THERAPEUTIC INDICATIONS

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.

POSOLOGY AND METHOD OF ADMINISTRATION

Dosage:

RESERVED FOR USE IN ADULTS:

Dosage

RESERVED FOR USE IN ADULTS.

The recommended dose for oxaliplatin in adjuvant setting is 85 mg/m2 intravenously, repeated every 2 weeks for 12 cycle (6 months).

The recommended dose for oxaliplatin in treatment of metastatic colorectal cancer is

85 mg/m2 intravenously repeated every two weeks.

Dosage given should be adjusted according to tolerability. Oxaliplatin should always be administered before fluoropyrimidines.

Oxaliplatin is administered as a 2-6 hour intravenous infusion in 250 to 500 ml of 5% glucose solution to give a concentration not less than 0.2 mg/ml.

Oxaliplatin was mainly use 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.

Population as risk

- Patient with renal impairment:

Oxaliplatin has not been studied in patients with severe renal impairment.

In patients with moderate renal impairment, treatment may be initiated at the recommended dose. There is no need for dose adjustment with patients with mild renal dysfunction.

- Patient with Hepatic Insufficiency:

Oxaliplatin has not been studied in patients with severe hepatic impairment. No increase in oxaliplatin acute toxicities was observed in the subset of patients in abnormal liver function. During clinical development, no specific dose adjustment was made in patients presenting with abnormal liver functions.

- Elderly subjects:

No Increase in severe toxicities was observed when oxaliplatin was used as a single agent or in combination with 5-fluorouracil(5-FU) in subject over the age of 65. Consequently, no specific dose adjustment is required for elderly subjects.

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% sucrose solution to give a concentration not less than 0.2 mg/ml must be infused either via central venous line or peripheral vein over 2-6 hours. Oxaliplatin infusion should always precede that of 5-Fluorouracil. In the event of extravasation, administration must be discontinued immediately.

Instruction for use

Oxaliplatin must be diluted prior to administration. Only the recommended diluent should be used to dilute the concentrate for solution for infusion (See “Instructions for use and handling”).

CONTRAINDICATIONS

Oxaliplatin is contraindicated in patients who:

- Have a history of hypersensitivity to oxaliplatin.

- are breast feeding.

- Have myelosuppression (neutrophils < 2x109/l and/or platelet count of < 100x109l) before the first cycle treatment.

- Have sensory peripheral sensitive neuropathy with functional impairment prior to the first cycle of treatment

- have severe renal insufficiency (creatinine clearance < 30 ml/min)

SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE

For use in pregnant women see section 4.6 “Pregnancy and Lactation”.

- Due to limited information on safety in patients with moderate renal impairment, administration should only be considered after suitable appraisal of the benefit/risk for the patient. In this case, renal function should be closely monitored and dose adjusted according to toxicity.

- Patients with a history of allergic reactions to platinum compounds should be the monitored for allergic symptoms. Allergic reaction can occur during any cycle. In case of symptoms 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 laryngo-pharyngeal dysesthesia within or during the hours following the two-hour infusion, the next oxaliplatin infusion should be administered over six hours. To prevent such dysaesthesia, inform the patient to avoid exposure to cold and to avoid ingesting fresh/cold food or/and beverages during or within the hours following oxaliplatin administration.

- If neurological symptoms (paresthesia, dysesthesia) occur, the following recommended oxaliplatin dosage adjustment, based on the duration and severity of these symptoms, should be performed:

· If symptoms last for more than 7 days and are painful, the subsequent oxaliplatin dose should be reduced from 85 to 65 mg/m² (treatment of metastatic) or to 75 mg/ml² (adjuvant treatment)

· if paresthesia without functional impairment persists until the next cycle, the oxaliplatin dose should be reduced from 85 to 65 mg/m² (metastatic treatment) or to 75 mg/m² (adjuvant treatment)

· if paresthesia with functional impairment persists until the next cycle, oxaliplatin administration should be discontinued

· if symptoms improve following discontinuation of oxaliplatin therapy, resumption of therapy may be considered.

- Patient must be informed that the symptoms of sensory peripheral neurophathy may persist after the end of the treatment. Moderate Localized paraesthesia which may interfere with functional activities may persist for more than 3 years after the discontinuation of adjuvant treatment.

- Signs and symptoms of Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES, Posterior Reversible Encephalopathy Syndrome) could be headache, altered mental functioning, seizures, abnormal vision from blurriness to blindness, associated or not with hypertension. Diagnosis of RPLS is based upon confirmation by brain imaging.

- Gastrointestinal toxicity which manifests as nausea and vomiting warrants prophylactic and/or therapeutic anti-emetic therapy.

- Dehydration, paralytic ileus, intestinal obstruction, hypocalemia, metabolic acidosis and impairment of renal function may be caused by severe diarrhea and/or vomiting, particularly when oxaliplatin is used in combination 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.

- If haematological toxicity occurs (neutrophils < 1.5x109/l or platelet < 50x109/l), administration of the next cycle should be postponed until haematological values return to acceptable levels. A full blood count with cell differential should be performed prior to initiating oxaliplatin therapy and before each subsequent cycle.

- Patients must be adequately informed of the risk of diarrhoea/emesis, mucositis/stomatitis and neutropenia after oxaliplatin and 5-fluorouracil administration in order to contact their treating physician for appropriate management.

- In the event of mucositis/stomatitis with or without neutropenia, the subsequent administration should be postponed until the mucositis/stomatitis has regressed to a grade less than or equal to 1 and/or neutrophil count ≥ 1.5x109/l.

- For oxaliplatin combined with 5-fluorouracil (with or without folinic acid), the usual dose adjustments for 5-fluorouracil associated toxicities should apply.

- If severe/life-threatening (grade-4) diarrhoea, severe (grade-3-4) neutropenia (neutrophils <1x109/l), febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection with an absolute neutrophil count < 1.0 x 109/L, a single temperature of > 38.3°C or a sustained temperature of > 38°C for more than one hour), or severe (grade-3-4) thrombocytopenia (platelets

<50x109/l) occur, oxaliplatin must be discontinued until improvement or resolution, in addition to any 5-fluorouracil dosage reductions required, and a reduction in the dose of oxaliplatin from 85 to 65 mg/m² (metastatic treatment) or to 75 mg/m² (adjuvant treatment).

- Sepsis, neutropenic sepsis and septic shock have been reported in patients treated with oxaliplatin, including fatal outcomes8 (see section 11). If any of these events occurs, oxaliplatin should be discontinued.

- Disseminated intravascular coagulation (DIC), including fatal outcomes, has been reported in association with Oxaliplatin treatment. If DIC is present, Oxaliplatin treatment should be discontinued and appropriate treatment should be administered.

- In 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.

- QT prolongation may lead to an increased risk for ventricular arrhythmias including Torsade de Pointes, which can be fatal (see section 11). 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, oxaliplatin treatment should be discontinued.

- 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.

- 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.

INTERACTIONS WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION

In patients who have received a single dose of 85 mg/m² of oxaliplatin, immediately prior to the administration of 5-fluorouracil, no charge 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

No data are currently available concerning the safety of oxaliplatin in pregnant women. Based on pre-clinical findings, the use of oxaliplatin, is likely to be lethal and/or teratogenic to the foetus at the recommended therapeutic dose, and is therefore not recommended during pregnancy should only be considered once the patients has been clearly informed as to the risks to the foetus and her consent obtained.

Passage into breast milk has not been studied. Breast-feeding is contra-indicated during oxaliplatin with oxaliplatin.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

No data available

UNDESIRABLE EFFECTS

The most common undesirable effects experienced during the combination of oxaliplatin with 5-fluorouracil/folinic acid (5-FU/FA) are gastrointestinal (diarrhea, nausea, vomiting and mucositis), haematological (neutropenia, thrombocytopenia) and neurological (acute and dose cumulative sensory peripheral neuropathy). These undesirable events have been generally more frequent and more severe with oxaliplatin in combination with 5-FU/FA than with 5-FU/FA alone.

The incidences shown in the table below were obtained during clinical studies on the treatment of metastases and on adjuvant treatment (which included 416 and 1108 patients, respectively, in this oxaliplatin + 5-FU/FA arm, repectively) and form post- marketing surveillance.

The frequencies shown in the table were defined using the following criteria: very common (>1/10), common (>100, ≤1/10), uncommon (>1/1000, ≤1/100), rare (>1/10000, ≤1/1000) and very rare (≤1/10000), including isolated cases.

Further information is given after the table.

* see detailed section below

* * Special Warnings and Special Precautions for Use.

Haematological toxiticy

Digestive toxicity

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

Dehydration, paralytic ileus, intestinal obstruction, hypocalemia, metabolic acidosis and renal impairment may be caused by severe diarrhea and/or vomiting, particularly when oxaliplatin is combined with 5-fluorouracil (see 4.4 “Special warnings and precautions for use”).

Nervous system:

The dose limiting toxicity of oxaliplatin is neurological. This mainly involves sensory peripheral neurophaty characterized 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 cycles of treatment, increases with the number of cycles.

Depending on the duration of symptoms, the onset of pain and/or functional disorder requires dose adjustment or even treatment discontinuation (see 4.4 “Special warnings and precautions for use”).

Such functional impairment, which includes difficulty in executing delicate movements, is a possible consequence of sensory damage. The risk of onset of persistent symptoms with a cumulated dose of 850 mg/m² (i.e. 10 cycles) is around 10%, and around 20% for a cumulated dose of 1020 mg/m² (i.e. 12 cycles).

In most cases, neurological symptoms improve or are totally resolved when treatment is discontinued.

Six months after treatment discontinuation in the adjuvant setting of colon cancer, 87% of patients had no or mild symptoms. After more than 3 years of follow-up, about 3% of patients presented with either persisting, localized paraesthesia of moderate intensity (2.3%) or paraesthesia that may interfere with functional activities (0.5%).

Acute neurosensory manifestations have been reported (see 5.3 “Preclinical safety data”). They start within hours of administration and often occur on exposure to cold.

They are characterized by transient paraesthesia, dysaesthesia and hypoaesthesia, or as an acute syndrome of laryngopharyngeal dysaesthesia. This acute syndrome, the incidence of which is estimated between 1% and 2%, is characterized by subjective sensations of dysphagia or dyspnoea, without any objective sign of respiratory distress (no cyanosis or hypoxia) or by laryngospasm or bronchospasm (no stridor or wheezing); jaw spasm, abnormal tongue sensation, dysarthria and a feeling of chest pressure have also been observed.

Although antihistamines and bronchodilators have been administered in such cases, the symptoms are rapidly reversible, even in the absence of treatment, prologation of the infusion during subsequent cycles helps to reduce the incidence of this syndrome (see 4.4 “Special warnings and precautions for use”).

Other neurological symptoms, such as dysarthria, loss of 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 not known:

- Infections and infestations

Septic shock, including fatal outcomes

- Blood and lymphatic system disorders

Haemolytic uremic syndrome, autoimmune, pancytopenia, pancytopenia, secondary leukemia.

- Nervous system disorders:

Convulsion, ischemic and hemorrhagic cerebrovascular disorder

- Cardiac disorders:

QT prolongation, which may lead to ventricular arrhythmias including Torsade de Pointes, which may be fatal

Acute coronary syndrome, including myocardial infarction, coronary arteriospasm and angina pectoris have been described in patients treated with oxaliplatin in combination with 5-FU and bevacizumab

- Respiratory, thoracic and mediastinal disorders

Laryngospasm, pneumonia and bronchopneumonia, including fatal outcomes.

- Gastrointestinal disorders

· intestinal ischaemia, including fatal outcomes.

· duodenal ulcer, and complications, such as duodenal ulcer haemorrhage or perforation, which can be fatal.

· esophagitis

- Musculoskeletal and connective tissue disorders

rhabdomyolysis, including fatal outcomes

Immune system disorders

delayed hypersensitivity.

Skin and subcutaneous tissue disorders

hypersensitivity vasculitis.

Allergic reactions

OVERDOSE

There is no known antidote to oxaliplatin. In the event of overdose, exacerbation of undesirable effects can be expected. Monitoring of haematological parameters must be initiated, together with symptomatic treatment of other toxicities.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

CYTOTOXIC Agent

(Other antineoplastic agent) ATC code : L01XA 03

Oxaliplatin is an antineoplastic agent belonging to a new class of platinum compounds in which the platinum atom is complexed with 1,2-diaminocyclohexane (“DACH”) and an oxalate group.

Oxaliplatin is a single enantiomer, (cis-[(1R,2R)-1,1-cyclohexanediamine-

N,N’]oxalate(20)-0,0’)platinum.

Oxaliplatin exhibits a wide spectrum of both in vitro cytotoxicity and in vivo antitumour activity in a variety of tumour model systems, including human colorectal cancer models.

Oxaliplatin also demonstrates in vitro and in vivo activity in various cisplatin-resistant cell lines.

Synergistic cytotoxic activity with 5-fluorouracil has been demonstrated both In vitro and in vivo. Studies on the mechanism of action, although not completely elucidated, show that the aqua-derivatives resulting from the biotransformation of oxaliplatin, interact with DNA to form both intra and inter-strand cross-links, resulting in the disruption of DNA synthesis leading to cytotoxic and antitumour effects.

In patients with metastatic colorectal cancer, the efficacy of oxaliplatin (85 mg/m² repeated every two weeks) in combination with 5-fluorouracil/folinic acid has been reported in three clinical studies:

· In first-line treatment, the 2-am comparative phase III EFC2962 study randomized

420 patients either to 5-FU/FA alone (LV5FU2, N=210) or the combination of oxaliplatin with 5-FU/FA (FOLFOX4, N=210).

· In pretreated patients, the comparative three arms phase III study EFC4584 randomised 821 patients refractory to an irinotecan (CPT-11) + 5-FU/FA combination either to 5-FU/FA alone (LV5FU2, N=275), oxaliplatin single agent (N=275), or combination of oxaliplatin with 5-FU/FA (FOLFOX4, N=271).

· Finally, the uncontrolled phase II EFC2964 study included patients refractory to 5-FU/FA alone, that were treated with the oxaliplatin and 5-FU/FA combination (FOLFOX4, N=57).

The two randomized clinical trials, EFC2962 in front-line therapy and EFC4584 in pretreated patients, demonstrated a significantly higher response rate and a prolonged progression free survival (PPS)/time to progression (TTP) as compared to treatment with 5-FU/FA alone. In EFC4584 performed in between the combination of oxaliplatin and 5-FU/FA did not reach statistical significance.

NA : not applicable

NA : not applicable

NA : not applicable

In pretreated patients (EFC4584), who were symptomatic at baseline, a higher proportion of those treated with oxaliplatin and 5-FU/FA experienced a significant improvement of their disease-related symptoms compared to those treated with 5- FU/FA alone (27.7% vs 14.6% p = 0.0033).

In non-pretreated patients (EFC2962), no statistically significant difference between the two treatment groups was found for any of the quality of life dimensions.

However, the quality of life scores were generally better in the control arm for measurement of global health status and pain and worse in the oxaliplatin arm for nausea and working.

In the adjuvant setting, the MOSAIC comparative phase III study (EFC3313) randomized 2246 patients (899 stage II/Duke’s B2 and 1347 stage III/Duke’s C) further to complete resection of the primary tumour of colon cancer either to 5- FU/FA alone (LV5FU2, N=1123 (B2/C = 448/675) or to combination of oxaliplatin and 5-FU/FA (FOLFOX4, N=1123 (B2/C) = 451/672).

**EFC3313: Disease-free survival at 3 years (ITT analysis)* in the Overall population**

* Median follow-up at 44.2 months (all patients followed for at least 3 years).

The study demonstrated a significant global advantage in 3 years disease-free survival for the oxaliplatin and 5-FU/FA combination (FOLVOX4) over 5-FU/FA alone (LV5FU2).

**EFC3313: Disease-free survival at 3 years (ITT analysis)* according to stage of disease**

* Median follow-up at 44.2 months (all patients followed for at least 3 years).

Overall survival (ITT analysis)

At time of the analysis of the 3-year disease free survival, which was the primary endpoint of the MOSAIC trial, 85.1% of the patients were still alive in the FOLFOX4 arm versus 83.8% in the LV5FU2 arm. This translated into an overall reduction in mortality risk of 10% in favour of FOLVOX4 not reaching statistical significance (hazard ratio = 0.90).

The figures were 92.2% versus 92.4% in the stage II (Duke’s B2) sub-population (hazard ratio = 1.01) and 80.4% versus 78.1 in the stage III (Duke’s C) sub- population (hazard ratio = 0.87), for FOLFOX4 and LS5FU2, respectively.

Pharmacokinetic properties

The pharmacokinetics of individual active compounds have not been determined. The pharmacokinetics of ultrafiltrable platinum, representing a mixture of all unbound, active and inactive platinum species, following a two-hour infusion of oxaliplatin at 130 mg/m² every three weeks for 1 to 5 cycles and oxaliplatin at 85 mg/m² every two weeks for 1 to 3 cycles are as follows:

Mean values of AUC _0-48 and calculated on cycle 3 (85 mg/m²) or on cycle 5 (130 mg/m²).

Mean values of AUC, V_∞, CL, and CLR _0-48 calculated on cycle 1.

Values of Cfinal, Cmax, AUC, _AUC0-48, and CL calculated using non compartmental analysis.

T_½ α, T_½ β, and T_½ γ calculated using non compartmental analysis (cycles 1-3 combined).

At the end of a 2-hour infusion, 15% of the administered platinum is present in the systemic circulation, the remaining 85% being rapidly distributed into tissues or eliminated in the urine. Irreversible binding to red blood cells and plasma, results in half lives in these matrices that are dose to the natural turnover of red blood cells and serum albumin. No accumulation as observed in plasma ultrafiltrate following 85 mg/m² every two weeks or 130 mg/m² every three weeks and steady state was attained by cycle one in this matrix. Inter- and intra-subject variability is generally low.

In vitro, metabolites result from non-enzymatic degradation and there is no evidence of cytochrome P-450-mediated metabolism of the diaminocyclohexane (DACH) ring. Oxaliplatin undergoes extensive biotransformation, and no intact drug was detectable in plasma ultrafiltrate at the end of a 2h-infusion. Several cytotoxic metabolites including the monochloro-, dichloro-, and diaquo-DACH platinum species have been identified in the systemic circulation together with a number of inactive conjugates at later time points.

Platinum is predominantly excreted in urine, with clearance mainly in the 48 hours following administration.

By day 5, approximately 54% of the total dose was recovered in the urine and < 3% in the faeces. A significant decrease in clearance from 17.6 ± 2.18 l/h to 9.95

± 1.91 l/h in renal impairment was observed together with a statistically significant decrease in distribution volume from 330 ± 40.9 to 241 ± 36.1 l. The effect of severe renal impairment on platinum clearance has not been evaluated.

PRECLINICAL SAFETY DATA

The target organs identified in species used during preclinical studies (mice, rats, dogs, and/or monkeys) following single doses and repeated doses included the bone marrow, the gastrointestinal system, the kidney, testes, the nervous system, and the heart. The toxicities in target organs observed in animals are concistent with those observed with other platinum agents and other cytotoxic drugs interacting with DNA and used in the treatment of human cancer, with the exception of the effects produced on the hearth. Effects on the heart were only observed in the dog and included electrophysiological abnormalities with lethal ventricular fibrillation.

Cardiotoxicity was considered as specific to the dog not only because it was observed in the dog, but also because doses similar to those producing lethal cardiotoxicity in dogs (150 mg/m²) were well-tolerated in man. Preclinical studies using rat sensory neurons suggest the acute neurosensory symptoms related to Oxaliplatin may be linked to an interaction with voltage-gated Na+ channels. Oxaliplatin is mutagenic and clastogenic in mammalian have been performed concerning its carcinogenic potential. Oxaliplatin is considered as probably being carcinogenic.

PHARMACEUTICAL PARTICULARS

List of excipients

Water for Injection

Incompatibilities

This medicinal product should not be mixed with other medicinal products, apart from those indicated in section 6.6.

· DO NOT use in association with alkaline medicinal products or media (in particular 5-fluorouracil, base solutions, trometamol and folinic acid products containing trometamol as an excipient).

· DO NOT dilute for infusion with saline solution.

· DO NOT mix with other medicinal products in the same infusion bag or infusion line (see Section 6.6 for instructions concerning simultaneous administration with folinic acid).

· DO NOT see injection equipment containing aluminium.

Shelf life

2 years

After dilution in 5% glucose solution, the physicochemical stability has been demonstrated for 24 hours at 2°C to 8°C or 6 hours at 25°C.

However from a microbiological point of view, the product should be used immediately. If not used immediately, the conditions and duration of storage after dilution and prior to use are the sole responsibility of the user, but the duration of storage should not exceed 24 hours at 2°C to 8°C unless dilution was performed under controlled, validated and aseptic conditions.

Special precautions for storage

Store the vial in the outer packaging, protected from light.

Do not freeze.

Nature and contents of container

10 ml or 20 ml vial (Type I colourless glass) with a stopper (bromobutyl)

Instructions for Handling

The handling of this cytotoxic agent by nursing or medical personnel requires every precaution to guarantee the protection of the handler and his surroundings.

Special precaution for administration

- NEVER use injection material containing aluminium.

- NEVER administer undiluted.

- NEVER dilute the product with saline solution.

- NEVER mix with any other medicines in the same infusion bag, or administer simultaneously by the same infusion line (particularly 5-fluorouracil, base solutions, trometamol and folinic acid products containing trometamol as an excipient). Oxaliplatin may be co-administered with folinic acid using a Y-line placed immediately before the site of injection. The medicine must not be combined in the same infusion bag. Folinic acid must be diluted with isotonic infusion solutions such as 5% glucose solution but NEVER with saline or alkaline solutions. Flush the infusion line after administering oxaliplatin.

- USE ONLY the recommended solvent (see below).

Concentrate for solution for infusion

Inspect visually prior to use. Only clear solutions without particles should be used. The medicinal product is for single use only. Any unused should be discarded.

Dilution prior to infusion

Withdraw the required amount of concentrate for solution from the vial and then dilute with 250 to 500 ml of 5% glucose solution to give an oxaliplatin concentration not less than 0.2 mg/ml.

Administer by intravenous infusion

Inspect visually prior to use. Only clear solutions without particles should be used. The medicinal product is for single use only. Any unused should be discarded.

NEVER use sodium chloride solution for dilution.

Infusion

The administration of oxaliplatin does not require prehydration.

Oxaliplatin diluted in 250 to 500 ml of 5% glucose solution to give an oxaliplatin concentration not less than 0.2 mg/ml must be infused either by peripheral vein or central venous line over 2 to 6 hours. When oxaliplatin is administered with 5- fluorouracil, the oxaliplatin infusion should precede that of 5-fluorouracil.

Waste Disposal

Any unused product, as well as all materials used for dilution and administration, must be destroyed in compliance with hospital standard procedures applicable to cytotoxic agents with due regard to current laws related to the disposal of hazardous waste.

NATURE AND CONTENTS OF CONTAINER

ELOXATIN 50 mg vials 10 ml (colourless glass), box of 1 Reg. No. DKI1359202649A1

ELOXATIN 100 mg vials 20 ml (colourless glass), box of 1 Reg. No. DKI1359202649A1

HARUS DENGAN RESEP DOKTER

Manufactured by:

Sanofi-Aventis Deutschland GmbH, Frankfurt (Main) - Germany

Registered by:

PT Aventis Pharma, Jakarta – Indonesia

Date of text revision:

As on approval date

This information is intended for Health Care Professional only. See local product information for full details information

Eloxatin