PEMETREXED MYLAN

Posology Pemetrexed Mylan must only be administered under the supervision of a physician qualified in the use of anti-cancer chemotherapy. Pemetrexed Mylan in combination with cisplatin The recommended dose of Pemetrexed Mylan is 500 mg/m2 of body surface area (BSA) administered as an intravenous infusion (IV) over 10 minutes on the first day of each 21-day cycle.

The recommended dose of cisplatin is 75 mg/m2 BSA infused over two hours approximately 30 minutes after completion of the pemetrexed infusion on the first day of each 21-day cycle. Patients must receive adequate anti-emetic treatment and appropriate hydration prior to and/or after receiving cisplatin (see also cisplatin Summary of Product Characteristics for specific dosing advice).

Pemetrexed Mylan as single agent In patients treated for non-small cell lung cancer after prior chemotherapy, the recommended dose of Pemetrexed Mylan is 500 mg/m2 BSA administered as an intravenous infusion (IV) over 10 minutes on the first day of each 21-day cycle.

Pre-medication 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 pemetrexed administration. 4). 4). Patients must take oral folic acid or a multivitamin containing folic acid (350 to 1000 micrograms) on a daily basis.

At least five doses of folic acid must be taken during the seven days preceding the first dose of pemetrexed, and dosing must continue during the full course of therapy and for 21 days after the last dose of pemetrexed. Patients must also receive an intramuscular injection of vitamin B12 (1000 micrograms) in the week preceding the first dose of pemetrexed and once every three cycles thereafter.

Subsequent vitamin B12 injections may be given on the same day as pemetrexed. Monitoring Patients receiving pemetrexed should be monitored before each dose with a complete blood count, including a differential white cell count (WCC) and platelet count.

Prior to each chemotherapy administration blood chemistry tests should be collected to evaluate renal and hepatic function. Before the start of any cycle of chemotherapy, patients are required to have the following: absolute neutrophil count (ANC) should be ≥ 1500 cells/mm3 and platelets should be ≥ 100,000 cells/mm3.

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. Rarely seen events include Stevens-Johnson syndrome and toxic epidermal necrolysis.

Tabulated list of adverse reactions The table 4 lists the adverse drug events regardless of causality associated with pemetrexed used either as a monotherapy treatment or in combination with cisplatin from the pivotal registration studies (JMCH, JMEI, JMBD, JMEN and PARAMOUNT) and from the post marketing period.

ADRs are listed by MedDRA body system organ class. The following convention has been used for classification of frequency: very common: ≥ 1/10; common: ≥ 1/100 to < 1/10; uncommon: ≥ 1/1,000 to < 1/100; rare: ≥ 1/10,000 to < 1/1,000; very rare: < 1/10,000 and not known (frequency cannot be estimated from the available data).

Table 4. Frequencies of all grades adverse drug events regardless of causality from the pivotal registration studies: JMEI (Pemetrexed vs Docetaxel), JMDB (Pemetrexed and Cisplatin versus GEMZAR and Cisplatin, JMCH (Pemetrexed plus Cisplatin versus Cisplatin), JMEN and PARAMOUNT (Pemetrexed plus Best Supportive Care versus Placebo plus Best Supportive Care) and from post-marketing period.

System Organ Class (MedDRA) Very common Common Uncommon Rare Very rare Not known Infections and infestations Infectiona Pharyngitis Sepsisb Dermo- hypodermitis Blood and lymphatic system disorders Neutropenia Leukopenia Haemoglobin decreased Febrile neutropenia Platelet count decreased Pancytopenia Autoimmune haemolytic anaemia Immune System disorders Hypersensiti- vity Anaphylac- tic shock Metabolism and nutrition disorders Dehydration Nervous system disorders Taste disorder Peripheral motor neuropathy Peripheral sensory neuropathy Dizziness Cerebrovascu lar accident Ischaemic stroke Haemorrhage intracranial Eye disorders Conjunctivitis Dry eye Lacrimation increased Keratoconjunc tivitis sicca Eyelid oedema Ocular surface disease Cardiac disorders Cardiac failure Arrhythmia Angina Myocardial infarction Coronary artery disease Arrhythmia supraventricu lar Vascular disorders Peripheral ischaemiac Respiratory, thoracic and mediastinal disorders Pulmonary embolism Interstitial pneumonitisb d Gastrointestina l disorders Stomatitis Anorexia Vomiting Diarrhoea Nausea Dyspepsia Constipation Abdominal pain Rectal haemorrhage Gastrointesti nal haemorrhage Intestinal perforation Oesophagitis Colitis e Hepatobiliary Aalanine Hepatitis disorders aminotransfera se increased Aspartate aminotransfera se increased Skin and subcutaneous tissue disorders Rash Skin exfoliati on Hyperpigment ation Pruritus Erythema multiforme Alopecia Urticaria Erythema StevensJohns on syndromeb Toxic epidermal necrolysisb Pemphigoi d Dermatitis bullous Acquired epidermoly sis bullosa Erythematous oedemaf Pseudocell u- litis Dermatitis Eczema Prurigo Renal and urinary disorders Creatinine clearance decreased Blood creatinine increasede Renal failure Glomerular filtration rate decreased Nephrogeni c diabetes insipidus Renal tubular necrosis General disorders and administration site conditions Fatigue Pyrexia Pain Oedema Chest pain Mucosal inflammation Investigations Gamma- glutamyltransf erase increased Injury, poisoning and procedural complications Radiation oesophagitis Radiation pneumonitis 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 Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

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.

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.

2). Skin reactions have been reported in patients not pre-treated with a corticosteroid. 2). An insufficient number of patients has been studied with creatinine clearance of below 45 ml/min. 2). 5). 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. 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.

1. 6). 5).