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Mekinist is a brand name for Trametinib. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: Melanoma Trametinib as monotherapy or in combination with dabrafenib 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). Trametinib monotherapy has not demonstrated clinical activity in patients…
Verbatim from this product's EMA label. Tap a section to expand.
Treatment with trametinib should only be initiated and supervised by a physician experienced in the administration of anti-cancer medicinal products. Patient selection Before taking trametinib, 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 trametinib is 2 mg once daily, regardless of body weight. 5 mg trametinib once daily for a body weight of 38 to 50 kg • 2 mg trametinib once daily for a body weight of 51 kg or more The recommended dose of trametinib film-coated tablets for patients with a body weight less than 26 kg has not been established.
Please refer to the dabrafenib summary of product characteristics (SmPC) for information on the recommended dose of dabrafenib, when used in combination with trametinib. Duration of treatment It is recommended that patients continue treatment with trametinib until patients no longer derive 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 trametinib is missed, it should only be taken if it is more than 12 hours until the next scheduled dose.
If a dose of dabrafenib is missed, when trametinib is given in combination with dabrafenib, the dose of dabrafenib should only be taken if it is more than 6 hours until the next scheduled dose. Dose modification The management of adverse reactions may require dose reduction, treatment interruption or treatment discontinuation (see Tables 1 and 2).
Dose modifications are not recommended for adverse reactions of cutaneous squamous cell carcinoma (cuSCC) or new primary melanoma (see dabrafenib SmPC for further details). 5 mg once daily 1 mg once daily NA = Not applicable Dose adjustment for trametinib below 1 mg once daily is not recommended for adults and adolescents with a body weight ≥51 kg.
Table 2 Dose modification schedule based on the grade of any adverse reactions (excluding pyrexia) Grade (CTCAE)* Recommended trametinib dose modifications Used as monotherapy or in combination with dabrafenib Grade 1 or Grade 2 (Tolerable) Continue treatment and monitor as clinically indicated.
Summary of the safety profile The safety of trametinib monotherapy has been evaluated in the integrated safety population of 329 patients with BRAF V600 mutant unresectable or metastatic melanoma treated with trametinib 2 mg once daily in studies MEK114267, MEK113583, and MEK111054.
1). The most common adverse reactions (incidence ≥20%) for trametinib were rash, diarrhoea, fatigue, oedema peripheral, nausea, and dermatitis acneiform. 13 The safety of trametinib in combination with dabrafenib 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 trametinib 2 mg once daily and dabrafenib 150 mg twice daily.
1). The most common adverse reactions (incidence ≥20%) for trametinib in combination with dabrafenib were: pyrexia, fatigue, nausea, rash, chills, diarrhoea, headache, arthralgia, vomiting, cough, haemorrhage and peripheral oedema. Tabulated list of adverse reactions Adverse reactions associated with trametinib obtained from clinical studies and post-marketing surveillance are tabulated below for trametinib monotherapy (Table 4) and trametinib in combination with dabrafenib (Table 5).
Adverse reactions are listed below by MedDRA system organ class.
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 Very rare <1/10 000 Not known (cannot be estimated from the available data) Categories have been assigned based on absolute frequencies in the clinical study data.
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 4 Adverse reactions with trametinib monotherapy System organ class Frequency (all grades) Adverse reactions Infections and infestations Common Folliculitis Paronychia Cellulitis Rash pustular Blood and lymphatic system disorders Common Anaemia Immune system disorders Common Hypersensitivitya Metabolism and nutrition disorders Common Dehydration Nervous system disorders Common Peripheral neuropathy (including sensory and motor neuropathy) Eye disorders Common Vision blurred Periorbital oedema Visual impairment Uncommon Chorioretinopathy Papilloedema Retinal detachment Retinal vein occlusion Cardiac disorders Common Left ventricular dysfunction Ejection fraction decreased Bradycardia Uncommon Cardiac failure Not known Atrioventricular blockb 14 Vascular disorders Very common Hypertension Haemorrhagec Common Lymphoedema Respiratory, thoracic and mediastinal disorders Very common Cough Dyspnoea Common Pneumonitis Uncommon Interstitial lung disease Gastrointestinal disorders Very common Diarrhoea Nausea Vomiting Constipation Abdominal pain Dry mouth Common Stomatitis Uncommon Gastrointestinal perforation Colitis Skin and subcutaneous tissue disorders Very common Rash Dermatitis acneiform Dry skin Pruritus Alopecia Common Erythema Palmar-plantar erythrodysaesthesia syndrome Skin fissures Skin chapped Musculoskeletal and connective tissue disorders Uncommon Rhabdomyolysis General disorders and administration site conditions Very common Fatigue Oedema peripheral Pyrexia Common Face oedema Mucosal inflammation Asthenia Investigations Very common Aspartate aminotransferase increased Common Alanine aminotransferase increased Blood alkaline phosphatase increased Blood creatine phosphokinase increased a May present with symptoms such as fever, rash, increased liver transaminases, and visual disturbances.
When trametinib is given in combination with dabrafenib, the SmPC of dabrafenib must be consulted prior to initiation of treatment. For additional information on warnings and precautions associated with dabrafenib treatment, please refer to the dabrafenib SmPC.
7 BRAF V600 testing The efficacy and safety of trametinib have not been evaluated in patients whose melanoma tested negative for the BRAF V600 mutation. Trametinib monotherapy compared to BRAF inhibitors Trametinib monotherapy has not been compared with a BRAF inhibitor in a clinical study in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma.
Based on cross-study comparisons, overall survival and progression-free survival data appear to show similar effectiveness between trametinib and BRAF inhibitors; however, overall response rates were lower in patients treated with trametinib than those reported in patients treated with BRAF inhibitors.
Trametinib in combination with dabrafenib in patients with melanoma who have progressed on a BRAF inhibitor There are limited data in patients taking the combination of trametinib with dabrafenib 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 trametinib is used in combination with dabrafenib. Cutaneous malignancies Cutaneous squamous cell carcinoma (cuSCC) Cases of cuSCC (including keratoacanthoma) have been reported in patients treated with trametinib in combination with dabrafenib.
Cases of cuSCC can be managed with excision and do not require treatment modification. 4). New primary melanoma New primary melanoma was reported in patients receiving trametinib in combination with dabrafenib. Cases of new primary melanoma can be managed with excision and do not require treatment modification.
1.
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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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 trametinib dose should not exceed the recommended starting dose indicated in Table 1. Pyrexia If a patient’s temperature is ≥38ºC, therapy should be interrupted (trametinib when used as monotherapy, and both trametinib and dabrafenib 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). Trametinib, or both trametinib and dabrafenib 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 pyrexia is recurrent and/or was accompanied by other severe symptoms including dehydration, hypotension or renal failure.
If treatment-related toxicities occur when trametinib is used in combination with dabrafenib, 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).
5 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 ocular therapy, dabrafenib should be withheld until resolution of ocular inflammation, and then dabrafenib should be restarted reduced by one dose level. 4). RAS mutation-positive non-cutaneous malignancies The benefits and risks must 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 […]
b Including atrioventricular block complete. c Events include but are not limited to: epistaxis, haematochezia, gingival bleeding, haematuria, and rectal, haemorrhoidal, gastric, vaginal, conjunctival, intracranial and post-procedural haemorrhage.
15 Table 5 Adverse reactions with trametinib in combination with dabrafenib 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 Common Peripheral neuropathy (including sensory and motor neuropathy) Eye disorders Common Vision blurred Visual impairment Uveitis Uncommon Chorioretinopathy Retinal detachment Periorbital oedema Cardiac disorders Common Ejection fraction decreased Bradycardia Uncommon Cardiac failure Left ventricular dysfunction Atrioventricular blocke Not known Myocarditis Vascular disorders Very common Hypertension Haemorrhagef Common Hypotension Lymphoedema Respiratory, thoracic and mediastinal disorders Very common Cough Common Pneumonitis Dyspnoea Rare Interstitial lung disease 16 Gastrointestinal disorders Very common Abdominal paing 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 generalisedh Actinic keratosis Night sweats Hyperkeratosis Alopecia Palmar-plantar […]
4). Non-cutaneous malignancies Based on its mechanism of action, dabrafenib may increase the risk of non-cutaneous malignancies when RAS mutations are present. 4). No dose modification of trametinib is required for RAS mutation-positive malignancies when taken in combination with dabrafenib.
8). The potential for these events in patients with low platelet counts (<75 000) has not been established as such patients were excluded from clinical studies. The risk of haemorrhage may be increased with concomitant use of antiplatelet or anticoagulant therapy.
If haemorrhage occurs, patients should be treated as clinically indicated. 8). In clinical studies, the median time to onset of the first occurrence of left ventricular dysfunction, cardiac failure and LVEF decrease was between 2 and 5 months.
Trametinib should be used with caution in patients with impaired left ventricular function. Patients with left ventricular dysfunction, New York Heart Association Class II, III, or IV heart failure, acute coronary syndrome within the past 6 months, clinically significant uncontrolled arrhythmias, and uncontrolled hypertension were excluded from clinical studies; safety of use in this population is therefore unknown.
2 regarding dose modification). In patients receiving trametinib in combination with dabrafenib, there have been occasional reports of acute, severe left ventricular dysfunction 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. 8). 4). In patients receiving trametinib in combination with dabrafenib, pyrexia may be accompanied by severe rigors, dehydration, and hypotension which in some cases can lead to acute renal insufficiency.
1). 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.
Patients should be evaluated for signs and symptoms of infection. Therapy can be restarted once the fever resolves. 2). 8). Blood […]