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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

OXALIPLATIN 5 mg/ml powder for solution for infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

50 mg vial: each 30 ml vial contains 50 mg oxaliplatin for reconstitution in 10 ml of solvent.

100 mg vial: each 50 ml vial contains 100 mg oxaliplatin for reconstitution in 20 ml of solvent.

One ml of reconstitued solution contains oxaliplatin 5 mg.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder for solution for infusion.

White lyophilised powder.

4    CLINICAL PARTICULARS

4.1    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 tumour.

•    Treatment of metastatic colorectal cancer.

4.2 Posology and method of administration

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. It is forbidden to smoke, eat or drink in this area (see section 6.6).

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.

Dosage given should be adjusted according to tolerability (section 4.4).

Oxaliplatin should always be administered before fluoropyrimidines - i.e. 5 fluorouracil (5 FU).

Oxaliplatin is administered as a 2- to 6-hour intravenous infusion in 250 to 500 ml of glucose 5 % (50 mg/ml) 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 (5 FU) based regimens. For the two-weekly treatment schedule 5 fluorouracil (5 FU) regimens combining bolus and continuous infusion were used.

Special Populations:

-    Renal impairment:

Oxaliplatin has not been studied in patients with severe renal impairment (see section 4.3).

In patients with moderate renal impairment, treatment may be initiated at the normally recommended dose (see section 4.4). There is no need for dose adjustment in patients with mild renal dysfunction.

-    Hepatic insufficiency:

In a phase I study including patients with several levels of hepatic impairment, the frequency and severity of the hepatobiliary disorders appeared to be related to a 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 (5 FU) in patients over the age of 65. In consequence no specific dose adaptation is required for elderly patients.

-    Pediatric 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 (see section 5.1).

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 glucose 5 % (50 mg/ml) 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 (5 FU).

In the event of extravasation, administration must be discontinued immediately.

Instructions for use:

Oxaliplatin must be reconstituted and further diluted before use. Only glucose 5 % (50 mg/ml) diluent is to be used to reconstitute and then dilute the freeze-dried medicinal product (see section 6.6).

4.3 Contraindications

Oxaliplatin is contraindicated in patients who

-    have a hypersensitivity to oxaliplatin or to the excipient lactose monohydrate,

-    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).

4.4 Special warnings and precautions for use

Due to limited information on safety in patients with moderately impaired 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. Cross reaction sometimes fatal have been reported with all platinum salts.

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 coadministered 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 (see section 4.8), 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. 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.

Gastrointestinal toxicity, which manifests as nausea and vomiting, warrants prophylactic and/or therapeutic anti-emetic therapy (see section 4.8).

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). In single cases pancreatitis is reported.

If haematological toxicity occurs (neutrophils < 1.5x10⁹/l or platelets < 50x10⁹/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.

Patients must be adequately informed of the risk of diarrhoea/emesis, mucositis/stomatitis and neutropenia after oxaliplatin and 5 fluorouracil (5 FU) 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 ^1.5x10⁹/1.

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

If grade 4 diarrhoea (WHO), 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 (5 FU) 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 or pulmonary fibrosis (see section 4.8).

In cases of abnormal liver function function test results or portal hypertension which does not obviously result from liver metastases, very rare cases of drug induced hepatic vascular disorder should be considered.

For use in pregnant women, see section 4.6.

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 (see section 4.6).

4.5 Interaction with other medicinal products and other forms of interaction

In patients who have received a single dose of 85 mg/m² of oxaliplatin, immediately before administration of 5 fluorouracil (5 FU), no change in the level of exposure to 5 fluorouracil (5 FU) has been observed.

4.6 Pregnancy and lactation

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.

Excretion in breast milk has not been studied. Breast-feeding is contra-indicated during oxaliplatin therapy.

Oxaliplatin may have an anti-fertility effect (see section 4.4).

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However oxaliplatin treatment resulting in an increase risk of dizziness, nausea and vomiting, and other neurologic symptoms that affect gait and balance may lead to a minor or moderate influence on the ability to drive and use machines.

Vision abnormalities, in particular transient vision loss (reversible following therapy discontinuation), may affect patients' ability to drive and use machines. Therefore, patients

should be warned of the potential effect of these events on the ability to drive or use machines.

4.8 Undesirable effects

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.

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 arm) 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 (>1/1,000, <1/100), rare ( 1/10,000, <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Further details are given after the table.

MedDRA Organ System Classes	Very common	Common	Uncommon	Rare
Infections and infestations*	- Infection	-    Rhinitis -    Upper respiratory tract infection -    Febrile neutropenia /Neutropenic sepsis
Blood and lymphatic system disorders*	-    Anaemia -    Neutropenia -    Thrombocytopenia -    Leukopenia -    Lymphopenia			-    Immunoallergic thrombocytopenia -    Haemolytic anaemia
Immune system disorders*	- Allergy/allergic reaction+	- Anaphylactic/ Anaphylactoid reactions ++
Metabolism and nutrition disorders	-    Anorexia -    Glycaemia abnormalities -    Hypokalaemia -    Natraemia abnormalities	- Dehydration	- Metabolic acidosis
Psychiatric disorders		-    Depression -    Insomnia	- Nervousness
Nervous system disorders*	-    Peripheral sensory neuropathy -    Sensory disturbance -    Dysgeusia -Headache	-    Dizziness -    Motor neuritis -    Meningism		- Dysarthria
Eye disorders		-    Conjunctivitis -    Visual disturbance		-    Visual acuity reduced transiently -    Visual field disturbances -    Optic neuritis -    Transient vision

				loss, reversible following therapy discontinuation
Ear and labyrinth disorders			- Ototoxicity	- Deafness
Vascular disorders	- Epistaxis	-    Haemorrhage -    Flushing -    Deep vein thrombosis -    Pulmonary embolism -    Hypertension
Respiratory, thoracic and mediastinal disorders	-    Dyspnoea -    Cough	- Hiccups		-    Interstitial lung disease, sometimes fatal -    Pulmonary fibrosis**
Gastrointestinal disorders*	-    Nausea -    Diarrhoea -    Vomiting -    Stomatitis/ mucositis -    Abdominal pain -    Constipation	-    Dyspepsia -    Gastroesophageal reflux -    Rectal haemorrhage -    Gastrointestinal haemorrhage	-    Ileus -    Intestinal obstruction	- Colitis including Clostridium difficile diarrhoea
Skin and subcutaneous tissue disorders	-    Skin disorder -    Alopecia	-    Skin exfoliation (i.e Hand & Foot syndrome) -    Rash erythematous -    Rash -    Hyperhidrosis -    Nail disorder
Musculoskeletal, connective tissue and bone disorders	- Back pain	-    Arthralgia -    Bone pain
Renal and urinary disorders		-    Haematuria -    Dysuria -    Micturition frequency abnormal
General disorders and administration site conditions	-    Fatigue -    Fever+++ -    Asthenia -    Pain -    Injection site reaction++++
Investigations	-    Hepatic enzyme increase -    Blood alkaline phosphatase increase -    Blood bilirubin increase -    Blood lactate deshydrogenase increase -    Weight increase (adjuvant setting)	-    Blood Creatinine increase -    Weight decrease (metastatic setting)

* See detailed section below ** See section 4.4

+ Very frequent: allergy/allergic reactions, occurring most often during perfusion, sometimes fatal (frequent allergic reactions such as skin rash, in particular urticaria, conjunctivitis, rhinitis.

++ Frequent anaphylactic reactions, including bronchospasm, angiodema, low blood pressure and anaphylactic shock.

Occurrence of cross reactions sometimes fatal have been reported with all platinum salts.

+++ Very common fever, rigors (tremors), either from infection (with or without febrile neutropenia) or isolated fever 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 (see section 4.4).

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 a liver disorder, including peliosis hepatis, nodular regenerative hyperplasia, perisinusoidal fibrosis. Clinical manifestations may be portal hypertension and/or increased transaminases.

Very rare (< 1/10,000):

Pancreatitis

Renal and urinary disorders Very rare (<1/10,000):

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

Haematological toxicity:

Postmarketing experience with frequency unknown: Hemolytic uremic syndrome

Digestive toxicity :

Incidence by patient (%), by grade

Oxaliplatin and 5 FU/FA 85 mg/m2	Metastatic Setting			Adjuvant Setting
every 2 weeks	All grades	Gr 3	Gr 4	All grades	Gr 3	Gr 4

Nausea	69.9	8	< 1	73.7	4.8	0.3
Diarrhoea	60.8	9	2	56.3	8.3	2.5
Vomiting	49.0	6	1	47.2	5.3	0.5
Mucositis/Stomatitis	39.9	4	< 1	42.1	2.8	0.1

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) (see section 4.4).

Nervous system

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 (see section 4.4).

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 localised paraesthesias of moderate intensity (2.3 %) or with paraesthesias that may interfere with functional activities (0.5 %).

Acute neurosensory manifestations (see section 5.3) have been reported. They start within hours of administration and often occur on exposure to cold. They usually present as transient paraesthesia, dysaesthesia and hypoesthesia. An acute syndrome of pharyngolaryngeal dysaesthesia occurs in 1 % and 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 (see section 4.4).

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, 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.

Postmarketing experience with frequency unknown:

Convulsion and Reversible Posterior Leukoencephalopathy Syndrome (RPLS).

Allergic reactions:

Incidence by patient (%), by grade

Oxaliplatin and 5 FU/FA 85 mg/m2	Metastatic Setting			Adjuvant Setting
every 2 weeks	All grades	Gr 3	Gr 4	All grades	Gr 3	Gr 4
Allergic reactions / Allergy	9.1	1	< 1	10.3	2.3	0.6

4.9 Overdose

There is no known antidote to oxaliplatin. In cases of overdose, exacerbation of adverse events can be expected. Monitoring of haematological parameters should be initiated and symptomatic treatment given

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other antineoplastic agents, platinum compounds ATC code: L01XA 03

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

Oxaliplatin is a single enantiomer, (SP-4-2)-[(1R,2R)-Cyclohexane-1,2-diamine-kN, kN'] [ethanedioato(2-)-kO¹, kO²] [platinium].

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 models. A synergistic cytotoxic action has been observed in combination with 5 fluorouracil (5 FU) both in vitro and in vivo.

Studies on the mechanism of action of oxaliplatin, although not completely elucidated, show that the aqua-derivatives resulting from the biotransformation of oxaliplatin, interact with DNA to form both inter and intra-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) combined with 5 fluorouracil/folinic acid (5 FU/FA) is reported in three clinical studies:

-    In front-line treatment, the 2-arm comparative phase III EFC2962 study randomised 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 randomised clinical trials, EFC2962 in front-line therapy and EFC4584 in pretreated patients, demonstrated a significantly higher response rate and a prolonged progression free survival (PFS)/time to progression (TTP) as compared to treatment with 5 FU/FA alone.

In EFC4584 performed in refractory pretreated patients, the difference in median overall survival (OS) between the combination of oxaliplatin and 5 FU/FA did not reach statistical significance.

Response rate unt	er FOLFOX4 versus LV5FU2
Response rate, % (95 % CI) independent radiological review ITT analysis	LV5FU2	FOLFOX4	Oxaliplatin Single agent
Front-line treatment EFC2962 Response assessment every 8 weeks	22 (16-27)	49 (42-46)	NA*
	P value = 0.0001
Pretreated patients EFC4584 (refractory to CPT-11 + 5 FU/FA) Response assessment every 6 weeks	0.7 (0.0-2.7)	11.1 (7.6-15.5)	1.1 (0.2-3.2)
	P value < 0.0001
Pretreated patients EFC2964 (refractory to 5 FU/FA) Response assessment every 12 weeks	NA*	23 (13-36)	NA*
NA: Not Applicable Median Progression Free Survival (PFS) / Media FOLFOX4 versus LV5I		n Time to Progression (TTP) ?U2
Median PFS/TTP, Months (95 % CI) independent radiological review ITT analysis	LV5FU2	FOLFOX4	Oxaliplatin Single agent
Front-line treatment EFC2962 (PFS)	6.0 (55-6.5)	8.2 (7.2-8.8)	NA*
	Log-rank P value = 0.0003
Pretreated patients EFC4584 (TTP) (refractory to CPT-11 + 5 FU/FA)	2.6 (1.8-2.9)	5.3 (4.7-6.1)	2.1 (1.6-2.7)
	Log-rank P value < 0.0001
Pretreated patients EFC2964 (refractory to 5 FU/FA)	NA*	5.1 (3.1-5.7)	NA*

* NA: Not Applicable

Median Overall Survival (OS) under FOLFOX4 versus LV5FU2

Median OS, months (95 % CI) ITT analysis	LV5FU2	FOLFOX4	Oxaliplatin Single agent
Front-line treatment EFC2962	14.7 (13.0-18.2)	16.2 (14.7-18.2)	NA*
	Log-rank P value = 0.12
Pretreated patients EFC4584 (refractory to CPT-11 + 5	8.8	9.9	8.1

FU/FA)	(7.3 - 9.3)	(9.1-10.5)	(7.2-8.7)
	Log-rank P value = 0.09
Pretreated patients EFC2964 (refractory to 5 FU/FA)	NA*	10.8 (9.3-12.8)	NA*

*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 vomiting.

In the adjuvant setting, the MOSAIC comparative phase III study (EFC3313) randomised 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).

EFC 3313 3-year disease free survival (ITT analysis)* for the overall population.

Treatment arm	LV5FU2	FOLFOX4
Percent 3-year disease free survival (95 % CI)	73.3 (70.6-75.9)	78.7 (76.2-81.1)
Hazard ratio (95 % CI)	0.76 (0.64-0.89)
Stratified log rank test	P=0.0008

* median follow up 44.2 months (all patients followed for at least 3 years)

The study demonstrated an overall significant advantage in 3-year disease free survival for the oxaliplatin and 5 FU/FA combination (FOLFOX4) over 5 FU/FA alone (LV5FU2).

EFC 3313 3-year Disease Free Survival (ITT analysis)* according to Stage of disease

Patient stage	Stage II (Duke's B2)		Stage III (Duke's C)
Treatment arm	LV5FU2	FOLFOX4	LV5FU2	FOLFOX4
Percent 3-year disease free	84.3	87.4	65.8	72.8
survival (95 % CI)	(80.9-87.7)	(84.3-90.5)	(62.2-69.5)	(69.4-76.2)
Hazard ratio (95 % CI)	0.79		0.75
	(0.57-1.09)		(0.62-0.90)
Log-rank test	P=0.151		P=0.002

* median follow up 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 FOLFOX4 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 LV5FU2, respectively.

Oxaliplatin single agent has been evaluated in pediatric population in 2 Phase I (69 patients) and 2 Phase II (90 patients) studies. A total of 159 pediatric patients (7 months-22 years of age) with solid tumors have been treated. The effectiveness of oxaliplatin single agent in the pediatric populations treated has not been established. Accrual in both Phase II studies was stopped for lack of tumor response.

5.2 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:

Summary of Platinum Pharmacokinetic Parameter Estimates in Ultrafiltrate Following Multiple Doses of Oxaliplatin at 85 mg/m² Every Two Weeks or at 130 mg/m² Every Three Weeks

Dose	C max	AUC0-48	AUC	t1/^a	haP	tmY	V ss	CL
	p g/mL	p g.h/mL	p g.h/mL	h	h	h	L	L/h
85 mg/m2 Mean	0.814	4.19	4.68	0.43	16.8	391	440	17.4
SD	0.193	0.647	1.40	0.35	5.74	406	199	6.35
130 mg/m2 Mean	1.21	8.20	11.9	0.28	16.3	273	582	10.1
SD	0.10	2.40	4.60	0.06	2.90	19.0	261	3.07

Mean AUC_0-48, and C_max values were determined on Cycle 3 (85 mg/m²) or cycle 5 (130 mg/m²).

Mean AUC, V_ss, CL, and CL_R0-48 values were determined on Cycle 1.

C_end, C_max, AUC, AUC_0-48, V_ss and CL values were determined by non-compartmental analysis.

ti_/2a, ty₂p, and ty₂y, were determined by 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 close to the natural turnover of red blood cells and serum albumin. No accumulation was 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.

Biotransformation in vitro is considered to be the result of non-enzymatic degradation and there is no evidence of cytochrome P450-mediated metabolism of the diaminocyclohexane (DACH) ring.

Oxaliplatin undergoes extensive biotransformation in patients, and no intact active substance was detectable in plasma ultrafiltrate at the end of a 2h-infusion. Several cytotoxic biotransformation products 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.

5.3 Preclinical safety data

The target organs identified in preclinical species (mice, rats, dogs, and/or monkeys) in single- and multiple-dose studies included the bone marrow, the gastrointestinal system, the kidney, the testes, the nervous system, and the heart. The target organ toxicities observed in animals are consistent with those produced by other platinum-containing medicinal products and DNA-damaging, cytotoxic medicinal products used in the treatment of human cancers with the exception of the effects produced on the heart. Effects on the heart were observed only in the dog and included electrophysiological disturbances with lethal ventricular fibrillation. Cardiotoxicity is considered specific to the dog not only because it was observed in the dog alone but also because doses similar to those producing lethal cardiotoxicity in dogs (150 mg/m²) were well-tolerated by humans.

Preclinical studies using rat sensory neurons suggest that the acute neurosensory symptoms related to Oxaliplatin may involve an interaction with voltage-gated Na+ channels.

Oxaliplatin was mutagenic and clastogenic in mammalian test systems and produced embryo-fetal toxicity in rats. Oxaliplatin is considered a probable carcinogen, although carcinogenic studies have not been conducted

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate.

6.2 Incompatibilities

The diluted medicinal product should not be mixed with other medicinal products in the same infusion bag or infusion line. Under instructions for use described in section 6.6, oxaliplatin can be co-administered with folinic acid (FA) via a Y-line.

- DO NOT mix with alkaline medicinal products or solutions, in particular 5 fluorouracil (5 FU), folinic acid (FA) preparations containing trometamol as an excipient and trometamol salts of others active substance. Alkaline medicinal products or solutions will adversely affect the stability of oxaliplatin (see section 6.6).

- DO NOT reconstitute or dilute oxaliplatine with saline or other solutions containing chloride ions (including calcium, potassium or sodium chlorides).

- 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 (FA)).

- DO NOT use injection equipment containing aluminium.

6.3 Shelf life

3 years.

Reconstituted solution in the original vial:

From a chemical and physical point of view, the reconstituted solution could be stored at 25 °C up to 48 hours. The reconstituted solution could be then either diluted immediately or stored 48 hours before dilution.

Solution for infusion:

After dilution of the reconstituted solution in glucose 5 % (50 mg/ml) solution, chemical and physical in-use stability has been demonstrated for 48 hours at 25 °C.

From a microbiological point of view, the reconstituted solution and the solution for infusion should be used immediately.

If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 °C to 8 °C unless reconstitution / dilution has been taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

For storage conditions of the reconstituted and the diluted medicinal product, see section 6.3

6.5 Nature and contents of container

30 ml vial (type I clear glass) of oxaliplatin powder (50 mg) with bromobutyl rubber stopper and cap (type flip off).

50 ml vial (type I clear glass) of oxaliplatin powder (100 mg) with bromobutyl rubber stopper and cap (type flip off).

Pack sizes: 1, 2, 3, 5, 10 or 50 vials per box.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

As with other potentially toxic compounds, caution should be exercised when handling and preparing oxaliplatin solutions.

Instructions _ for Handling

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

Special precautions for administration

-    DO NOT use injection equipment containing aluminium.

-    DO NOT administer undiluted.

-    Only glucose 5 % (50 mg/ml) infusion solution is to be used as a diluent. DO NOT reconstitute or dilute for infusion with sodium chloride or chloride containing solutions.

-    DO NOT mix with any other medicinal products in the same infusion bag or administer simultaneously by the same infusion line. DO NOT mix with alkaline medicinal products or solutions, in particular 5 fluorouracil (5 FU), folinic acid (FA) preparations containing trometamol as an excipient and trometamol salts of others active substances. Alkaline medicinal products or solutions will adversely affect the stability of oxaliplatin.

Instruction for use with folinic acid (FA) (as calcium folinate or disodium folinate):

Oxaliplatin 85 mg/m2 intravenous infusion in 250 to 500 ml of glucose 5 % (50 mg/ml) solution is given at the same time as folinic acid (FA) intravenous infusion in glucose 5 % (50 mg/ml) solution, over 2 to 6 hours, using a Y-line placed immediately before the site of infusion. These two medicinal products should not be combined in the same infusion bag. Folinic acid (FA) must not contain trometamol as an excipient and must only be diluted using isotonic glucose 5 % (50 mg/ml) solution, never in alkaline solutions or sodium chloride or chloride containing solutions.

Instruction for use with 5 fluorouracil (5 FU):

Oxaliplatin should always be administred before fluoropyrimidines - i.e. 5 fluorouracil (5 FU).

After oxaliplatin administration, flush the line and then administer 5 fluorouracil (5 FU).

For additional information on medicinal products combined with oxaliplatin, see the corresponding manufacturer’s summary of products characteristics.

-    USE ONLY the recommended solvents (see below).

-    Any reconstituted solution that shows evidence of precipitation should not be used and should be destroyed with due regard to legal requirements for disposal of hazardous waste (see below).

Reconstitution of the solution

-    Water for injections or glucose 5 % (50 mg/ml) solution should be used to reconstitute the solution.

-    For a vial of 50 mg: add 10 ml of solvent to obtain a concentration of 5 mg oxaliplatin/ml.

-    For a vial of 100 mg: add 20 ml of solvent to obtain a concentration of 5 mg oxaliplatin/ml.

From a chemical and physical point of view, the reconstituted solution could be stored at 25 °C up to 48 hours. The reconstituted solution could be then either diluted immediately or stored 48 hours before dilution with glucose 5 % (50 mg/ml) solution.Inspect visually prior to use. Only clear solutions without particles should be used.

The medicinal product is for single use only. Any unused solution should be discarded.

Dilution _for intravenous infusion

Withdraw the required amount of reconstituted solution from the vial(s) and then dilute with 250 to 500 ml of a glucose 5 % (50 mg/ml) solution to give an oxaliplatin concentration between not less than 0.2 mg/ml and 0.7 mg/ml.

Administer by intravenous infusion.

After dilution in glucose 5 % (50 mg/ml) solution, chemical and physical in-use stability has been demonstrated for 48 hours at 25 °C.

From a microbiological point of view, the reconstituted solution and the infusion preparation should be used immediately.

If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 °C to 8 °C unless reconstitution / dilution has been taken place in controlled and validated aseptic conditions.

Inspect visually priori to use. Only clear solutions without particles should be used. The medicinal product is for single use only. Any unused infusion solution should be discarded (see chapter “Disposal” below).

NEVER use sodium chloride or chloride containing solutions for either reconstitution or dilution.

The compatibility of oxaliplatin solution for infusion has been tested with representative, PVC-based, administration sets.

Infusion

The administration of oxaliplatin does not require prehydration.

Oxaliplatin diluted in 250 to 500 ml of a glucose 5 % (50 mg/ml) solution to give a 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 (5 FU), the oxaliplatin infusion must precede the administration of 5 fluorouracil (5 FU).

Disposal

Remnants of the medicinal product as well as all materials that have been used for reconstitution, for dilution and administration must be destroyed according to hospital standard procedures applicable to cytotoxic agents in accordance with local requirements_related to the disposal of hazardous waste.

7    MARKETING AUTHORISATION HOLDER

Generics [UK] Ltd t/a Mylan, Station Close, Potters Bar, Hertfordshire, EN6 1TL, United Kingdom.

8 MARKETING AUTHORISATION NUMBER(S)

PL 04569/0854

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

23/11/2010

10 DATE OF REVISION OF THE TEXT

09/02/2011