FINLEE 10mg dispersible tablets medication leaflet

Finlee 10 mg dispersible tablets

Each dispersible tablet contains dabrafenib mesilate equivalent to 10 mg of dabrafenib.

Each dispersible tablet contains <0.00078 mg of benzyl alcohol.

For the full list of excipients, see section 6.1.

Dispersible tablet.

White to slightly yellow, round, biconvex 6 mm tablet debossed with “D” on one side and “NVR” onthe other.

Low-grade glioma

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

Treatment with Finlee should be initiated and supervised by a qualified physician experienced in theuse 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 alternativevalidated test.

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

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

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

Table 1 Dosing regimen by body weight

Recommended dose Recommended dose

Body weight* (mg dabrafenib) (number of 10 mg tablets)twice daily twice daily8 to 9 kg 20 mg 210 to 13 kg 30 mg 314 to 17 kg 40 mg 418 to 21 kg 50 mg 522 to 25 kg 60 mg 626 to 29 kg 70 mg 730 to 33 kg 80 mg 834 to 37 kg 90 mg 938 to 41 kg 100 mg 1042 to 45 kg 110 mg 1146 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 ofadministration”, for dosing instructions for treatment with trametinib when used in combination with

Finlee.

Treatment with Finlee should continue until disease progression or until the development ofunacceptable 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 individualpatient 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 scheduleddose. If vomiting occurs after taking Finlee, an additional dose should not be administered and thenext dose should be taken at the next scheduled time.

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

If treatment-related toxicities occur, then both dabrafenib and trametinib should be simultaneouslydose reduced, interrupted or discontinued. Exceptions where dose modifications are necessary for onlyone of the two treatments are detailed below for uveitis, RAS mutation-positive non-cutaneousmalignancies (primarily related to dabrafenib), left ventricular ejection fraction (LVEF) reduction,retinal vein occlusion (RVO), retinal pigment epithelial detachment (RPED) and interstitial lungdisease (ILD)/pneumonitis (primarily related to trametinib).

Dose modifications or interruptions are not recommended for adverse reactions of cutaneousmalignancies (see section 4.4).

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

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 onedose level when resuming therapy.

Refer to Table 3 for dose level guidance.

Grade 4 Discontinue permanently, or interrupt therapy until Grade 0 to 1and 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

Reduced dose

Recommended dose (number of 10 mg tablets)

Body weight (mg dabrafenib) twice dailytwice daily First reduction Second Thirdlevel reduction level reduction level8 to 9 kg 20 mg 1 N/A N/A10 to 13 kg 30 mg 2 1 N/A14 to 17 kg 40 mg 3 2 118 to 21 kg 50 mg 3 2 122 to 25 kg 60 mg 4 3 226 to 29 kg 70 mg 5 4 230 to 33 kg 80 mg 5 4 334 to 37 kg 90 mg 6 5 338 to 41 kg 100 mg 7 5 342 to 45 kg 110 mg 7 6 446 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 followingthe same dosing steps as de-escalation may be considered. The dabrafenib dose should not exceed therecommended dose indicated in Table 1.

Dose modifications for selected adverse reactions

If a patient’s temperature is ≥38°C, therapy with dabrafenib and trametinib should be interrupted. Incase of recurrence, therapy can also be interrupted at the first symptom of pyrexia. Treatment withanti-pyretics such as ibuprofen or acetaminophen/paracetamol should be initiated. The use of oralcorticosteroids should be considered in those instances in which anti-pyretics are insufficient. Patientsshould be evaluated for signs and symptoms of infection and, if necessary, treated in line with localpractice (see section 4.4). Therapy should be restarted if the patient is symptom-free for at least24 hours either (1) at the same dose level, or (2) reduced by one dose level if the pyrexia is recurrentand/or was accompanied by other severe symptoms including dehydration, hypotension or renalfailure.

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

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

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

RAS mutation-positive non-cutaneous malignancies

The benefits and risks must be considered before continuing treatment with dabrafenib in patients witha non-cutaneous malignancy that has a RAS mutation. No dose modification of trametinib is requiredwhen taken in combination with dabrafenib (see section 4.4).

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

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

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

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

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

The safety and efficacy of combination therapy with dabrafenib and trametinib in children below1 year of age have not been established. No data are available. Studies in juvenile animals have showneffects of dabrafenib which were not observed in adult animals (see section 5.3). Longer-term safetydata in paediatric patients are currently limited.

Finlee is for oral use.

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

It is recommended that the doses of Finlee are taken at similar times every day, leaving an interval ofapproximately 12 hours between doses. The once-daily dose of trametinib should be taken at the sametime 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 canbe administered via the tube.

Instructions for preparation and administration are provided in section 6.6.

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

Finlee is intended for use in combination with trametinib powder for oral solution as there are limitedefficacy 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 oftreatment. For additional information on warnings and precautions associated with trametinibtreatment, 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 BRAFglioma. Dabrafenib should not be used in patients with wild-type BRAF glioma (see section 5.1).

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

Cutaneous malignancies such as cutaneous squamous cell carcinoma (cuSCC) includingkerathoacanthoma and new primary melanoma have been observed in adult patients treated withdabrafenib in combination with trametinib (see section 4.8). It is recommended that skin examinationbe performed prior to initiation of therapy with dabrafenib and monthly throughout treatment and forup to six months after treatment. Monitoring should continue for 6 months following discontinuationof dabrafenib or until initiation of another anti-neoplastic therapy.

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

In vitro experiments have demonstrated paradoxical activation of mitogen-activated protein kinase(MAP kinase) signalling in BRAF wild-type cells with RAS mutations when exposed to BRAFinhibitors. This may lead to increased risk of non-cutaneous malignancies with dabrafenib exposure(see section 4.8) when RAS mutations are present. RAS-associated malignancies have been reportedin adult clinical studies, both with another BRAF inhibitor (chronic myelomonocytic leukaemia andnon-cutaneous SCC of the head and neck) as well as with dabrafenib monotherapy (pancreaticadenocarcinoma, 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 orconcurrent cancer associated with RAS mutations. Patients should be screened for occult pre-existingmalignancies.

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

Abnormal findings should be managed according to clinical practices.

Haemorrhagic events have been reported in adult and paediatric patients taking dabrafenib incombination with trametinib (see section 4.8). Major haemorrhagic events and fatal haemorrhageshave occurred in adult patients taking dabrafenib in combination with trametinib. The potential forthese events in patients with low platelet counts (<75 000/mm3) has not been established as suchpatients were excluded from clinical studies. The risk of haemorrhage may be increased withconcomitant use of antiplatelet or anticoagulant therapy. If haemorrhage occurs, patients should betreated as clinically indicated.

Visual impairment

Ophthalmological reactions, including uveitis and iridocyclitis, have been reported in paediatricpatients taking dabrafenib in combination with trametinib (see section 4.8), in some cases with a timeto onset of several months. In clinical studies in adult patients treated with dabrafenib,ophthalmological reactions, including uveitis, iridocyclitis and iritis, have been reported. Patientsshould be routinely monitored for visual signs and symptoms (such as change in vision, photophobiaand eye pain) while on therapy.

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

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

Systemic corticosteroid treatment may be necessary.

RPED and RVO may occur with dabrafenib in combination with trametinib. Please refer to thetrametinib powder for oral solution SmPC (section 4.4). No dose modification of dabrafenib isrequired when taken in combination with trametinib following diagnosis of RVO or RPED.

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 normalbaseline renal function). In paediatric patients who received dabrafenib in combination withtrametinib, the median time to onset of the first occurrence of pyrexia was 1.5 months. In adultpatients with unresectable or metastatic melanoma who received dabrafenib in combination withtrametinib and developed pyrexia, approximately half of the first occurrences of pyrexia happenedwithin the first month of therapy and approximately one third of the patients had 3 or more events.

Patients with serious non-infectious febrile events responded well to dose interruption and/or dosereduction and supportive care.

Therapy with dabrafenib and trametinib 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. Theuse of oral corticosteroids should be considered in those instances in which anti-pyretics areinsufficient. Patients should be evaluated for signs and symptoms of infection. Therapy can berestarted once the fever resolves. If fever is associated with other severe signs or symptoms, therapyshould be restarted at a reduced dose once fever resolves and as clinically appropriate (seesection 4.2).

Dabrafenib in combination with trametinib has been reported to decrease LVEF in both adult andpaediatric patients (see section 4.8). In clinical studies in paediatric patients, the median time to onsetof 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 ofacute, severe left ventricular dysfunction due to myocarditis. Full recovery was observed whenstopping treatment. Physicians should be alert to the possibility of myocarditis in patients who developnew 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 whentaken in combination with trametinib.

Renal failure has been identified in ≤1% of adult patients treated with dabrafenib in combination withtrametinib. Observed cases in adult patients were generally associated with pyrexia and dehydrationand responded well to dose interruption and general supportive measures. Granulomatous nephritis hasalso been reported in adult patients. Patients should be routinely monitored for serum creatinine whileon 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 adverse reactions have been reported in adult and paediatric patients in clinical studies withdabrafenib in combination with trametinib (see section 4.8). It is recommended that patients have liverfunction monitored every four weeks for 6 months after treatment initiation. Liver monitoring may becontinued thereafter as clinically indicated.

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

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

Rash has been observed in 49% of paediatric patients in clinical studies when dabrafenib is used incombination with trametinib (see section 4.8). The majority of these cases were Grade 1 or 2 and didnot require any dose interruptions or dose reductions.

Cases of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome, and drugreaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal,have been reported during treatment with dabrafenib/trametinib combination therapy in adult patients.

Before initiating treatment, patients should be advised of the signs and symptoms and monitoredclosely for skin reactions. If signs and symptoms suggestive of SCARs appear, treatment should bewithdrawn.

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 treatmentas indicated. Please refer to the trametinib powder for oral solution SmPC for additional information.

Pancreatitis has been reported in adult and paediatric patients treated with dabrafenib in combinationwith trametinib in clinical studies (see section 4.8). Unexplained abdominal pain should be promptlyinvestigated to include measurement of serum amylase and lipase. Patients should be closelymonitored when restarting treatment after an episode of pancreatitis.

Pulmonary embolism or deep vein thrombosis can occur. If patients develop symptoms of pulmonaryembolism or deep vein thrombosis such as shortness of breath, chest pain or arm or leg swelling, theyshould immediately seek medical care. Permanently discontinue treatment for life-threateningpulmonary embolism.

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

Cases of sarcoidosis have been reported in adult patients treated with dabrafenib in combination withtrametinib, mostly involving the skin, lung, eye and lymph nodes. In the majority of the cases,treatment with dabrafenib and trametinib was maintained. In case of a diagnosis of sarcoidosis,relevant treatment should be considered.

Women of childbearing potential/Fertility in males

Before initiating treatment in women of childbearing potential, appropriate advice on effectivemethods of contraception should be provided. Women of childbearing potential must use effectivemethods of contraception during therapy and for 2 weeks following discontinuation of dabrafenib andfor 16 weeks following discontinuation of trametinib. Male patients taking dabrafenib in combinationwith trametinib should be informed of the potential risk for impaired spermatogenesis, which may beirreversible (see section 4.6).

Haemophagocytic lymphohistiocytosis

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

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

Effects of other medicinal products on dabrafenib

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

Effects of dabrafenib on other medicinal products

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

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

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

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

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

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 fromthe 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 renalimpairment, as benzyl alcohol may accumulate over time and cause metabolic acidosis.

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

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

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

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

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

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

Effect of dabrafenib on other medicinal products

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

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

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

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

Administration of dabrafenib 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-warfarinincreased 18% and 19%.

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

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

* Analgesics (e.g. fentanyl, methadone)

* Antibiotics (e.g. clarithromycin, doxycycline)

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

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

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

* Antipsychotics (e.g. haloperidol)

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

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

* Corticosteroids (e.g. dexamethasone, methylprednisolone)

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

* Hormonal contraceptives (see section 4.6)

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

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

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

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

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

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

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

Effects of dabrafenib on substance transport systems

Dabrafenib is an in vitro inhibitor of human organic anion transporting polypeptide (OATP) 1B1(OATP1B1), OATP1B3 and BCRP. Following co-administration of a single dose of rosuvastatin(OATP1B1, OATP1B3 and BCRP substrate) with repeat-dose dabrafenib in adult patients, Cmax ofrosuvastatin increased 2.6-fold whereas the AUC was only minimally changed (7% increase). Theincreased 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 and4.5 of the trametinib powder for oral solution SmPC.

Women of childbearing potential must use effective methods of contraception during therapy and for2 weeks following discontinuation of dabrafenib and for 16 weeks following discontinuation oftrametinib.

Dabrafenib may decrease the efficacy of oral or any systemic hormonal contraceptives and aneffective alternative method of contraception, such as a barrier method, should be used (seesection 4.5).

There are no data from the use of dabrafenib in pregnant women. Animal studies have shownreproductive toxicity and embryo-foetal developmental toxicities, including teratogenic effects (seesection 5.3). Dabrafenib should not be administered to pregnant women unless the potential benefit tothe mother outweighs the possible risk to the foetus. If the patient becomes pregnant while takingdabrafenib, the patient should be informed of the potential hazard to the foetus. Please see also thetrametinib powder for oral solution SmPC (section 4.6) for additional information on trametinib.

It is not known whether dabrafenib is excreted in human milk. A risk to the breast-feeding childcannot be excluded. A decision should be made whether to discontinue breast-feeding or discontinuedabrafenib, taking into account the benefit of breast-feeding for the child and the benefit of therapy forthe woman.

There are no data in humans for dabrafenib in combination with trametinib. Dabrafenib may impairmale 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 informedof the potential risk for impaired spermatogenesis, which may be irreversible. Please see the trametinibpowder for oral solution SmPC for additional information.

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

In clinical studies of paediatric patients treated with dabrafenib in combination with trametinib, themost 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) adversereactions 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 previouslyestablished in adult patients. The following additional adverse reactions have so far only been reportedin adult patients treated with dabrafenib capsules and trametinib tablets: cutaneous squamous cellcarcinoma, seborrhoeic keratosis, peripheral neuropathy (including sensory and motor neuropathy),lymphoedema, dry mouth, actinic keratosis, renal failure (common), melanoma, acrochordon,sarcoidosis, chorioretinopathy, pneumonitis, acute renal failure, nephritis, cardiac failure, leftventricular dysfunction, interstitial lung disease, rhabdomyolysis (uncommon), gastrointestinalperforation, haemophagocytic lymphohistiocytosis (rare), tumour lysis syndrome, myocarditis,

Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (frequency notknown). In addition, cases of biocular panuveitis or biocular iridocyclitis suggestive of Vogt-

Koyanagi-Harada syndrome have been reported in adult patients.

The safety of dabrafenib in combination with trametinib has been evaluated in a pooled safety set of171 paediatric patients across two studies in patients with BRAF V600 mutation-positive advancedsolid tumours. Four (2.3%) patients were 1 to <2 years of age, 39 (22.8%) patients were 2 to <6 yearsof age, 54 (31.6%) patients were 6 to <12 years of age and 74 (43.3%) patients were 12 to <18 years ofage at enrolment. The mean treatment duration was 2.3 years.

Adverse reactions (Table 4) are listed below by MedDRA system organ class ranked by frequencyusing 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 beestimated from the available data). Within each frequency grouping, adverse reactions are presented inorder of decreasing seriousness.

Table 4 Adverse reactions with dabrafenib in combination with trametinib

Very common Paronychia, nasopharyngitis*1

Common Urinary tract infection, cellulitis

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

Very common Skin papilloma

Very common Neutropenia*2, anaemia, leukopenia*

Common Thrombocytopenia*

Common Hypersensitivity

Common Dehydration, decreased appetite

Very common Headache, dizziness*3

Common Vision blurred, visual impairment, uveitis*4

Uncommon Retinal detachment, periorbital oedema

Common Ejection fraction decreased, bradycardia*

Uncommon Atrioventricular block5

Very common Haemorrhage*6

Common Hypertension, hypotension

Very common Cough*

Common Dyspnoea

Very common Abdominal pain*, constipation, diarrhoea, nausea, vomiting

Common Pancreatitis, stomatitis

Uncommon Colitis*

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

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

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

Very common Arthralgia, pain in extremity

Common Myalgia*, muscle spasms*13

Very common Pyrexia*, fatigue*14, weight increased

Common Mucosal inflammation, face oedema*, chills, oedema peripheral, influenza-likeillness

Very common Transaminases increased*15

Common Hyponatraemia, hypophosphataemia, hyperglycaemia, blood alkaline phosphataseincreased, gamma-glutamyltransferase increased, blood creatine phosphokinaseincreased

*Denotes grouped term of two or more MedDRA preferred terms that were considered clinically similar.

1 nasopharyngitis includes pharyngitis2 neutropenia includes neutrophil count decreased and febrile neutropenia3 dizziness includes vertigo4 uveitis includes iridocyclitis5 atrioventricular block includes atrioventricular block first degree6 haemorrhage includes epistaxis, haematuria, contusion, haematoma, international normalised ratioincreased, anal haemorrhage, catheter site haemorrhage, cerebral haemorrhage, ecchymosis, extraduralhaematoma, gastrointestinal haemorrhage, haematochezia, petechiae, post-procedural haemorrhage, rectalhaemorrhage, red blood cell count decreased, upper gastrointestinal haemorrhage, uterine haemorrhage,heavy menstrual bleeding and purpura7 dermatitis acneiform includes acne and acne pustular8 dry skin includes xerosis and xeroderma9 rash includes rash maculo-papular, rash pustular, rash erythematous, rash papular, rash macular10 dermatitis exfoliative generalised includes skin exfoliation and dermatitis exfoliative11 photosensitivity includes photosensitivity reaction and sunburn12 acute febrile neutrophilic dermatosis is an adverse drug reaction seen also with dabrafenib monotherapy(Tafinlar)13 muscle spasms include musculoskeletal stiffness14 fatigue includes malaise and asthenia15 transaminases increased includes aspartate aminotransferase (AST) increased, alanine aminotransferase(ALT) increased and hypertransaminasaemia

Weight increased

Weight increase has only been reported in the paediatric population. It was reported as an adversereaction in 16% of paediatric patients including Grade 3 cases in 5% of patients, with adiscontinuation rate of 0.6% of patients. The median time to onset of the first occurrence of thereported weight increase in paediatric patients receiving dabrafenib in combination with trametinibwas 3.5 months. Weight increase from baseline of ≥2 BMI (body mass index)-for-age percentilecategories was observed in 36% of patients.

Haemorrhagic events were observed in 34% of paediatric patients, with Grade 3 events occurring in1.2% of patients. The most frequent haemorrhagic event (epistaxis) was reported in 18% of paediatricpatients. The median time to onset of the first occurrence of haemorrhagic events in paediatric patientswas 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 anticoagulanttherapy. If haemorrhage occurs, patients should be treated as clinically indicated (see section 4.4).

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 onemonth.

Patients with LVEF lower than the institutional lower limit of normal were not included in clinicalstudies with dabrafenib. Dabrafenib in combination with trametinib should be used with caution inpatients with conditions that could impair left ventricular function (see sections 4.2 and 4.4). Pleaserefer to the trametinib powder for oral solution SmPC (section 4.4).

Fever has been reported in clinical studies with dabrafenib in combination with trametinib (seesection 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 withinthe first month of therapy and approximately one-third of the patients had 3 or more events. In 1% ofpatients 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 renalfunction). The onset of these serious non-infectious febrile events was typically within the first monthof therapy. Patients with serious non-infectious febrile events responded well to dose interruptionand/or dose reduction and supportive care (see sections 4.2 and 4.4).

Hepatic adverse reactions have been reported in adult and paediatric clinical studies with dabrafenib incombination with trametinib. In the paediatric safety population, increased ALT and AST were verycommon, reported in 13% and 16% of patients, respectively (see section 4.4). Please refer to thetrametinib powder for oral solution SmPC for additional information.

Hypertension was reported in 2.3% of paediatric patients, with Grade 3 events occurring in 1.2% ofpatients. The median time to onset of the first occurrence of hypertension in paediatric patients was5.4 months.

Hypotension was reported in 4.1% of paediatric patients, with Grade ≥3 events occurring in 2.3% ofpatients. The median time to onset of the first occurrence of hypotension in paediatric patients was2.2 months.

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

Arthralgia

Arthralgia was reported very commonly in the integrated adult and paediatric safety populations ofdabrafenib in combination with trametinib. In the paediatric safety population, arthralgia was reportedin 13% of patients, with <1% of patients with Grade 3 severity. Arthralgia was reported in 25% ofadult patients, although these were mainly Grade 1 and 2 in severity with Grade 3 occurringuncommonly (<1%).

Hypophosphataemia

Hypophosphataemia has been reported commonly in the integrated adult and paediatric safetypopulations of dabrafenib in combination with trametinib in 4% and 5.8% of patients, respectively. Itshould 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 was reported in 1.2% of paediatric patients, with <1% of patients with Grade 3 severity. Inclinical studies in adult patients, one pancreatitis event occurred on the first day of dabrafenib dosingof a metastatic melanoma patient and recurred following rechallenge at a reduced dose. Unexplainedabdominal 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 (seesection 4.4).

In the integrated adult safety population for dabrafenib in combination with trametinib, 2% of patientsdeveloped cuSCC with a median time to onset of 18 to 31 weeks. The median time to diagnosis of thefirst occurrence of cuSCC was 223 days (range 56 to 510 days). All adult patients who developedcuSCC or new primary melanoma continued on treatment without dose modification (see section 4.4).

Activation of MAP kinase signalling in BRAF wild-type cells which are exposed to BRAF inhibitorsmay lead to increased risk of non-cutaneous malignancies, including those with RAS mutations (seesection 4.4). Non-cutaneous malignancies were reported in <1% of patients in the integrated adultsafety population of dabrafenib in combination with trametinib. Cases of RAS-driven malignancieshave been seen with dabrafenib in combination with trametinib. Patients should be monitored asclinically appropriate.

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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

Dabrafenib is an inhibitor of RAF kinases. Oncogenic mutations in BRAF lead to constitutiveactivation of the RAS/RAF/MEK/ERK pathway. The most commonly observed BRAF mutation is

V600E, which has been identified in 19% of paediatric LGG and approximately 5% of paediatric

HGG.

Combination with trametinib

Trametinib is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellularsignal regulated kinase 1 (MEK1) and MEK2 activation and kinase activity. MEK proteins arecomponents of the extracellular signal-related kinase (ERK) pathway. In human cancers, this pathwayis often activated by mutated forms of BRAF which activates MEK. Trametinib inhibits activation of

MEK by BRAF and inhibits MEK kinase activity.

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

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

Table 5 Kinase inhibitory activity of dabrafenib against RAF kinases

Kinase Inhibitory concentration 50 (nM)

BRAF V600E 0.65

BRAF WT 3.2

CRAF WT 5.0

The clinical efficacy and safety of dabrafenib plus trametinib combination therapy in paediatricpatients aged 1 to <18 years with BRAF V600 mutation-positive glioma was evaluated in a multi-centre, open-label, Phase II clinical study (EudraCT 2015-004015-20). Patients with low-grade glioma(WHO 2016 Grades 1 and 2) who required first systemic therapy were randomised in a 2:1 ratio todabrafenib plus trametinib or carboplatin plus vincristine, and patients with relapsed or refractoryhigh-grade glioma (WHO 2016 Grades 3 and 4) were enrolled into a single-arm dabrafenib plustrametinib cohort.

BRAF mutation status was identified prospectively via a local test, or a central laboratory real-timepolymerase chain reaction (PCR) test when a local test was not available. In addition, retrospectivetesting of available tumour samples by the central laboratory was performed to confirm the BRAF

V600E mutation.

Dabrafenib and trametinib dosing in the clinical study was age- and weight-dependent, withdabrafenib dosed orally at 2.625 mg/kg twice daily for ages <12 years and at 2.25 mg/kg twice dailyfor ages 12 years and older; trametinib was dosed orally at 0.032 mg/kg once daily for ages <6 yearsand at 0.025 mg/kg once daily for ages 6 years and older. Dabrafenib doses were capped at 150 mgtwice daily and trametinib doses at 2 mg once daily. Carboplatin and vincristine were dosed based onage and body surface area at doses of 175 mg/m2 and 1.5 mg/m2, respectively, as weekly infusions.

Carboplatin and vincristine were administered in one 10-week induction course followed by eight 6-week cycles of maintenance therapy.

The primary efficacy endpoint in both cohorts was overall response rate (ORR, sum of confirmedcomplete/CR and partial responses/PR) by independent review based on RANO (2017) criteria for the

LGG cohort and RANO (2010) criteria for the HGG cohort. The primary analysis was performedwhen all patients in both cohorts had completed at least 32 weeks of therapy. The final analysis wasperformed 2 years after completion of enrolment in both cohorts.

BRAF mutation-positive paediatric low-grade glioma (WHO Grades 1 and 2)

In the low-grade glioma cohort, 110 patients were randomised to dabrafenib plus trametinib (n=73) orcarboplatin plus vincristine (n=37). Median age was 9.5 years, with 34 patients (30.9%) aged12 months to <6 years, 36 patients (32.7%) aged 6 to <12 years and 40 patients (36.4%) aged 12 to<18 years; 60% were female. The majority of patients (80%) had Grade 1 glioma at initial diagnosis.

The most common pathologies were pilocytic astrocytoma (30.9%), ganglioglioma (27.3%) and LGGnot otherwise specified (NOS) (18.2%). Metastatic sites were present in 9 patients (8.2%). Priorsurgery was reported in 91 patients (82.7%), among those patients the procedure at last surgery wasresection in 28 patients (25.5%). Systemic corticosteroid use was reported in 44 patients (41.5%).

At the time of the primary analysis, the ORR in the dabrafenib plus trametinib arm showed astatistically significant improvement over carboplatin plus vincristine. The subsequent hierarchicaltesting also demonstrated a statistically significant improvement in progression-free survival (PFS)over chemotherapy (Table 6).

At the time of the primary analysis, conducted after all patients had completed at least 32 weeks oftreatment or had discontinued earlier, the overall survival (OS) data were still immature (one deathwas reported in the carboplatin plus vincristine (C+V) arm).

Table 6 Response and progression-free survival based on independent review in the pivotalstudy G2201 (LGG cohort, primary analysis)

Dabrafenib + Trametinib Carboplatin + Vincristine(D+T) (C+V)

N=73 N=37

Best overall response

Complete response (CR), n (%) 2 (2.7) 1 (2.7)

Partial response (PR), n (%) 32 (43.8) 3 (8.1)

Stable disease (SD), n (%) 30 (41.1) 15 (40.5)

Progressive disease (PD), n (%) 8 (11.0) 12 (32.4)

Unknown, n (%) 1 (1.4) 6 (16.2)1

Overall response rate

ORR (CR+PR), (95% CI) 46.6% (34.8 - 58.6%) 10.8% (3.0 - 25.4%)

Odds ratio2, p-value 7.19 (2.3 - 22.4), p<0.001

Risk difference 35.8% (20.6 - 51.0)

Progression-free survival (PFS)

Median (months), (95% CI) 20.1 (12.8 - NE) 7.4 (3.6 - 11.8)

Hazard ratio (95% CI), p-value 0.31 (0.17 - 0.55), p<0.001

NE=not estimable1 4 patients randomised to C+V discontinued prior to receiving treatment.2 Odds ratio (D+T vs C+V) and 95% CI are from a logistic regression with treatment as the only covariate, i.e. itis the odds of observing a response in the D+T arm compared to the odds of observing a response in the C+Varm. Odds ratio >1 favours D+T.

At the time of the final analysis (median duration of follow-up: 39.0 months), the ORR based onindependent review was 54.8% in the D+T arm and 16.2% in the C+V arm with an odds ratio of 6.26.

The analysis also confirmed improved PFS over chemotherapy based on independent review with anestimated 64% risk reduction in progression/death (hazard ratio 0.36). The median PFS was24.9 months in the D+T arm and 7.2 months in the C+V arm. No additional deaths were reported ineither arm at the time of the final analysis.

Figure 1 Kaplan-Meier curves for progression-free survival based on independent review inthe pivotal study G2201 (LGG cohort, final analysis)100%80%60%40%20%

DD++TT ((n//N =4 444/7/733))

CC++VV ((n//N =2 266//3377))0%0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

Time (months)

D+DT+ T 73 66 62 57 48 44 39 38 34 27 20 14 10 5 5 3 3 0

C+CV+ V 37 21 16 12 8 6 6 6 5 4 2 0 0 0 0 0 0 0

BRAF mutation-positive paediatric high-grade glioma (WHO Grades 3 and 4)

In the single-arm high-grade glioma cohort, 41 patients with relapsed or refractory HGG were enrolledand treated with dabrafenib plus trametinib. Median age was 13.0 years, with 5 patients (12.2%) aged12 months to <6 years, 10 patients (24.4%) aged 6 to <12 years and 26 patients (63.4%) aged 12 to<18 years; 56% were female. The histological grade at initial diagnosis was Grade 4 in 20 patients(48.8%), Grade 3 in 13 patients (31.7%), Grade 2 in 4 patients (9.8%), Grade 1 in 3 patients (7.3%)and missing in 1 patient (2.4%). The most common pathologies were glioblastoma multiforme(31.7%), anaplastic pleomorphic xanthoastrocytoma (14.6%), HGG NOS (9.8%) and pleomorphicxanthoastrocytoma (9.8%). Prior surgery was reported in 40 patients (97.6%), among those patientsthe procedure at last surgery was resection in 24 patients (58.5%). Prior antineoplastic chemotherapywas reported for 33 patients (80.5%). Prior radiotherapy was reported for 37 patients (90.2%).

Systemic corticosteroid use while on study treatment was reported in 24 patients (58.5%).

At the time of the final analysis (median duration of follow-up: 45.2 months), the ORR based onindependent review was 56.1% (23/41), (95% CI: 39.7, 71.5): CR in 14 patients (34.1%) and PR in9 patients (22.0%). The median duration of response (DoR) was 27.4 months (95% CI: 9.2, NE).

The pharmacokinetic properties of dabrafenib have mostly been determined in adult patients using thesolid (capsule) formulation. The pharmacokinetics of dabrafenib following single or repeat weight-adjusted dosing were also evaluated in 243 paediatric patients. The population pharmacokineticanalysis included 61 patients aged 1 to <6 years, 77 patients aged 6 to <12 years and 105 patients aged12 to <18 years. Clearance was comparable with clearance in adult patients. Weight was identified as asignificant covariate of dabrafenib clearance. Age was not a significant additional covariate. Thepharmacokinetic exposures of dabrafenib at the recommended weight-adjusted dose in paediatricpatients were within range of those observed in adults.

Probability (%)

The dabrafenib dispersible tablet suspension was absorbed rapidly with a median time to achieve peakplasma concentration of 1.5 hours post-dose. The mean absolute oral bioavailability of dabrafenibcapsules was 94.5%. The suspension is expected to have 20% lower bioavailability. Based on datafrom adult patients with the capsule formulation, a decrease in exposure was observed with repeatdosing, likely due to induction of its own metabolism. Mean accumulation AUC Day 18/Day 1 ratiowas 0.73.

Dabrafenib exposure (Cmax and AUC) increased in a dose-proportional manner between 12 mg and300 mg following single-dose administration, but the increase was less than dose-proportional afterrepeat twice-daily dosing.

In the pivotal paediatric study, steady-state geometric mean (%CV) Cmax and AUCtau were 1330 ng/ml(93.5%) and 4910 ng*hr/ml (54.0%) in the LGG cohort and 1520 ng/ml (65.9%) and 4300 ng*hr/ml(44.7%) in the HGG cohort.

Administration of a single 150 mg dose of the dispersible tablet suspension with a low-fat, low-caloriemeal reduced the bioavailability (Cmax and AUC decreased by 35% and 29%, respectively) anddelayed the absorption of dabrafenib when compared to the fasted state in an adult healthy volunteerstudy.

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

The metabolism of dabrafenib is primarily mediated by CYP2C8 and CYP3A4 to form hydroxy-dabrafenib, which is further oxidised via CYP3A4 to form carboxy-dabrafenib. Carboxy-dabrafenibcan be decarboxylated via a non-enzymatic process to form desmethyl-dabrafenib. Carboxy-dabrafenib is excreted in bile and urine. Desmethyl-dabrafenib may also be formed in the gut andreabsorbed. Desmethyl-dabrafenib is metabolised by CYP3A4 to oxidative metabolites. Hydroxy-dabrafenib terminal half-life parallels that of parent with a half-life of 10 hrs while the carboxy- anddesmethyl- metabolites exhibited longer half-lives (21 to 22 hours). In paediatric patients, the meanmetabolite-to-parent AUC ratios (%CV) following repeat-dose administration of the capsules or of thedispersible tablet suspension were 0.64 (28%), 15.6 (49%) and 0.69 (62%) for hydroxy-, carboxy-, anddesmethyl-dabrafenib, respectively. Based on exposure, relative potency, and pharmacokineticproperties, both hydroxy- and desmethyl-dabrafenib are likely to contribute to the clinical activity ofdabrafenib while the activity of carboxy-dabrafenib is not likely to be significant.

Terminal half-life of dabrafenib following an intravenous single microdose in adult patients was2.6 hours. Dabrafenib terminal half-life after a single oral dose of the dispersible tablet formulationwas 11.5 hours (CV of 67.7%) in an adult healthy volunteer study. The apparent clearance ofdabrafenib in paediatric patients (median body weight: 38.7 kg) was 11.8 L/h (CV of 49%).

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

Effects of other medicinal products on dabrafenib

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

Effects of dabrafenib on other medicinal products

Although dabrafenib and its metabolites, hydroxy-dabrafenib, carboxy-dabrafenib and desmethyl-dabrafenib, were inhibitors of human organic anion transporter 1 (OAT1) and OAT3 in vitro, anddabrafenib and its desmethyl- metabolite were found to be inhibitors of organic cation transporter 2(OCT2) in vitro, the risk of a drug-drug interaction with these transporters is minimal based on clinicalexposure of dabrafenib and its metabolites.

A population pharmacokinetic analysis in adult patients indicates that mildly elevated bilirubin and/or

AST levels (based on National Cancer Institute [NCI] classification) do not significantly affectdabrafenib oral clearance. In addition, mild hepatic impairment as defined by bilirubin and AST didnot have a significant effect on dabrafenib metabolite plasma concentrations. No data are available inpatients with moderate to severe hepatic impairment. As hepatic metabolism and biliary secretion arethe primary routes of elimination of dabrafenib and its metabolites, administration of dabrafenibshould be undertaken with caution in patients with moderate to severe hepatic impairment (seesection 4.2).

A population pharmacokinetic analysis in adult patients suggests that mild renal impairment does notaffect oral clearance of dabrafenib. Although data in moderate renal impairment are limited these datamay indicate no clinically relevant effect. No data are available in patients with severe renalimpairment (see section 4.2).

A population pharmacokinetic analysis in adult patients showed no significant differences in thepharmacokinetics of dabrafenib between Asian and Caucasian patients. There are insufficient data toevaluate the potential effect of other races on dabrafenib pharmacokinetics.

Based on population pharmacokinetic analyses in adult and paediatric patients, estimated clearance ofdabrafenib was slightly lower in female patients, but the difference was not considered clinicallyrelevant.

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

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

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

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

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

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

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

Combination with trametinib

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

Mannitol (E 421)

Microcrystalline cellulose (E 460)

Crospovidone (E 1202)

Hypromellose (E 464)

Acesulfame potassium (E 950)

Magnesium stearate (E 470b)

Artificial berry flavour (maltodextrin, propylene glycol [E 1520], artificial flavours, triethyl citrate[E 1505], benzyl alcohol [E 1519])

Silica, colloidal anhydrous (E 551)

Not applicable.

Dispersible tablet2 years.

Dispersible tablet suspension

Use within 30 minutes of preparation.

This medicinal product does not require any special temperature storage conditions.

Store in the original package in order to protect from moisture.

Opaque white high-density polyethylene (HDPE) bottle with polypropylene child-resistant screw capand a silica gel desiccant.

Each bottle contains 210 dispersible tablets and two 2 g desiccant canisters. Patients should beinstructed to keep the desiccant canisters in the bottle and not to swallow them.

Packs containing:

* 1 bottle (210 dispersible tablets) and 2 dosing cups.

* 2 bottles (420 dispersible tablets) and 2 dosing cups.

Each dosing cup is 30 ml in volume with 5 ml graduated increments.

Not all pack sizes may be marketed.

Preparation of the dispersible tablet suspension

* The prescribed dose of Finlee dispersible tablets should be placed in the dosing cup containingapproximately 5 ml or 10 ml of still drinking water.

* The amount of still drinking water depends on the prescribed number of dispersible tablets. Fora dose of 1 to 4 dispersible tablets, use approximately 5 ml of water; for a dose of 5 to15 dispersible tablets, use approximately 10 ml of water.

* It may take 3 minutes (or more) to fully disperse the tablets.

* The contents should be gently stirred with the handle of a stainless steel teaspoon and thenadministered immediately.

* Administer the suspension no later than 30 minutes after preparation (after the tablets have fullydispersed). If more than 30 minutes have passed, do not use the suspension.

* After administration of the prepared suspension, there will be tablet residue inside the dosingcup. The residue may be difficult to see. Add approximately 5 ml of still drinking water to theempty dosing cup and stir with the handle of the stainless steel teaspoon to re-suspend anyremaining particles. The entire contents of the dosing cup should be administered.

Administration using a feeding tube or an oral syringe

* Once the suspension is prepared, withdraw all of the suspension from the dosing cup into asyringe compatible with a feeding tube or oral administration.

* If administering via a feeding tube, flush the feeding tube with still drinking water beforeadministering, and dispense the suspension into the feeding tube as per the manufacturer’sinstructions, and flush the feeding tube with still drinking water after administering.

* If administering via an oral syringe, place the end of the oral syringe inside the mouth with thetip touching the inside of either cheek. Slowly push the plunger all the way down to deliver thefull dose.

A complete and illustrated set of instructions for use is provided at the end of the package leaflet“Instructions for use”.

The dosing cup can be used for up to 4 months after first use. After 4 months, the dosing cup can bethrown away in the household waste.

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

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/23/1767/001-002

15 November 2023

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

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