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ELOXATIN 5MG/ML CONCENTRATE FOR SOLUTION FOR INFUSION

Active substance(s): OXALIPLATIN / OXALIPLATIN / OXALIPLATIN

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Eloxatin 5mg/ml concentrate for solution for infusion

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
1ml concentrate for solution for infusion contains 5mg oxaliplatin.
10ml of concentrate for solution for infusion contains 50mg of oxaliplatin
20ml of concentrate for solution for infusion contains 100mg of oxaliplatin
40ml of concentrate for solution for infusion contains 200mg of oxaliplatin
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Concentrate for solution for infusion
Clear, colourless liquid

4

CLINICAL PARTICULARS

4.1

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

4.2

Posology and method of administration
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 until disease progression or
unacceptable toxicity.
Dosage given should be adjusted according to tolerability (see section 4.4).
Oxaliplatin should always be administered before fluoropyrimidines – i.e.
5-fluorouracil.
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 must not be administered in patients with severe renal impairment (see
sections 4.3 and 5.2). In patients with mild to moderate renal impairment, the
recommended dose of oxaliplatin is 85 mg/m2 (see sections 4.4 and 5.2).
- Hepatic insufficiency:
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.
- Paediatric patients:
There is no relevant indication for use of oxaliplatin in children. The effectiveness
of oxaliplatin single agent in the paediatric populations with solid tumors has not
been established (see section 5.1).

Method of administration
Oxaliplatin is administered by intravenous infusion.
The administration of oxaliplatin does not require hyperhydration.

Oxaliplatin diluted in 250 to 500 ml of 5% glucose solution to give a
concentration not less than 0.2 mg/ml must be infused via a central venous line or
peripheral vein over 2 to 6 hours. Oxaliplatin infusion must always precede the
administration of 5-fluorouracil.
In the event of extravasation, administration must be discontinued immediately.
Instructions for use:
Oxaliplatin must be diluted before use. Only 5% glucose diluent is to be used to
dilute the concentrate for solution for infusion product. (see section 6.6).

4.3

Contraindications
Oxaliplatin is contraindicated in patients who
- have a known history of hypersensitivity to oxaliplatin.
- are breast feeding.
- have myelosuppression prior to starting first course, as evidenced by baseline
neutrophils <2x109/l and/or platelet count of <100x109/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)
(see section 5.2)

4.4

Special warnings and precautions for use
Oxaliplatin should only be used in specialised departments of oncology and
should be administered under the supervision of an experienced oncologist.
Renal impairment
Patients with mild to moderate renal impairment should be closely monitored
for adverse reactions and the dose adjusted according to toxicity (see section
5.2).
Hypersensitivity reactions
Special surveillance should be ensured for patients with a history of allergic
manifestations 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 contra-indicated. 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 dose 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. Localized
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 also
known as PRES, Posterior Reversible Encephalopathy Syndrome) 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, dehydration and haematological changes
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.

Cases of intestinal ischemia, including fatal outcomes, have been reported with
oxaliplatin treatment. In case of intestinal ischemia, oxaliplatin treatment
should be discontinued and appropriate measures initiated. (see section 4.8).
If haematological toxicity occurs (neutrophils < 1.5x109/L or platelets
< 50x109/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. Myelosuppressive effects may be additive to those of
concomitant chemotherapy. Patient with severe and persistent
myelosuppression are at high risk of infectious complications. Sepsis,
neutropenic sepsis and septic shock have been reported in patients treated with
oxaliplatin including fatal outcomes (see section 4.8.). If any of these events
occurs, oxaliplatin should be discontinued.
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 ≥ 1.5x109/L.
For oxaliplatin combined with 5-fluorouracil (with or without folinic acid), the
usual dose adjustments for 5-fluorouracil associated toxicities should apply.
If grade 4 diarrhoea, grade 3-4 neutropenia (neutrophils < 1.0x109/L), febrile
neutropenia (fever of unknown origin without clinically or microbiologically
documented infection with an absolute neutrophil count < 1.0 x 109/L,
temperature > 38.3°C or a sustained temperature > 38°C for more than one hour),
or grade 3-4 thrombocytopenia (platelets < 50x109/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 dose reductions
required.
Pulmonary
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).

Blood disorders
Haemolytic-uraemic syndrome (HUS) is a life-threatening side effect
(frequency not known). Oxaliplatin should be discontinued at the first signs of
any evidence of microangiopathic haemolytic anaemia, such as rapidly falling

haemoglobin with concomitant thrombocytopenia, elevation of serum
bilirubin, serum creatinine, blood urea nitrogen, or LDH. Renal failure may
not be reversible with discontinuation of therapy and dialysis may be required.
Disseminated intravascular coagulation (DIC), including fatal outcomes, has
been reported in association with oxaliplatin treatment. If DIC is present,
oxaliplatin treatment should be discontinued and appropriate treatment should
be administered. (see section 4.8)

QT prolongation
QT prolongation may lead to an increased risk for ventricular arrhythmias
including Torsade de Pointes, which can be fatal (see section 4.8). The QT
interval should be closely monitored on a regular basis before and after
administration of oxaliplatin. Caution should be exercised in patients with a
history or a predisposition for prolongation of QT, those who are taking
medicinal products known to prolong QT interval, and those with electrolyte
disturbances such as hypokalemia, hypocalcaemia, or hypomagnesaemia. In
case of QT prolongation, oxaliplatin treatment should be discontinued. (see
sections 4.5 and 4.8).
Rhabdomyolysis
Rhabdomyolysis has been reported in patients treated with oxaliplatin,
including fatal outcomes. In case of muscle pain and swelling, in combination
with weakness, fever or darkened urine, oxaliplatin treatment should be
discontinued. If rhabdomyolysis is confirmed, appropriate measures should be
taken. Caution is recommended if medicinal products associated with
rhabdomyolysis are administered concomitantly with oxaliplatin. (see sections
4.5 and 4.8)
Gastrointestinal ulcer/ Gastrointestinal ulcer haemorrhage and perforation
Oxaliplatin treatment can cause gastrointestinal ulcer and potential complications,
such as gastrointestinal haemorrhage and perforation, which can be fatal. In case
of gastrointestinal ulcer, oxaliplatin treatment should be discontinued and
appropriate measures taken. (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 druginduced hepatic vascular disorders should be considered.
Pregnancy
For use in pregnant women, see section 4.6.
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 antifertility effect which could be irreversible.
Women should not become pregnant during treatment with oxaliplatin and
should use an effective method of contraception (see section 4.6).
Peritoneal hemorrhage may occur when oxaliplatin is administered by
intraperitoneal route (off-label route of administration).

4.5

Interaction with other medicinal products and other forms of interaction
2

In patients who have received a single dose of 85 mg/m of oxaliplatin, immediately
before administration of 5-fluorouracil, no change in the level of exposure to 5fluorouracil 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.
Caution is advised when oxaliplatin treatment is co-administered with other medicinal
products known to cause QT interval prolongation. In case of combination with such
medicinal products, the QT interval should be closely monitored (see section 4.4).
Caution is advised when oxaliplatin treatment is administered concomitantly with
other medicinal products known to be associated with rhabdomyolysis. (see section
4.4).

4.6

Fertility, pregnancy and lactation
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 appraising 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.
Breast-feeding
Excretion in breast milk has not been studied. Breast-feeding is contraindicated during oxaliplatin therapy.

Fertility
Oxaliplatin may have an anti-fertility effect (see section 4.4).
Due to the potential genotoxic effects of oxaliplatin, appropriate contraceptive
measures must be taken during and after cessation of therapy during 4 months
for women and 6 months for men.
4.7

Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been
performed. However oxaliplatin treatment resulting in an increase risk of
dizziness, nausea and vomiting, and other neurologic symptoms that affect gait
and balance may lead to a 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.

4.8

Undesirable effects
Summary of the safety profile
The most frequent adverse events of oxaliplatin in combination with 5fluorouracil/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.
Tabulated list of adverse reactions
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.
Frequencies in this table are defined using the following convention: very common
(≥1/10) common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000,
<1/1000), very rare (<1/10000), not known (cannot be estimated from the available
data).
Further details are given after the table.

MedDRA Organ
system classes
Infections and
infestations*

Very common
- Infection

Common
- Rhinitis
- Upper respiratory
tract infection

Uncommon
Sepsis+

Rare

Blood and
lymphatic system
disorders*

Immune system
disorders*
Metabolism and
nutrition
disorders
Psychiatric
disorders
Nervous system
disorders*

- Anaemia
- Neutropenia
-Thrombocyto
penia
- Leukopenia
- Lymphopenia
- Allergy/allergic
reaction++
- Anorexia
- Hyperglycaemia
- Hypokalaemia
- Hypernatraemia

- Peripheral
sensory
neuropathy
- Sensory
disturbance
- Dysgeusia
- Headache

- Neutropenic
sepsis
- Febrile
neutropenia+

- Immunoallergic
thrombocytopenia
- Haemolytic anaemia

- Dehydration
- Hypocalcaemia

- Metabolic
acidosis

- Depression
- Insomnia
- Dizziness
- Motor neuritis
- Meningism

- Nervousness
- Dysarthria
- Reversible Posterior
Leukoencephalopathy
syndrome (RPLS, or
PRES) (see section
4.4)

- Conjunctivitis
- Visual
disturbance

Eye disorders

- Ototoxicity

Ear and labyrinth
disorders
Vascular
disorders

Respiratory,
thoracic and
mediastinal
disorders
Gastrointestinal
disorders*

- Dyspnoea
- Cough
- Epistaxis

- Haemorrhage
- Flushing
- Deep vein
thrombosis
- Hypertension
- Hiccups
- Pulmonary
embolism

- Nausea
- Diarrhoea
- Vomiting
- Stomatitis
/Mucositis
- Abdominal pain
- Constipation

- Dyspepsia
-Gastroesophageal reflux
- Gastrointestinal
haemorrhage
- Rectal
haemorrhage

Skin and
subcutaneous
tissue disorders

- Skin disorder
- Alopecia

- Skin exfoliation
(i.e. Hand & Foot
syndrome)
- Rash

- Ileus
- Intestinal
obstruction

- Visual acuity reduced
transiently
- Visual field
disturbances
- Optic neuritis
- Transient vision loss,
reversible following
therapy discontinuation
- Deafness

- Interstitial lung
disease, sometimes
fatal
- Pulmonary fibrosis**
- Colitis including
clostridium difficile
diarrhoea
- Pancreatitis

Musculoskeletal
and connective
tissue disorders
Renal and
urinary disorders

- Back pain

General disorders
and
administration
site conditions

- Fatigue
- Fever+++
- Asthenia
- Pain
- Injection site
reaction++++
- Hepatic enzyme
increase
- Blood alkaline
phosphatase
increase
- Blood bilirubin
increase
- Blood lactate
dehydrogenase
increase
- Weight increase
(adjuvant setting)

Investigations

erythematous
- Rash
- Hyperhidrosis
- Nail disorder
- Arthralgia
- Bone pain
- Haematuria
- Dysuria
- Micturition
frequency
abnormal

- Blood creatinine
increase
- Weight decrease
(metastatic setting)

*
**
+
++

See detailed section below
See section 4.4.
Common neutropenic sespsis, including fatal outcomes.
Very common allergies/allergic reactions, occurring mainly during infusion,
sometimes fatal. Common allergic reactions include skin rash, particularly urticaria,
conjunctivitis, and rhinitis. Common anaphylactic or anaphylactoid reactions include
bronchospasm, angioeodema, hypotension, sensation of chest pain 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).
Description of selected adverse reactions
Blood and lymphatic system disorders

Oxaliplatin and
5-FU/FA

Incidence by patient (%), by grade
Metastatic Setting

Adjuvant Setting

85 mg/m²
every 2 weeks
Anemia
Neutropenia
Thrombocytopenia
Febrile neutropenia

All
grades

Gr 3

Gr 4

All
grades

Gr 3

Gr 4

82.2
71.4
71.6
5.0

3
28
4
3.6

<1
14
<1
1.4

75.6
78.9
77.4
0.7

0.7
28.8
1.5
0.7

0.1
12.3
0.2
0.0

Rare (>1/10000, <1/1000)
Disseminated intravascular coagulation (DIC), including fatal outcomes (see section
4.4).
Post-marketing experience with frequency not known:
Haemolytic uremic syndrome
Autoimmune pancytopenia
Infections and infestations

Oxaliplatin and 5FU/FA 85 mg/m2
Every 2 weeks

Sepsis (including sepsis
and neutropenic sepsis)

Incidence by patient (%)
Metastatic Setting

Adjuvant Setting

All
grades

All
grades

1.5

1.7

Postmarketing experience with frequency not known
Septic shock, including fatal outcomes.

Immune system disorders
Incidence of allergic reactions by patient (%), by grade
Oxaliplatin and
Metastatic Setting
Adjuvant Setting
5-FU/FA
85 mg/m²
every 2 weeks
All
All
Gr 3
Gr 4
Gr 3
Gr 4
grades
grades
Allergic reactions /
Allergy

9.1

1

<1

10.3

2.3

0.6

Nervous system disorders
The dose limiting toxicity of oxaliplatin is neurological. It involves a sensory
peripheral neuropathy characterised by dysaesthesia and/or paraesthesia of the
extremities with or without cramps, often triggered by the cold. These symptoms
occur in up to 95% of patients treated. The duration of these symptoms, which

usually regress between courses of treatment, increases with the number of
treatment cycles.
The onset of pain and/or a functional disorder are indications, depending on the
duration of the symptoms, for dose adjustment, or even treatment discontinuation (see
section 4.4).
This functional disorder includes difficulties in executing delicate movements and is a
possible consequence of sensory impairment. The risk of occurrence of persistent
symptoms for a cumulative dose of 850 mg/m² (10 cycles) is approximately 10% and
20% for a cumulative dose of 1020 mg/m² (12 cycles).
In the majority of the cases, the neurological signs and symptoms improve or totally
recover when treatment is discontinued. In the adjuvant setting of colon cancer, 6
months after treatment cessation, 87 % of patients had no or mild symptoms. After up
to 3 years of follow up, about 3 % of patients presented either with persisting
localized paresthesias of moderate intensity (2.3%) or with paresthesias that may
interfere with functional activities (0.5%).
Acute neurosensory manifestations (see section 5.3) have been reported. They start
within hours of administration and often occur on exposure to cold. They usually
present as transient paresthesia, dysesthesia and hypoesthesia. An acute syndrome
of pharyngolaryngeal dysesthesia occurs in 1% - 2% of patients and is characterised
by subjective sensations of dysphagia or dyspnoea/feeling of suffocation, without
any objective evidence of respiratory distress (no cyanosis or hypoxia) or of
laryngospasm or bronchospasm (no stridor or wheezing); Although antihistamines
and bronchodilators have been administered in such cases, the symptoms are rapidly
reversible even in the absence of treatment. Prolongation of the infusion helps to
reduce the incidence of this syndrome (see section 4.4). Occasionally other
symptoms that have been observed include jaw spasm/muscle spasms/muscle
contractions-involuntary/muscle twitching/myoclonus, coordination abnormal/gait
abnormal/ataxia/balance disorders, throat or chest
tightness/pressure/discomfort/pain. In addition, cranial nerve dysfunctions may be
associated with above mentioned events, or also occur as an isolated event 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 in visual acuity, visual field
disorders.
Other neurological symptoms such as dysarthria, loss of deep tendon reflex and
Lhermitte's sign were reported during treatment with oxaliplatin. Isolated cases of
optic neuritis have been reported.
Post-marketing experience with frequency not known:
Convulsion
Cardiac disorders
Post-marketing experience with frequency not known
QT prolongation, which may lead to ventricular arrhythmias including Torsade de
Pointes, which may be fatal (see section 4.4).
Respiratory, thoracic and mediastinal disorders
Post-marketing experience with frequency not known:

Laryngospasm

Gastrointestinal disorders
Incidence by patient (%), by grade
Oxaliplatin and
Metastatic Setting
5-FU/FA
85 mg/m²
every 2 weeks
All
Gr 3
Gr 4
grades
Nausea
Diarrhoea
Vomiting
Mucositis/Stomatitis

Adjuvant Setting

All
grades

Gr 3

Gr 4

69.9

8

<1

73.7

4.8

0.3

60.8
49.0
39.9

9
6
4

2
1
<1

56.3
47.2
42.1

8.3
5.3
2.8

2.5
0.5
0.1

Prophylaxis and/or treatment with potent antiemetic agents is indicated.
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) (see section 4.4).
Post marketing experience with frequency not known
Intestinal ischemia, including fatal outcomes (see section 4.4).
Gastrointestinal ulcer and perforation, which can be fatal. (see section 4.4).
Hepato-biliary disorders
Very rare (<1/10,000):
Liver sinusoidal obstruction syndrome, also known as veno-occlusive disease of liver,
or pathological manifestations related to such liver disorder, including peliosis
hepatis, nodular regenerative hyperplasia, perisinusoidal fibrosis. Clinical
manifestations may be portal hypertension and/or increased transaminases.
Musculoskeletal and connective tissue disorders
Post-marketing experience with frequency not known
Rhabdomyolysis, including fatal outcomes (see section 4.4).
Renal and urinary disorders
Very rare (<1/10,000):
Acute tubular necrosis, acute interstitial nephritis and acute renal failure.
Skin and Subcutaneous tissue disorders
Post-marketing experience with frequency not known
Hypersensitivity vasculitis

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

4.9

Overdose
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.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: other antineoplastic agents, platinum compounds.
ATC code: L01XA 03
Mechanism of action
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, (SP-4-2)-[(1R,2R)-Cyclohexane-1,21

2

diamine-kN, kN'] [ethanedioato(2-)-kO , kO ] 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 5fluorouracil 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 crosslinks, resulting in the disruption of DNA synthesis leading to cytotoxic and
antitumour effects.
Clinical efficacy and safety

In patients with metastatic colorectal cancer, the efficacy of oxaliplatin
2

(85mg/m repeated every two weeks) combined with 5-fluorouracil/folinic
acid (5-FU/FA) is reported in three clinical studies:
-

-

-

In front-line treatment, the 2-arm comparative phase III EFC2962 study
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, the comparative three arms phase III study
EFC4584 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 5FU/FA (FOLFOX4, N=271).
Finally, the uncontrolled phase II EFC2964 study included patients
refractory to 5-FU/FA alone, that were treated with the oxaliplatin and 5FU/FA combination (FOLFOX4, N=57).

The two randomised clinical trials, EFC2962 in front-line therapy and
EFC4584 in pretreated patients, demonstrated a significantly higher response
rate and a prolonged progression free survival (PFS)/time to progression (TTP)
as compared to treatment with 5-FU/FA alone. In EFC4584 performed in
refractory pretreated patients, the difference in median overall survival (OS)
between the combination of oxaliplatin and 5-FU/FA did not reach statistical
significance.
Response rate under FOLFOX4 versus LV5FU2
Response rate, %
(95% CI)
LV5FU2
FOLFOX4
Oxaliplatin
independent radiological
Single agent
review ITT analysis
Front-line treatment EFC2962
Response assessment every
8 weeks
Pretreated patients
EFC4584
(refractory to CPT-11 + 5FU/FA)
Response assessment every 6
weeks
Pretreated patients
EFC2964
(refractory to 5-FU/FA)
Response assessment every
12weeks
* NA: Not Applicable

22
(16-27)

49
(42-56)

NA*

P value = 0.0001
0.7
(0.0-2.7)

11.1
(7.6-15.5)

1.1
(0.2-3.2) )

P value < 0.0001
NA*

23
(13-36)

NA*

Median Progression Free Survival (PFS) / Median Time to Progression (TTP)
FOLFOX4 versus LV5FU2
Median PFS/TTP,
Months (95% CI)
LV5FU2
FOLFOX4 Oxaliplatin
independent radiological
Single
review ITT analysis
agent
Front-line treatment
6.0
8.2
NA*
EFC2962 (PFS)
(5.5-6.5)
(7.2-8.8)
Log-rank P value =
0.0003
Pretreated patients EFC4584
2.1
(TTP)
2.6
5.3
(1.6-2.7)
(refractory to CPT-11 +
(1.8-2.9)
(4.7-6.1)
5-FU/FA)
Log-rank P value <
0.0001
Pretreated patients
EFC2964
NA*
5.1
NA*
(refractory to 5-FU/FA)
(3.1-5.7)
*NA: Not Applicable

Median Overall Survival (OS) under FOLFOX4 versus LV5FU2
Median OS, months
(95% CI)
LV5FU2
FOLFOX
Oxaliplatin
ITT analysis
4
Single
agent
Front-line treatment
14.7
16.2
NA*
EFC2962
(13.0-18.2) (14.7-18.2)
Log-rank P value = 0.12
Pretreated patients
EFC4584
(refractory to
CPT-11 + 5-FU/FA)

8.8
(7.3 - 9.3)

9.9
(9.1-10.5)

8.1
(7.2-8.7)

Log-rank P value = 0.09
Pretreated patients
EFC2964
(refractory to 5-FU/FA)
*NA: Not Applicable

NA*

10.8
(9.3-12.8)

NA*

In pretreated patients (EFC4584), who were symptomatic at baseline, a higher
proportion of those treated with oxaliplatin and 5-FU/FA experienced a significant
improvement of their disease related symptoms compared to those treated with 5FU/FA alone (27.7% versus 14.6% p = 0.0033).
In non-pretreated patients (EFC2962), no statistically significant difference between
the two treatment groups was found for any of the quality of life dimensions.
However, the quality of life scores were generally better in the control arm for

measurement of global health status and pain and worse in the oxaliplatin arm for
nausea and vomiting.
In the adjuvant setting, the MOSAÏC comparative phase III study (EFC3313)
randomised 2246 patients (899 stage II/Dukes B2 and 1347 stage III/Dukes C) further
to complete resection of the primary tumour of colon cancer either to 5-FU/FA alone
(LV5FU2, N=1123 (B2/C = 448/675) or to combination of oxaliplatin and 5-FU/FA
(FOLFOX4, N=1123 (B2/C) = 451/672).
EFC 3313 3-year disease free survival (ITT analysis)* for the overall population
Treatment arm
LV5FU2
FOLFOX4
Percent 3-year disease free survival
(95% CI)
Hazard ratio (95% CI)

73.3
78.7
(70.6-75.9)
(76.2-81.1)
0.76
(0.64-0.89)
Stratified log rank test
P=0.0008
* median follow up 44.2 months (all patients followed for at least 3 years)
The study demonstrated an overall significant advantage in 3-year disease free
survival for the oxaliplatin and 5-FU/FA combination (FOLFOX4) over 5-FU/FA
alone (LV5FU2).
EFC 3313 3-year Disease Free Survival (ITT analysis)* according to Stage of
disease
Patient stage
Stage II
Stage III
(Dukes B2)
(Dukes C)
Treatment arm
LV5FU2
FOLFOX4 LV5FU2
FOLFOX4
Percent 3-year disease
free survival

84.3
(80.9-87.7)

87.4
(84.390.5)

65.8
(62.269.5)

72.8
(69.4-76.2)

(95% CI)
Hazard ratio (95% CI) 0.79
0.75
(0.57-1.09)
(0.62-0.90)
Log-rank test
P=0.151
P=0.002
* median follow up 44.2 months (all patients followed for at least 3 years)
Overall Survival (ITT analysis)
At time of the analysis of the 3-year disease free survival, which was the primary
endpoint of the MOSAIC trial, 85.1% of the patients were still alive in the FOLFOX4
arm versus 83.8% in the LV5FU2 arm. This translated into an overall reduction in
mortality risk of 10% in favour of FOLFOX4 not reaching statistical significance
(hazard ratio = 0.90).
The figures were 92.2% versus 92.4% in the stage II (Dukes B2) sub-population
(hazard ratio = 1.01) and 80.4% versus 78.1% in the stage III (Dukes C) subpopulation (hazard ratio = 0.87), for FOLFOX4 and LV5FU2, respectively.
Paediatric population

Oxaliplatin single agent has been evaluated in paediatric population in 2 Phase I (69
patients) and 2 Phase II (166 patients) studies. A total of 235 paediatric patients (7
months-22 years of age) with solid tumours have been treated. The effectiveness of
oxaliplatin single agent in the paediatric populations treated has not been established.
Accrual in both Phase II studies was stopped for lack of tumour response.
5.2

Pharmacokinetic properties
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:
Summary of Platinum Pharmacokinetic Parameter Estimates in Ultrafiltrate
2

Following Multiple Doses of Oxaliplatin at 85 mg/m Every Two Weeks or at 130
2

mg/m Every Three Weeks
Dose
85 mg/m2
Mean
SD
130 mg/m2
Mean
SD

Cmax
µg/m
L

AUC0-48
µg.h/m
L

AUC
µg.h/m
L

t1/2α
h

t1/2β
h

t1/2γ
h

Vss
L

CL
L/h

0.814

4.19

4.68

0.43

16.8

391

440

17.4

0.193

0.647

1.40

0.35

5.74

406

199

6.35

1.21

8.20

11.9

0.28

16.3

273

582

10.1

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
and
CL
values
were
determined
on
Cycle
1.
Cmax, AUC, AUC0-48, Vss and CL values were determined by non-compartmental analysis.
t1/2α, t1/2β, and 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 130mg/m2 every three weeks and steady state was attained
by cycle one in this matrix. Inter- and intra-subject variability is generally low.
Biotransformation in vitro is considered to be the result of non-enzymatic degradation
and there is no evidence of cytochrome P450-mediated metabolism of the
diaminocyclohexane
(DACH)
ring.
Oxaliplatin
undergoes
extensive
biotransformation in patients, and no intact drug was detectable in plasma ultrafiltrate
at the end of a 2h-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.
The effect of renal impairment on the disposition of oxaliplatin was studied in
patients with varying degrees of renal function. Oxaliplatin was administered at a
dose of 85 mg/m2 in the control group with a normal renal function (CLcr >
80 ml/min, n=12) and in patients with mild (CLcr = 50 to 80 ml/min, n=13) and
moderate (CLcr = 30 to 49 ml/min, n=11) renal impairment, and at a dose of
65mg/m2 in patients with severe renal impairment (CLcr < 30 ml/min, n=5).
Median exposure was 9, 4, 6, and 3 cycles, respectively, and PK data at cycle 1
were obtained in 11, 13, 10, and 4 patients respectively.
There was an increase in plasma ultrafiltrate (PUF) platinum AUC, AUC/dose and a
decrease in total and renal CL and Vss with increasing renal impairment especially
in the (small) group of patients with severe renal impairment: point estimate (90%
CI) of estimated mean ratios by renal status versus normal renal function for
AUC/dose were 1.36 (1.08, 1.71), 2.34 (1.82, 3.01) and 4.81 (3.49, 6.64) for
patients with mild and moderate and in severe renal failure respectively.
Elimination of oxaliplatin is significantly correlated with the creatinine clearance.
Total PUF platinum CL was respectively 0.74 (0.59, 0.92), 0.43 (0.33, 0.55) and 0.21
(0.15, 0.29) and for Vss respectively 0.52 (0.41, 0.65), 0.73 (0.59, 0.91) and 0.27
(0.20, 0.36) for patients with mild, moderate and severe renal failure respectively.
Total body clearance of PUF platinum was therefore reduced by respectively 26% in
mild, 57% in moderate, and 79% in severe renal impairment compared to patients
with normal function.
Renal clearance of PUF platinum was reduced in patients with impaired renal
function by 30% in mild, 65% in moderate, and 84% in severe renal impairment
compared to patients with normal function.
There was an increase in beta half life of PUF platinum with increasing degree of
renal impairment mainly in the severe group. Despite the small number of patients
with severe renal dysfunction, these data are of concern in patients in severe renal
failure and should be taken into account when prescribing oxaliplatin in patients with
renal impairment (see sections 4.2, 4.3 and 4.4).

5.3

Preclinical safety data
The target organs identified in preclinical 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
2

mg/m ) were well-tolerated by humans. Preclinical 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.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Water for injections

6.2

Incompatibilities
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.

6.3

-

DO NOT mix with alkaline medicinal products or solutions, in particular
5-fluorouracil, folinic acid preparations containing trometamol as an
excipient and trometamol salts of others 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).

-

DO NOT mix with other medicinal products in the same infusion bag or
infusion line (see section 6.6 for instructions concerning simultaneous
administration with folinic acid).

-

DO NOT use injection equipment containing aluminium.

Shelf life
3 years
After dilution in 5% glucose, chemical and physical in-use stability has been
demonstrated for 48 hours at +2°C to +8°C and for 24 hours at +25°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 unless dilution has taken place in controlled and validated
aseptic conditions.

6.4

Special precautions for storage
Keep the vial in the outer carton in order to protect from light.
Do not freeze.
For storage conditions of the diluted medicinal product, see section 6.3.

6.5

Nature and contents of container
1 vial with 10 ml concentrate (Type I clear glass) with bromobutyl elastomer stopper
1 vial with 20 ml concentrate (Type I clear glass) with bromobutyl elastomer stopper
1 vial with 40 ml concentrate (Type I clear glass) with bromobutyl elastomer stopper

Pack size: 1 vial per box.
Not all pack sizes may be marketed.
6.6

Special precautions for disposal
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 healthcare 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 integrity of the product, 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 chapter “Disposal”.
If oxaliplatin concentrate or solution for infusion, should come into contact
with skin, wash immediately and thoroughly with water.
If oxaliplatin concentrate or solution for infusion, should come into contact
with mucous membranes, wash immediately and thoroughly with water.

Special precautions for administration
-

DO NOT use injection equipment containing aluminium.
DO NOT administer undiluted.
Only glucose 5% infusion solution is to be used as a diluent. DO NOT
dilute for infusion with sodium chloride or chloride containing solutions.
DO NOT mix with any other medicinal products 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 others 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 500ml of 5% glucose solution is
given at the same time as folinic acid intravenous infusion in 5% glucose
solution, over 2 to 6 hours, using a Y-line placed immediately before the site
of infusion.
These two medicinal products 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 5fluorouracil.
For additional information on drugs combined with oxaliplatin, see the
corresponding manufacturer’s summary of product characteristics.
Concentrate for solution for infusion
Inspect visually prior to use. Only clear solutions without particles should be
used.
The medicinal product is for single use only. Any unused concentrate should
be discarded.
Dilution for intravenous infusion
Withdraw the required amount of concentrate from the vial(s) and then dilute
with 250ml to 500ml of a 5% glucose solution to give an oxaliplatin
concentration between 0.2mg/ml and 2mg/ml; concentration range for which
the physico-chemical stability of oxaliplatin has been demonstrated.
Administer by IV infusion.
After dilution in 5% glucose, chemical and physical in-use stability has been
demonstrated for 48 hours at +2°C to +8°C and for 24 hours at +25°C.
From a microbiological point of view, this infusion preparation 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 unless dilution has taken place in controlled and validated
aseptic conditions.
Inspect visually prior to use. Only clear solutions without particles should be
used.
The medicinal product is for single use only. Any unused infusion solution
should be discarded (see chapter “disposal” below).
NEVER use sodium chloride or chloride containing solutions for dilution.
The compatibility of Oxaliplatin solution for infusion has been tested with
representative, PVC-based, administration sets.
Infusion
The administration of oxaliplatin does not require prehydration.
Oxaliplatin diluted in 250 to 500ml of a 5% glucose solution to give a
concentration not less than 0.2mg/ml must be infused either by peripheral vein
or central venous line over 2 to 6 hours. When oxaliplatin is administered with
5-fluorouracil, the oxaliplatin infusion must precede the administration of 5fluorouracil.
Disposal
Remnants of the medicinal product as well as all materials that have been used
for dilution and administration must be destroyed according to hospital
standard procedures applicable to cytotoxic agents and with due regard to
current laws related to the disposal of hazardous waste.

7

MARKETING AUTHORISATION HOLDER
Aventis Pharma Limited
One Onslow Street,
Guildford
Surrey,
GU1 4YS
United Kingdom
Trading as:
sanofi-aventis
One Onslow Street
Guildford
Surrey
GU1 4YS
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 04425/0296

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
15/12/2005 / 10/11/2009

10

DATE OF REVISION OF THE TEXT
24/06/2016

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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