 of gastrointestinal toxicity and decreased lymphoid cellularity of the thymus were observed at lower exposures than in dogs given trametinib alone. Otherwise, similar toxicities were observed as in comparable monotherapy studies.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content

Microcrystalline cellulose

Magnesium stearate Colloidal silicone dioxide

Capsule shell

Red iron oxide (E172)

Titanium dioxide (E171)

Hypromellose (E464)

Printing ink

Black iron oxide (E172)

Shellac

Propylene glycol

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

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

Each bottle contains either 28 or 120 hard capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7 MARKETING AUTHORISATION HOLDER

Novartis Pharmaceuticals UK Limited, 2nd Floor, The WestWorks Building, White City Place, 195 Wood Lane,

London, W12 7FQ

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

Tafinlar 50 mg hard capsules

PLGB 00101/1148

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

01/01/2021