Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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.
The efficacy and safety of trametinib have not been evaluated in patients whose melanoma tested negative for the BRAF V600 mutation.
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.
There are limited data in patients taking the combination of trametinib with dabrafenib who have progressed on a prior BRAF inhibitor. These data show that the efficacy of the combination will be lower in these patients (see section 5.1). 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, cutaneous and non-cutaneous, can occur when trametinib is used in combination with dabrafenib.
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. Please refer to the dabrafenib SmPC (section 4.4).
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. Please refer to the dabrafenib SmPC (section 4.4).
Based on its mechanism of action, dabrafenib may increase the risk of non-cutaneous malignancies when RAS mutations are present. When trametinib is used in combination with dabrafenib please refer to the dabrafenib SmPC (section 4.4). No dose modification of trametinib is required for RAS mutation positive malignancies when taken in combination with dabrafenib.
Haemorrhagic events, including major haemorrhagic events and fatal haemorrhages, have occurred in patients taking trametinib as monotherapy and in combination with dabrafenib (see section 4.8). The potential for these events in patients with low platelet counts (<75,000) has not been established as such patients were excluded from clinical trials. 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.
Trametinib has been reported to decrease LVEF, when used as monotherapy or in combination with dabrafenib (see section 4.8). In clinical trials, 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 trials; safety of use in this population is therefore unknown. LVEF should be evaluated in all patients prior to initiation of treatment with trametinib, one month after initiation of therapy, and then at approximately 3-monthly intervals while on treatment (see section 4.2 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.
Fever has been reported in clinical trials with trametinib as monotherapy and in combination with dabrafenib (see section 4.8). The incidence and severity of pyrexia are increased with the combination therapy (see dabrafenib SmPC section 4.4). 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.
Therapy (trametinib when used as monotherapy, and both trametinib and dabrafenib when used in combination) should be interrupted if the patient’s temperature is ≥38ºC (see section 5.1). 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. If fever is associated with other severe signs or symptoms, therapy should be restarted at a reduced dose once fever resolves and as clinically appropriate (see section 4.2).
Elevations in blood pressure have been reported in association with trametinib as monotherapy and in combination with dabrafenib, in patients with or without pre-existing hypertension (see section 4.8). Blood pressure should be measured at baseline and monitored during treatment with trametinib, with control of hypertension by standard therapy as appropriate.
In a Phase III trial, 2.4% (5/211) of patients treated with trametinib monotherapy developed ILD or pneumonitis; all five patients required hospitalisation. The median time to first presentation of ILD or pneumonitis was 160 days (range: 60 to 172 days). In studies MEK115306 and MEK116513 <1% (2/209) and 1% (4/350), respectively, of patients treated with trametinib in combination with dabrafenib developed pneumonitis or ILD (see section 4.8).
Trametinib 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. Trametinib should be permanently discontinued for patients diagnosed with treatment-related ILD or pneumonitis (see section 4.2). If trametinib is being used in combination with dabrafenib then therapy with dabrafenib may be continued at the same dose.
Disorders associated with visual disturbance, including RPED and RVO, may occur with trametinib as monotherapy and in combination with dabrafenib. Symptoms such as blurred vision, decreased acuity, and other visual phenomena have been reported in the clinical trials with trametinib (see section 4.8). In clinical trials uveitis and iridocyclitis have also been reported in patients treated with trametinib in combination with dabrafenib.
Trametinib is not recommended in patients with a history of RVO. The safety of trametinib in subjects with predisposing factors for RVO, including uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes, has not been established.
If patients report new visual disturbances, such as diminished central vision, blurred vision or loss of vision at any time while on trametinib therapy, a prompt ophthalmological assessment is recommended. If RPED is diagnosed, the dose modification schedule in Table 3 should be followed (see section 4.2); if uveitis is diagnosed, please refer to dabrafenib SmPC section 4.4. In patients who are diagnosed with RVO, treatment with trametinib should be permanently discontinued. No dose modification of dabrafenib is required when taken in combination with trametinib following diagnosis of RVO or RPED. No dose modification of trametinib is required when taken in combination with dabrafenib following diagnosis of uveitis.
Rash has been observed in about 60% of patients in trametinib monotherapy studies and in about 24% of patients when trametinib is used in combination with dabrafenib (see section 4.8). The majority of these cases were Grade 1 or 2 and did not require any dose interruptions or dose reductions.
Rhabdomyolysis has been reported in patients taking trametinib as monotherapy or in combination with dabrafenib (see section 4.8). In some cases, patients were able to continue trametinib. In more severe cases hospitalisation, interruption or permanent discontinuation of trametinib or trametinib and dabrafenib combination was required. Signs or symptoms of rhabdomyolysis should warrant an appropriate clinical evaluation and treatment as indicated.
Renal failure has been identified in patients treated with trametinib in combination with dabrafenib in clinical trials. Please refer to the dabrafenib SmPC (section 4.4).
Pancreatitis has been reported in patients treated with trametinib in combination with dabrafenib in clinical trials. Please refer to the dabrafenib SmPC (section 4.4).
Hepatic adverse reactions have been reported in clinical trials with trametinib as monotherapy and in combination with dabrafenib (see section 4.8). It is recommended that patients receiving treatment with trametinib monotherapy or in combination with dabrafenib have liver function monitored every four weeks for 6 months after treatment initiation with trametinib. Liver monitoring may be continued thereafter as clinically indicated.
As metabolism and biliary excretion are the primary routes of elimination of trametinib, administration of trametinib should be undertaken with caution in patients with moderate to severe hepatic impairment (see sections 4.2 and 5.2).
Pulmonary embolism or deep vein thrombosis can occur when trametinib is used as monotherapy or in combination with dabrafenib. If patients develop symptoms of pulmonary embolism or deep vein thrombosis such as shortness of breath, chest pain, or arm or leg swelling, they should immediately seek medical care. Permanently discontinue trametinib and dabrafenib for life-threatening pulmonary embolism.
Cases of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with dabrafenib/trametinib combination therapy. 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, dabrafenib and trametinib should be withdrawn.
Colitis and gastrointestinal perforation, including fatal outcome, have been reported in patients taking trametinib as monotherapy and in combination with dabrafenib (see section 4.8). Treatment with trametinib monotherapy or in combination with dabrafenib should be used with caution in patients with risk factors for gastrointestinal perforation, including history of diverticulitis, metastases to the gastrointestinal tract and concomitant use of medicinal products with a recognised risk of gastrointestinal perforation.
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.
In post-marketing experience, haemophagocytic lymphohistiocytosis (HLH) has been observed in patients treated with trametinib in combination with dabrafenib. Caution should be taken when trametinib is administered in combination with dabrafenib. If HLH is confirmed, administration of trametinib and dabrafenib should be discontinued and treatment for HLH initiated.
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodiumfree’.
As trametinib is metabolised predominantly via deacetylation mediated by hydrolytic enzymes (e.g. carboxyl-esterases), its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions (see section 5.2). Drug-drug interactions via these hydrolytic enzymes cannot be ruled out and could influence the exposure to trametinib.
Trametinib is an in vitro substrate of the efflux transporter P-gp. As it cannot be excluded that strong inhibition of hepatic P-gp may result in increased levels of trametinib, caution is advised when co-administering trametinib with medicinal products that are strong inhibitors of P-gp (e.g. verapamil, cyclosporine, ritonavir, quinidine, itraconazole).
Based on in vitro and in vivo data, trametinib is unlikely to significantly affect the pharmacokinetics of other medicinal products via interaction with CYP enzymes or transporters (see section 5.2).
Trametinib may result in transient inhibition of BCRP substrates (e.g. pitavastatin) in the gut, which may be minimised with staggered dosing (2 hours apart) of these agents and trametinib.
Based on clinical data, no loss of efficacy of hormonal contraceptives is expected when co-administered with trametinib monotherapy (see section 5.2).
When trametinib is used in combination with dabrafenib see sections 4.4 and 4.5 of the dabrafenib SmPC for interactions.
Patients should take trametinib as monotherapy or in combination with dabrafenib at least one hour prior to or two hours after a meal due to the effect of food on trametinib absorption (see section 4.2 and 5.2).
Female patients of reproductive potential must be advised to use effective methods of contraception during treatment with trametinib and for 16 weeks after stopping treatment.
Use with dabrafenib may render hormonal contraceptives less effective and therefore an alternative method of contraception, such as a barrier method, should be used when trametinib is used in combination with dabrafenib. Refer to the dabrafenib SmPC for further information.
There are no adequate and well-controlled studies of trametinib in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). Trametinib should not be administered to pregnant women. If trametinib is used during pregnancy, or if the patient becomes pregnant while taking trametinib, the patient should be informed of the potential hazard to the foetus.
It is not known whether trametinib is excreted in human milk. Because many medicinal products are excreted in human milk, a risk to the breast-feeding infant cannot be excluded. Trametinib should not be administered to breast-feeding mothers. A decision should be made whether to discontinue breast-feeding or discontinue trametinib, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
There are no data in humans for trametinib as monotherapy or in combination with dabrafenib. In animals, no fertility studies have been performed, but adverse effects were seen on female reproductive organs (see section 5.3). Trametinib may impair fertility in humans.
Effects on spermatogenesis have been observed in animals given dabrafenib. Male patients taking trametinib in combination with dabrafenib should be informed of the potential risk for impaired spermatogenesis, which may be irreversible. Refer to the dabrafenib SmPC for further information.
Trametinib has minor influence on the ability to drive and use machines. The clinical status of the patient and the adverse reaction profile should be borne in mind when considering the patient’s ability to perform tasks that require judgement, motor and cognitive skills. Patients should be made aware of potential for fatigue, dizziness or eye problems that might affect these activities.
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. Of these patients, 211 were treated with trametinib for BRAF V600 mutant melanoma in the randomised open-label Phase III study MEK114267 (METRIC) (see section 5.1). The most common adverse reactions (incidence ≥20%) for trametinib were rash, diarrhoea, fatigue, oedema peripheral, nausea, and dermatitis acneiform.
The safety of trametinib in combination with dabrafenib has been evaluated in the integrated safety population of 1,076 patients with BRAF V600 mutant unresectable or metastatic melanoma, Stage III BRAF V600 mutant melanoma following complete resection (adjuvant treatment) and advanced NSCLC treated with trametinib 2 mg once daily and dabrafenib 150 mg twice daily. Of these patients, 559 were treated with the combination for BRAF V600 mutant melanoma in two randomised Phase III studies, MEK115306 (COMBI-d) and MEK116513 (COMBI-v), 435 were treated with the combination in the adjuvant treatment of Stage III BRAF V600 mutant melanoma after complete resection in a randomised Phase III study BRF115532 (COMBI-AD) and 82 were treated with the combination for BRAF V600 mutant NSCLC in a multi-cohort, non-randomised Phase II study BRF113928 (see section 5.1).
The most common adverse reactions (incidence ≥20%) for trametinib in combination with dabrafenib were: pyrexia, fatigue, nausea, chills, headache, diarrhoea, vomiting, arthralgia and rash.
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 body 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, Not known (cannot be estimated from the available data) Categories have been assigned based on absolute frequencies in the clinical trial 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 infestation | Common | Folliculitis Paronychia Cellulitis Rash pustular |
| Blood and lymphatic system disorders | Common | Anaemia |
| Immune system disorders | Common | Hypersensitivitya |
| Metabolism and nutrition disorders | Common | Dehydration |
| 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 | |
| Vascular disorders | Very common | Hypertension Haemorrhageb |
| 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 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
b Events include but are not limited to: epistaxis, haematochezia, gingival bleeding, haematuria, and rectal, haemorrhoidal, gastric, vaginal, conjunctival, intracranial and post-procedural haemorrhage.
Table 5. Adverse reactions with trametinib in combination with dabrafenib:
| System Organ Class | Frequency (all grades) | Adverse Reactions |
|---|---|---|
| Infections and infestations | Very common | Nasopharyngitis |
| Common | Urinary tract infection 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 | Common | Neutropenia Anaemia Thrombocytopenia Leukopenia |
| Immune system disorders | Uncommon | Hypersensitivityd Sarcoidosis |
| Rare | Haemophagocytic lymphohistiocytosis | |
| Metabolism and nutrition disorders | Very common | Decreased appetite |
| Common | Dehydration Hyponatraemia Hypophosphataemia Hyperglycaemia | |
| Nervous system disorders | Very common | Headache Dizziness |
| Eye disorders | Common | Vision blurred Visual impairment Uveitis |
| Uncommon | Chorioretinopathy Retinal detachment Periorbital oedema | |
| Cardiac disorders | Common | Ejection fraction decreased |
| Uncommon | Bradycardia | |
| Not known | Myocarditis | |
| Vascular disorders | Very common | Hypertension Haemorrhagee |
| Common | Hypotension Lymphoedema | |
| Respiratory, thoracic and mediastinal disorders | Very common | Cough |
| Common | Dyspnoea | |
| Uncommon | Pneumonitis | |
| Gastrointestinal disorders | Very common | Abdominal painf Constipation Diarrhoea Nausea Vomiting |
| Common | Dry mouth Stomatitis | |
| Uncommon | Pancreatitis Colitis | |
| Rare | Gastrointestinal perforation | |
| Skin and subcutaneous disorders | Very common | Dry skin Pruritus Rash Erythemag |
| Common | Dermatitis acneiform Actinic keratosis Night sweats Hyperkeratosis Alopecia Palmar-plantar erythrodysaesthesia syndrome Skin lesion Hyperhidrosis Panniculitis Skin fissures Photosensitivity | |
| Not Known | Stevens-Johnson syndrome Drug reaction with eosinophilia and systemic symptoms Dermatitis exfoliative generalised | |
| Musculoskeletal and connective tissue disorders | Very common | Arthralgia Myalgia Pain in extremity Muscle spasmsh |
| Renal and urinary disorders | Uncommon | Renal failure Nephritis |
| General disorders and administration site conditions | Very common | Fatigue Chills Asthenia Oedema peripheral Pyrexia Influenza-like illness |
| Common | Mucosal inflammation Face oedema | |
| Investigations | Very common | Alanine aminotransferase increased Aspartate aminotransferase increased |
| Common | Blood alkaline phosphatase increased Gamma-glutamyltransferase increased Blood creatine phosphokinase increased |
a Cutaneous squamous cell carcinoma (cuSCC): SCC, SCC of the skin, SCC in situ (Bowen’s disease) and keratoacanthoma
b Papilloma, skin papilloma
c Malignant melanoma, metastatic malignant melanoma, and superficial spreading melanoma Stage III
d Includes drug hypersensitivity
e Bleeding from various sites, including intracranial bleeding and fatal bleeding
f Abdominal pain upper and abdominal pain lower
g Erythema, generalised erythema
h Muscle spasms, musculoskeletal stiffness
New malignancies, cutaneous and non-cutaneous, can occur when trametinib is used in combination with dabrafenib. Please refer to the dabrafenib SmPC.
Haemorrhagic events, including major haemorrhagic events and fatal haemorrhages, occurred in patients taking trametinib as monotherapy and in combination with dabrafenib. The majority of bleeding events were mild. Fatal intracranial haemorrhages occurred in the integrated safety population of trametinib in combination with dabrafenib in <1% (8/1076) of patients. The median time to onset of the first occurrence of haemorrhagic events for the combination of trametinib and dabrafenib was 94 days in the melanoma Phase III studies and 75 days in the NSCLC study for the patients who had received prior anti-cancer therapy.
The risk of haemorrhage may be increased with concomitant use of antiplatelet or anticoagulant therapy. If haemorrhage occurs, treat as clinically indicated (see section 4.4).
Trametinib has been reported to decrease LVEF when used as monotherapy or in combination with dabrafenib. In clinical trials, the median time to first occurrence of left ventricular dysfunction, cardiac failure and LVEF decrease was between 2 to 5 months. In the integrated safety population of trametinib in combination with dabrafenib, decreased LVEF has been reported in 6% (65/1076) 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 trametinib. Trametinib should be used with caution in patients with conditions that could impair left ventricular function (see sections 4.2 and 4.4).
Pyrexia has been reported in clinical trials with trametinib as monotherapy and in combination with dabrafenib; however, the incidence and severity of pyrexia are increased with the combination therapy. Please refer to sections 4.4 and 4.8 of the dabrafenib SmPC.
Hepatic adverse reactions have been reported in clinical trials with trametinib as monotherapy and in combination with dabrafenib. Of the hepatic adverse reactions, increased ALT and AST were the most common events and the majority were either Grade 1 or 2. For trametinib monotherapy, more than 90% of these liver events occurred within the first 6 months of treatment. Liver events were detected in clinical trials with monitoring every four weeks. It is recommended that patients receiving treatment with trametinib monotherapy or in combination with dabrafenib have liver function monitored every four weeks for 6 months. Liver monitoring may be continued thereafter as clinically indicated (see section 4.4).
Elevations in blood pressure have been reported in association with trametinib as monotherapy and in combination with dabrafenib, in patients with or without pre-existing hypertension. Blood pressure should be measured at baseline and monitored during treatment, with control of hypertension by standard therapy as appropriate (see section 4.4).
Patients treated with trametinib or combination with dabrafenib may develop ILD or pneumonitis. Trametinib 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. For patients diagnosed with treatment-related ILD or pneumonitis trametinib should be permanently discontinued (see sections 4.2 and 4.4).
Disorders associated with visual disturbances, including RPED and RVO, have been observed with trametinib. Symptoms such as blurred vision, decreased acuity, and other visual disturbances have been reported in the clinical trials with trametinib (see sections 4.2 and 4.4).
Rash has been observed in about 60% of patients when given as monotherapy and in about 24% of patients in trametinib and dabrafenib combination studies in the integrated safety population. The majority of these cases were Grade 1 or 2 and did not require any dose interruptions or dose reductions (see sections 4.2 and 4.4).
Rhabdomyolysis has been reported in patients taking trametinib alone or in combination with dabrafenib. Signs or symptoms of rhabdomyolysis should warrant an appropriate clinical evaluation and treatment as indicated (see section 4.4).
Pancreatitis has been reported with dabrafenib in combination with trametinib. Please see the dabrafenib SmPC.
Renal failure has been reported with dabrafenib in combination with trametinib. Please see the dabrafenib SmPC.
In the Phase III study with trametinib in patients with unresectable or metastatic melanoma (n=211), 49 patients (23%) were ≥65 years of age, and 9 patients (4%) were ≥75 years of age. The proportion of subjects experiencing adverse reactions (AR) and serious adverse reactions (SAR) was similar in the subjects aged <65 years and those aged ≥65 years. Patients ≥65 years were more likely to experience ARs leading to permanent discontinuation of medicinal product, dose reduction and dose interruption than those <65 years.
In the integrated safety population of trametinib in combination with dabrafenib (n=1,076) 265 patients (25%) were ≥65 years of age; 62 patients (6%) were ≥75 years of age. The proportion of patients experiencing ARs was similar in those aged <65 years and those aged ≥65 years in all studies. Patients ≥65 years were more likely to experience SARs and ARs leading to permanent discontinuation of medicinal product, dose reduction and dose interruption than those <65 years.
No dosage adjustment is required in patients with mild or moderate renal impairment (see section 5.2). Trametinib should be used with caution in patients with severe renal impairment (see sections 4.2 and 4.4).
No dosage adjustment is required in patients with mild hepatic impairment (see section 5.2). Trametinib should be used with caution in patients with moderate or severe hepatic impairment (see sections 4.2 and 4.4).
The safety and efficacy of the combination of trametinib and dabrafenib have been evaluated in a multi-cohort, open-label, Phase II study in patients with BRAF V600 mutant melanoma with brain metastases. The safety profile observed in these patients appears to be consistent with the integrated safety profile of the combination.
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 the national reporting system listed in Appendix V.
Not applicable.
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