Chemical formula: C₂₆H₂₃FIN₅O₄ Molecular mass: 615.395 g/mol PubChem compound: 11707110
Trametinib interacts in the following cases:
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.
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 coadministering trametinib with medicinal products that are strong inhibitors of P-gp (e.g. verapamil, cyclosporine, ritonavir, quinidine, itraconazole).
There are no data with trametinib in patients with severe renal impairment; therefore, the potential need for dose adjustment cannot be determined. Trametinib should be used with caution in patients with severe renal impairment.
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.
The risk of haemorrhage may be increased with concomitant use of antiplatelet or anticoagulant therapy.
There are no data in humans for trametinib. In animals, no fertility studies have been performed, but effects were seen on female reproductive organs. 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. Please refer to the dabrafenib SmPC for further information.
Trametinib is not recommended in patients with a history of retinal vein occlusion (RVO). The safety of trametinib in patients 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.
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.
Trametinib must be withheld in patients with suspected interstitial lung disease 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 in patients diagnosed with treatment-related ILD or pneumonitis. Therapy with dabrafenib may be continued at the same dose.
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. 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.
Trametinib 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.
There are no data from the use of trametinib in pregnant women. Animal studies have shown reproductive toxicity. Trametinib should not be administered to pregnant women unless the potential benefit to the mother outweighs the possible risk to the foetus. 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. A risk to the breast-feeding child 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.
Women of childbearing potential must use effective methods of contraception during treatment with trametinib and for 16 weeks after stopping treatment.
Use with dabrafenib may decrease the efficacy of oral or any systemic hormonal contraceptives and an effective alternative method of contraception, such as a barrier method, should be used during trametinib/dabrafenib combination therapy. Please refer to the dabrafenib SmPC for further information.
There are no data in humans for trametinib. In animals, no fertility studies have been performed, but effects were seen on female reproductive organs. 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. Please 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 of trametinib 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 the potential for fatigue, dizziness or eye problems to 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). 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.
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 1) and trametinib in combination with dabrafenib (Table 2).
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 1. 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 2. 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.
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.
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.
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.
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.
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.
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.
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.
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.
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. Trametinib should be used with caution in patients with severe renal impairment.
No dosage adjustment is required in patients with mild hepatic impairment. Trametinib should be used with caution in patients with moderate or severe hepatic impairment.
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.
In clinical studies of paediatric patients treated with trametinib in combination with dabrafenib, the most common adverse reactions (reported at a frequency ≥20%) were: pyrexia (65%), rash (47%), headache (40%), vomiting (38%), fatigue (35%), dry skin (34%), diarrhoea (31%), haemorrhage (30%), nausea (26%), dermatitis acneiform (26%), neutropenia (25%), abdominal pain (23%) and cough (22%). The most frequently reported severe (Grade ¾) adverse reactions were: neutropenia (15%), pyrexia (9%), transaminases increased (6%) and weight increased (5%). Long-term data on growth and skeletal maturation in paediatric patients are currently limited.
The safety profile in paediatric patients was largely consistent with the safety profile previously established in adult patients. The following additional adverse reactions have so far only been reported in adult patients treated with trametinib tablets and dabrafenib capsules: cutaneous squamous cell carcinoma, seborrhoeic keratosis, lymphoedema, dry mouth, actinic keratosis, photosensitivity, renal failure (common), melanoma, acrochordon, sarcoidosis, chorioretinopathy, pneumonitis, acute renal failure, nephritis, cardiac failure, left ventricular dysfunction, interstitial lung disease, rhabdomyolysis (uncommon), gastrointestinal perforation, haemophagocytic lymphohistiocytosis (rare), myocarditis, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (frequency not known).
The safety of trametinib in combination with dabrafenib has been evaluated in a pooled safety set of 171 paediatric patients across two studies in patients with BRAF V600 mutation-positive advanced solid tumours. Four (2.3%) patients were 1 to <2 years of age, 39 (22.8%) patients were 2 to <6 years of age, 54 (31.6%) patients were 6 to <12 years of age and 74 (43.3%) patients were 12 to <18 years of age at enrolment. The mean treatment duration was 80 weeks.
Adverse reactions in the integrated paediatric safety population (Table 3) are listed below by MedDRA system organ class 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 reported in the integrated paediatric safety population of trametinib in combination with dabrafenib (n=171):
| Infections and infestations | |
| Very common | Paronychia |
| Common | Urinary tract infection, cellulitis, nasopharyngitis1* |
| Neoplasms benign, malignant, and unspecified (incl cysts and polyps) | |
| Common | Skin papilloma |
| Blood and lymphatic system disorders | |
| Very common | Neutropenia*2, anaemia, leukopenia* |
| Common | Thrombocytopenia* |
| Immune system disorders | |
| Common | Hypersensitivity |
| Metabolism and nutrition disorders | |
| Common | Dehydration, decreased appetite |
| Nervous system disorders | |
| Very common | Headache, dizziness*3 |
| Eye disorders | |
| Common | Vision blurred, visual impairment, uveitis*4 |
| Uncommon | Retinal detachment, periorbital oedema |
| Cardiac disorders | |
| Common | Ejection fraction decreased, bradycardia* |
| Vascular disorders | |
| Very common | Haemorrhage*5 |
| Common | Hypertension, hypotension |
| Respiratory, thoracic, and mediastinal disorders | |
| Very common | Cough* |
| Common | Dyspnoea |
| Gastrointestinal disorders | |
| Very common | Abdominal pain*, constipation, diarrhoea, nausea, vomiting |
| Common | Pancreatitis, stomatitis |
| Uncommon | Colitis* |
| Skin and subcutaneous tissue disorders | |
| Very common | Dermatitis acneiform*6, dry skin*7, pruritus, rash*8, erythema |
| Common | Dermatitis exfoliative generalised*9, alopecia, palmar-plantar erythrodysaesthesia syndrome, folliculitis, skin lesion, panniculitis, hyperkeratosis |
| Uncommon | Skin fissures, night sweats, hyperhidrosis |
| Musculoskeletal and connective tissue disorders | |
| Very common | Arthralgia, pain in extremity |
| Common | Myalgia*, muscle spasms*10 |
| General disorders and administration site conditions | |
| Very common | Pyrexia*, fatigue*11, weight increased |
| Common | Mucosal inflammation, face oedema*, chills, oedema peripheral, influenza-like illness |
| Investigations | |
| Very common | Transaminases increased*12 |
| Common | Hyponatraemia, hypophosphataemia, hyperglycaemia, blood alkaline phosphatase increased, gammaglutamyltransferase increased, blood creatine phosphokinase increased |
* Denotes grouped term of two or more MedDRA preferred terms that were considered clinically similar.
1 nasopharyngitis includes pharyngitis
2 neutropenia includes neutrophil count decreased and febrile neutropenia
3 dizziness includes vertigo
4 uveitis includes iridocyclitis
5 haemorrhage includes epistaxis, haematuria, contusion, haematoma, international normalised ratio increased, anal haemorrhage, catheter site haemorrhage, cerebral haemorrhage, ecchymosis, extradural haematoma, gastrointestinal haemorrhage, haematochezia, petechiae, post-procedural haemorrhage, rectal haemorrhage, red blood cell count decreased, upper gastrointestinal haemorrhage and uterine haemorrhage
6 dermatitis acneiform includes acne and acne pustular
7 dry skin includes xerosis and xeroderma
8 rash includes rash maculo-papular, rash pustular, rash erythematous, rash papular, rash macular
9 dermatitis exfoliative generalised includes skin exfoliation and dermatitis exfoliative
10 muscle spasms include musculoskeletal stiffness
11 fatigue includes malaise and asthenia
12 transaminases increased includes aspartate aminotransferase (AST) increased and alanine aminotransferase (ALT) increased
Weight increase has only been reported in the paediatric population. It was reported as an adverse reaction in 16% of paediatric patients including Grade 3 cases in 4.7% of patients, with a discontinuation rate of 0.6% of patients. The median time to onset of the first occurrence of the reported weight increase in paediatric patients receiving trametinib in combination with dabrafenib was 3.1 months. Weight increase from baseline of ≥2 BMI (body mass index)-for-age percentile categories was observed in 29.8% of patients.
Haemorrhagic events were observed in 30% of paediatric patients, with Grade 3 events occurring in 1.2% of patients. The most frequent haemorrhagic event (epistaxis) was reported in 18% of paediatric patients. The median time to onset of the first occurrence of haemorrhagic events in paediatric patients was 2.4 months. Haemorrhagic events, including major haemorrhagic events and fatal haemorrhages, occurred in adult patients taking trametinib in combination with dabrafenib.
The risk of haemorrhage may be increased with concomitant use of antiplatelet or anticoagulant therapy. If haemorrhage occurs, patents should be treated as clinically indicated.
Decreased LVEF has been reported in 5.3% of paediatric patients, with Grade 3 events occurring in <1% of patients. The median time to onset for the first occurrence of LVEF decrease was around one month. In clinical studies in adult patients, the median time to first occurrence of left ventricular dysfunction, cardiac failure and LVEF decrease was between 2 to 5 months.
Patients with LVEF lower than the institutional lower limit of normal were not included in clinical studies with trametinib. Trametinib in combination with dabrafenib should be used with caution in patients with conditions that could impair left ventricular function.
Pyrexia has been reported in clinical studies with trametinib as monotherapy and in combination with dabrafenib; however, the incidence and severity of pyrexia are increased with the combination therapy. Pyrexia was reported in 65% of paediatric patients, with Grade 3 events occurring in 8.8% of patients. Please refer to the dabrafenib dispersible tablets SmPC.
Hepatic adverse reactions have been reported in adult and paediatric clinical studies with trametinib in combination with dabrafenib. In the paediatric safety population, increased ALT and AST were very common, reported in 12.3% and 15.2% of patients, respectively. The hepatic adverse reactions of increased ALT and AST were the most common events in adult patients, the majority of these events 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 studies with monitoring every four weeks. It is recommended that patients receiving treatment with trametinib have liver function monitored every four weeks for 6 months. Liver monitoring may be continued thereafter as clinically indicated.
Hypertension was reported in 2.3% of paediatric patients, with Grade 3 events occurring in 1.2% of patients. The median time to onset of the first occurrence of hypertension in paediatric patients was 5.4 months.
Hypotension was reported in 3.5% of paediatric patients, with Grade ≥3 events occurring in 2.3% of patients. The median time to onset of the first occurrence of hypotension in paediatric patients was 1.5 months.
Blood pressure should be measured at baseline and monitored during treatment, with control of hypertension by standard therapy as appropriate.
Patients treated with trametinib 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.
In paediatric patients treated with trametinib in combination with dabrafenib, ophthalmological reactions, including uveitis 1.8% and iridocyclitis 1.2%, have been reported. Grade 3 uveitis occured in <1% of paediatric patients. Retinal pigment epithelial detachment (RPED) occurred in <1% of paediatric patients. Disorders associated with visual disturbances, including RPED and RVO, have also been observed with trametinib in adult patients. Symptoms such as blurred vision, decreased acuity and other visual disturbances have been reported in adult clinical studies with trametinib.
Rash has been observed in about 47% of paediatric 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.
Rhabdomyolysis has been reported in adult patients taking trametinib. Signs or symptoms of rhabdomyolysis should warrant an appropriate clinical evaluation and treatment as indicated.
Pancreatitis was reported in 1.2% of paediatric patients, with <1% of patients with Grade 3 severity. Unexplained abdominal pain should be promptly investigated to include measurement of serum amylase and lipase. Patients should be closely monitored when restarting treatment after an episode of pancreatitis.
Renal failure has been reported with trametinib in combination with dabrafenib. Renal failure due to pyrexia-associated pre-renal azotaemia or granulomatous nephritis was uncommon in adult patients; however, trametinib has not been studied in patients with renal insufficiency (defined as creatinine >1.5 x ULN). Caution should be used in this setting.
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