Oxaliplatin Ebewe

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  • Handelsname:
  • Oxaliplatin Ebewe 5 mg/ml Pulver zur Herstellung einer Infusionslösung
  • Einheiten im Paket:
  • 1x 50 mg (Durchstechflasche), Laufzeit: 36 Monate,1 x 100 mg (Durchstechflasche), Laufzeit: 36 Monate,1 x 150 mg (Durchstechflas
  • Verschreibungstyp:
  • Arzneimittel zur einmaligen Abgabe auf aerztliche Verschreibung
  • Verwenden für:
  • Menschen
  • Art der Medizin:
  • allopathic Droge

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  • Erhältlich in:
  • Oxaliplatin Ebewe 5 mg/ml Pulver zur Herstellung einer Infusionslösung
    Österreich
  • Sprache:
  • Deutsch

Therapeutische Informationen

  • Therapiebereich:
  • Oxaliplatin
  • Produktbesonderheiten:
  • Abgabe durch eine (öffentliche) Apotheke

Weitere Informationen

Status

  • Quelle:
  • AGES
  • Zulassungsnummer:
  • 1-26435
  • Berechtigungsdatum:
  • 17-05-2006
  • Letzte Änderung:
  • 08-03-2018

Öffentlichen Beurteilungsberichts

Österreichische Agentur für Gesundheit und Ernährungssicherheit GmbH, www.ages.at,

Schnirchgasse 9, A-1030 Wien, DVR: 0014541, Firmenbuch: FN 223056z, Registergericht: Handelsgericht Wien,

Konto Nr.: 50670871619, BLZ: 12.000, IBAN: AT971200050670871619, BIC/SWIFT: BKAUATWW, UID: ATU 54088605

Public Assessment Report

Scientific discussion

Oxaliplatin Ebewe 5 mg/ml powder

for solution for infusion

(Oxaliplatin)

AT/H/0185/01/MR

Applicant: Ebewe

Date: 27.11.2007

This module reflects the scientific discussion for the approval of Oxaliplatin Ebewe 5mg/ml

powder

for

solution

for

infusion,

AT/H/0185/01/MR.

The

procedure

was

finalised

on

20

November 2007. For information on changes after this date please refer to the module ‘Update’.

2/35

Table of contents

Page

TABLE OF CONTENTS

Summary of Product Characteristics

03

Package Leaflet

19

Labelling

27

SCIENTIFIC DISCUSSION DURING INITIAL PROCEDURE

I

RECOMMENDATION

30

II

EXECUTIVE SUMMARY

30

II.1

Problem statement

30

II.2

About the product

30

II.3

General comments on the submitted dossier

31

II.4

General comments on compliance with GMP, GLP, GCP and agreed

ethical principles

31

III

SCIENTIFIC OVERVIEW AND DISCUSSION

32

III.1

Quality aspects

32

III.2

Non clinical aspects

33

III.3

Clinical aspects

33

III.4

Risk Management Plan

34

IV

OVERALL CONCLUSION, BENEFIT RISK ASSESSMENT AND

REDOMMENDATION

34

V

RECOMMENDED CONDITIONS FOR MARKETING

AUTHORISATION

35

3/35

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Oxaliplatin “Ebewe” 5mg/ml powder for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial with lyophilised powder contains 50, 100 or 150mg of oxaliplatin.

One vial of 50mg: Each vial contains 50 mg oxaliplatin for reconstitution in 10 ml of solvent.

One vial of 100mg: Each vial contains 100 mg oxaliplatin for reconstitution in 20 ml of solvent.

One vial of 150mg: Each vial contains 150 mg oxaliplatin for reconstitution in 30 ml of solvent.

1ml of reconstituted solution for infusion contains 5mg of oxaliplatin.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for solution for infusion

White to off-white compact powder.

4. CLINICAL PARTICULARS

4.1. Therapeutic indications

Oxaliplatin “Ebewe” in combination with 5-fluorouracil (5 FU) and folinic acid (FA) is indicated for:

- adjuvant treatment of stage III (Duke’s C) colon cancer after complete resection of primary tumour,

- treatment of metastatic colorectal cancer

4.2. Posology and method of administration

The preparation of injectable solutions of cytotoxic agents must be carried out by trained specialist

personnel with knowledge of the medicines used, under conditions that guarantee integrity of the

medicinal product, protection of the environment and in particular protection of the personnel handling

the medicines, according to hospital policy. It requires a preparation area reserved for this purpose. It

is forbidden to smoke, eat or drink in this area.

Posology

FOR ADULTS ONLY

The recommended dose of oxaliplatin used in adjuvant treatment is 85mg/m

body surface area,

administered intravenously every 2 weeks for 12 cycles (6 months).

The recommended dose of oxaliplatin for the treatment of metastatic colorectal cancer is 85mg/m

body

surface area, administered intravenously every 2 weeks.

Dosage given should be adjusted according to tolerability (see section 4.4).

The administration of oxaliplatin should always precede that of fluoropyrimidines, i.e. 5-

fluorouracil (5-FU).

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

solution, so that the concentration of the infusion solution is 0.2mg/ml to 0.7mg/ml, whereas 0.7mg/ml is

4/35

the highest concentration for a dose of oxaliplatin of 85mg/m

Oxaliplatin was mainly used in combination with 5-fluorouracil based continuous infusion regimens.

For the two-weekly treatment schedule 5-fluorouracil (5-FU) regimens combining bolus and continuous

infusion were used.

Special Populations

Patients with renal impairment:

Oxaliplatin has not been studied in patients with severe renal impairment (see section 4.3).

In patients with moderate renal impairment, treatment may be initiated at the normally

recommended dose (see section 4.4.). There is no need for dose adjustment in patients with

mild renal dysfunction.

Patients with hepatic impairment:

In a phase I study including patients with different levels of hepatic impairment, frequency

and severity of hepatobiliary disorders seemed to be related with disease progression 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 (5-FU) in patients over the age of 65. In consequence no

specific dose adaptation is required for elderly patients.

Method of administration

Oxaliplatin is administered by intravenous infusion.

The administration of oxaliplatin does not require hyperhydration.

Oxaliplatin diluted in 250 to 500ml of 5% glucose solution (50mg/ml) to obtain concentrations of

0.2mg/ml or higher must be infused via a central or peripheral venous line over 2 to 6 hours.

Oxaliplatin infusion must always precede that of 5-fluorouracil (5-FU).

In the event of extravasation, administration must be discontinued immediately.

Instructions for use:

Lyophilised oxaliplatin must be reconstituted and further diluted before use, for which only

recommended diluents must be used (section 6.6 “Special precautions for disposal and other handling”

Reconstitution: water for injection or 5% glucose solution, further diluted with: 5% glucose solution).

4.3. Contraindications

Oxaliplatin is contraindicated in patients who

have a known hypersensitivity to oxaliplatin or any of the excipients,

are breastfeeding,

have myelosuppression prior to initial administration, as evidenced by

baseline neutrophils < 2 x 10

/l and/or platelet count of < 100 x 10

/l ,

have a peripheral sensitive neuropathy with functional impairment prior to initial

administration,

suffer from severely impaired renal function (creatinine clearance < 30ml/min).

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.

Due to limited safety information in patients with moderately impaired renal function, administration

should only be considered after suitable appraisal of the benefit/risk for the patient.

In this case, renal function should be closely monitored and dose should be adjusted according to

toxicity.

Patients with a known history of allergic reactions to platinum compounds should be monitored for

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allergic symptoms. In case of anaphylactic-like reactions to oxaliplatin, the infusion must be

immediately discontinued and appropriate symptomatic measures must be initiated. Oxaliplatin re-

challenge is contraindicated for such patients.

In case of oxaliplatin extravasation, the infusion must be stopped immediately and local symptomatic

treatment should be initiated.

Neurological toxicity of oxaliplatin should be carefully monitored, especially if co-administered with

other medications with specific neurological toxicity. A neurological examination should be

performed before each administration and periodically thereafter.

For patients who develop acute laryngopharyngeal dysaesthesia (see section 4.8.) during or within

several hours after a 2-hour infusion, the subsequent oxaliplatin infusion must be administered over 6

hours.

If neurological symptoms (paraesthesia, dysaesthesia) occur, oxaliplatin dosage should be adjusted

based on duration and severity of existing symptoms:

If symptoms last longer than 7 days and are troublesome, the subsequent oxaliplatin dose

should be reduced from 85 to 65mg/m

(treatment of metastatic colorectal cancer) or to

75mg/m

(adjuvant treatment), respectively.

If paraesthesia without functional impairment persists until the next cycle, the subsequent

oxaliplatin dose should be reduced from 85 to 65mg/m

(treatment of metastatic colorectal

cancer) or to 75mg/m

(adjuvant treatment), respectively.

If paraesthesia with functional impairment persists until the next cycle, oxaliplatin

treatment should be suspended.

If symptoms improve following suspension of oxaliplatin treatment, therapy

continuation may be considered.

Patients should be informed about the possibility of persistent symptoms of peripheral sensory

neuropathy after the end of the treatment. Localised moderate paraesthesia or paraesthesia with

functional activity interference may persist over a period of up to 3 years following treatment

cessation in the adjuvant setting.

Gastrointestinal toxicity of oxaliplatin, i.e. symptoms such as nausea and vomiting, requires

prophylactic and/or therapeutic use of antiemetics (see section 4.8.).

Dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis and renal

impairment may be caused by severe diarrhoea/emesis particularly when combining oxaliplatin with

5-fluorouracil (5-FU).

If haematological changes occur (neutrophils < 1.5 x 10

/l or platelets < 50 x 10

/l), administration of

the next therapy cycle should be postponed until haematological values return to acceptable levels. A

full blood count with white cell differential should be performed prior to start of oxaliplatin therapy

and before each subsequent cycle.

Patients must be adequately informed about the risk of diarrhoea/emesis, mucositis/stomatitis and

neutropenia following oxaliplatin and 5-fluorouracil (5-FU) administration so they can immediately

contact their physician for appropriate treatment.

If mucositis/stomatitis occurs with or without neutropenia, the next treatment should be delayed until

mucositis/stomatitis recover to grade I or less and/or until the neutrophil count is ≥ 1.5 x 10

For oxaliplatin combined with 5-fluorouracil (5-FU) (with or without folinic acid), the usually

recommended 5-fluorouracil doses must be adjusted based on its toxicity.

In the case of WHO grade 4 diarrhoea, grade 3-4 neutropenia (neutrophils < 1 x 10

/l), grade 3-4

thrombocytopenia (platelets < 50 x 10

/l) occur, the dose of oxaliplatin should be reduced from

85mg/m

to 65mg/m

(treatment of metastatic colorectal cancer) or to 75mg/m

(adjuvant treatment),

respectively, in addition to any 5-fluorouracil (5-FU) dose reductions required.

In cases of unexplained respiratory symptoms such as non-productive cough, dyspnoea, crackles or

radiological pulmonary infiltrates, oxaliplatin should be discontinued until further pulmonary testing

has ruled out interstitial lung disease or pulmonary fibrosis (see section 4.8).

In case of pathological liver parameters or portal hypertension, which apparently is not caused by liver

metastases, medicinal product-induced hepatic vascular disorders should be considered, which might

occur in very rare cases.

For use of medicinal product in pregnant women see section 4.6.

In preclinical studies genotoxic effects have been observed. Consequently male patients should not

father children during oxaliplatin treatment and over a period of 6 months thereafter. Furthermore,

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male patients should seek advice on conservation of sperm prior to treatment because oxaliplatin may

have an antifertility effect which could be irreversible. Effective contraception must be used

throughout the treatment and following the treatment for 4 months in women and 6 months in men.

(see section 4.6).

4.5. Interaction with other medicinal products and other forms of interaction

In patients who have received a single dose of 85mg/m² of oxaliplatin, immediately before

administration of 5-fluorouracil (5-FU), no change in plasma levels of 5-fluorouracil (5-FU) has been

observed.

In vitro, no significant displacement of oxaliplatin binding to plasma proteins has been observed with

the following agents: erythromycin, salicylates, granisetron, paclitaxel, and sodium valproate.

4.6. Pregnancy and lactation

To date, there is no available information on the safety of oxaliplatin use in pregnant women. In

experimental animal studies reproduction toxicity has been observed. Therefore, the use of oxaliplatin

is not recommended during pregnancy. Furthermore, use of oxaliplatin is not recommended in women

of childbearing age who are not using effective contraceptive methods.

Treatment with oxaliplatin during pregnancy should be considered only after the patient was duly

informed about the risk for the foetus and after obtaining the patient's consent.

During treatment with oxaliplatin, effective contraceptive methods should be used, and over a period

of 4 months thereafter in women, and 6 months in men.

Oxaliplatin passage into breast milk has not been studied. Breastfeeding is contraindicated during

oxaliplatin therapy.

Oxaliplatin may affect fertility (see section 4.4.).

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, the risk of dizziness, nausea and vomiting and other neurological symptoms affecting gait

and balance is increased during treatment with oxaliplatin, thus the ability to drive and use machines

may be affected mildly to moderately.

4.8. Undesirable effects

The most frequent adverse effects of oxaliplatin in combination with 5-fluorouracil and folinic acid (5-

FU and FA) were of gastrointestinal (diarrhoea, nausea, vomiting and mucositis), haematological

(neutropenia, thrombocytopenia) and neurological nature (acute and dose cumulative peripheral

sensory neuropathy).

Overall, these side effects were more frequent and severe when 5-FU/FA was administered in

combination with oxaliplatin compared to 5-FU/FA alone.

The side effect frequency data reported in the table below are derived from clinical trials on the

treatment of metastases and adjuvant treatment (including 416 and 1,108 patients, respectively, in the

oxaliplatin + 5-fluorouracil (5-FU)/folinic acid (FA) treatment arm) and from post marketing

surveillance.

Frequencies in this table are defined using the following convention: very common (≥ 1/10) common

(≥ 1/100 < 1/10), uncommon (≥ 1/1,000 < 1/100), rare (≥ 1/10,000 < 1/1,000), very rare (< 1/10,000) ,

not known (cannot be estimated from the available data).

Further details are given following this table.

MedDRA

classification

Very common

Common

Uncommon

Rare

Very rare

Infections and

infestations*

Infections

Rhinitis, upper

respiratory tract

infections, febrile

neutropenia / neutropenic

sepsis

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Blood and lymphatic

system disorders *

Anaemia,

neutropenia,

thrombocytopenia,

leukopenia,

lymphopenia

Immunoallergic

thrombocytopenia,

haemolytic

anaemia

Immune system

disorders*

Allergy, allergic

reactions+

Metabolism and

nutrition disorders

Anorexia, abnormal

blood glucose

levels, hypokalemia,

changes in sodium

serum levels

Dehydration

Metabolic

acidosis

Psychiatric disorders

Depression, insomnia

Nervousness

Nervous system

disorders *

Peripheral sensory

neuropathy, sensory

disturbance, taste

disorders, headache

Dizziness, motor

neuritis, meningism

Dysarthria

Eye disorders

Conjunctivitis, impaired

vision

Transient

reduction of visual

acuity, visual field

disturbances, optic

neuritis

Ear and labyrinth

disorders

Ototoxicity

Deafness

Vascular disorders

Epistaxis

Haemorrhage,

flush, deep vein

thrombosis,

pulmonary embolism

Respiratory, thoracic

and mediastinal

disorders

Dyspnoea, coughing

Hiccup

Interstitial lung

disease,

pulmonary

fibrosis **

Gastrointestinal

disorders*

Nausea,

diarrhoea, vomiting,

stomatitis/mucositis,

abdominal pain,

constipation

Dyspepsia,

gastro-oesophageal

reflux, rectal

haemorrhage

Ileus, intestinal

obstruction

Colitis

including

Clostridium

difficile

diarrhoea

Hepato-biliary

disorders

Increase of hepatic

enzymes

Liver sinusoidal

obstruction

syndrome (see

below)

Skin and

subcutaneous tissue

disorders

Skin disorders,

alopecia

Skin exfoliation

(e.g. hand and foot

syndrome),

erythematous rash,

rash,

increased

sweating, nail

disorders

Musculoskeletal

system, connective

tissue and bone

disorders

Back pain

Arthralgia, bone pain

Renal and urinary

disorders

Haematuria, Dysuria,

abnormal micturition

frequency

Acute

tubulointerstitial

nephropathy

leading to acute

renal failure

General disorders

and administration

site conditions

Fever++, fatigue,

asthenia, pain,

injection site

8/35

reactions+++

Investigations

Increased levels of

hepatic enzymes,

blood alkaline

phosphatase , blood

bilirubin, blood

lactate

dehydrogenase

(LDH), weight gain

(adjuvant setting)

Creatinine increases,

loss of weight (in case of

metastases)

See detailed information in the section below

See section 4.4.

Common allergic reactions such as skin rash (particularly urticaria), conjunctivitis, rhinitis.

Common anaphylactic reactions, including bronchospasm, sensation of chest pain,

angioedema, hypotension and anaphylactic shock.

Very commonly fever, rigors (tremor), either from infection (with or without febrile

neutropenia) or possibly from immunological mechanism.

Injection site reactions including local pain, reddening, swelling and thrombosis have been

reported. Extravasation may result in local pain and inflammation, which may be severe and lead to

complications including necrosis, especially when oxaliplatin is infused through peripheral veins (see.

4.4.).

Hepatobiliary disorders:

Very rare (< 1/10,000): Hepatic sinusoidal obstruction syndrome, also known as veno-occlusive liver

disease, or pathological manifestations related to such liver disorder, including peliosis hepatis,

nodular regenerative hyperplasia and perisinusoidal fibrosis. Clinical manifestations may be portal

hypertension and/or increased transaminases.

9/35

HAEMATOLOGICAL TOXICITY

Incidence by patient (%) and by grade

Treatment of metastases

Adjuvant therapy

Oxaliplatin/5 FU/FA,

85 mg/m

every 2

weeks

All grades

Grade 3

Grade 4

All grades

Grade

Grade

Anaemia

82.2

<1

75.6

Neutropenia

71.4

78.9

28.8

12.3

Thrombocytopenia

71.6

<1

77.4

Febrile neutropenia

Neutropenic sepsis

GASTROINTESTINAL TOXICITY

Incidence by patient (%) and by grade

Treatment of metastases

Adjuvant therapy

Oxaliplatin/5 FU/FA,

85 mg/m

every 2

weeks

All grades

Grade 3

Grade 4

All grades

Grade

Grade

Nausea

69.9

< 1

73.7

Diarrhoea

60.8

56.3

Vomiting

49.0

47.2

Mucositis / Stomatitis

39.9

< 1

42.1

Prophylaxis and/or treatment with potent antiemetic agents is indicated.

Dehydration,

paralytic

ileus,

intestinal

obstruction,

hypokalemia,

metabolic

acidosis

renal

impairment may be caused by severe diarrhoea/emesis particularly when combining oxaliplatin with

5-fluorouracil (5-FU) (see section 4.4).

NERVOUS SYSTEM

Oxaliplatin shows dose limiting neurological toxicity. 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

treatment,

increases

with

number

treatment cycles.

The onset of pain and/or functional disorders is an indication for dose adjustments or even treatment

discontinuation, depending on the duration of these symptoms (see section 4.4).

These functional disorders include difficulties in executing delicate movements and are a possible

consequence of sensory impairment. The risk of occurrence of persistent symptoms for a cumulative

dose of 850mg/m

(10 cycles) is approximately 10% and 20% for a cumulative dose of 1,020 mg/m

(12 cycles). In the majority of the cases, the neurological signs and symptoms improved or totally

recovered when treatment was 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 persistent localised paraesthesia of moderate intensity (2.3%) or

with paraesthesia with functional impairment (0.5%).

Acute neurosensory manifestations (see section 5.3.) have been reported, appearing within hours of

administration and often related to exposure to the cold. They may present as transient paraesthesia,

dysaesthesia and hypoesthesia or as an acute syndrome of pharyngolaryngeal dysaesthesia. This acute

syndrome of pharyngolaryngeal dysaesthesia, with an incidence between 1% and 2%, is characterised

by subjective sensations of dysphagia or dyspnoea, 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

10/35

were rapidly reversible even in the absence of treatment. Prolongation of the infusion helps to reduce

the incidence of these side effects (see section 4.4). In addition, the following symptoms were

occasionally

observed:

spasms,

muscle

spasms,

involuntary

muscle

contractions,

muscle

twitching, myoclonus, impaired coordination, abnormal gait, ataxia, balance disorders, throat or chest

tightness, feeling of pressure, discomfort, pain. In addition, cranial nerve dysfunctions may be

associated, 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.

ALLERGIC REACTIONS

Incidence by patient (%) and by grade

Treatment of metastases

Adjuvant therapy

Oxaliplatin/5 FU/FA,

85mg/m

every 2

weeks

All grades

Grade 3

Grade 4

All grades

Grade

Grade

Allergic

reactions/Allergy

< 1

10.3

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: L01XA03

Oxaliplatin is an antineoplastic medicinal product belonging to a new class of platinum-derived

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-1,2-diamine-kN, kN']

[ethanedioato(2-)-kO

1

, kO

2

] platinum.

Oxaliplatin shows a wide spectrum of both in vitro cytotoxicity and in vivo antitumour activity in a

variety of tumour model systems including human colorectal cancer models.

Oxaliplatin also demonstrates in vitro and in vivo activity in various cisplatin resistant models.

A synergistic cytotoxic action has been observed in combination with 5-fluorouracil (5-FU) both in

vitro and in vivo.

Studies on the mechanism of action of oxaliplatin, although not completely elucidated, show that the

aqua-derivatives resulting from the biotransformation of oxaliplatin interact with DNA to form both

inter- and intra-strand cross-links, resulting in the disruption of DNA synthesis leading to cytotoxic

and antitumour effects.

In patients with metastatic colorectal cancer, the efficacy of oxaliplatin (85mg/m

repeated every two

weeks) combined with 5-fluorouracil/folinic acid (5-FU/FA) has been studied in three clinical trials:

First-Line Therapy: a 2-arm comparative randomised phase III study (EFC2962) with 420

patients that were either treated with 5-fluorouracil (5-FU)/folinic acid (FA) alone (LV5 FU2,

11/35

210 patients) or with a combination of oxaliplatin and 5-fluorouracil (5-FU)/folinic acid (FA)

(FOLFOX4, 210 patients).

Pre-treated patients: a 3-arm comparative randomised phase III study (EFC4584) with 821

patients refractory to irinotecan (CPT-11) and 5-FU/folinic acid combination, that were either

treated with 5-fluorouracil (5-FU)/folinic acid (FA) alone (LV5FU2, 275 patients), oxaliplatin

monotherapy (275 patients), or with a combination of oxaliplatin and 5-fluorouracil (5-

FU)/folinic acid (FA) (FOLFOX4, 271 patients).

An uncontrolled phase II study (EFC2964) included patients non-responding to 5-fluorouracil

(5-FU)/folinic acid (FA) alone, and that were treated with a combination of oxaliplatin and 5-

fluorouracil (5-FU)/folinic acid (FA) (FOLFOX4, 57 patients)

The two randomised clinical trials, EFC2962 (first-line therapy) and EFC4584 (in pre-treated patients),

showed significantly higher response rates and a prolonged progression free survival (PFS) / time to

progression (TTP) compared to treatment with 5-fluorouracil (5-FU)/folinic acid (FA) alone.

In the study EFC4584, including refractory pre-treated patients, the difference in median overall

survival (OS) between the combination of oxaliplatin and 5-fluorouracil (5-FU)/folinic acid (FA) did

not reach statistical significance.

Response rate under FOLFOX4 versus LV5FU2

Response rate (%)

(95% CI)

independent

radiological

review

with ITT analysis

LV5FU2

FOLFOX4

Oxaliplatin

monotherapy

(16-27)

(42-46)

Initial treatment

EFC2962

Response assessment every 8 weeks

P value = 0.0001

0.7 (0.00-2.7)

11.1

(7.6-15.5)

Pre-treated patients:

EFC4584

(refractory to CPT-11 +

5-FU/folinic acid)

Response assessment every 6 weeks

P value < 0.0001

(0.2-3.2)

Pre-treated patients:

EFC2964

(refractory to

5-FU/folinic acid)

Response

assessment

every

weeks

(13-36)

NA = not applicable

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Median Progression Free Survival (PFS) / Median Time to Progression (TTP) under FOLFOX4

versus LV5FU2

Median PFS/TTP, months (95%

CI)

independent

radiological

review

with ITT analysis

LV5FU2

FOLFOX4

Oxaliplatin

monotherapy

(5.5-6.5)

(7.2-8.8)

Initial treatment

EFC2962 (PFS)

Log-rank P value = 0.0003

(1.8-2.9)

(4.7-6.1)

Pre-treated patients:

EFC4584 (TTP)

(refractory to CPT-11 +

5-FU/FA)

Log-rank P value p<0.0001

(1.6-2.7)

Pre-treated patients

EFC2964

(refractory to

5-FU/folinic acid)

(3.1-5.7)

NA = not applicable

Median Overall Survival (OS) under FOLFOX4 versus LV5FU2

Median OS, months

(95% CI)

with ITT analysis

LV5FU2

FOLFOX4

Oxaliplatin

monotherapy

14.7

(13.0-18.2)

16.2

(14.7-18.2)

Initial treatment

EFC2962

Log-rank P value = 0.12

(7.3-9.3)

(9.1-10.5)

Pre-treated patients

EFC4584

(refractory to CPT-11 +

5-FU/folinic acid)

Log-rank P value = 0.09

(7.2-8.7)

Pre-treated patients

EFC2964

(refractory to

5-FU/folinic acid)

10.8

(9.3-12.8)

NA = not applicable

In pre-treated patients (EFC 4584), who were symptomatic at baseline, a higher proportion of those

treated with oxaliplatin/5-fluorouracil/folinic acid experienced a significant improvement of their

disease-related symptoms compared to those treated with 5-fluorouracil/folinic acid alone (27.7% vs

14.6%; p<0.0033). In non-pretreated patients (EFC 2962), no statistically significant difference

between the two treatment groups was found for any of the quality of life parameters. However,

quality of life scores were generally better in the control arm in terms of general well-being and pain

and worse in the oxaliplatin arm regarding nausea and vomiting.

In the adjuvant setting, the comparative MOSAIC phase III study (EFC3313) randomised 2,246

patients (899 stage II/Duke’s B2 and 1,347 stage III/Duke’s C) further to complete resection of the

primary colon cancer tumour either to 5-FU/folinic acid alone (LV5-FU2, 1,123 patients; B2/C =

448/675) or to a combination of oxalplatin and 5-FU/folinic acid (FOLFOX4, 1,123 patients; B2/C =

451/672).

Study EFC 3313, 3-year disease free survival (ITT analysis)* for the overall population

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*Median follow-up over 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 5FU/folinic acid combination (FOLFOX4) over 5FU/folinic acid alone (LV5-FU2).

Study EFC 3313, 3-year disease free survival (ITT analysis)* according to disease stage

Disease stage

Stage II

(Duke’s B2)

Stage III

(Duke’s C)

Treatment group

LV5-FU2

FOLFOX4

LV5-FU2

FOLFOX4

Percent

3-year

disease

free

survival (95% CI)

84.3

87.4

(80.9-87.7)

(84.3-90.5)

65.8

72.8

(62.2-69.5) (69.4-76.2)

Hazard ratio (95% CI)

0.79

(0.57-1.09)

0.75

(0.62-0.90)

P value (log rank test)

P = 0.151

P = 0.002

*Median follow-up over 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 study, 85.1% of the patients were still alive in the FOLFOX4 arm versus 83.8% in the LV5-

FU2 arm. This resulted in an overall mortality risk reduction of 10% in favour of FOLFOX4, without

reaching statistical significance (hazard ratio = 0.90). The figures were 92.2% versus 92.4% in the

stage II (Duke’s B2) sub-population (hazard ratio = 1.01) and 80.4% versus 78.1% in the stage III

(Duke’s C) sub-population (hazard ratio = 0.87), for FOLFOX4 and LV5-FU2, respectively.

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 130mg/m² every three weeks for 1 to

5 cycles and oxaliplatin at 85mg/m² every two weeks for 1 to 3 cycles is as follows:

Treatment group

LV5-FU2

FOLFOX4

Percentage 3-year

disease free survival

(95% CI)

73.3

(70.6-75.9)

78.7

(76.2-81.1)

Hazard ratio (95% CI)

0.76

(0.64-0.89)

P value (stratified log

rank test)

P = 0.0008

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Summary of Platinum Pharmacokinetic Parameters in Ultrafiltrate following Multiple Doses of

oxaliplatin at 85mg/m

2

every 2 weeks or at 130mg/m

2

every 3 weeks

Dose

Cmax

(µg/ml)

AUC

0-48

(µg.h/ml)

AUC

(µg.h/ml)

t

1/2

α

(h)

t

1/2

β

(h)

t

1/2

γ

(h)

V

ss

(l)

Cl

(l/h)

85mg/m²

Mean SD

0.814

0.193

4.19

0.647

4.68

1.40

0.43

0.35

16.8

5.74

17.4

6.35

130mg/m²

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

and C

values were determined for cycle 3 (85mg/m

) or cycle 5 (130mg/m

Mean AUC, V

, CL and CI

R0-48

values were determined for cycle 1.

, AUC, AUC

0-48

, and CL values were determined by non-compartmental analysis.

1/2α

1/2β

1/2γ

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 platinum accumulation was observed

in plasma ultrafiltrate following 85mg/m

every two weeks or 130mg/m

every three weeks and steady

state was attained at cycle one in this matrix. Inter- and intra-subject variability is generally low.

Biotransformation in vitro is considered to be the result of non-enzymatic degradation and there is no

evidence of cytochrome P450-mediated metabolism of the diaminocyclohexane (DACH) ring.

oxaliplatin undergoes extensive biotransformation in patients, and no intact active substance is

detectable in plasma ultrafiltrate at the end of a 2h-infusion. Several cytotoxic biotransformation

products

including

monochloro-,

dichloro-

diaquo-DACH

platinum

species

have

been

identified in the systemic circulation together with a number of inactive conjugates at later points in

time.

Platinum is predominantly excreted in urine, with clearance mainly within 48 hours following

administration.

By day 5, approximately 54% of the total dose was detected in the urine and < 3% in the faeces.

In patients with renal impairment a significant decrease of clearance from 17.6 ± 2.18 1/h to 9.95 ±

1.91 l/h was observed, together with a significant decrease of distribution volumes from 330 ± 40.9 to

241 ± 36.1 l. The effect on platinum clearance in patients with severe renal impairment has not been

evaluated.

5.3. Preclinical safety data

Target organs identified in preclinical species (mice, rats, dogs, and/or monkeys) for single- and

multiple-dose administration, included the bone marrow, the digestive system, kidneys, testes, the

nervous system, and the heart. The toxicities observed in these target organs are consistent with those

produced by other platinum-containing medicinal products and DNA-damaging, cytotoxic medicinal

products used for the treatment of human cancers with the exception of the effects produced on the

heart. Effects on the heart were observed only in dogs and included electrophysiological disturbances

with lethal ventricular fibrillation. Cardiotoxicity is considered specific to dogs not only because it

was observed in dogs alone, but also because doses similar to those producing lethal cardiotoxicity in

dogs (150mg/m

) were well tolerated by humans. Preclinical studies using rat sensory neurons suggest

that the acute oxaliplatin related neurosensory symptoms may be based on interaction with voltage-

dependent 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 so far.

6. PHARMACEUTICAL PARTICULARS

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6.1. List of excipients

Lactose monohydrate.

6.2. Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in

section 6.6.

The diluted medicinal product must not be mixed with other medicinal products in the same infusion

bag or infusion line. As described in section 6.6, oxaliplatin may be co-administered with folinic acid

(FA) via a Y-piece.

DO NOT use in association with alkaline medicinal products or solutions (in particular: 5-

fluorouracil (5-FU), folinic acid products containing trometamol as excipient, and trometamol

salts of other active substances). Alkaline medicinal products or preparations affect the stability

of oxaliplatin (see section 6.6).

DO NOT reconstitute or dilute with saline solution or other solutions containing chloride ions

(including calcium, potassium or sodium chloride).

DO NOT mix with other medicinal products in the same infusion bag or infusion line (see

section 6.6. Instructions concerning simultaneous administration with folinic acid (FA).

DO NOT use injection equipment containing aluminium.

6.3. Shelf life

Medicinal product as packaged for sale: 3 years

Reconstituted solution in original vial:

The reconstituted solution should be diluted immediately.

Solution for infusion:

After dilution of the reconstituted solution in glucose 5%, chemical and physical in-use stability has

been demonstrated for 24 hours at 2°C to 8°C.

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.

6.4. Special precautions for storage

No special precautions for storage.

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5. Nature and contents of container

Colourless glass vials type 1 (with 50, 100 or 150 mg powder) with grey rubber stoppers of

chlorobutyl elastomer with/without transparent plastic container (ONKO-Safe).

Pack size: 1 vial per box.

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6.6. Special precautions for disposal and other handling

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 medical personnel requires every precaution to guarantee the

protection of the handler and his surroundings.

The preparation of injectable solutions of cytotoxic agents must be carried out by trained specialist

personnel with knowledge of the medicinal product used, under conditions that guarantee integrity of

the medicinal product, protection of the environment and in particular protection of the personnel

handling the medicines, according to hospital guidelines. It requires a preparation area reserved for

this purpose. It is forbidden to smoke, eat or drink in this area.

Personnel

must

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 precaution and considered as contaminated waste.

Contaminated waste should be incinerated in suitably labelled rigid containers. See section “Disposal”

below.

If oxaliplatin powder, reconstituted solution or solution for infusion should come into contact with

skin, wash immediately and thoroughly with water.

If oxaliplatin powder, reconstituted solution 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 material containing aluminium.

DO NOT administer undiluted.

Must be diluted using only 5% glucose solution (50mg/ml).

DO NOT use by extravascular administration.

DO NOT dilute with sodium chloride or other solutions containing chloride for infusion.

DO NOT mix with any other medicinal products in the same infusion bag or administer

simultaneously via the same infusion line.

DO NOT use in association with alkaline medicinal products or solutions, in particular: 5-

fluorouracil (5-FU), folinic acid (FA) products containing trometamol as excipient, and trometamol

salts of other active substances. Alkaline medicinal products or preparations affect the stability of

oxaliplatin.

Instruction for use with folinic acid (as calcium folinate or disodium folinate)

Oxaliplatin 85mg/m² intravenous infusion in 250 to 500 ml of 5% glucose solution (50 mg/ml) 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 5-fluorouracil.

For additional information on medicinal products combined with oxaliplatin, see the corresponding

manufacturer's summary of product characteristics.

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

destroyed with due regard to legal requirements for disposal of hazardous waste (see below).

Reconstitution of the powder

Water for injections or 5 % glucose solution (50 mg/ml) should be used to reconstitute the

solution.

For a vial of 50 mg: add 10 ml of solvent to obtain a concentration of 5 mg oxaliplatin/ml.

For a vial of 100 mg: add 20 ml of solvent to obtain a concentration of 5 mg oxaliplatin/ml.

For a vial of 150 mg: add 30 ml of solvent to obtain a concentration of 5 mg oxaliplatin/ml.

From a microbiological and chemical point of view, the reconstituted solution should be diluted

immediately with 5% glucose solution.

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

The medicinal product is for single use only. Any unused solution should be discarded (see below

“Disposal”).

Dilution for intravenous infusion

Withdraw the required amount of reconstituted solution from the vial(s) and then dilute with 250 ml to

500 ml of a 5 % glucose (50 mg/ml) solution to give an oxaliplatin concentration between not less than

0.2 mg/ml and 0.7 mg/ml concentration range for which the physico-chemical stability of oxaliplatin

has been demonstrated.

Administer by IV infusion.

After dilution in 5% glucose (50 mg/ml), chemical and physical in-use stability has been demonstrated

for 24 hours at +2°C to +8°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.

It is not allowed to store the infusion preparation longer than 24 hours.

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

The medicinal product is for single use only. Any unused solution should be discarded (See chapter

“disposal” below).

NEVER use sodium chloride solution for either reconstitution or 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 500 ml of a 5% glucose (50 mg/ml) solution to give a concentration not

less than 0.2 mg/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 5-fluorouracil.

Disposal

Remnants of the medicinal product as well as all materials that have been used for reconstitution, for

dilution and administration must be destroyed according to hospital standard procedures applicable to

cytotoxic agents in accordance with the local requirements related to the disposal of hazardous waste.

18/35

7. MARKETING AUTHORISATION HOLDER

EBEWE Pharma Ges.m.b.H. Nfg. KG

Mondseestrasse 11

A-4866 Unterach, Austria

8. MARKETING AUTHORISATION NUMBER

1-26435

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

17. May 2006

10. DATE OF REVISION OF THE TEXT

November 2007

19/35

PACKAGE LEAFLET: INFORMATION FOR THE USER

Oxaliplatin „Ebewe“ 5 mg/ml powder for solution for infusion

Oxaliplatin

Read all of this leaflet carefully before you are given this medicine.

Keep this leaflet. You may need to read it again.

If you have further questions, please ask your doctor.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,

please tell your doctor.

In this leaflet:

What Oxaliplatin „Ebewe“ is and what it is used for

Before you are given Oxaliplatin „Ebewe“

How Oxaliplatin „Ebewe“ is given

Possible side effects

How to store Oxaliplatin „Ebewe“

Further information

1.

WHAT OXALIPLATIN „EBEWE“ IS AND WHAT IT IS USED FOR

Oxaliplatin „Ebewe“ is an anticancer drug and contains platinum.

Oxaliplatin „Ebewe“ is used to treat cancer of the large bowel (treatment of stage III colon cancer after

complete resection of primary tumour, metastatic cancer of colon and rectum).

Oxaliplatin „Ebewe“ is used in combination with other anticancer medicines called 5-fluorouracil and

folinic acid.

2.

BEFORE YOU ARE GIVEN OXALIPLATIN „EBEWE“

You should not be given Oxaliplatin „Ebewe“ if you:

are allergic (hypersensitive) to oxaliplatin or any of the other ingredients of Oxaliplatin

„Ebewe“

are breast-feeding

already have a reduced number of blood cells

already have tingling and numbness in the fingers and/or toes, and have difficulty

performing delicate tasks, such as buttoning clothes

have severe kidney problems

Take special care (check with your doctor) if you:

have ever suffered an allergic reaction to platinum-containing medicines such as

carboplatin, cisplatin

have moderate kidney problems

have any liver problems

experience numbness or tingling in your fingers or toes or difficulty in swallowing. These

symptoms can persist after the end of the treatment up to 3 years and may not be reversible.

Your doctor will perform a neurological examination regularly, especially if other drugs are

co-administered which affect the nerves.

experience persistent or severe diarrhoea, nausea or vomiting.

experience sore lips or mouth ulcers.

20/35

abnormal bruising, bleeding, or signs of infection such as a sore throat and high temperature.

As oxaliplatin can cause a reduction of the number of blood cells, your doctor will check your

blood frequently.

experience unexplained respiratory symptoms such as a non-productive cough, difficulty in

breathing or crackles.

notice a sensation of discomfort close to or at the injection site during the infusion (possible

leakage into the surrounding tissue)

also receive 5-fluorouracil, because the risk of diarrhoea, vomiting, sore mouth and blood

abnormalities is increased

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,

including medicines obtained without a prescription.

Pregnancy and breast-feeding

Ask your doctor or pharmacist for advice before taking any medicine.

You must not use oxaliplatin during pregnancy unless clearly indicated by your doctor.

You must not become pregnant during treatment with oxaliplatin and must use an effective method of

contraception. If pregnancy occurs during your treatment, you must immediately inform your doctor.

You should take appropriate contraceptive measures during and after cessation of therapy during 4

months for women and 6 months for men.

You must not breast-feed while you are treated with oxaliplatin.

Oxaliplatin may have an anti-fertility effect, which could be irreversible. Male patients are therefore

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.

Driving and using machines

Oxaliplatin treatment may result in an increase risk of dizziness, nausea and vomiting, and other

neurological symptoms that affect gait and balance. These can influence your ability to drive and use

machines, so do not do either until you are sure of how Oxaliplatin affects you.

3.

HOW OXALIPLATIN „EBEWE“ IS GIVEN

Dosage

Oxaliplatin „Ebewe“ is only to be given to adults.

Oxaliplatin „Ebewe“ will be prescribed for you by a specialist in cancer treatment. You will

be treated under medical supervision. Oxaliplatin „Ebewe“ is given by injection into a vein

(an intravenous infusion) over a 2 to 6 hour period.

Oxaliplatin „Ebewe“ will be made up by a healthcare professional.

The dose of Oxaliplatin „Ebewe“ is based on your body surface area. This is calculated from

your height and weight.

The usual dose for adults including the elderly is 85 mg/m

of body surface area once every 2

weeks before the infusion of the other anticancer medicines.

The dose you receive will also depend on results of blood tests and whether you have previously

experienced side effects with Oxaliplatin „Ebewe“.

Duration of treatment

The duration of the treatment will be determined by your doctor.

Your treatment will last a maximum of 6 months when used after complete resection of your tumour.

21/35

Your doctor will ensure that the correct dose for your condition is given. In case of overdose, you may

experience increased side effects. Your doctor may give you symptomatic treatment for these side

effects.

If you have any further questions on the use of this product, ask your doctor.

4.

POSSIBLE SIDE EFFECTS

Like all medicines, Oxaliplatin „Ebewe“ can cause side effects, although not everybody gets them. If

you experience any side effect it is important that you inform your doctor before your next

treatment.

Tell your doctor immediately, if you notice any of the following:

persistent or severe diarrhoea or vomiting

stomatitis/mucositis (sore lips or mouth ulcers)

swelling of the face, lips, mouth or throat

unexplained respiratory symptoms such as non-productive cough, difficulty in breathing or

crackles

difficulty in swallowing

numbness or tingling in your fingers or toes

extreme tiredness

abnormal bruising or bleeding

signs of infection, such as sore throat and high temperature

sensation of discomfort close to or at the injection site during the infusion.

Very common side effects (in more than 1 of 10 patients) are:

A disorder of the nerves which can cause weakness, tingling or numbness in the fingers, toes,

around the mouth or in the throat that may sometimes occur in association with cramps. This is

often triggered by exposure to cold e.g. opening a refrigerator or holding a cold drink. You

may also have difficulty in performing delicate tasks, such as buttoning clothes. Although in

the majority of cases these symptoms resolve completely there is a possibility of persistent

symptoms after the end of the treatment

A tingling shock-like sensation passing down the arms or chest when the neck is flexed

(Lhermitte´s sign)

An unpleasant sensation in the throat, in particular when swallowing, and give the sensation of

shortness of breath. This sensation, if it happens, usually occurs during or within hours of the

infusion and may be triggered by exposure to the cold. Although unpleasant, it will not last

long and usually subsides without the need for any treatment

Jaw spasm, abnormal tongue sensation, possibly affecting speech, and a feeling of chest

pressure. Your doctor may decide to alter your treatment as a result

Taste alteration

Headache

Sore throat and high temperature (signs of infection)

Reduction in the number of white blood cells, which make infections more likely

Reduction in red blood cells, which can make the skin pale and cause weakness or

breathlessness

Reduction in blood platelets, which increases risk of bleeding or bruising

Your doctor will take blood to check that you have sufficient blood cells before you start treatment

and before each subsequent course.

Nosebleeds

Allergic reactions - skin rash including red itchy skin, inflammation of the conjunctiva,

swelling of the hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty in

swallowing or breathing) and you may feel you are going to faint

Shortness of breath, coughing

Loss or lack of appetite

22/35

Nausea (feeling sick), vomiting (being sick) - medication to prevent sickness is usually given

to you by your doctor before treatment and may be continued after treatment.

Diarrhoea, if you suffer from persistent or severe diarrhoea or vomiting, contact your doctor

immediately for advice.

Sore mouth or lips, mouth ulcers

Stomach pain, constipation

Skin disorder

Hair loss

Back pain

Tiredness, loss of strength/weakness, body pain

Pain or redness close to or at the injection site during the infusion

Fever

Weight gain

Abnormal levels of glucose (sugar) in your blood e.g. too high levels which may cause a great

thirst, dry mouth or a need to urinate more often

Rigors (tremors)

Low blood levels of potassium, which can cause abnormal heart rhythm and can be recognised

by muscle cramps, muscle weakness or fatigue.

Abnormal levels of sodium blood levels e.g. low sodium levels which can cause tiredness and

confusion, muscle twitching, fits or coma.

Abnormal blood tests which show changes of liver function (increase of alkaline phosphatase,

bilirubin, LDH and hepatic enzymes)

Common side effects (in less than 1 in 10 but more than 1 in 100 patients)are:

Reduction in the number of a special form of white blood cells accompanied by fever and/or

generalized infection / infections of the respiratory tract

Dehydration

Depression

Difficulty sleeping

Dizziness

Inflammation of nerves leading to muscle spasms, cramps, loss of certain reflexes

Neck stiffness, intolerance/dislike of bright light and headache

Conjunctivitis, visual problems

Abnormal bleeding, blood in the urine and stools

Blood clot, usually in a leg, which causes pain, swelling or redness

Blood clot in the lungs which causes chest pain and breathlessness

Runny nose

Upper respiratory tract infection

Flushing

Chest pain, hiccups

Indigestion and heartburn

Loss of weight

Peeling skin, skin rash, increased sweating and nail disorder

Joint pain and bone pain

Pain on passing urine or a change in frequency when passing urine

Abnormal blood tests which show changes of kidney function (e.g. increase of creatinine)

Uncommon side effects (in less than 1 in 100 but more than 1 in 1,000 patients) are:

Nervousness

Hearing problems (ototoxicity)

Impaired or blocked bowel passage

Disturbance in the body's acid-base balance

Rare side effects (in less than 1 in 1,000 but more than 1 in 10,000 patients) are:

Reduction in blood platelets due to an allergic reaction associated with bruises and abnormal

bleeding (immunoallergic thrombocytopenia)

Reduction in red blood cells caused by cell destruction

23/35

Slurred speech

Temporary fall in visual acuity; visual field disturbances

Deafness

Unexplained respiratory symptoms, difficulties in breathing, scarring of the lungs which

causes shortness of breath

Bowel inflammation causing abdominal pain or diarrhoea, including severe bacterial infection

(Clostridium difficile)

Inflammation of the optic nerve

Very rare effects (in less than 1 in 10,000 patients) are

Inflammation of the pancreas

Liver disease that your doctor will monitor you for

Changes in kidney function

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,

please tell your doctor or pharmacist.

Oxaliplatin „Ebewe“ should not come into contact with the eyes or skin. If there is any

accidental spillage, tell the doctor or nurse immediately.

5.

HOW TO STORE OXALIPLATIN „EBEWE“

Keep out of the reach and sight of children.

Do not use this medicine after the expiry date, which is stated on the pack. The expiry date refers to

the last day of that month.

This medicinal product does not require any special storage conditions.

Reconstituted concentrate solution in the original vial:

The reconstituted concentrate solution should be diluted immediately.

Solution for infusion after dilution:

After dilution of the reconstituted solution in glucose 5 % solution, chemical and physical in-use

stability has been demonstrated for 24 hours at + 2°C to + 8°C.

From a microbiological point of view, the solution for infusion should be used immediately.

If not used immediately, in-use storage times and conditions prior to use are the responsibility of the

user.

6.

FURTHER INFORMATION

What Oxaliplatin „Ebewe“ contains

The active substance is oxaliplatin. The other ingredient is lactose monohydrate.

50 mg vial: Each vial contains 50 mg oxaliplatin for reconstitution in 10 ml of solvent.

100 mg vial: Each vial contains 100 mg oxaliplatin for reconstitution in 20 ml of solvent.

150 mg vial: Each vial contains 150 mg oxaliplatin for reconstitution in 30 ml of solvent.

One ml of the reconstituted concentrate solution contains 5 mg oxaliplatin.

What Oxaliplatin „Ebewe“ looks like and contents of the pack

This medicinal product is a powder for solution for infusion.

Each vial contains a white to off-white powder for solution for infusion containing 50 mg, 100 mg or

150 mg oxaliplatin. The vials are supplied in cartons of one (1).

Oxaliplatin „Ebewe“ has to be dissolved and made into a solution before it can be injected into a vein.

24/35

Marketing Authorisation Holder and Manufacturer

Marketing authorisation holder:

EBEWE Pharma Ges.m.b.H. Nfg. KG

4866 Unterach

Austria

Tel: +43 / 7665 / 8123-0

Fax: +43 / 7665 / 8123-129

Manufacturer:

EBEWE Pharma Ges.m.b.H. Nfg. KG

4866 Unterach

Austria

Oncotec Pharma Produktion GmbH

Streetzer Weg 15a

06862 Rodleben, OT Tornau

Germany

This medicinal product is authorised in the Member States of the EEA under the following

names:

Oxaliplatin "Ebewe" 5mg/ml Pulver zur Herstellung einer Infusionslösung

Oxaliplatin “Ebewe” 5 mg/ml powder for infusion

Ebeoxal 5 mg/ml prášek pro prípravu infuzního roztoku

Ebeoxal 5 mg/ml Pulver zur Herstellung einer Infusionslösung

Ebeoxal EBEWE PHARMA

GR (EL):

PLAXITIN 5 mg/ml κόνις γιa dιάλυµa pρος έγχυsη

Oxaliplatino EBEWE PHARMA 5 mg/ml polvo para solución para

perfusión

Oxitropic 5mg/ml infuusiokuiva-aine, liuosta varten

EBEOXAL 5 mg/ml, poudre pour solution pour perfusion

Ebeoxal 5 mg/ml polvere per soluzione per infusione

Oxaliplatin “Ebewe”

Oxaliplatin “Ebewe” 5 mg/ml powder for infusion

Oxaliplatin “Ebewe” 5 mg/ml poeder voor oplossing voor infusie

Ebeoxal 5mg/ml pulver til infusjonsvæske, oppløsning

Oxaliplatin “Ebewe” 5 mg/ml powder for infusion

Oxitropic 5mg/ml pulver till infusionsvätska, lösning

Ebeoxal 5 mg/ml prášok na infúzny roztok

SLO:

Oxaliplatin “Ebewe” 5 mg/ml prašek za raztopino za infundiranje

Oxaliplatin 5 mg/ml powder for infusion

This leaflet was last approved in November 2007.

--------------------------------------------------------------------------------------------------------------

The following information is intended for medical or healthcare professionals only:

Special precautions for disposal and other handling

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

oxaliplatin solutions.

Instructions for Handling

25/35

The handling of this cytotoxic agent by nursing or medical personnel requires every precaution to

guarantee the protection of the handler and his surroundings.

The preparation of injectable solutions of cytotoxic agents must be carried out by trained specialist

personnel with knowledge of the medicines used, in conditions that guarantee the protection of the

environment and in particular the protection of the personnel handling the medicines in accordance

with the hospital policy. It requires a preparation area reserved for this purpose. It is forbidden to

smoke, eat or drink in this area.

Personnel must be provided with appropriate handling materials, notably long sleeved gowns,

protection masks, caps, protective goggles, sterile single-use gloves, protective covers for the work

area, containers and collection bags for waste.

Excreta and vomit must be handled with care.

Pregnant women must be warned to avoid handling cytotoxic agents.

Any broken container must be treated with the same precautions and considered as contaminated

waste. Contaminated waste should be incinerated in suitably labelled rigid containers. See below

section “Disposal”.

If oxaliplatin powder, reconstituted solution or infusion solution should come into contact with skin,

wash immediately and thoroughly with water.

If oxaliplatin powder, reconstituted solution or infusion solution should come into contact with

mucous membranes, wash immediately and thoroughly with water.

Special precautions for administration

DO NOT use injection material containing aluminium.

DO NOT administer undiluted.

DO NOT use by extravascular administration.

Only glucose 5% infusion solution (50 mg/ml) is to be used as a diluent.

DO NOT reconstitute or dilute for infusion with sodium chloride or chloride containing solutions.

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

the same infusion line.

DO NOT mix with alkaline drugs or solutions, in particular 5-fluorouracil, folinic acid

preparations containing trometamol as an excipient and trometamol salts of other drugs. Alkaline

drugs or solutions will adversely affect the stability of oxaliplatin.

Instruction for use with folinic acid (as calcium folinate or disodium folinate)

Oxaliplatin 85mg/m² IV infusion in 250 to 500 ml of 5% glucose solution (50 mg/ml) is given at the

same time as folinic acid IV infusion in 5% glucose solution, over 2 to 6 hours, using a Y-line placed

immediately before the site of infusion.

These two drugs should not be combined in the same infusion bag. Folinic acid must not contain

trometamol as an excipient and must only be diluted using isotonic 5% glucose solution, never in

alkaline solutions or sodium chloride or chloride containing solutions.

Instruction for use with 5-fluorouracil

Oxaliplatin should always be administered before fluoropyrimidines – i.e. 5-fluorouracil.

After oxaliplatin administration, flush the line and then administer 5-fluorouracil.

For additional information on drugs combined with oxaliplatin, see the corresponding manufacturer's

summary of product characteristics.

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

destroyed with due regard to legal requirements for disposal of hazardous waste (see below).

26/35

Reconstitution of the powder

Water for injections or 5 % glucose solution (50 mg/ml) should be used to reconstitute the

solution.

For a vial of 50 mg: add 10 ml of solvent to obtain a concentration of 5 mg oxaliplatin/ml.

For a vial of 100 mg: add 20 ml of solvent to obtain a concentration of 5 mg oxaliplatin/ml.

For a vial of 150 mg: add 30 ml of solvent to obtain a concentration of 5 mg oxaliplatin/ml.

From a microbiological and chemical point of view, the reconstituted solution should be diluted

immediately with 5% glucose solution.

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

The medicinal product is for single use only. Any unused solution should be discarded (see below

“Disposal”).

Dilution before infusion

Withdraw the required amount of reconstituted concentrate solution from the vial(s) and then dilute

with 250 ml to 500 ml of a 5 % glucose solution to give an oxaliplatin concentration between not less

than 0.2 mg/ml and 0.7 mg/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 24

hours at +2°C to +8°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. It is not allowed to store the infusion preparation longer than 24 hours.

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

The medicinal product is for single use only. Any unused solution should be discarded.

NEVER use sodium chloride solution for either reconstitution or 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 500 ml of a 5% glucose solution to give a concentration not less than 0.2

mg/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 5-fluorouracil.

Disposal

Remnants of the medicinal product as well as all materials that have been used for reconstitution, for

dilution and administration must be destroyed according to hospital standard procedures applicable to

cytotoxic agents with due regard to current laws related to the disposal of hazardous waste.

27/35

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE

PACKAGING

1.

NAME OF THE MEDICINAL PRODUCT

Oxaliplatin „Ebewe“ 5 mg/ml powder for solution for infusion

Oxaliplatin

2.

STATEMENT OF ACTIVE SUBSTANCE(S)

50 mg vial: Each vial contains 50 mg oxaliplatin for reconstitution in 10 ml of solvent

100 mg vial: Each vial contains 100 mg oxaliplatin for reconstitution in 20 ml of solvent

150 mg vial: Each vial contains 150 mg oxaliplatin for reconstitution in 30 ml solvent

1 ml of reconstituted solution for infusion contains 5 mg oxaliplatin.

3.

LIST OF EXCIPIENTS

Excipient: Lactose monohydrate

4.

PHARMACEUTICAL FORM AND CONTENTS

Powder for solution for infusion

50 mg

100 mg

150 mg

1 vial

5.

METHOD AND ROUTE(S) OF ADMINISTRATION

For intravenous use after reconstitution and dilution.

Read the package leaflet before use.

6.

SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE REACH AND SIGHT OF CHILDREN

Keep out of the reach and sight of children.

7.

OTHER SPECIAL WARNING(S), IF NECESSARY

Cytostatic agent

Pregnant women should avoid handling cytotoxic agents.

In case of contact with skin, mucous membranes, wash immediately with water.

Do not administer undiluted.

8.

EXPIRY DATE

9.

SPECIAL STORAGE CONDITIONS

28/35

10.

SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF

APPROPRIATE

Single use vial – discard appropriately any content remaining after first use.

The disposal of cytotoxic agents should be in accordance with the local requirements.

11.

NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

EBEWE Pharma Ges.m.b.H Nfg.KG

Mondseestrasse 11

4866 Unterach, Austria

Phone: +43 7665 8123 0

Fax: +43 7665 8123 11

e-mail: office@ebewe.com

12.

MARKETING AUTHORISATION NUMBER(S)

MA no.:

13.

BATCH NUMBER

Batch

14.

GENERAL CLASSIFICATION FOR SUPPLY

[To be completed nationally]

15.

INSTRUCTIONS ON USE

Reconstituted solution must be diluted immediately.

Use immediately after dilution.

16.

INFORMATION IN BRAILLE

Justification for not including Braille accepted

29/35

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

LABEL OF VIAL

1.

NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Oxaliplatin „Ebewe“ 5 mg/ml powder for solution for infusion

Oxaliplatin

For intravenous use only.

2.

METHOD OF ADMINISTRATION

For intravenous use after reconstitution and dilution.

3.

EXPIRY DATE

4.

BATCH NUMBER

Batch

5.

CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

1 ml of reconstituted solution for infusion contains 5 mg oxaliplatin.

6.

OTHER

Cytostatic agent

30/35

Scientific discussion during initial procedure

I.

RECOMMENDATION

Based on the review of the data on quality, safety and efficacy, the RMS considered that the

application for Oxaliplatin Ebewe 5mg/ml powder for solution for infusion, indicated for the

treatment of metastatic colorectal carcinoma in combination with 5-fluorouracil and folinic

acid and for adjuvant therapy of colon carcinoma stage III (Dukes C) after complete resection

of the primary tumour, could be approved. A national marketing authorisation was granted on

17.5.2006.

II.

EXECUTIVE SUMMARY

II.1

Problem statement

This is a generic application for a medicinal product containing the active substance

oxaliplatin.

The application refers to a reference product which has been authorised for not less than 6/10

years in the EEA, which is Eloxatine 5 mg/ml, powder for solution for infusion (Sanofi

Aventis France, authorised 12 April 1996). Eloxatine has been registered through a mutual

recognition procedure (FR/H/144/01) in BE, DE, ES, IT, LU, NL, SE and UK with day 90 on

5.7.1999. The originator product was registered in AT in a second MRP (FR/H/284/01) with

AT, BE, CZ, DE, DK, EL, ES, FI, HU, IE, IS, IT, LU, MT, NL, NO, PL, PT, SE, SI, SK as

CMS. This procedure was concluded on 22.12.2005.

II.2

About the product

The active substance of the product in question is oxaliplatin, which is presented in the

pharmaceutical form of a powder for solution for infusion. For the originator product Eloxatin

a powder for solution for infusion as well as a concentrate for solution for infusion have been

registered.

The pharmacodynamics, pharmacokinetics and toxicology of the active substance are well

known.

Oxaliplatin is a third generation platinum analogue (ATC code L01XA03) for the treatment of

colorectal cancer. The activity profile differs from other platinum compounds cisplatin and

carboplatin, and cross-resistance with these compounds has not yet been described. Oxaliplatin

contains the DACH carrier ligand, 1,2-diaminocyclohexane, that makes inter- and intra-DNA

covalent bonds between guanine residues. These crosslinks inhibit DNA replication and

transcription irrespective the cell cycle status of the tumour cell, thus resulting in cell death.

DACH also influences the tissue distribution of the molecule.

Oxaliplatin 5 mg/ml powder for solution for infusion is indicated for the treatment of

metastatic colorectal carcinoma in combination with 5-fluorouracil and folinic acid and for

adjuvant therapy of colon carcinoma stage III (Dukes C) after complete resection of the

primary tumour. The intravenous administration route is intended for the finished product

Oxaliplatin 5 mg/ml powder for solution for infusion.

31/35

II.3

General comments on the submitted dossier

For Oxaliplatin Ebewe an article 10(1) generic application was submitted in BG, CZ, DE,

DK, EL, ES, FI, FR, IT, LV, MT, NL, NO, RO, SE, SI, SK, UK with reference to the

medicinal product authorised in the Member State where the application is made.

The dossier submitted was considered of sufficient quality.

II.4

General comments on compliance with GMP, GLP, GCP and agreed ethical

principles

The RMS has been assured that acceptable standards of GMP are in place for these product

types at all sites responsible for the manufacture and assembly of this product prior to

granting its National authorisation.

32/35

III.

SCIENTIFIC OVERVIEW AND DISCUSSION

III.1

Quality aspects

DRUG SUBSTANCE

Oxaliplatin is described in the PhEur. The white or almost white, crystalline powder is

slightly soluble in water, very slightly soluble in methanol and practically insoluble in

ethanol. Oxaliplatin possesses two chiral carbon atoms (C

and C

). The enantiomer which is

therapeutically used is the R,R-form.

Both suppliers of the drug substance have received a certificate of suitability according to Ph.

Eur.

both

drug

substance

manufacturers

specification

including

Eur.

tests

supplemented by the tests on residual solvents is established. Analytical results of three

batches of each supplier are presented.

Both CEPs include a re-test period of 3 years without any storage restrictions, nevertheless,

corresponding data are submitted in the dossier.

DRUG PRODUCT

Oxaliplatin, 5 mg/ml, powder for infusion is a lyophilised preparation containing oxaliplatin

and lactose monohydrate. It is available in three different sizes (50 mg , 100 mg or 150 mg

oxaliplatin per vial). Nitrogen according to Ph. Eur. is used as inert gas.

Aim of pharmaceutical development was a lyophilised preparation containing oxaliplatin in a

concentration

mg/ml

after

reconstitution.

overages

used.

Comprehensive

information on the development work of the formulation is given. The proposed product is

compared to the originator product regarding content and impurity profile demonstrating

comparable and acceptable amounts of impurities. The container closure system is justified.

The drug product is manufactured by Oncotec Pharma GmbH, Germany. EBEWE Pharma

Ges.m.b.H. Nfg.KG, Austria, is responsible for final release of the drug product. An aseptic

manufacturing procedure involving sterile filtration of the compounded solution is used.

Process validation was performed on pilot and production batches. The applicant commits to

perform additional validation studies if the batch size of the 150 mg strength will ever be

increased.

The excipients (lactose monohydrate, water for injection in bulk, nitrogen) are described in

Eur.

specifications

comply

with

pharmacopoeial

specifications.

Representative certificate of analysis are enclosed in the dossier.

Quality control of the drug product comprises relevant quality indicating parameters. All tests

recommended by either Ph. Eur. monograph on Parenteral Preparations and by ICH topic

Q6A are performed, respective limits are set. All methods used are described adequately

respectively reference to Ph. Eur. is given. Validation data according to ICH topic Q2 (R1)

33/35

are provided. Certificates of analyses of several batches for each strength are presented.

Within these batches drug substance of either source is used. The applicant commits to lower

the limit for the sum of unknown impurites if possible on the basis of the data of future

stability tests.

The following packaging materials are used for Oxaliplatin, 5 mg/ml, powder for infusion:

Colourless glass vials, hydrolytic class 1 (Ph. Eur.), Chlorobutylrubber stoppers (Type I Ph.

Eur.), Aluminium seal with flip-off or equivalent. The container closure system meets the

requirements of Ph. Eur. and thus is appropriate to be used as immediate packaging material

for the drug product. The applicant commits to have the next 3 batches of stoppers tested by

the manufacturer West Pharmaceutical Services for endotoxins according to Ph. Eur. 2.6.14.

Subsequently one batch of stoppers will be tested per year and in case of an OOS result this

will promptly be reported to the authorities.

Long-term and accelerated stability studies have been undertaken in line with relevant CHMP

and ICH recommendations. Various pilot and production batches are followed during stability

studies covering a period up to 36 months for long-term studies respectively 12 months for

accelerated studies. All results comply with specifications. A shelf-life of 3 years without any

special storage recommendations can be granted. The applicant commits to put the first three

production batches of the 150 mg preparation on stability studies.

In addition a number of in-use stability trials (including photostability tests) were performed

to demonstrate the stability during simulated in-use conditions. Storage of the infusion

solution can generally not be recommended, however, the infusion preparation may be stored

for maximum 24h at 2-8°C as lined out in the SPC.

III.2

Non clinical aspects

Pharmacodynamic,

pharmacokinetic

toxicological

properties

oxaliplatin

well

known. As oxaliplatin is a widely used, well-known active substance, no further studies are

required and the applicant provides none. An Overview based on literature review is, thus,

appropriate.

Non-clinical

Overview

pre-clinical

pharmacology,

pharmacokinetics

toxicology was written by Klaus Seibel, a pharmacologist, both experienced in pharmacology

and toxicology.

III.3

Clinical aspects

Pharmacokinetics

Based on the data provided, Oxaliplatin Ebewe 5 mg/ml powder for solution for infusion is

considered a generic of Eloxatin® powder for solution for infusion. No bioequivalence study

is required.

Pharmacodynamics

Not Applicable.

Clinical efficacy and safety

As oxaliplatin is a widely used, well-known active substance, no further studies are required

34/35

and the applicant provides none. The Clinical Overview on clinical pharmacology, efficacy

and safety was written by Klaus Seibel, a pharmacologist and doctor of internal medicine and

is adequate in view of the indications presently sought.

The indications sought for Oxaliplatin Ebewe are analogous to the indications approved for

the originator Eloxatin® as worded in the proposed SPC:

Oxaliplatin Ebewe in combination with 5-fluorouracil and folinic acid is indicated for:

Treatment of metastatic colorectal cancer.

Adjuvant treatment of stage III (Duke’s C) colon cancer after complete

resection of primary tumour.

The indications and the posology for Oxaliplatin as sought are endorsed.

III.4

Risk Management Plan

Non-clinical and clinical safety specifications

Pharmacovigilance Plan

The RMS considers that the Pharmacovigilance system as described by the applicant fulfils

the requirements and provides adequate evidence that the applicant has the services of a

qualified person responsible for pharmacovigilance and has the necessary means for the

notification of any adverse reaction suspected of occurring either in the Community or in a

third country.

Risk Minimisation Plan

In reference to the EMEA Guideline CHMP/96268/2005 the applicant considers no need for a

risk minimisation plan as the substance in questions is well known. The RMS endorses this

position.

IV.

OVERALL

CONCLUSION,

BENEFIT

RISK

ASSESSMENT

AND

RECOMMENDATION

As the benefits and risks of the generic product Oxaliplatin Ebewe are similar to those of the

reference product Eloxatine registered in France since 12 April 1996, the RMS recommends

approval of marketing authorisation.

The SPC has been adapted to the actual version of the originator product Eloxatin registered

in Austria (FR/H/284/01/MR) and is acceptable.

The PIL has been adapted and is very similar to the harmonised PIL from MRP procedures

FI/H/584-589/01/MR.

A User Test was conducted and showed that the leaflet is readable and patients/users will be

able to understand the information given and thus the requirements of Article 59(3) and 61(1)

of Directive 2001/83/EC as amended by directive 2004/27/EC are fulfilled.

The labelling was considered appropriate.

35/35

The Member States mutually recognised the RMSs evaluation of the marketing authorisation.

There was no discussion in the CMD(h). Agreement between Member States was reached

through a written procedure.

V.

RECOMMENDED

CONDITIONS

FOR

MARKETING

AUTHORISATION

V.1

Conditions for the marketing authorisation

Legal Status

The product is subject to medical prescription which may not be renewed

Specific obligations

The applicant undersigned the following commitments:

The applicant commits to perform additional process validation studies if the batch

size of the 150 mg strength will ever be increased.

The applicant commits to lower the limit for the sum of unknown impurites if possible

on the basis of the data of future stability tests.

The applicant commits to have the next 3 batches of stoppers tested by the

manufacturer West Pharmaceutical Services for endotoxins according to Ph. Eur.

2.6.14. Subsequently one batch of stoppers will be tested per year and in case of an

OOS result this will promptly be reported to the authorities.

The applicant commits to put the first three production batches of the 150 mg

preparation on stability studies.

Packungsbeilage: zusammensetzung, kinische angaben, nebenwirkungen, wechselwirkungen, dosierung, schwangerschaft, stillzeit

GEBRAUCHSINFORMATION: INFORMATION FÜR DEN ANWENDER

Oxaliplatin Ebewe 5 mg/ml Pulver zur Herstellung einer Infusionslösung

Wirkstoff: Oxaliplatin

Lesen Sie die gesamte Packungsbeilage vor Beginn der Behandlung sorgfältig durch,

denn sie enthält wichtige Informationen.

Heben Sie die Packungsbeilage auf. Vielleicht möchten Sie diese später nochmals lesen.

Wenn Sie weitere Fragen haben, wenden Sie sich an Ihren Arzt.

Wenn

Nebenwirkungen

bemerken,

wenden

sich

Ihren

Arzt

oder

medizinische

Fachpersonal.

Dies

gilt

auch

für

Nebenwirkungen,

nicht

dieser

Packungsbeilage angegeben sind. Siehe Abschnitt 4.

Was in dieser Packungsbeilage steht:

Was ist Oxaliplatin Ebewe und wofür wird es angewendet?

Was sollten Sie vor der Anwendung von Oxaliplatin Ebewe beachten?

Wie ist Oxaliplatin Ebewe anzuwenden?

Welche Nebenwirkungen sind möglich?

Wie ist Oxaliplatin Ebewe aufzubewahren?

Inhalt der Packung und weitere Informationen

1.

WAS IST OXALIPLATIN EBEWE UND WOFÜR WIRD ES ANGEWENDET?

Oxaliplatin Ebewe ist ein Arzneimittel gegen Krebs und enthält den Wirkstoff Oxaliplatin.

Oxaliplatin Ebewe wird zur Behandlung von Darmkrebs nach operativer Entfernung oder wenn

dieser bereits metastasiert ist, angewendet. Die Anwendung erfolgt in Kombination mit weiteren

Arzneimitteln gegen Krebs (5-Fluoruracil [5-FU] und Folinsäure [FA]).

2.

WAS

SOLLTEN

SIE

VOR

DER

ANWENDUNG

VON

OXALIPLATIN

EBEWE

BEACHTEN?

Oxaliplatin Ebewe darf nicht angewendet werden,

wenn Sie allergisch gegen Oxaliplatin oder einen der in Abschnitt 6. genannten sonstigen

Bestandteile dieses Arzneimittels sind

wenn Sie stillen

wenn Sie bereits eine verringerte Anzahl von Blutzellen haben

wenn Sie bereits an Kribbeln oder Taubheit der Finger und/oder Zehen leiden und

Schwierigkeiten

bei

feinmotorischen

Tätigkeiten

Zuknöpfen

Kleidungsstücken haben

wenn Sie schwerwiegende Nierenprobleme haben

Warnhinweise und Vorsichtsmaßnahmen

Sprechen Sie mit Ihrem Arzt, bevor Oxaliplatin Ebewe bei Ihnen angewendet wird,

wenn

jemals

eine

allergische

Reaktion

platinhaltiges

Arzneimittel

Carboplatin oder Cisplatin erlitten haben. Allergische Reaktionen können während einer

Oxaliplatin Infusion auftreten.

wenn Sie leichte oder mäßige Nierenbeschwerden haben

wenn

Leberprobleme

oder

abweichende

Leberfunktionswerte

während

Behandlung haben

wenn Sie Herzerkrankungen, wie z. B. ein abnormes elektrisches Signal, auch

Verlängerung des QT-Intervalls genannt, einen unregelmäßigen Herzschlag oder in Ihrer

Familiengeschichte Herzprobleme haben oder hatten.

Anwendung von Oxaliplatin Ebewe zusammen mit anderen Arzneimitteln

Informieren Sie Ihren Arzt oder Apotheker, wenn Sie andere Arzneimittel einnehmen/anwenden,

kürzlich andere Arzneimittel eingenommen/angewendet haben oder beabsichtigen, andere

Arzneimittel einzunehmen/anzuwenden.

Schwangerschaft,Stillzeit und Fortpflanzungsfähigkeit

Schwangerschaft

Es wird nicht angeraten, während der Behandlung mit Oxaliplatin Ebewe schwanger zu

werden. Sie müssen eine wirksame Empfängnisverhütungsmethode anwenden. Während

und bis zu 4 Monate nach Beendigung der Behandlung müssen Frauen eine geeignete

Empfängnisverhütungsmethode anwenden.

Wenn Sie schwanger sind oder eine Schwangerschaft planen, ist es sehr wichtig, dass Sie

diesen Umstand vor Beginn der Behandlung mit Ihrem Arzt besprechen.

Wenn Sie während Ihrer Behandlung schwanger werden, müssen Sie sofort Ihren Arzt

informieren.

Stillzeit

Während der Behandlung mit Oxaliplatin Ebewe dürfen Sie nicht stillen.

Fortpflanzungsfähigkeit

Oxaliplatin

Ebewe

kann

eine

Unfruchtbarkeit

hervorrufen,

dauerhaft

sein

kann.

Männliche Patienten sollten sich hinsichtlich einer Spermakonservierung beraten lassen.

Männlichen Patienten wird empfohlen, kein Kind während und bis zu 6 Monaten nach der

Therapie zu zeugen und in dieser Zeit geeignete Verhütungsmaßnahmen anzuwenden.

Fragen Sie vor der Einnahme von allen Arzneimitteln Ihren Arzt oder Apotheker um Rat.

Verkehrstüchtigkeit und das Bedienen von Maschinen

Achtung: Dieses Arzneimittel kann die Reaktionsfähigkeit und Verkehrstüchtigkeit

beeinträchtigen.

Die Behandlung mit Oxaliplatin kann das Risiko für Schwindel, Übelkeit und Erbrechen sowie

für andere neurologische Symptome, die den Gang und den Gleichgewichtssinn betreffen,

erhöhen. Wenn dieser Fall eintritt, dürfen Sie kein Fahrzeug lenken und keine Maschinen

bedienen. Wenn Sie während der Behandlung mit Oxaliplatin Sehstörungen haben, dürfen Sie

kein Fahrzeug lenken, keine schweren Maschinen bedienen und keine gefährlichen Tätigkeiten

ausführen.

3.

WIE IST OXALIPLATIN EBEWE ANZUWENDEN?

Diese Arzneimittel wird durch medizinisches Fachpersonal angewendet; wenden Sie es nicht

selbst an.

Oxaliplatin Ebewe ist nur für Erwachsene indiziert.

Dosierung

Die Dosis von Oxaliplatin Ebewe richtet sich nach Ihrer Körperoberfläche, die aus Ihrer

Körpergröße

Ihrem

Gewicht

errechnet

wird.

übliche

Dosis

für

Erwachsene

einschließlich älterer Patienten beträgt 85 mg/m² Körperoberfläche. Die Dosis, die Ihnen

verabreicht wird, wird auch von den Ergebnissen Ihrer Blutkontrollen abhängig sein sowie

davon, ob bei Ihnen bei einer früheren Anwendung von Oxaliplatin Ebewe Nebenwirkungen

aufgetreten sind.

Art der Anwendung

Oxaliplatin

Ebewe

wird

Ihnen

einem

Behandlung

Krebserkrankungen

erfahrenen Arzt verschrieben.

Sie werden von medizinischem Fachpersonal behandelt, das die für Sie erforderliche Dosis

von Oxaliplatin Ebewe hergestellt haben wird.

Oxaliplatin Ebewe wird als langsame Injektion in eine Vene (intravenöse Infusion) über einen

Zeitraum von 2 bis 6 Stunden gegeben. Wenn ein unangenehmes Gefühl oder Schmerzen

an der Injektionsstelle auftreten, informieren Sie sofort das medizinische Fachpersonal.

Oxaliplatin Ebewe wird Ihnen gemeinsam mit Folinsäure und vor der Infusion von 5-

Fluorouracil verabreicht werden.

Häufigkeit der Anwendung

Die Infusionen sollten alle 2 Wochen wiederholt werden.

Dauer der Behandlung

Ihr Arzt entscheidet darüber, wie lange die Behandlung dauern wird.

Wenn Ihr Tumor vollständig entfernt wurde, wird die Behandlung höchstens 6 Monate dauern.

Wenn eine größere Menge von Oxaliplatin Ebewe angewendet wurde, als angewendet

werden sollte

Da Ihnen Oxaliplatin Arcana im Ebewe verabreicht wird, ist es unwahrscheinlich, dass zu viel

oder zu wenig angewendet wird. Informieren Sie jedoch Ihren Arzt oder Apotheker, wenn Sie

diesbezüglich Bedenken haben.

Im Falle einer Überdosierung kann es zu einer Verstärkung von Nebenwirkungen kommen. In

diesen Fällen wird Ihr Arzt geeignete Maßnahmen zur Behandlung der Nebenwirkungen

ergreifen.

Wenn die Anwendung von Oxaliplatin Ebewe vergessen wurde

Ihr Arzt bestimmt wann Sie dieses Arzneimittel erhalten. Wenn Sie glauben, dass eine Dosis

vergessen wurde, kontaktieren Sie Ihren Arzt so schnell wie möglich.

Wenn Sie Fragen zur Anwendung dieses Arzneimittels haben, wenden Sie sich an Ihren Arzt.

4.

WELCHE NEBENWIRKUNGEN SIND MÖGLICH?

Wie alle Arzneimittel kann auch dieses Arzneimittel Nebenwirkungen haben, die aber nicht bei

jedem auftreten müssen.

Wenn bei Ihnen irgendeine Nebenwirkung auftritt, ist es wichtig, dass Sie Ihren Arzt vor

der nächsten Behandlung darüber informieren.

Informieren Sie sofort Ihren Arzt, wenn Sie Folgendes bei sich bemerken:

Prickeln und/oder Taubheitsgefühl in den Fingern oder Zehen, um den Mund oder im

Rachen. Dies kann manchmal in Verbindung mit Krämpfen auftreten. Möglicherweise

haben Sie Probleme bei der Ausführung von Aufgaben, die Fingerspitzengefühl erfordern,

wie z. B. beim Zuknöpfen von Kleidung (Symptome einer peripheren Neuropathie) (sehr

häufig)

Symptome einer allergischen oder anaphylaktischen Reaktion mit plötzlichen Anzeichen,

wie Hautausschlag, Juckreiz oder Nesselsucht, Schluckbeschwerden, Schwellungen von

Gesicht, Lippen, Zunge oder anderen Teilen des Körpers, Atemnot, pfeifende Atmung oder

Atembeschwerden, extreme Müdigkeit (möglicherweise fühlen Sie sich, als würden Sie

gleich in Ohnmacht fallen). In den meisten Fällen, traten diese Symptome während oder

unmittelbar nach der Infusion auf, es wurden aber auch verzögerte allergische Reaktionen

Stunden oder sogar Tage nach der Infusion beobachtet (sehr häufig).

abnormale Blutergüsse, Blutungen oder Anzeichen einer Infektion, wie z. B. Halsschmerzen

und erhöhte Temperatur (aufgrund einer Abnahme der Blutplättchen oder der weißen

Blutkörperchen) (sehr häufig)

anhaltender oder starker Durchfall oder anhaltendes oder starkes Erbrechen (sehr häufig)

unerklärliche

Symptome

Atemwegen

trockener

Husten,

Atemnot

oder

Rasselgeräusche (sehr häufig)

Stomatitis/Mukositis (wunde Lippen oder Mundgeschwüre) (sehr häufig)

Blut oder dunkelbraune, kaffeefarbene Stückchen in Ihrem Erbrochenen (Anzeichen für

eine gastrointestinale Blutung) (häufig)

eine Gruppe von Beschwerden wie Kopfschmerzen, veränderte geistige Funktion, Krämpfe

und Störung des Sehvermögens von Unschärfe bis Sehverlust – dies sind Anzeichen eines

nach

Behandlung

rückläufigen

Leukoenzephalopathie-Syndroms,

eine

seltene

neurologische Erkrankung) (selten)

extreme

Müdigkeit

verminderter

Anzahl

roten

Blutkörperchen

Atemnot

(hämolytische

Anämie)

(selten),

allein

oder

Kombination

einer

niedrigen

Blutplättchenzahl, abnormales Auftreten blauer Flecke (Thrombozytopenie) (selten) und

einer Nierenerkrankung, bei der Sie wenig oder gar keinen Urin ausscheiden (Symptome

eines hämolytischen urämischen Syndroms) (Häufigkeit nicht bekannt)

Andere bekannte Nebenwirkungen sind:

Sehr häufige Nebenwirkungen (kann mehr als 1 Behandelten von 10 betreffen):

einigen

Menschen

beim

Beugen

Nackens

einer

kribbelnden,

schockartigen Empfindung, die sich die Arme oder den Rumpf hinunterzog.

Oxaliplatin Ebewe kann manchmal ein unangenehmes Gefühl im Rachen, insbesondere

beim Schlucken, und das Gefühl von Atemnot verursachen. Wenn dieses Gefühl, das

durch Kälte ausgelöst werden kann, aufkommt, dann normalerweise während der Infusion

oder wenige Stunden danach. Auch wenn es unangenehm ist, ist es nur von kurzer Dauer

und verschwindet normalerweise wieder, ohne dass es behandelt werden muss. Ihr Arzt

wird entscheiden, ob Ihre Behandlung dadurch geändert werden muss.

Oxaliplatin Ebewe kann zu Durchfall, leichter Übelkeit und Erbrechen führen. Sie erhalten

jedoch in der Regel von Ihrem Arzt vor der Behandlung ein Medikament, das vorbeugend

gegen die Übelkeit wirkt. Dieses können Sie auch nach der Behandlung einnehmen.

Oxaliplatin Ebewe führt zu einer vorübergehenden Senkung der Zahl der Blutzellen. Diese

verringerte Zahl an roten Blutzellen kann zu blasser Haut und Schwäche und Atemnot

führen (Anämie). Ihr Arzt wird Ihnen vor der ersten Behandlung und auch vor jedem

nachfolgenden Therapiezyklus Blut abnehmen, um zu überprüfen, ob die Anzahl Ihrer

Blutkörperchen ausreichend ist.

Beschwerden in der Nähe der Einstichstelle oder an der Einstichstelle während der Infusion

Fieber, Schüttelfrost (Zittern), leichte bis starke Müdigkeit, Schmerzen im gesamten Körper

Gewichtsveränderungen,

verminderter

Appetit

oder

Appetitlosigkeit,

Geschmacksstörungen, Verstopfung

Kopfschmerzen, Rückenschmerzen

Schwellung der zu Ihren Muskeln führenden Nerven, Nackensteifigkeit, abnormales Gefühl

in der Zunge, das die Sprechweise verändern kann Bauchschmerzen

abnormale Blutungen, einschließlich Nasenbluten

Husten, Schwierigkeiten beim Atmen

allergische

Reaktionen,

Hautausschläge,

juckend

sein

können,

leichter

Haarausfall (Alopezie)

Veränderungen des Blutbilds, einschließlich derjenigen, die auf Leberfunktionsstörungen

hinweisen

Hauterkrankungen

Hohe

Blutzuckerspiegel,

großem

Durst,

trockenem

Mund

oder

häufigerem

Wasserlassen führen kann

Niedriger Kaliumgehalt im Blut, wodurch Herzrhythmusstörungen hervorgerufen werden

können, die durch Muskelkrämpfe, Muskelschwäche oder Erschöpfung erkannt werden

können

Hoher

Natriumgehalt

Blut,

Verwirrtheit,

Muskelzuckungen

oder

Herzrhythmusstörungen verursachen kann

Häufige Nebenwirkungen (kann bis zu 1 von 10 Behandelten betreffen):

Infektionen aufgrund einer verminderten Zahl weißer Blutkörperchen

schwerwiegende

Infektion

Blutes

zusätzlich

einer

Verringerung

weißen

Blutkörperchen (neutropenische Sepsis), die tödlich sein kann

Verdauungsstörungen und Sodbrennen, Schluckauf, Hitzewallungen, Schwindel

vermehrtes Schwitzen, Nagelprobleme, Hautablösungen

Brustschmerzen

laufende Nase, Infekte der oberen Atemwege

Gelenk- und Knochenschmerzen

Schmerzen

beim

Wasserlassen

Veränderungen

Nierenfunktion,

veränderte

Häufigkeit der Blasenentleerung, Entwässerung

Blut im Harn/Stuhl

hoher Blutdruck

Depression, Schlafstörungen

Bindehautentzündung, Sehstörungen

Schwindel

Entzündung der Nerven, die zu Muskelspasmen, Krämpfen und zum Verlust bestimmter

Reflexe führt

steifer Nacken, Empfindlichkeit/Abneigung gegenüber hellem Licht, Kopfschmerzen

Blutgerinnsel,

normalerweise

einem

Bein,

Schmerzen,

Schwellungen

oder

Rötungen führt

Blutgerinnsel in der Lunge, das zu Schmerzen im Brustkorb und Atemlosigkeit führt

Gewichtsverlust

Hautausschlag

Niedriger Gehalt an Kalzium im Blut

Gelegentliche Nebenwirkungen (kann bis zu 1 von 100 Behandelten betreffen):

schwerwiegende Infektion des Blutes (Sepsis), die tödlich sein kann

Nervosität

Gehörprobleme (Ototoxizität)

eingeschränkte oder blockierte Darmpassage

Störungen des Säure-Base-Gleichgewichts im Körper

Seltene Nebenwirkungen (kann bis zu 1 von 1.000 Behandelten betreffen):

Verringerung der Anzahl von Blutplättchen aufgrund einer allergischen Reaktion; macht sich

bemerkbar durch Blutergüsse und anormale Blutungen (autoimmune Thrombozytopenie)

Taubheit (Verlust des Hörvermögens)

Vernarbungen und Verdickungen in der Lunge mit Atemnot, die manchmal tödlich sein kann

(interstitielle Lungenerkrankung)

Verringerung der Anzahl von Blutplättchen durch Zerstörung dieser Zellen

Sprechstörungen

vorübergehende Verminderung der Sehschärfe, Störungen des Sehfeldes, reversibler,

kurzzeitiger Sehverlust, Entzündung des Sehnervs

Darmentzündung,

Bauchschmerzen

oder

Durchfall

führt,

einschließlich

schwerwiegender bakterieller Infektion (Clostridium difficile)

Pankreatitis (Entzündung der Bauchspeicheldrüse)

unerwartete

Blutungen

oder

Blutergüsse

aufgrund

ausgedehnter

Blutgerinnsel

kleinen Blutgefäßen des Körpers (disseminierte intravaskuläre Gerinnung), die tödlich sein

können.

Sehr seltene Nebenwirkungen (kann bis zu 1 von 10.000 Behandelten betreffen):

Gefäßerkrankungen der Leber

Veränderungen in der Nierenfunktion, eine Nierenerkrankung, bei der Sie wenig oder gar

keinen Urin ausscheiden (Symptome eines akuten Nierenversagens)

Nicht bekannt (Häufigkeit auf Grundlage der verfügbaren Daten nicht abschätzbar)

Krampfanfälle (unkontrollierte Schüttelbewegungen des Körpers)

schwerwiegende Infektion des Blutes und niedriger Blutdruck (septischer Schock), die

tödlich sein können

krampfartige

Verengung

Kehlkopfs,

Atembeschwerden

verursachen

kann

(Laryngospasmus)

Autoimmunreaktionen,

Reduktion

aller

Blutzelllinien

führt

(autoimmunbedingte

Panzytopenie)

anormaler Herzrhythmus (QT-Verlängerung), der im Elektrokardiogramm (EKG) zu sehen

sein kann und tödlich sein kann.

Muskelschmerzen

Schwellungen

Kombination

Schwäche,

Fieber

oder

rotbraunem Urin (Symptome von Muskelschäden, genannt Rhabdomyolyse), die tödlich

sein können.

Bauchschmerzen, Übelkeit, blutiges oder kaffeesatzartiges Erbrechen oder dunklen Stuhl

(Teerstuhl)

(Symptome

eines

Gastrointestinalulkus

möglichen

Blutungen

oder

Perforation), die tödlich sein können.

Verringerung der Durchblutung des Darms (intestinale Ischämie), die tödlich sein kann.

Meldung von Nebenwirkungen

Wenn Sie Nebenwirkungen bemerken, wenden Sie sich an Ihren Arzt oder medizinisches

Fachpersonal.

Dies

gilt

auch

für

Nebenwirkungen,

nicht

dieser

Packungsbeilage

angegeben sind. Sie können Nebenwirkungen auch direkt über das nationale Meldesystem

anzeigen:

Bundesamt für Sicherheit im Gesundheitswesen

Traisengasse 5

1200 WIEN

ÖSTERREICH

Fax: + 43 (0) 50 555 36207

Website: http://www.basg.gv.at/

Indem Sie Nebenwirkungen melden, können Sie dazu beitragen, dass mehr Informationen über

die Sicherheit dieses Arzneimittels zur Verfügung gestellt werden.

Oxaliplatin Ebewe sollte nicht mit den Augen oder der Haut in Kontakt kommen. Sollten

Sie einen versehentlichen Austritt der Flüssigkeit aus der Infusionsflasche bemerken,

sagen Sie sofort dem Arzt oder dem medizinischen Fachpersonal Bescheid.

5.

WIE IST OXALIPLATIN EBEWE AUFZUBEWAHREN?

Bewahren Sie dieses Arzneimittel für Kinder unzugänglich auf.

Sie dürfen das Arzneimittel nach dem auf dem Umkarton bzw. Etikett nach „Verwendbar bis“

angegebenen Verfalldatum nicht mehr verwenden. Das Verfalldatum bezieht sich auf den

letzten Tag des angegebenen Monats.

Vor der Zubereitung sind für dieses Arzneimittel keine besonderen Lagerungsbedingungen

erforderlich.

Rekonstituierte Lösung in der Original-Durchstechflasche:

Die rekonstituierte Lösung sollte sofort weiterverdünnt werden.

Infusionslösung nach Verdünnen:

Nach Verdünnen der rekonstituierten Lösung mit 5 %-iger Glucoselösung konnte die chemische

und physikalische Stabilität der gebrauchsfertigen Lösung bei + 2°C bis + 8°C über einen

Zeitraum von 24 Stunden gezeigt werden.

mikrobiologischer

Sicht

sollte

gebrauchsfertige

Infusionslösung

sofort

verwendet

werden.

Wenn die Infusionslösung nicht sofort verwendet wird, liegt die Verantwortlichkeit für die

Aufbewahrung beim Anwender.

Nach Beendigung der Infusion wird Oxaliplatin Ebewe mit der gebotenen Sorgfalt durch den

Arzt oder das medizinische Fachpersonal entsorgt.

6.

INHALT DER PACKUNG UND WEITERE INFORMATIONEN

Was Oxaliplatin Ebewe enthält

Der Wirkstoff ist Oxaliplatin.

Der sonstige Bestandteil ist Lactose-Monohydrat.

50 mg Durchstechflasche: Jede Durchstechflasche enthält 50 mg Oxaliplatin zur Rekonstitution

in 10 ml Lösungsmittel.

Durchstechflasche:

Jede

Durchstechflasche

enthält

100 mg

Oxaliplatin

Rekonstitution in 20 ml Lösungsmittel.

Durchstechflasche:

Jede

Durchstechflasche

enthält

150 mg

Oxaliplatin

Rekonstitution in 30 ml Lösungsmittel.

1 ml der rekonstituierten Infusionslösung enthält 5 mg Oxaliplatin.

Wie Oxaliplatin Ebewe aussieht und Inhalt der Packung

Dieses Arzneimittel ist ein Pulver zur Herstellung einer Infusionslösung.

Jede Durchstechflasche enthält ein weißes bis naturweißes Pulver zur Herstellung einer

Infusionslösung, das 50 mg, 100 mg oder 150 mg Oxaliplatin enthält.

Die Durchstechflaschen sind in Packungen mit einem 1 Stück erhältlich.

Es werden möglicherweise nicht alle Packungsgrößen in den Verkehr gebracht.

Oxaliplatin Ebewe muss aufgelöst und eine Infusionslösung muss hergestellt werden, bevor es

in eine Vene verabreicht werden kann.

Pharmazeutischer Unternehmer und Hersteller

EBEWE Pharma Ges.m.b.H. Nfg. KG, 4866 Unterach, Österreich

Dieses Arzneimittel ist in den Mitgliedsstaaten des Europäischen Wirtschaftsraumes (EWR)

unter den folgenden Bezeichnungen zugelassen:

Bulgarien:

Oxaliplatin “Ebewe” 5 mg/ml powder for infusion

Malta:

Oxaliplatin “Ebewe” 5 mg/ml powder for infusion

Rumänien:

Oxaliplatin “Ebewe” 5 mg/ml powder for infusion

Slowenien:

Oxaliplatin “Ebewe” 5 mg/ml prašek za raztopino za infundiranje

Z.Nr.: 1-26435

Diese Packungsbeilage wurde zuletzt überarbeitet im Februar 2018.

-----------------------------------------------------------------------------------------------------------------------------

Die folgenden Informationen sind für medizinisches Fachpersonal bestimmt:

Besondere

Vorsichtsmaßnahmen

für

die

Beseitigung

und

sonstige

Hinweise

zur

Handhabung

Wie bei anderen potenziell toxischen Substanzen muss die Handhabung und Zubereitung von

Oxaliplatin-Lösungen mit Vorsicht durchgeführt werden.

Hinweise zur Handhabung

Die Handhabung dieses zytotoxischen Agens durch das ärztliche oder Pflegepersonal erfordert

jede Vorsichtsmaßnahme, die den Schutz des Anwenders und seiner Umgebung gewährleistet.

Zubereitung

Injektionslösungen

zytotoxischer

Arzneimittel

muss

durch

speziell

ausgebildetes

Personal

Kenntnis

verwendeten

Arzneimittel

erfolgen,

unter

Bedingungen,

Schutz

Umgebung

insbesondere

Schutz

damit

befassten

Personals

gewährleisten

Übereinstimmung

Klinikgrundsätzen.

Dies

erfordert das Vorhandensein eines für diese Zwecke vorgesehenen Arbeitsplatzes. Es ist

verboten, in diesem Bereich zu rauchen, zu essen oder zu trinken.

Dem Personal muss geeignetes Arbeitsmaterial zur Verfügung gestellt werden, insbesondere

langärmelige

Kittel,

Schutzmasken,

Kopfbedeckungen,

Schutzbrillen,

sterile

Einmal-

Handschuhe, Schutzabdeckung für den Arbeitsplatz, Behälter und Sammelbehältnisse für

Abfall.

Exkremente und Erbrochenes müssen mit Vorsicht behandelt werden.

Schwangere müssen vor dem Umgang mit zytotoxischen Substanzen gewarnt werden und

diesen vermeiden.

Jedes zerbrochene Behältnis muss mit derselben Sorgfalt behandelt werden und ist als

kontaminierter Abfall zu betrachten. Kontaminierter Abfall sollte in geeignet gekennzeichneten

festen Behältnissen verbrannt werden. Siehe unten: Abschnitt „Entsorgung”.

Sollte das Oxaliplatin-Pulver, die rekonstituierte Lösung oder die Infusionslösung mit der Haut in

Kontakt kommen, ist sofort sorgfältig mit Wasser zu spülen.

Sollte das Oxaliplatin-Pulver, die rekonstituierte Lösung oder die Infusionslösung mit der

Schleimhaut in Kontakt kommen, ist sofort sorgfältig mit Wasser zu spülen.

Besondere Vorsichtshinweise für die Anwendung

DARF NICHT mit aluminiumhaltigen Injektionsmaterialien verwendet werden.

DARF NICHT unverdünnt verabreicht werden.

Nur 5 %-ige (50 mg/ml) Glucoselösung für die Verdünnung verwenden.

DARF NICHT für die Infusion mit Lösungen rekonstituiert oder verdünnt werden, die

Natriumchlorid oder andere Chloride enthalten.

DARF NICHT mit anderen Arzneimitteln in demselben Infusionsbeutel oder in derselben

Infusionsleitung gemischt werden.

DARF NICHT mit alkalischen Arzneimitteln oder Lösungen, insbesondere 5-Fluorouracil,

Folinsäure-Zubereitungen,

Trometamol

Bestandteil

enthalten,

sowie

Trometamolsalzen anderer Wirkstoffe gemischt werden.

Hinweise für die Anwendung mit Folinsäure (wie Calciumfolinat oder Dinatriumfolinat)

250 bis 500 ml 5 %-ige (50 mg/ml) Glucose-Infusionslösung, die 85 mg/m² Oxaliplatin enthält,

wird gleichzeitig mit Folinsäure-Infusionslösung (Folinsäure in 5 %-iger Glucoselösung) über

einen Y-Zugang, der unmittelbar am Infusionsort liegt, über 2 bis 6 Stunden intravenös

infundiert.

Diese

beiden

Arzneimittel

dürfen

nicht

demselben

Infusionsbeutel

gemischt

werden.

Folinsäure

darf

kein

Trometamol

Bestandteil

enthalten

darf

ausschließlich

isotonischer 5 %-iger (50 mg/ml) Glucoselösung verdünnt werden, aber niemals mit alkalischen

Lösungen, Natriumchloridlösung oder anderen chloridhaltigen Lösungen.

Hinweise für die Anwendung mit 5-Fluorouracil

Oxaliplatin soll immer vor Fluoropyrimidinen, z.B. 5-Fluorouracil, verabreicht werden.

Nach der Gabe von Oxaliplatin den Zugang durchspülen und danach 5-Fluorouracil geben.

Für

weitere

Informationen

Arzneimittelkombinationen

Oxaliplatin

siehe

entsprechenden Zusammenfassungen der Merkmale des Arzneimittels anderer Hersteller.

Rekonstituierte Lösungen, die Anzeichen von Ausfällungen zeigen, sollten nicht verwendet

werden und sollten unter Beachtung der gesetzlichen Anforderungen für die Entsorgung

gefährlicher Abfälle vernichtet werden (siehe unten).

Rekonstitution des Pulvers

Zur Rekonstitution der Lösung ist Wasser für Injektionszwecke oder 5 %-ige (50 mg/ml)

Glucoselösung zu verwenden.

Für eine Durchstechflasche mit 50 mg: mit 10 ml Lösungsmittel versetzen, um eine

Oxaliplatin-Konzentration von 5 mg/ml zu erhalten.

Für eine Durchstechflasche mit 100 mg: mit 20 ml Lösungsmittel versetzen, um eine

Oxaliplatin-Konzentration von 5 mg/ml zu erhalten.

Für eine Durchstechflasche mit 150 mg: mit 30 ml Lösungsmittel versetzen, um eine

Oxaliplatin-Konzentration von 5 mg/ml zu erhalten.

Aus mikrobiologischer und chemischer Sicht sollte die rekonstituierte Lösung sofort mit 5 %-iger

(50 ml/ml) Glucoselösung verdünnt werden.

Die Lösung ist vor Gebrauch visuell zu prüfen. Nur klare Lösungen ohne Partikel dürfen

verwendet werden.

Das Arzneimittel ist nur zur einmaligen Verwendung bestimmt. Nicht verbrauchte Lösung ist zu

verwerfen (siehe unten: „Entsorgung“).

Verdünnung vor der Infusion

erforderliche

Menge

rekonstituierten

konzentrierten

Lösung

wird

Durchstechflasche entnommen und mit 250–500 ml einer 5 %-igen Glucoselösung (50 mg/ml)

verdünnt,

eine

Oxaliplatin-Konzentration

zwischen

nicht

weniger

mg/ml

0,7 mg/ml

erhalten.

Dies

entspricht

Konzentrationsbereich,

für

physiko-

chemische Stabilität von Oxaliplatin belegt worden ist.

Die Infusionslösung wird intravenös verabreicht.

Nach

Verdünnung

%-iger

(50 mg/ml)

Glucoselösung

wurde

chemische

physikalische Stabilität über 24 Stunden bei + 2°C bis + 8°C nachgewiesen.

Aus mikrobiologischer Sicht sollte die gebrauchsfertige Infusion sofort verwendet werden.

Falls die Lösung nicht sofort verabreicht wird, fällt die Einhaltung der Lagerungszeiten und

-bedingungen in den Verantwortungsbereich des Anwenders. Die gebrauchsfertige Lösung darf

keinesfalls länger als 24h aufbewahrt werden.

Die Lösung ist vor Gebrauch visuell zu prüfen. Nur klare Lösungen ohne Partikel dürfen

verwendet werden.

Das Arzneimittel ist nur zur einmaligen Verwendung bestimmt. Nicht verbrauchte Lösungen sind

zu verwerfen (siehe unten „Entsorgung“).

NIEMALS mit Kochsalzlösung rekonstituieren oder verdünnen.

Die Kompatibilität von Oxaliplatin-Infusionslösung mit handelsüblichen aus PVC bestehenden

Infusionssystemen wurde getestet.

Infusion

Bei der Applikation von Oxaliplatin ist keine Hyperhydratation erforderlich.

Oxaliplatin, verdünnt in 250 bis 500 ml einer 5 %-igen Glucoselösung (50 mg/ml), um eine

Konzentration von nicht weniger als 0,2 mg/ml zu erhalten, muss über eine periphere Vene

oder einen zentralvenösen Zugang über 2 bis 6 Stunden infundiert werden. Wird Oxaliplatin

zusammen mit 5-Fluorouracil gegeben, muss die Oxaliplatin-Infusion vor Verabreichung der

5-Fluorouracil-Infusion erfolgen.

Entsorgung

Reste des Arzneimittels sowie sämtliche Materialien, die bei der Rekonstitution, Verdünnung

Applikation

verwendet

wurden,

müssen

entsprechend

krankenhausüblicher

Standardverfahren für zytotoxische Stoffe unter Beachtung der gesetzlichen Vorschriften für die

Entsorgung gefährlicher Abfälle vernichtet werden.

Es gibt keine Sicherheitswarnungen betreffend dieses Produktes.

11-10-2018

Oxaliplatin Kabi 5 mg/ml

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