ABBREVIATED PRESCRIBING INFORMATION
Non-fixed dose combination of MEKINIST® and TAFINLAR®
Before prescribing Mekinist and Tafinlar in combination, please refer to the Summary of Product Characteristics (SmPC) of both products.
Presentation of each product:
MEKINIST (trametinib) 0.5 mg and 2.0 mg film-coated tablets. Each film-coated tablet contains trametinib dimethyl sulfoxide equivalent to 0.5 mg and 2.0 mg of trametinib respectively.
TAFINLAR (dabrafenib) 50 mg and 75 mg hard capsules. Each capsule contains dabrafenib mesilate, equivalent to 50 mg and 75 mg of dabrafenib respectively.
Indications: Combination of Mekinist and Tafinlar:
- for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation
- for the adjuvant treatment of adult patients with stage III melanoma with a BRAF V600 mutation following complete resection
- for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with a BRAF V600 mutation.
Dosage and Administration: Adults: recommended dose of Mekinist is 2mg once daily in combination with Tafinlar 150mg twice daily. Dose modification: Management of ADRs may require treatment interruption, dose reduction, or discontinuation. Elderly: No initial dose adjustment required in patients >65 years. Paediatrics: Safety and efficacy not established in patients <18 years. Renal impairment: No dose adjustment required in mild or moderate impairment. Caution advised in severe renal impairment. Hepatic impairment: No dose adjustment required in mild hepatic impairment. Caution advised in moderate and severe hepatic impairment. In the adjuvant melanoma setting, patients should be treated for a period of 12 months unless there is disease recurrence or unacceptable toxicity.
Contraindications: Hypersensitivity to active substance or excipients.
Warnings/Precautions for Mekinist (used as a monotherapy or in combination with Tafinlar): Left ventricular ejection fraction (LVEF) reduction/Left ventricular dysfunction: Cases of LVEF decrease have been reported. Should be used with caution when conditions could impair left ventricular fraction. All patients should be evaluated for LVEF prior to initiation of treatment with continued evaluation during treatment. Consider dose modification guidelines. In patients receiving Mekinist in combination with Tafinlar, there have been occasional reports of acute, severe LVEF due to myocarditis. Full recovery was observed when stopping treatment. Physicians should be alert to the possibility of myocarditis in patients who develop new or worsening cardiac signs or symptoms. Haemorrhage: Haemorrhagic events including major and fatal haemorrhagic events occurred in patients taking Mekinist as monotherapy and in combination with Tafinlar. Hypertension: Blood pressure should be measured at baseline and monitored during treatment with Mekinist, with control of hypertension by standard therapy as appropriate. Interstitial lung disease (ILD)/Pneumonitis: Mekinist should be withheld in patients with suspected ILD or pneumonitis, including patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnoea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Mekinist should be permanently discontinued for patients diagnosed with treatment-related ILD or pneumonitis. If Mekinist is being used in combination with Tafinlar then therapy with Tafinlar may be continued at the same dose. Rhabdomyolysis: Signs or symptoms of rhabdomyolysis should warrant an appropriate clinical evaluation and treatment as indicated. Visual impairment: visual disturbances, including chorioretinopathy or retinal pigment epithelial detachment (RPED) and retinal vein occlusion (RVO) have been observed. Not recommended for patients with history of RVO. Ophthalmological evaluation should be performed at baseline and during treatment if clinically warranted. If retinal abnormality is observed, treatment should be interrupted immediately and referral to specialist should be considered. Permanently discontinue treatment if RVO is noticed. Rash: observed in 60% of patients in monotherapy and 24% of patients in combination with Tafinlar. Severe cutaneous adverse reactions (SCARs): SCARs, including Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported with Mekinist in combination with Tafinlar. Before initiating treatment, patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of SCARs appear, Mekinist and Tafinlar should be withdrawn. Deep vein thrombosis (DVT)/pulmonary embolism (PE): can occur when used as a monotherapy or in combination with Tafinlar. Seek immediate medical care if patients develop symptoms of DVT or PE. Pyrexia: Pyrexia including severe rigors, dehydration and hypotension (including acute renal insufficiency) reported. Incidence and severity increased when Mekinist used in combination with Tafinlar. Monitoring serum creatinine and other evidence of renal function impairment during and following severe pyrexia events. Serious non-infectious febrile events observed. For management of pyrexia, therapy should be interrupted if the patient’s temperature is ≥38oC (100.4°F). In case of recurrence, therapy can also be interrupted at the first symptom of pyrexia. Colitis and gastrointestinal perforation: Colitis and gastrointestinal perforation, including fatal outcome, have been reported. Treatment with Mekinist monotherapy or in combination with Tafinlar should be used with caution in patients with risk factors for gastrointestinal perforation, including a history of diverticulitis, metastases to the gastrointestinal tract and concomitant use of medications with a recognized risk of gastrointestinal perforation. If patients develop symptoms of colitis and gastrointestinal perforation they should immediately seek medical care. Sarcoidosis: Cases of sarcoidosis have been reported in patients treated with trametinib in combination with dabrafenib, mostly involving the skin, lung, eye and lymph nodes. In the majority of the cases, treatment with trametinib and dabrafenib was maintained. In case of a diagnosis of sarcoidosis, relevant treatment should be considered. It is important not to misinterpret sarcoidosis as disease progression Sodium: This medicine contains less than 1mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium free’
Warnings/Precautions for Tafinlar (used as a monotherapy or in combination with Mekinist): Pyrexia including severe rigors, dehydration and hypotension (including acute renal insufficiency) reported. Incidence and severity increased when used in combination with Mekinist. During and following severe pyrexia events, serum creatinine and other evidence of renal function should be monitored. Serious non-infections febrile events have been observed. For management of pyrexia therapy should be interrupted if the patient’s temperature is ≥38oC (100.4°F). In case of recurrence, therapy can also be interrupted at the first symptom of pyrexia. Cutaneous squamous cell carcinoma (cuSCC) and new primary melanoma: skin examination prior, during and for 6 months after discontinuation of treatment or until initiation of another anti-neoplastic therapy. Non-cutaneous secondary/recurrent malignancy: monitoring as clinically appropriate for up to 6 months after discontinuation of Tafinlar or until initiation of another anti-neoplastic therapy. Pancreatitis: unexplained abdominal pain should be promptly investigated to include measurement of serum amylase & lipase. Close monitoring when re-starting Tafinlar. Uveitis: monitoring patients for visual signs and symptoms during therapy. Colitis and gastrointestinal perforation: Colitis and gastrointestinal perforation, including fatal outcome, have been reported in patients taking dabrafenib in combination with trametinib. Sarcoidosis : Cases of sarcoidosis have been reported in patients treated with dabrafenib in combination with trametinib, mostly involving the skin, lung, eye and lymph nodes. In the majority of the cases, treatment with dabrafenib and trametinib was maintained. In case of a diagnosis of sarcoidosis, relevant treatment should be considered. It is important not to misinterpret sarcoidosis as disease progression.
Mekinist: Effect of trametinib on other medicinal products: Based on clinical data, no loss of efficacy of hormonal contraceptives is expected when co-administered with trametinib monotherapy
Tafinlar: Effect of other medicinal products on dabrafenib: Caution with co-administration of strong inhibitors (e.g. ketoconazole, gemfibrozil, nefazodone, clarithromycin, ritonavir, saquinavir, telithromycin, itraconazole, voriconazole, posaconazole, atazanavir) of CYP2C8 or CYP3A4. Avoid co-administration with strong inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, or St John’s wort (Hypericum perforatum) of CYP2C8 and CYP3A4. Avoid agents that increase gastric pH, when possible. Effect of dabrafenib on other medicinal products: Avoid concomitant use with medicinal products that are sensitive substrates of certain metabolising enzymes or transporters, if monitoring for efficacy and dose adjustment is not possible. Please refer to Section 4.5 of SPC for groups of medicinal products that can be affected. A drug utilisation review (DUR) is essential on initiating dabrafenib treatment. Exercise caution when co-administering with warfarin and consider additional INR (lnternational Normalised Ratio) monitoring. Exercise caution when co-administering with digoxin and additional monitoring is recommended. Effects of dabrafenib on substance transport systems: Tafinlar inhibits OATP1B1 and OATP1B3. Monitoring recommended of drugs that are sensitive substrates of OATP1B1 and OATP1B3 and known to have a narrow therapeutic index with regards to high peak concentrations (Cmax).
Fertility, Pregnancy & Lactation: Women of child-bearing potential: When Mekinist and Tafinlar are use in combination, use effective methods of contraception during therapy and for at least 16 weeks after stopping treatment. Tafinlar may decrease the efficacy of oral or any systemic hormonal contraceptives; use an effective alternative method of contraception. Pregnancy: Caution should be exercised by considering the expected benefit to the mother against possible risk to the foetus. Breast-feeding: Caution should be exercised by considering the benefit of breastfeeding for the child and the benefit of therapy for the woman. Fertility: Mekinist may impair human fertility. Tafinlar represents a potential risk for impaired spermatogenesis, which may be irreversible.
Ability to Drive and Use Machines: Trametinib and Dabrafenib have minor influence. Patients should be made aware of the potential for fatigue, dizziness and eye problems.
Adverse reactions with Mekinist monotherapy in metastatic melanoma: Very common (≥ 1/10): hypertension, haemorrhage, cough; dyspnoea, diarrhoea, nausea, vomiting, constipation, abdominal pain, dry mouth, rash, dermatitis acneiform, dry skin, pruritus, alopecia, fatigue, oedema peripheral, pyrexia, asparate aminotransferase increased. common (≥ 1/100, < 1/10): folliculitis; paronychia; cellulitis; rash pustular; anaemia; hypersensitivity; dehydration; vision blurred; periorbital oedema; visual impairment; left ventricular dysfunction; ejection fraction decreased; bradycardia; lymphoedema; pneumonitis; stomatitis; erythema; palmar-plantar erythrodysaesthesia syndrome; skin fissures; skin chapped; face oedema; mucosal inflammation; asthenia; alanine aminotransferase increased; blood alkaline phosphatase increased; blood creatine phosphokinase increased.
Adverse reactions with Tafinlar monotherapy: Very common (≥ 1/10): papilloma; decreased appetite; headache; cough; nausea, vomiting, diarrhoea; hyperkeratosis, alopecia, rash, PPE, arthralgia, myalgia, pain in extremity, pyrexia, fatigue, chills, asthenia. common (≥ 1/100, < 1/10): cuSCC; seborrhoeic keratosis; skin tags; basal cell carcinoma; hypophosphataemia; hyperglycaemia; constipation; dry skin; pruritus; actinic keratosis; skin lesion; erythema; photosensitivity reaction; influenza-like illness.
Adverse reactions observed when Mekinist and Tafinlar are used in combination: Very common (≥ 1/10):, nasopharyngitis, decreased appetite, headache, dizziness, hypertension, haemorrhage, cough; abdominal pain, constipation, diarrhoea, nausea, vomiting, alanine aminotransferase increased, aspartate aminotransferase increased, dry skin, pruritus, rash, erythema, arthralgia, myalgia, pain in extremity, muscle spasms, fatigue, oedema peripheral, pyrexia, chills, asthenia, influenza-like illness. common (≥ 1/100, < 1/10): urinary tract infection, cellulitis; folliculitis; paronychia; rash pustular; cuSCC; papilloma; seborrhoeic keratosis; neutropenia,; anaemia; thrombocytopenia; leukopenia; dehydration; hyponatraemia; hypophosphataemia; hyperglycaemia; vision blurred; visual impairment; uveitis; ejection fraction decreased; hypotension; lymphoedema; dyspnoea; dry mouth; stomatitis; dermatitis acneiform; actinic keratosis; night sweats; hyperkeratosis; alopecia; palmar-plantar erythrodysaesthesia syndrome; skin lesion; hyperhidrosis; panniculitis; skin fissures; photosensitivity; mucosal inflammation; face oedema; blood alkaline; phosphatase increased; gamma-glutamyltransferase increased; blood creatine phosphokinase increased.
For more details on adverse reactions, please see SmPC.
Mekinist is supplied in bottles of 30 tablets. Tafinlar is supplied in packs of 120 hard capsules.
Legal category: POM.
Marketing Authorisation Numbers:
Mekinist: EU/1/14/931/002 (0.5mg), EU/1/14/931/006 (2.0mg).
Tafinlar: EU/1/13/865/002 (50 mg), EU/1/13/865/004 (75 mg).
Marketing Authorisation Holder: Novartis Europharm Ltd, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland.
Date of revision of text: Aug 2021
Full prescribing information is available upon request from: Novartis Ireland Limited, Vista Building, Elm Park Business Park, Elm Park, Dublin 4. Tel: 01-2601255 or at www.medicines.ie. Detailed information on this product is also available on the website of the European Medicines Agency http://www.ema.europa.eu.