Tafinlar

/ Novartis

Treatment with dabrafenib should be initiated and supervised by a qualified physician experienced in the use of anticancer medicinal products.
Before taking dabrafenib, patients must have confirmation of tumour BRAF V600 mutation using a validated test. In ATC, confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with dabrafenib and trametinib.
The efficacy and safety of dabrafenib have not been established in patients with wild-type BRAF melanoma,wild-type BRAF NSCLC or wild-type BRAF ATC. Dabrafenib should not be used in patients with wild-type BRAF melanoma, wild-type BRAF NSCLC or wild-type BRAF ATC.
The recommended dose of dabrafenib, either used as monotherapy or in combination with trametinib, is 150 mg (two 75 mg capsules) twice daily (corresponding to a total daily dose of 300 mg). The recommended dose of trametinib, when used in combination with dabrafenib, is 2 mg once daily (QD).
Duration of treatment: Treatment should continue until the patient no longer derives benefit or the development of unacceptable toxicity (See Table 2 at the attached doctor’s leaflet). In the adjuvant melanoma setting, patients should be treated for a period of 12 months unless there is disease recurrence or unacceptable toxicity.
In ATC, treatment should continue until disease recurrence or unacceptable toxicity.
Missed doses: If a dose of dabrafenib is missed, it should not be taken if it is less than 6 hours until the next dose. If a dose of trametinib is missed, when dabrafenib is given in combination with trametinib, only take the dose of trametinib if it is more than 12 hours until the next scheduled dose. See prescribing information for full details.
Dose modification: Two dabrafenib capsule strengths, 50 mg and 75 mg, are available to effectively manage dose modification requirements. For the management of adverse reactions may require treatment interruption, dose reduction, or treatment discontinuation: See prescribing information for full details. Dose modifications or interruptions are not recommended for adverse reactions of cutaneous squamous cell carcinoma (cuSCC) or new primary melanoma. See prescribing information for full details. Therapy should be interrupted if the patient’s temperature is ≥ 38.5ºC. Patients should be evaluated for signs and symptoms of infection.
Hepatic impairment: No dose adjustment is required for patients with mild hepatic impairment. There are no clinical data in subjects with moderate to severe hepatic impairment and the potential need for dose adjustment cannot be determined. Hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites and patients with moderate to severe hepatic impairment may have increased exposure. Dabrafenib should be used with caution in patients with moderate or severe hepatic impairment when administered as monotherapy or in combination with trametinib.
Paediatric population: The safety and efficacy of dabrafenib have not yet been established in children and adolescents (<18 years). No clinical data are available. Studies in juvenile animals have shown adverse effects of dabrafenib which had not been observed in adult animals.
Method of administration: The dabrafenib capsules are to be swallowed whole with water. The capsules should not be chewed or crushedopened and should not be mixed with food or liquids due to chemical instability of dabrafenib.
See prescribing information for full details.

Melanoma: Dabrafenib as monotherapy or in combination with trametinib is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation.
Adjuvant treatment of melanoma: Dabrafenib in combination with trametinib is indicated for the adjuvant treatment of adult patients with Stage III melanoma with a BRAF V600 mutation, following complete resection.
Non-small cell lung cancer (NSCLC): Dabrafenib in combination with trametinib is indicated for the treatment of adult patients with
advanced non-small cell lung cancer with a BRAF V600 mutation.
Anaplastic Thyroid Cancer (ATC): Dabrafenib is indicated, in combination with trametinib, for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options.

Hypersensitivity to the active substance or to any of the excipients.

When dabrafenib is given in combination with trametinib, the SmPC of trametinib must be consulted prior to intiation of combination treatment. For additional information on warnings and precautions associated with trametinib treatment, please refer to the trametinib SmPC.
BRAF V600 testing: The efficacy and safety of dabrafenib have not been established in patients with wild-type BRAF melanoma therefore dabrafenib should not be used in patients with wild-type BRAF melanoma.
Dabrafenib in combination with trametinib in patients who have progressed on a BRAF inhibitor: There are limited data in patients taking the combination of dabrafenib with trametinib who have progressed on a prior BRAF inhibitor. These data show that the efficacy of the
combination will be lower in these patients. Therefore, other treatment options should be considered before treatment with the combination in this prior BRAF inhibitor treated population. The sequencing of treatments following progression on a BRAF inhibitor therapy has not been established.
New Malignancies: New malignancies, cutaneous and non-cutaneous, can occur when dabrafenib is used as monotherapy or in combination with trametinib.
Cutaneous Squamous Cell Carcinoma (cuSCC): Cases of cuSCC (including keratoacanthoma) have been reported in patients treated with dabrafenib alone and in combination with trametinib. It is recommended that skin examination be performed prior to initiation of therapy with dabrafenib and monthly throughout treatment and for up to six months after treatment for cuSCC. Monitoring should continue for 6 months following discontinuation of dabrafenib or until initiation of another anti-neoplastic therapy.
Haemorrhage: Haemorrhagic events, including major haemorrhagic and fatal haemorrhages, have occurred in patients taking the combination of dabrafenib with trametinib. Please refer to the trametinib Prescribing Information for additional information.
Visual impairment: In clinical trials ophthalmologic reactions, including uveitis, iridocyclitis and/or iritis have been reported in patients treated with dabrafenib as monotherapy and in combination with trametinib. Patients should be routinely monitored for visual signs and symptoms (such as
change in vision, photophobia and eye pain) while on therapy.
Pyrexia: Fever has been reported in clinical trials with dabrafenib as monotherapy and in combination with trametinib. The onset of these serious non-infectious febrile events was typically within the first month of dabrafenib as monotherapy. The incidence and severity of pyrexia are increased with combination therapy. Therapy should be interrupted if the patient’s temperature is ≥38ºC. 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.
LVEF reduction/Left ventricular dysfunction: Dabrafenib in combination with trametinib has been reported to decrease LVEF. No dose modification of dabrafenib is required when taken in combination with trametinib.
Renal failure: Renal failure has been identified in <1% of patients treated with dabrafenib alone and in ≤1% of patients treated with dabrafenib in combination with trametinib. Observed cases were generally associated with pyrexia and dehydration and responded well to dose interruption and general supportive measures. Granulomatous nephritis has been reported. Patients should be routinely monitored for serum creatinine while on therapy. If creatinine increases, dabrafenib may need to be interrupted as clinically appropriate. Dabrafenib has not been studied in patients with renal insufficiency (defined as creatinine >1.5 x ULN) therefore caution should be used in this setting.
Hepatic events: It is recommended that patients receiving treatment with dabrafenib in combination with trametinib have liver function monitored every four weeks for 6 months after treatment initiation with trametinib. Liver monitoring may be continued thereafter as clinically indicated.
Hypertension: Elevations in blood pressure have been reported in association with dabrafenib in combination with trametinib, in patients with or without pre-existing hypertension.
Interstitial lung disease (ILD)/Pneumonitis: Cases of pneumonitis or ILD have been reported in clinical trials with dabrafenib in combination with trametinib. If dabrafenib is being used in combination with trametinib then therapy with dabrafenib may be continued at the same dose.
Rash: Rash has been observed in about 24% of patients in clinical trials when dabrafenib is used in combination with trametinib. The majority of these cases were Grade 1 or 2 and did not require any dose interruptions or dose reductions.
Rhabdomyolysis: Rhabdomyolysis has been reported in patients taking dabrafenib in combination with trametinib.
Pancreatitis: Pancreatitis has been reported in <1% of patients treated with dabrafenib. Unexplained abdominal pain should be promptly investigated to include measurement of serum amylase and lipase. Patients should be closely monitored when restarting dabrafenib after an episode of pancreatitis.
Deep vein thrombosis /Pulmonary embolism: Pulmonary embolism or deep vein thrombosis can occur when dabrafenib is used in combination with trametinib. If patients develop symptoms of pulmonary embolism or deep vein thrombosis such as shortness of breath, chest pain, or arm or leg swelling, they should immediately seek medical care. Permanently discontinue trametinib and dabrafenib for lifethreatening pulmonary embolism.
Severe cutaneous adverse reactions: Cases of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be lifethreatening or fatal, have been reported during treatment with dabrafenib/trametinib combination therapy. Before initiating treatment, patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of SCARs appear, dabrafenib and trametinib should be withdrawn.
Gastrointestinal disorders: Colitis and gastrointestinal perforation, including fatal outcome, have been reported in patients taking dabrafenib in combination with trametinib.
Sarcoidosis: Cases of sarcoidosis have been reported in patients treated with dabrafenib in combination with trametinib, mostly involving the skin, lung, eye and lymph nodes. In the majority of the cases, treatment with dabrafenib and trametinib was maintained. In case of a diagnosis of sarcoidosis, relevant treatment should be considered. It is important not to misinterpret sarcoidosis as disease progression.
Haemophagocytic lymphohistiocytosis: 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. 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.
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. 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 metabolizing enzymes or transporters 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. 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 prescribing information for full details.

The most common adverse reactions (incidence ≥15%) for dabrafenib monotherapy were: hyperkeratosis, headache, pyrexia, arthralgia, fatigue, nausea, papilloma, alopecia, rash and vomiting.
The most common adverse reactions (incidence ≥20%) for dabrafenib in combination with trametinib were: pyrexia, fatigue,nausea, chills, headache, diarrhoea, vomiting, arthralgia and rash.
See prescribing information for full details.

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

Pregnancy: Women of childbearing potential must use effective methods of contraception during therapy and for 4 weeks following discontinuation of dabrafenib and 4 months following the last dose of trametinib when given in combination with dabrafenib. Dabrafenib may decrease the efficacy of hormonal contraceptives and an alternate method of contraception, such as barrier methods, should be used. There are no data from the use of dabrafenib in pregnant women. Animal studies have shown reproductive toxicity and embryofoetal developmental toxicities, including teratogenic effects. Dabrafenib should not be administered to pregnant women unless the potential benefit to the mother outweighs the possible risk to the foetus. If the patient becomes pregnant while taking dabrafenib, the patient should be informed of the potential hazard to the foetus. Please see trametinib SmPC when used in combination with trametinib.
Lactation: It is not known whether dabrafenib is excreted in human milk. Because many medicinal products are excreted in human milk, a risk to the breast-feeding child cannot be excluded. A decision should be made whether to discontinue breast-feeding or discontinue dabrafenib, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

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

Before/after meal: Patients should take dabrafenib as monotherapy or in combination with trametinib at least one hour prior to or two hours after a meal due to the effect of food on dabrafenib absorption.
Storage: Do not store above 30°C. The expiry date of the product is indicated on the label and packaging. Use within 6 months after opening.