DBL™ Oxaliplatin for injection

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Oxaliplatin 50 mg
Available from:
Pfizer New Zealand Limited
INN (International Name):
Oxaliplatin 50 mg
Dosage:
50 mg
Pharmaceutical form:
Powder for injection
Composition:
Active: Oxaliplatin 50 mg Excipient: Lactose monohydrate
Units in package:
Vial, glass, Type I clear glass, 1 vial, 1 dose unit
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Heraeus Deutschland GmbH & Co. KG
Therapeutic indications:
DBL™ Oxaliplatin, in combination with 5-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.
Product summary:
Package - Contents - Shelf Life: Vial, glass, Type I clear glass, 1 vial - 1 dose units - 36 months from date of manufacture stored at or below 30°C. (below 30°C)
Authorization number:
TT50-8287a
Authorization date:
2009-01-09

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NEW ZEALAND DATA SHEET

1.

PRODUCT NAME

Oxaliplatin for Injection 20 mg Powder for injection

Oxaliplatin for Injection 50 mg Powder for injection

Oxaliplatin for Injection 100 mg Powder for injection

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial of DBL Oxaliplatin for Injection (oxaliplatin powder for injection) contains either

20 mg, 50 mg or 100 mg oxaliplatin.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

DBL Oxaliplatin for Injection is a sterile lyophilised powder for infusion.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

DBL Oxaliplatin, in combination with 5-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.

4.2 Dose and method of administration

Dose

In combination with fluorouracil and folinic acid the recommended dose for the treatment of

advanced colorectal cancer is either 85 mg/m

intravenously repeated every two weeks.

In combination with fluorouracil and folinic acid the recommended dose for adjuvant

treatment is 85 mg/m

intravenously repeated every two weeks for 12 cycles (6 months).

Dose Adjustments

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

oxaliplatin adjusted accordingly.

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Neurological Toxicity

If acute neurological reactions occur, e.g., acute pharyngolaryngeal dysaesthesia, increase the

oxaliplatin infusion time from 2 hours to 6 hours. This decreases C

by 30% and may

lessen acute toxicities.

If sensory loss or paraesthesia persists longer than 7 days or interferes with function (grade 2

toxicity), reduce oxaliplatin dose by 25%.

If sensory loss or paraesthesia interferes with activities of daily living (grade 3 toxicity),

oxaliplatin should be discontinued.

Haematological Toxicity

If haematological toxicity (neutrophils <1.5 x 10

/L or platelets <75 x 10

/L) is present before

starting treatment or prior to the next course:

Delay treatment until neutrophil count is ≥1.5 x 10

/L and platelet count is ≥75 x 10

Reduce the 85 mg/m

oxaliplatin dose to 75 mg/m

every two weeks and FU dose by

20% (adjuvant treatment)

Reduce the 85 mg/m

oxaliplatin dose to 65 mg/m

every two weeks and FU dose by

20% (advanced treatment)

Gastrointestinal Toxicity

If grade 3-4 gastrointestinal reactions occur, as assessed according to US

National Cancer

Institute

criteria:

Delay treatment until resolution of the adverse reactions and

Reduce the 85 mg/m

oxaliplatin dose to 75 mg/m

every two weeks and FU dose by

20% (adjuvant treatment)

Reduce the 85 mg/m

oxaliplatin dose to 65 mg/m

every two weeks and FU dose by

20% (advanced treatment)

Toxicity Associated with Fluorouracil

Dose adjustments should also be made for fluorouracil associated toxicities (see

relevant

product information

Oxaliplatin should be administered before fluorouracil.

Oxaliplatin is administered as a 2- to 6-hour intravenous infusion in 250 to 500 mL of 5%

glucose injection.

Preparation and Administration

Special precautions for administration

DO NOT use any injection material containing aluminium

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DO NOT administer undiluted

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

containing chlorides

DO NOT mix with any other medication or administer simultaneously by the same

infusion line (in particular fluorouracil and folinic acid). A Y-tube may be used (refer to

infusion instructions under section 6.6)

USE ONLY the recommended diluents (refer to reconstitution and dilution instructions

under section 6.6).

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

should be destroyed.

4.3 Contraindications

Oxaliplatin is contraindicated in patients who:

have a known history of hypersensitivity to oxaliplatin,

are pregnant,

are breastfeeding,

have myelosuppression prior to starting first course, as evidenced by baseline neutrophils

<1.5 x 10

/L and/or platelet count of <75 x 10

have a peripheral sensory neuropathy with functional impairment prior to first course,

have severely impaired renal function (creatinine clearance less than 30 mL/min).

4.4 Special warnings and precautions for use

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 injection administration. Patients with a history of allergic reactions to platinum

compounds should be monitored for allergic symptoms. In case of an anaphylactic-type

reaction to oxaliplatin, the infusion should be immediately discontinued and appropriate

symptomatic treatment initiated. Rechallenge with oxaliplatin is contraindicated.

Immunosuppressant Effects/Increased Susceptibility to Infections

Administration of live or live attenuated vaccines in patients immunocompromised by

chemotherapeutic agents, may result in serious or fatal infections. Vaccination with a live

vaccine should be avoided in patients receiving oxaliplatin. Killed or inactivated vaccines

may be administered; however, the response to such vaccines may be diminished.

Neurological Toxicity

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Neurological

toxicity

(see

section

4.8)

oxaliplatin

should

carefully

monitored,

especially if co-administered with other medications with specific neurological toxicity. A

neurological examination should be performed before initiation of each administration, and

periodically thereafter. It is not known whether patients with pre-existing medical conditions

associated with peripheral nerve damage have a reduced threshold for oxaliplatin induced

peripheral neuropathy.

For patients who develop acute laryngopharyngeal dysaesthesias, during or within 48 hours

following the 2-hour infusion, the next oxaliplatin infusion should be administered over 6

hours. To prevent such dysaesthesia, advise the patient to avoid exposure to cold and to avoid

ingesting

cold

food

and/or

beverages

during

within

hours

following

oxaliplatin

administration.

Gastrointestinal Toxicity

Gastrointestinal toxicity, which manifests as nausea and vomiting, warrants prophylactic anti-

emetic

therapy,

including

5-HT3

antagonists

corticosteroids.

Dehydration,

ileus,

intestinal obstruction, hypokalemia, metabolic acidosis and renal impairment may be caused

by severe diarrhoea/emesis, particularly when combining oxaliplatin with fluorouracil (see

section 4.2).

Haematological Toxicity

Monitor haematological toxicity with a full blood count and white cell differential count prior

to starting therapy and before each subsequent course. Idiosyncratic haematological toxicity

may occur, especially in patients who have received previous myelotoxic treatment (see

section 4.2).

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 section 4.8).

Hepatic Toxicity

Reactions related to liver sinusoidal obstruction syndrome, including nodular regenerative

hyperplasia, have been reported (see section 4.8). In the case of abnormal liver function test

results or portal hypertension which could not be explained by liver metastases, reactions

related to liver sinusoidal obstruction syndrome should be investigated and very rare cases of

drug induced hepatic vascular disorders should be considered.

Renal Impairment

Oxaliplatin has not been studied in patients with severe renal impairment. It is therefore

contraindicated in patients with severe renal impairment.

There is limited information on safety in patients with moderately impaired renal function,

and administration should only be considered after suitable appraisal of the benefit/risk for

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the patient, however, treatment may be initiated at the normally recommended dose. In this

situation, renal function should be closely monitored and dose adjusted according to toxicity.

There is no need for dose adjustment in patients with mild renal dysfunction.

Hepatic Impairment

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.

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.

Paediatric Population

Oxaliplatin is not recommended for use in children as safety and efficacy have not been

established in this group of patients.

Advice to Patients

Patients must be adequately informed of the risk of diarrhoea/emesis and neutropenia after

oxaliplatin/fluorouracil

administration

that

they

urgently

contact

their

treating

physician for appropriate management.

Patients and caregivers should be informed of the expected side effects of oxaliplatin

and, in particular, patients should be advised to:

Avoid cold foods and drinks and cover skin prior to exposure to cold during or within 48

hours following oxaliplatin administration, since neurological effects may be precipitated

or exacerbated by exposure to cold.

Contact their doctor immediately if they develop fever, particularly in association with

persistent diarrhoea or evidence of infection since this may indicate low blood count.

Contact their doctor if persistent vomiting, diarrhoea, signs of dehydration, cough or

breathing difficulties or signs of allergic reaction occur.

Vision

abnormalities,

particular

transient

vision

loss

(reversible

following

therapy

discontinuation), may affect patient’s ability to drive and use machines (see section 4.7).

4.5 Interaction with other medicines and other forms of interaction

In patients who have received a single dose of 85 mg/m

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/m

every 3 weeks, increases of 20% in fluorouracil plasma concentrations have been observed.

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In vitro

, little or no displacement of oxaliplatin binding to plasma proteins has been observed

with the following agents; erythromycin, salicylates, granisetron, paclitaxel, and sodium

valproate.

The lack of Cytochrome P450 mediated metabolism indicates that oxaliplatin is unlikely to

modulate

P450

metabolism

concomitant

medications

through

competitive

mechanism.

4.6 Fertility, pregnancy and lactation

Fertility

In dogs dosed with oxaliplatin, a decrease in testicular weight accompanied with testicular

hypoplasia approaching aplasia was seen at doses ≥15 mg/m

. However, no effects on

fertility were seen in male and female rats at doses up to 12 mg/m

/day for 5 days/cycle.

Pregnancy - Category D

1

Reproductive toxicity studies showed no teratogenic activity in rats or rabbits at intravenous

doses up to 6 and 9 mg/m

/day respectively (½ 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 fetus. Oxaliplatin is probably toxic to the human fetus at the recommended therapeutic

dose, and is therefore contraindicated during pregnancy.

with

other

cytotoxic

agents,

effective

contraceptive

measures

should

taken

potentially fertile patients prior to initiating chemotherapy with oxaliplatin.

Lactation

There are no data on the excretion of oxaliplatin into milk of animals or humans. Oxaliplatin

is contraindicated in breast feeding women.

4.7 Effects on ability to drive and use machinery

Vision

abnormalities,

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.

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.

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4.8 Undesirable effects

Neurological

Adjuvant

Advanced

very common:

Sensory

peripheral

neuropathy,

dysgeusia, neuritis

Primarily

sensory

peripheral

neuropathy

(e.g.,

loss

deep

tendon

reflexes,

dysaesthesia,

paraesthesia,

Lhermitte’s

sign),

dysgeusia, neuritis

common:

Pharyngolaryngeal dysaesthesia,

jaw spasm, abnormal tongue

sensation, feeling of chest pressure

rare:

Dysarthria

Reversible Posterior

Leukoencephalopathy Syndrome

(RPLS, also known as PRES) (see

section 4.4)

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 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 section 4.2).

In the adjuvant setting, for a cumulative dose of 850 mg/m

(10 cycles) the risk of occurrence

of persistent symptoms is 10% and for a cumulative dose of 1020 mg/m

(12 cycles) the risk

of occurrence is 20%.

In the advanced setting, in EFC 2962, 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/m

. Two percent were withdrawn due

persisting

paraesthesia

(i.e.

persisting

between

treatment

cycles),

after

cumulative

oxaliplatin doses of 759-1100 mg/m

In the majority of cases, the neurological signs and symptoms improve when treatment is

discontinued. Analysis of patients in EFC 2962 showed that of the 34 patients who developed

Grade 3 neurotoxicity (the maximum grade in that study), 25 (73.5%) had an improvement of

their symptoms in a median time of 13.2 weeks. Eight of the 34 patients (23%) had complete

resolution of their symptoms. The mean duration of the Grade 3 neurotoxicity was 13.6

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weeks. The mean cumulative oxaliplatin dose at date of onset was 913.6 mg/m

(range:

169.7-1713.15 mg/m

). 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

vocal

cord

paralysis,

abnormal

tongue

sensation

dysarthria,

sometimes

described

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

Adjuvant

Advanced

very common:

Epistaxis

Epistaxis

common

Deep vein thrombosis,

thromboembolic events,

hypertension

Deep vein thrombosis,

thromboembolic events,

hypertension

Post marketing experience with unknown frequency – haemolytic uremic syndrome

Haematological

Adjuvant

Advanced

very common:

Epistaxis,

anaemia

(all

grades),

neutropenia

(all

grades),

thrombocytopenia (all grades)

Anaemia

(all

grades),

neutropenia

(all

grades),

thrombocytopenia

(all

grades)

Post marketing experience with unknown frequency – autoimmune pancytopenia

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 10

/L) and

Substantially increased the incidence of thrombocytopenia (Table 1-2).

Gastrointestinal

Adjuvant

Advanced

very common:

Diarrhoea,

nausea,

vomiting,

stomatitis,

anorexia,

abdominal

pain, mucositis, constipation

Diarrhoea,

nausea,

vomiting,

stomatitis, anorexia, abdominal pain,

mucositis,

dehydration,

ileus,

intestinal

obstruction,

hypokalemia,

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metabolic acidosis, constipation

common:

Dyspepsia, gastrointestinal

haemorrhage

Gastrointestinal haemorrhage

rare:

Colitis,

including

Clostridium

difficile

diarrhoea

Pancreatitis

Post marketing experience with unknown frequency - ascites

Addition of oxaliplatin to fluorouracil and folinic acid:

Increased the incidence of severe nausea, vomiting, diarrhoea and stomatitis in the

adjuvant setting (see Table 1) and substantially increased these effects in the advanced

cancer setting (see Table 2).

Hepatobiliary

Adjuvant

Advanced

very common:

Elevation of transaminases and

alkaline phosphatases activities

very rare:

Reactions related to liver

sinusoidal obstruction syndrome,

including peliosis heptatis,

nodular regenerative hyperplasia,

perisinusoidal fibrosis. Clinical

manifestations may be portal

hypertension and/or increased

transaminases.

Reactions related to liver sinusoidal

obstruction syndrome, including

peliosis hepatits, nodular

regenerative hyperplasia,

perisinusoidal fibrosis. Clinical

manifestations may be portal

hypertension and/or increased

transaminases.

Post marketing experience with unknown frequency – focal nodular hyperplasia, hepatic

failure.

Musculoskeletal

Adjuvant

Advanced

very common:

Arthralgia

Back pain*, arthralgia

* Back pain. If associated with haemolysis, which has been rarely reported, should be investigated.

Hypersensitivity

Adjuvant

Advanced

very common:

Skin rash (particularly urticaria),

conjunctivitis, rhinitis, injection

site reactions

Skin

rash

(particularly

urticaria),

conjunctivitis, rhinitis, injection site

reactions

common:

Bronchospasm, sensation of chest

pain,

angioedema,

hypotension,

anaphylactic shock

Bronchospasm,

sensation

chest

pain,

angioedema,

hypotension,

anaphylactic shock

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Sensory

Adjuvant

Advanced

very common:

Taste perversion

common:

Conjunctivitis

uncommon:

Ototoxicity

rare:

Deafness, optic neuritis, loss of

visual acuity, visual field

disturbances, transient vision loss

(reversible following therapy

discontinuation).

Deafness, optic neuritis, loss of

visual acuity, visual field

disturbances, transient vision loss

(reversible following therapy

discontinuation).

Renal

Adjuvant

Advanced

common:

Altered renal function

very rare:

Renal tubular necrosis

In clinical and post-marketing setting: very rare – Acute tubulo-interstitial nephropathy

leading to acute renal failure.

Respiratory

Adjuvant

Advanced

very common:

Cough

Cough

common:

Rhinitis, dyspnoea, hiccups

Hiccups

rare:

Acute interstitial lung disease

(sometimes fatal), pulmonary

fibrosis

Immune system

Adjuvant

Advanced

very common:

Infections, fever, rigors (tremors),

fatigue, asthenia

Infections,

fever,

rigors

(tremors),

fatigue, asthenia

common:

Febrile neutropenia

Febrile neutropenia

rare:

Autoimmune

haemolytic

anaemia

and thrombocytopenia

Skin

Adjuvant

Advanced

very common:

Alopecia, rash

common:

Alopecia, rash

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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.

Care of Intravenous Site

Extravasation may result in local pain and inflammation that may be severe and lead to

complications, including necrosis. Injection site reaction, including redness, swelling, and

pain, have been reported.

The following table provides adverse events reported in the study (see section 5.1) in

decreasing order of frequency in the oxaliplatin and infusional FU/FA combination.

Table 1: FU/FA ± Oxaliplatin in adjuvant treatment of colon cancer - EFC3313

(MOSAIC), all grades and grade 3-4 toxicities - all cycles - % patients

Arm A

FOLFOX4

N=1108

Arm B

FU/FA

N=1111

All

Gr 3

Gr 4

All

Gr 3

Gr 4

Laboratory

Granulocytopenia

78.9

28.8

12.3

39.9

Thrombocytopenia

77.4

19.0

Anaemia

75.6

66.9

Adverse events

Paraesthesia

92.0

12.4

15.6

Nausea

73.7

61.1

Diarrhoea

56.3

48.4

Vomiting

47.2

24.0

Stomatitis/mucositis

42.1

39.7

Skin disorder

31.5

35.5

Alopecia

30.2

28.1

Fever

27.3

12.2

Infection

25.2

24.9

Injection site reaction

11.1

10.4

Allergic reaction

10.3

Thrombosis/phlebitis

Neutropenic sepsis

Febrile neutropenia

The following table provides adverse events reported in the study (see section 5.1) in

decreasing order of frequency in previously untreated patients with Advanced Colorectal

Cancer, for oxaliplatin and infusional FU/FA combination.

Table 2: FU/FA ± Oxaliplatin in previously untreated patients with advanced colorectal

cancer, all grades and grade 3-4 toxicities - all cycles - % patients

Incidence of

Toxicity by

patient %

EFC 2962

N9741

N=208

Control arm q

2w

N=209

Oxaliplatin 85

q 2w

N=256

Irinotecan 125

q 6w

N=259

Folfox 4

Oxaliplatin 85 q

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FU bolus +

CIV

FU bolus +

CIV

FU bolus x 4

weekly

2w

FU bolus + CIV

All

Gr.

Gr. 3-

4

All

Gr.

Gr. 3-

4

All

Gr.

Gr. 3-

4

All Gr.

Gr. 3-4

Paraesthesias**

11.5

67.0

16.7

15.6

77.2

17.8

Laryngopharyngeal

dysesthesia

38.2

Neurosensory

12.0

Nausea

53.4

72.2

67.2

14.5

71.0

Vomiting

29.3

54.1

43.4

13.3

40.9

Diarrhoea

43.8

58.9

12.0

65.2

28.5

56.0

11.6

Stomatitis

35.6

44.0

25.0

37.5

Anaemia

80.8

85.2

28.1

27.0

Neutropenia

30.8

74.6

43.1

80.1

46.1

82.2

54.1

Thrombocytopenia

28.8

75.6

26.2

71.4

Fever without

neutropenia

14.9

33.0

16.2

Infection

27.9

31.6

Asthenia

21.6

23.4

Fatigue

12.9

58.2

10.5

70.3

Alopecia

19.2

17.7

44.1

37.5

Skin

32.2

28.7

23.1

46.4

17.4

21.6

29.2

Alkaline

phosphatase

39.9

56.5

16.2

Creatinine increase

*14.8% febrile neutropenia reported in the IFL (Irinotecan FU/LV) arm and 4.2% in the FOLFOX4 arm

**Various studies used different data convention. Breakdown data collection by laryngopharyngeal dysesthesia and

neurosensory was not done in EFC2962

NA: Not applicable

CIV: continuous intravenous infusion

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%)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It

allows

continued

monitoring

benefit/risk

balance

medicine.

Healthcare

professionals

asked

report

suspected

adverse

reactions

https://nzphvc.otago.ac.nz/reporting/.

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.

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For advice on the management of overdose please contact the National Poisons Centre on

0800 POISON (0800 764766).

5.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Mechanism of action

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

in vivo

activity in various cisplatin resistant

models.

A synergistic cytotoxic action has been observed in combination with fluorouracil both

in vitro

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.

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/m

as 2 hour infusion, folinic acid 200 mg/m

over 2 hours, followed by a FU bolus of

400 mg/m

, then a FU infusion of 600 mg/m

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 (Table 3). 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.

Table 3: Disease free survival and overall survival - ITT population

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Disease Stage

FOLFOX4

FU/FA

Hazard Ratio

[95% CI]

Disease-free Survival -

4 year probability (%)

of Surviving disease-

free [95% CI]

75.9

[73.4, 78.5]

(n=1123)

69.1

[66.3, 71.9]

(n=1123)

0.76

[0.65, 0.90]

85.1

[81.7, 88.6]

(n=451)

81.3

[77.6, 85.1]

(n=448)

0.80

[0.58, 1.11]

69.7

[66.2, 73.3]

(n=672)

61.0

[57.1, 64.8]

(n=675)

0.75

[0.62, 0.90]

Overall Survival* -

4 year probability (%)

of Surviving [95% CI]

84.0

[81.7, 86.3]

(n=1123)

82.4

[80.0, 84.8]

(n=1123)

0.89

[0.72, 1.09]

91.0

[88.1, 93.9]

(n=451)

91.1

[88.3, 93.9]

(n=448)

0.98

[0.63, 1.53]

79.2

[76.0, 82.5]

(n=672)

76.6

[73.2, 80.0]

(n=675)

0.86

[0.68, 1.08]

*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):

total

1,132

patients

have

been

enrolled

three

pivotal

trials,

untreated

(EFC7462/N9741, EFC2962) and pretreated patients (EFC2964). These studies evaluated the

efficacy of oxaliplatin at the same dose intensity (85 mg/m

/2 weeks and 125 mg/m

/3 weeks)

when added to different FU-FA doses and regimens, in terms of progression free survival and

tumour response.

EFC7462/N9741:

was a multicentre open label randomised, three arm phase III study of

irinotecan and FU/LV (IFL), or oxaliplatin and irinotecan (IROX), or oxaliplatin and FU/LV

(FOLFOX4)

initial

treatment

patients

with

advanced

colorectal

cancer.

Therapy

consisted of two week FOLFOX4, six week IFL, or three week IROX treatment cycles.

A total of 795 patients were enrolled and 773 treated from May 1999 in 301 centres in the

United States and Canada.

Treatment arms

FOLFOX4 day 1: oxaliplatin 85 mg/m

over two hours, folinic acid 200 mg/m

over two

hours, followed by an FU bolus of 400 mg/m

, then an FU infusion of 600 mg/m

over 22

hours. Folinic acid and FU repeated on day 2. Cycle repeated every two weeks.

IFL day 1: irinotecan 125 mg/m

over 90 minutes, folinic acid 20 mg/m

over 15 minutes or

IV push, FU bolus of 500 mg/m

weekly x 4. Cycle repeated every six weeks.

IROX day 1: oxaliplatin 85 mg/m

over two hours, irinotecan 200 mg/m

over 30 minutes.

Cycle repeated every three weeks.

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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 4, 5, 6 and 7.

Table 4: Summary of time to progression – ITT population

EFC7462/N9741

Time to progression

IFL

(n=264)

FOLFOX4

(n=267)

IROX

(n=264)

Number of progressors n (%)

216 (81.8)

221 (82.8)

236 (89.4)

Median TTP (months)

95% confidence interval

(6.0 – 7.5)

(7.8 – 9.8)

(5.8 – 7.6)

p-Value (Log-rank test)

Hazard ratio (95% confidence interval)

FOLFOX4 vs. IFL: p = 0.0014

FOLFOX4 vs. IFL: 0.74 (0.61 – 0.89)

IROX vs. IFL: p = 0.8295

IROX vs. IFL: 1.02 (0.85 – 1.23)

Table 5: Summary of overall survival – ITT population

EFC7462/N9741

Overall survival

IFL

(n=264)

FOLFOX4

(n=267)

IROX

(n=264)

Number of deaths n (%)

192 (72.7)

155 (58.1)

175 (66.3)

Median survival (months)

14.6

19.4

17.6

95% confidence interval

(12.4 – 16.7)

(17.9 – 21.0)

(15.8 – 19.6)

p-Value (Log-rank test)

Hazard ratio (95% confidence interval)

FOLFOX4 vs. IFL: p<0.0001

FOLFOX4 vs. IFL: 0.65 (0.53 – 0.80)

IROX vs. IFL: p = 0.0252

IROX vs. IFL: 0.79 (0.65 – 0.97)

Table 6: Summary of confirmed overall response – patients (n, %) with measurable

disease

EFC7462/N9741

Overall response

IFL

n=212

(%)

FOLFOX4

n=210

(%)

IROX

n=215

(%)

Complete and partial response

69 (32.5)

95 (45.2)

74 (34.4)

95% confidence interval

(26.2 – 38.9)

(38.5 – 52.0)

(28.1 – 40.8)

Complete response

5 (2.4)

13 (6.2)

7 (3.3)

Partial response

64 (30.2)

82 (39.0)

67 (31.2)

Regression

3 (1.4)

1 (0.5)

Stable disease

94 (44.3)

75 (35.7)

86 (40.0)

p-Value (chi-squared test)

FOLFOX4 vs. IFL: p<0.0075

IROX vs. IFL: p = 0.0252

Patients with measurable disease at randomisation that became too small to measure during the study were

classified as regression and not partial response in this study.

Table 7: Number of deaths – treated patients n (%)

EFC7462/N9741

IFL

(n=256)

(%)

FOLFOX4

(n=259)

(%)

IROX

(n=258)

(%)

Number of deaths within 30 days

12 (4.7)

8 (3.1)

8 (3.1)

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of last dose

Number of deaths within 60 days

of first dose

13 (5.1)

6 (2.3)

8 (3.1)

Number of deaths during the entire

study

189 (73.8)

149 (57.5)

170 (65.9)

EFC2962:

multinational

multicentre

randomised

phase

study

previously

untreated patients, comparing two-weekly fluorouracil bolus plus infusion and high dose

folinic acid (FU/FA regimen: Day 1: folinic acid 200 mg/m

over 2 hours, followed by a FU

bolus of 400 mg/m

, then a FU infusion of 600 mg/m

over 22 hours. Repeated on Day 2) to

the same regimen combined with oxaliplatin at the dosage of 85 mg/m

every two weeks. A

total of 420 patients were enrolled and 417 treated from August 1995 to July 1997 in 35

centres from 9 countries. The median number of treatment cycles was 12 in the FU/FA plus

oxaliplatin group and 11 in the FU/FA group. Confirmed responses after independent

radiological review (intent to treat analysis n = 420) are as shown in Table 8.

Table 8: Confirmed responses after independent radiological review in study EFC2962

FU/FA + Oxp

n = 210

FU/FA

n = 210

Difference

Objective Response Rate* %

49.0

21.9

p = 0.0001

[95% CI]

[42, 56]

[16,27]

Complete

Partial

47.6

21.4

Median progression free survival (months)**

[95% CI]

[7.2, 8.8]

[5.5, 6.5]

p = 0.0003

(log rank)

Median survival time (months)

[95% CI]

[14.7, 18.2]

14.7

[13.7, 18.2]

p= 0.109

(log rank)

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

**. Independent expert review.

Oxp = oxaliplatin

FU/FA = fluorouracil and folinic acid

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

open

label

multicentre

study

which

patients

whose

disease

progressed

fluorouracil/folinic

acid

regimens

continued

same

fluorouracil/folinic acid regimen with the addition of oxaliplatin 85 mg/m

two weekly. The

two study regimens were as follows:

Regimen 1

: Day 1; folinic acid 200 mg/m

over 2 hours, followed by a FU bolus of

400 mg/m

, then a FU infusion of 600 mg/m

over 22 hours. Repeated on day 2.

Regimen

2:

folinic

acid

500 mg/m

over

hours,

followed

infusion

1500 mg/m

over 22 hours, Repeated on day 2.

The results are shown in Table 9.

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Table 9: Confirmed responses in study EFC2964

Regimen 1

n = 57

Regimen 2

n = 40

All Treated

Patients

n = 97

Confirmed Responses n (%) [95% CI]

Expert assessment

13 (23%)

[13-36]

7 (18%)

[7-33]

20 (21%)

[13-30]

Investigator assessment

11 (19%)

[10-32]

10 (25%)

[13-41]

21 (22%)

[14-31]

Median progression free survival (months)

[95% CI]

[3.1 - 5.7]

[3.0 - 5.5]

[3.4 - 5.5]

Median overall survival (months)

[95% CI]

11.1

[8.3 - 13.0]

10.5

[8.6 - 13.4]

11.0

[9.1 - 12.9]

5.2 Pharmacokinetic properties

pharmacokinetics

individual

active

compounds

have

been

determined.

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/m

every

three weeks for one to five cycles and at 85 mg/m

every two weeks for one to three cycles as

follows:

Summary of platinum pharmacokinetic parameter estimates in ultrafiltrate following

multiple doses of oxaliplatin at 85 mg/m

2

every two weeks or at 130 mg/m

2

every three

weeks

Dose

C

max

(µg/mL)

AUC

0-48

(μg/mL.h)

AUC

0-inf

(μg/mL.h)

t

½

α

(h)

t

½

β

(h)

t

½

γ

(h)

V

ss

(L)

CL

(L/h)

85 mg/m

Mean

0.814

0.193

4.19

0.647

4.68

1.40

0.43

0.35

16.8

5.74

17.4

6.35

130 mg/m

Mean

1.21

0.10

8.20

2.40

11.9

4.60

0.28

0.06

16.3

2.90

19.0

10.1

3.07

Mean AUC

0-48

values were determined on Cycle 3 (85 mg/m

) or Cycle 5 (130 mg/m

Mean AUC

0-∞

and CL values were determined on Cycle 1

, AUC, AUC

0-48

and CL values were determined by non-compartmental analysis

α, t

β and t

γ 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/m

every two weeks or 130 mg/m

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.

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Oxaliplatin

undergoes

extensive

biotransformation

patients,

intact

drug

detectable

plasma

ultrafiltrate

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.

5.3 Preclinical safety data

Genotoxicity

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

in vitro

in vivo

Carcinogenicity

The carcinogenic potential of oxaliplatin has not been studied, but compounds with similar

mechanisms of action and genotoxicity profiles have been reported to be carcinogenic.

Oxaliplatin should be considered a probable carcinogen.

Reproductive and developmental toxicity

In dogs dosed with oxaliplatin, a decrease in testicular weight accompanied with testicular

hypoplasia approaching aplasia was seen at doses ≥15 mg/m

. However, no effects on

fertility were seen in male and female rats at doses up to 12 mg/m

/day for 5 days/cycle.

6.

PHARMACEUTICAL PARTICUALRS

6.1 List of excipients

Lactose monohydrate

6.2 Incompatibilities

Oxaliplatin is incompatible with chloride containing solutions and basic solutions (including

fluorouracil),

therefore

oxaliplatin

should

mixed

with

these

administered

simultaneously via the same IV line. There is no data for compatibility with other medicines.

6.3 Shelf life

36 months

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6.4 Special precautions for storage

Store below 30°C.

6.5 Nature and contents of container

DBL Oxaliplatin for injection 20 mg – 1 vial per pack

DBL Oxaliplatin for injection 50 mg – 1 vial per pack

DBL Oxaliplatin for injection 100 mg – 1 vial per pack

6.6 Special precautions for disposal and other handling

Instructions for Use/Handling

As with other potentially toxic compounds, caution should be exercised when handling and

preparing oxaliplatin solutions.

The handling of this cytotoxic agent by health care personnel requires every precaution to

guarantee

protection

handler

their

surroundings.

essential

appropriate protective clothing, including protective goggles, mask and gloves. Pregnant

women must be warned to avoid handling cytotoxic agents. If oxaliplatin concentrate,

premixed

solution

infusion

solution

should

come

into

contact

with

skin,

mucous

membranes or eyes, wash immediately and thoroughly with water.

Preparation of Infusion Solution

Reconstitution of the Solution

The lyophilised powder is reconstituted by adding 4 mL (for the 20 mg vial), 10 mL (for the

50 mg vial) or 20 mL (for the 100 mg vial) of Water for Injections or 5% glucose injection.

resulting

solution

contains

5 mg

oxaliplatin

per mL.

Do

not

administer

the

reconstituted solution without further dilution

Chemical and physical in-use stability has been demonstrated for 48 hours at 2-8°C and

30°C. From a microbiological point of view, the reconstituted solution should be diluted

immediately with 5% glucose injection. If not diluted immediately, in-use storage times and

conditions prior to use are the responsibility of the user and would normally not be longer

than 24 hours at 2°C to 8°C.

Reconstitution should take place in controlled and validated aseptic conditions. Inspect

visually prior to use. Only clear solutions without particles should be used. DBL

Oxaliplatin

for injection vials contain no preservative and are for single use only. Discard any remaining

contents.

Dilution before Infusion

The reconstituted solution must be further diluted in an infusion solution of 250-500 mL of

5% glucose injection. From a microbiological and chemical point of view, this infusion

preparation should be used immediately. Inspect visually prior to use. Only clear solutions

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without particles should be used. The product is for single use only. Discard any remaining

contents.

NEVER

use sodium chloride solution for either reconstitution or dilution.

Infusion

The administration of oxaliplatin does not require prehydration. Oxaliplatin diluted in 250 to

500 mL of a glucose 5% injection must be infused either by central venous line or peripheral

vein over 2 to 6 hours. When oxaliplatin is administered with fluorouracil, the oxaliplatin

infusion should precede that of fluorouracil.

Oxaliplatin

co-administered

with

folinic

acid

infusion

using

Y-tube

placed

immediately before the site of injection. The medicines should not be combined in the same

infusion bag. Folinic acid must be diluted using isotonic infusion solutions such as 5%

glucose solution but

NOT

sodium chloride solutions or alkaline solutions.

Flush the line after oxaliplatin administration.

While oxaliplatin has minimal to no vesicant potential, extravasation may result in local pain

and inflammation which may be severe and lead to complications especially when oxaliplatin

is infused through a peripheral vein. In case of oxaliplatin extravasation, the infusion must be

stopped immediately and the usual local symptomatic treatment initiated.

Disposal

All materials that have been used for reconstitution, for dilution and administration must be

destroyed according to local statutory requirements.

7.

MEDICINE SCHEDULE

Prescription Medicine

8.

SPONSOR

Pfizer New Zealand Limited

P O Box 3998

Auckland, New Zealand, 1140

Toll Free Number: 0800 736 363

9.

DATE OF FIRST APPROVAL

23 Jul 2009

10. DATE OF REVISION OF THE TEXT

10 January 2020

Summary table of changes

Section changed

Summary of new information

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Section changed

Summary of new information

Minor editorial changes.

- Addition of a warning concerning immunosuppressant

effects/increased susceptibility to infection and the risks associated

with vaccine use.

- Additional information under subheading Hepatic Toxicity.

- Additional information on vision abnormalities.

Additional warning relating to vision abnormalities and the effects on

driving.

Update to the following sections to include additional adverse effects:

Neurological

Vascular Disorders

Haematological

Gastrointestinal

Hepatobiliary

Musculoskeletal

Hypersensitivity

Sensory

Respiratory

Immune System

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