Natpem 100 mg/500 mg/1000 mg Solution

NATPEM is indicated for the treatment of patients with malignant pleural mesothelioma in combination with cisplatin. NATPEM is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology. NATPEM is indicated as monotherapy for the treatment of patients with locally advanced or metastatic adenocarcinoma of the lung after prior chemotherapy. NATPEM is indicated as monotherapy for the maintenance treatment of locally advanced or metastatic adenocarcinoma of the lung in patients whose disease has not progressed immediately following standard chemotherapy.

Posology: NATPEM 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 NATPEM 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 NATPEM infusion on the first day of each 21-day cycle. Patients should receive appropriate hydration prior to and/or after receiving cisplatin.

Adenocarcinoma of the lung: Single medicine use: Adults: In patients treated for adenocarcinoma of the lung, the recommended dose of NATPEM is 500 mg/m2 administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle. Combination use with cisplatin: Adults: In patients treated for non-small cell lung cancer: the recommended dose of NATPEM 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 the NATPEM infusion on the first day of each 21-day cycle. Patients should receive appropriate hydration prior to and/or after receiving cisplatin.

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 NATPEM 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 NATPEM should also receive vitamin supplementation (see section 4.4). Patients must take oral folic acid or multivitamin containing folic acid (350 to 1000 mcg) on a daily basis. At least 5 daily doses of folic acid must be taken during the 7 days preceding the first dose of NATPEM, and dosing should continue during the full course of therapy and for 21 days after the last dose of NATPEM. Patients must also receive an intramuscular injection of vitamin B12 (1000 mcg) in the week preceding the first dose of NATPEM and every 3 cycles thereafter.

Monitoring: Patients receiving NATPEM should be monitored before each dose with a full blood count, including a differential and platelet count. Periodic blood chemistry tests should be collected to evaluate renal and hepatic function. Absolute neutrophil count (ANC) should be u2265 1500 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 sufficient time for recovery. Upon recovery, patients may be retreated using the guidelines in Tables 1, 2 and 3, which are applicable for NATPEM used as a single medicine or in combination with cisplatin.

Table 1: Dose modification table for NATPEM (as single medicine or in combination) and cisplatin: haematological toxicities

• Nadir ANC < 500/mm3 and nadir platelets u2265 50 000/mm3 75 % of previous dose (both NATPEM and cisplatin)
• Nadir platelets u2264 50 000/mm3 regardless of nadir ANC 50 % of previous dose (both NATPEM and cisplatin)
• Nadir platelets u2264 50 000/mm3 with bleeding a, regardless of nadir ANC 50 % of previous dose (both NATPEM and cisplatin)

a These criteria meet the National Cancer Institute Common Toxicity Criteria (CTC v2.0; NCI 1998) definition of u2265 CTC Grade 2 bleeding.

If patients develop non-haematological toxicities (excluding neurotoxicity) u2265 Grade 3, treatment should be withheld until resolution to less than or equal to the patient's pre-therapy value. Treatment should be resumed according to the guidelines in Table 2.

Table 2: Dose modification table for NATPEM (as single medicine or in combination) and cisplatin: non-haematological toxicities a, b

• Any Grade 3 or 4 toxicities except mucositis 75 % of previous dose 75 % of previous dose
• Any diarrhoea requiring hospitalisation (irrespective of grade) or Grade 3 or 4 diarrhoea 75 % of previous dose 75 % of previous dose
• Grade 3 or 4 mucositis 50 % of previous dose 100 % of previous dose

a National Cancer Institute Common Toxicity Criteria b Excluding neurotoxicity

In the event of neurotoxicity, the recommended dose adjustment for NATPEM and cisplatin is documented in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is observed.

Table 3: Dose modification table for NATPEM (as single medicine or in combination) and cisplatin: neurotoxicity

• CTC * Grade 0 u2013 1 100 % of previous dose 100 % of previous dose
• 2 100 % of previous dose 50 % of previous dose

* Common Toxicity Criteria (CTC)

Treatment with NATPEM should be discontinued if a patient experiences any haematologic or non-haematologic Grade 3 or 4 toxicity after two dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.

Elderly: There has been no indication that patients 65 years of age or older are at increased risk of adverse events compared to patients younger than 65 years old. No dose reductions other than those recommended for all patients are necessary.

Patients with renal impairment (standard Cockcroft and Gault formula or glomerular filtration rate measured by Tc99m-DPTA serum clearance method): Pemetrexed is primarily eliminated unchanged by renal excretion. Patients with creatinine clearance of u2265 45 mL/min required no dosage adjustments other than those recommended to all patients. There are insufficient data on the use of NATPEM in patients with creatinine clearance below 45 mL/min; therefore, the use of NATPEM is not recommended (see section 4.4).

Patients with hepatic impairment: No relationships between aspartate aminotransferase (AST) / serum glutamic-oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT) / serum glutamic pyruvic transaminase (SGPT), or total bilirubin and NATPEM pharmacokinetics were identified. However, patients with hepatic impairment such as bilirubin > 1,5 times the upper limit of normal and/or transaminase > 3,0 times the upper limit of normal (hepatic metastases absent) or > 5,0 times the upper limit of normal (hepatic metastases present) have not been specifically studied.

Paediatrics: NATPEM is not recommended for use in patients under 18 years of age, as safety and efficacy have not been established in this group of patients.

Method of administration: For intravenous use.

• Hypersensitivity to pemetrexed or to any of the excipients listed in section 6.1.
• Concomitant yellow fever vaccine (see section 4.5).

NATPEM 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 NATPEM should not be given to patients until absolute neutrophil count (ANC) returns to u2265 1500 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 NATPEM 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 NATPEM 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 nonsteroidal 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 NATPEM administration (see section 4.5). In patients with mild to moderate renal insufficiency eligible for NATPEM 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 NATPEM administration (see section 4.5).

Serious renal events, including acute renal failure, have been reported with PEMETREXED 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 in post marketing setting with PEMETREXED alone or with other chemotherapeutic medicines (see section 4.8). 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, therefore drainage of third space fluid collection prior to NATPEM 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 with PEMETREXED 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).

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

NATPEM 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 NATPEM 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 NATPEM (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 radio-sensitising medicines. Cases of radiation recall have been reported in patients who received radiotherapy weeks or years previously.

NATPEM is mainly eliminated unchanged renally by tubular secretion and to a lesser extent by glomerular filtration. Concomitant administration of nephrotoxic medicines (e.g. aminoglycoside, loop diuretics, platinum compounds, ciclosporin) could potentially result in delayed clearance of NATPEM. This combination should be used with caution. If necessary, creatinine clearance should be closely monitored.

Concomitant administration of substances that are also tubularly secreted (e.g. probenecid, penicillin) could potentially result in delayed clearance of NATPEM. Caution should be made when these medicines are combined with NATPEM. If necessary, creatinine clearance should be closely monitored.

In patients with normal renal function (creatinine clearance u2265 80 mL/min), high doses of non-steroidal anti-inflammatory medicines (NSAIDs, such as ibuprofen > 1600 mg/day) and acetylsalicylic acid at higher dose (u2265 1,3 g daily) may decrease NATPEM elimination and, consequently, increase the occurrence of NATPEM adverse reactions. Therefore, caution should be made when administering higher doses of NSAIDs or acetylsalicylic acid, concurrently with NATPEM 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 NATPEM with NSAIDs (e.g. ibuprofen) or acetylsalicylic acid at higher dose should be avoided for 2 days before, on the day of, and 2 days following NATPEM 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 NATPEM 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 NATPEM administration (see section 4.4). If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression and gastrointestinal toxicity.

Aspirin administered in low to moderate doses (325 mg orally every 6 hours) does not affect the pharmacokinetics of NATPEM. The pharmacokinetics of NATPEM are not influenced by concurrently administered cisplatin or carboplatin. Similarly, the pharmacokinetics of total platinum are unaltered by NATPEM. Oral folic acid and intramuscular vitamin B12 supplementation do not affect the pharmacokinetics of NATPEM. NATPEM undergoes limited hepatic metabolism. Results from in vitro studies with human liver microsomes indicated that NATPEM would not be predicted to cause clinically significant inhibition of the metabolic clearance of medicines metabolised by CYP3A, CYP2D6, CYP2C9, and CYP1A2.

Interactions common to all cytotoxics: Due to the increased thrombotic risk in patients with cancer, the use of anticoagulation treatment is frequent. The high intra-individual variability of the coagulation status during diseases and the possibility of interaction between oral anticoagulants and anticancer chemotherapy require increased frequency of INR (international normalised ratio) monitoring, if it is decided to treat the patient with oral anticoagulants.

Concomitant use with yellow fever vaccine is contraindicated as there is a risk of fatal generalised vaccinate disease (see section 4.3).

Concomitant use of live attenuated vaccines is not recommended (except yellow fever, for which concomitant use is contraindicated) as there is a risk of systemic, possibly fatal, disease. The risk is increased in patients who are already immunosuppressed by their underlying disease. Use an inactivated vaccine where it exists (poliomyelitis) (see section 4.4).

Women of childbearing potential / contraception in males and females: Women of childbearing potential must use effective contraception during treatment with NATPEM. NATPEM 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.

Pregnancy: There is no data on the use of NATPEM in pregnant women but NATPEM, like other anti-metabolites, is suspected to cause serious birth defects when administered during pregnancy. Animal studies have shown reproductive toxicity. NATPEM should not be used during pregnancy due to the potential hazard to the foetus. Women should also be advised to avoid becoming pregnant while being treated with NATPEM.

Breastfeeding: It is not known whether NATPEM is excreted in human milk and adverse reactions on the breastfeeding child cannot be excluded. Breastfeeding must be discontinued during NATPEM therapy.

Fertility: Owing to the possibility of NATPEM treatment causing irreversible infertility, men are advised to seek counselling on sperm storage before starting NATPEM treatment.

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

Infections and infestations: Frequent: infection a, pharyngitis, sepsis b Less frequent: dermo-hypodermitis

Blood and the lymphatic system disorders: Frequent: neutropenia, leukopenia, decreased haemoglobin, febrile neutropenia, decreased platelet count Less frequent: pancytopenia, autoimmune haemolytic anaemia

Immune system disorders: Frequent: hypersensitivity Less frequent: anaphylactic shock

Metabolism and nutrition disorders: Frequent: dehydration

Nervous system disorders: Frequent: taste disorder, peripheral motor neuropathy, sensory neuropathy, dizziness Less frequent: cerebrovascular accident, ischaemic stroke, intracranial haemorrhage

Eye disorders: Frequent: conjunctivitis, dry eye, increased lacrimation, keratoconjunctivitis sicca, eyelid oedema, ocular surface disease

Cardiac disorders: Frequent: cardiac failure, dysrhythmia Less frequent: angina, myocardial infarction, coronary artery disease, supraventricular dysrhythmia

Vascular disorders: Less frequent: peripheral ischaemia c

Respiratory, thoracic and mediastinal disorders: Less frequent: pulmonary embolism, interstitial pneumonitis bd

Gastrointestinal disorders: Frequent: stomatitis, anorexia, vomiting, diarrhoea, nausea, dyspepsia, constipation, abdominal pain, mucositis Less frequent: rectal haemorrhage, gastrointestinal haemorrhage, intestinal perforation, oesophagitis, colitis e

Hepatobiliary disorders: Frequent: increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST) Less frequent: hepatitis

Skin and subcutaneous tissue disorders: Frequent: rash, skin exfoliation, hyperpigmentation, pruritus, erythema multiforme, alopecia, urticaria, desquamation Less frequent: erythema, Stevens-Johnson syndrome b, toxic epidermal necrolysis b, pemphigoid, bullous dermatitis, acquired epidermolysis bullosa, erythematous oedema f, pseudocellulitis, dermatitis, eczema, prurigo

Renal and urinary disorders: Frequent: decreased creatine clearance, increased blood creatinine e, renal failure, decreased glomerular filtration rate Frequency not known: nephrogenic diabetes insipidus, renal tubular necrosis

General disorders and administration site conditions: Frequent: fatigue, pyrexia, pain, oedema, chest pain, mucosal inflammation

Investigations: Frequent: increased gamma-glutamyltransferase

Injury, poisoning and procedural complications: Less frequent: radiation oesophagitis, radiation pneumonitis, radiation recall phenomenon.

a with and without neutropenia b in some cases fatal c sometimes leading to extremity necrosis d with respiratory insufficiency e seen only in combination with cisplatin f mainly of the lower limbs

Reported symptoms of overdose include neutropenia, anaemia, thrombocytopenia, mucositis, sensory polyneuropathy and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia and anaemia. In addition, infection with or without fever, diarrhoea, and/or mucositis may be seen. In the event of suspected overdose, patients should be monitored with blood counts and should receive supportive therapy as necessary. The use of leucovorin in the management of NATPEM overdose should be considered.