Pexitaz 100 / 500 100 / 500 mg Powder for solution for infusion

PEXITAZ is indicated for the treatment of patients with malignant pleural mesothelioma in combination with cisplatin. PEXITAZ 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. PEXITAZ is indicated as monotherapy for the treatment of patients with locally advanced or metastatic adenocarcinoma of the lung after prior chemotherapy. PEXITAZ 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.

PEXITAZ should only be administered under the supervision of a medical practitioner qualified in the use of anti-cancer chemotherapy. For instructions on dilution of the product before administration, (see section 6.6).

Posology:

Malignant pleural mesothelioma Combination use with cisplatin:

• Adults: In patients treated for malignant pleural mesothelioma, the recommended dose of PEXITAZ 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 PEXITAZ 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 patient treated with adenocarcinoma of the lung, the recommended dose of PEXITAZ 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 PEXITAZ 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 PEXITAZ 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 PEXITAZ administration. The corticosteroid should be equivalent to 4mg of dexamethasone administered orally twice a day (see section 4.4). To reduce toxicity, patients treated with PEXITAZ should also receive vitamin supplementation (see section 4.4). Patients must take oral folic acid or a 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 PEXITAZ, and dosing should continue during the full course of therapy and for 21 days after the last dose of PEXITAZ. Patients must also receive an intramuscular injection of vitamin B12 (1000 mcg) in the week preceding the first dose of PEXITAZ and every 3 cycles thereafter.

Monitoring: Patients receiving PEXITAZ 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 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 below which are applicable for PEXITAZ used as a single agent or in combination with cisplatin.

• PEXITAZ is contraindicated in patients with known hypersensitivity to pemetrexed or to any of the excipients of PEXITAZ listed in section 6.1.
• Pregnancy and breastfeeding (see section 4.6).
• Concomitant yellow fever vaccine (see section 4.5).

Pemetrexed can suppress bone marrow function as manifested by neutropenia, thrombocytopenia, anaemia or pancytopenia (see section 4.8). Myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy and PEXITAZ 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 overall 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, 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 have been studied with creatinine clearance of < 45 ml/min. Therefore the use of PEXITAZ 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 u2013 79 ml/min) should avoid taking non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, and aspirin (> 1.3 g daily) with short-elimination half-lives for at least 2 days prior to, on the day of, and at least 2 days after administration of PEXITAZ.

All patients eligible for pemetrexed therapy should avoid taking NSAIDs with long elimination half-lives at least 5 days prior to, on the day of, and at least 2 days after 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 medicines. 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. Thus, drainage of third space fluid collection prior to PEXITAZ treatment in normal renal function should be considered, but may not be necessary.

Due to the gastrointestinal toxicity of pemetrexed given in combination with cisplatin, severe dehydration has been reported. Therefore, patients should receive adequate antiemetic treatment and appropriate hydration prior to and/or after receiving PEXITAZ 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 reported 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 sections 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 6 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 PEXITAZ (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.

Excipient Warning: PEXITAZ 100 contains 11 mg (< 1 mmol) sodium per vial, i.e. it is essentially u201csodium-freeu201d. PEXITAZ 500 contains approximately 54 mg (2,35 mmol) sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

Pemetrexed is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. In vitro studies indicated that pemetrexed is actively secreted by OAT3 (organic anion transporter 3). Concomitant administration of nephrotoxic medicines (e.g. aminoglycoside, loop diuretics, platinum compounds, ciclosporin and) could result in delayed clearance of pemetrexed. This combination should be used with caution. If necessary, creatinine clearance should be closely monitored.

Concomitant administration of pemetrexed with OAT3 (organic anion transporter 3) inhibitors (e.g. probenecid, penicillin, proton pump inhibitors (PPIs)) results in delayed clearance of pemetrexed. Caution should be made when these drugs are combined with pemetrexed. If necessary, creatinine clearance should be closely monitored.

Acetylsalicylic acid, administered in low to moderate doses (325 mg orally every 6 hours) does not affect the pharmacokinetics of pemetrexed. In patients with normal renal function (creatinine clearance u2265 80 mL /min), high doses of non-steroidal anti-inflammatory drugs (NSAIDs, such as ibuprofen > 1600 mg/day) and acetylsalicylic acid at higher dose (u2265 1.3 g daily) may decrease pemetrexed elimination and, consequently, increase the occurrence of pemetrexed adverse events. Therefore, caution should be made when administering higher doses of NSAIDs or acetylsalicylic acid, concurrently with PEXITAZ 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 pemetrexed with NSAIDs (e.g. ibuprofen) with shorter half-lives or acetylsalicylic acid at higher dose should be avoided for 2 days before, on the day of, and 2 days following pemetrexed 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 pemetrexed as in PEXITAZ 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 PEXITAZ 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 pemetrexed is not influenced by concurrently administered cisplatin or carboplatin. Similarly, the pharmacokinetics of total platinum is unaltered by pemetrexed. Oral folic acid and intramuscular vitamin B12 supplementation do not affect the pharmacokinetics of pemetrexed as in PEXITAZ. Pemetrexed undergoes limited hepatic metabolism. Results from reported 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.

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 contraindicated: Yellow fever vaccine: risk of fatal generalised vaccinale disease (see section 4.3).

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

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

Pregnancy: There is no data on the use of pemetrexed as in PEXITAZ in pregnant women. Animal studies have reported reproductive toxicity such as birth defects and other defects on the development of the fetus, the course of gestation and peri and post-development. The potential risk for humans is unknown. Therefore the use of pemetrexed as in PEXITAZ should be avoided during pregnancy due to the potential hazard to the fetus. Women should also be advised to avoid becoming pregnant while being treated with PEXITAZ.

Breastfeeding: It is not known whether pemetrexed is excreted in human milk. Therefore it is not recommended that breast feeding be continued during PEXITAZ therapy.

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

Pemetrexed may cause fatigue. Therefore patients should be cautioned against driving or operating machinery if this occurs.

Summary of the safety profile: The most commonly reported undesirable effects related to pemetrexed, whether used as monotherapy or in combination, are bone marrow suppression manifested as anaemia, neutropenia, leukopenia, thrombocytopenia; and gastrointestinal toxicities, manifested as anorexia, nausea, vomiting, diarrhoea, constipation, pharyngitis, mucositis, and stomatitis. Other undesirable effects include renal toxicities, increased aminotransferases, alopecia, fatigue, dehydration, rash, infection/sepsis and neuropathy. Less frequently reported events include Stevens-Johnson syndrome and Toxic epidermal necrolysis.

Following are the reported undesirable effects related to pemetrexed, whether used as monotherapy or in combination as per reported clinical studies and post-marketing:

Tabulated summary of adverse reactions:

System organ class Frequent Less frequent Frequency unknown Infections and infestations Sepsis Blood and lymphatic system disorders Decreased neutrophils / granulocytes, leucocytes, haemoglobin and platelets. Pancytopenia Immune-mediated haemolytic anaemia Immune system disorders Allergic reaction/ Hypersensitivity, Anaphylactic shock. Metabolism and nutrition disorders Dehydration Nervous System disorders Sensory neuropathy Dysgeusia, Motor neuropathy Cerebrovascular accident, Transient ischaemic attack, Eye disorders Eyelid oedema, Conjunctivitis Increased lacrimation Cardiac disorders Chest pain, supraventricular dysrhythmia, Myocardial infarction angina pectoris. Vascular disorders Peripheral ischaemia Respiratory, thoracic and mediastinal disorders Pulmonary embolism interstitial pneumonitis. Gastrointestinal disorders Nausea, vomiting, stomatitis, mucositis/pharyngitis, anorexia, diarrhoea (without colostomy), constipation, dyspepsia/heartburn, abdominal pain. Colitis (including intestinal and rectal bleeding, sometimes fatal, intestinal perforation, intestinal necrosis and typhlitis), oesophagitis/radiation oesophagitis. Hepato-biliary disorders Increased alanine and aspartate aminotransferase (ALT and AST). Hepatitis, increased gamma-glutamyl transferase (GGT). Skin and subcutaneous tissue disorders Rash/desquamation, pruritus, alopecia, hyperpigmentation, erythema multiforme, Urticaria. Bullous conditions including Stevens-Johnson syndrome and toxic epidermal necrolysis which in some cases were fatal; infectious and non-infectious disorders of the dermis, the hypodermis and/or the subcutaneous tissue (e.g. acute bacterial dermo-hypodermitis, pseudocellulitis, dermatitis). Renal and urinary disorders Decreased creatinine clearance, renal disorders (combined term includes increased serum/blood creatinine, decreased glomerular filtration rate, renal failure and renal/genitourinary- other) Nephrogenic diabetes insipidus, renal tubular necrosis. General disorders and administration site conditions Fatigue, fever, pain, Oedema, Erythematous oedema mainly of the lower limbs. Injury, poisoning and procedural complications Radiation recall, radiation pneumonitis.

Reported symptoms of overdose include neutropenia, anaemia, thrombocytopenia 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 pemetrexed overdose should be considered.