Armisarte (Previously Pemetrexed Actavis)

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 (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 gemcitabine 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 Dermohypo dermitis 9 Blood and lymphatic system disorders Neutropenia Leukopenia Haemoglobin decreased Febrile neutropenia Platelet count decreased Pancytopenia Autoimmune haemolytic anaemia Immune System disorders Hypersensitivi ty Anaphylactic shock Metabolism and nutrition disorders Dehydration Nervous system disorders Taste disorder Peripheral motor neuropathy Peripheral sensory neuropathy Dizziness Cerebrovascul ar 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 supraventricul ar Vascular disorders Peripheral ischaemiac Respiratory, thoracic and mediastinal disorders Pulmonary embolism Interstitial pneumonitisbd Gastrointes- tinal disorders Stomatitis Anorexia Vomiting Diarrhoea Nausea Dyspepsia Constipation Abdominal pain Rectal haemorrhage Gastrointestina l haemorrhage Intestinal perforation Oesophagitis Colitis e Hepatobiliary disorders Aalanine aminotransfera se increased Aspartate aminotransfera se increased Hepatitis 10 Skin and subcutaneous tissue disorders Rash Skin exfoliation Hyperpigment ation Pruritus Erythema multiforme Alopecia Urticaria Erythema Stevens- Johnson syndromeb Toxic epidermal necrolysisb Pemphigoi d Dermatitis bullous Acquired epidermoly sis bullosa Erythema- tous oedemaf Pseudocell ulitis Dermatitis Eczema Prurigo Renal and urinary disorders Creatinine clearance decreased Blood creatinine increasede Renal failure Glomerular filtration rate decreased Nephroge- nic 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 pheno- menon a with and without neutropenia b in some cases fatal c sometimes leading to extremity necrosis d with respiratory insufficiency eseen 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.

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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.

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.

8). Immunodepressed status is common in cancer patients. 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. 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.

1. 6). 5).