For Healthcare Professionals Outside the US

For patients with BRAF V600 mutation–positive unresectable or metastatic melanoma

For patients with BRAF V600 mutation–positive advanced non-small cell lung cancer (NSCLC)

Important Safety Information

Combination of Tafinlar® and Mekinist®

Important note: Before prescribing the combination of Tafinlar® (dabrafenib) with Mekinist® (trametinib), consult full prescribing information of both products.

Presentation of each product:

• Each Tafinlar hard capsule contains dabrafenib mesylate equivalent to 50 mg or 75 mg of dabrafenib. 

• Each Mekinist film-coated tablet contains 0.5 mg or 2 mg of trametinib.

Indications: ♦Tafinlar and Mekinist, respectively as monotherapy, or as combination therapy for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation. ♦Mekinist as monotherapy has not demonstrated clinical activity in patients who progressed on a prior BRAF inhibitor therapy. ♦Tafinlar and Mekinist in combination for the treatment of patients with advanced non-small cell lung cancer with a BRAF V600 mutation.

Dosage and administration: Adults: Recommended dose is 150 mg Tafinlar twice daily in combination with Mekinist 2 mg once daily. Dose modifications: Management of adverse reactions may require treatment interruption, dose reduction or treatment discontinuation.

Special populations: Children (< 18 years): Safety and efficacy not established. Elderly (> 65 years): No dose adjustment required. Renal impairment: Mild or moderate: no dose adjustment required. Severe: should be used with caution. Hepatic impairment: Mild: no dose adjustment required. Moderate or severe: should be used with caution.

Contraindications: None.

Warnings and precautions for Tafinlar (used as 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. Monitoring serum creatinine and renal function. Serious non-infectious febrile events observed. For management of Pyrexia, dose modification guidelines should be followed. 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 and lipase. Close monitoring when re-starting Tafinlar. Uveitis: Monitoring patients for visual signs and symptoms during therapy. Tafinlar in combination with Mekinist: Hemorrhage: Hemorrhagic events, including major and fatal hemorrhagic events have occurred in patients taking Tafinlar in combination with Mekinist.

Warnings and precautions for Mekinist (used as monotherapy or in combination with Tafinlar): Left ventricular ejection fraction (LVEF) reduction/Left ventricular dysfunction: Cases of LVEF decrease reported. Should be used with caution when conditions could impair left ventricular function. All patients should be evaluated for LVEF prior to initiation of treatment with continued evaluation during treatment. Consider dose modification guidelines. Hemorrhage: Hemorrhagic events, including major and fatal hemorrhagic events occurred in patients taking Mekinist as monotherapy and in combination with Tafinlar. Visual impairment: Visual disturbances, including chorioretinopathy or retinal pigment epithelial detachment (RPED) and retinal vein occlusion (RVO) observed. Not recommended for patients with history of RVO. Ophthalmological evaluation should be performed at baseline and during treatment if clinically warranted. If retinal abnormally 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 30% of patients in combination with Tafinlar. Deep vein thrombosis (DVT)/pulmonary embolism (PE): Can occur when used as 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. During and following severe pyrexia events serum creatinine and other evidence of renal function should be monitored. Serious non-infectious febrile events have been observed. For management of pyrexia, dose modification guidelines should be followed. 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.

Women of child-bearing potential: Use effective methods of contraception during therapy and for 4 weeks and 4 months following discontinuation of Tafinlar and Mekinist, respectively. Hormonal contraception efficacy may decrease when Tafinlar and Mekinist are used in combination; use an alternate method of contraception.

Pregnancy: Not recommended.

Breast-feeding: Not recommended.

Fertility:

Tafinlar represents a potential risk for impaired spermatogenesis, which may be irreversible.

Mekinist may impair human fertility.

Adverse events with Tafinlar monotherapy:

Very common (≥10%): Papilloma, decreased appetite, headache, cough, nausea, vomiting, diarrhoea, skin effects (rash, hyperkeratosis), alopecia, palmar-plantar erythrodysaesthesia syndrome, arthralgia, myalgia, pain in extremity, asthenia, chills, fatigue, pyrexia.

Common (1 to 10%): Nasopharyngitis, acrochordon (skin tags), cutaneous squamous cell carcinoma (SCC) including SCC of the skin, SCC in situ (Bowen’s disease) and keratoacanthoma, seborrheic keratosis, hypophosphataemia, hyperglycaemia, constipation, skin effects (actinic keratosis, skin lesion, dry skin, erythema, pruritus), photosensitivity reaction, influenza-like illness.

Uncommon (0.1 to 1%): New primary melanoma, hypersensitivity, uveitis, pancreatitis, panniculitis, renal failure, acute renal failure.

Rare (0.01 to 0.1%): Tubulointerstitial nephritis.

Adverse events with Mekinist monotherapy:

Very common (≥10%): hypertension, haemorrhage, cough, dyspnoea, diarrhoea, nausea, vomiting, constipation, abdominal pain, dry mouth, rash, dermatitis acneiform, dry skin, pruritus, alopecia, fatigue, oedema peripheral, pyrexia.

Common (1 to 10%): Folliculitis, paronychia, cellulitis, rash pustular, anaemia, dehydration, vision blurred, periorbital oedema, visual impairment, left ventricular dysfunction, ejection fraction decreased, bradycardia, lymphoedema, epistaxis, pneumonitis stomatitis, skin chapped, erythema, palmar-plantar erythrodysaesthesia syndrome, skin fissures, blood creatine phosphokinase increased, face oedema, mucosal inflammation, asthenia, aspartate aminotransferase increased, alanine aminotransferase increased, blood alkaline phosphatase increased.

Uncommon (0.1 to 1%): .Hypersensitivity, chorioretinopathy, retinal vein occlusion, papilloedema, retinal detachment, cardiac failure, interstitial lung disease, gastrointestinal perforation, colitis.

Adverse events with Tafinlar and Mekinist used in combination:

Very common (≥10%): Abdominal pain, alanine aminotransferase increased, arthralgia, aspartate aminotransferase increased, asthenia incl. fatigue and malaise, blood alkaline phosphatase increased, chills, constipation, cough, decreased appetite, dermatitis acneiform, diarrhoea, dizziness, dry skin, erythema, fatigue, haemorrhage, headache, hyperkeratosis incl. hyperkeratosis, actinic and seborrhoeic keratosis and keratosis pilaris, hypertension, hyponatraemia, hypotension, muscle spasms, myalgia, nasopharyngitis, nausea, neutropenia, oedema (generalized and peripheral), pain in extremity, pruritus, pyrexia, rash, urinary tract infection, vomiting.

Common (1 to 10%): Acrochordon (skin tags), alopecia, anaemia, blood creatine phosphokinase increased, bradycardia, cellulitis, cutaneous squamous cell carcinoma (SCC) including SCC of the skin, dehydration, detachment of retina/retinal pigment epithelium, dry mouth, dyspnoea, ejection fraction decreased, erythema, face oedema, folliculitis, gamma-glutamyltransferase increased, hyperglycaemia, hyperhidrosis, hypertension, hyponatraemia, hypophosphataemia, hypotension, influenza-like illness, leukopenia, lymphoedema, mucosal inflammation, muscle spasms, night sweats, palmar-plantar erythrodysaesthesia syndrome, pancreatitis acute, panniculitis, papilloma including skin papilloma, paronychia, photosensitivity reaction, pulmonary embolism, rash pustular, renal failure, SCC in situ (Bowen’s disease) and keratoacanthoma, seborrhoeic keratosis, skin fissures, skin lesion, stomatitis, thrombocytopenia, tubulointerstitial nephritis, vision blurred, visual impairment.

Uncommon (0.1 to 1%): Cardiac failure, chorioretinopathy, colitis, gastrointestinal perforation, hypersensitivity, interstitial lung disease, left ventricular dysfunction, nephritis, new primary melanoma, pancreatitis, periorbital oedema, pneumonitis, renal failure acute, retinal detachment, rhabdomyolysis, uveitis.

For a complete list of adverse events, consult the full prescribing information.

Interactions:

Tafinlar: Caution with combination with strong inhibitors or inducers of CYP2C8 or CYP3A4. Caution with drugs that affect gastric pH. Tafinlar may induce CYP3A4, CYP2C9, CYP2B6, CYP2C8, CYP2C19, UGT and P-gp. Efficacy of medicinal products metabolized by these enzymes may be reduced. Monitoring recommended.

Mekinist: none known.

Packs and prices: Country-specific.

Legal classification: Country-specific.