Special Warning : אזהרת שימוש

4.4    Special warnings and precautions for use

Pemetrexed can suppress bone marrow function as manifested by neutropenia, thrombocytopenia and anaemia (or pancytopenia) (see section 4.8). Myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy and pemetrexed should not be given to patients until absolute neutrophil 
count (ANC) returns to ≥ 1500 cells/mm3 and platelet count returns to ≥ 100,000 cells/mm3.
Dose reductions for subsequent cycles are based on nadir ANC, platelet count and maximum non-haematologic toxicity seen from the previous cycle (see section 4.2).

Less toxicity and reduction in Grade 3/4 haematologic and non-haematologic toxicities such as neutropenia, febrile neutropenia and infection with Grade 3/4 neutropenia were reported when pre-treatment with folic acid and vitamin B12 was administered. Therefore, all patients treated with pemetrexed must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related toxicity (see section 4.2).

Skin reactions have been reported in patients not pre-treated with a corticosteroid. Pre- treatment with dexamethasone (or equivalent) can reduce the incidence and severity of skin reactions (see section 4.2).

An insufficient number of patients has been studied with creatinine clearance of below 45 ml/min. Therefore, the use of pemetrexed in patients with creatinine clearance of < 45 ml/min is not recommended (see section 4.2).

Patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 ml/min) should avoid taking non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and acetylsalicylic acid (> 1.3 g daily) for 2 days before, on the day of, and 2 days following pemetrexed administration (see section 4.5).
In patients with mild to moderate renal insufficiency eligible for pemetrexed therapy NSAIDs with long elimination half-lives should be interrupted for at least 5 days prior to, on the day of, and at least 2 days following pemetrexed administration (see section 4.5).

Serious renal events, including acute renal failure, have been reported with pemetrexed alone or in association with other chemotherapeutic agents. Many of the patients in whom these occurred had underlying risk factors for the development of renal events including dehydration or pre-existing hypertension or diabetes. Nephrogenic diabetes insipidus and renal tubular necrosis were also reported in post marketing setting with pemetrexed alone or with other chemotherapeutic agents. Most of these events resolved after pemetrexed withdrawal. Patients should be regularly monitored for acute tubular necrosis, decreased renal function and signs and symptoms of nephrogenic diabetes insipidus (e.g.
hypernatraemia).

The effect of third space fluid, such as pleural effusion or ascites, on pemetrexed is not fully defined. A phase 2 study of pemetrexed in 31 solid tumour patients with stable third space fluid demonstrated no difference in pemetrexed dose normalized plasma concentrations or clearance compared to patients without third space fluid collections.
Thus, drainage of third space fluid collection prior to pemetrexed treatment should be considered but may not be necessary.

Due to the gastrointestinal toxicity of pemetrexed given in combination with cisplatin, severe dehydration has been observed. Therefore, patients should receive adequate antiemetic treatment and appropriate hydration prior to and/or after receiving treatment.

Serious cardiovascular events, including myocardial infarction and cerebrovascular events have been uncommonly reported during clinical studies with pemetrexed, usually when given in combination with another cytotoxic agent. Most of the patients in whom these events have been observed had pre-existing cardiovascular risk factors (see section 4.8).

Immunodepressed status is common in cancer patients. As a result, concomitant use of live attenuated vaccines is not recommended (see section 4.3 and 4.5).

Pemetrexed can have genetically damaging effects. Sexually mature males are advised not to father a child during the treatment and up to 3 months thereafter. Contraceptive measures or abstinence are recommended. Owing to the possibility of pemetrexed treatment causing irreversible infertility, men are advised to seek counselling on sperm storage before starting treatment.

Women of childbearing potential must use effective contraception during treatment with pemetrexed and for 6 months following completion of treatment (see section 4.6).

Cases of radiation pneumonitis have been reported in patients treated with radiation either prior, during or subsequent to their pemetrexed therapy. Particular attention should be paid to these patients and caution exercised with use of other radiosensitising agents.

Cases of radiation recall have been reported in patients who received radiotherapy weeks or years previously.

Excipients
Pemetrexed Taro 100 mg powder for concentrate for solution for infusion This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium-free’.
Pemetrexed Taro 500 mg powder for concentrate for solution for infusion This medicinal product contains 54 mg sodium per vial, equivalent to 2.7% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Pemetrexed Taro 1000 mg powder for concentrate for solution for infusion This medicinal product contains approximately 108 mg of sodium per vial, equivalent to 5.4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Effects on Driving

4.7      Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.
However, it has been reported that pemetrexed may cause fatigue. Therefore, patients should be cautioned against driving or operating machines if this event occurs.