Apimex 100mg or 500mg Injection

APIMEX is indicated for the treatment of patients with malignant pleural mesothelioma in combination with cisplatin. APIMEX is indicated as monotherapy for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after prior chemotherapy.

Posology APIMEX should only be administered under the supervision of a medical practitioner qualified in the use of anti-cancer chemotherapy. Malignant pleural mesothelioma: Combination use with cisplatin: Adults: In patients treated for malignant pleural mesothelioma, the recommended dose of APIMEX is 500 mg/m2 administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours approximately 30 minutes after completion of APIMEX infusion on the first day of each 21-day cycle. Patients should receive appropriate hydration prior to and/or after receiving cisplatin (see section 4.4). See cisplatin professional information for specific dosing advice. Non-small cell lung cancer: Single medicine use: Adults: In patients treated for non-small cell lung cancer, the recommended dose of APIMEX is 500 mg/m2 administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle. Premedication regimen: To reduce the incidence and severity of skin reactions, a corticosteroid should be given the day prior to, on the day of, and the day after APIMEX administration. The corticosteroid should be equivalent to 4 mg of dexamethasone administered orally twice a day (see section 4.4). To reduce toxicity, patients treated with APIMEX should also receive vitamin supplementation (see section 4.8). Patients should take oral folic acid or a multivitamin containing folic acid (350 to 1 000 u03bcg) on a daily basis. At least five doses of folic acid must be taken during the seven days preceding the first dose of APIMEX. Dosing must continue during the full course of therapy and for 21 days after the last dose of APIMEX. Patients should also receive an intramuscular injection of vitamin B12 (1 000 u03bcg) in the week preceding the first dose of APIMEX and once every three cycles thereafter. Monitoring: Patients receiving APIMEX should be monitored before each dose with a full blood count, including a differential white cell count (WCC) and platelet count. Periodic blood chemistry tests should be done to evaluate renal and hepatic function. The absolute neutrophil count (ANC) should be u2265 1 500 cells/mm3 and platelets should be u2265 100 000 cells/mm3 prior to the start of each cycle. Dose adjustments: Dose adjustments at the start of a subsequent cycle should be based on nadir haematologic counts or maximum non-haematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow enough time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 1, 2, and 3, which are applicable for APIMEX used as monotherapy or in combination with cisplatin.

• Hypersensitivity to pemetrexed or any of the ingredients of APIMEX

APIMEX 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 u2265 1 500 cells/mm3 and platelet count returns to u2265 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 APIMEX in patients with creatinine clearance of 1.3 g daily) for 2 days before, on the day of, and 2 days following APIMEX 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 (contained in APIMEX) alone, or in association with other chemotherapeutic medicines. 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. 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 unknown. In patients with clinically significant third space fluid, consideration could be given to draining the effusion prior to APIMEX administration. Due to the gastrointestinal toxicity of APIMEX 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 reported, usually when given in combination with another cytotoxic medicine. 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 4.5). APIMEX can have genetically damaging effects. Sexually mature males are advised not to father a child during the treatment and up to 6 months thereafter. Contraceptive measures or abstinence are recommended. Owing to the possibility of APIMEX 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 (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 substances. Cases of radiation recall have been reported in patients who received radiotherapy weeks or years previously.

Pemetrexed is mainly eliminated unchanged renally by tubular secretion and to a lesser extent by glomerular filtration. Concomitant administration of nephrotoxic medicines (such as aminoglycosides, loop diuretics, platinum compounds, ciclosporin) with APIMEX could potentially result in delayed clearance of pemetrexed. This combination should be used with caution. Creatinine clearance may need to be closely monitored if necessary. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid, penicillin) could potentially result in delayed clearance of pemetrexed. Caution should be made when these medicines are combined with APIMEX. If necessary, creatinine clearance should be closely monitored. In patients with normal renal function (creatinine clearance u2265 80 ml/min), high doses of NSAIDs, such as ibuprofen > 1 600 mg/day) and aspirin at higher doses (u2265 1, 3 g daily) may decrease pemetrexed elimination and, consequently, increase the occurrence of side effects. Therefore, caution should be made when administering higher doses of NSAIDs or aspirin, concurrently with APIMEX to patients with normal function (creatinine clearance u2265 80 ml/min). In patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 ml/min), the concomitant administration of APIMEX with NSAIDs (e.g., ibuprofen) or aspirin at higher doses should be avoided for 2 days before, on the day of, and 2 days following APIMEX administration (see section 4.4). In the absence of data regarding potential interaction with NSAIDs having longer half-lives such as piroxicam or rofecoxib, the concomitant administration with APIMEX in patients with mild to moderate renal insufficiency should be interrupted for at least 5 days prior to, on the day of, and at least 2 days following APIMEX administration (see section 4.4). If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression and gastrointestinal toxicity. The pharmacokinetics of APIMEX are not influenced by concurrently administered cisplatin or carboplatin. Similarly, the pharmacokinetics of total platinum are unaltered by APIMEX. Oral folic acid and intramuscular vitamin B12 supplementation do not affect the pharmacokinetics of APIMEX. Pemetrexed undergoes limited hepatic metabolism. Results from in vitro studies with human liver microsomes indicated that pemetrexed would not be predicted to cause clinically significant inhibition of the metabolic clearance of drugs metabolised by CYP3A, CYP2D6, CYP2C9, and CYP1A2.

Pregnancy Safety in pregnancy and lactation has not been established. Animal studies have shown reproductive toxicity such as birth defects and other defects on the development of the foetus, the course of gestation and peri- and post-development. APIMEX should be avoided during pregnancy due to the potential risk to the foetus. Women should also be advised to avoid becoming pregnant while being treated with APIMEX. Contraception in males and females Women of childbearing potential must use effective contraception during treatment with APIMEX. Pemetrexed can have genetically damaging effects. Sexually mature males are advised not to father a child during the treatment and up to 6 months thereafter. Contraceptive measures or abstinence are recommended. Breastfeeding It is not known whether pemetrexed is excreted in human milk. It is therefore recommended that breastfeeding is discontinued during APIMEX therapy. Fertility Owing to the possibility of APIMEX treatment causing irreversible infertility, men are advised to seek counselling on sperm storage before starting treatment.

Caution should be exercised when driving or operating machines or tools, as fatigue and dizziness may occur (see section 4.8).

Infections and infestations Less frequent: Infections, sepsis, colitis, interstitial pneumonitis, infection without neutropenia, radiation pneumonitis Blood and lymphatic system disorders Frequent: Decreased neutrophils/granulocytes, decreased leukocytes, decreased haemoglobin, decreased platelets, febrile neutropenia Less frequent: Pancytopenia, haemolytic anaemia Immune system disorders Frequent: Hypersensitivity reactions, anaphylactic shock Metabolism and nutrition disorders Frequent: Dehydration Nervous system disorders Frequent: Sensory neuropathy, motor neuropathy, taste disturbance Less frequent: Dizziness Eye disorders Frequent: Conjunctivitis Less frequent: Increased lacrimation Cardiac disorders Less frequent: Supraventricular dysrhythmias Frequency not known: Myocardial infarction Vascular disorders Less frequent: Pulmonary embolism Frequency not known: Cerebrovascular events (see section 4.4), peripheral ischaemia which may lead to extremity necrosis Gastrointestinal disorders Frequent: Nausea, anorexia, vomiting, diarrhoea, constipation, stomatitis/pharyngitis, mucositis, dyspepsia, abdominal pain Less frequent: Colitis, oesophagitis, radiation oesophagitis Hepatobiliary disorders Frequent: ALT (SGPT) elevation, AST (SGOT) elevation Less frequent: Hepatitis Skin and subcutaneous tissue disorders Frequent: Rash/ desquamation, alopecia, pruritus, erythema multiforme, hyperpigmentation Less frequent: Stevens-Johnson syndrome, toxic epidermal necrolysis (see section 4.4), radiation recall Musculoskeletal and connective tissue disorders Frequency unknown: Myalgia, arthralgia Renal and urinary disorders Frequent: Renal disorders (includes increased serum/blood creatinine, decreased glomerular filtration rate) Frequency unknown: Acute renal failure General disorders and administration site conditions Frequent: Fatigue, pain, oedema, fever

Symptoms Neutropenia, anaemia, thrombocytopenia and rash have been reported. Other complications may include bone marrow suppression, infection with or without fever, diarrhoea and mucositis. Management Patients should be monitored with blood counts and should receive supportive therapy as necessary. The use of leucovorin in the management of APIMEX overdosage should be considered.