Presentation and Status in Health Basket
10 ml X 50 mg (concentrate for solution for infusion)
20 ml X 100 mg (concentrate for solution for infusion)
40 ml X 200 mg (concentrate for solution for infusion)
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 unacceptable toxicity. The recommended dose of oxaliplatin for the treatment of metastatic pancreatic adenocarcinoma is 85 mg/m² given as a 2-hour intravenous infusion, immediately followed by leucovorin (400 mg/m², 2-hour intravenous infusion) with the addition after 30 minutes of irinotecan (180 mg/m², 90-minute intravenous infusion through a Y-connector) and immediately followed by 5-fluorouracil (400 mg/m² intravenous bolus followed by 2,400 mg/m² continuous intravenous infusion for 46 hours), in 2-week cycles up to 6 months.
Dosage given should be adjusted according to tolerability. It should always be administered before fluoropyrimidines – i.e. 5-fluorouracil. It is administered as a 2- to 6- hour intravenous infusion in 250 to 500 ml of 5% glucose solution to give a concentration between 0.2 mg/ml and 0.7mg/ml; 0.70mg/ml is the highest concentration in clinical practice for an oxaliplatin dose of 85mg/m². This drug was mainly 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.
It’s in combination with leucovorin, irinotecan and 5-fluorouracil should only be administered to patients less than 76 years-old, with ECOG performance status (Eastern Cooperative Oncology Group) 0-1, who have no cardiac ischaemia, and normal or nearly normal level of bilirubin.
Renal impairment: It must not be administered in patients with severe renal impairment. In patients with mild to moderate renal impairment, the recommended dose of oxaliplatin is 85mg/m².
Hepatic insufficiency: 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 subjects: 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 adaption is required for elderly patients.
Paediatric patients: There is no relevant indication for use of oxaliplatin in children. The effectiveness of oxaliplatin single agent in the paediatric populations with solid tumors has not been established.
Method of administration: This drug is administered by intravenous infusion. The administration of oxaliplatin does not require hyperhydration.
Oxaliplatin diluted in 250 to 500 ml of 5% glucose solution to give a concentration not less than 0.2 mg/ml must be infused via a central venous line or a 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.
Instructions for use: Oxaliplatin must be diluted before use. Only 5% glucose diluent is to be used to dilute the concentrate for solution for infusion product.
Oxaliplatin in combination with 5-fluorouracil (5-FU) and folinic acid (FA) is indicated for:
– Adjuvant treatment of stage III (Duke‘s C) colon cancer after complete resection of primary tumour.
– Treatment of metastatic colorectal cancer.
Oxaliplatin in combination with leucovorin, irinotecan and 5-fluorouracil is indicated for the first-line treatment of patients with metastatic pancreatic adenocarcinoma (based on NCCN guidelines, version 2.2014).
Oxaliplatin is contraindicated in patients who:
– have a known history of hypersensitivity to oxaliplatin,
– are breast-feeding,
– have myelosuppression prior to starting first course, as evidenced by baseline neutrophils <2×10^9/l and/or platelets count <100×10^9/l,
– have a peripheral sensitive neuropathy with functional impairment prior to first course,
– have a severely impaired renal function (creatinine clearance less than 30 ml/min).
Renal impairment: Patients with mild to moderate renal impairment should be closely monitored for adverse reactions and the dose adjusted according to toxicity. Haemolytic-uraemic syndrome (HUS) is a life-threatening side effect. Oxaliplatin should be discontinued at the first signs of any evidence of microangiopathic haemolytic anaemia, such as rapidly falling haemoglobin with concomitant thrombocytopenia, elevation of serum bilirubin, serum creatinine, blood urea nitrogen, or LDH. Renal failure may be not reversible with discontinuation of therapy and dialysis may be required.
Hypersensitivity reactions: Special surveillance should be ensured for patients with a history of allergic manifestations to other products containing platinum. In case of anaphylactic manifestations 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. For patients who develop acute laryngopharyngeal dysaesthesia 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 dosage 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 treatment. Localized moderate paresthesias or paresthesias 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. RPLS is a rare, reversible, rapidly evolving neurological condition, which can include seizure, hypertension, headache, confusion, blindness, and other visual and neurological disturbances. Diagnosis of RPLS is based upon onfirmation by brain imaging, preferably MRI (Magnetic Resonance Imaging).
Nausea, vomiting, diarrhoea, dehydration and haematological changes:
Gastrointestinal toxicity, which manifests as nausea and vomiting, warrants prophylactic and/or therapeutic anti-emetic therapy. Dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis and renal impairment may be caused by severe diarrhea/emesis particularly when combining oxaliplatin with 5-fluorouracil. Cases of intestinal ischaemia, including fatal outcomes, have been reported with oxaliplatin treatment. In case of intestinal ischaemia, oxaliplatin treatment should be discontinued and appropriate measures initiated. Oxaliplatin treatment can cause duodenal ulcer (DU) and potential complications, such as duodenal ulcer haemorrhage and perforation, which can be fatal. In case of duodenal ulcer, oxaliplatin treatment should be discontinued and appropriate measures taken. Do not use oxaliplatin intraperitoneally. Peritoneal hemorrhage may occur when oxaliplatin is administered by intraperitoneal route (off-label route of administration). If haematological toxicity occurs (neutrophils <1.5×10^9/l or platelets <50×10^9/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. Sepsis, neutropenic sepsis and septic shock have been reported in patients treated with it, including fatal outcomes. If any of these events occurs, it should be discontinued. Disseminated intravascular coagulation (DIC), including fatal outcomes, has been reported in association with oxaliplatin treatment. If DIC is present, this treatment should be discontinued and appropriate treatment should be administered. Patients must be adequately informed of the risk of diarrhoea/emesis, mucositis/stomatitis and neutropenia after it and 5-fluorouracil administration so they can urgently contact their treating physician for appropriate management. If mucositis/stomatitis occurs with or without neutropenia, the next treatment should be delayed until recovery from mucositis/stomatitis to grade 1 or less and/or until the neutrophil count is ≥ 1.5×10^9/l. For oxaliplatin combined with 5-fluorouracil (with or without folinic acid), the usual dose adjustments for 5-fluorouracil associated toxicities should apply. If grade 4 diarrhoea, grade 3-4 neutropenia (neutrophils <1.0×10^9/l), febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection with an absolute neutrophil count < 1.0 x 10^9/l, a single temperature of > 38.3°C or a sustained temperature of > 38°C for more than one hour), or grade 3-4 thrombocytopenia (platelets <50×10^9/l) occur, it must be discontinued until improvement or resolution, and the dose of It should be reduced by 25% at subsequent cycles, in addition to any 5-FU dose reductions required.
Pulmonary: In the case of unexplained respiratory symptoms such as non-productive cough, dyspnoea, crackles or radiological pulmonary infiltrates, it should be discontinued until further pulmonary investigations exclude an interstitial lung disease.
Hepatic: In case of abnormal liver function test results or portal hypertension which does not obviously result from liver metastases, very rare cases of drug-induced hepatic vascular disorders should be considered.
Cardiac: QT prolongation may lead to an increased risk for ventricular arrhythmias including Torsade de Pointes, which can be fatal. Caution should be exercised in patients with a history or a predisposition for prolongation of QT, those who are taking medicinal products known to prolong QT interval, and those with electrolyte disturbances such as hypokalemia, hypocalcaemia, or hypomagnesaemia. In case of QT prolongation, this treatment should be discontinued.
Musculoskeletal and connective tissue: Rhabdomyolysis has been reported in patients treated with oxaliplatin, including fatal outcomes. In case of muscle pain and swelling, in combination with weakness, fever or darkened urine, oxaliplatin treatment should be discontinued. If rhabdomyolysis is confirmed, appropriate measures should be taken. Caution is recommended if medicinal products associated with rhabdomyolysis are administered concomitantly with oxaliplatin.
Combined therapy of oxaliplatin with leucovorin, irinotecan and 5-fluorouracil (FOLFIRINOX): Risk of neutropenia: Patients treated with FOLFIRINOX may receive prophylactic G-CSF, as per American Society of Clinical Oncology (ASCO) guidelines and/or current institutional guidelines, to reduce the risk or manage neutropenia complications (febrile neutropenia, prolonged neutropenia or neutropenic infection). Primary prophylaxis with G-CSF should be considered in patients with high-risk clinical features (e.g. age>65 years, poor nutritional status, or other serious comorbidities) that predispose them to increased complications from prolonged neutropenia. The use of G-CSF has been shown to limit the incidence and severity of neutropenia. When using oxaliplatin in combination with leucovorin, irinotecan and 5-fluorouracil, beyond the information
contained in the leaflet of it, the information in the leaflets of each of the other drugs as part of combination therapy should also be checked.
Fertility: Genotoxic effects were observed with it in the preclinical studies. Therefore male patients treated with it are advised not to father a child during and up to 6 months after treatment and to seek advice on conservation of sperm prior to treatment because it may have an anti-fertility effect which could be irreversible. Women should not become pregnant during treatment with it and should use an effective method of contraception.
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.
For full details see prescribing information.
In patients who have received a single dose of 85 mg/m² oxaliplatin, immediately before administration of 5-fluorouracil, no change in the level of exposure to 5-fluorouracil has been observed.
In vitro, no significant displacement of oxaliplatin binding to plasma proteins has been observed with the following agents: erythromycin, salicylates, granisetron, paclitaxel, and sodium valproate.
Caution is advised when oxaliplatin treatment is co-administered with other medicinal products known to cause QT interval prolongation. In case of combination with such medicinal products, the QT interval should be closely monitored. Caution is advised when oxaliplatin treatment is administered concomitantly with other medicinal products known to be associated with rhabdomyolysis.
Pregnancy and Lactation
Pregnancy: To date there is no available information on safety of use in pregnant women. In animal studies, reproductive toxicity was observed. Consequently, oxaliplatin is not recommended during pregnancy and in women of childbearing potential not using contraceptive measures. The use of oxaliplatin should only be considered after suitably appraising the patient of the risk to the foetus and with the patient’s consent. Appropriate contraceptive measures must be taken during and after cessation of therapy during 4 months for women and 6 months for men.
Lactation: Excretion in breast milk has not been studied. Breast-feeding is contra-indicated during oxaliplatin therapy. Oxaliplatin may have an anti-fertility effect.
There is no known antidote to oxaliplatin. In case of overdose, exacerbation of adverse events can be expected. Monitoring of haematological parameters should be initiated and symptomatic treatment given.
Storage: Keep the vial in the outer carton in order to protect from light. Store below +25°C, Do not freeze.