Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use
Hepatic impairment
Patients must meet specific criteria on hepatic function parameters to start treatment with 
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Trabectedin Teva 0.25 mg and 1 mg. Since the systemic exposure to trabectedin may be increased due to hepatic impairment and therefore, the risk of hepatotoxicity might be increased, patients with clinically relevant liver diseases, such as active chronic hepatitis, should be closely monitored and the dose adjusted if needed. Patients with elevated bilirubin at the time of initiation of a new treatment cycle must not be treated with trabectedin (see section 4.2).

Renal impairment
Creatinine clearance must be monitored prior to and during treatment. Trabectedin as a single agent must not be used in patients with creatinine clearance < 30 ml/min (see section 4.2).

Neutropenia and thrombocytopenia
Grades 3 or 4 neutropenia and thrombocytopenia associated with trabectedin therapy have been very commonly reported. A full blood cell count including differential and platelet counts must be performed at baseline, weekly for the first two cycles and then once between cycles (see section 4.2). Patients who develop fever should promptly seek medical attention. If this occurs, active supportive therapy should be started immediately.

Trabectedin Teva 0.25 mg and 1 mg should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm3 and platelet counts of less than 100,000 cells/mm3. If severe neutropenia (ANC < 500 cells/mm3) lasting more than 5 days or associated with fever or infection occurs, dose reduction is recommended (see section 4.2).

Nausea and vomiting
Antiemetic prophylaxis with corticosteroids such as dexamethasone must be administered to all patients (see section 4.2).

Rhabdomyolysis and severe CPK elevations (> 5 x ULN)
Trabectedin must not be used in patients with CPK > 2.5 x ULN (see section 4.2).
Rhabdomyolysis has been uncommonly reported usually in association with myelotoxicity, severe liver function test abnormalities and/or renal or multiorgan failure.
Therefore, CPK should be closely monitored whenever a patient may be experiencing any of these toxicities or muscle weakness or muscle pain. If rhabdomyolysis occurs, supportive measures such as parenteral hydration, urine alkalinisation and dialysis should be promptly established, as indicated. Treatment with trabectedin should be discontinued until the patient fully recovers.

Caution should be taken if medicinal products associated with rhabdomyolysis (e.g., statins) are administered concomitantly with trabectedin, since the risk of rhabdomyolysis may be increased.

Liver function test (LFT) abnormalities
Reversible acute increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) have been reported in most patients treated with trabectedin. Grade 3 or 4 transaminase elevations occurred very commonly; grade 4 transaminase elevations occurred commonly. The median time to the occurrence of ALT or AST increase to grade 3 or 4 levels was 8 days.
Elevated levels decreased to below grade 3 or 4 in about 8 days. Transaminase elevations were non-cumulative and decreased in magnitude and incidence with each subsequent cycle.
Trabectedin must not be used in patients with elevated bilirubin at the time of initiation of cycle.
Patients with increases in AST, ALT and alkaline phosphatase between cycles may necessitate dose reduction (see section 4.2).

Injection site reactions

The use of central venous access is strongly recommended (see section 4.2). Patients may develop a potentially severe injection site reaction when trabectedin is administered through a peripheral venous line.

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Trabectedin extravasation may cause tissue necrosis requiring debridement. There is no specific antidote for extravasation of trabectedin. Extravasation should be managed by local standard practice.

Allergic reactions

During postmarketing experience, hypersensitivity reactions with very rare occurrence of fatal outcome, have been reported in association with trabectedin administration (see sections 4.3 and 4.8).

Cardiac dysfunction

Patients should be monitored for cardiac-related adverse events or myocardial dysfunction.
A thorough cardiac assessment including determination of left ventricular ejection fraction (LVEF) by echocardiogram or multigated acquisition scan (MUGA) should be conducted before initiation of trabectedin and at 2- to 3-month intervals thereafter until trabectedin is discontinued.

Patients with LVEF less than the lower limit of normal (LVEF < LLN), prior cumulative anthracycline dose of > 300mg/m2, aged > 65 years, or a history of cardiovascular disease (especially in those with cardiac medication) may be at increased risk of cardiac dysfunction at treatment with trabectedin as monotherapy or in combination with doxorubicin.

For patients with grade 3 or 4 cardiac adverse events indicative of cardiomyopathy or for patients with a LVEF that decreases below the LLN (assessed as either an absolute decrease of LVEF of ≥ 15% or < LLN with an absolute decrease of ≥ 5%), trabectedin should be discontinued.

Capillary leak syndrome (CLS)

Cases of Capillary Leak Syndrome (CLS) have been reported with trabectedin (including cases with fatal outcomes). If symptoms of possible CLS develop, such as unexplained oedema with or without hypotension, the treating physician should reassess serum albumin level. A rapid decline in serum albumin level may be indicative of CLS. If a diagnosis of CLS is confirmed after exclusion of other causes, the treating physician should discontinue trabectedin and initiate CLS treatment according to institutional guidelines (see sections 4.2 and 4.8).

Others
Co-administration of trabectedin with potent inhibitors of the enzyme CYP3A4 should be avoided (see section 4.5). If this is not possible, close monitoring of toxicities is required and dose reductions of trabectedin should be considered.

Caution should be taken if medicinal products associated with hepatotoxicity are administered concomitantly with trabectedin, since the risk of hepatotoxicity may be increased.

Concomitant use of trabectedin with phenytoin may reduce phenytoin absorption leading to an exacerbation of convulsions. Combination of trabectedin with phenytoin or live attenuated vaccines is not recommended and with yellow fever vaccine is specifically contraindicated (see section 4.3).

Women of childbearing potential must use effective contraception during treatment and 3 months thereafter, and immediately inform the treating physician if a pregnancy occurs (see section 5.3). Men in fertile age must use effective contraception during treatment and 5 months after treatment (see section 4.6).

Immediately inform the treating physician if a pregnancy occurs.

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This medicine contains 1.28 mmol (or 50.22 mg) potassium per 2.7 mg of trabectedin. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet.

Effects on Driving

4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and to use machines have been performed.
However, fatigue and/or asthenia have been reported in patients receiving trabectedin.
Patients who experience any of these adverse reactions during therapy must not drive or operate machines.