Consumer medicine information

Oxaliplatin Kabi Concentrated Injection

Oxaliplatin

BRAND INFORMATION

Brand name

Oxaliplatin Kabi

Active ingredient

Oxaliplatin

Schedule

What is in this leaflet

This leaflet answers some common questions about Oxaliplatin 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 oxaliplatin against the benefits it is expected to have for you.

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

What Oxaliplatin is used for

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

Cancer cells are normal cells which have changed 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 Oxaliplatin because they believe that the benefit of Oxaliplatin 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.

Oxaliplatin is only available on a prescription from your doctor.

Before you are given Oxaliplatin

When you must not be receive it

You should not be given Oxaliplatin 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 Oxaliplatin 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 oxaliplatin 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.

How Oxaliplatin is given

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

Oxaliplatin is not recommended to be given to children.

If you take receive too much (overdose)

Your doctor will decide what dose of Oxaliplatin 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.

While you are being given Oxaliplatin

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.

Visual disturbance is a rare side effect of oxaliplatin. Contact your doctor if this happens to you, and do not drive or use machinery until your vision is clear.

Side Effects

Tell your doctor or nurse as soon as possible if you do not feel well while Oxaliplatin is being given to you. You should also tell your doctor if you do not feel well between courses of Oxaliplatin.

All medicines can have side effects. It is important to understand the side effects that Oxaliplatin may cause, even though you may not experience them yourself. As well as the more predictable side effects of Oxaliplatin, there are other effects that occur much more rarely.

If you notice any side effects or anything unusual it is important to discuss this with 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 Oxaliplatin, and some of the checks made before each treatment to prevent excessive side effects.

Physical Condition. Before each treatment with Oxaliplatin 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. Oxaliplatin 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 Oxaliplatin. Mild nausea and vomiting is more common. Medication to prevent the sickness caused by Oxaliplatin will be given before treatment, and may sometimes be continued after treatment.
Diarrhoea. Severe diarrhoea may occur during treatment with Oxaliplatin.

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

Low Blood Counts. Oxaliplatin 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 Oxaliplatin are:

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
voice disturbance (rare)
loss of hearing (rare)
lung disorders (rare)
visual disturbance (rare)
headache (rare)
confusion (rare)
seizures or fits (rare)
inflammation of the pancreas (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.

After being given Oxaliplatin Injection Concentrate

Storage

If you need to store Oxaliplatin before you take it with you to hospital, keep the vial in the original carton and make sure it is stored in a cool dry place below 25°C and protected from light. Do not freeze.

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

This is not all the information that is available on Oxaliplatin. If you have any more questions or are not sure about anything speak to your doctor or pharmacist.

Product Description

Oxaliplatin Kabi concentrated injection 5mg/mL comes as a concentrated solution for injection in a glass vial.

Each carton contains one (1) vial.

Each Oxaliplatin Kabi vial contains the active ingredient, oxaliplatin 50mg or 100mg.

The concentrated solution for injection also contains the inactive ingredients succinic acid, sodium hydroxide and water for injections.

Supplier

Oxaliplatin Kabi is supplied in Australia by:
Fresenius Kabi Australia Pty Limited
964 Pacific Highway
Pymble NSW 2073
Telephone: (02) 9391 5555

Oxaliplatin 50 mg/10 mL Concentrated Injection
AUST R 157759

Oxaliplatin 100 mg / 20 mL Concentrated Injection
AUST R 157761

® = Registered Trademark

This information leaflet was prepared in May 2010.

Published by MIMS October 2010

BRAND INFORMATION

Brand name

Oxaliplatin Kabi

Active ingredient

Oxaliplatin

Schedule

Name of the medicine

Oxaliplatin.

Excipients.

Succinic acid, sodium hydroxide and water for injections.

Description

Oxaliplatin concentrated injection 5 mg/mL is a solution intended for infusion by dilution with 5% Glucose Injection prior to intravenous infusion.
Oxaliplatin is an antineoplastic substance belonging to a new class of platinum-based compounds. Oxaliplatin is described chemically as [SP-4-2]-(1R,2R) (cyclohexane-1,2-diamine- k²N,N' (oxalato (2-)k²O¹,O²] platinum (II) or (SP-4-2) [(1R,2R)- cyclohexane-1,2- diamine-kN,kN´] [ethanedioato(2-)-kO¹,kO²] platinum. Empirical formula: C₈H₁₄N₂O₄Pt. Molecular weight: 397.3. CAS: 61 825-94-3.
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.
Oxaliplatin Kabi concentrated injection also contains succinic acid, sodium hydroxide and water for injections.

Pharmacology

Oxaliplatin is an antineoplastic active substance belonging to a new class of platinum based compounds in which the platinum atom is complexed with 1,2-diaminocyclohexane (DACH) and an oxalate group. Oxaliplatin is a single enantiomer, the cis-[oxalato (trans-l-1,2-DACH) platinum].

Pharmacodynamics.

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 130 mg/m² every three weeks for 1 to 5 cycles and oxaliplatin at 85 mg/m² every two weeks for 1 to 3 cycles are as follows. (See Table 1.)

At the end of a 2-hour infusion, 15% of the administered platinum is present in the systemic circulation, the remaining 85% being rapidly distributed into tissues or eliminated in the urine. Irreversible binding to red blood cells and plasma, results in half-lives in these matrices that are close to the natural turnover of red blood cells and serum albumin. No accumulation was observed in plasma ultrafiltrate following 85 mg/m² every two weeks or 130 mg/m² every three weeks and steady state was attained by cycle one in this matrix. Inter- and intra-subject variability is generally low.
Biotransformation in vitro is considered to be the result of non-enzymatic degradation and there is no evidence of cytochrome P450 mediated metabolism of the diaminocyclohexane (DACH) ring.
Oxaliplatin undergoes extensive biotransformation in patients, and no intact active substance 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 12-57 mL/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 85 mg/m² as 2 hour infusion, folinic acid 200 mg/ m² over 2 hours, followed by a FU bolus of 400 mg/m², then a 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 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, the primary endpoint, compared to patients treated with FU/FA (see Table 2). 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.

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 (85 mg/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.

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 centers in the United States and Canada.
Treatment arms - FOLFOX4 Day 1: oxaliplatin 85 mg/m² over 2 hours, folinic acid 200 mg/m² over 2 hours, followed by a FU bolus of 400 mg/m², then a FU infusion of 600 mg/m² over 22 hours. Folinic acid and FU repeated on Day 2. Cycle repeated every 2 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 6 weeks.
IROX Day 1: oxaliplatin 85 mg/m² over 2 hours, irinotecan 200 mg/m² over 30 minutes. Cycle repeated every 3 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.

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 200 mg/m² over 2 hours, followed by a FU bolus of 400 mg/m², then a 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 were enrolled and 417 treated from August 1995 to July 1997 in 35 centers 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 7.
The FU/FA + 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, post-study treatment with other agents may have influenced survival.

EFC2964.

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 two-weekly. The two study regimens were; Regimen 1: Day 1; folinic acid 200 mg/m² over 2 hours, followed by a FU bolus of 400 mg/m², then a FU infusion of 600 mg/m² over 22 hours. Repeated on Day 2.
Regimen 2: folinic acid 500 mg/m² over 2 hours, followed by a FU infusion of 1500 mg/m² over 22 hours, repeated on Day 2.
The results were as shown in Table 8.

Indications

Oxaliplatin, in combination with fluorouracil and folinic acid, is indicated for:
adjuvant treatment of stage III (Duke’s C) colon cancer after complete resection of the primary tumour;
treatment of advanced colorectal cancer.

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 30 mL/min).

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

Haematological toxicity.

Haematological toxicity should be monitored 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 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.
Due to limited information on safety in patients with moderately impaired renal function, administration should only be considered after suitable appraisal of the benefit/risk for the patient, but 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 and genotoxicity.

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.

Effects on fertility.

In dogs, with oxaliplatin, a decrease in testicular weight accompanied with testicular hypoplasia approaching aplasia was seen at doses ≥ 15 mg/m². However, no effects on fertility were seen in male and female rats at doses up to 12 mg/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 9 mg/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.

Excretion of oxaliplatin into breast milk has not been studied. Oxaliplatin is contraindicated in breast feeding women.
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.

Interactions

In patients who have received a single dose of 85 mg/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 130 mg/m² every 3 weeks, increases of 20% in fluorouracil plasma concentrations have been observed.
In vitro, no significant displacement of oxaliplatin binding to plasma proteins has been observed with the following agents; erythromycin, salicylates, granisetron, paclitaxel, and sodium valproate.
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 CYP450 metabolism of concomitant medications through a competitive mechanism.

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 Oxaliplatin Kabi 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.

Adverse Effects

Note.

Very common ≥ 1/10 (≥ 10%); common ≥ 1/100 and < 1/10 (≥ 1% and < 10%); uncommon ≥ 1/1000 and < 1/100 (≥ 0.1% and < 1.0%); rare ≥ 1/10,000 and < 1/1000 (≥ 0.01% and < 0.1%); very rare < 1/10,000 (< 0.01%).

Neurological.

(See Table 11.)

Post marketing experience with unknown frequency - convulsion.
Neurological adverse effects are the dose-limiting toxicity. A primarily sensory peripheral neuropathy occurs in 85-95% of patients. These symptoms usually develop at the end of the 2-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 (10 cycles) the risk of occurrence of persistent symptoms is 10% and for a cumulative dose of 1020 mg/m² (12 cycles) the risk of occurrence is 20%.
In the advanced setting, in EFC2962, 16% of patients receiving oxaliplatin + FU/FA developed paraesthesia and associated functional impairment lasting longer than two weeks, after a median cumulative oxaliplatin dose of 874 mg/m². Two percent were withdrawn due to persisting paraesthesia (i.e. persisting between treatment cycles), after cumulative oxaliplatin doses of 759-1100 mg/m².
In the majority of cases, the neurological signs and symptoms improve when treatment is discontinued. Analysis of patients in EFC2962 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: 169.7-1713.15 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, 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 spasm/muscle contractions - involuntary/muscle twitching/myoclonus, coordination abnormal/gait abnormal/ataxia/balance disorders, throat or chest tightness/pressure/ discomfort/pain.

Vascular disorders.

(See Table 12.)

Post marketing experience with unknown frequency - haemolytic uremic syndrome.

Haematological.

(See Table 13.)

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.

(See Table 14.)

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.

(See Table 15.)

Musculoskeletal.

(See Table 16.)

Hypersensitivity.

(See Table 17.)

Sensory.

(See Table 18.)

Renal.

(See Table 19.)

In clinical and post-marketing setting: very rare - acute tubular necrosis, acute interstitial nephritis, and acute renal failure.

Respiratory.

(See Table 20.)

Immune system.

(See Table 21).

Skin.

(See Table 22).

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

Dosage.

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 (6 months).