OXALIPLATIN MEDAC

Posology FOR ADULTS ONLY The recommended dose of oxaliplatin for adjuvant treatment is 85 mg/m² body surface area (BSA) intravenously every 2 weeks for 12 cycles of therapy (6 months). The recommended dose of oxaliplatin for the treatment of metastasising colorectal carcinoma is 85 mg/m² body surface area (BSA) intravenously every 2 weeks until disease progression or unacceptable toxicity.

4). e. 5-fluorouracil (5 FU). 7 mg/ml is the highest concentration in clinical practice for an oxaliplatin dose of 85 mg/m². Oxaliplatin has been used mainly in combination with treatment regimens based on continuous 5-fluorouracil infusion.

For the treatments given every 2 weeks 5-fluorouracil has been used as a combination of a bolus and a continuous infusion. 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 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 population There is no relevant indication for the use of Oxaliplatin medac in children. 1). Method of administration Oxaliplatin is administered by intravenous infusion.

The administration of oxaliplatin 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. Precautions to be taken before handling or administering the medicinal product Oxaliplatin must be diluted before use. Only 5 % glucose solution must be used to dilute the concentrate for solution for infusion.

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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 the 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 1,108 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 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare (≥ 1/10,000 to < 1/1,000); Very rare (< 1/10,000); Not known (cannot be estimated from the available data). Further details are given after the table.

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

Common anaphylactic or anaphylactoid reactions, including bronchospasm, sensation of chest pain, angiooedema, hypotension and anaphylactic shock. Delayed hypersensitivity has also been reported with oxaliplatin hours or even days after the infusion.

+++ Very common fever, rigors (tremors), either from infection (with or without febrile neutropenia) or possibly from immunological mechanism. ++++ Injection site reactions including local pain, redness, swelling and thrombosis have been reported.

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The use of oxaliplatin should be restricted to medical institutions specialising in management of cytotoxic chemotherapy, and should only be carried out under the supervision of a qualified oncologist. 2). Hypersensitivity reactions Special surveillance should be ensured for patients with a history of allergic manifestations to other products containing platinum.

In case of anaphylactic reactions the infusion should be interrupted immediately and an appropriate symptomatic treatment started. Re-administration of oxaliplatin to such patients is contraindicated. 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 first few 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 7 days and are troublesome, the subsequent oxaliplatin dose should be reduced from 85 mg/m² 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 mg/m² 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.

Localised moderate paraesthesias or paraesthesias that may interfere with functional activities can persist after up to 3 years following treatment cessation in the adjuvant setting. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) Cases of Reversible Posterior Leukoencephalopathy Syndrome (RPLS also known as PRES, Posterior Reversible Encephalopathy Syndrome) have been reported in patients receiving oxaliplatin in combination chemotherapy.

8). Diagnosis of RPLS is based upon confirmation by brain imaging, preferably MRI (Magnetic Resonance Imaging). 8). Dehydration, paralytic ileus, intestinal obstruction, hypokalaemia, metabolic acidosis and renal impairment may be caused by severe diarrhoea/emesis particularly when combining oxaliplatin with 5-fluorouracil.

Cases of intestinal ischemia, including fatal outcomes, have been reported with oxaliplatin treatment. 8). 5 x 109/l or platelets < 50 x 109/l), administration of the next course of therapy should be postponed until haematological values return to acceptable levels.

A full blood count with white cell differential should be performed prior to start of therapy and before each subsequent course. Myelosuppressive effects may be additive to those of concomitant chemotherapy. Patient with severe and persistent myelosuppression are at high risk of infectious complications.

8). If any of these events occurs, oxaliplatin should be discontinued. Patients must be adequately informed of the risk of diarrhoea/emesis, mucositis/stomatitis and neutropenia after oxaliplatin and 5-fluorouracil administration so that they can urgently contact their treating physician for appropriate management.

5 x 109/l. For oxaliplatin combined with 5-fluorouracil (with or without folinic acid), the usual dose adjustments for 5-fluorouracil associated toxicities should apply. 3°C or a sustained temperature > 38°C for more than 1 hour), or grade 3 – 4 thrombocytopenia (platelets < 50 x 109/l) occur, the dose of oxaliplatin should be reduced from 85 mg/m² to 65 mg/m² (metastatic setting) or 75 mg/m² (adjuvant setting), in addition to any 5-fluorouracil dose reductions required.

Pulmonary In the case of unexplained respiratory symptoms such as non-productive cough, dyspnoea, crackles or radiological pulmonary infiltrates, oxaliplatin should be discontinued until further pulmonary investigations exclude an interstitial lung […]

1. • Breastfeeding. • Myelosuppression prior to starting first course, as evidenced by baseline neutrophils < 2 x 109/l and/or platelet count of < 100 x 109/l. • Peripheral sensitive neuropathy with functional impairment prior to first course.

2).