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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Oxaliplatin 5 mg/ml concentrate for solution for infusion

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml of 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.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Concentrate for solution for infusion.

The solution has a pH between 4.0 and 7.0.

Clear, colourless liquid, free from visible particles.

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 (Dukes C) colon cancer after complete resection of primary tumour

Treatment of metastatic colorectal cancer

4.2 Posology and method of administration

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 until disease progression or unacceptable toxicity.

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

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

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 has mainly been 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 must not be administered in patients with severe renal impairment (see sections 4.3 and 5.2).

In patients with mild to moderate renal impairment, the recommended dose of oxaliplatin is 85 mg/m² (see sections 4.4 and 5.2).

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 population

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.

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 tumours 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 a 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 diluted before use.Only glucose 5 % (50 mg/ml) diluent is to be used to dilute the concentrated solution for infusion (see section 6.6).

4.3 Contraindications

Oxaliplatin is contraindicated in patients who

•    have a known history of hypersensitivity to the active substance.

•    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 sensory neuropathy with functional impairment prior to first course.

•    have a severely impaired renal function (creatinine clearance less than 30 ml/min)(see section 5.2).

4.4 Special warnings and precautions for use

Oxaliplatin should only be used in specialised departments of oncology and should be administered under the supervision of an experienced oncologist.

Renal impairment

Patients with mild to moderate renal impairment should be closely monitored for adverse reactions and dose adjusted according to toxicity (see section 5.2).

Hypersensitivity reactions

Special surveillance should be ensured for patients with a history of allergic manifestations to other products containing platinum. In case of anaphylactic 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 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.

Peripheral neuropathy

If neurological symptoms (paraesthesia, dysaesthesia) occur, the following

recommended oxaliplatin dose adjustment should be based on the duration and

severity of these symptoms:

•    If symptoms last longer than 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.

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 (see section 4.8). Diagnosis of RPLS is based upon confirmation by brain imaging, preferably MRI (Magnetic Resonance Imaging).

Nausea, vomiting, diarrhoea, dehydration, and haematologic changes

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, hypokalaemia, metabolic acidosis and renal impairment may be caused by severe diarrhoea/emesis particularly when combining oxaliplatin with 5 FU.

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. (see section 4.8).

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. Myelosuppressive effects may be additive to those of concomitant chemotherapy. Patient with severe and persistent myelosuppression are at high risk of infectious complications. Sepsis, neutropenic sepsis and septic shock have been reported in patients treated with oxaliplatin including fatal outcomes (see section 4.8.). If any of these events occurs, oxaliplatin should be discontinued.

Patients must be adequately informed of the risk of diarrhoea/emesis, mucositis/stomatitis and neutropenia after oxaliplatin/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 >1.5 x 109/L.

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, grade 3-4 neutropenia (neutrophils < 1.0x109/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 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 FU dose reductions required.

Pulmonary

In the case of unexplained respiratory symptoms such as non-productive cough, dyspnoea, crackles or radiological pulmonary infiltrates, oxaliplatin should be discontinued until further pulmonary investigations exclude an interstitial lung disease or pulmonary fibrosis (see section 4.8).

Blood disorders

Haemolytic-uraemic syndrome (HUS) is a life-threatening side effect (frequency not known). 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 not be reversible with discontinuation of therapy and dialysis may be required.

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. (see section 4.8) Caution should be exercised in patients with conditions that are associated with DIC such as infections, sepsis, etc.

QT prolongation

QT prolongation may lead to an increased risk for ventricular arrhythmias including Torsade de Pointes, which can be fatal (see section 4.8). The QT interval should be closely monitored on a regular basis before and after administration of oxaliplatin. 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. (see sections 4.5 and 4.8).

Rhabdomyolysis

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. (see sections 4.5 and 4.8)

Gastrointestinal ulcer/ Gastrointestinal ulcer haemorrhage and perforation

Oxaliplatin treatment can cause gastrointestinal ulcer and potential complications, such as gastrointestinal haemorrhage and perforation, which can be fatal. In case of gastrointestinal ulcer, oxaliplatin treatment should be discontinued and appropriate measures taken. (see section 4.8)

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.

Pregnancy

For use in pregnant women, see section 4.6.

Fertility

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).

Peritoneal hemorrhage may occur when oxaliplatin is administered by intraperitoneal route (off-label route of administration).

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.

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 (see section 4.4). Caution is advised when oxaliplatin treatment is administered concomitantly with other medicinal products known to be associated with rhabdomyolysis. (see section 4.4).

4.6 Fertility, 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.

Breast-feeding

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

Fertility

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

Due to the potential genotoxic effects of oxaliplatin, appropriate contraceptive measures must be taken during and after cessation of therapy during 4 months for women and 6 months for men.

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 otherneurologic 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

Summary of the safety profile

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

Tabulated list of adverse reactions

The frequencies reported in the table below are derived from clinical trials in the metastatic and adjuvant settings (having included 416 and 1108 patients respectively in the oxaliplatin +5 fluorouracil (5FU)/folinic acid (FA) 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 (> 1/1000, <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.

MedDRA Organ system classes	Very common	Common	Uncommon	Rare	Not Known
Infections and infestations *	- Infection	-    Rhinitis -    Upper respiratory tract infection -    Neutropenic sepsis+	Sepsis+
Blood and lymphatic system disorders*	-    Anaemia -    Neutropenia -    Thrombocyto- penia -    Leukopenia -    Lymphopenia	- Febrile neutropenia		-    Immunoallergic thrombocytopenia -    Haemolytic anaemia	- Autoimmune pancytopenia
Immune system disorders*	- Allergy/ allergic reaction++
Metabolism and nutrition disorders	-    Anorexia -    Hyperglycaemia -    Hypokalaemia -    Hypernatraemia	-    Dehydration -    Hypocalcaemia	- Metabolic acidosis
Psychiatric disorders		-    Depression -    Insomnia	-Nervousness
Nervous system disorders*	-    Peripheral sensory neuropathy -    Sensory disturbance -    Dysgeusia -    Headache	-    Dizziness -    Motor neuritis -    Meningism		-    Dysarthria -    Reversible Posterior Leukoencephalopathy syndrome (RPLS
Eye disorders		-    Conjunctivitis -    Visual disturbance		-    Visual acuity reduced transiently -    Visual field disturbances -    Optic neuritis -    Transient vision loss, reversible following therapy discontinuation

++ 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. Delayed hypersensitivity has also been reported with oxaliplatin hours or even days after the infusion.

+++ Very common fever, rigors (tremors), either from infection (with or without febrile neutropenia) or possibly from immunological mechanism.

++++ Injection site reactions including local pain, redness, swelling and thrombosis have been reported.

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).

Description of selected adverse reactions

Blood and lymphatic system disorders

Incidence by patient (%), by grade

Oxaliplatin / 5 FU/FA 85 mg/m2 every 2 weeks	Metastatic setting			Adjuvant setting
	All grades	gr 3	gr 4	All grades	gr 3	gr4
Anaemia	82.2	3	<1	75.6	0.7	0.1
Neutropenia	71.4	28	14	78.9	28.8	12.3
Thrombocyto-penia	71.6	4	<1	77.4	1.5	0.2
Febrile neutropenia	5.0	3.6	1.4	0.7	0.7	0.0

Rare (>1/10000, <1/1000)

Disseminated intravascular coagulation (DIC), including fatal outcomes (see section 4.4).

Post-marketing experience with frequency not known Hemolytic uremic syndrome Infections and infestations

Incidence by patient (%)

Oxaliplatin and 5-FU/FA 85 mg/m2Every 2 weeks	Metastatic Setting	Adjuvant Setting
	All grades	All grades
Sepsis (including sepsis and neutropenic sepsis)	1.5	1.7

Post-marketing experience with frequency not known Septic shock, including fatal outcomes.

Immune system disorders

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

Oxaliplatin / 5 FU/FA 85 mg/m2 every 2 weeks	Metastatic setting			Adjuvant setting
	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

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 (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 paresthesias of moderate intensity (2.3 %) or with paresthesias 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 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 oflaryngospasm 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 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 not known Convulsion

Cardiac disorders

Post-marketing experience with _ frequency not known

QT prolongation, which may lead to ventricular arrhythmias including Torsade de Pointes, which may be fatal (see section 4.4).

Respiratory, thoracic and mediastinal disorders

Post-marketing experience with frequency not known Laryngospasm

Gastrointestinal disorders

Incidence by patient (%), by grade

Oxaliplatin/ 5 FU/FA 85 mg/m2 every 2 weeks	Metastatic setting			Adjuvant setting
	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, hypokalaemia, 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).

Post-marketing experience with _ frequency not known

Intestinal ischaemia, including fatal outcomes (see section 4.4).Gastrointestinal ulcer and perforation, which can be fatal. (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 liver disorder, including peliosis hepatis, nodular regenerative hyperplasia, perisinusoidal fibrosis. Clinical manifestations may be portal hypertension and/or increased transaminases.

Musculoskeletal and connective tissue disorders

Post-marketing experience with _ frequency not known Rhabdomyolysis, including fatal outcomes (see section 4.4).

Renal and urinary disorders

Very rare (<1/10,000):

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at Website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms

There is no known antidote to oxaliplatin. In cases of overdose, exacerbation of adverse events can be expected.

Management

Monitoring of haematological parameters should be initiated and symptomatic treatment given.

5 PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Other antineoplastic agents, platinum compounds, ATC code: L01XA03

Mechanism of action

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] 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 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.

Clinical efficacy and safety

In patients with metastatic colorectal cancer, the efficacy of oxaliplatin (85mg/m2 repeated every two weeks) combined with 5 fluorouracil (5 FU)/folinic acid (FA) is reported in three clinical studies:

•    In front-line treatment, the 2-arm comparative phase III EFC2962 study randomized 420 patients either to 5 fluorouracil (5 FU)/folinic acid (FA) alone (LV5FU2, N = 210) or the combination of oxaliplatin with 5 fluorouracil (5 FU)/folinic acid (FA) (FOLFOX4, N=210)

•    In pretreated patients the comparative 3-arm phase III EFC4584 study randomized 821 patients refractory to an irinotecan (CPT-11) + 5 fluorouracil (5 FU)/folinic acid (FA) combination either to 5 fluorouracil (5 FU)/ folinic acid (FA) alone (LV5FU2, N = 275), oxaliplatin single agent (N = 275), or combination of oxaliplatin with 5 fluorouracil (5 FU)/ folinic acid (FA) (FOLFOX4, N = 271)

•    Finally, the uncontrolled phase II EFC2964 study included patients refractory to5 fluorouracil (5 FU)/ folinic acid (FA) alone, that were treated with the oxaliplatin and 5 fluorouracil (5 FU)/folinic acid (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 study EFC4584 performed in pretreated refractory patients, the difference in the median overall survival (OS) between the combination of oxaliplatin and 5 fluorouracil (5 FU)/folinic acid (FA) did not reach statistical significance.

Response rate under 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 (42-56)	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) / Median Time to Progression (TTP)

FOLFOX4 versus LV5FU2

Median PFS/TTP, months (95% CI) independent radiological review ITT analysis	LV5FU2	FOLFOX4	Oxaliplatin Single agent
Front-line treatment EFC2962 (PFS)	6.0 (5.5-6.5)	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 FU / FA)	8.8 (7.3 - 9.3)	9.9 (9.1-10.5)	8.1 (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/5 fluorouracil (5 FU)/folinic acid (FA) experienced a significant improvement of their disease-related symptoms compared to those treated with 5 fluorouracil (5 FU)/folinic acid (FA) alone (27.7 % versus 14.6 %, p<0.0033). In non pretreated patients (EFC2962), no statistical 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 comparative MOSAIC phase III study (EFC3313) randomised 2246 patients (899 stage II/ Dukes B2 and 1347 stage III/ Dukes 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 (FOLFOX 4, 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	73.3	78.7
survival (95 % CI)	(70.6-75.9)	(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 (Dukes B2)		Stage III	(Dukes C)
Treatment arm	LV5FU2	FOLFOX4	LV5FU2	FOLFOX4
Percent 3-year disease free survival	84.3	87.4	65.8	72.8
(95 % CI)	(80.9 87.7)	(84.3-90.5)	(62.2 69.5)	(69.4-76.2)
Hazard ratio (95 %	0.79		0.75
CI)	(0.57-1.09)		(0.62-0.90)

* 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 (Dukes B2) sub-population (hazard ratio = 1.01) and 80.4 % versus 78.1 % in the Stage III (Dukes C) subpopulation (hazard ratio = 0.87), for FOLFOX4 and LV5FU2, respectively.

Paediatric population

Oxaliplatin single agent has been evaluated in paediatric population in 2 Phase I (69 patients) and 2 Phase II (166 patients) studies. A total of 235 paediatric patients (7 months-22 years of age) with solid tumours have been treated. The effectiveness of oxaliplatin single agent in the paediatric populations treated has not been established. Accrual in both Phase II studies was stopped for lack of tumour response.

5.2 Pharmacokinetic properties

Adsorption and distribution

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 pg/mL	AUC0-48 pg.h/m L	AUC pg.h/m L	ti/2<xh	t1/2Ph	tiayh	Vss L	CL 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 and CLvalues were determined on Cycle 1.

C_max, AUC, AUC_0-48, V_ss and CL values were determined by non-compartmental analysis. ti_/2a, t_i/2p, and t_1/2y,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

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 2 h-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.

Elimination

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.

Special populations

Renal impairment

The effect of renal impairment on the disposition of oxaliplatin was studied in patients with varying degrees of renal function. Oxaliplatin was administered at a dose of 85 mg/m2 in the control group with a normal renal function (CLcr> 80 ml/min, n=12) and in patients with mild (CLcr = 50 to 80 ml/min, n=13) and moderate (CLcr = 30 to 49 ml/min, n=11) renal impairment, and at a dose of 65 mg/m2 in patients with severe renal impairment (CLcr< 30 ml/min, n=5). Median exposure was 9, 4, 6, and 3 cycles, respectively, and PK data at cycle 1 were obtained in 11, 13, 10, and 4 patients respectively.

There was an increase in plasma ultrafiltrate (PUF) platinum AUC, AUC/dose and a decrease in total and renal CL and Vss with increasing renal impairment especially in the (small) group of patients with severe renal impairment: point estimate (90% CI) of estimated mean ratios by renal status versus normal renal function for AUC/dose were 1.36 (1.08, 1.71), 2.34 (1.82, 3.01) and 4.81 (3.49, 6.64) for patients with mild and moderate and in severe renal failure respectively.

Elimination of oxaliplatin is significantly correlated with the creatinine clearance. Total PUF platinum CL was respectively 0.74 (0.59, 0.92), 0.43 (0.33, 0.55) and 0.21 (0.15, 0.29) and for Vss respectively0.52 (0.41, 0.65), 0.73 (0.59, 0.91) and 0.27 (0.20, 0.36) for patients with mild, moderate and severe renal failure respectively. Total body clearance of PUF platinum was therefore reduced by respectively 26% in mild, 57% in moderate, and 79% in severe renal impairment compared to patients with normal function.

Renal clearance of PUF platinum was reduced in patients with impaired renal function by 30% in mild, 65% in moderate, and 84% in severe renal impairment compared to patients with normal function.

There was an increase in beta half life of PUF platinum with increasing degree of renal impairment mainly in the severe group. Despite the small number of patients with severe renal dysfunction, these data are of concern in patients in severe renal failure and should be taken into account when prescribing oxaliplatin in patients with renal impairment (see sections 4.2, 4.3 and 4.4).

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-foetal toxicity in rats. Oxaliplatin is considered a probable carcinogen, although carcinogenic studies have not been conducted.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Water for injections

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 substances. Alkaline medicinal products or solutions will adversely affect the stability of oxaliplatin (see section 6.6).

-    DO NOT dilute oxaliplatin 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

Unopened vial: 2 years

After dilution in 5% glucose, chemical and physical in-use stability has been demonstrated for 48 hours at 2°C to 8°C and for 24 hours at 25°C.

From a microbiological point of view, 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 dilution has taken place in controlled and validated aseptic conditions.

6.4    Special precautions for storage

Do not freeze. Keep the vial in the outer carton in order to protect from light.

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

6.5    Nature and contents of container

20 ml Type I clear glass vial, with bromobutyl rubber stopper and flip off aluminium seal containing 10 ml of concentrate.

20 ml Type I clear glass vial, with bromobutyl rubber stopper and flip off aluminium seal containing 20 ml of concentrate.

50 ml Type I clear glass vial, with bromobutyl rubber stopper and flip off aluminium seal containing 40 ml of concentrate.

Pack size: 1 vial per carton.

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.

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.

Personnel must be provided with appropriate handling materials, notably long sleeved gowns, protection masks, caps, protective goggles, sterile single-use gloves, protective covers for the work area, containers and collection bags for waste.

Excreta and vomit must be handled with care.

Pregnant women must be warned to avoid handling cytotoxic agents.

Any broken container must be treated with the same precautions and considered as contaminated waste. Contaminated waste should be incinerated in suitably labelled rigid containers. See below chapter “Disposal”.

If oxaliplatin concentrate or solution for infusion, should come into contact with skin, wash immediately and thoroughly with water.

If oxaliplatin concentrate or solution for infusion, should come into contact with mucous membranes, wash immediately and thoroughly with water.

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 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 administered 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 product characteristics.

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 concentrate should be discarded (see disposal below).

Dilution for intravenous infusion

Withdraw the required amount of concentrate from the vial(s) and then dilute with 250 ml 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. The concentration range over which the physico-chemical stability of oxaliplatin has been demonstrated is 0.2 mg/ml to 2.0 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 +2 °C to +8 °C and for 24 hours at +25 °C.

From a microbiological point of view, this 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 dilution has taken place in controlled and validated aseptic conditions (not to exceed 48 hours).

Inspect visually prior 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 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 via a central venous line or a peripheral vein 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 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

QILU PHARMA SPAIN S.L.U Paseo de la Castellana 40,

8°, Madrid 28046, Spain

8    MARKETING AUTHORISATION NUMBER(S)

PL 44570/0002

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

09/09/2016

10    DATE OF REVISION OF THE TEXT

09/09/2016