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Tafinlar is a brand name for Dabrafenib. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: Melanoma Dabrafenib as monotherapy or in combination with trametinib is indicated for the treatment of adults and adolescents aged 12 years and older with unresectable or metastatic melanoma with a BRAF V600 mutation (see sections 4.4 and 5.1). Adjuvant treatment of melanoma Dabrafenib in combination with trametinib…
Verbatim from this product's EMA label. Tap a section to expand.
Treatment with dabrafenib should be initiated and supervised by a qualified physician experienced in the use of anti-cancer medicinal products. Patient selection Before taking dabrafenib, patients must have confirmation of tumour BRAF V600 mutation assessed by a CE-marked in vitro diagnostic (IVD) medical device with the corresponding intended purpose.
If no CE-marked IVD is available, an alternative validated test should be used. Posology In adults, the recommended dose of dabrafenib is 150 mg (two 75 mg capsules) twice daily, regardless of body weight. In adolescents (aged 12 to <18 years) with melanoma, the recommended dose of dabrafenib is based on body weight (see also Table 1): • 75 mg dabrafenib twice daily for a body weight of 26 to 37 kg • 100 mg dabrafenib twice daily for a body weight of 38 to 50 kg • 150 mg dabrafenib twice daily for a body weight of 51 kg or more The recommended dose of dabrafenib capsules for patients with a body weight less than 26 kg has not been established.
Please refer to the trametinib summary of product characteristics (SmPC) for information on the recommended dose of trametinib, when used in combination with dabrafenib. Duration of treatment Treatment should continue until the patient no longer derives benefit or the development of unacceptable toxicity (see Table 2).
In the adjuvant melanoma setting, patients should be treated for a period of 12 months unless there is 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 scheduled dose.
If a dose of trametinib is missed, when dabrafenib is given in combination with trametinib, the dose of trametinib should only be taken 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). 4). 4 No dose modifications are required for uveitis as long as effective local therapies can control ocular inflammation.
4). Recommended dose level reductions and recommendations for dose modifications are provided in Tables 1 and 2, respectively. Table 1 Recommended dose level reductions Dose level Adults Adolescents Body weight 26 to 37 kg Body weight 38 to 50 kg Body weight ≥51 kg Recommended starting dose 150 mg twice daily 75 mg twice daily 100 mg twice daily 150 mg twice daily 1st dose reduction level 100 mg twice daily 50 mg twice daily 75 mg twice daily 100 mg twice daily 2nd dose reduction level 75 mg twice daily NA 50 mg twice daily 75 mg twice daily 3rd dose reduction level 50 mg twice daily NA NA 50 mg twice daily NA = Not applicable Dose adjustment for dabrafenib below 50 mg twice daily is not recommended.
Summary of the safety profile The safety of dabrafenib monotherapy is based on the integrated safety population from five clinical studies, BRF113683 (BREAK-3), BRF113929 (BREAK-MB), BRF113710 (BREAK-2), BRF113220, and BRF112680, which included 578 patients with BRAF V600 mutant unresectable or metastatic melanoma treated with dabrafenib 150 mg twice daily.
The most common adverse reactions (incidence ≥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 evaluated in the integrated safety population of 1 188 adult patients with BRAF V600 mutant unresectable or metastatic melanoma, Stage III BRAF V600 mutant melanoma following complete resection (adjuvant treatment), advanced NSCLC and advanced DTC treated with dabrafenib 150 mg twice daily and trametinib 2 mg once daily.
1). The most common adverse reactions (incidence ≥20%) for dabrafenib in combination with trametinib were: pyrexia, fatigue, nausea, rash, chills, diarrhoea, headache, arthralgia, vomiting, cough, haemorrhage and peripheral oedema. Tabulated list of adverse reactions Adverse reactions associated with dabrafenib obtained from clinical studies and post-marketing surveillance are tabulated below for dabrafenib monotherapy (Table 3) and dabrafenib in combination with trametinib (Table 4).
Adverse reactions are listed below by MedDRA system organ class and ranked by frequency using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000) and not known (cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 3 Adverse reactions with dabrafenib monotherapy System organ class Frequency (all grades) Adverse reactions Neoplasms benign, malignant and unspecified (incl cysts and polyps) Very common Papilloma Common Cutaneous squamous cell carcinoma Seborrhoeic keratosis Acrochordon (skin tags) Basal cell carcinoma Uncommon New primary melanoma Immune system disorders Uncommon Hypersensitivity Metabolism and nutrition disorders Very common Decreased appetite Common Hypophosphataemia Hyperglycaemia Nervous system disorders Very common Headache Common Peripheral neuropathy (including sensory and motor neuropathy) Eye disorders Uncommon Uveitis Respiratory, thoracic and mediastinal disorders Very common Cough Gastrointestinal disorders Very common Nausea Vomiting Diarrhoea Common Constipation Uncommon Pancreatitis 16 Skin and subcutaneous tissue disorders Very common Hyperkeratosis Alopecia Rash Palmar-plantar erythrodysaesthesia syndrome Common Dry skin Pruritus Actinic keratosis Skin lesion Erythema Photosensitivity Uncommon Acute febrile neutrophilic dermatosis Panniculitis Musculoskeletal and connective tissue disorders Very common Arthralgia Myalgia Pain in extremity Renal and urinary disorders Uncommon Renal failure, acute kidney injury Nephritis General disorders and administration site conditions Very common Pyrexia Fatigue Chills Asthenia Common Influenza-like illness Injury, poisoning and procedural complications Common Potentiation of radiation toxicity Table 4 Adverse reactions with dabrafenib in combination with trametinib System organ class Frequency (all grades) Adverse reactions Infections and infestations Very common Nasopharyngitis Urinary tract infection Common Cellulitis Folliculitis Paronychia Rash pustular Neoplasms benign, malignant and unspecified (incl cysts and polyps) Common Cutaneous squamous cell carcinomaa Papillomab Seborrhoeic keratosis Uncommon New primary melanomac Acrochordon (skin tags) Blood and lymphatic system disorders Very common Neutropenia Anaemia Common Thrombocytopenia Leukopenia Immune system disorders Uncommon Hypersensitivityd Sarcoidosis Rare Haemophagocytic lymphohistiocytosis Metabolism and nutrition disorders Very common Decreased appetite Common Dehydration Hyponatraemia Hypophosphataemia Hyperglycaemia Not known Tumour lysis syndrome Nervous system disorders Very common Headache Dizziness 17 Common Peripheral neuropathy (including sensory and motor neuropathy) Eye disorders Common Vision blurred Visual impairment Uveitise Uncommon Chorioretinopathy Retinal detachment Periorbital oedema Cardiac disorders Common Ejection fraction decreased Bradycardia Uncommon Cardiac failure Left ventricular dysfunction Atrioventricular blockf Not known Myocarditis Vascular disorders Very common Hypertension Haemorrhageg Common Hypotension Lymphoedema Respiratory, thoracic and mediastinal disorders Very common Cough Common Pneumonitis Dyspnoea Rare Interstitial lung disease Gastrointestinal disorders Very common Abdominal painh Constipation Diarrhoea Nausea Vomiting Common Dry mouth Stomatitis Uncommon Gastrointestinal perforation Pancreatitis Colitis Skin and subcutaneous tissue disorders Very common Dry skin Pruritus Rash Erythema Dermatitis acneiform Common Dermatitis exfoliative generalisedi Actinic keratosis Night sweats Hyperkeratosis Alopecia Palmar-plantar erythrodysaesthesia syndrome Skin lesion Hyperhidrosis Panniculitis Skin fissures Photosensitivity Uncommon Acute febrile neutrophilic dermatosis Not known Stevens-Johnson syndrome Drug reaction with eosinophilia and systemic symptoms Tattoo-associated skin reactions 18 Musculoskeletal and connective tissue disorders Very common Arthralgia Myalgia Pain in extremity Muscle spasmsj Uncommon Rhabdomyolysis Renal and urinary disorders Common Renal failure, acute kidney injury Rare Nephritis General disorders and administration site conditions Very common Fatigue Chills Asthenia Oedema peripheral Pyrexia Weight increase (abnormal weight gain)k Influenza-like illness Common Mucosal inflammation Face oedema Investigations Very common Alanine […]
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.
1). Dabrafenib in combination with trametinib in patients with melanoma who have progressed on a BRAF inhibitor 7 There are limited data in patients taking the combination of dabrafenib with trametinib who have progressed on a prior BRAF inhibitor.
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.
New malignancies New malignancies, cutaneous and non-cutaneous, can occur when dabrafenib is used as monotherapy or in combination with trametinib. 8). In the Phase III clinical studies MEK115306 and MEK116513 in patients with unresectable or metastatic melanoma, cuSCC occurred in 10% (22/211) of patients receiving dabrafenib as a monotherapy and in 18% (63/349) of patients receiving vemurafenib as a monotherapy, respectively.
Across the pivotal combination therapy studies in melanoma and advanced NSCLC, cuSCC occurred in 2% of patients receiving dabrafenib in combination with trametinib. 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.
In the Phase III study BRF115532 (COMBI-AD) in the adjuvant treatment of melanoma, 1% (6/435) of patients receiving dabrafenib in combination with trametinib as compared to 1% (5/432) of patients receiving placebo had developed cuSCC at the time of the primary analysis.
During the long-term (up to 10 years) off-treatment follow-up, 2 additional patients reported cuSCC in each treatment arm. Overall, the median time to onset of the first occurrence of cuSCC in the combination arm of the adjuvant treatment study was approximately 21 weeks and was 34 weeks in the placebo arm.
1.
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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Table 2 Dose modification schedule based on the grade of any adverse reactions (excluding pyrexia) Grade (CTCAE)* 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 to 1 and reduce by one dose level when resuming therapy. Grade 4 Discontinue permanently, or interrupt therapy until Grade 0 to 1 and reduce by one dose level when resuming therapy.
* The intensity of clinical adverse reactions graded by the Common Terminology Criteria for Adverse Events (CTCAE) When an individual’s adverse reactions are under effective management, dose re-escalation following the same dosing steps as de-escalation may be considered.
The dabrafenib dose should not exceed the recommended starting dose indicated in Table 1. Pyrexia If a patient’s temperature is ≥38°C, therapy should be interrupted (dabrafenib when used as monotherapy, and both dabrafenib and trametinib when used in combination).
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.
4). Dabrafenib, or both dabrafenib and trametinib when used in combination, should be restarted if the patient is symptom-free for at least 24 hours either (1) at the same dose level, or (2) reduced by one dose level if the pyrexia is recurrent and/or was accompanied by other severe symptoms including dehydration, hypotension or renal failure.
5 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 uveitis, RAS mutation-positive non-cutaneous malignancies (primarily related to dabrafenib), left ventricular ejection fraction (LVEF) reduction, retinal vein occlusion (RVO), retinal pigment epithelial detachment (RPED) and interstitial lung disease (ILD)/pneumonitis (primarily related to trametinib).
Dose modification exceptions (where only one of the two therapies is dose reduced) for selected adverse reactions Uveitis No dose modifications are required for uveitis as long as effective local therapies can control ocular inflammation.
If uveitis does not respond to local […]
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 studies in patients treated with dabrafenib. In clinical studies in unresectable or metastatic melanoma,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 malignancies In vitro experiments have demonstrated paradoxical activation of mitogen-activated protein kinase (MAP kinase) signalling in BRAF wild-type cells with RAS mutations when exposed to BRAF inhibitors.
8) when RAS mutations are present. RAS-associated malignancies have been reported in clinical studies, both with another BRAF inhibitor (chronic myelomonocytic leukaemia and non- cutaneous SCC of the head and neck) as well as with dabrafenib monotherapy (pancreatic adenocarcinoma, bile duct adenocarcinoma) and with dabrafenib in combination with the MEK inhibitor, trametinib (colorectal cancer, pancreatic cancer).
8 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 are recommended before and at the end of treatment or when considered clinically indicated. Complete blood cell counts and blood chemistry should be performed as clinically indicated. The benefits and risks should be considered before administering dabrafenib in 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. 8). 4) for additional information. Visual impairment In […]