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 C_max 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 C_max 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 C_max (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.

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, C_max of rosuvastatin increased 2.6-fold whereas the AUC was only minimally changed (7% increase). The increased C_max of rosuvastatin is unlikely to have clinical relevance.

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.

In vitro, dabrafenib produced dose-dependent increases in CYP2B6 and CYP3A4. In a clinical drug interaction study, C_max 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. C_max 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)
• 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)
• Corticosteroids (e.g. dexamethasone, methylprednisolone)
• HIV antivirals (e.g. amprenavir, atazanavir, darunavir, delavirdine, efavirenz, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir)
• Hormonal contraceptives
• 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.

There are no clinical data in subjects with severe renal impairment and the potential need for dose adjustment cannot be determined. Dabrafenib should be used with caution in patients with severe renal impairment when administered as monotherapy or in combination with trametinib.

There are no clinical data in subjects with moderate to severe hepatic impairment and the potential need for dose adjustment cannot be determined. 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.

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. 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 when used in combination with trametinib.

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 C_max. These changes in dabrafenib AUC and C_max 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.

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 C_max and AUC with increases of 16 and 23%, respectively, in dabrafenib C_max 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.

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 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.

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. 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 also the trametinib powder for oral solution SmPC for additional information on trametinib.

It is not known whether dabrafenib is 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.

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 for 16 weeks following discontinuation of trametinib. Dabrafenib may decrease the efficacy of oral or any systemic hormonal contraceptives and an effective alternative method of contraception, such as a barrier method, should be used.

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. 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 when used in combination with trametinib.

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, dizziness or eye problems to affect these activities.

Clinical studies of adult patients

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.

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 1) and dabrafenib in combination with trametinib (Table 2). 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 1. Adverse reactions with dabrafenib monotherapy:

Table 2. Adverse reactions with dabrafenib in combination with trametinib:

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. 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. 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. 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.

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.

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.

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.

Clinical studies of paediatric patients

Summary of the safety profile

In clinical studies of paediatric patients treated with dabrafenib in combination with trametinib, the most common adverse reactions (reported at a frequency ≥20%) were: pyrexia (65%), rash (47%), headache (40%), vomiting (38%), fatigue (35%), dry skin (34%), diarrhoea (31%), haemorrhage (30%), nausea (26%), dermatitis acneiform (26%), neutropenia (25%), abdominal pain (23%) and cough (22%). The most frequently reported severe (Grade ¾) adverse reactions were: neutropenia (15%), pyrexia (9%), transaminases increased (6%) and weight increased (5%). Long-term data on growth and skeletal maturation in paediatric patients are currently limited.

The safety profile in paediatric patients was largely consistent with the safety profile previously established in adult patients. The following additional adverse reactions have so far only been reported in adult patients treated with dabrafenib capsules and trametinib tablets: cutaneous squamous cell carcinoma, seborrhoeic keratosis, lymphoedema, dry mouth, actinic keratosis, photosensitivity, renal failure (common), melanoma, acrochordon, sarcoidosis, chorioretinopathy, pneumonitis, acute renal failure, nephritis, cardiac failure, left ventricular dysfunction, interstitial lung disease, rhabdomyolysis (uncommon), gastrointestinal perforation, haemophagocytic lymphohistiocytosis (rare), myocarditis, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (frequency not known).

Tabulated list of adverse reactions

The safety of dabrafenib in combination with trametinib has been evaluated in a pooled safety set of 171 paediatric patients across two studies in patients with BRAF V600 mutation-positive advanced solid tumours. Four (2.3%) patients were 1 to <2 years of age, 39 (22.8%) patients were 2 to <6 years of age, 54 (31.6%) patients were 6 to <12 years of age and 74 (43.3%) patients were 12 to <18 years of age at enrolment. The mean treatment duration was 80 weeks.

Adverse reactions in the integrated paediatric safety population (Table 3) 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 paediatric safety population of dabrafenib in combination with trametinib (n=171):

^* Denotes grouped term of two or more MedDRA preferred terms that were considered clinically similar.
¹ nasopharyngitis includes pharyngitis
² neutropenia includes neutrophil count decreased and febrile neutropenia
³ dizziness includes vertigo
⁴ uveitis includes iridocyclitis
⁵ haemorrhage includes epistaxis, haematuria, contusion, haematoma, international normalised ratio increased, anal haemorrhage, catheter site haemorrhage, cerebral haemorrhage, ecchymosis, extradural haematoma, gastrointestinal haemorrhage, haematochezia, petechiae, post-procedural haemorrhage, rectal haemorrhage, red blood cell count decreased, upper gastrointestinal haemorrhage and uterine haemorrhage
⁶ dermatitis acneiform includes acne and acne pustular
⁷ dry skin includes xerosis and xeroderma
⁸ rash includes rash maculo-papular, rash pustular, rash erythematous, rash papular, rash macular
⁹ dermatitis exfoliative generalised includes skin exfoliation and dermatitis exfoliative
¹⁰ muscle spasms include musculoskeletal stiffness
¹¹ fatigue includes malaise and asthenia
¹² transaminases increased includes aspartate aminotransferase (AST) increased and alanine aminotransferase (ALT) increased

Description of selected adverse reactions

Weight increased

Weight increase has only been reported in the paediatric population. It was reported as an adverse reaction in 16% of paediatric patients including Grade 3 cases in 4.7% of patients, with a discontinuation rate of 0.6% of patients. The median time to onset of the first occurrence of the reported weight increase in paediatric patients receiving dabrafenib in combination with trametinib was 3.1 months. Weight increase from baseline of ≥2 BMI (body mass index)-for-age percentile categories was observed in 29.8% of patients.

Haemorrhage

Haemorrhagic events were observed in 30% of paediatric patients, with Grade 3 events occurring in 1.2% of patients. The most frequent haemorrhagic event (epistaxis) was reported in 18% of paediatric patients. The median time to onset of the first occurrence of haemorrhagic events in paediatric patients was 2.4 months. Haemorrhagic events, including major haemorrhagic events and fatal haemorrhages, have occurred in adult patients taking dabrafenib in combination with trametinib.

The risk of haemorrhage may be increased with concomitant use of antiplatelet or anticoagulant therapy. If haemorrhage occurs, patients should be treated as clinically indicated.

Left ventricular ejection fraction (LVEF) reduction/Left ventricular dysfunction

Decreased LVEF has been reported in 5.3% of paediatric patients, with Grade 3 events occurring in <1% of patients. The median time to onset for the first occurrence of LVEF decrease was around one month.

Patients with LVEF lower than the institutional lower limit of normal were not included in clinical studies 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 powder for oral solution SmPC.

Pyrexia

Fever has been reported in clinical studies with dabrafenib in combination with trametinib. Pyrexia was reported in 65% of paediatric patients, with Grade 3 events occurring in 8.8% of patients. Approximately half of the first occurrences of pyrexia in adult patients 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 adult safety population, 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). 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.

Hepatic events

Hepatic adverse reactions have been reported in adult and paediatric clinical studies with dabrafenib in combination with trametinib. In the paediatric safety population, increased ALT and AST were very common, reported in 12.3% and 15.2% of patients, respectively. Please refer to the trametinib powder for oral solution SmPC for additional information.

Blood pressure changes

Hypertension was reported in 2.3% of paediatric patients, with Grade 3 events occurring in 1.2% of patients. The median time to onset of the first occurrence of hypertension in paediatric patients was 5.4 months.

Hypotension was reported in 3.5% of paediatric patients, with Grade ≥3 events occurring in 2.3% of patients. The median time to onset of the first occurrence of hypotension in paediatric patients was 1.5 months.

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 adult and paediatric safety populations of dabrafenib in combination with trametinib. In the paediatric safety population, arthralgia was reported in 12.3% of patients, with <1% of patients with Grade 3 severity. Arthralgia was reported in 25% of adult patients, although these were mainly Grade 1 and 2 in severity with Grade 3 occurring uncommonly (<1%).

Hypophosphataemia

Hypophosphataemia has been reported commonly in the integrated adult and paediatric safety populations of dabrafenib in combination with trametinib in 4% and 5.8% of patients, respectively. It should be noted that Grade 3 events occurred in 1% of adult patients. In paediatric patients, hypophosphataemia occurred only with Grade 1 and 2 severity.

Pancreatitis

Pancreatitis was reported in 1.2% of paediatric patients, with <1% of patients with Grade 3 severity. In clinical studies in adult patients, one pancreatitis event occurred on the first day of dabrafenib dosing of a metastatic melanoma patient and recurred following rechallenge at a reduced dose. Unexplained abdominal pain should be promptly investigated to include measurement of serum amylase and lipase. Patients should be closely monitored when restarting treatment after an episode of pancreatitis.

Cutaneous malignancies

In the integrated adult safety population for dabrafenib in combination with trametinib, 2% of patients developed cuSCC with a median time to onset of 18 to 31 weeks. The median time to diagnosis of the first occurrence of cuSCC was 223 days (range 56 to 510 days). All adult patients who developed cuSCC or new primary melanoma continued on treatment without dose modification.

Non-cutaneous malignancies

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. Non-cutaneous malignancies were reported in <1% of patients in the integrated adult safety population of dabrafenib in combination with trametinib. Cases of RAS-driven malignancies have been seen with dabrafenib in combination with trametinib. Patients should be monitored as clinically appropriate.

Renal failure

Renal failure due to pyrexia-associated pre-renal azotaemia or granulomatous nephritis was uncommon in adult patients; 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.