OXALIPLATIN

The preparation of injectable solutions of cytotoxic agents must be carried out by trained specialist personnel with knowledge of the medicinal products used, in conditions that guarantee the integrity of the medicinal product, the protection of the environment and in particular the protection of the personnel handling the medicinal products, in accordance with the hospital policy.

It requires a preparation area reserved for this purpose. 6). Posology FOR ADULTS ONLY The recommended dose for oxaliplatin in adjuvant setting is 85 mg/m² intravenously repeated every two weeks for 12 cycles (6 months). The recommended dose for oxaliplatin in treatment of metastatic colorectal cancer is 85 mg/m² intravenously repeated every 2 weeks until disease progression or the onset of unacceptable toxicity.

4). e. 5 fluorouracil (5 FU). 70 mg/ml is the highest concentration reported in clinical practice for an oxaliplatin dose of 85 mg/m2. Oxaliplatin concentrate for solution for infusion has mainly been used in combination with continuous infusion 5-fluorouracil based regimens.

For the two-weekly treatment schedule 5-fluorouracil regimens combining bolus and continuous infusion were used. 2). 2). - Hepatic impairment In a phase I study including patients with several levels of hepatic impairment, frequency and severity of hepato-biliary disorders appeared to be related to progressive disease and impaired liver function tests at baseline.

No specific dose adjustment for patients with abnormal liver function tests was performed during clinical development. - Elderly patients: No increase in severe toxicities was observed when oxaliplatin was used as a single agent or in combination with 5-fluorouracil in patients over the age of 65.

In consequence no specific dose adaptation is required for elderly patients.

Paediatric patients:

There is no relevant indication for use of oxaliplatin in children. 1). Method of administration Oxaliplatin concentrate for solution for infusion is administered by intravenous infusion. The administration of Oxaliplatin concentrate for solution for infusion does not require hyperhydration.

2 mg/ml must be infused via a central venous line or peripheral vein over 2 to 6 hours. Oxaliplatin infusion must always precede the administration of 5-fluorouracil. In the event of extravasation, administration must be discontinued immediately.

Summary of the safety profile The most frequent adverse events of oxaliplatin in combination with 5- fluorouracil/folinic acid (5-FU/FA) were gastrointestinal (diarrhoea, nausea, vomiting and mucositis), haematological (neutropenia, thrombocytopenia) and neurological (acute and dose cumulative peripheral sensory neuropathy).

Overall, these adverse events were more frequent and severe with oxaliplatin and 5-FU/FA combination than with 5-FU/FA alone. Tabulated list of adverse reactions The frequencies reported in the table below are derived from clinical trials in the metastatic and adjuvant settings (having included 416 and 1108 patients respectively in the oxaliplatin + 5-FU/FA treatment arms) and from post marketing experience.

Frequencies in this table are defined using the following convention: very common (≥1/10), common (≥ 1/100 , <1/10), uncommon (≥ 1/1000 , <1/100), rare (≥ 1/10000, <1/1000), very rare (<1/10000), not known (cannot be estimated from the available data).

Further details are given after the table. 4) - Oesophagitis Hepatobilia ry - Liver sinusoidal Focal nodular disorders obstruction syndrome, also known as veno- occlusive disease of liver, or pathological manifestatio ns related to such liver disorder, including peliosis hepatis, nodular regenerative hyperplasia, perisinusoid al fibrosis.

-Portal hypertension and/or increased transaminase s. e. 4) Metabolis m and nutrition disorders - Anorexia - Hyperglyca emia - Hypokalae mia - Hypernatrae mia - Dehydrat ion - Hypocal caemia - Metaboli c acidosis Infections and infestations * - Infection - Rhinitis - Upper respirator y tract infection - Neutrope nic sepsis Sepsis+ -Septic shock, including cases with a fatal outcomes.

4 + Common neutropenic sespsis, including fatal outcomes. ++ Very common allergies/allergic reactions, occurring mainly during infusion, sometimes fatal. Common allergic reactions include skin rash (particularly urticaria), conjunctivitis and rhinitis.

Oxaliplatin concentrate for solution for infusion should only be used in specialised departments of oncology and should be administered under the supervision of an experienced oncologist. 2). Hypersensitivity reactions Special surveillance should be ensured for patients with a history of allergic reaction to other products containing platinum.

In case of anaphylactic reaction the infusion should be interrupted immediately and an appropriate symptomatic treatment started. Re-administration of oxaliplatin to such patients is contra-indicated. Cross reactions, sometimes fatal, have been reported with all platinum compounds.

In case of oxaliplatin extravasation, the infusion must be stopped immediately and usual local symptomatic treatment initiated. Neurological symptoms Neurological toxicity of oxaliplatin should be carefully monitored, especially if co- administered with other medicinal products with specific neurological toxicity.

A neurological examination should be performed before each administration and periodically thereafter. 8), during or within the hours following the 2-hour infusion, the next oxaliplatin infusion should be administered over 6 hours. Peripheral neuropathy If neurological symptoms (paraesthesia, dysaesthesia) occur, the following recommended oxaliplatin dose adjustment should be based on the duration and severity of these symptoms: - If symptoms last longer than seven days and are troublesome, the subsequent oxaliplatin dose should be reduced from 85 to 65 mg/m2 (metastatic setting) or 75 mg/m2 (adjuvant setting).

- If paraesthesia without functional impairment persists until the next cycle, the subsequent oxaliplatin dose should be reduced from 85 to 65 mg/m2 (metastatic setting) or 75 mg/m2 (adjuvant setting). - If paraesthesia with functional impairment persists until the next cycle, oxaliplatin should be discontinued.

- If these symptoms improve following discontinuation of oxaliplatin therapy, resumption of therapy may be considered. Patients should be informed of the possibility of persistent symptoms of peripheral sensory neuropathy after the end of the treatment.

1. - are breast-feeding. - have myelosuppression prior to starting first course, as evidenced by baseline neutrophils <2x109/l and/or platelet count of <100x109l. - have a peripheral sensitive neuropathy with functional impairment prior to first course.

2).