Consumer medicine information

Oxalatin

Oxaliplatin

BRAND INFORMATION

Brand name

Oxalatin

Active ingredient

Oxaliplatin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Oxalatin.

What is in this leaflet

This leaflet answers some common questions about OXALATIN injection. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of using OXALATIN against the benefits it is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet as you may need to read it again.

What OXALATIN is used for

OXALATIN is used to treat cancer of the large intestine and rectum (colorectal cancer). OXALATIN is used with two other anti-cancer drugs, fluorouracil (FU), and folinic acid. The active ingredient in OXALATIN is called oxaliplatin.

Cancer cells have changed from normal cells so that they grow in an uncontrolled way. Oxaliplatin works by interfering with cancer cell growth. Because of the similarities between cancer cells and normal cells, anti cancer drugs often have unwanted effects on the body.

Your doctors have decided to treat you with OXALATIN because they believe that the benefit of OXALATIN treatment will be greater than the unwanted effects.

Many of the side effects from anti cancer drugs are predictable and can be prevented or lessened. Your doctor and other staff will take all of the precautions needed to reduce the unwanted effects of treatment.

OXALATIN is only available on a prescription from your doctor.

Before you are given OXALATIN

When you must not receive it

You should not be given OXALATIN if you are allergic to the active ingredient 'oxaliplatin'. If you have had an allergic reaction to oxaliplatin before, you should not receive it again.

You must not receive OXALATIN if you are pregnant or breastfeeding. Oxaliplatin may cause birth defects if you are being treated with it at the time of conception or it is given to women who are already pregnant. Adequate contraception is required during treatment with oxaliplatin. You should discuss this with your doctor. Nursing mothers are advised not to breastfeed while receiving oxaliplatin, as the effect of breast milk from such patients is unknown.

You must not receive OXALATIN if you have severe kidney disease.

What you should tell your doctor

You must tell your doctor if:

  • you have had a reaction to any other platinum compound
  • you have severe kidney disease
  • you have nerve damage (neuropathy)
  • you have any other medical condition that he or she is not aware of
  • you are taking any other medicines, including medicines that you have bought without a prescription from a pharmacy, supermarket or health food shop.

Your doctor or pharmacist can tell you what to do if you are taking any of these medicines.

How OXALATIN is given

OXALATIN will be given to you as an infusion into one of your veins (this is called an intravenous infusion). The infusion will be given over 2-6 hours.

The dose of OXALATIN is calculated according to your body surface area, which is calculated from your weight and height. The usual dose is 85mg/m2 every two weeks. Your doctor may change the dose in some circumstances.

Each course of treatment is called a cycle; your doctor will tell you how many cycles you will receive.

OXALATIN will be used with fluorouracil (FU) and folinic acid.

OXALATIN is not recommended in children.

While you are being given OXALATIN

Things you must do

Avoid cold foods and drinks and cover skin prior to exposure to cold during or within 48 hours following being given oxaliplatin, since neurological effects may be brought on or worsened by exposure to cold.

Contact your doctor immediately if you develop fever, particularly in association with persistent diarrhoea or evidence of infection since this may indicate low blood count.

Contact your doctor if persistent vomiting, diarrhoea, signs of dehydration, cough or breathing difficulties or signs of allergic reaction occur.

Be aware that this medication may affect your vision, which may impair your ability to drive and use machines.

Side effects

Tell your doctor or nurse as soon as possible if you do not feel well while OXALATIN is being given to you. You should also tell your doctor if you do not feel well between courses of OXALATIN. All medicines can have side effects. It is important to understand the side effects that OXALATIN may cause, even though you may not experience them. As well as the predictable side effects of OXALATIN, there are other effects that occur much more rarely.

If you have any side effects or notice anything unusual it is important to inform your doctor before your next treatment.

Your doctor will decide whether such effects are because of your treatment, and what action needs to be taken.

This section explains the side effects of OXALATIN, and some of the checks made before each treatment to prevent excessive side effects.

  • Physical Condition. Before each treatment with OXALATIN you will be examined for any condition that may be affected by chemotherapy (for example, infection, or loss of feeling).
    This will include those conditions caused by previous treatment, those caused by your disease, and those caused by other things.
  • Loss of feeling. OXALATIN can affect nerves in the hands and feet. This is common soon after treatment and can appear as tingling or numbness in the fingers or toes, and may be made worse by cold temperatures or by contact with cold water or other cold objects. These symptoms often go away between treatments, but may last longer and get worse with repeated treatment. In some patients the limbs may become weak or painful. However, in most patients these symptoms improve after treatment is stopped. Tell your doctor if any of these things happen. Your doctor will examine you before treatment to see if you are affected.
  • Nausea and Vomiting. Severe nausea and vomiting is uncommon with OXALATIN. Mild nausea and vomiting is more common. Medication to prevent the sickness caused by OXALATIN will be given before treatment, and may sometimes be continued after treatment.
  • Diarrhoea. Severe diarrhoea may occur during treatment with OXALATIN.

If you suffer from persistent or severe diarrhoea or vomiting, contact your doctor urgently for treatment advice.

  • Low Blood Counts. OXALATIN can affect the body's ability to make blood cells. There are three types of blood cells checked before each treatment; platelets, which help control bleeding; white blood cells, which help fight infection; and red blood cells which move oxygen around the body. If your blood count is too low, your treatment may be postponed, or the dose reduced. Tell your doctor if you notice any bruising or abnormal bleeding, or have an infection. These may be signs of a low blood count.
  • Difficulty swallowing. Some patients may experience a sudden, temporary feeling of difficulty with swallowing or breathing. This sensation, if it occurs, usually happens during the infusion or within hours after the infusion. It may be triggered by swallowing a cold drink.
    Although unpleasant, this feeling does not last long, and goes away by itself. Tell your doctor if this happens to you.

Other known side effects of OXALATIN include:

  • mucositis (sore lips or mouth ulcers)
  • abdominal pain
  • constipation
  • anorexia
  • changes to liver function
  • mild hair loss (alopecia)
  • fever
  • inflammation around the injection site
  • tiredness
  • skin rash
  • allergic reactions
  • conjunctivitis
  • altered taste
  • abnormal tongue sensation
  • nose bleeds
  • feeling of chest pressure
  • hiccups
  • voice disturbance (rare)
  • loss of hearing (rare)
  • lung disorders (rare)
  • visual disturbance (rare)

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything else that is making you feel unwell.

If you receive too much (overdose)

Your doctor will decide what dose of OXALATIN you need, and this will be given under close supervision, usually in a hospital setting. The risk of an overdosage in these circumstances is low. In the event of an overdose occurring, your doctor will decide on the treatment necessary.

Storage

If you need to store OXALATIN before you take it with you to hospital, make sure it is stored in a cool dry place where the temperature does not exceed 25°C. Protect from light.

Do not use it after the expiry date printed on the vial.

Product description

OXALATIN comes in a powder in a glass vial. Each OXALATIN vial contains the active ingredient, oxaliplatin 50mg or 100mg. Besides the active ingredient, OXALATIN powder for injection also contains mannitol.

Australian Registration Numbers:
OXALATIN (oxaliplatin 50mg) powder for injection: AUST R 126124
OXALATIN (oxaliplatin 100mg) powder for injection: AUST R 126125

Sponsor

OXALATIN is supplied in Australia by:
Spirit Pharmaceuticals Pty Ltd
117 Harrington Street
The Rocks Sydney NSW 2000
Australia

This leaflet was last updated on 27 August 2010.

Published by MIMS October 2015

BRAND INFORMATION

Brand name

Oxalatin

Active ingredient

Oxaliplatin

Schedule

S4

 

Name of the medicine

Oxaliplatin.

Excipients

Mannitol.

Description

Chemical name: (SP-4-2)-[(1R,2R)-cyclohexane-1, 2-diamine-kN, kN1] [ethanedioato(2-)-kO,1,kO2] platinum.
Chemical abstracts name: [(1R,2R)-1, 2-cyclohexanediamine-N,N'] [oxalate(2-)O,O'] platine(II). Molecular formula: C8H14N2O4Pt. MW: 397.22. CAS: 61825-94-3. 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.

Pharmacology

Pharmacodynamics.

Oxaliplatin is an antineoplastic drug belonging to a 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-l-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 interstrand and intrastrand 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 130 mg/m2 every three weeks for one to five cycles and oxaliplatin at 85 mg/m2 every two weeks for one to three cycles are shown in Table 1.
At the end of a two 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. Intersubject and intrasubject variability is generally low.
Biotransformation in vitro is considered to be the result of nonenzymatic 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 two 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 to 9.95 ± 1.91 L/hour in renal impairment (creatinine clearance 12 to 57 mL/minute) 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 85 mg/m2 as a two hour infusion, folinic acid 200 mg/m2 over two hours, followed by an FU bolus of 400 mg/m2, then an FU infusion of 600 mg/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 1,108 patients were treated in the FOLFOX4 arm and 1,111 in the FU/FA arm. The median number of cycles received in both arms was 12.
In the intent to treat (ITT) population, after a median of four years follow up, patients treated with FOLFOX4 had significantly increased disease free survival, the primary endpoint, compared to patients treated with FU/FA (see Table 2). In the subgroup 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.

Treatment of advanced colorectal cancer. Use in combination with fluorouracil and folinic acid (FU/FA).

A total of 1,312 patients has been enrolled in three pivotal trials for untreated (EFC7462/N9741, EFC2962) and pretreated patients (EFC2964). These studies evaluated the efficacy of oxaliplatin at the same dose intensity (85 mg/m2/two 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, three 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 two week FOLFOX4, six week IFL or three week IROX treatment cycles. A total of 795 patients was enrolled and 773 treated from May 1999 in 301 centres in the United States and Canada.
Treatment arms. FOLFOX4 day 1: oxaliplatin 85 mg/m2 over two hours, folinic acid 200 mg/m2 over two hours, followed by an FU bolus of 400 mg/m2, then an FU infusion of 600 mg/m2 over 22 hours. Folinic acid and FU repeated on day 2. Cycle repeated every two weeks.
IFL day 1: irinotecan 125 mg/m2 over 90 minutes, folinic acid 20 mg/m2 over 15 minutes or IV push, FU bolus of 500 mg/m2 weekly x 4. Cycle repeated every six weeks.
IROX day 1: oxaliplatin 85 mg/m2 over two hours, irinotecan 200 mg/m2 over 30 minutes. Cycle repeated every three weeks.
This study has demonstrated a statistically significant longer TTP (time to progression) and OS (overall survival), 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. See Tables 3, 4, 5 and 6.
EFC2962 was a multinational multicentre randomised phase III study in previously untreated patients, comparing a two weekly fluorouracil bolus plus infusion and high dose folinic acid (FU/FA regimen, day 1: folinic acid 200 mg/m2 over two hours, followed by an FU bolus of 400 mg/m2, then an FU infusion of 600 mg/m2 over 22 hours; repeated on day 2) to the same regimen combined with oxaliplatin at the dosage of 85 mg/m2 every two weeks. A total of 420 patients was enrolled and 417 treated from August 1995 to July 1997 in 35 centres from nine countries. The median number of treatment cycles was 12 in the FU/FA plus oxaliplatin group and eleven in the FU/FA group. Confirmed responses after independent radiological review (intent to treat analysis n = 420) are shown in Table 7.
The FU/FA plus oxaliplatin group had a statistically significant greater response rate and longer progression free survival. There was no significant difference in overall survival between the two groups. However, the study was not powered to detect a difference in overall survival. Additionally, in both groups, poststudy 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 85 mg/m2 twice weekly. The two study regimens were as follows.
Regimen 1, day 1: folinic acid 200 mg/m2 over two hours, followed by an FU bolus of 400 mg/m2, then an FU infusion of 600 mg/m2 over 22 hours, repeated on day 2.
Regimen 2, day 1: folinic acid 500 mg/m2 over two hours, followed by an FU infusion of 1,500 mg/m2 over 22 hours, repeated on day 2.
The results are shown in Table 8.

Indications

In combination with fluorouracil and folinic acid: adjuvant treatment of stage III (Duke's C) colon cancer after complete resection of the primary tumour; and treatment of advanced colorectal cancer.

Contraindications

Known history of hypersensitivity to oxaliplatin.
Pregnancy.
Breastfeeding.
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.
Peripheral sensory neuropathy with functional impairment prior to first course.
Severely impaired renal function (creatinine clearance less than 30 mL/minute).

Precautions

General.

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

Allergic reactions.

Anaphylactic-like reactions to oxaliplatin have been reported, and may occur within minutes of oxaliplatin administration. Patients with a history of allergic reactions to platinum compounds should be monitored for allergic symptoms. 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 Reactions) of oxaliplatin should be carefully monitored, especially if coadministered 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 two hour infusion, the next oxaliplatin infusion should be administered over six 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.

Gastrointestinal toxicity.

Gastrointestinal toxicity, which manifests as nausea and vomiting, warrants prophylactic antiemetic therapy, including 5HT3 antagonists and corticosteroids. Dehydration, ileus, intestinal obstruction, hypokalaemia, 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.

Oxaliplatin has been associated with pulmonary fibrosis (0.7% of study patients), which may be fatal. In the case of unexplained respiratory symptoms such as nonproductive 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 Reactions).

Hepatic toxicity.

Reactions related to liver sinusoidal obstruction syndrome, including nodular regenerative hyperplasia, have been reported (see Adverse Reactions). 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.

Impaired renal function

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.

Impaired hepatic function

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.

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.

Carcinogenesis, mutagenesis, impairment of fertility

Carcinogenicity.

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.

Genotoxicity.

Oxaliplatin was shown to be mutagenic and clastogenic in mammalian test systems in vitro and in vivo.

Effects on fertility.

In dogs dosed with oxaliplatin, a decrease in testicular weight accompanied with testicular hypoplasia approaching aplasia was seen at doses greater than or equal to 15 mg/m2. However, no effects on fertility were seen in male and female rats at doses up to 12 mg/m2/day for five days/cycle.

Use in pregnancy.

(Category D)
Reproductive toxicity studies showed no teratogenic activity in rats or rabbits at intravenous doses up to 6 and 9 mg/m2/day, respectively, (1/20 of the maximum recommended clinical dose, based on body surface area). However, increased embryonic deaths, decreased fetal 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 fetus. Oxaliplatin is probably toxic to the human fetus 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 breastfeeding women.

Use in children

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

Instructions 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 doctor for appropriate management.
Patients and caregivers should be informed of the expected side effects of oxaliplatin 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.

Interactions

In patients who have received a single dose of oxaliplatin 85 mg/m2 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 130 mg/m2 every three 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 intravenous line. There are 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.

Adverse Effects

Adverse reactions recorded in clinical trials are shown in Tables 9 and 10.

Note.

Very common: ≥ 1/10 (≥ 10%), common: ≥ 1/100 and < 1/10 (≥ 1% and < 10%), uncommon: ≥ 1/1,000 and < 1/100 (≥ 0.1% and < 1%), rare: ≥ 1/10,000 and < 1/1,000 (≥ 0.01% and < 0.1%), very rare: < 1/10,000 (< 0.01%).

Neurological.

Very common: sensory peripheral neuropathy (adjuvant). Primarily sensory peripheral neuropathy (eg loss of deep tendon reflexes, dysaesthesia, paraesthesia, Lhermitte's sign) (advanced).
Common: pharyngolaryngeal dysaesthesia, jaw spasm, abnormal tongue sensation, feeling of chest pressure (advanced).
Rare: dysarthria (advanced).
Neurological adverse reactions are the dose limiting toxicity. A primarily sensory peripheral neuropathy occurs in 85 to 95% of patients. These symptoms usually develop at the end of the two hour oxaliplatin infusion or within a few hours, abate spontaneously within the next hours or days, and frequently recur with further cycles. They may be precipitated by or exacerbated by exposure to cold temperatures or objects. They usually present as transient paraesthesia, dysaesthesia and hypoaesthesia. There may be functional impairment such as difficulty in executing fine movements. The duration of symptoms increases with the number of treatment cycles. Symptoms usually recede between courses of treatment. If symptoms persist or pain or functional impairment develops, the dose should be reduced or treatment discontinued (see Dosage and Administration).
In the adjuvant setting, for a cumulative dose of 850 mg/m2 (ten cycles) the risk of occurrence of persistent symptoms is 10% and for a cumulative dose of 1,020 mg/m2 (12 cycles) the risk of occurrence is 20%.
In the advanced setting, in EFC 2962, 16% of patients receiving oxaliplatin plus FU/FA developed paraesthesia and associated functional impairment lasting longer than two weeks, after a median cumulative oxaliplatin dose of 874 mg/m2. 2% were withdrawn due to persisting paraesthesia (i.e. persisting between treatment cycles), after cumulative oxaliplatin doses of 759 to 1,100 mg/m2. In the majority of cases, the neurological signs and symptoms improve when treatment is discontinued. Analysis of patients in EFC 2962 showed that of the 34 patients who developed grade 3 neurotoxicity (the maximum grade in that study), 25 (73.5%) had an improvement of their symptoms in a median time of 13.2 weeks. Eight of the 34 patients (23%) had complete resolution of their symptoms. The mean duration of the grade 3 neurotoxicity was 13.6 weeks. The mean cumulative oxaliplatin dose at date of onset was 913.6 mg/m2 (range: 169.7 to 1,713.15 mg/m2). The median follow up time for these 34 patients was 55.71 weeks.
An acute pharyngolaryngeal dysaesthesia syndrome occurs in 1 to 2% of patients. It often occurs on exposure to cold and changes in temperature. It is characterised by subjective sensations of dysphagia and dyspnoea, feeling of suffocation, without evidence of respiratory distress (no cyanosis or hypoxia, laryngospasm or bronchospasm).
Other symptoms occasionally observed, particularly of cranial nerve dysfunction, may be either associated with other symptoms or also may occur in isolation, e.g. 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 spasm/ muscle contractions (involuntary/ muscle twitching/ myoclonus), coordination abnormal/ gait abnormal/ ataxia/ balance disorders, throat or chest tightness/ pressure/ discomfort/ pain.

Haematological.

Very common: epistaxis, anaemia (all grades), neutropenia (all grades), thrombocytopenia (all grades) (adjuvant). Anaemia (all grades), neutropenia (all grades), thrombocytopenia (all grades) (advanced). In both adjuvant and advanced cancer treatment, addition of oxaliplatin to fluorouracil and folinic acid:
substantially increased the incidence of neutropenia and severe neutropenia (neutrophils < 1.0 x 109/L); and
substantially increased the incidence of thrombocytopenia (see Tables 9 and 10).

Gastrointestinal.

Very common: diarrhoea, nausea, vomiting, stomatitis, anorexia, abdominal pain, mucositis, constipation (adjuvant). Diarrhoea, nausea, vomiting, stomatitis, anorexia, abdominal pain, mucositis, constipation, dehydration, ileus, intestinal obstruction, hypokalaemia, metabolic acidosis, constipation (advanced).
Common: dyspepsia (adjuvant).
Rare: colitis, including Clostridium difficile diarrhoea (advanced).
Addition of oxaliplatin to fluorouracil and folinic acid:
increased the incidence of severe nausea, vomiting, diarrhoea and stomatitis in the adjuvant setting (see Table 9) and substantially increased these effects in the advanced cancer setting (see Table 10).

Hepatobiliary.

Very common: elevation of transaminases and alkaline phosphatase activities (advanced).
Very rare: reactions related to liver sinusoidal obstruction syndrome, including peliosis, nodular regenerative hyperplasia, perisinusoidal fibrosis and portal hypertension (adjuvant and advanced).

Musculoskeletal.

Very common: back pain*, arthralgia (advanced). *Back pain: If associated with haemolysis, which has been rearely reported, should be investigated.

Hypersensitivity.

Very common: skin rash (particularly urticaria), conjunctivitis, rhinitis (adjuvant and advanced).
Common: bronchospasm, sensation of chest pain, angioedema, hypotension, anaphylactic shock (adjuvant and advanced).

Sensory.

Very common: taste perversion (adjuvant).
Common: conjunctivitis (adjuvant).
Uncommon: ototoxicity (advanced).
Rare: deafness, optic neuritis, loss of visual acuity (advanced).

Renal.

Common: altered renal function (advanced).
Very rare: renal tubular necrosis (advanced).
In clinical and postmarketing setting. Very rare: acute tubulointerstitial nephropathy leading to acute renal failure.

Respiratory.

Common: rhinitis, dyspnoea (adjuvant).
Rare: acute interstitial lung disease, pulmonary fibrosis (advanced).

Immune system.

Very common: infections, fever, rigors (tremors) (adjuvant and advanced).
Common: febrile neutropenia (adjuvant and advanced).
Rare: autoimmune haemolytic anaemia and thrombocytopenia (advanced).

Skin.

Very common: alopecia, rash (adjuvant)
Common: alopecia, rash (advanced).
Moderate alopecia has been reported in 2% of patients treated with oxaliplatin as a single agent; the combination of oxaliplatin and fluorouracil did not increase the incidence of alopecia observed with fluorouracil alone.

Dosage and Administration

In combination with fluorouracil and folinic acid, the recommended dose for the treatment of advanced colorectal cancer is 85 mg/m2 intravenously repeated every two weeks.
In combination with fluorouracil and folinic acid the recommended dose for adjuvant treatment is 85 mg/m2 intravenously repeated every two weeks for 12 cycles (six months).

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 two to six hours. This decreases Cmax by 30% and may lessen acute toxicities.
If sensory loss or paraesthesia persists longer than seven 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 greater than or equal to 1.5 x 109/L and platelet count is greater than or equal to 75 x 109/L; and reduce the oxaliplatin 85 mg/m2 dose to 75 mg/m2 every two weeks and FU dose by 20% (adjuvant treatment); or reduce the oxaliplatin 85 mg/m2 dose to 65 mg/m2 every two weeks and FU dose by 20% (advanced treatment).

Gastrointestinal toxicity.

If grade 3 to 4 gastrointestinal reactions occur, as assessed according to US National Cancer Institute criteria, delay treatment until resolution of the adverse reactions; and reduce the oxaliplatin 85 mg/m2 dose to 75 mg/m2 every two weeks and FU dose by 20% (adjuvant treatment); or reduce the oxaliplatin 85 mg/m2 dose to 65 mg/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, Section 9b).
Oxaliplatin should be administered before fluorouracil.
Oxaliplatin is administered as a two to six hour intravenous infusion in glucose 5% injection 250 to 500 mL.

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, below).
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.

Reconstitution of the solution. The lyophilised powder is reconstituted by adding water for injections or glucose 5% injection 10 mL (for the 50 mg vial) or 20 mL (for the 100 mg vial). The resulting solution contains oxaliplatin 5 mg/mL. Do not administer the reconstituted solution without further dilution.
Chemical and physical in-use stability has been demonstrated for 24 hours at 2 to 8°C when protected from light. From a microbiological point of view, the reconstituted solution should be diluted immediately with glucose 5% injection. If not diluted 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 to 8°C. 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. Product is for single use only. Discard any residue.

Dilution before infusion.

The reconstituted solution or the concentrate must be further diluted in an infusion solution of glucose 5% injection 250 to 500 mL. From a microbiological and chemical point of view, this infusion preparation should be used immediately. Inspect visually prior to use. Only clear solutions without particles should be used. The product is for single use in one patient only. Discard any residue. Never use sodium chloride solution for either reconstitution or dilution.

Infusion.

The administration of oxaliplatin does not require prehydration. Oxaliplatin diluted in glucose 5% injection 250 to 500 mL must be infused either by central venous line or peripheral vein over two to six hours. When oxaliplatin is administered with fluorouracil, the oxaliplatin infusion should precede that of fluorouracil.
Oxaliplatin can be coadministered 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 glucose 5% 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 or dilution and administration must be destroyed according to local statutory requirements.

Overdosage

There is no known antidote to oxaliplatin.

Symptoms.

In cases of overdose, exacerbation of adverse events can be expected.

Treatment.

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

Presentation

Vial (sterile lyophilised powder for infusion with rubber stopper, aluminium cap and polypropylene cover), 50 mg; 100 mg.

Storage

Unopened product: store below 25°C, protect from light.

Poison Schedule

S4.