Table of Contents
1. Name of the medicinal product
2. Qualitative and quantitative composition
3. Pharmaceutical form
4. Clinical particulars
4.1 Therapeutic indications
4.2 Posology and method of administration
4.3 Contraindications
4.4 Special warnings and precautions for use
4.5 Interaction with other medicinal products and other forms of interaction
4.6 Fertility, pregnancy and lactation
4.7 Effects on ability to drive and use machines
4.8 Undesirable effects
4.9 Overdose
5. Pharmacological properties
5.1 Pharmacodynamic properties
5.2 Pharmacokinetic properties
5.3 Preclinical safety data
6. Pharmaceutical particulars
6.1 List of excipients
6.2 Incompatibilities
6.3 Shelf life
6.4 Special precautions for storage
6.5 Nature and contents of container
6.6 Special precautions for disposal and other handling
7. Marketing authorisation holder
8. Marketing authorisation number(s)
9. Date of first authorisation/renewal of the authorisation
10. Date of revision of the text
1. Name of the medicinal product
Tafinlar® 50 mg hard capsules
Tafinlar® 75 mg hard capsules
2. Qualitative and quantitative composition
Each hard capsule contains dabrafenib mesilate equivalent to 50 mg of dabrafenib.
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).
Opaque dark red capsules, approximately 18 mm long, with capsule shell imprinted with 'GS TEW' and '50 mg'.
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 is indicated in monotherapy for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation (see section 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 is 150 mg (two 75 mg capsules) twice daily (corresponding to a total daily dose of 300 mg). Dabrafenib should be taken at least one hour before, or at least 2 hours after a meal, and leaving an interval of approximately 12 hours between doses. Dabrafenib should be taken at similar times every day to increase patient compliance.
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 is missed, it should not be taken if it is less than 6 hours until the next 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).
Recommended dose level reductions and recommendations for dose modifications are provided in Table 1 and Table 2, respectively. Posology adjustments resulting in a dose lower than 50 mg twice daily are not recommended.
Table 1: Recommended dabrafenib dose level reductions
Dose level
Resulting dose/schedule
Full dose
150 mg twice daily
First reduction
100 mg twice daily
Second reduction
75 mg twice daily
Third reduction
50 mg twice daily
Table 2: Dabrafenib dose modification schedule based on the grade of any Adverse Events (AE)
Grade (CTC-AE)*
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 0-1 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 dose should not exceed 150 mg twice daily.
Non-Caucasian patients
The safety and efficacy of dabrafenib in non-Caucasian patients have not been established. No data are available.
Older people
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.
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.
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 capsules are to be swallowed whole with water. They should not be chewed or crushed and should not be mixed with food or liquids due to chemical instability of 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
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).
Pyrexia
Fever has been reported in clinical trials. In 1 % of patients in clinical trials, 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 therapy. Patients with serious non-infectious febrile events responded well to dose interruption and/or dose reduction and supportive care.
Therapy with dabrafenib should be interrupted if the patient's temperature is ≥ 38.5°C. 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. 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).
Cutaneous Squamous Cell Carcinoma (cuSCC)
Cases of cuSCC (which include those classified as keratoacanthoma or mixed keratoacanthoma subtype) have been reported in patients treated with dabrafenib (see section 4.8). It is recommended that skin examination be performed prior to initiation of therapy with dabrafenib and monthly throughout treatment and for up to six months after treatment 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 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. These cases were identified within the first 5 months of therapy, were managed with excision and did 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 when RAS mutations are present. Cases of RAS-associated malignancies have been reported, both with another BRAF inhibitor (Chronic myelomonocytic leukemia and non-cutaneous SCC of the head and neck) and with dabrafenib when administered 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.
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.
Renal failure
Renal failure has been identified in < 1 % of patients treated with dabrafenib. 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).
Uveitis
Ophthalmologic reactions, including uveitis and iritis have been reported. Patients should be routinely monitored for visual signs and symptoms (such as, change in vision, photophobia and eye pain) while on therapy.
Pancreatitis
Pancreatitis has been reported in < 1 % of dabrafenib-treated subjects. One of the events occurred on the first day of 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). 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.
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 may result 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, 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.
Pharmacokinetic data showed an increase in repeat dose dabrafenib Cmax (26 %) and AUC (57 %) with ketoconazole (a CYP3A4 inhibitor), and increases in hydroxy- and desmethyl-dabrafenib AUC (increases of 48 and 61 %, respectively). A decrease of 33 % in AUC was noted for carboxy-dabrafenib.
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.
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, doxycyline)
• Anticancer agents (e.g. cabazitaxel)
• Anticoagulants (e.g. acenocoumarol, warfarin (see section 4.4))
• Antiepileptic (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 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.
Effect of food on dabrafenib
Patients should take dabrafenib 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. Dabrafenib may decrease the efficacy of hormonal contraceptives and an alternate method of contraception 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.
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. 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 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 safety profile is based on data from five clinical monotherapy 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.
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
≥ 1/10
Common
≥ 1/100 to < 1/10
Uncommon
≥ 1/1,000 to < 1/100
Rare
≥ 1/10,000 to < 1/1,000
Not known
(cannot be estimated from the available data)
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
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:
Ireland
IMB Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.imb.ie; e-mail: imbpharmacovigilance@imb.ie
United Kingdom
the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Description of selected adverse reactions
Pyrexia
Fever has been reported in clinical trials. In 1 % of patients in clinical trials, serious non-infectious febrile events were identified as fever accompanied by severe rigors, dehydration, hypotension and/or acute renal insufficiency or pre-renal origin in subjects with normal baseline renal function. The onset of these serious non-infectious febrile events was typically within the first month of therapy. Patients with serious non-infectious febrile events responded well to dose interruption and/or dose reduction and supportive care (see sections 4.2 and 4.4).
Cutaneous squamous cell carcinoma
Cutaneous squamous cell carcinomas (including those classified as keratoacanthoma or mixed keratoacanthoma subtype) occurred in 9 % of patients treated with dabrafenib. Approximately 70 % of events occurred within the first 12 weeks of treatment with a median time to onset of 8 weeks. Ninety-six percent of patients who developed cuSCC continued on treatment without dose modification.
New primary melanoma
New primary melanomas have been reported in clinical trials with dabrafenib. Cases were managed with excision and did not require treatment modification (see section 4.4).
Non-cutaneous malignancy
Activation of MAP-kinase signalling in BRAF wild type cells which are exposed to BRAF inhibitors may lead to increased risk of non-cutaneous malignancies, including those with RAS mutations (see section 4.4). Cases of RAS-driven malignancies have been seen with dabrafenib. Patients should be monitored as clinically appropriate.
QT prolongation
One subject in the integrated safety population experienced a QTcB > 500 ms and only 3 % experienced worst-case QTc prolongation of > 60 msec.
LVEF decrease
Decreased LVEF has been reported in 1 % of patients with most cases being asymptomatic and reversible. Patients with LVEF lower than the institutional lower limit of normal were not included in clinical trials with dabrafenib.
Arthralgia
Arthralgia was reported very commonly in clinical trials with dabrafenib (25 %) although these were mainly grade 1 and 2 in severity with Grade 3 occurring uncommonly (< 1 %) and no Grade 4 occurrences being reported.
Hypophosphataemia
Hypophosphataemia has been reported commonly in clinical trials with dabrafenib (7 %). It should be noted that approximately half of these occurrences (4 %) were Grade 3 in severity.
Pancreatitis
Pancreatitis has been reported in dabrafenib-treated subjects. 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 (see section 4.4).
Renal failure
Renal failure due to pyrexia-associated pre-renal azotaemia or granulomatous nephritis was uncommon; however dabrafenib has not been studied in patients with renal insufficiency (defined as creatinine > 1.5 x ULN). Caution should be used in this setting (see section 4.4).
Special populations
Elderly
Of the total number of patients in clinical studies of dabrafenib (N = 578), 22 % were 65 years of age and older, and 6 % were 75 years of age and older. Compared with younger subjects (< 65), more subjects ≥ 65 years old had adverse reactions that led to study drug dose reductions (22 % versus 12 %) or interruptions (39 % versus 27 %). In addition, older patients experienced more serious adverse reactions compared to younger patients (41 % versus 22 %). No overall differences in efficacy were observed between these subjects and younger subjects.
4.9 Overdose
There is no specific treatment for an overdose of dabrafenib. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitor, ATC code: L01XE23
Mechanism of action
Dabrafenib is an inhibitor of RAF kinases. Oncogenic mutations in BRAF lead to constitutive activation of the RAS/RAF/MEK/ERK pathway. BRAF mutations have been identified at a high frequency in specific cancers, including approximately 50 % of melanoma. The most commonly observed BRAF mutation is V600E which accounts for approximately 90 % of the BRAF mutations that are seen in melanoma.
Preclinical data generated in biochemical assays demonstrated that dabrafenib inhibits BRAF kinases with activating codon 600 mutations (Table 4).
Table 4: Kinase inhibitory activity of dabrafenib against RAF kinases
Kinase
Inhibitory concentration 50 (nM)
BRAF V600E
0.65
BRAF V600K
0.50
BRAF V600D
1.8
BRAF WT
3.2
CRAF WT
5.0
Dabrafenib demonstrated suppression of a downstream pharmacodynamic biomarker (phosphorylated ERK) and inhibited cell growth of BRAF V600 mutant melanoma cell lines, in vitro and in animal models.
In subjects with BRAF V600 mutation positive melanoma, administration of dabrafenib resulted in inhibition of tumour phosphorylated ERK relative to baseline.
Determination of BRAF mutation status
Before taking dabrafenib, patients must have BRAF V600 mutation-positive tumour status confirmed by a validated test. In the Phase II and III clinical trials, screening for eligibility required central testing for BRAF V600 mutation using a BRAF mutation assay conducted on the most recent tumour sample available. Primary tumour or tumour from a metastatic site was tested with an investigational use only assay (IUO). The IUO is an allele-specific polymerase chain reaction (PCR) assay performed on DNA extracted from formalin-fixed paraffin-embedded (FFPE) tumour tissue. The assay was specifically designed to differentiate between the V600E and V600K mutations. Only subjects with BRAF V600E or V600K mutation positive tumors were eligible for study participation.
Subsequently, all patient samples were re-tested using the bioMerieux (bMx) THxID BRAF validated assay, which has CE marking. The bMx THxID BRAF assay is an allele-specific PCR performed on DNA extracted from FFPE tumour tissue. The assay was designed to detect the BRAF V600E and V600K mutations with high sensitivity (down to 5 % V600E and V600K sequence in a background of wild-type sequence using DNA extracted from FFPE tissue). Non-clinical and clinical studies with retrospective bi-directional Sanger sequencing analyses have shown that the test also detects the less common BRAF V600D mutation and V600E/K601E mutation with lower sensitivity. Of the specimens from the non-clinical and clinical studies (n = 876) that were mutation positive by the THxID BRAF assay and subsequently were sequenced using the reference method, the specificity of the assay was 94 %.
Clinical efficacy and safety
The efficacy of dabrafenib in the treatment of adult patients with BRAF V600 mutation positive unresectable or metastatic melanoma has been eva luated in 3 studies (BRF113683 [BREAK-3], BRF113929 [BREAK-MB], and BRF113710 [BREAK-2]) including patients with BRAF V600E and/or V600K mutations.
Included in these studies were in total 402 subjects with BRAF V600E and 49 subjects with BRAF V600K mutation. Patients with melanoma driven by BRAF mutations other than V600E were excluded from the confirmatory trial and with respect to patients with the V600K mutation in single arm studies the activity appears lower than in V600E tumours.
No data is available in patients with melanoma harbouring BRAF V600 mutations others than V600E and V600K. Efficacy of dabrafenib in subjects previously treated with a protein kinase inhibitor has not been investigated.
Previously untreated patients (Results from the Phase III study [BREAK-3])
The efficacy and safety of dabrafenib were eva luated in a Phase III randomized, open-label study [BREAK 3] comparing dabrafenib to dacarbazine (DTIC) in previously untreated patients with BRAF V600E mutation positive advanced (unresectable Stage III) or metastatic (Stage IV) melanoma. Patients with melanoma driven by BRAF mutations other than V600E were excluded.
The primary objective for this study was to eva luate the efficacy of dabrafenib compared to DTIC with respect to progression-free survival (PFS) per investigator assessment. Patients on the DTIC arm were allowed to cross over to dabrafenib after independent radiographic confirmation of initial progression. Baseline characteristics were balanced between treatment groups. Sixty percent of patients were male and 99.6 % were Caucasian ; the median age was 52 years with 21 % of patients being ≥ 65 years, 98.4 % had ECOG status of 0 or 1, and 97 % of patients had metastatic disease.
At the pre-specified analysis with a 19 December 2011 data cut, a significant improvement in the primary endpoint of PFS (HR = 0.30; 95 % Cl 0.18, 0.51; p < 0.0001) was achieved. Efficacy results from the primary analysis and a post-hoc analysis with 6-months additional follow up are summarized in Table 5. Overall survival data from a further post-hoc analysis based on a 18 December 2012 data cut are shown in Figure 1.
Table 5: Efficacy in previously untreated patients (BREAK-3 Study, 25 June 2012)
Data as of December 19, 2011
Data as of June 25, 2012
Dabrafenib
N=187
DTIC
N=63
Dabrafenib
N=187
DTIC
N=63
Progression-free survival
Median, months (95 % CI)
5.1 (4.9, 6.9)
2.7 (1.5, 3.2)
6.9 (5.2,9.0)
2.7 (1.5,3.2)
HR (95 % CI)
0.30 (0.18, 0.51)
P < 0.0001
0.37 (0.24, 0.58)
P < 0.0001
Overall responsea
% (95 % CI)
53 (45.5, 60.3)
19 (10.2, 30.9)
59 (51.4, 66.0)
24 (14, 36.2)
Duration of response
Median, months (95 % CI)
N=99
5.6 (4.8, NR)
N=12
NR (5.0, NR)
N=110
8.0 (6.6, 11.5)
N=15
7.6 (5.0, 9.7)
Abbreviations: CI: confidence interval; DTIC: dacarbazine; HR: hazard ratio; NR: not reached
a. Defined as confirmed complete +partial response.
As of 25 June 2012 cut-off, thirty five subjects (55.6 %) of the 63 randomized to DTIC had crossed over to dabrafenib and 63 % of subjects randomised to dabrafenib and 79 % of subjects randomised to DTIC had progressed or died. Median PFS after cross-over was 4.4 months.
Table 6: Survival data from the primary analysis and post-hoc analyses
Cut-off date
Treatment
Number of deaths (%)
Hazard Ratio (95% CI)
December 19, 2011
DTIC
9 (14%)
0.61 (0.25, 1.48) (a)
dabrafenib
21 (11%)
June 25, 2012
DTIC
21 (33%)
0.75 (0.44, 1.29) (a)
dabrafenib
55 (29%)
December 18, 2012
DTIC
28 (44%)
0.76 (0.48, 1.21) (a)
dabrafenib
78 (42%)
(a) Patients were not censored at the time of cross-over
Overall survival data from a further post-hoc analysis based on the 18 December 2012 data cut demonstrated a 12 month OS rate of 63 % and 70 % for DTIC and dabrafenib treatments respectively.
Figure 1: Kaplan-Meier curves of overall survival (BREAK-3) (18 December 2012)
Patients with brain metastases (Results from the Phase II study (BREAK-MB)
BREAK-MB was a multi-centre, open-label, two-cohort, Phase II study designed to eva luate the intracranial response of dabrafenib in subjects with histologically confirmed (Stage IV) BRAF-mutation positive (V600E or V600K) melanoma metastatic to the brain. Subjects were enrolled into Cohort A (subjects with no prior local therapy for brain metastasis) or Cohort B (subjects who received prior local therapy for brain metastasis).
The primary endpoint of the study was overall intracranial response rate (OIRR) in the V600E patient population, as assessed by investigators. The confirmed OIRR and other efficacy results per investigator assessment are presented in Table 7.
Table 7: Efficacy data in patients with brain metastases (BREAK-MB Study)
All Treated Subjects Population
BRAF V600E (Primary)
BRAF V600K
Cohort A
N=74
Cohort B
N=65
Cohort A
N=15
Cohort B
N=18
Overall intracranial response rate, % (95 % CI)a
39% (28.0, 51.2)
P < 0.001b
31% (19.9, 43.4)
P < 0.001b
7% (0.2, 31.9)
22% (6.4, 47.6)
Duration of intracranial response, median, months (95% CI)
N=29
4.6 (2.8, NR)
N=20
6.5 (4.6, 6.5)
N=1
2.9 (NR, NR)
N=4
3.8 (NR, NR)
Overall response, % (95% CI)a
38% (26.8, 49.9)
31% (19.9, 43.4)
0 (0, 21.8)
28% (9.7, 53.5)
Duration of response, median, months (95% CI)
N=28
5.1 (3.7, NR)
N=20
4.6 (4.6, 6.5)
NA
N=5
3.1 (2.8, NR)
Progression-free survival, median, months (95% CI)
3.7 (3.6, 5.0)
3.8 (3.6, 5.5)
1.9 (0.7, 3.7)
3.6 (1.8, 5.2)
Overall survival, median, months (95% CI)
Median, months
7.6 (5.9, NR)
7.2 (5.9, NR)
3.7 (1.6, 5.2)
5.0 (3.5, NR)
Abbreviations: CI: confidence interval; NR: not reached; NA: not applicable
a - Confirmed response.
b –This study was designed to support or reject the null hypothesis of OIRR ≤10% (based on historical results) in favour of the alternative hypothesis of OIRR ≥ 30% in BRAF V600E mutation positive subjects.
Patients who were previously untreated or failed at least one prior systemic therapy (Results from the Phase II [BREAK-2])
BRF113710 (BREAK-2) was a multi-centre, single-arm, study that enrolled 92 subjects with metastatic melanoma (Stage IV) with confirmed BRAF V600E or V600K mutation-positive melanoma.
The investigator assessed confirmed response rate in patients with BRAF V600E metastatic melanoma (n=76) was 59 % (95 % CI: 48.2, 70.3) and the median duration of response was 5.2 months (95 % CI: 3.9, not calculable) based on a median follow-up time of 6.5 months. In patients with BRAF V600K mutation positive metastatic melanoma (n=16) the response rate was 13 % (95 % CI: 0.0, 28.7) with a median duration of response of 5.3 months (95 % CI: 3.7, 6.8). Although limited by the low number of patients, median OS appeared consistent with data in patients with BRAF V600E positive tumours.
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with dabrafenib in one or more subsets of the paediatric population in melanoma (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Absorption
Dabrafenib is absorbed orally with median time to achieve peak plasma concentration of 2 hours post-dose. Mean absolute bioavailability of oral dabrafenib is 95 % (90 % CI: 81, 110 %). Dabrafenib exposure (Cmax and AUC) increased in a dose proportional manner between 12 and 300 mg following single-dose administration, but the increase was less than dose-proportional after repeat twice daily dosing. A decrease in exposure was observed with repeat dosing, likely due to induction of its own metabolism. Mean accumulation AUC Day 18/Day 1 ratios was 0.73. Following administration of 150 mg twice daily, geometric mean Cmax, AUC(0-) and predose concentration (C) were 1478 ng/ml, 4341 ng*hr/ml and 26 ng/ml, respectively.
Administration of dabrafenib with food reduced the bioavailability (Cmax and AUC decreased by 51 % and 31 % respectively) and delayed absorption of dabrafenib capsules when compared to the fasted state.
Distribution
Dabrafenib binds to human plasma protein and is 99.7 % bound. The steady-state volume of distribution following intravenous microdose administration is 46 L.
Dabrafenib is a substrate of human P-glycoprotein (Pgp) and murine BCRP in vitro. However, these transporters have minimal impact on dabrafenib oral bioavailability and elimination and the risk for clinically relevant drug-drug interactions with inhibitors of Pgp or BCRP is low.
Neither dabrafenib nor its 3 main metabolites were demonstrated to be inhibitors of Pgp in vitro.
Biotransformation
The metabolism of dabrafenib is primarily mediated by CYP2C8 and CYP3A4 to form hydroxy-dabrafenib, which is further oxidized via CYP3A4 to form carboxy-dabrafenib. Carboxy-dabrafenib can 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 and reabsorbed. Desmethyl-dabrafenib is metabolized by CYP3A4 to oxidative metabolites. Hydroxy-dabrafenib terminal half-life parallels that of parent with a half-life of 10 hrs while the carboxy- and desmethyl-metabolites exhibited longer half-lives (21-22 hours). Mean metabolite to parent AUC ratios following repeat-dose administration were 0.9, 11 and 0.7 for hydroxy-, carboxy-, and desmethyl-dabrafenib, respectively. Based on exposure, relative potency, and pharmacokinetic properties, both hydroxy- and desmethyl-dabrafenib are likely to contribute to the clinical activity of dabrafenib; while the activity of carboxy-dabrafenib is not likely to be significant.
Elimination
Terminal half-life following an intravenous single microdose is 2.6 hours. Dabrafenib terminal half-life after a single dose is 8 hours due to absorption-limited elimination after oral administration (flip-flop pharmacokinetics). IV plasma clearance is 12 L/hr.
After an oral dose, the major route of elimination of dabrafenib is metabolism, mediated via CYP3A4 and CYP2C8. Dabrafenib related material is excreted primarily in faeces, with 71 % of an oral dose recovered in faeces and 23 % in urine as metabolites only.
Special patient populations
Hepatic impairment
A population pharmacokinetic analysis indicates that mildly elevated bilirubin and/or AST levels (based on National Cancer Institute [NCI] classification) do not significantly affect dabrafenib oral clearance. In addition, mild hepatic impairment as defined by bilirubin and AST did not have a significant effect on dabrafenib metabolite plasma concentrations. No data are available in patients with moderate to severe hepatic impairment. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, administration of dabrafenib should be undertaken with caution in patients with moderate to severe hepatic impairment (see section 4.2).
Renal impairment
A population pharmacokinetic analysis suggests that mild renal impairment does not affect oral clearance of dabrafenib. Although data in moderate renal impairment are limited these data may indicate no clinically relevant effect. No data are available in subjects with severe renal impairment (see section 4.2).
Elderly
Based on the population pharmacokinetic analysis, age had no significant effect on dabrafenib pharmacokinetics. Age greater than 75 years was a significant predictor of carboxy- and desmethyl-dabrafenib plasma concentrations with a 40 % greater exposure in subjects ≥ 75 years of age, relative to subjects < 75 years old.
Body weight and gender
Based on the population pharmacokinetic analysis, gender and weight were found to influence dabrafenib oral clearance; weight also impacted oral volume of distribution and distributional clearance. These pharmacokinetic differences were not considered clinically relevant.
Race
There are insufficient data to eva luate the potential effect of race on dabrafenib pharmacokinetics.
Paediatric population
No studies have been conducted to investigate the pharmacokinetics of dabrafenib in paediatric patients.
5.3 Preclinical safety data
Carcinogenicity studies with dabrafenib have not been conducted. Dabrafenib was not mutagenic or clastogenic using in vitro tests in bacteria and cultured mammalian cells, and an in vivo rodent micronucleus assay.
In combined female fertility, early embryonic and embryofetal development studies in rats numbers of ovarian corpora lutea were reduced in pregnant females at 300 mg/kg/day (approximately 3 times human clinical exposure based on AUC), but there were no effects on estrous cycle, mating or fertility indices. Developmental toxicity including embryo-lethality and ventricular septal defects were seen at 300 mg/kg/day, and delayed skeletal development and reduced fetal 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 the human clinical exposure based on AUC). Testicular changes in rat and dog were still present following a 4-week recovery period (see section 4.6).
Cardiovascular effects, including coronary arterial degeneration/necrosis and/or haemorrhage, cardiac atrioventricular valve hypertrophy/haemorrhage and atrial fibrovascular proliferation were seen in dogs (≥ 2 times clinical exposure based on AUC). Focal arterial/perivascular inflammation in various tissues was observed in mice and an increased incidence of hepatic arterial degeneration and spontaneous cardiomyocyte degeneration with inflammation (spontaneous cardiomyopathy) was observed in rats (≥ 0.5 and 0.6 times clinical exposure for rats and mice respectively). Hepatic effects, including hepatocellular necrosis and inflammation, were observed in mice (≥ 0.6 times clinical 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 shallow and/or laboured breathing.
Reversible haematological effects have been observed in dogs and rats given dabrafenib. In studies of up to 13 weeks, decreases in reticulocyte counts and/or red cell mass were observed in dogs and rats (≥ 10 and 1.4 times clinical exposure, respectively).
In juvenile toxicity studies in rats, effects on growth (shorter long bone length), renal toxicity (tubular deposits, increased incidence of cortical cysts and tubular basophilia and reversible increases in urea and/or creatinine concentrations), testicular toxicity (degeneration and tubular dilation) and earlier vaginal opening (with no associated effects on ovarian weights or morphologic changes in female reproductive tissues) were observed.
Dabrafenib was phototoxic in an in vitro mouse fibroblast 3T3 Neutral Red Uptake (NRU) assay.
6. Pharmaceutical particulars
6.1 List of excipients
Capsules content
Microcrystalline cellulose
Magnesium stearate
Colloidal silicone dioxide
Capsule shell
Red iron oxide (E172)
Titanium dioxide (E171)
Hypromellose (E464)
Printing ink:
Black iron oxide (E172)
Shellac
Propylene glycol
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Opaque white high density polyethylene (HDPE) bottle with polypropylene screw cap and a silica gel desiccant.
Each bottle contains either 28 or 120 hard capsules
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
GlaxoSmithKline Trading Services Limited
6900 Cork Airport Business Park
Kinsale Road
Cork
Republic of Ireland
8. Marketing authorisation number(s)
EU/1/13/865/001 – Tafinlar 50 mg – 28 hard capsules
EU/1/13/865/002 – Tafinlar 50 mg – 120 hard capsules
EU/1/13/865/003 – Tafinlar 75 mg – 28 hard capsules
EU/1/13/865/004 – Tafinlar 75 mg – 120 hard capsules
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 26 August 2013
10. Date of revision of the text
20 February 2014
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
