4.1. Therapeutic indications

Low-grade glioma

Finlee in combination with trametinib is indicated for the treatment of paediatric patients aged 1 year and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy.

High-grade glioma

Finlee in combination with trametinib is indicated for the treatment of paediatric patients aged 1 year and older with high-grade glioma (HGG) with a BRAF V600E mutation who have received at least one prior radiation and/or chemotherapy treatment.

4.2. Posology and method of administration

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

Before taking Finlee, patients must have confirmation of BRAF V600E mutation assessed by a CE-marked in vitro diagnostic (IVD) medical device with the corresponding intended purpose. If the CE-marked IVD is not available, confirmation of BRAF V600E should be assessed by an alternative validated test.

Finlee is used in combination with trametinib powder for oral solution. See the summary of product characteristics (SmPC) for posology of trametinib powder for oral solution.

Finlee is not to be replaced with other dabrafenib formulations as bioequivalence was not shown (see section 5.2).

Posology

The recommended twice-daily dose of Finlee is determined by body weight (Table 1).

Table 1 Dosing regimen by body weight

Body weight*

Recommended dose

(mg dabrafenib)

twice daily

Recommended dose

(number of 10 mg tablets)

twice daily

8 to 9 kg

20 mg

2

10 to 13 kg

30 mg

3

14 to 17 kg

40 mg

4

18 to 21 kg

50 mg

5

22 to 25 kg

60 mg

6

26 to 29 kg

70 mg

7

30 to 33 kg

80 mg

8

34 to 37 kg

90 mg

9

38 to 41 kg

100 mg

10

42 to 45 kg

110 mg

11

46 to 50 kg

130 mg

13

≥51 kg

150 mg

15

*Round body weight to the nearest kg, if necessary.

The recommended dose for patients with a body weight less than 8 kg has not been established.

Please refer to the trametinib powder for oral solution SmPC, “Posology” and “Method of administration”, for dosing instructions for treatment with trametinib when used in combination with Finlee.

Duration of treatment

Treatment with Finlee should continue until disease progression or until the development of unacceptable toxicity. There are limited data in patients older than 18 years of age with glioma, therefore continued treatment into adulthood should be based on benefits and risks to the individual patient as assessed by the physician.

Missed or delayed doses

If a dose of Finlee is missed, it should only be taken if it is more than 6 hours until the next scheduled dose. If vomiting occurs after taking Finlee, an additional dose should not be administered and the next dose should be taken at the next scheduled time.

Dose modification

The management of adverse reactions may require dose reduction, treatment interruption or treatment discontinuation (see Tables 2 and 3).

If treatment-related toxicities occur, then both dabrafenib and trametinib 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 modifications or interruptions are not recommended for adverse reactions of cutaneous malignancies (see section 4.4).

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

Grade (CTCAE)*

Recommended dabrafenib dose modifications

Grade 1 or Grade 2 (Tolerable)

Continue treatment and monitor as clinically indicated.

Grade 2 (Intolerable) or Grade 3

Interrupt therapy until toxicity is Grade 0 to 1 and reduce by one dose level when resuming therapy.

Refer to Table 3 for dose level guidance.

Grade 4

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

Refer to Table 3 for dose level guidance.

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

Table 3 Recommended dose reduction levels for adverse reactions

Body weight

Recommended dose

(mg dabrafenib)

twice daily

Reduced dose

(number of 10 mg tablets)

twice daily

First reduction level

Second reduction level

Third reduction level

8 to 9 kg

20 mg

1

N/A

N/A

10 to 13 kg

30 mg

2

1

N/A

14 to 17 kg

40 mg

3

2

1

18 to 21 kg

50 mg

3

2

1

22 to 25 kg

60 mg

4

3

2

26 to 29 kg

70 mg

5

4

2

30 to 33 kg

80 mg

5

4

3

34 to 37 kg

90 mg

6

5

3

38 to 41 kg

100 mg

7

5

3

42 to 45 kg

110 mg

7

6

4

46 to 50 kg

130 mg

9

7

4

≥51 kg

150 mg

10

8

5

N/A=not applicable

Permanently discontinue Finlee if unable to tolerate 10 mg twice daily or a maximum of 3 dose reductions.

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 the recommended dose indicated in Table 1.

Dose modifications for selected adverse reactions

Pyrexia

If a patient's temperature is ≥38°C, therapy with dabrafenib and trametinib should be interrupted. 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). Therapy 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.

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 must 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 (see section 4.4).

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

If an absolute decrease of >10% in LVEF compared to baseline occurs, and the ejection fraction is below the institution's lower limit of normal (LLN), please refer to the trametinib powder for oral solution SmPC (section 4.2) for dose modification instructions for trametinib. No dose modification of dabrafenib is required when taken in combination with trametinib (see section 4.4).

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 powder for oral solution SmPC (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 powder for oral solution SmPC (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.

Special populations

Hepatic impairment

No dose adjustment is required in patients with mild hepatic impairment. There are no clinical data in patients 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.

Renal impairment

No dose adjustment is required in patients with mild or moderate renal impairment. There are no clinical data in patients 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.

Paediatric population

The safety and efficacy of combination therapy with dabrafenib and trametinib in children below 1 year of age have not been established. No data are available. Studies in juvenile animals have shown effects of dabrafenib which were not observed in adult animals (see section 5.3). Longer-term safety data in paediatric patients are currently limited.

Method of administration

Finlee is for oral use.

Finlee should be taken without food, at least one hour prior to or two hours after a meal (see section 5.2). Breast-feeding and/or baby formula may be given on demand if a patient is unable to tolerate the fasting conditions.

It is recommended that the doses of Finlee are taken at similar times every day, leaving an interval of approximately 12 hours between doses. 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 Finlee.

If the patient is unable to swallow and has a nasogastric tube in situ, the Finlee tablet suspension can be administered via the tube.

Instructions for preparation and administration are provided in section 6.6.

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

Finlee is intended for use in combination with trametinib powder for oral solution as there are limited efficacy data for dabrafenib monotherapy and for trametinib monotherapy in BRAF V600 mutation-positive glioma. The trametinib powder for oral solution SmPC must be consulted prior to intiation of treatment. For additional information on warnings and precautions associated with trametinib treatment, please refer to the trametinib powder for oral solution SmPC.

BRAF V600E testing

The efficacy and safety of dabrafenib have not been established in patients with wild-type BRAF glioma. Dabrafenib should not be used in patients with wild-type BRAF glioma (see section 5.1).

New malignancies

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

Cutaneous malignancies

Cutaneous malignancies such as cutaneous squamous cell carcinoma (cuSCC) including kerathoacanthoma and new primary melanoma have been observed in adult patients treated with dabrafenib in combination with trametinib (see section 4.8). 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. Monitoring should continue for 6 months following discontinuation of dabrafenib or until initiation of another anti-neoplastic therapy.

Suspicious skin lesions should be managed with dermatological excision and do not require treatment modifications. Patients should be instructed to inform their physicians immediately if new skin lesions develop.

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 adult clinical studies, 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 trametinib (colorectal cancer, pancreatic cancer).

The benefits and risks should be considered before administering dabrafenib in patients with a prior or concurrent cancer associated with RAS mutations. Patients should be screened for occult pre-existing malignancies.

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 have been reported in adult and paediatric patients taking dabrafenib in combination with trametinib (see section 4.8). Major haemorrhagic events and fatal haemorrhages have occurred in adult patients taking dabrafenib in combination with trametinib. The potential for these events in patients with low platelet counts (<75 000/mm3) has not been established as such patients were excluded from clinical studies. 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.

Visual impairment

Ophthalmological reactions, including uveitis and iridocyclitis, have been reported in paediatric patients taking dabrafenib in combination with trametinib (see section 4.8), in some cases with a time to onset of several months. In clinical studies in adult patients treated with dabrafenib, ophthalmological reactions, including uveitis, iridocyclitis and iritis, have been reported. 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.

Cases of biocular panuveitis or biocular iridocyclitis suggestive of Vogt-Koyanagi-Harada-like syndrome have been reported in patients treated with dabrafenib in combination with trametinib. Withhold dabrafenib until resolution of ocular inflammation and consider consulting an ophthalmologist. Systemic corticosteroid treatment may be necessary.

RPED and RVO may occur with dabrafenib in combination with trametinib. Please refer to the trametinib powder for oral solution SmPC (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 adult and paediatric clinical studies with dabrafenib (see section 4.8). 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). In paediatric patients who received dabrafenib in combination with trametinib, the median time to onset of the first occurrence of pyrexia was 1.5 months. In adult 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. Patients with serious non-infectious febrile events responded well to dose interruption and/or dose reduction and supportive care.

Therapy with dabrafenib and trametinib 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).

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

Dabrafenib in combination with trametinib has been reported to decrease LVEF in both adult and paediatric patients (see section 4.8). In clinical studies in paediatric patients, the median time to onset of the first occurrence of LVEF decrease was around one month. In clinical studies in adult patients, the median time to onset of the first occurrence of left ventricular dysfunction, cardiac failure and LVEF decrease was between 2 and 5 months.

In patients receiving dabrafenib in combination with trametinib, there have been occasional reports of acute, severe left ventricular dysfunction due to myocarditis. Full recovery was observed when stopping treatment. Physicians should be alert to the possibility of myocarditis in patients who develop new or worsening cardiac signs or symptoms. Please refer to the trametinib powder for oral solution SmPC (section 4.4) for additional information. No dose modification of dabrafenib is required when taken in combination with trametinib.

Renal failure

Renal failure has been identified in ≤1% of adult patients treated with dabrafenib in combination with trametinib. Observed cases in adult patients were generally associated with pyrexia and dehydration and responded well to dose interruption and general supportive measures. Granulomatous nephritis has also been reported in adult patients. Patients should be routinely monitored for serum creatinine while on therapy. If creatinine increases, treatment 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 reactions have been reported in adult and paediatric patients in clinical studies with dabrafenib in combination with trametinib (see section 4.8). It is recommended that patients have liver function monitored every four weeks for 6 months after treatment initiation. Liver monitoring may be continued thereafter as clinically indicated.

Blood pressure changes

Both hypertension and hypotension have been reported in patients in clinical studies with dabrafenib in combination with trametinib (see section 4.8). Blood pressure should be measured at baseline and monitored during treatment, with control of hypertension by standard therapy as appropriate.

Interstitial lung disease (ILD)/Pneumonitis

Cases of pneumonitis or ILD have been reported in adult patients in clinical studies with dabrafenib in combination with trametinib. Please refer to the trametinib powder for oral solution SmPC for additional information.

Rash

Rash has been observed in 49% of paediatric patients in clinical studies 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.

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 in adult patients. 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, treatment should be withdrawn.

Rhabdomyolysis

Rhabdomyolysis has been reported in adult patients taking dabrafenib in combination with trametinib. Signs or symptoms of rhabdomyolysis should warrant an appropriate clinical evaluation and treatment as indicated. Please refer to the trametinib powder for oral solution SmPC for additional information.

Pancreatitis

Pancreatitis has been reported in adult and paediatric patients treated with dabrafenib in combination with trametinib in clinical studies (see section 4.8). 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.

Deep vein thrombosis (DVT)/Pulmonary embolism (PE)

Pulmonary embolism or deep vein thrombosis can occur. 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 treatment for life-threatening pulmonary embolism.

Gastrointestinal disorders

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

Sarcoidosis

Cases of sarcoidosis have been reported in adult 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.

Women of childbearing potential/Fertility in males

Before initiating treatment in women of childbearing potential, appropriate advice on effective methods of contraception should be provided. 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. Male patients taking dabrafenib in combination with trametinib should be informed of the potential risk for impaired spermatogenesis, which may be irreversible (see section 4.6).

Haemophagocytic lymphohistiocytosis

In post-marketing experience, haemophagocytic lymphohistiocytosis (HLH) has been observed in adult 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).

Excipients

Potassium

This medicinal product contains potassium, less than 1 mmol (39 mg) per maximum daily dose, i.e. essentially 'potassium-free'.

Benzyl alcohol

This medicinal product contains <0.00078 mg benzyl alcohol in each dispersible tablet.

Benzyl alcohol may cause allergic reactions.

Patients below 3 years of age should be monitored for respiratory symptoms.

Patients who are, or may become, pregnant should be advised of the potential risk to the foetus from the excipient benzyl alcohol, which may accumulate over time and cause metabolic acidosis.

Dabrafenib dispersible tablets should be used with caution in patients with hepatic or renal impairment, as benzyl alcohol may accumulate over time and cause metabolic acidosis.

4.5. Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

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 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 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 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 in adult 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.

Also refer to the guidance for medicinal product interactions for trametinib found in sections 4.4 and 4.5 of the trametinib powder for oral solution SmPC.

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 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 (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 also the trametinib powder for oral solution SmPC (section 4.6) for additional information on trametinib.

Breast-feeding

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.

Fertility

There are no data in humans for dabrafenib in combination with trametinib. Dabrafenib may impair male and female fertility as effects on male and female reproductive organs have been seen in animals (see section 5.3). Male patients taking dabrafenib in combination with trametinib should be informed of the potential risk for impaired spermatogenesis, which may be irreversible. Please see the trametinib powder for oral solution SmPC for additional information.

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, dizziness or eye problems to affect these activities.

4.8. Undesirable effects

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 (70%), rash (49%), headache (47%), vomiting (40%), fatigue (36%), dry skin (35%), diarrhoea (34%), haemorrhage (34%), nausea (29%), dermatitis acneiform (29%), abdominal pain (28%), neutropenia (26%), cough (24%) and transaminases increased (22%). The most frequently reported severe (Grade 3/4) adverse reactions were: neutropenia (15%), pyrexia (11%), transaminases increased (6%) and weight increased (5%). Long-term data on growth and skeletal maturation in paediatric patients are currently limited (see section 5.3).

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, peripheral neuropathy (including sensory and motor neuropathy), lymphoedema, dry mouth, actinic keratosis, renal failure, potentiation of radiation toxicity (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), tumour lysis syndrome, myocarditis, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms, tattoo-associated skin reactions (frequency not known). In addition, cases of biocular panuveitis or biocular iridocyclitis suggestive of Vogt-Koyanagi-Harada syndrome have been reported in adult patients.

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 2.3 years.

Adverse reactions (Table 4) 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 4 Adverse reactions with dabrafenib in combination with trametinib

Infections and infestations

Very common

Paronychia, nasopharyngitis*1

Common

Urinary tract infection, cellulitis

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Very common

Skin papilloma

Blood and lymphatic system disorders

Very common

Neutropenia*2, anaemia, leukopenia*

Common

Thrombocytopenia*

Immune system disorders

Common

Hypersensitivity

Metabolism and nutrition disorders

Common

Dehydration, decreased appetite

Nervous system disorders

Very common

Headache, dizziness*3

Eye disorders

Common

Vision blurred, visual impairment, uveitis*4

Uncommon

Retinal detachment, periorbital oedema

Cardiac disorders

Common

Ejection fraction decreased, bradycardia*

Uncommon

Atrioventricular block5

Vascular disorders

Very common

Haemorrhage*6

Common

Hypertension, hypotension

Respiratory, thoracic and mediastinal disorders

Very common

Cough*

Common

Dyspnoea

Gastrointestinal disorders

Very common

Abdominal pain*, constipation, diarrhoea, nausea, vomiting

Common

Pancreatitis, stomatitis

Uncommon

Colitis*

Skin and subcutaneous tissue disorders

Very common

Dermatitis acneiform*7, dry skin*8, pruritus, rash*9, erythema

Common

Dermatitis exfoliative generalised*10, alopecia, palmar-plantar erythrodysaesthesia syndrome, folliculitis, skin lesion, panniculitis, hyperkeratosis, photosensitivity*11

Uncommon

Acute febrile neutrophilic dermatosis12, skin fissures, night sweats, hyperhidrosis

Musculoskeletal and connective tissue disorders

Very common

Arthralgia, pain in extremity

Common

Myalgia*, muscle spasms*13

General disorders and administration site conditions

Very common

Pyrexia*, fatigue*14, weight increased

Common

Mucosal inflammation, face oedema*, chills, oedema peripheral, influenza-like illness

Investigations

Very common

Transaminases increased*15

Common

Hyponatraemia, hypophosphataemia, hyperglycaemia, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, blood creatine phosphokinase increased

*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 atrioventricular block includes atrioventricular block first degree

6 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, uterine haemorrhage, heavy menstrual bleeding and purpura

7 dermatitis acneiform includes acne and acne pustular

8 dry skin includes xerosis and xeroderma

9 rash includes rash maculo-papular, rash pustular, rash erythematous, rash papular, rash macular

10 dermatitis exfoliative generalised includes skin exfoliation and dermatitis exfoliative

11 photosensitivity includes photosensitivity reaction and sunburn

12 acute febrile neutrophilic dermatosis is an adverse drug reaction seen also with dabrafenib monotherapy (Tafinlar)

13 muscle spasms include musculoskeletal stiffness

14 fatigue includes malaise and asthenia

15 transaminases increased includes aspartate aminotransferase (AST) increased, alanine aminotransferase (ALT) increased and hypertransaminasaemia

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 5% 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 3.5 months. Weight increase from baseline of ≥2 BMI (body mass index)-for-age percentile categories was observed in 36% of patients.

Haemorrhage

Haemorrhagic events were observed in 34% 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 2.6 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 (see section 4.4).

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 of 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 (see sections 4.2 and 4.4). Please refer to the trametinib powder for oral solution SmPC (section 4.4).

Pyrexia

Fever has been reported in clinical studies with dabrafenib in combination with trametinib (see section 4.4). Pyrexia was reported in 70% of paediatric patients, with Grade 3 events occurring in 11% 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 (see sections 4.2 and 4.4).

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 13% and 16% of patients, respectively (see section 4.4). 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 4.1% 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 2.2 months.

Blood pressure should be measured at baseline and monitored during treatment, with control of hypertension by standard therapy as appropriate (see section 4.4).

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 13% 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 (see section 4.4).

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 (see section 4.4).

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 (see section 4.4). 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 (see section 4.4).

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

No acute overdose symptoms have been reported in paediatric patients who received dabrafenib in combination with trametinib in clinical studies. There is no specific treatment for overdose. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.