TAFINLAR Hard capsule Ref.[8932] Active ingredients: Dabrafenib

Source: European Medicines Agency (EU)  Revision Year: 2024  Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland

Contraindications

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

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% (19/1 076) 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 had developed cuSCC at the time of the primary analysis. During the long-term (up to 10 years) off-treatment follow-up, 2 additional patients reported cuSCC in each treatment arm. Overall, the median time to onset of the first occurrence of cuSCC in the combination arm of the adjuvant treatment study was approximately 21 weeks and was 34 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 patients 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 ¾) 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 ≥38ºC (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 restarting 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.

Haemophagocytic lymphohistiocytosis

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

Tumour lysis syndrome (TLS)

The occurrence of TLS, which may be fatal, has been associated with the use of dabrafenib in combination 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. Patients with risk factors for TLS should be closely monitored and prophylactic hydration should be considered. 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 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).

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. Dabrafenib should be used with caution if strong inhibitors (e.g. ketoconazole, gemfibrozil, nefazodone, clarithromycin, ritonavir, saquinavir, telithromycin, itraconazole, voriconazole, posaconazole, atazanavir) are co-administered with dabrafenib. Co-administration of dabrafenib with potent inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, or St John’s wort (Hypericum perforatum)) of CYP2C8 or CYP3A4 should be avoided.

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 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 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)
  • 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. 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. P-gp 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.

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.

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.

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 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 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 reactions associated with dabrafenib obtained from clinical studies and post-marketing surveillance are tabulated below for dabrafenib monotherapy (Table 3) and dabrafenib in combination with trametinib (Table 4). Adverse reactions are listed below by MedDRA system organ class and 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 with dabrafenib monotherapy:

System organ class Frequency (all grades) Adverse reactions
Neoplasms benign, malignant
and unspecified (incl cysts and
polyps)
Very common Papilloma
CommonCutaneous squamous cell carcinoma
Seborrhoeic keratosis
Acrochordon (skin tags)
Basal cell carcinoma
Uncommon New primary melanoma
Immune system disorders Uncommon Hypersensitivity
Metabolism and nutrition
disorders
Very common Decreased appetite
Common Hypophosphataemia
Hyperglycaemia
Nervous system disorders Very common Headache
Common Peripheral neuropathy (including
sensory and motor neuropathy)
Eye disorders Uncommon Uveitis
Respiratory, thoracic and
mediastinal disorders
Very common Cough
Gastrointestinal disorders Very commonNausea
Vomiting
Diarrhoea
Common Constipation
Uncommon Pancreatitis
Skin and subcutaneous tissue
disorders
Very commonHyperkeratosis
Alopecia
Rash
Palmar-plantar erythrodysaesthesia
syndrome
CommonDry skin
Pruritus
Actinic keratosis
Skin lesion
Erythema
Photosensitivity
Uncommon Acute febrile neutrophilic dermatosis
Panniculitis
Musculoskeletal and
connective tissue disorders
Very commonArthralgia
Myalgia
Pain in extremity
Renal and urinary disorders Uncommon Renal failure, acute renal failure
Nephritis
General disorders and
administration site conditions
Very commonPyrexia
Fatigue
Chills
Asthenia
Common Influenza-like illness

Table 4. Adverse reactions with dabrafenib in combination with trametinib:

System organ class Frequency (all grades) Adverse reactions
Infections and infestations Very common Nasopharyngitis
CommonUrinary tract infection
Cellulitis
Folliculitis
Paronychia
Rash pustular
Neoplasms benign,
malignant and unspecified
(incl cysts and polyps)
CommonCutaneous squamous cell carcinomaa
Papillomab
Seborrhoeic keratosis
Uncommon New primary melanomac
Acrochordon (skin tags)
Blood and lymphatic system
disorders
CommonNeutropenia
Anaemia
Thrombocytopenia
Leukopenia
Immune system disorders Uncommon Hypersensitivityd
Sarcoidosis
Rare Haemophagocytic lymphohistiocytosis
Metabolism and nutrition
disorders
Very common Decreased appetite
CommonDehydration
Hyponatraemia
Hypophosphataemia
Hyperglycaemia
Not known Tumour lysis syndrome
Nervous system disorders Very common Headache
Dizziness
Common Peripheral neuropathy (including
sensory and motor neuropathy)
Eye disorders CommonVision blurred
Visual impairment
Uveitis
UncommonChorioretinopathy
Retinal detachment
Periorbital oedema
Cardiac disorders Common Ejection fraction decreased
Atrioventricular blocke
Uncommon Bradycardia
Not known Myocarditis
Vascular disorders Very common Hypertension
Haemorrhagef
Common Hypotension
Lymphoedema
Respiratory, thoracic and
mediastinal disorders
Very commonCough
Common Dyspnoea
Uncommon Pneumonitis
Gastrointestinal disorders Very commonAbdominal paing
Constipation
Diarrhoea
Nausea
Vomiting
Common Dry mouth
Stomatitis
Uncommon Pancreatitis
Colitis
Rare Gastrointestinal perforation
Skin and subcutaneous tissue
disorders
Very commonDry skin
Pruritus
Rash
Erythemah
CommonDermatitis acneiform
Actinic keratosis
Night sweats
Hyperkeratosis
Alopecia
Palmar-plantar erythrodysaesthesia
syndrome
Skin lesion
Hyperhidrosis
Panniculitis
Skin fissures
Photosensitivity
Uncommon Acute febrile neutrophilic dermatosis
Not knownStevens-Johnson syndrome
Drug reaction with eosinophilia and
systemic symptoms
Dermatitis exfoliative generalised
Musculoskeletal and
connective tissue disorders
Very commonArthralgia
Myalgia
Pain in extremity
Muscle spasmsi
Renal and urinary disorders Uncommon Renal failure
Nephritis
General disorders and
administration site
conditions
Very commonFatigue
Chills
Asthenia
Oedema peripheral
Pyrexia
Influenza-like illness
Common Mucosal inflammation
Face oedema
Investigations Very common Alanine aminotransferase increased
Aspartate aminotransferase increased
CommonBlood alkaline phosphatase increased
Gamma-glutamyltransferase increased
Blood creatine phosphokinase
increased

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).
a Cutaneous squamous cell carcinoma (cu SCC): SCC, SCC of the skin, SCC in situ (Bowen’s disease) and keratoacanthoma
b Papilloma, skin papilloma
c Malignant melanoma, metastatic malignant melanoma, and superficial spreading melanoma stage III
d Includes drug hypersensitivity
e Atrioventricular block, atrioventricular block first degree, atrioventricular block second degree, atrioventricular block complete
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% (8/1 076) of patients in the integrated safety population 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 in combination with trametinib as compared to <1% (3/432) of patients receiving placebo developed non-cutaneous malignancies. During the long-term (up to 10 years) off-treatment follow-up, 9 additional patients reported non-cutaneous malignancies in the combination arm and 4 in in the placebo arm. 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% (65/1 076) 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=1 076), 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 national reporting system listed in Appendix V.

Incompatibilities

Not applicable.

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