Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

When trametinib is given in combination with dabrafenib, the Prescribing Information 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 Prescribing Information.


BRAF V600 testing

The efficacy and safety of trametinib have not been evaluated in patients whose solid tumor 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. 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

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. Please refer to the dabrafenib Prescribing Information (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 Prescribing Information (section 4.4).

Non-cutaneous malignancies

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 Prescribing Information (section 4.4). No dose modification of trametinib is required for RAS mutation-positive malignancies when taken in combination with dabrafenib.

Haemorrhage

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.
LVEF reduction/Left ventricular dysfunction

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.

Pyrexia

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 Prescribing Information 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).

Hypertension

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.

Interstitial lung disease (ILD)/Pneumonitis

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.

Visual impairment

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 5 should be followed (see section 4.2); if uveitis is diagnosed, please refer to dabrafenib Prescribing Information 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

Rash has been observed in about 60% of patients in trametinib monotherapy studies and in about 24% of adult patients and 54% of pediatric 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

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

Renal failure has been identified in patients treated with trametinib in combination with dabrafenib in clinical trials. Please refer to the dabrafenib Prescribing Information (section 4.4).

Pancreatitis

Pancreatitis has been reported in patients treated with trametinib in combination with dabrafenib in clinical trials. Please refer to the dabrafenib Prescribing Information (section 4.4).

Hepatic events

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.

Hepatic 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 (see sections 4.2 and 5.2).

Deep vein thrombosis (DVT)/Pulmonary embolism (PE)

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.

Severe cutaneous adverse reactions

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.

Gastrointestinal disorders

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.

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.

Haemophagocytic lymphohistiocytosis

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.

Tumour lysis syndrome (TLS)

The occurrence of TLS, which may be fatal, has been associated with the use of trametinib in combination with dabrafenib (see section 4.8). Risk factors for TLS include high tumour burden, pre-existing chronic renal insufficiency, oliguria, dehydration, hypotension and acidic urine. Patients with risk factors for TLS should be closely monitored and prophylactic hydration should be considered. TLS should be treated promptly, as clinically indicated.
Sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium- free’.

Effects on Driving

4.7    Effects on ability to drive and use machines

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.