other antineoplastic agents, platinum compounds ATC code: L01XA 03

Oxaliplatin

1 ml concentrate for solution for infusion contains 5 mg oxaliplatin. 10 ml of concentrate for solution for infusion contains 50 mg of oxaliplatin 20 ml of concentrate for solution for infusion contains 100 mg of oxaliplatin 40 ml of concentrate for solution for infusion contains 200 mg of oxaliplatin

Concentrate for solution for infusion Clear, colourless liquid

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 tumor.

• Treatment of metastatic colorectal cancer.

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.

Dosage given should be adjusted according to tolerability.

Oxaliplatin should always be administered before fluoropyrimidines – i.e. 5-fluorouracil.

Oxaliplatin 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 0.70 mg/ml; 0.70 mg/ml is the highest concentration in clinical practice for an oxaliplatin dose of 85 mg/m².

Oxaliplatin 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.

Special Populations

- Renal impairment:

Oxaliplatin must not be administered in patients with severe renal impairment. In patients with mild to moderate renal impairment, the recommended dose of oxaliplatin is 85 mg/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 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. The effectiveness of oxaliplatin single agent in the paediatric populations with solid tumors has not been established.

Method of administration

Oxaliplatin 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 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.

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.

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 <2x10⁹/l and/or platelet count of <100x10⁹/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)

Due to limited information on safety in patients with moderatelyimpaired renal function, administration should only be considered after suitable appraisal of the benefit/risk for the patient.

In this situation, renal function should be closely monitored and dose adjusted according to toxicity.

Patients with a history of allergic reaction to platinum compounds should be monitored for allergic symptoms. In case of an anaphylactic-like reaction to oxaliplatin, the infusion should be immediately discontinued and appropriate symptomatic treatment initiated. Oxaliplatin rechallenge is contra-indicated.

In case of oxaliplatin extravasation, the infusion must be stopped immediately and usual local symptomatic treatment initiated.

Neurological toxicity of oxaliplatin should be carefully monitored, especially if co-administered with other medications 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.

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 the 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.

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 diarrhoea/emesis particularly when combining oxaliplatin with 5-fluorouracil.

If haematological toxicity occurs (neutrophils < 1.5x10⁹/l or platelets < 50x10⁹/l), administration of the next course of therapy should be postponed until haemotological 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.

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.

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 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.

If grade 4 diarrhoea, grade 3-4 neutropenia (neutrophils < 1.0x10⁹/l), grade 3-4 thrombocytopenia (platelets < 50x10⁹/l) occur, the dose of oxaliplatin should be reduced from 85 to 65 mg/m² (metastatic setting) or 75 mg/m² (adjuvant setting), in addition to any 5-fluorouracil dose reductions required.

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 disease.

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.

Genotoxic effects were observed with oxaliplatin in the preclinical studies. Therefore male patients treated with oxaliplatin 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 oxaliplatin may have an anti-fertility effect which could be irreversible.

Women should not become pregnant during treatment with oxaliplatin and should use an effective method of contraception.

In patients who have received a single dose of 85 mg/m² of 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.

The most frequent adverse events of oxaliplatin in combination with 5-fluorouracil/folinic acid (5-FU/FA) were gastrointestinal (diarrhea, nausea, vomiting and mucositis), haematological (neutropenia, thrombocytopenia) and neurological (acute and dose cumulative peripheral sensory neurophathy). Overall, these adverse events were more frequent and severe with oxaliplatin and 5-FU/FA combination than with 5-FU/FA alone.

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.

* See detailed section below

** See Precautions

+ Very common allergies/allergic reactions, occurring mainly during infusion, sometimes fatal. Common allergic reactions include skin rash, particularly urticaria, conjunctivitis, and rhinitis.

Common anaphylactic or anaphylactoid reactions, include bronchospasm, angioeodema, hypotension, sensation of chest pain and anaphylactic shock.

++ 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. Extravasation may also result in local pain and inflammation which may be severe and lead to complications including necrosis, especially when oxaliplatin is infused through a peripheral vein.

Blood and lymphatic system disorders

Incidence by patient (%), by grade

Postmarketing experience with frequency unknown

Hemolytic uremic syndrome

Immune system disorders

Incidence of allergic reactions by patient (%), by grade

Nervous system disorders

The dose limiting toxicity of oxaliplatin is neurological. It involves a sensory peripheral neuropathy characterised by dysaesthesia and/or paraesthesia of the extremities with or without cramps, often triggered by the cold. These symptoms occur in up to 95% of patients treated. The duration of these symptoms, which usually regress between courses of treatment, increases with the number of treatment cycles.

The onset of pain and/or a functional disorder are indications, depending on the duration of the symptoms, for dose adjustment, or even treatment discontinuation.

This functional disorder includes difficulties in executing delicate movements and is a possible consequence of sensory impairment. The risk of occurrence of persistent symptoms for a cumulative dose of 850 mg/m² (10 cycles) is approximately 10% and 20% for a cumulative dose of 1020 mg/m² (12 cycles).

In the majority of the cases, the neurological signs and symptoms improve or totally recover when treatment is discontinued. In the adjuvant setting of colon cancer, 6 months after treatment cessation, 87 % of patients had no or mild symptoms. After up to 3 years of follow up, about 3 % of patients presented either with persisting localized paresthesias of moderate intensity (2.3%) or with paresthesias that may interfere with functional activities (0.5%).

Acute neurosensory manifestations have been reported. They start within hours of administration and often occur on exposure to cold. They usually present as transient paresthesia, dysesthesia and hypoesthesia. An acute syndrome of pharyngolaryngeal dysesthesia occurs in 1% - 2% of patients and is characterised by subjective sensations of dysphagia or dyspnoea/feeling of suffocation, without any objective evidence of respiratory distress (no cyanosis or hypoxia) or of laryngospasm or bronchospasm (no stridor or wheezing); Although antihistamines and bronchodilators have been administered in such cases, the symptoms are rapidly reversible even in the absence of treatment. Prolongation of the infusion helps to reduce the incidence of this syndrome. Occasionally other symptoms that have been observed include jaw spasm/muscle spasms/muscle contractions-involuntary/muscle twitching/myoclonus, coordination abnormal/gait abnormal/ ataxia/ balance disorders, throat or chest tightness/ pressure/ discomfort/pain. In addition, cranial nerve dysfunctions may be associated with above mentioned events, or also occur as an isolated event such as ptosis, diplopia, aphonia/ dysphonia/ hoarseness, sometimes described as vocal cord paralysis, abnormal tongue sensation or dysarthria, sometimes described as aphasia, trigeminal neuralgia/ facial pain/ eye pain, decrease in visual acuity, visual field disorders.

Other neurological symptoms such as dysarthria, loss of deep tendon reflex and Lhermitte's sign were reported during treatment with oxaliplatin. Isolated cases of optic neuritis have been reported.

Post marketing experience with frequency unknown

Convulsion

Gastrointestinal disorders

Incidence by patient (%), by grade

Prophylaxis and/or treatment with potent antiemetic agents is indicated.

Dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis and renal impairment may be caused by severe diarrhoea/emesis particularly when combining oxaliplatin with 5 fluorouracil (5 FU).

Hepato-biliary disorders

Very rare (< 1/10,000):

Liver sinusoidal obstruction syndrome, also known as veno-occlusive disease of liver, or pathological manifestations related to such liver disorder, including peliosis hepatis, nodular regenerative hyperplasia, perisinusoidal fibrosis. Clinical manifestations may be portal hypertension and/or increased transaminases.

Renal and urinary disorders

Very rare (< 1/10,000):

Acute tubular necrosis, acute interstitial nephritis and acute renal failure.

Sanofi-aventis

(POM)

23 January 2012