4.1 Therapeutic indications
Oxaliplatin in combination with 5-fluorouracil (5-FU) and folinic acid (FA) is indicated for:
 Adjuvant treatment of stage III (Duke's C) colon cancer after complete resection of primary
tumour
 Treatment of metastatic colorectal cancer.

4.2 Posology and method of administration
Posology
FOR ADULTS ONLY
The recommended dose for oxaliplatin in adjuvant setting is 85 mg/m² intravenously repeated every two
weeks for 12 cycles (6 months).
The recommended dose for oxaliplatin in treatment of metastatic colorectal cancer is 85 mg/m²
intravenously repeated every 2 weeks.
Dosage given should be adjusted according to tolerability (see section 4.4).

Oxaliplatin is administered as a 2- to 6-hour intravenous infusion in 250 to 500 ml of 5% glucose solution
to give a concentration between 0.2 mg/ml and 0.70 mg/ml; 0.70 mg/ml is the highest concentration in
clinical practice for an oxaliplatin dose of 85 mg/m².
Oxaliplatin was mainly used in combination with continuous infusion 5-fluorouracil based regimens. For
the two-weekly treatment schedule 5-fluorouracil regimens combining bolus and continuous infusion
were used.
Special Populations
- Renal impairment
Oxaliplatin has not been studied in patients with severe renal impairment (See section 4.3).
In patients with moderate renal impairment, treatment may be initiated at the normally recommended
dose (see section 4.4). There is no need for dose adjustment in patients with mild renal dysfunction.
- Hepatic impairment
In a phase I study including patients with several levels of hepatic impairment, frequency and severity of
hepato-biliary disorders appeared to be related to progressive disease and impaired liver function tests at
baseline. No specific dose adjustment for patients with abnormal liver function tests was performed
during clinical development.
- Elderly patients
No increase in severe toxicities was observed when oxaliplatin was used as a single agent or in
combination with 5-fluorouracil in patients over the age of 65. In consequence no specific dose adaptation
is required for elderly patients.
Method of administration
Oxaliplatin is administered by intravenous infusion.
The administration of oxaliplatin does not require hyperhydration.
Oxaliplatin diluted via a central venous line or peripheral vein in 250 to 500 ml of 5% glucose solution to
give a concentration not less than 0.2 mg/ml must be infused over 2 to 6 hours. Oxaliplatin infusion
should always precede that of 5-fluorouracil.
In the event of extravasation, administration must be discontinued immediately.
The preparation of injectable solution of cytotoxic agents must be carried out by trained specialist
personnel with knowledge of the medicinal produsts used, in condition that guarantee the integrity of
medical product, the protection of the environment and in the particular the protection of the personnel
handling the medicinal products, in accordance with the hospital policy. It requires a preparation area
reserved for this purpose. It is forbidden to smoke, eat or drink in this area.
Instructions for use
See section 6.6.

Oxaliplatin is contraindicated in patients who: - have a known history of hypersensitivity to the active substance or to any of the excipient(s) listed in section 6.1. - are breast-feeding. - have myelosuppression prior to starting first course, as evidenced by baseline neutrophils < 2 x 109/l and/or platelet count of < 100 x 109/l. - have a peripheral sensitive neuropathy with functional impairment prior to first course. - have a severely impaired renal function (creatinine clearance less than 30 ml/min).

Oxaliplatin should only be used in specialised departments of oncology and should be administered
under the supervision of an experienced oncologist.
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. In this situation, renal
function should be closely monitored and dose adjusted according to toxicity.
Hypersensitivity reactions
Special surveillance should be ensured for patients with a history of allergic reactions to other products
containing platinum. In case of anaphylactic manifestations the infusion should be interrupted
immediately and an appropriate symptomatic treatment started. Re-administration of oxaliplatin to such
patients is contraindicated. Cross reactions, sometimes fatal, have been reported with all platinum
compounds.
In case of oxaliplatin extravasation, the infusion must be stopped immediately and usual local
symptomatic treatment initiated.
Neurological symptoms
Neurological toxicity of oxaliplatin should be carefully monitored, especially if co-administered with
other medicinal products with specific neurological toxicity. A neurological examination should be
performed before each administration and periodically thereafter.
For patients who develop acute laryngopharyngeal dysaesthesia (see section 4.8), during or within the
hours following the 2-hour infusion, the next oxaliplatin infusion should be administered over 6 hours.
Peripheral neuropathy
If neurological symptoms (paraesthesia, dysaesthesia) occur, the following recommended oxaliplatin
dosage adjustment should be based on the duration and severity of these symptoms:
- If symptoms last longer than seven days and are troublesome, the subsequent oxaliplatin dose should be
reduced from 85 to 65 mg/m2 (metastatic setting) or 75 mg/m2 (adjuvant setting).
- If paraesthesia without functional impairment persists until the next cycle, the subsequent oxaliplatin
dose should be reduced from 85 to 65 mg/m2 (metastatic setting) or 75 mg/m2 (adjuvant setting).
- If paraesthesia with functional impairment persists until the next cycle, oxaliplatin should be
discontinued.
- If these symptoms improve following discontinuation of oxaliplatin therapy, resumption of therapy may
be considered.

Patients should be informed of the possibility of persistent symptoms of peripheral sensory neuropathy
after the end of the treatment. Localised moderate paresthesias or paresthesias that may interfere with
functional activities can persist after up to 3 years following treatment cessation in the adjuvant setting.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
Cases of Reversible Posterior Leukoencephalopathy Syndrome (RPLS) have been reported in patients
receiving oxaliplatin in combination chemotherapy. RPLS is a rare, reversible, rapidly evolving
neurological condition, which can include seizure, hypertension, headache, confusion, blindness, and
other visual and neurological disturbances (see section 4.8). Diagnosis of RPLS is based upon
confirmation by brain imaging, preferably MRI (Magnetic Resonance Imaging).
Nausea, vomiting, diarrhoea and dehydration
Gastrointestinal toxicity, which manifests as nausea and vomiting, warrants prophylactic and/or
therapeutic anti-emetic therapy (see section 4.8).
Dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis and renal impairment
may be caused by severe diarrhoea/emesis particularly when combining oxaliplatin with 5-fluorouracil
(5-FU).
If haematological toxicity occurs (neutrophils < 1.5 x 109/l or platelets < 50 x 109/l), administration of the
next course of therapy should be postponed until haemotological values return to acceptable levels. A full
blood count with white cell differential should be performed prior to start of therapy and before each
subsequent course.
Patients must be adequately informed of the risk of diarrhoea/emesis, mucositis/stomatitis and
neutropenia after oxaliplatin and 5-fluorouracil administration so that they can urgently contact their
treating physician for appropriate management.
If mucositis/stomatitis occurs with or without neutropenia, the next treatment should be delayed until
recovery from mucositis/stomatitis to grade 1 or less and/or until the neutrophil count is ≥ 1.5 x 109/l.
For oxaliplatin combined with 5-fluorouracil (with or without folinic acid (FA)), the usual dose
adjustments for 5-fluorouracil associated toxicities should apply.
If grade 4 diarrhoea, grade 3-4 neutropenia (neutrophils < 1.0 x 109/l), grade 3-4 thrombocytopenia
(platelets < 50 x 109/l) occur, the dose of oxaliplatin should be reduced from 85 to 65 mg/m2 (metastatic
setting) or 75 mg/m2 (adjuvant setting), in addition to any 5-fluorouracil (5-FU) dose reductions required.
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 (see section 4.8).
Hepatic
In case of abnormal liver function test results or portal hypertension which does not obviously result from
liver metastases, very rare cases of drug-induced hepatic vascular disorders should be considered.

In patients who have received a single dose of 85 mg/m2 of oxaliplatin, immediately before
administration of 5-fluorouracil (5-FU), no change in the level of exposure to 5-fluorouracil (5-FU) has
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.

Pregnancy
To date there is no available information on safety of use in pregnant women. In animal studies,
reproductive toxicity was observed. Consequently, oxaliplatin is not recommended during pregnancy and
in women of childbearing potential not using contraceptive measures.
The use of oxaliplatin should only be considered after suitably apprising the patient of the risk to the
foetus and with the patient’s consent.
Appropriate contraceptive measures must be taken during and after cessation of therapy during 4 months
for women and 6 months for men.
Breast-Feeding
Excretion in breast milk has not been studied. Breast-feeding is contra-indicated during oxaliplatin
therapy.
Fertility
Genotoxic effects were observed with oxaliplatin in the preclinical studies. Therefore male patients
treated with oxaliplatin are advised not to father a child during and up to 6 months after treatment and to
seek advice on conservation of sperm prior to treatment because oxaliplatin may have an anti-fertility
effect which could be irreversible.
Women should not become pregnant during treatment with oxaliplatin and should use an effective
method of contraception.
Oxaliplatin may have an anti-fertility effect.

No studies on the effects on the ability to drive and use machines have been performed. However,
oxaliplatin treatment resulting in an increased risk of dizziness, nausea and vomiting, and other
neurologic symptoms that affect gait and balance may lead to minor or moderate influence on the ability
to drive and use machines.
Vision abnormalities, in particular transient vision loss (reversible following therapy discontinuation),
may affect patients´ ability to drive and use machines. Therefore, patients should be warned of the
potential effect of these events on the ability to drive or use machines.

The most frequent adverse events of oxaliplatin in combination with 5-fluorouracil/folinic acid (5-
FU/FA) were gastrointestinal (diarrhoea, nausea, vomiting and mucositis), haematological (neutropenia,
thrombocytopenia) and neurological (acute and dose cumulative peripheral sensory neurophathy).
Overall, these adverse events were more frequent and severe with oxaliplatin and 5-FU/FA combination
than with 5-FU/FA alone.
The frequencies reported in the table below are derived from clinical trials in the metastatic and adjuvant
settings (having included 416 and 1108 patients respectively in the oxaliplatin + 5-FU/FA treatment arms)
and from post marketing experience.

MedDRA Organ
system classes
Very common Common Uncommon Rare
Investigations
- Hepatic enzyme
increase
- Blood alkaline
phosphatise increase
- Blood bilirubin
increase
- Blood lactate
dehydrogenase
increase
- Weight increase
(adjuvant setting)
- Blood creatinine
increase
- Weight decrease
(metastatic setting)
Blood and
lymphatic system
disorders*
- Anaemia
- Neutropenia
- Thrombocytopenia
- Leukopenia
- Lymphopenia
- Febrile
neutropenia
- Immunoallergic
thrombocytopenia
- Haemolytic anaemia
Nervous system
disorders*
- Peripheral sensory
neuropathy
- Sensory disturbance
- Dysgeusia
- Headache
- Dizziness
- Motor neuritis
- Meningism
- Dysarthria
- Reversible Posterior
Leukoencephalopathy
syndrome (RPLS) (see
section 4.4)
Eye disorders - Conjunctivitis
- Visual
disturbance
- Visual acuity reduced
transiently
- Visual field
disturbances
- Optic neuritis
- Transient vision loss,
reversible following
therapy
discontinuation
Ear and
labyrinth
disorders
- Ototoxicity - Deafness
Respiratory,
thoracic and
mediastinal
disorders
- Dyspnoea
- Cough
- Epistaxis
- Hiccups
- Pulmonary
embolism
- Interstitial lung
disease, sometimes
fatal
- Pulmonary fibrosis**
Gastrointestinal
disorders*
- Nausea
- Diarrhoea
- Vomiting
- Stomatitis/ Mucositis
- Abdominal pain
- Constipation
- Dyspepsia
- Gastroesophageal
reflux
- Gastrointestinal
haemorrhage
- Rectal
haemorrhage
- Ileus
- Intestinal
obstruction
- Colitis including
clostridium difficile
diarrhoea
- Pancreatitis
Renal and
urinary disorders
- Haematuria
- Dysuria

Micturition
frequency
abnormal
Skin and
subcutaneous
tissue disorders
- Skin disorder
- Alopecia
- Skin exfoliation
(i.e. Hand & Foot
syndrome)
- Rash
erythematous
- Rash
- Hyperhidrosis
- Nail disorder
Musculoskeletal
and connective
tissue disorders
- Back pain - Arthralgia
- Bone pain
Metabolism and
nutrition
disorders
- Anorexia
- Hyperglycaemia
- Hypokalaemia
- Hypernatraemia
- Dehydration - Metabolic
acidosis
Infections and
infestations*
- Infection - Rhinitis
- Upper respiratory
tract infection
- Neutropenic
sepsis
Vascular
disorders
- Haemorrhage
- Flushing
- Deep vein
thrombosis
- Hypertension
General
disorders and
administration
site conditions
- Fatigue
- Fever++
- Asthenia
- Pain
- Injection site
reaction+++
Immune system
disorders*
- Allergy / allergic
reaction+
Psychiatric
disorders
- Depression
- Insomnia
-
Nervousness

* See detailed section below.
** See section 4.4.
+ Very common: frequent allergy/allergic reactions, occurring mainly during perfusion, sometimes
fatal (frequent allergic reactions such as skin rash, in particularly urticaria, conjunctivitis,
rhinitis). Common anaphylactic reactions, including bronchospasm, angioeodema, low blood
pressure and anaphylactic shock. Delayed hypersensitivity has also been reported with
oxaliplatin hours or even days after the infusion.
++ Very common fever, rigors (tremors), either from infection (with or without febrile neutropenia)
or possibly from immunological mechanism.
+++ Injection site reactions including local pain, redness, swelling and thrombosis have been reported.
Extravasation may also result in local pain and inflammation which may be severe and lead to
complications including necrosis, especially when oxaliplatin is infused through a peripheral vein
(see section 4.4).

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

Pharmacotherapeutic group: Platinum compounds, ATC code: L01XA 03
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-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 5-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.
In patients with metastatic colorectal cancer, the efficacy of oxaliplatin (85 mg/m2 repeated every two
weeks) combined with 5-fluorouracil/folinic acid (5-FU/FA) is reported in three clinical studies:
- In front-line treatment, a 2-arm comparative phase III study (de Gramont, A et al., 2000) randomised
420 patients either to 5-FU/FA alone (LV5FU2, N=210) or the combination of oxaliplatin with 5-
FU/FA (FOLFOX4, N=210).
- In pretreated patients, a comparative three arms phase III study (Rothenberg, ML et al., 2003)
randomised 821 patients refractory to an irinotecan (CPT-11) + 5-FU/FA combination either to 5-
FU/FA alone (LV5FU2, N=275), oxaliplatin single agent (N=275), or combination of oxaliplatin with
5-FU/FA (FOLFOX4, N=271).
- Finally, an uncontrolled phase II study (André, T et al., 1999) included patients refractory to 5-FU/FA
alone, that were treated with the oxaliplatin and 5-FU/FA combination (FOLFOX4, N=57)

Distribution
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:
Table 10: Summary of Platinum Pharmacokinetic Parameter Estimates in Ultrafiltrate
following Multiple Doses of Oxaliplatin at 85 mg/m2 Every Two Weeks or at 130
mg/m2 Every Three Weeks
Dose Cmax AUC0-48 AUC t1/2α t1/2β t1/2γ Vss CL
μg/ml μg * h /ml μg * h /ml h h h l l / h
85 mg/m2
Mean
0.814
4.19
4.68
0.43
16.8
391
440
17.4
SD 0.193 0.647 1.40 0.35 5.74 406 199 6.35
130 mg/m2
Mean
1.21
8.20
11.9
0.28
16.3
273
582
10.1
SD 0.10 2.40 4.60 0.06 2.90 19.0 261 3.07
Mean AUC0-48 and Cmax values were determined on Cycle 3 (85 mg/m2 ) or cycle 5 (130 mg/m2).
Mean AUC, Vss , CL, and CLR0-48 values were determined on Cycle 1.
Cend, Cmax, AUC, AUC0-48, Vss and CL values were determined by non-compartmental analysis.
t1/2α, t1/2β, t1/2γ were determined by compartmental analysis (Cycles 1-3 combined).
At the end of a 2-hour infusion, 15 % of the administered platinum is present in the systemic circulation,
the remaining 85 % being rapidly distributed into tissues or eliminated in the urine. Irreversible binding to
red blood cells and plasma, results in half-lives in these matrices that are close to the natural turnover of
red blood cells and serum albumin. No accumulation was observed in plasma ultrafiltrate following 85
mg/m2 every two weeks or 130 mg/m2 every three weeks and steady state was attained by cycle one in
this matrix. Inter- and intra-subject variability is generally low.
Biotransformation
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.

The target organs identified in non-clinical species (mice, rats, dogs, and/or monkeys) in single- and
multiple-dose studies included the bone marrow, the gastrointestinal system, the kidney, the testes, the
nervous system, and the heart. The target organ toxicities observed in animals are consistent with those
produced by other platinum-containing drugs and DNA-damaging, cytotoxic drugs used in the treatment
of human cancers with the exception of the effects produced on the heart. Effects on the heart were
observed only in the dog and included electrophysiological disturbances with lethal ventricular
fibrillation. Cardiotoxicity is considered specific to the dog not only because it was observed in the dog
alone but also because doses similar to those producing lethal cardiotoxicity in dogs (150 mg/m2) were
well-tolerated by humans. Non-clinical studies using rat sensory neurons suggest that the acute
neurosensory symptoms related to oxaliplatin may involve an interaction with voltage-gated Na+
channels.
Oxaliplatin was mutagenic and clastogenic in mammalian test systems and produced embryo-fetal
toxicity in rats. Oxaliplatin is considered a probable carcinogen, although carcinogenic studies have not
been conducted.

Lactose monohydrate.

The diluted medicinal product should not be mixed with other medications in the same infusion bag or
infusion line. Under instructions for use described in section 6.6, oxaliplatin can be co-administered with
folinic acid via a Y-line.
- DO NOT mix with alkaline drugs or solutions, in particular 5-fluorouracil, folinic acid
preparations containing trometamol as an excipient and trometamol salts of other drugs. Alkaline
drugs or solutions will adversely affect the stability of oxaliplatin (see section 6.6).
- DO NOT dilute oxaliplatin with saline or other solutions containing chloride ions (including
calcium, potassium or sodium chlorides).

Medicinal product as packaged for sale: 4 years Reconstituted concentrate solution in the original vial: The reconstituted concentrate solution should be diluted immediately. Solution for infusion after dilution: After dilution of the reconstituted solution in 5 % glucose solution, chemical and physical in-use stability has been demonstrated for 24 hours at 2°C to 8°C. From a microbiological point of view, the solution for infusion should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C.

Store below 30˚C, protect from light. Do not freeze.
For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

Type I glass vials with stoppers of chlorobutyl elastomer.
Supplied in packs of 1 vial containing oxaliplatin 50 mg, 100 mg or 150 mg.
Not all pack sizes may be marketed.

As with other potentially toxic compounds caution should be exercised when handling and preparing
oxaliplatin solutions.
Instructions for Handling
The handling of this cytotoxic agent by nursing or medical personnel requires every precaution to
guarantee the protection of the handler and his surroundings.
The preparation of injectable solutions of cytotoxic agents must be carried out by trained specialist
personnel with knowledge of the medicines used, in conditions that guarantee the protection of the
environment and in particular the protection of the personnel handling the medicines in accordance with the hospital policy. It requires a preparation area reserved for this purpose. It is forbidden to smoke, eat or
drink in this area.
Personnel must be provided with appropriate handling materials, notably long sleeved gowns, protection
masks, caps, protective goggles, sterile single-use gloves, protective covers for the work area, containers
and collection bags for waste.
Excreta and vomit must be handled with care.
Pregnant women must be warned to avoid handling cytotoxic agents.
Any broken container must be treated with the same precautions and considered as contaminated waste.
Contaminated waste should be incinerated in suitably labelled rigid containers. See below section
“Disposal”.
If oxaliplatin powder, reconstituted solution or infusion solution should come into contact with skin, wash
immediately and thoroughly with water.
If oxaliplatin powder, reconstituted solution or infusion solution should come into contact with mucous
membranes, wash immediately and thoroughly with water.
Special precautions for administration
- DO NOT use injection material containing aluminium.
- DO NOT administer undiluted.
- Only glucose 5% infusion solution (50 mg/ml) is to be used as a diluent.
- DO NOT reconstitute or dilute for infusion with sodium chloride or chloride containing solutions.
- DO NOT administer extravascularly.
- DO NOT mix with any other medication in the same infusion bag or administer simultaneously by the
same infusion line.
- DO NOT mix with alkaline drugs or solutions, in particular 5-fluorouracil, folinic acid preparations
containing trometamol as an excipient and trometamol salts of other drugs. Alkaline drugs or
solutions will adversely affect the stability of oxaliplatin.
Instruction for use with folinic acid (as calcium folinate or disodium folinate)
Oxaliplatin 85mg/m² IV infusion in 250 to 500 ml of 5% glucose solution (50 mg/ml) is given at the same
time as folinic acid IV infusion in 5% glucose solution, over 2 to 6 hours, using a Y-line placed
immediately before the site of infusion.
These two drugs should not be combined in the same infusion bag. Folinic acid must not contain
trometamol as an excipient and must only be diluted using isotonic 5% glucose solution, never in alkaline
solutions or sodium chloride or chloride containing solutions.
Instruction for use with 5-fluorouracil
Oxaliplatin should always be administered before fluoropyrimidines – i.e. 5-fluorouracil.
After oxaliplatin administration, flush the line and then administer 5-fluorouracil.
For additional information on drugs combined with oxaliplatin, see the corresponding manufacturer's
summary of product characteristics.
Any reconstituted solution that shows evidence of precipitation should not be used and should be
destroyed with due regard to legal requirements for disposal of hazardous waste (see below).