ELOXATIN(r)

NAME OF THE MEDICINE

Non-proprietary Name

Oxaliplatin concentrated solution for injection.

Chemical Structure

Oxaliplatin has the following chemical structure:

CAS Number

61 825-94-3.

DESCRIPTION

Oxaliplatin is designated chemically as [SP-4-2]-(1R,2R)-(cyclohexane-1,2-diamine- k2N,N'(oxalato(2-)-k2O1,O2]platinum (II) The empirical formula of oxaliplatin is C8H14N2O4Pt and its molecular weight is 397.3. Oxaliplatin is a white to off-white crystalline powder. It is slightly soluble in water, very slightly soluble in methanol and practically insoluble in ethanol. Eloxatin concentrated solution for injection also contains water for injections.

PHARMACOLOGY

Pharmacodynamics

Oxaliplatin is an antineoplastic drug belonging to a new class of platinum based compounds in which the platinum atom is complexed with 1,2-diaminocyclohexane (DACH) and an oxalate group. Oxaliplatin is a single enantiomer, the Cis-[oxalato(trans--1,2-DACH) platinum]. Oxaliplatin exhibits a wide spectrum of both in vitro cytotoxicity and in vivo antitumour activity in a variety of tumour model systems, including human colorectal cancer models. Oxaliplatin also demonstrates in vitro and in vivo activity in various cisplatin resistant models. A synergistic cytotoxic action has been observed in combination with fluorouracil both in vitro and in vivo. Studies on the mechanism of action of oxaliplatin, although not completely elucidated, show that the aqua-derivatives resulting from the biotransformation of oxaliplatin interact with DNA to form both inter- and intra-strand cross links, resulting in the disruption of DNA synthesis leading to cytotoxic and antitumour effects.

Pharmacokinetics

The pharmacokinetics of individual active compounds have not been determined. The pharmacokinetics of ultrafiltrable platinum, representing a mixture of all unbound, active and inactive platinum species, following a two hour infusion of oxaliplatin at 130mg/m2 every three weeks for 1 to 5 cycles and oxaliplatin at 85mg/m2 every two weeks for 1 to 3 cycles are as follows: Summary of Platinum Pharmacokinetic Parameter Estimates in Ultrafiltrate Following Multiple Doses of Oxaliplatin at 85mg/m2 Every Two Weeks or at 130mg/m2 Every Three Weeks

Mean AUC0-48 and Cmax values were determined on Cycle 3 (85mg/m2) or Cycle 5 (130mg/m2). Mean AUC, Vss, and CL values were determined on Cycle 1.

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

t1/2, t1/2 and t1/2 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 85mg/m2 every two weeks or 130mg/m2 every three weeks and steady state was attained by cycle one in this matrix. Inter- and intra-subject variability is generally low. Biotransformation in vitro is considered to be the result of non-enzymatic degradation and there is no evidence of cytochrome P450 mediated metabolism of the diaminocyclohexane (DACH) ring. Oxaliplatin undergoes extensive biotransformation in patients, and no intact drug was detectable in plasma ultrafiltrate at the end of a 2 hour infusion. Several cytotoxic biotransformation products including the monochloro, dichloro and diaquo DACH platinum species have been identified in the systemic circulation together with a number of inactive conjugates at later time points. Platinum is predominantly excreted in urine, with clearance mainly in the 48 hours following administration. By day 5, approximately 54% of the total dose was recovered in the urine and <3% in the faeces. A significant decrease in clearance of ultrafilterable platinum from 17.6 2.18 L/h to 9.95 1.91 L/h in renal impairment (creatinine clearance 12-57mL/min) was observed together with a statistically significant decrease in distribution volume from 330 40.9 to 241 36.1 L. The effect of severe renal impairment on platinum clearance has not been evaluated.

CLINICAL TRIALS

Adjuvant Treatment of Stage III (Duke's C) Colon Cancer

Use in combination with fluorouracil and folinic acid (FU/FA)

EFC3313 (MOSAIC)

EFC3313 (MOSAIC) was an international, multicentre, open-label, randomised phase III study comparing two treatment regimens (FOLFOX4 versus FU/FA) as adjuvant treatment of Duke's stage B2/C colon cancer. FOLFOX4 - Day 1; Oxaliplatin 85mg/m2 as 2 hour infusion, folinic acid 200mg/m2 over 2 hours, followed by a FU bolus of 400mg/m2, then a FU infusion of 600mg/m2 over 22 hours. Folinic acid and FU repeated on Day 2. FU/FA - the same regimen without oxaliplatin. Both were repeated every two weeks. A total of 1108 patients were treated in the FOLFOX4 arm and 1111 in the FU/FA arm. The median number of cycles received in both arms was 12. In the ITT population, after a median of 4 years follow-up, patients treated with FOLFOX4 had significantly increased disease-free survival (DFS), the primary endpoint, compared to patients treated with FU/FA (Table 1). In the sub-group analysis by disease stage, only patients with Stage III disease had significantly increased disease-free survival. The trial was not powered to show such a benefit with Stage II disease, but the trend indicated a small benefit is likely. This benefit is not as great as in Stage III patients. The trial was not powered to show significant benefit in overall survival (OS).

Table 1: Disease Free Survival and Overall Survival - ITT Population

* The trial was not powered to show significant benefit in overall survival.

Use in combination with capecitabine

NO16968

Data from a open-label, multi-centre, randomised, controlled phase III clinical trial in patients with stage III (Dukes' C) colon cancer supports the use of capecitabine in combination with oxaliplatin (XELOX) for the adjuvant treatment of patients with colon cancer (NO16968). In this trial, 944 patients were randomised to 3 week cycles for 24 weeks with capecitabine (1000mg/m2 twice daily for 2 weeks followed by a 7 day rest period) in combination with oxaliplatin (130mg/m2 intravenous infusion over 2 hours on day 1 every 3 weeks); 942 patients were randomised to bolus 5-FU and leucovorin. In the primary analysis (ITT population), median observation time was 57 months for DFS and 59 months for OS. XELOX group had a statistical significant improvement in DFS compared to 5-FU/LV (HR=0.80, 95% CI=[0.69; 0.93]; p=0.0045). The 3 year DFS rate was 71% for XELOX versus 67% for 5-FU/LV. The analysis for the secondary endpoint of relapse free survival (RFS) supports these results with a HR of 0.78 (95% CI=[0.67; 0.92]; p=0.0024) for XELOX vs. 5- FU/LV. XELOX showed a trend towards superior OS with a HR of 0.87 (95% CI=[0.72; 1.05]; p=0.1486). The 5 year OS rate was 78% for XELOX versus 74% for 5-FU/LV.

Treatment of Advanced Colorectal Cancer

Use in combination with fluorouracil and folinic acid (FU/FA)

A total of 1312 patients have been enrolled in 3 pivotal trials, for untreated (EFC7462/N9741, EFC2962) and pretreated patients (EFC2964). These studies evaluated the efficacy of oxaliplatin at the same dose intensity (85mg/m2/2 weeks) when added to different FU/FA doses and regimens, in terms of overall survival, progression free survival and tumour response.

EFC7462/N9741

was a multicentre open-label randomised, 3-arm phase III study of irinotecan and FU/LV (IFL), or oxaliplatin and irinotecan (IROX), or oxaliplatin and FU/LV (FOLFOX4) as initial treatment of patients with advanced colorectal cancer. Therapy consisted of 2-week FOLFOX4, 6-week IFL, or 3-week IROX treatment cycles.

A total of 795 patients were enrolled and 773 treated from May 1999 in 301 centres in the United States and Canada. Treatment arms - FOLFOX4 Day 1: oxaliplatin 85mg/m2 over 2 hours, folinic acid 200mg/m2 over 2 hours, followed by a FU bolus of 400mg/m2, then a FU infusion of 600mg/m2 over 22 hours. Folinic acid and FU repeated on Day 2. Cycle repeated every 2 weeks. IFL Day 1: irinotecan 125mg/m2 over 90 minutes, folinic acid 20mg/m2 over 15 minutes or IV push, FU bolus of 500mg/m2 weekly x 4. Cycle repeated every 6 weeks. IROX Day 1: oxaliplatin 85mg/m2 over 2 hours, irinotecan 200mg/m2 over 30 minutes. Cycle repeated every 3 weeks. This study has demonstrated a statistically significant longer TTP (time to progression) and OS, and a significantly higher overall RR (response rate) for oxaliplatin in combination with bolus/infusional FU/LV (FOLFOX4) compared with the IFL control arm. The IROX arm has a significantly longer OS compared with the IFL arm, while TTP and RR on the IROX arm were not significantly different from the IFL arm. Median durations of treatment for each group were 24, 24 and 21 weeks for IFL, FOLFOX4 and IROX (respectively).

Table 2: Summary of Time to Progression - ITT Population

P-value (Log-Rank Test) FOLFOX4 vs. IFL: P=0.0014 IROX vs. IFL: P=0.8295

Hazard Ratio (95% confidence interval) FOLFOX4 vs. IFL: 0.74 (0.61-0.89)

IROX vs. IFL: 1.02 (0.85-1.23)

Table 3: Summary of Overall Survival - ITT Population

P-value (Log-Rank Test) FOLFOX4 vs. IFL: P<0.0001 IROX vs. IFL: P=0.0252

Hazard Ratio (95% confidence interval) FOLFOX4 vs. IFL: 0.65 (0.53-0.80)

IROX vs. IFL: 0.79 (0.65-0.97)

Table 4: Summary of Confirmed Overall Response - Patients (N, %) with Measurable Disease

P-value (Chi-Squared Test) FOLFOX4 vs. IFL: P< =0.0075 IROX vs. IFL: P=0.6820

a

Patients with measurable disease at randomisation that became too small to measure during the study were classified as regression and not partial response in this study

Table 5: Number of Deaths - Treated Patients N (%)

EFC2962 was a multinational multicentre randomised phase III study in previously untreated patients, comparing two-weekly fluorouracil bolus plus infusion and high dose folinic acid (FU/FA regimen: Day 1; folinic acid 200mg/m2 over 2 hours, followed by a FU bolus of 400mg/m2, then a FU infusion of 600mg/m2 over 22 hours. Repeated on Day 2.) to the same regimen combined with oxaliplatin at the dosage of 85mg/m2 every two weeks. A total of 420 patients were enrolled and 417 treated from August 1995 to July 1997 in 35 centres from 9 countries. The median number of treatment cycles was 12 in the FU/FA plus oxaliplatin group and 11 in the FU/FA group. Confirmed responses after independent radiological review (intent to treat analysis n = 420) are as shown in Table 6. The FU/FA + oxaliplatin group had a statistically significant greater response rate and longer progression free survival. There was no significant difference in OS between the two groups, however, the study was not powered to detect a difference in OS. Additionally, in both groups, post- study treatment with other agents may have influenced survival. EFC2964 was an open label multicentre study in which patients whose disease had progressed on one of two fluorouracil/folinic acid regimens continued on the same fluorouracil/folinic acid regimen with the addition of oxaliplatin 85mg/m2 two weekly. The two study regimens were: Regimen 1: Day 1; folinic acid 200mg/m2 over 2 hours, followed by a FU bolus of 400mg/m2, then a FU infusion of 600mg/m2 over 22 hours. Repeated on Day 2. Regimen 2: folinic acid 500mg/m2 over 2 hours, followed by a FU infusion of 1500mg/m2 over 22 hours, repeated on Day 2. The results were as shown in Table 7.

1. Response rate assessed according to WHO-UICC criteria.

2. Independent expert review.

Treatment of Metastatic Colorectal Cancer

Use in combination with capecitabine, with or without bevacizumab

Study NO16966:

Data from a multicentre, randomised, controlled phase III clinical study support the use of capecitabine in combination with oxaliplatin or in combination with oxaliplatin and bevacizumab (BV) for the first-line treatment of metastatic colorectal cancer (Study NO16966). The study contained two parts: an initial 2-arm part in which patients were randomised to two different treatment groups, XELOX or FOLFOX-4, and a subsequent 2x2 factorial part with four different treatment groups, XELOX + placebo (P), FOLFOX-4+P, XELOX+BV, and FOLFOX-4+BV. The treatment regimens are summarised in Table 8 below.

Table 8: Treatment regimens in Study NO16966

Non-inferiority of the XELOX-containing arms compared with the FOLFOX-4-containing arms in the overall comparison was demonstrated in terms of progression-free survival (PFS) in the eligible per- protocol population (EPP), with progression determined by the study investigators who were not blinded to treatment allocation (see Table 9). The criterion set for concluding non-inferiority was that the upper limit of the 97.5% confidence interval for the hazard ratio for PFS was less than 1.23. The results for OS are similar to those reported for PFS.

Table 9: Key efficacy results for the non-inferiority analysis (EPP population, Study NO16966)

Study NO16966 also demonstrated superiority of the bevacizumab-containing arms over placebo- containing arms.

Study NO16967:

Data from a multicenter, randomised, controlled phase III clinical study support the use of capecitabine in combination with oxaliplatin for the second-line treatment of metastatic colorectal cancer. In this trial, 627 patients with metastatic colorectal cancer who have received prior treatment with irinotecan (CPT-11) in combination with a fluoropyrimidine regimen as first-line therapy were randomised to treatment with XELOX or FOLFOX-4 (Study NO16967). The treatment regimens used in study NO16967 are summarised in Table 10 below.

Table 10: Treatment regimens in Study NO16967

XELOX was demonstrated to be non-inferior to FOLFOX-4 in terms of PFS in the per-protocol population (PPP) (see Table 11). The criterion set for concluding non-inferiority was the upper limit of the 95% confidence interval for the hazard ratio for PFS was less than 1.30. The result for OS was similar to that for PFS.

Table 11: Key efficacy results for the non-inferiority analysis (PPP, Study NO16967)

Treatment of Oesophagogastric Cancer

Data from a randomised multicenter, phase III study comparing capecitabine to 5-FU and oxaliplatin to cisplatin in patients with previously untreated locally advanced or metastatic oesophagogastric cancer supports the use of oxaliplatin for the first-line treatment of advanced oesophagogastric cancer (REAL-2). In this trial, 1002 patients were randomised in a 2x2 factorial design to one of the following 4 arms:

Table 12: Treatment regimens in the REAL-2 Study

The primary efficacy analyses in the per-protocol population demonstrated non-inferiority in OS for capecitabine versus 5-FU-based regimens (hazard ratio 0.86, 95% CI: 0.80 to 0.99) and for oxaliplatin versus cisplatin-based regimens (hazard ratio 0.92, 95% CI: 0.80 to 1.10). The median OS was 10.9 months in capecitabine-based regimens and 9.6 months in 5-FU-based regimens. The median OS was 10.0 months in cisplatin-based regimens and 10.4 months in oxaliplatin-based regimens.

CONTRAINDICATIONS

Oxaliplatin is contraindicated in patients who: have a known history of hypersensitivity to oxaliplatin, are pregnant, are breast feeding, have myelosuppression prior to starting first course, as evidenced by baseline neutrophils <1.5 x 109/L and/or platelet count of <75 x 109 /L, have a peripheral sensory neuropathy with functional impairment prior to first course, have severely impaired renal function (creatinine clearance less than 30mL/min). If contraindications exist to any of the agents in combination regimens, that agent should not be used.

PRECAUTIONS

General

Oxaliplatin should be administered only by or under the supervision of an experienced clinical oncologist.

Allergic Reactions

Anaphylactic-like reactions to Eloxatin have been reported, and may occur within minutes of Eloxatin administration. Patients with a history of allergic reactions to platinum compounds should be monitored for allergic symptoms. Allergic reactions can occur during any cycle. In case of an anaphylactic-type reaction to oxaliplatin, the infusion should be immediately discontinued and appropriate symptomatic treatment initiated. Rechallenge with oxaliplatin is contraindicated.

Neurological Toxicity

Neurological toxicity (see ADVERSE EFFECTS) of oxaliplatin should be carefully monitored, especially if co-administered with other medications with specific neurological toxicity. A neurological examination should be performed before initiation of each administration, and periodically thereafter. It is not known whether patients with pre-existing medical conditions associated with peripheral nerve damage have a reduced threshold for oxaliplatin induced peripheral neuropathy. For patients who develop acute laryngopharyngeal dysaesthesias, during or within 48 hours following the 2-hour infusion, the next oxaliplatin infusion should be administered over 6 hours. To prevent such dysaesthesia, advise the patient to avoid exposure to cold and to avoid ingesting cold food and/or beverages during or within 48 hours following oxaliplatin 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 EFFECTS). Diagnosis of RPLS is based upon confirmation by brain imaging.

Gastrointestinal Toxicity

Gastrointestinal toxicity, which manifests as nausea and vomiting, warrants prophylactic anti-emetic therapy, including 5-HT3 antagonists and corticosteroids. Dehydration, ileus, intestinal obstruction, hypokalemia, metabolic acidosis and renal impairment may be caused by severe diarrhoea/emesis, particularly when combining oxaliplatin with fluorouracil.

Haematological Toxicity

Monitor haematological toxicity with a full blood count and white cell differential count prior to starting therapy and before each subsequent course. Idiosyncratic haematological toxicity may occur, especially in patients who have received previous myelotoxic treatment.

Pulmonary Toxicity

Eloxatin has been associated with pulmonary fibrosis (0.7% of study patients), which may be fatal. In the case of unexplained respiratory symptoms such as non-productive cough, dyspnoea, crackles or radiological pulmonary infiltrates, oxaliplatin should be discontinued until further pulmonary investigations exclude an interstitial lung disease or pulmonary fibrosis (see ADVERSE EFFECTS).

Hepatic Toxicity

Reactions related to liver sinusoidal obstruction syndrome, including nodular regenerative hyperplasia, have been reported (see ADVERSE EFFECTS). In the case of abnormal liver function test results or portal hypertension which could not be explained by liver metastases, reactions related to liver sinusoidal obstruction syndrome should be investigated, and very rare cases of drug induced hepatic vascular disorders should be considered.

Renal Impairment

Oxaliplatin has not been studied in patients with severe renal impairment. It is therefore contraindicated in patients with severe renal impairment. There is limited information on safety in patients with moderately impaired renal function, and administration should only be considered after suitable appraisal of the benefit/risk for the patient, however, treatment may be initiated at the normally recommended dose. In this situation, renal function should be closely monitored and dose adjusted according to toxicity. There is no need for dose adjustment in patients with mild renal dysfunction.

Hepatic Insufficiency

Oxaliplatin has not been studied in patients with severe hepatic impairment. No increase in oxaliplatin acute toxicities was observed in the subset of patients with abnormal liver function tests at baseline. No specific dose adjustment for patients with abnormal liver function tests was performed during clinical development.

Paediatric Use

Oxaliplatin is not recommended for use in children as safety and efficacy have not been established in this group of patients.

Use in the Elderly

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

Carcinogenicity, Mutagenicity and Impairment of Fertility

Oxaliplatin was shown to be mutagenic and clastogenic in mammalian test systems in vitro and in vivo. The carcinogenic potential of oxaliplatin has not been studied, but compounds with similar mechanisms of action and genotoxicity profiles have been reported to be carcinogenic. Oxaliplatin should be considered a probable carcinogen. In dogs dosed with oxaliplatin, a decrease in testicular weight accompanied with testicular hypoplasia approaching aplasia was seen at doses >= 15mg/m2. However, no effects on fertility were seen in male and female rats at doses up to 12mg/m2/day for 5 days/cycle.

Use in Pregnancy

Category D. Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details. Reproductive toxicity studies showed no teratogenic activity in rats or rabbits at intravenous doses up to 6 and 9mg/m2/day respectively (1/20 of the maximum recommended clinical dose, based on body surface area). However, increased embryonic deaths, decreased foetal weight and delayed ossifications were observed in rats. Related compounds with similar mechanisms of action have been reported to be teratogenic. There are no adequate and well- controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the foetus. Oxaliplatin is probably toxic to the human foetus at the recommended therapeutic dose, and is therefore contraindicated during pregnancy. As with other cytotoxic agents, effective contraceptive measures should be taken in potentially fertile patients prior to initiating chemotherapy with oxaliplatin.

Use in Lactation

There are no data on the excretion of oxaliplatin into milk of animals or humans. Oxaliplatin is contraindicated in breast feeding women.

INTERACTIONS WITH OTHER MEDICINES

In patients who have received a single dose of 85mg/m2 of oxaliplatin, immediately before administration of fluorouracil, no change in the level of exposure to fluorouracil has been observed. However, in patients dosed with fluorouracil weekly and oxaliplatin 130mg/m2 every 3 weeks, increases of 20% in fluorouracil plasma concentrations have been observed.

In vitro

little or no displacement of oxaliplatin binding to plasma proteins has been observed with the following agents; erythromycin, salicylates, granisetron, paclitaxel, and sodium valproate.

Oxaliplatin is incompatible with chloride containing solutions and basic solutions (including fluorouracil), therefore oxaliplatin should not be mixed with these or administered simultaneously via the same IV line. There is no data for compatibility with other drugs. The lack of Cytochrome P450 mediated metabolism indicates that oxaliplatin is unlikely to modulate the P450 metabolism of concomitant medications through a competitive mechanism. No clinically significant differences in exposure to capecitabine or its metabolites, free platinum or total platinum occured when capecitabine and oxaliplatin were administered in combination, with or without bevacizumab.

Advice to Patients

Patients must be adequately informed of the risk of diarrhoea/emesis and neutropenia after oxaliplatin/fluorouracil administration so that they can urgently contact their treating physician for appropriate management. Patients and caregivers should be informed of the expected side effects of Eloxatin and, in particular, patients should be advised to: Avoid cold foods and drinks and cover skin prior to exposure to cold during or within 48 hours following oxaliplatin administration, since neurological effects may be precipitated or exacerbated by exposure to cold. Contact their doctor immediately if they develop fever, particularly in association with persistent diarrhoea or evidence of infection since this may indicate low blood count. Contact their doctor if persistent vomiting, diarrhoea, signs of dehydration, cough or breathing difficulties or signs of allergic reaction occur. Vision abnormalities, in particular transient vision loss (reversible following therapy discontinuation), may affect patient's 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 AND ADMINISTRATION

Dosage

In combination with fluorouracil and folinic acid for adjuvant treatment of colon cancer, the recommended dose of oxaliplatin is 85 mg/m2 intravenously repeated every two weeks for 12 cycles (6 months). In combination with capecitabine for adjuvant treatment of colon cancer, the recommended dose of oxaliplatin is 130 mg/m2, administered as an intravenous infusion over 2 hours on day 1 of a three week cycle. For the recommended dose of capecitabine see CLINICAL TRIALS. In combination with fluorouracil and folinic acid for the treatment of advanced colorectal cancer, the recommended dose of oxaliplatin is 85mg/m2 intravenously repeated every two weeks. In combination with capecitabine with or without bevacizumab, for the treatment of metastatic colorectal cancer, the recommended dose of oxaliplatin is 130 mg/m2, administered as an intravenous infusion over 2 hours on day 1 of a three week cycle. For the recommended dose of capecitabine and bevacizumab, see CLINICAL TRIALS. In combination with epirubicin and either fluororuracil or capecitabine, for the treatment of oesophagogastric cancer, the recommended dose of oxaliplatin is 130 mg/m2, administered as an intravenous infusion over 2 hours on day 1 of a three week cycle. For the recommended doses of epirubicin, capecitabine and fluorouracil, see CLINICAL TRIALS.

Dosage Modification

Prior to each treatment cycle, patients should be evaluated for toxicity and the dose of oxaliplatin adjusted accordingly.

Neurological Toxicity

If acute neurological reactions occur e.g. acute pharyngolaryngeal dysaesthesia, increase the oxaliplatin infusion time from 2 hours to 6 hours. This decreases Cmax by 30% and may lessen acute toxicities. If sensory loss or paraesthesia persists longer than 7 days or interferes with function (grade 2 toxicity), reduce oxaliplatin dose by 25%. If sensory loss or paraesthesia interferes with activities of daily living (grade 3 toxicity), oxaliplatin should be discontinued.

Haematological Toxicity

If haematological toxicity (neutrophils <1.5 x 109/L or platelets <75 x 109/L) is present before starting treatment or prior to the next course: - Delay treatment until neutrophil count is 1.5 x 109/L and platelet count is 75 x 109/L and Reduce the 85mg/m2 oxaliplatin dose to 75mg/m2 every two weeks and FU dose by 20% (adjuvant treatment) Reduce the 85mg/m2 oxaliplatin dose to 65mg/m2 every two weeks and FU dose by 20% (advanced treatment)

Gastrointestinal Toxicity

If grade 3-4 gastrointestinal reactions occur, as assessed according to US National Cancer Institute criteria: - Delay treatment until resolution of the adverse effects and

• Reduce the 85mg/m2 oxaliplatin dose to 75mg/m2 every two weeks and FU dose by 20% (adjuvant treatment)

• Reduce the 85mg/m2 oxaliplatin dose to 65mg/m2 every two weeks and FU dose by 20% (advanced treatment)

Toxicity associated with fluorouracil

Dose adjustments should also be made for fluorouracil associated toxicities (see relevant Product Information). Oxaliplatin should be administered before fluorouracil. Oxaliplatin is administered as a 2- to 6-hour intravenous infusion in 250 to 500mL of 5% glucose injection. Toxicity associated with capecitabine, epirubicin and bevacizumab See relevant Product Information for capecitabine, epirubicin and bevacizumab-associated toxicities. Dose Modifications for Haematological Toxicity used in Studies NO16966 and NO16967

Table 20: Dose Modifications for Febrile Neutropenia, "XELOX" Arm

Treatment (including bevacizumab/placebo) was not to start unless toxicity (except anemia) was resolved to grade <= 1(eg, ANC >= 1.5 x109/L, platelets >= 75x109/L)

Table 21: Dose Modifications for Neutropenia, "XELOX" Arm

Laboratory value at start of a treatment cycle: Treatment start was delayed (including bevacizumab/placebo) until ANC

>= 1.5 x109/L, platelets >= 75x109/L, and the patient had recovered from non-hematologic toxicity to baseline or grade <= 1,

then treatment was started with doses indicated above.

Table 22: Dose Modifications for Thrombocytopenia and Anemia, "XELOX" Arm

Treatment did not start unless toxicity (except anemia) was resolved to grade <= 1(eg, ANC >= 1.5 x109/L, platelets >= 75x109/L)

Laboratory value at start of a treatment cycle: Treatment start was delayed (including bevacizumab/placebo) until ANC

>= 1.5 x109/L, platelets >= 75x109/L, and recovery from non-hematologic toxicity to baseline or grade <= 1, then treatment was started with doses indicated above. Dose Modifications for Non-haematological Toxicity used in Study NO16966

Table 23: Dose Modifications for Non-hematologic Adverse Events, "XELOX" Arm

• Allergic reactions

• Respiratory symptoms indicative of pulmonary fibrosis

• Interstitial pulmonary fibrosis not present at baseline

* No dose adjustment for capecitabine (if in the best interest of the patient)

Dose Modifications used in the REAL-2 Study Oxaliplatin was delayed for 1 week if neutrophil count < 1.0 x109/L, platelet count < 75 x109/L or the patient had persistent grade 1 or 2 neuropathy. After recovery from grade 2-4 thrombocytopenia or grade 3/4 neutropenia, the dose of oxaliplatin was reduced to 100 mg/m2. On recovery of persistent grade 1/2 neuropathy between cycles or grade 3/4 neuropathy for 7-14 days, the dose of oxaliplatin was reduced to 100 mg/m2. In the event of persistent grade 3/4 neuropathy, further oxaliplatin was omitted and carboplatin could be substituted at the investigators discretion. If laryngeal dysaesthesia occurred, subsequent oxaliplatin was administered as a 6-h infusion. If grade 3/4 diarrhoea or stomatitis occurred despite appropriate fluoropyrimidine dose reductions, subsequent oxaliplatin was reduced to 100 mg/m2.

Preparation and Administration

SPECIAL PRECAUTIONS FOR ADMINISTRATION

• DO NOT use any injection material containing aluminium

• DO NOT administer undiluted

• DO NOT mix or administer with sodium chloride injection or any other solution containing chlorides

• DO NOT mix with any other medication or administer simultaneously by the same infusion line (in particular fluorouracil and folinic acid). A Y-tube may be used (see Infusion).

• USE ONLY the recommended diluents (see below).

Any reconstituted solution that shows evidence of precipitation should not be used and should be destroyed.

Handling

As with other potentially toxic compounds, caution should be exercised when handling and preparing oxaliplatin solutions. The handling of this cytotoxic agent by health care personnel requires every precaution to guarantee the protection of the handler and their surroundings. It is essential to use appropriate protective clothing, including protective goggles, mask and gloves. Pregnant women must be warned to avoid handling cytotoxic agents. If oxaliplatin concentrate, premixed solution or infusion solution should come into contact with skin, mucous membranes or eyes, wash immediately and thoroughly with water.

Preparation of Infusion Solution

Dilution before Infusion

The concentrated solution MUST be further diluted in an infusion solution of 250-500mL of 5% glucose injection. After dilution in 5% glucose, chemical and physical in-use stability has been demonstrated for 48 hours at 2C to 8C and for 24 hours at 25C. From a microbiological point of view, this infusion preparation should be used immediately. To reduce microbiological hazard, use as soon as practicable after preparation. 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 2C to 8C. Reconstitution should take place in controlled and validated aseptic conditions. Inspect visually prior to use. Only clear solutions without particles should be used. Contains no antimicrobial agent. The product is for single use in one patient only. Discard any residue. NEVER use sodium chloride solution for dilution.

Infusion

The administration of oxaliplatin does not require prehydration. Oxaliplatin diluted in 250 to 500mL of a glucose 5% injection must be infused either by central venous line or peripheral vein over 2 to 6 hours. When oxaliplatin is administered with fluorouracil, the oxaliplatin infusion should precede that of fluorouracil. Oxaliplatin can be co-administered with folinic acid infusion using a Y-tube placed immediately before the site of injection. The drugs should not be combined in the same infusion bag. Folinic acid must be diluted using isotonic infusion solutions such as 5% glucose solution but NOT sodium chloride solutions or alkaline solutions. Flush the line after oxaliplatin administration. While oxaliplatin has minimal to no vesicant potential, extravasation may result in local pain and inflammation which may be severe and lead to complications especially when oxaliplatin is infused through a peripheral vein. In case of oxaliplatin extravasation, the infusion must be stopped immediately and the usual local symptomatic treatment initiated.

Disposal

All materials that have been used for reconstitution, for dilution and administration must be destroyed according to local statutory requirements.

OVERDOSAGE

There is no known antidote to oxaliplatin. In cases of overdose, exacerbation of adverse effects can be expected. Monitoring of haematological parameters should be initiated and symptomatic treatment given. The Poisons Information Centre, telephone number 131 126, should be contacted for advice on the management of an overdosage.

PRESENTATION AND STORAGE CONDITIONS

Eloxatin is a sterile concentrated solution for infusion, available in 50mg/10mL, 100mg/20mL and 200mg/40mL vials. Store below 30oC. Do not freeze.

NAME AND ADDRESS OF THE SPONSOR

sanofi-aventis australia pty ltd 12-24 Talavera Road Macquarie Park NSW 2113

POISON SCHEDULE OF THE MEDICINE

Schedule 4 (Prescription Only Medicine)

DATE OF FIRST INCLUSION IN THE ARTG

23rd May 2005

DATE OF MOST RECENT AMENDMENT

07 August 2012