Oxaliplatin zentiva

Overdose

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

There is no known antidote for Oxaliplatin Zentiva overdose. In addition to thrombocytopenia, the anticipated complications of an Oxaliplatin Zentiva overdose include hypersensitivity reaction, myelosuppression, nausea, vomiting, diarrhea and neurotoxicity. Several cases of overdoses have been reported with Oxaliplatin Zentiva. Adverse reactions observed were Grade 4 thrombocytopenia ( < 25,000/mm³) without any bleeding, anemia, sensory neuropathy such as paresthesia, dysesthesia, laryngospasm and facial muscle spasms, gastrointestinal disorders such as nausea, vomiting, stomatitis, flatulence, abdomen enlarged and Grade 4 intestinal obstruction, Grade 4 dehydration, dyspnea, wheezing, chest pain, respiratory failure, severe bradycardia and death.

Patients suspected of receiving an overdose should be monitored, and supportive treatment should be administered. The maximum dose of oxaliplatin that has been administered in a single infusion is 825 mg.

Contraindications

Oxaliplatin Zentiva is contraindicated in patients who:

- are breast feeding

- have myelosuppression prior to starting first course, as evidenced by baseline neutrophils <2x109/l and/or platelet count of <100x109l

- 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).

Oxaliplatin Zentiva should not be administered to patients with a history of known allergy to Oxaliplatin Zentiva or other platinum compounds.

Incompatibilities

Undesirable effects

Summary of the safety profile

The most frequent adverse events of Oxaliplatin Zentiva 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 Zentiva 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 1108 patients respectively in the Oxaliplatin Zentiva + 5-FU/FA treatment arms) and from post marketing experience.

Frequencies in this table are defined using the following convention: very common (>1/10) common (>1/100, <1/10), uncommon (>1/1000, ≤1/100), rare (>1/10000, ≤1/1000), very rare (≤1/10000), not known (cannot be estimated from the available data).

Further details are given after the table.

* See detailed section below

+ including fatal outcomes

++ 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, angiooedema, hypotension, sensation of chest pain and anaphylactic shock. Delayed hypersensitivity has also been reported with Oxaliplatin Zentiva 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 Zentiva is infused through a peripheral vein.

Description of selected adverse reactions

Blood and lymphatic system disorders

Incidence by patient (%), by grade

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

Disseminated intravascular coagulation (DIC), including fatal outcomes.

Post marketing experience with frequency unknown

Hemolytic uremic syndrome, autoimmune pancytopenia.

Infections and infestations

Incidence by patient (%), by grade

Post-marketing experience with frequency not known

Septic shock, including fatal outcomes.

Immune system disorders

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

Nervous system disorders

The dose limiting toxicity of Oxaliplatin Zentiva is neurological. It involves a sensory peripheral neuropathy characterized by dysaesthesia and/or paraesthesia of the extremities with or without cramps, often triggered by the cold.

These symptoms occur in up to 95% of patients treated. The duration of these symptoms, which usually regress between courses of treatment, increases with the number of treatment cycles.

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

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

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

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

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

Post marketing experience with frequency unknown

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.

Respiratory, thoracic and mediastinal disorders

Post-marketing experience with frequency not known:

Laryngospasm

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 Zentiva with 5 fluorouracil (5 FU).

Post marketing experience with frequency not known

Intestinal ischaemia, including fatal outcomes.

Gastrointestinal ulcer and perforation, which can be fatal.

Hepato-biliary disorders

Very rare (≤ 1/10000)

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.

Skin and subcutaneous tissue disorders

Post-marketing experience with frequency not known

Hypersensitivity vasculitis.

Renal and urinary disorders

Very rare (≤ 1/10000)

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.

The following serious adverse reactions are discussed in greater detail in other sections of the label:

• Anaphylaxis and Allergic reactions
• Neuropathy
• Severe Neutropenia
• Pulmonary Toxicities
• Hepatotoxicity
• Cardiovascular Toxicities
• Rhabdomyolysis

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

More than 1100 patients with stage II or III colon cancer and more than 4,000 patients with advanced colorectal cancer have been treated in clinical studies with Oxaliplatin Zentiva. The most common adverse reactions in patients with stage II or III colon cancer receiving adjuvant therapy were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue and stomatitis. The most common adverse reactions in previously untreated and treated patients were peripheral sensory neuropathies, fatigue, neutropenia, nausea, emesis, and diarrhea.

One thousand one hundred and eight patients with stage II or III colon cancer, who had undergone complete resection of the primary tumor, have been treated in a clinical study with Oxaliplatin Zentiva in combination with infusional 5-fluorouracil/leucovorin. The incidence of grade 3 or 4 adverse reactions was 70% on the Oxaliplatin Zentiva combination arm, and 31% on the infusional 5-fluorouracil/leucovorin arm. The adverse reactions in this trial are shown in the tables below. Discontinuation of treatment due to adverse reactions occurred in 15% of the patients receiving Oxaliplatin Zentiva and infusional 5-fluorouracil/leucovorin. Both 5fluorouracil/leucovorin and Oxaliplatin Zentiva are associated with gastrointestinal or hematologic adverse reactions. When Oxaliplatin Zentiva is administered in combination with infusional 5fluorouracil/leucovorin, the incidence of these events is increased.

The incidence of death within 28 days of last treatment, regardless of causality, was 0.5% (n=6) in both the Oxaliplatin Zentiva combination and infusional 5-fluorouracil/leucovorin arms, respectively. Deaths within 60 days from initiation of therapy were 0.3% (n=3) in both the Oxaliplatin Zentiva combination and infusional 5-fluorouracil/leucovorin arms, respectively. On the Oxaliplatin Zentiva combination arm, 3 deaths were due to sepsis/neutropenic sepsis, 2 from intracerebral bleeding and one from eosinophilic pneumonia. On the 5-fluorouracil/leucovorin arm, one death was due to suicide, 2 from Steven-Johnson Syndrome (1 patient also had sepsis), 1 unknown cause, 1 anoxic cerebral infarction and 1 probable abdominal aorta rupture.

The following table provides adverse reactions reported in the adjuvant therapy colon cancer clinical trial by body system and decreasing order of frequency in the Oxaliplatin Zentiva and infusional 5-fluorouracil/leucovorin arm for events with overall incidences ≥ 5% and for NCI grade 3/4 events with incidences ≥ 1%.

Table 3: Adverse Reactions Reported in Patients with Colon Cancer receiving Adjuvant Treatment ( ≥ 5% of all patients and with ≥ 1% NCI Grade 3/4 events)

The following table provides adverse reactions reported in the adjuvant therapy colon cancer clinical trial by body system and decreasing order of frequency in the Oxaliplatin Zentiva and infusional 5-fluorouracil/leucovorin arm for events with overall incidences ≥ 5% but with incidences < 1% NCI grade 3/4 events.

Table 4: Adverse Reactions Reported in Patients with Colon Cancer receiving Adjuvant Treatment ( ≥ 5% of all patients, but with < 1% NCI Grade 3/4 events)

Although specific events can vary, the overall frequency of adverse reactions was similar in men and women and in patients < 65 and ≥ 65 years. However, the following grade 3/4 events were more common in females: diarrhea, fatigue, granulocytopenia, nausea and vomiting. In patients ≥ 65 years old, the incidence of grade 3/4 diarrhea and granulocytopenia was higher than in younger patients. Insufficient subgroup sizes prevented analysis of safety by race. The following additional adverse reactions, were reported in ≥ 2% and < 5% of the patients in the Oxaliplatin Zentiva and infusional 5-fluorouracil/leucovorin combination arm (listed in decreasing order of frequency): pain, leukopenia, weight decrease, coughing.

The number of patients who developed secondary malignancies was similar; 62 in the Oxaliplatin Zentiva combination arm and 68 in the infusional 5-fluorouracil/leucovorin arm. An exploratory analysis showed that the number of deaths due to secondary malignancies was 1.96% in the Oxaliplatin Zentiva combination arm and 0.98% in infusional 5-fluorouracil/leucovorin arm. In addition, the number of cardiovascular deaths was 1.4% in the Oxaliplatin Zentiva combination arm as compared to 0.7% in the infusional 5-fluorouracil/leucovorin arm. Clinical significance of these findings is unknown.

Two hundred and fifty-nine patients were treated in the Oxaliplatin Zentiva and 5-fluorouracil/leucovorin combination arm of the randomized trial in patients previously untreated for advanced colorectal cancer. The adverse reaction profile in this study was similar to that seen in other studies and the adverse reactions in this trial are shown in the tables below. Both 5-fluorouracil and Oxaliplatin Zentiva are associated with gastrointestinal and hematologic adverse reactions. When Oxaliplatin Zentiva is administered in combination with 5-fluorouracil, the incidence of these events is increased.

The incidence of death within 30 days of treatment in the previously untreated for advanced colorectal cancer study, regardless of causality, was 3% with the Oxaliplatin Zentiva and 5-fluorouracil/leucovorin combination, 5% with irinotecan plus 5-fluorouracil/leucovorin, and 3% with Oxaliplatin Zentiva plus irinotecan. Deaths within 60 days from initiation of therapy were 2.3% with the Oxaliplatin Zentiva and 5-fluorouracil/leucovorin combination, 5.1% with irinotecan plus 5-fluorouracil/leucovorin, and 3.1% with Oxaliplatin Zentiva plus irinotecan. The following table provides adverse reactions reported in the previously untreated for advanced colorectal cancer study by body system and decreasing order of frequency in the Oxaliplatin Zentiva and 5-fluorouracil/leucovorin combination arm for events with overall incidences ≥ 5% and for grade 3/4 events with incidences ≥ 1%.

Table 5: Adverse Reactions Reported in Patients Previously Untreated for Advanced Colorectal Cancer Clinical Trial ( ≥ 5% of all patients and with ≥ 1% NCI Grade 3/4 events)

The following table provides adverse reactions reported in the previously untreated for advanced colorectal cancer study by body system and decreasing order of frequency in the Oxaliplatin Zentiva and 5-fluorouracil/leucovorin combination arm for events with overall incidences ≥ 5% but with incidences < 1% NCI Grade 3/4 events.

Table 6: Adverse Reactions Reported in Patients Previously Untreated for Advanced Colorectal Cancer Clinical Trial ( ≥ 5% of all patients but with < 1% NCI Grade 3/4 events)

Adverse reactions were similar in men and women and in patients < 65 and ≥ 65 years, but older patients may have been more susceptible to diarrhea, dehydration, hypokalemia, leukopenia, fatigue and syncope. The following additional adverse reactions, at least possibly related to treatment and potentially important, were reported in ≥ 2% and < 5% of the patients in the Oxaliplatin Zentiva and 5-fluorouracil/leucovorin combination arm (listed in decreasing order of frequency): metabolic, pneumonitis, catheter infection, vertigo, prothrombin time, pulmonary, rectal bleeding, dysuria, nail changes, chest pain, rectal pain, syncope, hypertension, hypoxia, unknown infection, bone pain, pigmentation changes, and urticaria.

Four hundred and fifty patients (about 150 receiving the combination of Oxaliplatin Zentiva and 5-fluorouracil/leucovorin) were studied in a randomized trial in patients with refractory and relapsed colorectal cancer. The adverse reaction profile in this study was similar to that seen in other studies and the adverse reactions in this trial are shown in the tables below.

Thirteen percent of patients in the Oxaliplatin Zentiva and 5-fluorouracil/leucovorin combination arm and 18% in the 5-fluorouracil/leucovorin arm of the previously treated study had to discontinue treatment because of adverse effects related to gastrointestinal, or hematologic adverse reactions, or neuropathies. Both 5-fluorouracil and Oxaliplatin Zentiva are associated with gastrointestinal and hematologic adverse reactions. When Oxaliplatin Zentiva is administered in combination with 5-fluorouracil, the incidence of these events is increased.

The incidence of death within 30 days of treatment in the previously treated study, regardless of causality, was 5% with the Oxaliplatin Zentiva and 5-fluorouracil/leucovorin combination, 8% with Oxaliplatin Zentiva alone, and 7% with 5-fluorouracil/leucovorin. Of the 7 deaths that occurred on the Oxaliplatin Zentiva and 5-fluorouracil/leucovorin combination arm within 30 days of stopping treatment, 3 may have been treatment related, associated with gastrointestinal bleeding or dehydration.

The following table provides adverse reactions reported in the previously treated study by body system and in decreasing order of frequency in the Oxaliplatin Zentiva and 5-fluorouracil/leucovorin combination arm for events with overall incidences ≥ 5% and for grade 3/4 events with incidences ≥ 1%. This table does not include hematologic and blood chemistry abnormalities; these are shown separately below.

Table 7: Adverse Reactions Reported In Previously Treated Colorectal Cancer Clinical Trial ( ≥ 5% of all patients and with ≥ 1% NCI Grade 3/4 events)

The following table provides adverse reactions reported in the previously treated study by body system and in decreasing order of frequency in the Oxaliplatin Zentiva and 5-fluorouracil/leucovorin combination arm for events with overall incidences ≥ 5% but with incidences < 1% NCI Grade 3/4 events.

Table 8: Adverse Reactions Reported In Previously Treated Colorectal Cancer Clinical Trial ( ≥ 5% of all patients but with < 1% NCI Grade 3/4 events)

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 drugs and DNA-damaging, cytotoxic drugs 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 Zentiva may involve an interaction with voltage-gated Na+ channels.

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

Therapeutic indications

Oxaliplatin Zentiva 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.

Oxaliplatin Zentiva, used in combination with infusional 5-fluorouracil/leucovorin, is indicated for:

• adjuvant treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor.
• treatment of advanced colorectal cancer.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: other antineoplastic agents, platinum compounds

ATC code: L01XA 03

Mechanism of action

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

Oxaliplatin Zentiva exhibits a wide spectrum of both in vitro cytotoxicity and in vivo anti-tumour activity in a variety of tumour model systems including human colorectal cancer models. Oxaliplatin Zentiva 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 Zentiva, although not completely elucidated, show that the aqua-derivatives resulting from the biotransformation of Oxaliplatin Zentiva, interact with DNA to form both inter and intra-strand cross-links, resulting in the disruption of DNA synthesis leading to cytotoxic and anti-tumour effects.

Clinical and efficacy and safety

In patients with metastatic colorectal cancer, the efficacy of Oxaliplatin Zentiva (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 Zentiva 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 Zentiva single agent (N=275), or combination of Oxaliplatin Zentiva 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 Zentiva 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 Zentiva 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 Zentiva and 5-FU/FA experienced a significant improvement of their disease related symptoms compared to those treated with 5-FU/FA alone (27.7% versus 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 Zentiva arm for nausea and vomiting. In the adjuvant setting, the MOSAÏC comparative 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 Zentiva 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 Zentiva 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 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) sub-population (hazard ratio = 0.87), for FOLFOX4 and LV5FU2, respectively.

Paediatric population

Oxaliplatin Zentiva 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 Zentiva single agent in the paediatric populations treated has not been established. Accrual in both Phase II studies was stopped for lack of tumour response.

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 Zentiva at 130 mg /m² every three weeks for 1 to 5 cycles and Oxaliplatin Zentiva 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 Zentiva at 85 mg/m2 Every Two Weeks or at 130 mg/m2 Every Three Weeks

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

Mean AUC, Vss, CL, and CLR0-48 values were determined on Cycle 1.

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

t1/2α, t1/2β, and t1/2γ, 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 Zentiva 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.

The effect of renal impairment on the disposition of Oxaliplatin Zentiva was studied in patients with varying degrees of renal function. Oxaliplatin Zentiva 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 Zentiva 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 Zentiva in patients with renal impairment.

The reactive oxaliplatin derivatives are present as a fraction of the unbound platinum in plasma ultrafiltrate. The decline of ultrafilterable platinum levels following oxaliplatin administration is triphasic, characterized by two relatively short distribution phases (t½α; 0.43 hours and t½β; 16.8 hours) and a long terminal elimination phase (t½γ; 391 hours). Pharmacokinetic parameters obtained after a single 2-hour intravenous infusion of Oxaliplatin Zentiva at a dose of 85 mg/m² expressed as ultrafilterable platinum were C max of 0.814 mcg /mL and volume of distribution of 440 L.

Interpatient and intrapatient variability in ultrafilterable platinum exposure (AUC0-48hr ) assessed over 3 cycles was moderate to low (23% and 6%, respectively). A pharmacodynamic relationship between platinum ultrafiltrate levels and clinical safety and effectiveness has not been established.

At the end of a 2-hour infusion of Oxaliplatin Zentiva, approximately 15% of the administered platinum is present in the systemic circulation. The remaining 85% is rapidly distributed into tissues or eliminated in the urine. In patients, plasma protein binding of platinum is irreversible and is greater than 90%. The main binding proteins are albumin and gamma-globulins. Platinum also binds irreversibly and accumulates (approximately 2-fold) in erythrocytes, where it appears to have no relevant activity. No platinum accumulation was observed in plasma ultrafiltrate following 85 mg/m² every two weeks.

Oxaliplatin undergoes rapid and extensive nonenzymatic biotransformation. There is no evidence of cytochrome P450-mediated metabolism in vitro.

Up to 17 platinum-containing derivatives have been observed in plasma ultrafiltrate samples from patients, including several cytotoxic species (monochloro DACH platinum, dichloro DACH platinum, and monoaquo and diaquo DACH platinum) and a number of noncytotoxic, conjugated species.

The major route of platinum elimination is renal excretion. At five days after a single 2-hour infusion of Oxaliplatin Zentiva, urinary elimination accounted for about 54% of the platinum eliminated, with fecal excretion accounting for only about 2%. Platinum was cleared from plasma at a rate (10 – 17 L/h) that was similar to or exceeded the average human glomerular filtration rate (GFR; 7.5 L/h). There was no significant effect of gender on the clearance of ultrafilterable platinum. The renal clearance of ultrafilterable platinum is significantly correlated with GFR.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Renal impairment

Patients with mild to moderate renal impairment should be closely monitored for adverse reactions and the dose adjusted according to toxicity.

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 Zentiva is contra-indicated. Cross reactions, sometimes fatal, have been reported with all platinum compounds.

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

Neurological symptoms

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

For patients who develop acute laryngopharyngeal dysaesthesia , during or within the hours following the 2-hour infusion, the next Oxaliplatin Zentiva infusion should be administered over 6 hours.

Peripheral neuropathy

If neurological symptoms (paraesthesia, dysaesthesia) occur, the following recommended Oxaliplatin Zentiva 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 Zentiva 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 Zentiva 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 Zentiva should be discontinued

- if these symptoms improve following discontinuation of Oxaliplatin Zentiva 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 Zentiva 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. 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.

Dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis and renal impairment may be caused by severe diarrhoea/emesis particularly when combining Oxaliplatin Zentiva with 5-fluorouracil.

Cases of intestinal ischemia, including fatal outcomes, have been reported with Oxaliplatin Zentiva treatment. In case of intestinal ischemia, Oxaliplatin Zentiva treatment should be discontinued and appropriate measures initiated.

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. 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 Zentiva including fatal outcomes. If any of these events occurs, Oxaliplatin Zentiva should be discontinued.

Patients must be adequately informed of the risk of diarrhoea/emesis, mucositis/ stomatitis and neutropenia after Oxaliplatin Zentiva and 5-fluorouracil administration so that they can urgently contact their treating physician for appropriate management.

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

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

If grade 4 diarrhoea, grade 3-4 neutropenia (neutrophils <1.0x109/l), febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection with an absolute neutrophil count < 1.0 x 109/L, temperature > 38.3°C or a sustained temperature > 38°C for more than one hour), or grade 3-4 thrombocytopenia (platelets < 50x109/l) occur, the dose of Oxaliplatin Zentiva 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 Zentiva should be discontinued until further pulmonary investigations exclude an interstitial lung disease.

Blood disorders

Haemolytic-uraemic syndrome (HUS) is a life-threatening side effect (frequency not known). Oxaliplatin Zentiva 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 Zentiva treatment. If DIC is present, Oxaliplatin Zentiva treatment should be discontinued and appropriate treatment should be administered.

QT prolongation

QT prolongation may lead to an increased risk for ventricular arrhythmias including Torsade de Pointes, which can be fatal. The QT interval should be closely monitored on a regular basis before and after administration of Oxaliplatin Zentiva. 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 Zentiva treatment should be discontinued.

Rhabdomyolysis

Rhabdomyolysis has been reported in patients treated with Oxaliplatin Zentiva, including fatal outcomes. In case of muscle pain and swelling, in combination with weakness, fever or darkened urine, Oxaliplatin Zentiva 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 Zentiva.

Gastrointestinal ulcer/ Gastrointestinal ulcer haemorrhage and perforation

Oxaliplatin Zentiva treatment can cause gastrointestinal ulcer and potential complications, such as gastrointestinal haemorrhage and perforation, which can be fatal. In case of gastrointestinal ulcer, Oxaliplatin Zentiva treatment should be discontinued and appropriate measures taken.

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

Fertility

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

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

Immunosuppressant effects/increased susceptibility to infections:

Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including Oxaliplatin Zentiva, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving Oxaliplatin Zentiva. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Included as part of the PRECAUTIONS section.

See BOXED WARNING

Grade 3/4 hypersensitivity, including anaphylactic/anaphylactoid reactions, to Oxaliplatin Zentiva has been observed in 2-3% of colon cancer patients. These allergic reactions which can be fatal, can occur within minutes of administration and at any cycle, and were similar in nature and severity to those reported with other platinum-containing compounds, such as rash, urticaria, erythema, pruritus, and, rarely, bronchospasm and hypotension. The symptoms associated with hypersensitivity reactions reported in the previously untreated patients were urticaria, pruritus, flushing of the face, diarrhea associated with oxaliplatin infusion, shortness of breath, bronchospasm, diaphoresis, chest pains, hypotension, disorientation and syncope. These reactions are usually managed with standard epinephrine, corticosteroid, antihistamine therapy, and require discontinuation of therapy. Rechallenge is contraindicated in these patients. Drug-related deaths associated with platinum compounds from anaphylaxis have been reported.

Oxaliplatin Zentiva is associated with two types of neuropathy:

An acute, reversible, primarily peripheral, sensory neuropathy that is of early onset, occurring within hours or one to two days of dosing, that resolves within 14 days, and that frequently recurs with further dosing. The symptoms may be precipitated or exacerbated by exposure to cold temperature or cold objects and they usually present as transient paresthesia, dysesthesia and hypoesthesia in the hands, feet, perioral area, or throat. Jaw spasm, abnormal tongue sensation, dysarthria, eye pain, and a feeling of chest pressure have also been observed. The acute, reversible pattern of sensory neuropathy was observed in about 56% of study patients who received Oxaliplatin Zentiva with 5-fluorouracil/leucovorin. In any individual cycle acute neurotoxicity was observed in approximately 30% of patients. In adjuvant patients the median cycle of onset for grade 3 peripheral sensory neuropathy was 9 in the previously treated patients the median number of cycles administered on the Oxaliplatin Zentiva with 5-fluorouracil/leucovorin combination arm was 6.

An acute syndrome of pharyngolaryngeal dysesthesia seen in 1-2% (grade 3/4) of patients previously untreated for advanced colorectal cancer, and the previously treated patients, is characterized by subjective sensations of dysphagia or dyspnea, without any laryngospasm or bronchospasm (no stridor or wheezing). Ice (mucositis prophylaxis) should be avoided during the infusion of Oxaliplatin Zentiva because cold temperature can exacerbate acute neurological symptoms.

A persistent ( > 14 days), primarily peripheral, sensory neuropathy that is usually characterized by paresthesias, dysesthesias, hypoesthesias, but may also include deficits in proprioception that can interfere with daily activities (e.g., writing, buttoning, swallowing, and difficulty walking from impaired proprioception). These forms of neuropathy occurred in 48% of the study patients receiving Oxaliplatin Zentiva with 5-fluorouracil/leucovorin. Persistent neuropathy can occur without any prior acute neuropathy event. The majority of the patients (80%) who developed grade 3 persistent neuropathy progressed from prior Grade 1 or 2 events. These symptoms may improve in some patients upon discontinuation of Oxaliplatin Zentiva.

In the adjuvant colon cancer trial, neuropathy was graded using a prelisted module derived from the Neuro-Sensory section of the National Cancer Institute Common Toxicity Criteria (NCI CTC) scale, Version 1, as follows:

Table 1: NCI CTC Grading for Neuropathy in Adjuvant Patients

Peripheral sensory neuropathy was reported in adjuvant patients treated with the Oxaliplatin Zentiva combination with a frequency of 92% (all grades) and 13% (grade 3). At the 28-day follow-up after the last treatment cycle, 60% of all patients had any grade (Grade 1=40%, Grade 2=16%, Grade 3=5%) peripheral sensory neuropathy decreasing to 39% at 6 months follow-up (Grade 1=31%, Grade 2=7%, Grade 3=1%) and 21% at 18 months of follow-up (Grade 1=17%, Grade 2=3%, Grade 3=1%).

In the advanced colorectal cancer studies, neuropathy was graded using a study-specific neurotoxicity scale, which was different from the NCI CTC scale, Version 2.0 (see below).

Table 2: Grading Scale for Paresthesias/Dysesthesias in Advanced Colorectal Cancer Patients

Overall, neuropathy was reported in patients previously untreated for advanced colorectal cancer in 82% (all grades) and 19% (grade 3/4), and in the previously treated patients in 74% (all grades) and 7% (grade 3/4) events. Information regarding reversibility of neuropathy was not available from the trial for patients who had not been previously treated for colorectal cancer.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES, Posterior Reversible Encephalopathy Syndrome) has been observed in clinical trials ( < 0.1%) and postmarketing experience. Signs and symptoms of RPLS could be headache, altered mental functioning, seizures, abnormal vision from blurriness to blindness, associated or not with hypertension. Diagnosis of RPLS is based upon confirmation by brain imaging.

Grade 3 or 4 neutropenia occurred in 41-44% of patients with colorectal cancer treated with Oxaliplatin Zentiva in combination with 5-flurouracil (5-FU) and leucovorin compared to 5% with 5-FU plus leucovorin alone. Sepsis, neutropenic sepsis and septic shock have been reported in patients treated with Oxaliplatin Zentiva, including fatal outcomes.

Delay Oxaliplatin Zentiva until neutrophils are ≥ 1.5 x 109/L. Withhold Oxaliplatin Zentiva for sepsis or septic shock. Dose reduce Oxaliplatin Zentiva after recovery from Grade 4 neutropenia or febrile neutropenia.

Oxaliplatin Zentiva has been associated with pulmonary fibrosis ( < 1% of study patients), which may be fatal. The combined incidence of cough and dyspnea was 7.4% (any grade) and < 1% (grade 3) with no grade 4 events in the Oxaliplatin Zentiva plus infusional 5-fluorouracil/leucovorin arm compared to 4.5% (any grade) and no grade 3 and 0.1% grade 4 events in the infusional 5fluorouracil/leucovorin alone arm in adjuvant colon cancer patients. In this study, one patient died from eosinophilic pneumonia in the Oxaliplatin Zentiva combination arm. The combined incidence of cough, dyspnea and hypoxia was 43% (any grade) and 7% (grade 3 and 4) in the Oxaliplatin Zentiva plus 5-fluorouracil/leucovorin arm compared to 32% (any grade) and 5% (grade 3 and 4) in the irinotecan plus 5-fluorouracil/leucovorin arm of unknown duration for patients with previously untreated colorectal cancer. In case of unexplained respiratory symptoms such as non-productive cough, dyspnea, crackles, or radiological pulmonary infiltrates, Oxaliplatin Zentiva should be discontinued until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.

Hepatotoxicity as evidenced in the adjuvant study, by increase in transaminases (57% vs. 34%) and alkaline phosphatase (42% vs. 20%) was observed more commonly in the Oxaliplatin Zentiva combination arm than in the control arm. The incidence of increased bilirubin was similar on both arms. Changes noted on liver biopsies include: peliosis, nodular regenerative hyperplasia or sinusoidal alterations, perisinusoidal fibrosis, and veno-occlusive lesions. Hepatic vascular disorders should be considered, and if appropriate, should be investigated in case of abnormal liver function test results or portal hypertension, which cannot be explained by liver metastases.

QT prolongation and ventricular arrhythmias including fatal Torsade de Pointes have been reported in postmarketing experiences following Oxaliplatin Zentiva administration. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating Oxaliplatin Zentiva and monitor these electrolytes periodically during therapy. Avoid Oxaliplatin Zentiva in patients with congenital long QT syndrome.

Rhabdomyolysis, including fatal cases, has been reported in patients treated with Oxaliplatin Zentiva. Discontinue Oxaliplatin Zentiva if any signs or symptoms of rhabdomyolysis occur..

Oxaliplatin Zentiva may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Oxaliplatin Zentiva in pregnant women. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Oxaliplatin Zentiva..

Standard monitoring of the white blood cell count with differential, hemoglobin, platelet count, and blood chemistries (including ALT, AST, bilirubin and creatinine) is recommended before each Oxaliplatin Zentiva cycle.

There have been reports while on study and from post-marketing surveillance of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received Oxaliplatin Zentiva plus 5-fluorouracil/leucovorin while on anticoagulants. Patients receiving Oxaliplatin Zentiva plus 5-fluorouracil/leucovorin and requiring oral anticoagulants may require closer monitoring.

Advise patients:

• To expect side effects of Oxaliplatin Zentiva, particularly its neurologic effects, both the acute, reversible effects and the persistent neurosensory toxicity. Patients should be informed that the acute neurosensory toxicity may be precipitated or exacerbated by exposure to cold or cold objects.
• To avoid cold drinks, use of ice, and should cover exposed skin prior to exposure to cold temperature or cold objects.
• Of the risk of low blood cell counts and to contact their physician immediately should fever, particularly if associated with persistent diarrhea, or evidence of infection develop.
• To contact their physician if persistent vomiting, diarrhea, signs of dehydration, cough or breathing difficulties occur, or signs of allergic reaction appear.
• To exercise caution when driving and using machines. No studies on the effects of the ability to operate cars and 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.
• Of the potential effects of vision abnormalities, in particular transient vision loss (reversible following therapy discontinuation), which may affect patients' ability to drive and use machines.

Long-term animal studies have not been performed to evaluate the carcinogenic potential of oxaliplatin. Oxaliplatin was not mutagenic to bacteria (Ames test) but was mutagenic to mammalian cells in vitro (L5178Y mouse lymphoma assay). Oxaliplatin was clastogenic both in vitro (chromosome aberration in human lymphocytes) and in vivo (mouse bone marrow micronucleus assay).

In a fertility study, male rats were given oxaliplatin at 0, 0.5, 1, or 2 mg/kg/day for five days every 21 days for a total of three cycles prior to mating with females that received two cycles of oxaliplatin on the same schedule. A dose of 2 mg/kg/day (less than one-seventh the recommended human dose on a body surface area basis) did not affect pregnancy rate, but caused developmental mortality (increased early resorptions, decreased live fetuses, decreased live births) and delayed growth (decreased fetal weight).

Testicular damage, characterized by degeneration, hypoplasia, and atrophy, was observed in dogs administered oxaliplatin at 0.75 mg/kg/day x 5 days every 28 days for three cycles. A no effect level was not identified. This daily dose is approximately one-sixth of the recommended human dose on a body surface area basis.

Based on direct interaction with DNA, Oxaliplatin Zentiva may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Oxaliplatin Zentiva in pregnant women. Reproductive toxicity studies in rats demonstrated adverse effects on fertility and embryo-fetal development at maternal doses that were below the recommended human dose based on body surface area. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant and use effective contraception while receiving treatment with Oxaliplatin Zentiva.

Pregnant rats were administered oxaliplatin at less than one-tenth the recommended human dose based on body surface area during gestation days 1-5 (pre-implantation), 6-10, or 11-16 (during organogenesis). Oxaliplatin caused developmental mortality (increased early resorptions) when administered on days 6-10 and 11-16 and adversely affected fetal growth (decreased fetal weight, delayed ossification) when administered on days 6-10. Administration of oxaliplatin to male and female rats prior to mating resulted in 97% post-implantation loss in animals that received approximately one-seventh the recommended human dose based on the body surface area.

It is not known whether Oxaliplatin Zentiva or its derivatives are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Oxaliplatin Zentiva, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

The effectiveness of oxaliplatin in children has not been established. Oxaliplatin has been tested in 2 Phase 1 and 2 Phase 2 trials in 235 patients ages 7 months to 22 years with solid tumors (see below) and no significant activity observed.

In a Phase 1/2 study, oxaliplatin was administered as a 2-hour intravenous infusion on Days 1, 8 and 15 every 4 weeks (1 cycle), for a maximum of 6 cycles, to 43 patients with refractory or relapsed malignant solid tumors, mainly neuroblastoma and osteosarcoma. Twenty eight pediatric patients in the Phase 1 study received oxaliplatin at 6 dose levels starting at 40 mg/m² with escalation to 110 mg/m². The dose limiting toxicity (DLT) was sensory neuropathy at the 110 mg/m² dose. Fifteen patients received oxaliplatin at a dose of 90 mg/m² intravenous in the Phase 2 portion of the study. At this dose, paresthesia (60%, G3/4: 7%), fever (40%, G3/4: 7%) and thrombocytopenia (40%, G3/4: 27%) were the main adverse reactions. No responses were observed.

In a second Phase 1 study, oxaliplatin was administered to 26 pediatric patients as a 2-hour intravenous infusion on day 1 every 3 weeks (1 cycle) at 5 dose levels starting at 100 mg/m² with escalation to 160 mg/m², for a maximum of 6 cycles. In a separate cohort, oxaliplatin 85 mg/m² was administered on day 1 every 2 weeks, for a maximum of 9 doses. Patients had metastatic or unresectable solid tumors mainly neuroblastoma and ganglioneuroblastoma. No responses were observed. The DLT was sensory neuropathy at the 160 mg/m² dose. Based on these studies, oxaliplatin 130 mg/m² as a 2-hour intravenous infusion on day 1 every 3 weeks (1 cycle) was used in subsequent Phase II studies. A dose of 85 mg/m² on day 1 every 2 weeks was also found to be tolerable.

In one Phase 2 study, 43 pediatric patients with recurrent or refractory embryonal CNS tumors received oxaliplatin 130 mg/m² every 3 weeks for a maximum of 12 months in absence of progressive disease or unacceptable toxicity. In patients < 10 kg the oxaliplatin dose used was 4.3 mg/kg. The most common adverse reactions reported were leukopenia (67%, G3/4: 12%), anemia (65%, G3/4: 5%), thrombocytopenia (65%, G3/4: 26%), vomiting (65%, G3/4: 7%), neutropenia (58%, G3/4: 16%) and sensory neuropathy (40%, G3/4: 5%). One partial response was observed.

In a second Phase 2 study, 123 pediatric patients with recurrent solid tumors, including neuroblastoma, osteosarcoma, Ewing sarcoma or peripheral PNET, ependymoma, rhabdomyosarcoma, hepatoblastoma, high grade astrocytoma, Brain stem glioma, low grade astrocytoma, malignant germ cell tumor and other tumors of interest received oxaliplatin 130 mg/m² every 3 weeks for a maximum of 12 months or 17 cycles. In patients < 12 months old the oxaliplatin dose used was 4.3 mg/kg. The most common adverse reactions reported were sensory neuropathy (52%, G3/4: 12%), thrombocytopenia (37%, G3/4: 17%), anemia (37%, G3/4: 9%), vomiting (26%, G3/4: 4%), ALT increased (24%, G3/4: 6%), AST increased (24%, G3/4: 2%), and nausea (23%, G3/4: 3%). Two partial responses were observed.

The pharmacokinetic parameters of ultrafiltrable platinum have been evaluated in 105 pediatric patients during the first cycle. The mean clearance in pediatric patients estimated by the population pharmacokinetic analysis was 4.7 L/h. The inter-patient variability of platinum clearance in pediatric cancer patients was 41%. Mean platinum pharmacokinetic parameters in ultrafiltrate were Cmax of 0.75 ± 0.24 mcg/mL, AUC0-48 of 7.52 ± 5.07 mcg•h/mL and AUCinf of 8.83 ± 1.57 mcg•h/mL at 85 mg/m² of oxaliplatin and Cmax of 1.10 ± 0.43 mcg/mL, AUC 0-48 of 9.74 ± 2.52 mcg•h/mL and AUCinf of 17.3 ± 5.34 mcg•h/mL at 130 mg/m² of oxaliplatin.

No significant effect of age on the clearance of ultrafilterable platinum has been observed.

In the adjuvant therapy colon cancer randomized clinical trial, 723 patients treated with Oxaliplatin Zentiva and infusional 5-fluorouracil/leucovorin were < 65 years and 400 patients were ≥ 65 years.

A descriptive subgroup analysis demonstrated that the improvement in DFS for the Oxaliplatin Zentiva combination arm compared to the infusional 5-fluorouracil/leucovorin alone arm appeared to be maintained across genders. The effect of Oxaliplatin Zentiva in patients ≥ 65 years of age was not conclusive. Insufficient subgroup sizes prevented analysis by race. Patients ≥ 65 years of age receiving the Oxaliplatin Zentiva combination therapy experienced more grade 3-4 granulocytopenia than patients < 65 years of age (45% versus 39%).

In the previously untreated for advanced colorectal cancer randomized clinical trial of Oxaliplatin Zentiva, 160 patients treated with Oxaliplatin Zentiva and 5-fluorouracil/leucovorin were < 65 years and 99 patients were ≥ 65 years. The same efficacy improvements in response rate, time to tumor progression, and overall survival were observed in the ≥ 65 year old patients as in the overall study population. In the previously treated for advanced colorectal cancer randomized clinical trial of Oxaliplatin Zentiva, 95 patients treated with Oxaliplatin Zentiva and 5-fluorouracil/leucovorin were < 65 years and 55 patients were ≥ 65 years. The rates of overall adverse reactions, including grade 3 and 4 events, were similar across and within arms in the different age groups in all studies. The incidence of diarrhea, dehydration, hypokalemia, leukopenia, fatigue and syncope were higher in patients ≥ 65 years old. No adjustment to starting dose was required in patients ≥ 65 years old.

The exposure (AUC) of unbound platinum in plasma ultrafiltrate tends to increase in renally impaired patients. Caution and close monitoring should be exercised when Oxaliplatin Zentiva is administered to patients with renal impairment. The starting Oxaliplatin Zentiva dose does not need to be reduced in patients with mild (creatinine clearance=50-80 mL/min) or moderate (creatinine clearance=30-49 mL/min) renal impairment. However, the starting dose of Oxaliplatin Zentiva should be reduced in patients with severe renal impairment (creatinine clearance < 30 mL/min).

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 Zentiva 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.

Dosage (Posology) and method of administration

Posology

FOR ADULTS ONLY

The recommended dose for Oxaliplatin Zentiva in adjuvant setting is 85 mg/m² intravenously repeated every two weeks for 12 cycles (6 months).

The recommended dose for Oxaliplatin Zentiva in treatment of metastatic colorectal cancer is 85 mg/m² intravenously repeated every 2 weeks until disease progression or unacceptable toxicity.

Dosage given should be adjusted according to tolerability.

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

Oxaliplatin Zentiva is administered as a 2- to 6-hour intravenous infusion in 250 to 500 ml of 5% glucose solution to give a concentration between 0.2 mg/ml and 0.70 mg/ml; 0.70 mg/ml is the highest concentration in clinical practice for an Oxaliplatin Zentiva dose of 85 mg/m².

Oxaliplatin Zentiva was mainly used in combination with continuous infusion 5-fluorouracil based regimens. For the two-weekly treatment schedule 5-fluorouracil regimens combining bolus and continuous infusion were used.

Special Populations

Renal impairment:

Oxaliplatin Zentiva must not be administered in patients with severe renal impairment. In patients with mild to moderate renal impairment, the recommended dose of Oxaliplatin Zentiva is 85 mg/m².

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 patients:

No increase in severe toxicities was observed when Oxaliplatin Zentiva 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 use of Oxaliplatin Zentiva in children. The effectiveness of Oxaliplatin Zentiva single agent in the paediatric populations with solid tumours has not been established.

Method of administration

Oxaliplatin Zentiva is administered by intravenous infusion.

The administration of Oxaliplatin Zentiva does not require hyperhydration.

Oxaliplatin Zentiva 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 Zentiva infusion must always precede the administration of 5-fluorouracil.

Instruction for use

Oxaliplatin Zentiva must be diluted before use. Only 5% glucose diluent is to be used to dilute the concentrate for solution for infusion product..

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

Oxaliplatin Zentiva (oxaliplatin injection) should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.

Administer Oxaliplatin Zentiva in combination with 5-fluorouracil/leucovorin every 2 weeks. For advanced disease, treatment is recommended until disease progression or unacceptable toxicity. For adjuvant use, treatment is recommended for a total of 6 months (12 cycles):

Day 1: Oxaliplatin Zentiva 85 mg/m² intravenous infusion in 250-500 mL 5% Dextrose injection, USP and leucovorin 200 mg/m² intravenous infusion in 5% Dextrose Injection, USP both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5-fluorouracil 400 mg/m² intravenous bolus given over 2-4 minutes, followed by 5-fluorouracil 600 mg/m² intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.

Day 2: Leucovorin 200 mg/m² intravenous infusion over 120 minutes, followed by 5-fluorouracil 400 mg/m² intravenous bolus given over 2-4 minutes, followed by 5-fluorouracil 600 mg/m² intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.

Figure 1

The administration of Oxaliplatin Zentiva does not require prehydration. Premedication with antiemetics, including 5-HT3 blockers with or without dexamethasone, is recommended.

For information on 5-fluorouracil and leucovorin, see the respective package inserts.

Prior to subsequent therapy cycles, patients should be evaluated for clinical toxicities and recommended laboratory tests. Prolongation of infusion time for Oxaliplatin Zentiva from 2 hours to 6 hours may mitigate acute toxicities. The infusion times for 5-fluorouracil and leucovorin do not need to be changed.

Neuropathy and other toxicities were graded using the NCI CTC scale version 1.

For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of Oxaliplatin Zentiva to 75 mg/m² should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The infusional 5-fluorouracil/leucovorin regimen need not be altered.

A dose reduction of Oxaliplatin Zentiva to 75 mg/m² and infusional 5-fluorouracil to 300 mg/m² bolus and 500 mg/m² 22 hour infusion is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment), or grade 4 neutropenia, or febrile neutropenia, or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥ 1.5 x 109/L and platelets ≥ 75 x 109/L.

Neuropathy was graded using a study-specific neurotoxicity scale. Other toxicities were graded by the NCI CTC, Version 2.0.

For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of Oxaliplatin Zentiva to 65 mg/m² should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The 5-fluorouracil/leucovorin regimen need not be altered.

A dose reduction of Oxaliplatin Zentiva to 65 mg/m² and 5-fluorouracil by 20% (300 mg/m² bolus and 500 mg/m² 22-hour infusion) is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment), or grade 4 neutropenia, or febrile neutropenia, or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥ 1.5 x 109/L and platelets ≥ 75 x 109/L.

In patients with normal renal function or mild to moderate renal impairment, the recommended dose of Oxaliplatin Zentiva is 85 mg/m². In patients with severe renal impairment, the initial recommended Oxaliplatin Zentiva dose should be reduced to 65 mg/m².

Do not freeze and protect from light the concentrated solution.

A final dilution must never be performed with a sodium chloride solution or other chloride-containing solutions.

The solution must be further diluted in an infusion solution of 250-500 mL of 5% Dextrose Injection, USP.

After dilution with 250-500 mL of 5% Dextrose Injection, USP, the shelf life is 6 hours at room temperature [20-25°C (68-77°F)] or up to 24 hours under refrigeration [2-8°C (36-46°F)]. After final dilution, protection from light is not required.

Oxaliplatin Zentiva is incompatible in solution with alkaline medications or media (such as basic solutions of 5-fluorouracil) and must not be mixed with these or administered simultaneously through the same infusion line. The infusion line should be flushed with 5% Dextrose Injection, USP prior to administration of any concomitant medication.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration and discarded if present.

Needles or intravenous administration sets containing aluminum parts that may come in contact with Oxaliplatin Zentiva should not be used for the preparation or mixing of the drug. Aluminum has been reported to cause degradation of platinum compounds.

Special precautions for disposal and other handling

As with other potentially toxic compounds, caution should be exercised when handling and preparing Oxaliplatin Zentiva 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 medicines 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 medicines, 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 Zentiva concentrate or infusion solution, should come into contact with skin, wash immediately and thoroughly with water.

If Oxaliplatin Zentiva concentrate or infusion solution, 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, folinic acid 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 Zentiva.

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

Oxaliplatin Zentiva 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 % 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 % solution, never in alkaline solutions or sodium chloride or chloride containing solutions.

Instruction for use with 5 fluorouracil (5 FU)

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

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

For additional information on medicinal products combined with Oxaliplatin Zentiva, 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.

Instructions for dilution

Withdraw the required amount of concentrate from the vial(s) and then dilute with 250 ml to 500 ml of a 5% glucose solution to give an Oxaliplatin Zentiva concentration between not less than 0.2 mg/ml and 0.7 mg/ml. The concentration range for which the physico-chemical stability of Oxaliplatin Zentiva has been demonstrated is 0.2 mg/ml to 0.7 mg/ml.

Administer by intravenous infusion.

Chemical and physical in-use stability has been demonstrated for 24 hours at room temperature (15-25°C) or for 48 hours under refrigeration (2°C-8°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.

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.

NEVER use sodium chloride or chloride containing solutions for dilution.

The compatibility of Oxaliplatin Zentiva solution for infusion has been tested with representative, PVC based, administrative sets.

Infusion

The administration of Oxaliplatin Zentiva does not require prehydration.

Oxaliplatin Zentiva diluted in 250 to 500 ml of a 5% glucose 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 Zentiva is administered with 5-fluorouracil, the Oxaliplatin Zentiva infusion must precede the administration of 5-fluorouracil.

Disposal

Any unused medicinal product or waste material should be disposed of according to standard procedures applicable to cytotoxic agents in accordance with local requirements.