Each hard capsule contains dabrafenib mesilate equivalent to 50 mg of dabrafenib.
Tafinlar 75 mg hard capsules
Each hard capsule contains dabrafenib mesilate equivalent to 75 mg of dabrafenib.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Hard capsule (capsule).
Tafinlar 50 mg hard capsules
Opaque dark red capsules, approximately 18 mm long, with capsule shell imprinted with 'GS TEW' and '50 mg'.
Tafinlar 75 mg hard capsules
Opaque dark pink capsules, approximately 19 mm long, with capsule shell imprinted with 'GS LHF' and '75 mg'.
4. Clinical particulars
4.1 Therapeutic indications
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 (see sections 4.4 and 5.1).
4.2 Posology and method of administration
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.
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 BRAF wild-type melanoma (see sections 4.4 and 5.1).
Posology
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).
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.
Dose modification
Two dabrafenib capsule strengths, 50 mg and 75 mg, are available to effectively manage dose modification requirements.
The management of adverse reactions may require treatment interruption, dose reduction, or treatment discontinuation (see Tables 1 and 2).
Dose modifications or interruptions are not recommended for adverse reactions of cutaneous squamous cell carcinoma (cuSCC) or new primary melanoma (see section 4.4).
Therapy should be interrupted if the patient's temperature is ≥ 38.5°C. Patients should be eva luated for signs and symptoms of infection (see section 4.4).
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, withhold dabrafenib until resolution of ocular inflammation and then restart dabrafenib reduced by one dose level (see section 4.4).
Recommended dose level reductions and recommendations for dose modifications are provided in Table 1 and Table 2, respectively.
Table 1: Recommended dose level reductions
Dose level
Dabrafenib dose
Used as monotherapy or in combination with trametinib
Trametinib dose*
Only when used in combination with dabrafenib
Starting dose
150 mg BID
2 mg QD
1st dose reduction
100 mg BID
1.5 mg QD
2nd dose reduction
75 mg BID
1 mg QD
3rd dose reduction (combination only)
50 mg BID
1 mg QD
Dose adjustment for dabrafenib below 50 mg BID is not recommended, whether used as monotherapy or in combination with trametinib. Dose adjustment for trametinib below 1 mg QD is not recommended, when used in combination with dabrafenib.
*Please refer to the trametinib SmPC, Posology and method of administration, for dosing instructions for treatment with trametinib monotherapy
Table 2: Dose modification schedule based on the grade of any Adverse Events (AE)
Grade (CTC-AE)*
Recommended dabrafenib dose modifications
Used as monotherapy or in combination with trametinib
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 0-1 and reduce by one dose level when resuming therapy.
Grade 4
Discontinue permanently, or interrupt therapy until grade 0-1 and reduce by one dose level when resuming therapy.
* The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events (CTC-AE) v4.0
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 150 mg twice daily.
If treatment related toxicities occur when dabrafenib is used in combination with trametinib, then both treatments 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 pyrexia, uveitis, RAS mutation positive non-cutaneous malignancies and QT prolongation (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 modification exceptions (where only one of the two therapies is dose reduced) for selected adverse reactions
Pyrexia
When dabrafenib is used alone and in combination with trametinib, therapy with dabrafenib should be interrupted if the patient's temperature is ≥ 38.5oC (please refer to Table 2 for dose modification guidance). Trametinib should be continued at the same dose. 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 eva luated for signs and symptoms of infection and if necessary treated in line with local practice (see section 4.4).
Upon resolution of pyrexia dabrafenib should be restarted with appropriate anti-pyretic prophylaxis, 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.
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 should 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.
QT prolongation
If during treatment the QTc exceeds 500 msec, dabrafenib treatment should be temporarily interrupted, electrolyte abnormalities (including magnesium) should be corrected, and cardiac risk factors for QT prolongation (e.g. congestive heart failure, bradyarrhythmias) should be controlled. Re-initiation of treatment should occur once the QTc decreases below 500 msec and at a lower dose. Permanent discontinuation of dabrafenib treatment is recommended if the QTc increase meets values of both > 500 msec and > 60 msec change from pre-treatment values. No dose modification of trametinib is required when taken in combination with dabrafenib.
Left ventricular ejection fraction (LVEF) reduction/Left ventricular dysfunction
If dabrafenib is being used in combination with trametinib and absolute decrease of > 10% in LVEF compared to baseline and the ejection fraction is below the institution's lower limit of normal (LLN), please refer to the trametinib SmPC (see section 4.2) for dose modification instructions for trametinib. No dose modification of dabrafenib is required when taken in combination with trametinib.
Retinal vein occlusion (RVO) and Retinal pigment epithelial detachment (RPED)
If patients report new visual disturbances such as diminished central vision, blurry vision, or loss of vision at any time while on combination therapy with dabrafenib and trametinib, please refer to the trametinib SmPC (see 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, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations, please refer to the trametinib SmPC (see 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.
Non-Caucasian patients
The safety and efficacy of dabrafenib in non-Caucasian patients have not been established. No data are available.
Elderly
No adjustment of the initial dose is required in patients > 65 years of age.
Renal impairment
No dose adjustment is required for patients with mild or moderate renal impairment. There are no clinical data in subjects 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 when administered as monotherapy or in combination with trametinib.
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 (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 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 (see section 5.3).
Method of administration
The dabrafenib capsules are to be swallowed whole with water. The capsules should not be chewed or opened and should not be mixed with food or liquids due to chemical instability of dabrafenib.
It is recommended that the doses of dabrafenib be taken at similar times every day, leaving an interval of approximately 12 hours between doses. When dabrafenib and trametinib are taken in combination, 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 dabrafenib.
Dabrafenib should be taken at least one hour before, or at least 2 hours after a meal.
If a patient vomits after taking dabrafenib, the patient should not retake the dose and should take the next scheduled dose.
Please refer to trametinib SmPC for information on method of administration when given in combination with dabrafenib.
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
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 (see sections 4.2 and 5.1).
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 (see section 5.1). Therefore, other treatment options should be considered before treatment with the combination in this prior BRAF inhibitor treated population. The sequencing of treatments following progression on a BRAF inhibitor therapy has not been established.
Trametinib in combination with dabrafenib in patients with brain metastases
The safety and efficacy of the combination of dabrafenib and trametinib has not been eva luated in patients with a BRAF V600 mutation-positive melanoma which has metastasised to the brain.
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 (see section 4.8). In the phase III study MEK115306, cuSCC occurred in 3% (6/209) of patients receiving trametinib in combination with dabrafenib and 10% (22/211) of patients receiving dabrafenib as a single agent. In the phase III study MEK116513, cuSCC occurred in 1% (5/350) of patients receiving trametinib in combination with dabrafenib and 18% (63/349) of patients receiving vemurafenib as a single agent. The median time to diagnosis of the first occurrence of cuSCC in study MEK115306 was 223 days (range 56 to 510 days) in the combination therapy arm and 60 days (range 9 to 653 days) in the dabrafenib monotherapy arm.
It is recommended that skin examination be performed prior to initiation of therapy with dabrafenib and monthly throughout treatment and for up to six months after treatment for cuSCC. Monitoring should continue for 6 months following discontinuation of dabrafenib or until initiation of another anti-neoplastic therapy.
Cases of cuSCC should be managed by dermatological excision and dabrafenib treatment or, if taken in combination, dabrafenib and trametinib should be continued without any dose adjustment. Patients should be instructed to immediately inform their physician if new lesions develop.
New primary melanoma
New primary melanomas have been reported in clinical trials in patients treated with dabrafenib. These cases were identified within the first 5 months of dabrafenib as monotherapy. Cases of new primary melanoma can be managed with excision and do not require treatment modification. Monitoring for skin lesions should occur as described for cuSCC.
Non-cutaneous secondary/recurrent malignancy
In vitro experiments have demonstrated paradoxical activation of mitogen activated protein kinase (MAP kinase) signalling in BRAF wild type cells with RAS mutations when exposed to BRAF inhibitors. This may lead to increased risk of non-cutaneous malignancies with dabrafenib exposure (see section 4.8) when RAS mutations are present. RAS-associated malignancies have been reported in clinical trials, both with another BRAF inhibitor (Chronic myelomonocytic leukemia and non-cutaneous SCC of the head and neck) as well as with dabrafenib monotherapy (pancreatic adenocarcinoma, bile duct adenocarcinoma) and with dabrafenib in combination with the MEK inhibitor, trametinib (colorectal cancer, pancreatic cancer).
Prior to initiation of treatment patients should undergo a head and neck examination with minimally visual inspection of oral mucosa and lymph node palpation, as well as chest/abdomen Computerised Tomography (CT) scan. During treatment patients should be monitored as clinically appropriate which may include a head and neck examination every 3 months and a chest/abdomen CT scan every 6 months. Anal examinations and pelvic examinations (for women) are recommended before and at the end of treatment or when considered clinically indicated. Complete blood cell counts should be performed as clinically indicated.
Carefully consider benefits and risks before administering dabrafenib to patients with a prior or concurrent cancer associated with RAS mutations. No dose modification of trametinib is required when taken in combination with dabrafenib.
Following discontinuation of dabrafenib, monitoring for non-cutaneous secondary/recurrent malignancies should continue for up to 6 months or until initiation of another anti-neoplastic therapy. Abnormal findings should be managed according to clinical practices.
Haemorrhage
Haemorrhagic events, including major haemorrhagic and fatal haemorrhages, have occurred in patients taking the combination of dabrafenib with trametinib (see section 4.8). Please refer to the trametinib SmPC for additional information (see section 4.4).
Visual impairment
In clincial trials ophthalmologic reactions, including uveitis, iridocyclitis and iritis/or have been reported in patients treated with dabrafenib as monotherapy and in combination with trametinib. Patients should be routinely monitored for visual signs and symptoms (such as, change in vision, photophobia and eye pain) while on therapy.
No dose modifications are required as long as effective local therapies can control ocular inflammation. If uveitis does not respond to local ocular therapy, withhold dabrafenib until resolution of ocular inflammation and then restart dabrafenib reduced by one dose level. No dose modification of trametinib is required when taken in combination with dabrafenib following diagnosis of uveitis.
RPED and RVO may occur with dabrafenib in combination with trametinib. Please refer to the trametinib SmPC (see section 4.4). No dose modification of dabrafenib is required when taken in combination with trametinib following diagnosis of RVO or RPED.
Pyrexia
Fever has been reported in clinical trials with dabrafenib as monotherapy and in combination with trametinib (see section 4.8). In 1 % of patients in clinical trials with dabrafenib monotherapy, serious non-infectious febrile events were identified defined as fever accompanied by severe rigors, dehydration, hypotension and/or acute renal insufficiency of pre-renal origin in subjects with normal baseline renal function (see section 4.8). The onset of these serious non-infectious febrile events was typically within the first month of dabrafenib as monotherapy. Patients with serious non-infectious febrile events responded well to dose interruption and/or dose reduction and supportive care.
The incidence and severity of pyrexia are increased with combination therapy. In the combination therapy arm of study MEK115306 pyrexia was reported in 57% (119/209) of patients with 7% Grade 3, as compared to the dabrafenib monotherapy arm with 33% (69/211) of patients reporting pyrexia, 2% Grade 3.
For patients who received dabrafenib in combination with trametinib and developed pyrexia, approximately half of the first occurrences of pyrexia happened within the first month of therapy and approximately one-third of the patients had 3 or more events.
Therapy with dabrafenib should be interrupted if the patient's temperature is ≥ 38.5°C (please refer to Table 2 for dose modification guidance). Patients should be eva luated for signs and symptoms of infection. Dabrafenib can be restarted once the fever resolves with appropriate prophylaxis using non-steroidal anti-inflammatory medicinal products or paracetamol. The use of oral corticosteroids should be considered in those instances in which anti-pyretics are insufficient. If fever is associated with other severe signs or symptoms, dabrafenib should be restarted at a reduced dose once fever resolves and as clinically appropriate (see section 4.2). No dose modification of trametinib is required when taken in combination with dabrafenib.
LVEF reduction/Left ventricular dysfunction
Dabrafenib in combination with trametinib has been reported to decrease LVEF (see section 4.8). Please refer to the trametinib SmPC for additional information (see section 4.4). No dose modification of dabrafenib is required when taken in combination with trametinib.
Renal failure
Renal failure has been identified in < 1 % of patients treated with dabrafenib alone and in ≤1 % of patients treated with dabrafenib in combination with trametinib. Observed cases were generally associated with pyrexia and dehydration and responded well to dose interruption and general supportive measures. Granulomatous nephritis has been reported (see section 4.8). Patients should be routinely monitored for serum creatinine while on therapy. If creatinine increases, dabrafenib may need to be interrupted as clinically appropriate. Dabrafenib has not been studied in patients with renal insufficiency (defined as creatinine > 1.5 x ULN) therefore caution should be used in this setting (see section 5.2).
Hepatic Events
Hepatic adverse events have been reported in clinical trials with dabrafenib in combination with trametinib (see section 4.8). It is recommended that patients receiving treatment with dabrafenib in combination with trametinib have liver function monitored every four weeks for 6 months after treatment initiation with trametinib. Liver monitoring may be continued thereafter as clinically indicated. Please refer to the trametinib SmPC for additional information.
Hypertension
Elevations in blood pressure have been reported in association with dabrafenib in combination with trametinib, in patients with or without pre-existing hypertension (see section 4.8). Please refer to the trametinib SmPC for additional information.
Interstitial lung disease (ILD)/Pneumonitis
Cases of pneumonitis or ILD have been reported in clinical trials with dabrafenib in combination with trametinib. Please refer to the trametinib SmPC section 4.4 for additional information. If dabrafenib is being used in combination with trametinib then therapy with dabrafenib may be continued at the same dose.
Rash
Rash has been observed in about 25% of patients in clincial studies when dabrafenib is used in combination with trametinib. Please refer to the trametinib SmPC section 4.4 for additional information.
Rhabdomyolysis
Rhabdomyolysis has been reported in patients taking dabrafenib in combination with trametinib (see section 4.8). Please refer to the trametinib SmPC section 4.4 for additional information.
Pancreatitis
Pancreatitis has been reported in < 1 % of dabrafenib-treated subjects as monotherapy and in combination with trametinib. One of the events occurred on the first day of dabrafenib dosing and recurred following re-challenge 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 re-starting dabrafenib after an episode of pancreatitis.
QT prolongation
Worst-case QTc prolongation of > 60 millisecond (msec) was observed in 3 % of dabrafenib-treated subjects (One > 500 msec in the integrated safety population). In the phase III study MEK115306 no patients treated with trametinib in combination with dabrafenib had worst-case QTcB prolongation to >500 msec; QTcB was increased more than 60 msec from baseline in 1 % (3/209) of patients. In the phase III study MEK116513 four patients (1%) treated with trametinib in combination with dabrafenib had a QTcB Grade 3 increase (> 500 msec). Two of these patients had a QTcB Grade 3 increase (> 500 msec) that was also an increase > 60 msec from Baseline.
Treatment with dabrafenib is not recommended in patients with uncorrectable electrolyte abnormalities (including magnesium), long QT syndrome or who are taking medicinal products known to prolong the QT interval.
Electrocardiogram (ECG) and electrolytes (including magnesium) must be monitored in all patients before treatment with dabrafenib, after one month of treatment and after dose modification. Further monitoring is recommended in particular in patients with moderate to severe hepatic impairment monthly during the first 3 months of treatment followed by every 3 months thereafter or more often as clinically indicated. Initiation of treatment with dabrafenib is not recommended in patients with QTc > 500 msec. If during treatment the QTc exceeds 500 msec, dabrafenib treatment should be temporarily interrupted, electrolyte abnormalities (including magnesium) should be corrected, and cardiac risk factors for QT prolongation (e.g. congestive heart failure, bradyarrhythmias) should be controlled. Re-initiation of treatment should occur once the QTc decreases below 500 msec and at a lower dose as described in Table 2. Permanent discontinuation of dabrafenib treatment is recommended if the QTc increase meets values of both > 500 msec and > 60 msec change from pre-treatment values (see section 4.2). No dose modification of trametinib is required when taken in combination with dabrafenib.
Deep vein thrombosis (DVT)/Pulmonary embolism (PE)
Pulmonary embolism or deep vein thrombosis can occur when dabrafenib is used in combination with trametinib. If patients develop symptoms of pulmonary embolism or deep vein thrombosis such as shortness of breath, chest pain, or arm or leg swelling, they should immediately seek medical care. Permanently discontinue trametinib and dabrafenib for life-threatening pulmonary embolism.
Effects of other substances 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).
Agents that increase gastric pH might decrease the bioavailability of dabrafenib and should be avoided when possible (see section 4.5).
Effects of dabrafenib on other substances
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 Normalized 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).
4.5 Interaction with other medicinal products and other forms of interaction
Effect of other medicinal products on dabrafenib
Dabrafenib is a substrate for the metabolising enzymes CYP2C8 and CYP3A4, while the active metabolites hydroxy-dabrafenib and desmethyl-dabrafenib are CYP3A4 substrates. Medicinal products that are strong inhibitors or inducers of CYP2C8 or CYP3A4 are therefore likely to increase or decrease, respectively, dabrafenib concentrations. Alternative agents should be considered during administration with dabrafenib when possible. 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.
Administration of ketoconazole (a CYP3A4 inhibitor) 400 mg once daily, with dabrafenib 75 mg twice daily, resulted in a 71 % increase in dabrafenib AUC and a 33 % increase in dabrafenib Cmax relative to administration of dabrafenib 75 mg twice daily alone. Co-administration resulted in increases in hydroxy- and desmethyl-dabrafenib AUC (increases of 82 % and 68 %, respectively). A decrease of 16 % in AUC was noted for carboxy-dabrafenib.
Administration of gemfibrozil (a CYP2C8 inhibitor) 600 mg twice daily, with dabrafenib 75 mg twice daily, resulted in a 47 % increase in dabrafenib AUC but did not alter dabrafenib Cmax relative to administration of dabrafenib 75 mg twice daily alone. Gemfibrozil had no clinically relevant effect on the systemic exposure to dabrafenib metabolites (≤ 13 %).
Dabrafenib solubility is pH-dependent with decreased solubility at higher pH. Medicinal products such as proton pump inhibitors that inhibit gastric acid secretion to elevate gastric pH may decrease the solubility of dabrafenib and reduce its bioavailability. No clinical study has been conducted to eva luate the effect of pH on dabrafenib pharmacokinetics. Due to the theoretical risk that pH-elevating agents may decrease oral bioavailability and exposure to dabrafenib, these medicinal products that increase gastric pH should, if possible, be avoided during treatment with 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 Pgp may also be induced as well as other transporters, e g MRP-2, BCRP and OATP1B1/1B3.
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 61 % and 74 %, respectively with co-administration of repeat dose dabrafenib using a formulation with lower bioavailability than dabrafenib formulation.
Administration of dabrafenib 150 mg twice daily and warfarin resulted in a decrease in AUC of S- and R- warfarin and of 37 % and 33 % 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)
• Anticancer agents (e.g. cabazitaxel)
• Anticoagulants (e.g. acenocoumarol, warfarin (see section 4.4))
• Statins metabolized 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 may increase and patients should be monitored for toxicity and dosage 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 of human organic anion transporting polypeptide (OATP) 1B1 (OATP1B1) and OATP1B3 and clinical relevance can not be excluded. Therefore caution is recommended at co-administration of dabrafenib and OATB1B1 or OATP1B3 substrates such as statins.
Although dabrafenib and its metabolites, hydroxy-dabrafenib, carboxy-dabrafenib and desmethyl-dabrafenib, were inhibitors of humanorganic anion transporter (OAT) 1 and OAT3 in vitro, the risk of a drug-drug interaction is minimal based on clinical exposure. Dabrafenib and desmethyl-dabrafenib were also shown to be moderate inhibitors of human breast cancer resistance protein (BCRP); however, based on clinical exposure, the risk of a drug-drug interaction is minimal.
Combination with trametinib
Co-administration of repeat dosing of trametinib 2 mg QD and dabrafenib 150 mg BID resulted in no clinically meaningful changes in trametinib or dabrafenib Cmax and AUC with increases of 16 and 23 %, respectively, in dabrafenib Cmax and AUC. A small decrease in trametinib bioavailability, corresponding to a decrease in AUC of 12 %, was estimated when trametinib is administered in combination with dabrafenib, a CYP3A4 inducer, using a population PK analysis.
When dabrafenib is used in combination with trametinib refer to the guidance for medicinal product interactions found in sections 4.4 and 4.5 of dabrafenib and trametinib SmPC.
Effect of food on dabrafenib
Patients should take dabrafenib as monotherapy or in combination with trametinib at least one hour prior to or two hours after a meal due to the effect of food on dabrafenib absorption (see section 5.2).
Paediatric population
Interaction studies have only been performed in adults.
4.6 Fertility, pregnancy and lactation
Women of chilbearing potential/Contraception in females
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 (see section 4.5).
Pregnancy
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 (see section 5.3). Dabrafenib should not be administered to pregnant women unless the potential benefit to the mother outweighs the possible risk to the foetus. If the patient becomes pregnant while taking dabrafenib, the patient should be informed of the potential hazard to the foetus. Please see trametinib SmPC ( see section 4.6) when used in combination with trametinib.
Breast-feeding
It is not known whether dabrafenib is excreted in human milk. Because many medicinal products are excreted in human milk, a risk to the breast-feeding child cannot be excluded. A decision should be made whether to discontinue breastfeeding or discontinue dabrafenib, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Fertility
There are no data in humans for dabrafenib as monotherapy or in combination with trametinib. Dabrafenib may impair male and female fertility as adverse effects on male and female reproductive organs have been seen in animals (see section 5.3). Male patients taking dabrafenib as monotherapy or in combination with trametinib should be informed of the potential risk for impaired spermatogenesis, which may be irreversible.
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 and eye problems to affect these activities.
4.8 Undesirable effects
Summary of the safety profile
The dabrafenib monotherapy safety profile is based on data from five clinical studies and included 578 patients with melanoma. The most frequently occurring adverse drug reactions (ADRs) (≥ 15 %) reported with dabrafenib were hyperkeratosis, headache, pyrexia, arthralgia, fatigue, nausea, papilloma, alopecia, rash and vomiting.
The safety of dabrafenib in combination with trametinib has been eva luated in 2 Phase III studies, MEK115306 and MEK116513, where an analysis of the safety of dabrafenib in combination with trametinib has been conducted in 209 and 350 patients, respectively, with BRAF V600 mutation positive unresectable or metastatic melanoma receiving dabrafenib (150 mg BID) and trametinib (2 mg QD) combination therapy (see section 5.1 combination therapy). The most common adverse reactions (≥ 20 %) for dabrafenib and trametinib combination therapy include pyrexia, fatigue, nausea, headache, chills, diarrhoea, rash, arthralgia, hypertension, vomiting and cough.
Tabulated summary of adverse reactions
ADRs which were reported are listed below by MedDRA body system organ class and by frequency. The following convention has been utilised for the classification of frequency:
Very common
Common
Uncommon
Rare
Not known
≥ 1/10
≥ 1/100 to < 1/10
≥ 1/1,000 to < 1/100
≥ 1/10,000 to < 1/1,000
(cannot be estimated from the available data)
Dabrafenib monotherapy
Table 3: Adverse reactions reported in melanoma trials
System Organ Class
Frequency (all grades)
Adverse Reactions
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Very common
Papilloma
Common
Cutaneous squamous cell carcinoma
Common
Seborrhoeic keratosis
Common
Acrochordon (skin tags)
Common
Basal cell carcinoma
Uncommon
New primary melanoma
Immune system disorders
Uncommon
Hypersensitivity
Uncommon
Panniculitis
Metabolism and nutrition disorders
Very common
Decreased appetite
Common
Hypophosphataemia
Common
Hyperglycaemia
Nervous system disorders
Very common
Headache
Eye disorders
Uncommon
Uveitis
Respiratory, thoracic and mediastinal disorders
Very common
Cough
Gastrointestinal disorders
Very common
Nausea
Very common
Vomiting
Very common
Diarrhoea
Common
Constipation
Uncommon
Pancreatitis
Skin and subcutaneous tissue disorders
Very common
Hyperkeratosis
Very common
Alopecia
Very common
Rash
Very common
Palmar –plantar erythrodysaesthesia syndrome
Common
Dry skin
Common
Pruritus
Common
Actinic keratosis
Common
Skin lesion
Common
Erythema
Musculoskeletal and connective tissue disorders
Very common
Arthralgia
Very common
Myalgia
Very common
Pain in extremity
Renal and urinary disorders
Uncommon
Renal failure, acute renal failure
Uncommon
Nephritis
General disorders and administration site conditions
Very common
Pyrexia
Very common
Fatigue
Very common
Chills
Very common
Asthenia
Common
Influenza-like illness
Investigations
Common
LVEF decrease
Uncommon
QT prolongation
Dabrafenib and trametinib combination therapy
Table 4: Adverse reactions occurring in the two randomised phase III combination studies MEK115306 (n = 209) and MEK116513a (n=350)
System Organ Class
Frequency (all grades)
Adverse Reactions
Infections and Infestations
Very Common
Urinary tract infection
Nasopharyngitis
Common
Cellulitis
Folliculitis
Paronychia
Rash pustular
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
