Eloxatin

Oxaliplatin.

Each vial contains: Oxaliplatin 5 mg.
Excipient/Inactive Ingredient: Water for injections.

Pharmacotherapeutic group: other antineoplastic agents, platinum compounds. ATC code: L01XA03.
Pharmacology: Pharmacodynamics: Oxaliplatin is an antineoplastic agent belonging to a new class of platinum compounds in which the platinum atom is complexed with 1,2-diaminocyclohexane ("DACH") and an oxalate group. Oxaliplatin is a single enantiomer, (SP-4-2)-[(1R,2R)-cyclohexane-1,2-diamine-kN, kN'] [ethanediato(2-)-kO¹, kO²] platinum.
Oxaliplatin exhibits a wide spectrum of both in vitro cytotoxicity and in vivo antitumor activity in various tumor model systems, including human colorectal cancer models.
Oxaliplatin has also shown in vitro and in vivo efficacy in various cisplatin-resistant cell lines. Synergistic cytotoxic activity with 5-fluorouracil (5-FU) has been demonstrated both in vitro and in vivo.
Studies on the mechanism of action, which has however not been completely elucidated, have shown that the aqua derivatives resulting from the biotransformation of oxaliplatin interact with DNA to form both intra- and inter-strand cross-links, resulting in interruption of DNA synthesis, which underlies the cytotoxic and antitumor effects.
In patients with metastatic colorectal cancer, the efficacy of oxaliplatin (85 mg/m² repeated every two weeks) in combination with 5-fluorouracil/folinic acid (5-FU/folinic acid) (5-FU/FA) has been reported in three clinical studies: as 1st-line treatment, in a 2-arm, comparative, phase III study (EFC2962), 420 patients were randomized either to 5-FU/FA alone (LV5FU2, N=210) or to oxaliplatin+5-FU/FA (FOLFOX4, N=210); in pretreated patients, in a 3-arm, comparative, phase III study (EFC4584), 821 patients, refractory to the irinotecan (CPT-11) + 5-FU/FA combination, were randomized to 5-FU/FA alone (LV5FU2, N=275), to single-agent oxaliplatin (N=275), or to oxaliplatin+5-FU/FA (FOLFOX4, N=271); finally, in a non-controlled phase II study (EFC2964), patients refractory to 5-FU/FA alone were treated with the oxaliplatin+5-FU/FA combination (FOLFOX4, N=57). (See Table 1, Table 2 and Table 3.)

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In pretreated patients who were symptomatic at baseline (EFC4584), a higher proportion of those treated with oxaliplatin + 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 in terms of quality of life.
However, the quality of life scores were generally better in the control group for overall performance status and pain, and less favorable in the oxaliplatin group for nausea/vomiting.
Concerning adjuvant treatment, the comparative, phase III MOSAIC study (EFC3313), included 2,246 patients (899 stage II/Dukes' B2 and 1,347 stage III/Dukes' C). After complete resection of the primary colon cancer tumor patients were randomized either to 5-FU/FA alone (LV5FU2, N=1,123 [B2/C = 448/675]) or to the combination of oxaliplatin + 5-FU/FA (FOLFOX4, N=1,123 [B2/C = 451/672]). (See Table 4.)

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The study demonstrated an overall significant superiority in 3-year disease-free survival for the oxaliplatin plus 5-FU/FA combination (FOLFOX4) compared to 5-FU/FA alone (LV5FU2). (See Table 5.)

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Overall Survival (ITT analysis): At the time of the 3-year disease-free survival analysis, which was the primary endpoint of the MOSAIC study, 85.1% of the patients were still alive in the FOLFOX4 arm versus 83.8% in the LV5FU2 arm. This showed an overall reduction in mortality risk of 10% in favor of FOLFOX4, without reaching statistical significance (hazard ratio = 0.90).
Results were 92.2% versus 92.4% in the stage II (Dukes' B2) sub-group (hazard ratio = 1.01) and 80.4% versus 78.1% in the stage III (Dukes' C) sub-group (hazard ratio = 0.87), for FOLFOX4 and LV5FU2, respectively.
Oxaliplatin as single-agent therapy was studied in children in 2 phase I studies (69 patients) and in 2 phase II studies (166 patients). A total of 235 pediatric patients (age range: 7 months to 22 years) with solid tumors were treated.
The efficacy of oxaliplatin administered alone was not established in the treated population. Enrollment in these two phase II studies was stopped due to lack of tumor response.
Pharmacokinetics: The pharmacokinetics of the various active metabolites have not been determined. The table as follows indicates the pharmacokinetic parameters of ultrafiltered platinum, i.e. all the unbound, active and inactive forms of platinum, following a two-hour infusion of oxaliplatin 130 mg/m² every three weeks for 1 to 5 cycles, and of oxaliplatin 85 mg/m² every two weeks for 1 to 3 cycles: See Table 6.

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Following a 2-hour infusion, 15% of administered platinum is found in the systemic circulation, the remaining 85% having been rapidly distributed into tissues or excreted in 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 of platinum was observed in plasma ultrafiltrate following an 85 mg/m² infusion every 2 weeks or a 130 mg/m² infusion every 3 weeks, and steady state was reached in cycle 1 in this matrix. Inter- and intra-individual variability was generally low.
In vitro, metabolites result from non-enzymatic degradation and there is no evidence of cytochrome P450-mediated biotransformation of the diaminocyclohexane (DACH) ring.
Oxaliplatin is highly metabolized in humans; no parent drug was detectable in plasma ultrafiltrate following a 2-hour infusion. Several cytotoxic metabolites including the monochloro-, dichloro- and diaquo-DACH platinum forms have been identified in the systemic circulation, as have a number of inactive metabolites at later timepoints.
Platinum is primarily excreted in the urine, with clearance mainly occurring in the 48 hours following administration.
At Day 5, approximately 54% of the dose is recovered in the urine and less than 3% in the feces.
A significant decrease in clearance from 17.6 ± 2.18 l/h to 9.95 ± 1.91 l/h has been observed in patients with renal failure together with a statistically significant decrease in volume of distribution from 330 ± 40.9 to 241 ± 36.1 l. The effect of severe renal failure on platinum clearance has not been studied.
The effect of renal failure on the bioavailability of oxaliplatin has been studied in patients with varying degrees of renal impairment. Oxaliplatin was administered at a dose of 85 mg/m² in the control group with normal renal function (creatinine clearance >80 ml/min, n = 12) and in patients with mild renal failure (creatinine clearance = 50 to 80 ml/min, n = 13) and moderate renal failure (creatinine clearance = 30 to 49 ml/min, n = 11) and at a dose of 65 mg/m² in patients with severe renal failure (creatinine clearance <30 ml/min, n = 5).
Median exposure was 9, 4, 6, and 3 cycles, respectively, and pharmacokinetic data at cycle 1 were obtained in groups of 11, 13, 10 and 4 patients, respectively.
There was an increase in plasma ultrafiltrate (PUF) platinum AUC, AUC/dose and a decrease in CL and total and renal Vss with increased renal impairment, particularly in the (small) group of patients with severe renal failure: point estimates (90% CI) of estimated mean ratios by renal function 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 to moderate renal failure and severe renal impairment, respectively.
Elimination of oxaliplatin is significantly correlated with 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 impairment. Total body clearance of PUF platinum was therefore reduced by 26% in patients with mild failure, 57% in patients with moderate renal failure, and 79% in patients with severe renal failure, compared with patients with normal function.
Renal clearance of PUF platinum was reduced by 30% in patients with mild renal failure, 65% in moderate renal failure, and 84% in severe renal failure, compared with patients with normal function.
There was an increase in the beta-half-life of PUF platinum with increased renal failure, mainly in the severe renal failure group. Despite the small number of patients with severe renal failure, these data should be taken into account when prescribing oxaliplatin to patients with renal failure (see Dosage & Administration, Contraindications and Precautions).
Toxicology: Preclinical safety data: The target organs identified in the species used in preclinical studies (mice, rats, dogs and/or monkeys) in single-dose and repeated-dose studies included bone marrow, the gastrointestinal system, the kidney, the testes, the nervous system and the heart. The toxicities in the target organs observed in animals are similar to those observed with other platinum-based agents and other cytotoxic drugs, which interact with DNA, used in the treatment of cancer in humans, with the exception of those on the heart. Effects on the heart were only observed in the dog and included electrophysiological abnormalities with lethal ventricular fibrillation. Cardiotoxicity is considered to be specific to dogs, not only because it was only observed in this species, but also because doses similar to lethal doses in the dog (150 mg/m²) were well tolerated in humans. Preclinical studies using rat sensory neurons suggested that the oxaliplatin-induced acute neurosensory symptoms may be related to an interaction with voltage-gated Na+ channels.
Oxaliplatin is mutagenic and clastogenic in mammalian cells and has demonstrated embryo-fetal toxicity in rats. Although no studies have been performed concerning its carcinogenic potential, oxaliplatin is considered to be probably carcinogenic.

Oxaliplatin, in combination with 5-fluorouracil (5-FU) and folinic acid (FA), is indicated for: adjuvant treatment of stage III (Dukes' C) colon cancer after complete resection of the primary tumor; treatment of metastatic colorectal cancer; treatment of locally advanced and metastatic hepatocellular carcinoma (HCC) patients who are not applicable for resection or local treatment.

The preparation of cytotoxic solutions for injection must always be carried out by trained specialist personnel with knowledge of the medicines used, under conditions ensuring drug integrity, the protection of the environment and in particular protection of the personnel handling the medicines, according to hospital practice. It requires a preparation area reserved for this purpose. It is forbidden to smoke, eat or drink in this area (see Special precautions for disposal and other handling under Cautions for Usage).
Dosage: For use in adults only.
The recommended dose of oxaliplatin as adjuvant treatment is 85 mg/m² intravenously, repeated every 2 weeks for 12 cycles (6 months).
The recommended dose of oxaliplatin as treatment of metastatic colorectal cancer is 85 mg/m² intravenously, repeated every 2 weeks until disease progression or unacceptable toxicity.
The dose should be adjusted depending on tolerability (see Precautions).
Oxaliplatin should always be administered before fluoropyrimidines, i.e. before 5-fluorouracil (5-FU) Oxaliplatin is administered as a 2- to 6-hour intravenous infusion in 250 to 500 ml of 5% glucose solution (50 mg/ml) in order to obtain a concentration of between 0.2 mg/ml and 0.7 mg/ml; 0.7 mg/ml is equivalent to the highest concentration observed in clinical practice for an 85 mg/m² dose of oxaliplatin.
Oxaliplatin has mostly been administered in combination with continuous infusion of 5-fluorouracil (5-FU). For the two-weekly treatment schedule, a 5-fluorouracil regimen with bolus and continuous infusion has been used.
Populations at risk: Patients with renal failure: Oxaliplatin must not be administered to patients with severe renal failure (see Contraindications and Pharmacology: Pharmacokinetic under Actions).
In patients with mild to moderate renal impairment, the recommended dose of oxaliplatin is 85 mg/m² (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Patients with hepatic impairment: In a phase I study including patients with varying degrees of hepatic impairment, the frequency and severity of hepatobiliary disorders appeared to be related to progression of the disease and to initial liver function abnormalities.
During clinical development, no dose adjustment was performed for patients with impaired liver function.
Elderly subjects: No increase in severe toxicities was observed when the drug was used as a single agent or in combination with 5-fluorouracil (5-FU) in patients over the age of 65. Therefore, no dose adjustment is required for elderly patients.
Pediatric patients: Oxaliplatin is not indicated for use in children. The efficacy of oxaliplatin administered alone in children with solid tumors has not been established (see Pharmacology: Pharmacodynamics under Actions).
Method of administration: Oxaliplatin is administered by intravenous infusion.
The administration of oxaliplatin does not require hyperhydration.
Oxaliplatin diluted in 250-500 ml of 5% glucose solution (50 mg/ml) to obtain a concentration not less than 0.2 mg/ml, must be infused either via central venous line or into a peripheral vein over 2-6 hours. Oxaliplatin infusion must always be given before 5-fluorouracil (5-FU).
In the event of extravasation, administration must be discontinued immediately.
Instructions for use: Oxaliplatin must be diluted before use. Only a 5% glucose solution (50 mg/ml) should be used to dilute the concentrate for solution for infusion (see Special precautions for disposal and other handling under Cautions for Usage).

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

Oxaliplatin is contraindicated: in patients with a known history of hypersensitivity to oxaliplatin or to any of the excipients; during breast-feeding; in patients with myelosuppression before the first treatment cycle (neutrophils <2x10⁹/l and/or platelet count <100x10⁹/l); in patients with peripheral sensory neuropathy with functional impairment before the first treatment cycle; in patients with severe renal failure (creatinine clearance <30 ml/min) (see Pharmacology: Pharmacokinetics under Actions).

Oxaliplatin must only be used in departments specialized in administering cytotoxics and must be administered under the supervision of a physician qualified in the use of cancer chemotherapy agents.

Oxaliplatin (Eloxatin) should only be used in specialised department of oncology and administered under the supervision of an experienced oncologist.
Due to limited information on safety in patients with severely impaired renal function, administration should be considered after suitable appraisal of the benefit/risk for the patient. In this situation, renal function should be closely monitored and the recommended initial oxaliplatin dose is 65 mg/m².
Patients with a history of allergic reaction to platinum compounds should be monitored for allergic symptoms. Allergic reactions can occur during any cycle. In case of an anaphylactic-like reaction to Oxaliplatin (Eloxatin), the infusion should be immediately discontinued and appropriate symptomatic treatment initiated. Oxaliplatin (Eloxatin) rechallenge is contraindicated.
In case of Oxaliplatin (Eloxatin) extravasation, the infusion must be stopped immediately and usual local symptomatic treatment initiated.
Sensory peripheral neurotoxicity of Oxaliplatin (Eloxatin) 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.
If neurological symptoms (paraesthesia, dysaesthesia) occur, the following recommended Oxaliplatin (Eloxatin) dosage adjustment, based on the duration and severity of these symptoms, should be performed: if symptoms last longer than 7 days and are troublesome, or if paraesthesia without functional impairment persists until the next cycle, the subsequent Oxaliplatin (Eloxatin) dose should be reduced by 25%; if paraesthesia with functional impairment persists until the next cycle, Oxaliplatin (Eloxatin) administration should be discontinued; if these symptoms improve following discontinuation of Oxaliplatin (Eloxatin) therapy, resumption of therapy may be considered.
For patients who develop acute laryngo-pharyngeal dysaesthesia (see Overdosage), during or within the hours following the 2-hour infusion, the next Oxaliplatin (Eloxatin) infusion should be administered over 6 hours. To prevent such dysaesthesia, inform the patient to avoid exposure to cold and to avoid ingesting fresh/cold food or/and beverages during or within the hours following Oxaliplatin (Eloxatin) administration.
Signs and symptoms of Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES, Posterior Reversible Encephalopathy Syndrome) could be headache, altered mental functioning, seizures, abnormal vision from blurriness to blindness, associated or not with hypertension (see Adverse Reactions). Diagnosis of RPLS is based upon confirmation by brain imaging.
Gastrointestinal toxicity, which manifests as nausea and vomiting, warrants prophylactic and/or therapeutic anti-emetic therapy (see Overdosage). Dehydration, ileus, intestinal obstruction, hypokaliaemia, metabolic acidosis, and even renal disorders, may be associated with severe diarrhoea/emesis, particularly when combining Oxaliplatin (Eloxatin) with 5-FU.
Cases of intestinal ischaemia, including fatal outcomes, have been reported with Oxaliplatin (Eloxatin) treatment. In case of intestinal ischaemia, Oxaliplatin (Eloxatin) treatment should be discontinued and appropriate measures initiated. (See Adverse Reactions).
If haematological toxicity (evidenced by baseline blood count values, e.g. neutrophils <1.5 x 10⁹/L or platelets <75 x 10⁹/L) occurs after a course of therapy or if myelosupression is present prior to the start (1st course) of therapy, administration of the next or the first course of therapy should be postponed until the blood count returns to acceptable levels. A full blood count with white cell differential should be performed prior to the start of therapy and before each subsequent course.
Patients must be adequately informed of the risk of diarrhea/emesis and neutropenia after Oxaliplatin (Eloxatin)/5-FU administration in order to contact urgently their treating physician for appropriate management.
For Oxaliplatin (Eloxatin) combined with 5-FU (with or without folinic acid), the usual dose adjustments for 5-FU associated toxicities should apply.
If severe/life-threatening diarrhoea, severe neutropenia (neutrophils <1.0 x 10⁹/L), febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection with an absolute neutrophil count <1.0 x 10⁹/L, a single temperature of >38.3°C or a sustained temperature of >38°C for more than one hour), or severe thrombocytopenia (platelets <50 x 10⁹/L) occur, Oxaliplatin (Eloxatin) must be discontinued until improvement or resolution, and the dose of Oxaliplatin (Eloxatin) should be reduced by 25% at subsequent cycles, in addition to any 5-FU dose reductions required.
Sepsis, neutropenic sepsis and septic shock have been reported in patients treated with oxaliplatin, including fatal outcomes (see Adverse Reactions). If any of these events occurs, Oxaliplatin (Eloxatin) should be discontinued.
Disseminated intravascular coagulation (DIC), including fatal outcomes, has been reported in association with Oxaliplatin (Eloxatin) treatment. If DIC is present, Oxaliplatin (Eloxatin) treatment should be discontinued and appropriate treatment should be administered (see Adverse Reactions).
In case of unexplained respiratory symptoms such as non-productive cough, dyspnoea, crackles or radiological pulmonary infiltrates, Oxaliplatin (Eloxatin) should be discontinued until further pulmonary investigations exclude an interstitial lung disease (see Adverse Reactions).
Haemolytic-uraemic syndrome (HUS) is a life-threatening side effect (see Adverse Reactions). 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 be not reversible with discontinuation of therapy and dialysis may be required.
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.
For details on dosage adjustment for bevacizumab, see the corresponding prescribing information.
QT prolongation may lead to an increased risk for ventricular arrhythmias including Torsade de Pointes, which can be fatal (see Adverse Reactions). Caution should be exercised in patients with a history or a predisposition for prolongation of QT, those who are taking medicinal products known to prolong QT interval, and those with electrolyte disturbances such as hypokalemia, hypocalcaemia, or hypomagnesaemia. In case of QT prolongation, oxaliplatin treatment should be discontinued. (See Interactions and Adverse Reactions.)
Rhabdomyolysis has been reported in patients treated with Oxaliplatin (Eloxatin), including fatal outcomes. In case of muscle pain and swelling, in combination with weakness, fever or darkened urine, Oxaliplatin (Eloxatin) 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 (Eloxatin). (See Interactions and Adverse Reactions.)
Oxaliplatin (Eloxatin) treatment can cause duodenal ulcer (DU) and potential complications, such as duodenal ulcer haemorrhage and perforation, which can be fatal. In case of duodenal ulcer, Oxaliplatin (Eloxatin) treatment should be discontinued and appropriate measures taken. (See Adverse Reactions.)
Do not use Oxaliplatin (Eloxatin) intraperitoneally. Peritoneal hemorrhage may occur when Oxaliplatin (Eloxatin) is administered by intraperitoneal route (off-label route of administration).
Effects on ability to drive and use machines: Effects on the ability to drive and use machines have not been studied. However, since oxaliplatin treatment causes an increased risk of dizziness, nausea, vomiting and other neurological symptoms that affect gait and balance, treatment may have a minor or moderate impact on the ability to drive and use machines. Visual disturbances, in particular transient loss of sight (reversible upon treatment discontinuation) may affect the ability to drive and to use machines. Patients must therefore be warned of these possible effects on the ability to drive and use machines.
Use in Children: Oxaliplatin (Eloxatin) single agent has been evaluated in 2 Phase I (69 patients) and 2 Phase II (166 patients) studies. A total of 235 pediatric patients (7 months-22 years of age) with solid tumors have been treated.
In a Phase I/II study, Oxaliplatin (Eloxatin) was administered as a 2-hour IV infusion on days 1, 8 and 15 q4w (1 cycle), for a maximum of 6 cycles, to 43 patients with refractory or relapsed malignant solid tumors, mainly neuroblastoma and osteosarcoma. Twenty eight (28) pediatric patients were treated in the Phase I study at 6 dose levels starting at 40 mg/m² and up to 110 mg/m². The dose limiting toxicity (DLT) was peripheral sensory neuropathy observed in 2 patients out of 3 patients treated at the 110 mg/m². Thus, the recommended dose (RD) was established as 90 mg/m² IV administered on days 1, 8 and 15 q4w. Fifteen (15) patients were treated at the recommended dose of 90 mg/m² IV obtained from the Phase I study and paresthesia (60%, G3/4: 6.7%), fever (40%, G3/4: 6.7%) and thrombocytopenia (40%, G3/4: 26.7%) were the main adverse events observed.
In a second Phase I study, Oxaliplatin (Eloxatin). was administered to 26 pediatric patients as a 2-hour IV infusion on day 1 q3w (1 cycle) at 5 dose levels starting at 100 mg/m² and up to 160 mg/m², for a maximum of 6 cycles. At the last dose level, Oxaliplatin (Eloxatin) 85 mg/m² was administered on day 1 q2w, for a maximum of 9 doses. Patients had metastatic or unresectable solid tumors mainly neuroblastoma and ganglioneuroblastoma, for which standard treatment does not exist or is no longer effective. The DLT was peripheral sensory neuropathy observed in the 2 patients treated at 160 mg/m² of Oxaliplatin (Eloxatin). The RD was 130 mg/m² q3w. A dose of 85 mg/m² q2w was also found to be tolerable.
Based on these studies, Oxaliplatin (Eloxatin) 130 mg/m² as a 2-hour IV infusion on day 1 q3w (1 cycle) was further used in Phase II studies.
In one Phase II study, 43 pediatric patients were treated for recurrent or refractory embryonal CNS tumors for a maximum of 12 months in absence of progressive disease or unacceptable toxicity. In patients <10 kg the Oxaliplatin (Eloxatin) dose used was 4.3 mg/kg. The most common adverse events reported were leukopenia (67.4%, G3/4: 11.6%), anemia (65.1%, G3/4: 4.7%), thrombocytopenia (65.1%, G3/4: 25.6%), vomiting (65.1%, G3/4: 7.0%), neutropenia (58.1%, G3/4: 16.3%) and peripheral sensory neuropathy (39.5%, G3/4: 4.7%). One partial response (objective response rate: 2.3%) was observed.
In a second Phase II study, 123 pediatric patients were treated for recurrent solid tumors, Ewing sarcoma or peripheral PNET, osteosarcoma, rhabdomyosarcoma and neuroblastoma, for a maximum of 12 months or 17 cycles. In patients <12 months old the Oxaliplatin (Eloxatin) dose used was 4.3 mg/kg. The most common adverse events reported were peripheral sensory neuropathy (53.2%, G3/4: 14.9%), thrombocytopenia (40.4%, G3/4: 25.5%), anemia (40.4%, G3/4: 14.9%), vomiting (31.9%, G3/4: 0%), nausea (29.8%, G3/4: 2.1%) and AST increased (25.5%, G3/4: 4.3%). No 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 4.70 L/h. The inter-patient variability of platinum clearance in pediatric cancer patients was 40.9%. 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 (Eloxain) and Cmax of 1.10 + 0.43 mcg/mL, AUC0-48 of 9.74 + 2.52 mcg.h/mL and AUCinf of 17.30 + 5.34 mcg.h/mL at 130 mg/m² of Oxaliplatin (Eloxatin). Pharmacokinetic/pharmacodynamic analysis was performed on the 43 pediatric patients who were evaluable for pharmacokinetics in the phase II studies. The results did not suggest any relationship between AUC and safety parameters tested as gastrointestinal disorders, nervous system disorders, renal and urinary disorders or hematological disorders, for this pediatric patient population.
The effectiveness of Oxaliplatin (Eloxatin) single agent in the pediatric populations described previously has not been established. Accrual in both Phase II studies was stopped for lack of tumor response.

There is no information available to date on the safety of oxaliplatin in pregnant women. Reproduction toxicity has been observed in animal studies. Use of oxaliplatin is therefore inadvisable during pregnancy and in women of child-bearing age who are not using contraception.
Oxaliplatin administration must only be considered after informing the patient specifically of the risk to the fetus and with her consent.
Appropriate contraceptive measures must be used during treatment and continued after the end of treatment for 4 months in female patients, and for 6 months in male patients.
Excretion in breast milk has not been studied. Breast-feeding is contraindicated during oxaliplatin treatment.
Oxaliplatin could have a negative effect on fertility (see Precautions).

The following CIOMS frequency rating is used, when applicable: Very common ≥10%; Common ≥1% and <10%; Uncommon ≥0.1% and <1%; Rare ≥0.01% and <0.1%; Very rare <0.01%, Unknown (cannot be estimated from available data).
Combination Therapy of Oxaliplatin With 5-Fu/Fa (Folfox): Investigations: Very common: Mild to moderate elevation of transaminases and alkaline phosphatases activities.
Infections and infestations: Common: Neutropenic sepsis, including fatal outcomes.
Uncommon: Sepsis, including fatal outcomes.
Blood and lymphatic system disorders: Very common: anaemia, neutropenia, thrombocytopenia (see Precautions).
The frequency increases when Oxaliplatin (Eloxatin) is administered (85 mg/m² every 2 weeks) in combination with 5-FU +/- folinic acid, as compared to a single agent administration (130 mg/m² every 3 weeks), e.g. anaemia (80% vs 60% of patients), neutropenia (70% vs 15%), thrombocytopenia (80% vs 40%).
Severe anaemia (Haemoglobin <8.0 g/dL) or thrombocytopenia (platelets <50 x 10⁹/L) occurs with a similar frequency (<5% of patients) when Oxaliplatin (Eloxatin) is administered as a single agent or in combination with 5-FU.
Severe neutropenia (neutrophils <1.0 x 10⁹/L) occurs with a greater frequency when Oxaliplatin (Eloxatin) is administered in combination with 5-FU than as a single agent (40% vs <3% of patients).
Common: Febrile neutropenia.
Rare: immuno-allergic haemolytic anaemia and thrombocytopenia.
Disseminated intravascular coagulation (DIC), including fatal outcomes. (See Precautions.)
Metabolism and nutrition disorders: Common: hypocalcemia.
Nervous system disorders: Very common: acute neuro-sensory manifestations.
These symptoms usually develop at the end of the 2-hour Oxaliplatin (Eloxatin) infusion or within a few hours, abate spontaneously within the next hours or days, and frequently recur with further cycles. They may be precipitated or exacerbated by exposure to cold temperatures or objects.
They usually present as transient paraesthesia, dysaesthesia and hypoaesthesia.
An acute syndrome of pharyngolaryngeal dysaesthesia occurs in 1-2% of patients and is characterized by subjective sensations of dysphagia or dyspnea/feeling of suffocation, without any evidence of respiratory distress (no cyanosis or hypoxia) or of laryngospasm or bronchospasm (no stridor or wheezing).
Other symptoms occasionally observed, particularly of cranial nerve dysfunction may be either associated with previously mentioned events, or also occur isolated 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 of visual acuity, visual field disorders. In addition, the following symptoms have been observed: jaw spasm/muscle spasms/muscle contractions-involuntary/muscle twitching/myoclonus, coordination abnormal/gait abnormal/ataxia/balance disorders, throat or chest tightness/pressure/discomfort/pain.
Dysaesthesia/paraesthesia of extremities and peripheral neuropathy.
The limiting toxicity of Oxaliplatin (Eloxatin) is neurological. It involves a sensory peripheral neuropathy characterised by peripheral dysaesthesia and/or paraesthesia with or without cramps, often triggered by the cold (85 to 95% of patients).
The duration of these symptoms, which usually recede between the cycles of treatment, increases with the number of treatment cycles. The onset of pain and/or a functional disorder and their duration are indications for dose adjustment, or even treatment discontinuation (see Precautions). This functional disorder, including difficulties in executing delicate movements, is a possible consequence of sensory impairment. The risk of occurrence of a functional disorder for a cumulative dose of approximately 800 mg/m² (i.e. 10 cycles) is 15% or less. The neurological signs and symptoms improve when treatment is discontinued in the majority of cases.
Dysgeusia.
Rare: dysarthria; loss of deep tendon reflexes; Lhermitte' sign; Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES) (see Precautions).
Eye disorders: Rare: visual acuity reduced transiently, visual field disturbances, optic neuritis; transient vision loss, reversible following therapy discontinuation.
Ear and labyrinth disorders: Rare: deafness.
Respiratory, thoracic and mediastinal disorders: Very common: cough.
Common: hiccups.
Rare: acute interstitial lung diseases, sometimes fatal; pulmonary fibrosis (see Precautions).
Gastrointestinal disorders: Very common: nausea, vomiting, diarrhoea; Dehydration, hypokalemia, metabolic acidosis, ileus, intestinal obstruction, renal disorders may be associated with severe diarrhoea/vomiting, particularly when Oxaliplatin (Eloxatin) is combined with 5-FU (see Precautions); stomatitis/mucositis; abdominal pain.
Common: gastrointestinal hemorrhage.
Rare: colitis, including Clostridium difficile diarrhoea; pancreatitis.
Renal and urinary disorders: Very rare: acute tubular necrosis, acute interstitial nephritis and acute renal failure.
Skin and subcutaneous tissue disorders: Common: alopecia (<5% of patients, as a single agent).
Musculoskeletal and connective tissue disorders: Very common: back pain. In case of such adverse reaction, haemolysis which has been rarely reported should be investigated.
Common: arthralgia.
Metabolism and nutrition disorders: Very common: anorexia.
Vascular disorders: Very common: epistaxis.
Common: deep vein thrombosis; thromboembolic events; hypertension.
General disorders and administration site conditions: Very common: fatigue; fever, rigors (tremors), either from infection (with or without febrile neutropenia) or possibly from immunological mechanism; asthenia; injection site reactions.
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 (Eloxatin) is infused through a peripheral vein.
Immune system disorders: Very common: allergic reactions such as: skin rash (particularly urticaria), conjunctivitis, rhinitis.
Common: anaphylactic reactions including bronchospasm, angioedema, hypotension, sensation of chest pain and anaphylactic shock.
Hepatobiliary disorders: Very rare: 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.
Postmarketing experience with frequency not known: Haemolytic uremic syndrome; Autoimmune pancytopenia; Pancytopenia; Secondary leukemia.
Infections and infestations: septic shock, including fatal outcomes.
Blood and lymphatic system disorders: haemolytic uremic syndrome.
Nervous system disorders: convulsion; Ischemic or haemorrhagic cerebrovascular disorder.
Cardiac disorders: QT prolongation, which may lead to ventricular arrhythmias including Torsade de Pointes,which may be fatal. (See Precautions.)
Gastrointestinal disorders: intestinal ischaemia, including fatal outcomes. (See Precautions.); duodenal ulcer, and complications, such as duodenal ulcer haemorrhage or perforation, which can be fatal. (See Precautions.)
Musculoskeletal and connective tissue disorders: rhabdomyolysis, including fatal outcomes. (See Precautions.)
Respiratory, thoracic and mediastinal disorders: laryngospasm; pneumonia, including and bronchopneumonia fatal outcomes.
Combination Therapy Of Oxaliplatin With 5-Fu/Fa (Folfox) And Bevacizumab: The safety of first line oxaliplatin combined with 5-FU/FA and bevacizumab was evaluated in 71 patients with metastatic colorectal cancer (TREE study).
In addition to the adverse events expected with FOLFOX regimen, adverse events reported with FOLFOX/bevacizumab combination included bleeding (45.1%; G3/4: 2.8%), proteinuria (11.3%; G3/4: 0%), impaired wound healing (5.6%), gastrointestinal perforation (4.2%) and hypertension (1.4%; G3/4: 1.4%).
For more details on bevacizumab safety information, see the corresponding prescribing information.

In patients who have received a single dose of 85 mg/m² of Oxaliplatin (Eloxatin) immediately before administration of 5-FU, no change in the level of exposure to 5-FU has been observed.
Caution is advised when Oxaliplatin (Eloxatin) 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 Adverse Reactions).
Caution is advised when Oxaliplatin (Eloxatin) treatment is administered concomitantly with other medicinal products known to be associated with rhabdomyolysis (see Adverse Reactions).

Special precautions for disposal and other handling: As with other potentially toxic agents, caution should be exercised when handling and preparing oxaliplatin.
Instructions for handling: Handling of this cytotoxic agent by healthcare personnel requires a set of precautions to ensure the protection of the handler and his/her surroundings.
The preparation of cytotoxic solutions for injection must always be carried out by trained specialist personnel with knowledge of the medicines used, under conditions ensuring drug integrity, the protection of the environment and in particular protection of the personnel handling the medicines, according to hospital practice. 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, particularly 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 must be incinerated in suitably labeled rigid containers (see Waste disposal as follows).
If the powder, reconstituted solution or solution for infusion should come into contact with the skin, immediately remove the product carefully with water.
If the powder, reconstituted solution or solution for infusion should come into contact with the mucous membranes, immediately remove the product carefully with water.
These provisions can be considered as part of the oncology network (Circular DGS/DH/98 No. 98/18 dated March 24, 1998), in collaboration with any appropriate unit that fulfills the conditions required.
Special precautions for administration: NEVER use injection material containing aluminum.
NEVER administer undiluted.
Only use a 5% glucose solution (50 mg/ml) to dilute. DO NOT use solutions containing chloride or sodium chloride to reconstitute or dilute for infusion.
NEVER mix with any other medicines in the same infusion bag or administer simultaneously by the same infusion line.
DO NOT mix with alkaline drugs or solutions, particularly 5-fluorouracil (5-FU), folinic acid (FA) preparations containing trometamol as an excipient and trometamol salts of other active substances. Alkaline solutions and medications negatively affect the stability of oxaliplatin.
Instructions for use with folinic acid (FA) (such as disodium folinate or calcium folinate): An IV infusion of oxaliplatin 85 mg/m² in 250 to 500 ml of 5% glucose solution (50 mg/ml) is administered at the same time as an IV infusion of folinic acid in a 5% glucose solution (50 mg/ml), over 2 to 6 hours, using a Y-line placed immediately before the site of injection.
These two drugs must not be mixed in the same infusion bag. Folinic acid (FA) must not contain trometamol as an excipient and must only be diluted in isotonic 5% glucose solution (50 mg/ml), never in alkaline solutions or solutions containing chloride or sodium chloride.
Instructions for use with 5-fluorouracil (5-FU): Oxaliplatin must always be administered before fluoropyrimidines, i.e. 5-fluorouracil (5-FU). After oxaliplatin administration, flush the infusion line and then administer 5-fluorouracil (5-FU).
For further information about medicines combined with oxaliplatin, see the respective manufacturer's Summary of Product Characteristics.
ONLY USE the recommended solvents.
Any reconstituted solution showing traces of precipitation must not be administered and must be disposed of in compliance with regulatory requirements relating to the disposal of toxic waste.
Reconstitution of the solution: Water for injections or a 5% glucose solution (50 mg/ml) should be used to reconstitute the solution.
For a 50-mg vial: add 10 ml of solvent to yield a concentration of 5 mg/ml.
For a 100-mg vial: add 20 ml of solvent to yield a concentration of 5 mg/ml.
From a microbiological and chemical perspective, the reconstituted solution should be immediately diluted in a 5% glucose solution (50 mg/ml).
Inspect visually before use. Only clear solutions with no particles can be used.
The medicinal product is for single use only. Any unused solution must be discarded.
Dilution for intravenous infusion: Withdraw the required amount of concentrate from the vial and then dilute with 250 to 500 ml of 5% glucose solution (50 mg/ml) to obtain an oxaliplatin concentration of between 0.2 mg/ml and 0.7 mg/ml. The concentration range for which the physical and chemical stability of oxaliplatin have been demonstrated is between 0.2 mg/ml and 2.0 mg/ml.
Administer by intravenous infusion.
After dilution in a 5% glucose solution, physical and chemical stability have been demonstrated for 24 hours between +2°C and +8°C.
From a microbiological point of view, the solution for infusion must be used immediately.
If the drug is not used immediately, the duration and conditions of storage before use are the sole responsibility of the user and should not normally exceed 24 hours at a temperature between +2°C and +8°C, unless the dilution was performed in duly controlled and validated aseptic conditions.
Inspect visually before use. Only clear solutions with no particles can be used.
The medicinal product is for single use only. Any unused solution must be disposed of (see Waste disposal as follows).
NEVER use solutions containing chloride or sodium chloride for reconstitution or dilution.
The compatibility of the oxaliplatin solution for infusion has been tested with standard PVC-based administration sets.
Infusion: The administration of oxaliplatin does not require prehydration.
Oxaliplatin diluted in 250 to 500 ml of a 5% glucose solution (50 mg/ml), to obtain a concentration not less than 0.2 mg/ml must be infused either by peripheral vein or a central venous line over 2 to 6 hours.
When oxaliplatin is administered with 5-fluorouracil (5-FU), the oxaliplatin infusion must be given before 5-fluorouracil (5-FU).
Waste disposal: Any unused product, as well as all materials that have been used for reconstitution, dilution and administration, must be destroyed according to standard hospital procedures relative to cytotoxic agents as per current laws related to the disposal of hazardous waste.
Incompatibilities: The diluted drug must not be mixed with other medicines in the same infusion bag or infusion line. Oxaliplatin may be co-administered with folinic acid via a Y-line, according to the Instructions for use as follows.
DO NOT mix with alkaline medications or solutions, particularly 5-fluorouracil, folinic acid preparations containing trometamol as an excipient and trometamol salts of other drugs. Alkaline solutions and medications negatively affect the stability of oxaliplatin.
DO NOT dilute with saline or other solutions containing chloride ions (including calcium, potassium and sodium chloride).
DO NOT mix with other drugs in the same infusion bag or infusion line.
DO NOT use injection equipment containing aluminum.

Store the vial in its outer packaging, protected from light.
Do not freeze.
See Incompatibilities under Cautions for Usage for the storage conditions of the diluted solution.
Shelf life: 3 years.
Physical and chemical stability after dilution in 5% glucose solution have been demonstrated for 48 hours between +2°C and +8°C or for 24 hours at +25°C.
From a microbiological point of view, the solution for infusion must be used immediately. If the drug is not used immediately, the storage times and conditions after dilution and before use are the sole responsibility of the user and should not exceed 24 hours at a temperature between +2°C and +8°C, unless the dilution was performed in duly controlled and validated aseptic conditions.

Cytotoxic Chemotherapy

L01XA03 - oxaliplatin ; Belongs to the class of platinum-containing antineoplastic agents. Used in the treatment of cancer.

Rx

Soln (conc for infusion) 5 mg/mL x 50 mg x 20 mL, 100 mg x 20 mL.