OXALIPLATIN MEDAC 5 MG / ML CONCENTRATE FOR SOLUTION FOR INFUSION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Oxaliplatin medac 5 mg/ml concentrate for solution for infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml concentrate for solution for infusion contains 5 mg oxaliplatin.

10 ml of concentrate for solution for infusion contain 50 mg of oxaliplatin

20 ml of concentrate for solution for infusion contain 100 mg of oxaliplatin

40 ml of concentrate for solution for infusion contain 200 mg of oxaliplatin

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Concentrate for solution for infusion.

Clear, colourless liquid, free from visible particles.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Oxaliplatin medac is used in combination with 5-fluorouracil (5-FU) and folinic acid (FA)

for adjuvant treatment of stage III (Dukes’ C) colon carcinoma after complete removal of the primary tumour,

for the treatment of metastasising colorectal carcinoma.

4.2 Posology and method of administration

Posology

FOR ADULTS ONLY

The recommended dose of oxaliplatin for adjuvant treatment is 85 mg/m2 body area (BA) intravenously every 2 weeks for 12 cycles of therapy (6 months).

The recommended dose of oxaliplatin for the treatment of metastasising colorectal carcinoma is 85 mg/m2 body area (BA) intravenously every 2 weeks until disease progression or unacceptable toxicity.

The dose should be adjusted in accordance with its tolerability (see section 4.4).

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

Oxaliplatin is administered as an intravenous infusion over a period of 2 to 6 hours in 250 to 500 ml of 5 % glucose solution to give a concentration between 0.2 mg/ml and 0.7 mg/ml; 0.7 mg/ml is the highest concentration in clinical practice for an oxaliplatin dose of 85 mg/m2.

Oxaliplatin has been used mainly in combination with treatment regimens based on continuous 5-fluorouracil infusion. For the treatments given every 2 weeks 5-fluorouracil has been used as a combination of a bolus and a continuous infusion.

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 impairment

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

No increase in severe toxicities was observed when oxaliplatin was used as a single agent or in combination with 5-fluorouracil in patients over the age of 65. In consequence no specific dose adaptation is required for elderly patients.

Paediatric population

There is no relevant indication for the use of Oxaliplatin medac in children. The efficacy of oxaliplatin single agent in children and adolescents 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 5 % glucose solution to give a concentration not less than 0.2 mg/ml must be infused via a central venous line or peripheral vein over 2 to 6 hours. Oxaliplatin infusion must always precede the administration of 5-fluorouracil.

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

Precautions to be taken before handling or administering the medicinal product Oxaliplatin must be diluted before use. Only 5 % glucose solution must be used to dilute the concentrate for solution for infusion. For instructions on dilution of the medicinal product before administration, see section 6.6

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Breast-feeding.

Myelosuppression prior to starting first course, as evidenced by baseline neutrophils < 2 × 109/l and/or platelet count of < 100 × 109/l.

Peripheral sensitive neuropathy with functional impairment prior to first course.

Severely impaired renal function (creatinine clearance less than 30 ml/min) (see section 5.2).

4.4 Special warnings and precautions for use

The use of oxaliplatin should be restricted to medical institutions specialising in management of cytotoxic chemotherapy, and should only be carried out under the supervision of a qualified oncologist.

Renal impairment

Patients with mild to moderate renal impairment should be closely monitored for adverse reactions and the 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 anaphylactoid reactions the infusion should be interrupted immediately and an appropriate symptomatic treatment started. Re-administration of oxaliplatin to such patients is contraindicated. Cross reactions, sometimes fatal, have been reported with all platinum compounds.

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

Neurological symptoms

Neurological toxicity of oxaliplatin should be carefully monitored, especially if co-administered with other medicinal products with specific neurological toxicity. A neurological examination should be performed before each administration and periodically thereafter.

For patients who develop acute laryngopharyngeal dysaesthesia (see section 4.8) during or within the first few 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. 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.

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 haematological 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-fluorouracil.

Cases of intestinal ischemia, including fatal outcomes, have been reported with oxaliplatin treatment. In case of intestinal ischemia, oxaliplatin treatment should be discontinued and appropriate measures initiated (see section 4.8).

If haematological toxicity occurs (neutrophils < 1.5 × 109/l or platelets < 50 × 109/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. 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 and 5-fluorouracil administration so that they can urgently contact their treating physician for appropriate management.

If mucositis/sto­matitis occurs with or without neutropenia, the next treatment should be delayed until recovery from mucositis/sto­matitis to grade 1 or less and/or until the neutrophil count is > 1.5 × 109/1.

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

If grade 4 (WHO) diarrhoea, grade 3 – 4 neutropenia (neutrophils < 1.0 × 109/1), febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection with an absolute neutrophil count < 1.0 × 109/l, temperature > 38.3°C or a sustained temperature > 38°C for more than one hour), or grade 3 – 4 thrombocytopenia (platelets < 50 × 109/l) occur, the dose of oxaliplatin should be reduced from 85 to 65 mg/m2 (metastatic setting) or 75 mg/m2 (adjuvant setting), in addition to any 5-fluorouracil dose reductions required.

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 (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).

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 hypokalaemia, 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 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 received a single dose of 85 mg/m2 of oxaliplatin immediately before administration of 5-fluorouracil, no change in the level of exposure to 5-fluorouracil has been observed.

In vitro, no significant displacement of oxaliplatin binding to plasma proteins has been observed with the following agents: erythromycin, salicylates, granisetron, paclitaxel, and sodium valproate.

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

There are no or limited amount of data from the use of oxaliplatin in pregnant women.. Studies in animals have shown reproductive toxicity (see section 5.3). Consequently, Oxaliplatin medac is not recommended during pregnancy and in women of childbearing potential not using contraception.

The use of oxaliplatin should only be considered after suitably apprising the patient of the risk to the foetus, and with the patient’s consent.

Contraception in males and females

Women of child-bearing potential have to use effective contraception during and for 4 months after treatment.

Men have to use effective contraception during and for 6 months after treatment.

Breast-feeding

It is unknown whether oxaliplatin/me­tabolites are excreted in human milk. Oxaliplatin medac is contraindicated during breast-feeding (see section 4.3).

Fertility

Oxaliplatin may have anti-fertility effects (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 results in an increased risk of dizziness, nausea and vomiting, and other neurological 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/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 the oxaliplatin and 5-FU/FA combination than with 5-FU/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 1,108 patients respectively in the oxaliplatin + 5-FU/FA treatment arms) and from post-marketing experience.

Frequencies in this table are defined using the following convention:

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

Further details are given after the table.

* See detailed section below

* * See section 4.4.

+ Common neutropenic sespsis, including fatal outcomes.

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

Common anaphylactic or anaphylactoid reactions, including bronchospasm, sensation of chest pain, angiooedema, hypotension 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

Infections and infestations

Incidence by patient (%)

Postmarketing experience with frequency not known Septic shock, including fatal outcomes.

Blood and lymphatic system disorders Incidence by patient (%), by grade

Rare (>1/10,000, <1/1,000)

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

Post-marketing experience with frequency not known

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

Immune system disorders

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

Nervous system disorders

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

The onset of pain and/or a functional disorder are indications, depending on the duration of the symptoms, for dose adjustment, or even treatment discontinuation (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 1,020 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 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 % — 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 or muscle contractions, involuntary muscle twitching or myoclonus, coordination abnormal, gait abnormal, ataxia or balance disorders, throat or chest tightness, pressure, discomfort and 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, ischemic and haemorrhagic cerebrovascular disorder.

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).

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

Respiratory, thoracic and mediastinal disorders

Post-marketing experience with frequency not known

Laryngospasm. Pneumonia and bronchopneumonia including fatal outcomes.

Gastrointestinal disorders

Incidence by patient (%), by grade

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 ischemia, including fatal outcomes (see section 4.4). Gastrointestinal ulcer and perforation, which can be fatal (see section 4.4). Oesophagitis.

Hepatobiliary 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.

Skin and subcutaneous tissue disorders

Post-marketing experience with frequency not known

Hypersensitivity vasculitis

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: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

Mechanism of action

Oxaliplatin is an antineoplastic medicinal product 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 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

2c<r       /2

In patients with metastatic colorectal cancer, the efficacy of oxaliplatin (85 mg/m repeated every 2 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 under FOLFOX4 versus LV5FU2

* NA: Not Applicable

Median Progression Free Survival (PFS) / Median Time to Progression (TTP) FOLFOX4 versus LV5FU2

NA : Not Applicable

Median Overall Survival (OS) under FOLFOX4 versus LV5FU2

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.

* 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

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

Overall survival (ITT analysis)

At the time of 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.

Paediatric population

Oxaliplatin single agent has been evaluated in the 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

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 2 weeks or at 130 mg/m every 3 weeks

Mean AUC0–48, and Cmax values were determined on Cycle 3 (85 mg/m2) or cycle 5 (130 mg/m2).

Mean AUC, Vss, and CL values were determined on Cycle 1.

Cmax, AUC, AUC0–48, Vss and CL values were determined by non-compartmental analysis.

t1/2a, ti/2p, and t1/2y, were determined by compartmental analysis (Cycles 1 –

3 combined).

Distribution

At the end of a 2-hour infusion, i5 % 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 2 weeks or 130mg/m2 every 3 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 drug 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.

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 % Cl) 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 respectively 0.52 (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 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. Oxaliplatin can be co-administered with folinic acid via a Y-line (see section 6.6).

DO NOT mix with alkaline medicinal products or solutions, in particular 5-fluorouracil, folinic acid preparations containing trometamol as an excipient and trometamol salts of other medicinal products. 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).

DO NOT use injection equipment containing aluminium.

6.3 Shelf life

3 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 6 hours at +25 °C.

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

6.4 Special precautions for storage

Keep the vial in the outer carton in order to protect from light.

Store between 15 °C and 25 °C. Do not freeze.

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

6.5 Nature and contents of container

Clear glass vials (type I) of 10 ml, 20 ml and 40 ml with polytetrafluo­roethylene coated chlorobutyl-isoprene blend rubber stopper and flip-off plastic button with aluminium seal.

Pack sizes:

Packs with 1 vial containing 10 ml, 20 ml or 40 ml of concentrate for solution for infusion.

6.6 Special precautions for disposal and other handling

7 MARKETING AUTHORISATION HOLDER

medac Gesellschaft für Spezialpräparate mbH

Theaterstr. 6

22880 Wedel

Germany

8 MARKETING AUTHORISATION NUMBER(S)

PL 11587/0086

9. DATE OF FIRST AUTHORISATION/RE­NEWAL OF THE AUTHORISATION

Date of first authorisation: 30/05/2014

Date of renewal of the authorisation: 11/09/2018