Carboplatin-Teva 10 mg/ml Concentrate for Solution for Infusion

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
Carboplatin
Available from:
Teva Pharma B.V.
ATC code:
L01XA; L01XA02
INN (International Name):
Carboplatin
Dosage:
10 milligram(s)/millilitre
Pharmaceutical form:
Concentrate for solution for infusion
Prescription type:
Product subject to prescription which may not be renewed (A)
Therapeutic area:
Platinum compounds; carboplatin
Authorization status:
Marketed
Authorization number:
PA0749/004/001
Authorization date:
2001-03-09

PACKAGE LEAFLET: INFORMATION FOR THE USER

CARBOPLATIN–TEVA 10 mg/ml CONCENTRATE FOR SOLUTION FOR INFUSION

carboplatin

Read all of this leaflet carefully before you start using this medicine.

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

If you have any further questions, ask your doctor or pharmacist or nurse.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even

if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side

effects not listed in this leaflet. See section 4.

WHAT IS IN THIS LEAFLET

1. What Carboplatin-Teva is and what it is used for

2. What you need to know before you receive Carboplatin-Teva

3. How to receive Carboplatin-Teva

4. Possible side effects

5. How to store Carboplatin-Teva

6. Contents of the pack and other information

1. What Carboplatin-Teva is and what it is used for

Carboplatin-Teva is a platinum containing compound. It is an anti-cancer agent, which is used either

alone or in combination with other medicines.

Carboplatin-Teva is used to treat advanced ovarian cancer and lung cancer (small cell cancer of the

lung).

Ask your doctor or nursing staff if you need additional information.

2. What you need to know before you receive Carboplatin-Teva

DO NOT receive Carboplatin-Teva if you:

are allergic (hypersensitive) to carboplatin, cisplatin or other platinum-containing compounds

or any of the other ingredients of this medicine (listed in section 6)

have severe kidney problems

have any bone marrow problems

suffer from significant bleeding (bleeding tumors)

are pregnant, may be pregnant or breast-feeding

are due to receive, or have recently received, the yellow fever vaccine.

Warnings and precautions

Talk to your doctor before you receive this medicine if you:

are elderly (over 65 years old).

Other precautions whilst you are receiving Carboplatin-Teva:

Your nervous system function will be checked regularly.

Your doctor may give you blood or urine tests to check your blood composition, kidney or

liver function before, during and after treatment with Carboplatin. This is necessary to

continue therapy.

Your doctor may prescribe anti sickness medicines to prevent nausea and vomiting.

If you have headache, altered mental functioning, seizures and abnormal vision from

blurriness to vision loss, tell your doctor.

If you develop extreme tiredness with decreased number of red blood cells, and shortness of

breath (haemolytic anaemia), alone or combined with low platelet count, abnormal bruising

(thrombocytopenia) and kidney disease where you pass little or no urine (symptoms of

Haemolytic-uraemic syndrome), tell your doctor.

If you have fever (temperature greater than or equal to 38°C), or chills, which could be signs

of infection, tell your doctor immediately. You may be at risk of getting an infection of the

blood.

During treatment with carboplatin you will be given medicines which help reduce a

potentially life-threatening complication known as tumour lysis syndrome, which is caused by

chemical disturbances in the blood due to the breakdown of dying cancer cells that release

their content to the bloodstream.

Children

The safety and effectiveness of carboplatin treatment in children has not been proven.

Children are at greater risk of developing hearing loss following treatment with carboplatin. Their

hearing should be regularly monitored on a long-term basis.

Other medicines and Carboplatin-Teva

Tell your doctor if you are taking, have recently taken or might take any other medicines. In

particular, talk to your doctor if you are taking any of the following medicines:

Myelosuppressive medicines such as cyclophosphamide or fluorouracil

Any drugs which can cause damage to either your kidneys or inner ears e.g.

- Aminoglycoside antibacterials, such as gentamicin, streptomycin

- Diuretics such as bumetanide or furosemide

Carboplatin may increase the toxic effects of these drugs. The combination of carboplatin

with these drugs should be avoided

Cisplatin (another anti-cancer agent)

Vaccines (live or killed virus)

Oral anticoagulants (medicines to thin the blood)

Cyclosporin, tacrolimus or sirolimus (used to suppress the immune system)

Phenytoin or fosphenytoin (medicines for epilepsy)

Chelating agents (substances/chemicals used to bind or inactivate metal poisons in the body).

DO NOT use Carboplatin-Teva if you are due to receive, or have recently received, yellow fever

vaccine.

Pregnancy, breast-feeding and fertility

Pregnancy

Carboplatin-Teva should not be given to you if you are pregnant unless clearly indicated by your

doctor, due to the possible risk of abnormalities in the developing foetus.

If you become pregnant or suspect that you may be pregnant during therapy, you must tell your

doctor immediately. If you are pregnant or become pregnant during therapy, genetic counselling

should be provided.

Female patients should use an effective method of contraception, e.g. the barrier method or

condoms, to avoid getting pregnant during treatment, and for at least 6 months after treatment with

carboplatin.

Male patients receiving treatment with carboplatin should also take adequate contraception

precautions to ensure that their partner does not become pregnant for the same period.

Breast-feeding

You should not breast-feed during your treatment with Carboplatin-Teva.

Fertility

Carboplatin-Teva may lead to irreversible infertility. Patients who may wish to become pregnant or

father a child in future are advised to seek specialist fertility advice prior to treatment.

Driving and using machines

Carboplatin-Teva can cause nausea, vomiting and vision abnormalities, and may affect your ability to

drive or operate machines. DO NOT drive or operate machinery until you are sure you are not

affected.

Carboplatin-Teva contains Mannitol.

If you have been told by your doctor that you have an intolerance to some sugars, talk to your doctor

before taking this medicine.

3. How to receive Carboplatin-Teva

The correct amount of medicine to treat your particular condition has been decided by your doctor.

This will be given by injection into a vein (intravenous injection) or it will be diluted in intravenous

fluid and given slowly by an IV drip.

Needles or intravenous sets containing aluminium parts that may come in contact with carboplatin

should not be used for preparation or administration. Aluminium reacts with carboplatin causing

precipitate formation and/or loss of potency.

Carboplatin-Teva should only be administered under the supervision of a physician experienced in

the use of cancer chemotherapeutic agents.

Adequate diagnostic and treatment facilities must be readily available to ensure appropriate

management of therapy, and treatment of possible complications.

The usual dose is:

Adults

400 mg/m

given as a single intravenous (into the vein) dose over a period of 15 to 60 minutes.

The elderly

For elderly patients (over 65 years old), the dosage may need adjusting depending on your physical

condition.

If you have received treatment previously or have kidney problems

Your dosage will be adjusted to suit you.

Combination therapy

The dosage will be adjusted when Carboplatin-Teva is to be given in combination with other

medicines.

Patients with risk factors

The dosage will be reduced for patients with risk factors such as prior chemotherapy and/or

radiotherapy, or low performance status.

If you receive more Carboplatin-Teva than you should

There is no specific antidote for Carboplatin-Teva over dosage. If you received too much carboplatin,

the doctor will stop the therapy and treat the symptoms.

If administration of Carboplatin-Teva is forgotten

Your doctor will decide on what time you will receive this medicine. If you think you have missed a

dose, please contact your doctor as soon as possible.

4. Possible side effects

Like all medicines, Carboplatin-Teva can cause side effects, although not everybody gets them.

If the following happens, tell your doctor immediately:

an allergic reaction (swelling of the lips, face or neck leading to severe difficulty in breathing; skin

rash or hives; low blood pressure).

This is a very serious but rare side effect. You may need urgent medical attention.

The following side effects have also been reported:

Very common (affects more than 1 patient in 10):

nausea and vomiting

stomach pain

reduction in the number of platelets associated with bruises and abnormal bleeding

(thrombocytopenia)

reduction in the number of red blood cells (anaemia: this may cause tiredness)

reduction in the number of white blood cells, which may lead to frequent infections

changes in blood and urine test results.

Common (affects fewer than 1 in 10 and more than 1 in 100):

sensation of tingling, pricking, or numbness of the skin with no apparent physical cause

(paraesthesia), slow reflexes, nervous system symptoms

ringing in ears (tinnitus), hearing loss, hearing problems

transient eye problems such as transient loss of sight

taste alteration

hair loss (alopecia)

infections

haemorrhage

allergic reactions such as rash, fever or low blood pressure

numbness or weakness in the arms or legs

heart disorders

respiratory disorders, lung disease, wheezing or coughing

diarrhoea and constipation

skin or mucous membrane disorders

urogenital disorder

tiredness and weakness

changes in blood test results.

Rare (affects fewer than 1 in 1,000 and more than 1 in 10,000):

loss of vision.

Frequency not known (frequency cannot be estimated from the available data):

reduced function of the bone marrow (myelosuppression)

secondary cancer

fever and chills

haemolytic-uraemic syndrome

dehydration

anorexia

low blood sodium levels

stroke

heart failure

blocked blood vessels, high or low blood pressure

mouth ulcers

rash, itching or reddening of the skin

skin reactions at the injection site

general feeling of being unwell

lung infection

pancreatitis

a group of symptoms such as headache, altered mental functioning, seizures and abnormal

vision from blurriness to vision loss (symptoms of reversible posterior leukoencephalopathy

syndrome, a rare neurological disorder)

muscle cramping, muscle weakness, confusion, visual loss or disturbances, irregular

heartbeat, kidney failure or abnormal blood test results (symptoms of tumor lysis syndrome

which can be caused by the rapid breakdown of tumour cells) (see section 2).

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side

effects not listed in this leaflet. You can also report side effects directly via HPRA

Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517.

Website: www.hpra.ie; E-mail: medsafety@hpra.ie. By reporting side effects you can help provide

more information on the safety of this medicine.

5. How to store Carboplatin-Teva

Keep out of the reach and sight of children.

Do not store above 25ºC. Keep the vial in the outer carton.

After dilution in Water for Injections, 0.9% sodium chloride injection or 5% dextrose injection, from

a microbiological point of view, the product should be used immediately. If not used immediately, in-

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

than 24 hours at 2ºC to 8ºC.

Since the formulations of carboplatin do not contain preservatives, it is recommended that any

solution remaining after this time should be discarded.

Do not use Carboplatin-Teva after the expiry date that is stated on the outer packaging. The expiry

date refers to the last day of that month.

Only use this product if it is a clear, colourless to faintly yellow solution, free from fibres and

particles of foreign matter.

For single use only.

Once opened any unused solution should be discarded using the appropriate precautions. Do not

throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw

away medicines you no longer use. These measures will help to protect the environment.

6. Contents of the pack and other information

What Carboplatin-Teva contains

The active substance is carboplatin 10 mg/ml.

The other ingredients are mannitol and water for injections.

What Carboplatin-Teva looks like and contents of the pack

Carboplatin-Teva Concentrate for Infusion comes as a clear, colourless to faintly yellow solution,

free from particles.

The product is available in packs containing a single 5 ml, 15 ml, 45 ml, or 60 ml clear amber glass

vial.

Each 5 ml vial contains 50 mg of the active ingredient carboplatin

Each 15 ml vial contains 150 mg of the active ingredient carboplatin

Each 45 ml vial contains 450 mg of the active ingredient carboplatin

Each 60 ml vial contains 600 mg of the active ingredient carboplatin.

Marketing Authorisation Holder and Manufacturer

The Marketing authorisation holder is:

Teva Pharma B.V.

Swensweg 5

2031GA Haarlem

Netherlands

The manufacturer is:

Pharmachemie B.V.,

Swensweg 5,

P.O. Box 552,

2003 RN Haarlem

The Netherlands

This leaflet was last revised: April 2017

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Carboplatin-Teva 10 mg/ml Concentrate for Solution for Infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1ml of concentrate for solution for infusion contains 10mg of carboplatin.

Each 5ml vial contains 50mg carboplatin;

Each 15 ml vial contains 150mg carboplatin;

Each 45 ml vial contains 450mg carboplatin;

Each 60ml vial contains 600 mg carboplatin.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Concentrate for solution for infusion (sterile concentrate).

Clear, colourless to faintly yellow solution, free from particles.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Carboplatin is indicated for the treatment of:

1) advanced ovarian carcinoma of epithelial origin in:

a) first line therapy

b)second line therapy, after other treatments have failed.

2)small cell carcinoma of the lung.

4.2 Posology and method of administration

Dosage and Administration:

Carboplatin should be used by the intravenous route only.

The recommended dosage of Carboplatin in previously untreated adult patients with normal kidney function, i.e. creatinine

clearance > 60 ml/min is 400 mg/m

as a single short term IV dose administered by a 15 to 60 minute infusion. Alternatively,

the Calvert formula shown below may be used to determine dosage:

Dose (mg) = target AUC (mg/ml x min) x [GFR ml/min + 25]

Target AUC

Planned chemotherapy

Patient treatment status

5-7 mg/ml.min

Single agent Carboplatin

Previously untreated

4-6 mg/ml.min

Single agent Carboplatin

Previously treated

4-6 mg/ml.min

Carboplatin plus cyclophosphamide

Previously untreated

Note: With the Calvert formula, the total dose of Carboplatin is calculated in mg, not mg/m

. Calvert's formula should not be

used in patients who have received extensive pretreatment**.

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** Patients are considered heavily pretreated if they have received any of the following:

- Mitomycin C

- Nitrosourea

- Combination therapy with doxorubicin/cyclophosphamide/cisplatin

- Combination therapy with 5 or more agents

- Radiotherapy ≥ 4500 rad, focused on a 20 x 20 cm field or on more than one field of therapy.

Therapy with carboplatin should be discontinued in the case of an unresponsive tumour, progressive disease and/or

occurrence of not tolerable side effects.

Therapy should not be repeated until four weeks after the previous Carboplatin course and/or until the neutrophil count is at

least 2,000 cells/mm

and the platelet count is at least 100,000 cells/mm

Reduction of the initial dosage by 20-25% is recommended for those patients who present with risk factors such as prior

myelosuppressive treatment and low performance status (ECOG-Zubrod 2-4 or Karnofsky below 80).

Determination of the haematological nadir by weekly blood counts during the initial courses of treatment with Carboplatin is

recommended for future dosage adjustment.

Impaired Renal Function:

Patients with creatinine clearance values of less than 60 ml/min are at greater risk to develop myelosuppression.

The optimal use of Carboplatin in patients presenting with impaired renal function requires adequate dosage adjustments and

frequent monitoring of both haematological nadirs and renal function.

In case of a glomerular filtration rate of ≤ 20 ml/min, carboplatin should not be administered at all.

All of the above dosing recommendations apply to the initial course of treatment.

Subsequent dosages should be adjusted according to the patient's tolerance and to the acceptable level of myelosuppression.

Combination Therapy:

The optimal use of Carboplatin in combination with other myelosuppressive agents requires dosage adjustments according to

the regimen and schedule to be adopted.

Paediatric patients

There is insufficient information to support a dosage recommendation in the paediatric population.

Elderly:

In patients of more than 65 years of age, dosage adjustment, initially or subsequently, may be necessary, dependent on the

physical condition of the patient.

Dilution and reconstitution:

For information on dilution and reconstitution please see section 6.6.

4.3 Contraindications

Carboplatin is contraindicated in patients with:

hypersensitivity to carboplatin or to any of the excipients

breast feeding

severe myelosuppression

bleeding

tumors

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pre-existing severe renal impairment (creatinine clearance < 30 mL/min)

, unless in the

judgement of the

physician and patient, the possible benefits of treatment outweigh the risks

concomitant use with yellow fever vaccine (see section 4.5).

4.4 Special warnings and precautions for use

Carboplatin should be administered by individuals under the supervision of a qualified physician who is experienced in the use

of anti-neoplastic therapy. Diagnostic and treatment facilities should be readily available for management of therapy and

possible complications.

Blood counts as well as renal and hepatic function tests must be done regularly and the drug should be

discontinued if abnormal depression of the bone marrow or abnormal renal or hepatic function is seen.

Haematologic toxicity

Leukopenia, neutropenia, and thrombocytopenia are dose-dependent and dose-limiting. Peripheral blood counts should be

monitored during carboplatin injection treatment frequently and, in case of toxicity, until recovery is achieved. Median day of

nadir is day 21 in patients receiving single agent carboplatin injection and day 15 in patients receiving carboplatin injection in

combination with other chemotherapeutic agents. In general, single intermittent courses of carboplatin injection should not be

repeated until leukocyte, neutrophil, and platelet counts have returned to normal. Therapy should not be repeated until 4

weeks after the previous carboplatin injection course and/or until the neutrophil count is at least 2,000 cells/mm

and the

platelet count is at least 100,000 cells/mm

Anaemia is frequent and cumulative requiring very rarely a transfusion.

Hemolytic anemia with the presence of serologic drug-induced antibodies has been reported in patients treated with

carboplatin. This event can be fatal.

Severity of myelosuppression is increased in patients with prior treatment (in particular with cisplatin) and/or impaired kidney

function. Initial carboplatin injection dosages in these groups of patients should be appropriately reduced (see section 4.2) and

the effects carefully monitored through frequent blood counts between courses.

Carboplatin combination therapy with other myelosuppressive compounds must be planned very carefully with respect to

dosages and timing in order to minimise additive effects. Supportive transfusional therapy may be required in patients who

suffer severe myelosuppression.

Myelosuppressive effects may be additive to those of concomitant chemotherapy. Patients with severe and persistent

myelosuppression are at high risk of infectious complications including fatal outcomes (see section 4.8). If any of these events

occurs, carboplatin dosing should be interrupted and dose modification or discontinuation should be considered.

Acute promyelocytic leukaemia and myelodysplastic syndrome (MDS)/ acute myeloid leukemia (AML) have been reported

years after therapy with carboplatin and other antineoplastic treatments.

Haemolytic-uraemic syndrome (HUS)

Haemolytic-uraemic syndrome (HUS) is a life-threatening side effect. Carboplatin should be discontinued at the first signs of

evidence

microangiopathic

haemolytic

anaemia,

such

rapidly

falling

haemoglobin

with

concomitant

thrombocytopaenia, elevation of serum bilirubin, serum creatinine, blood urea nitrogen, or LDH. Renal failure may not be

reversible with discontinuation of therapy and dialysis may be required.

Carboplatin can cause nausea and vomiting. Premedication with anti-emetics has been reported to be useful in reducing the

incidence and intensity of these effects.

Renal and hepatic function

Renal and hepatic function impairment may be encountered with Carboplatin. Very high doses of Carboplatin (≥ 5 times single

agent recommended dose) have resulted in severe abnormalities in hepatic and/or renal function. It is not clear whether an

appropriate hydration programme might overcome effects on renal function. Dose reduction or discontinuation of therapy is

required in the presence of moderate to severe alteration in renal or hepatic function test. (See Section 4.8).

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In patients with impaired renal function, the effect of carboplatin on the haematopoietic system is more pronounced and

longer-acting than in patients with normal renal function. In this risk group, therapy with carboplatin must be performed with

special caution (see section 4.2).

The incidence and severity of nephrotoxicity may increase in patients who have impaired kidney function before carboplatin

treatment. Impairment of renal function is also more likely in patients who have previously experienced nephrotoxicity as a

result of cisplatin therapy. Although no clinical evidence on compounding nephrotoxicity has been accumulated, it is

recommended not to combine carboplatin with aminoglycosides or other nephrotoxic compounds

Allergic reactions

As with other platinum-based drugs, allergic reactions appearing most often during perfusion may occur and necessitate

discontinuation of the perfusion and an appropriate symptomatic treatment. Cross reactions, sometimes fatal, have been

reported with all the platinum compounds (see section 4.3 and section 4.8).

Neurologic toxicity

Although peripheral neurologic toxicity is generally common and mild, limited to paresthesia and decrease of osteotendinous

reflexes, its frequency is increased in patients older than 65 years and/or in patients previously treated with cisplatin.

Monitoring and neurological examinations should be carried out at regular intervals..

Visual disturbances, including loss of vision, have been reported after the use of carboplatin injection in doses higher than

those recommended in patients with renal impairment. Vision appears to recover totally or to a significant extent within weeks

of stopping these high doses.

Use in elderly patients

In studies involving combination therapy with carboplatin and cyclophosphamide, elderly patients treated with carboplatin

were more likely to develop severe thrombocytopenia than younger patients. Because renal function is often decreased in the

elderly, renal function should be considered when determining dosage (see section 4.2).

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

Cases of Reversible Posterior Leukoencephalopathy Syndrome (RPLS) have been reported in patients receiving carboplatin in

combination chemotherapy. RPLS is a rare, reversible after treatment discontinuation, rapidly evolving neurological condition,

which can include seizure, hypertension, headache, confusion, blindness, and other visual and neurological disturbances (see

section 4.8). Diagnosis of RPLS is based upon confirmation by brain imaging, preferably MRI (Magnetic Resonance Imaging).

Venoocclusive liver disease

Cases of hepatic venoocclusive disease (sinusoidal obstruction syndrome) have been reported, some of which were fatal.

Patients should be monitored for signs and symptoms of abnormal liver function or portal hypertension which do not

obviously result from liver metastases.

Tumour lysis syndrome (TLS)

In post marketing experience tumour lysis syndrome (TLS) has been reported in patients following the use of carboplatin alone

or in combination with other chemotherapeutic agents. Patients at high risk of TLS, such as patients with high proliferative rate,

high tumor burden, and high sensitivity to cytotoxic agents, should be monitored closely and appropriate precaution taken.

Other

Auditory defects have been reported during carboplatin therapy. Ototoxicity may be more pronounced in children. Cases of

hearing loss with a delayed onset have been reported in paediatric patients. A long-term audiometric follow-up in this

population is recommended.

Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including

carboplatin, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving

carboplatin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

The carcinogenic potential of Carboplatin has not been studied but compounds with similar mechanisms of action and

mutagenicity have been reported to be carcinogenic (See section 5.3)

Safety and effectiveness of carboplatin administration in children are not proven.

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Aluminium containing equipment should not be used during preparation and administration of Carboplatin (See section 4.2,

4.5 and 6.2).

4.5 Interaction with other medicinal products and other forms of interactions

Due to the increase of thrombotic risk in case of tumoral diseases, the use of anticoagulative treatment is frequent.

The high intra-individual variability of the coagulabilty during diseases, and the eventuality of interaction between oral

anticoagulants and anticancer chemotherapy,

require, if it is decided to treat the patient with oral anticoagulants, to increase

frequency of the control of the INR monitoring.

Concomitant use contraindicated

Yellow fever vaccine: risk of generalised vaccinal disease mortal (see section Contraindications).

Concomitant use not recommended

Live attenuated vaccines (except yellow fever): risk of systemic, possible fatal disease. This risk is increased in

subjects who are already immunosuppressed by their underlying disease. Use an inactivated vaccine where this

exists (poliomyelitis).

Phenytoin, fosphenytoin: risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive

absorption by the cytotoxic drug or risk of toxicity enhancement or loss of efficacy of the cytotoxic drug due to

increased hepatic metabolism by phenytoin.

Concurrent administration of carboplatin and chelating agents should be avoided as it can theoretically lead to a

decrease of the antineoplastic effect of carboplatin. However, the antineoplastic effect of carboplatin was not

influenced by diethyl-dithiocarbamate in animal experiments or in clinical use.

Concomitant use to take into consideration

Cyclosporin (and by extrapolation tacrolimus and sirolimus): excessive immunosuppression with risk of

lymphoproliferation.

Aminoglycosides: the concomitant use of carboplatin with aminoglycosides antibiotics should be taken into

account due to the cumulative nephrotoxicity and ear toxicity, particularly in renal failure patient.

Loop diuretics: the concomitant use of carboplatin with loop diuretic should be taken into account due to the

cumulative nephrotoxicity and ear toxicity.

When combining carboplatin with other myelosuppressive compounds, the myelosuppressive effect of carboplatin

and/or the other compounds may be more pronounced. Patients receiving concomitant therapy with other

nephrotoxic agents are likely to experience more severe and prolonged myelotoxicity due to decreased renal

clearance of carboplatin.

Carboplatin may interact with aluminium to form a black precipitate. Needles, syringes, catheters or IV administration sets that

contain aluminium parts which may come into contact with carboplatin, should not be used for the preparation or

administration of the drug.

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4.6 Fertility, pregnancy and lactation

Pregnancy

Carboplatin injection can cause foetal harm when administered to a pregnant woman. Carboplatin injection has been shown to

be embryotoxic and teratogenic in rats receiving the drug during organogenesis. No controlled studies in pregnant women

have been conducted. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the

patient should be apprised of the potential hazard to the foetus. Women with child-bearing potential should be advised to

avoid becoming pregnant.

Fertility

Gonadal suppression resulting in amenorrhea or azospermia may occur in patients receiving antineoplastic therapy. These

effects appear to be related to dose and length of therapy and may be irreversible. Prediction of the degree of testicular or

ovarian function impairment is complicated by the common use of combinations of several antineoplastics, which makes it

difficult to assess the effects of individual agents.

Men of sexually mature age treated with carboplatin are recommended not to father a child during treatment and up to 6

month afterwards and to ask advice about spermatic preservation prior to initiation of the therapy because of the possibility of

irreversible infertility due to therapy with carboplatin.

Lactation:

It is not known whether Carboplatin is excreted in human milk. If treatment becomes necessary during the lactation period,

breastfeeding must be stopped.

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, carboplatin may cause

nausea, vomiting, vision abnormalities and ototoxicity; therefore, patients should be warned on the potential effect of these

events on the ability to drive or to use machines.

4.8 Undesirable effects

The frequency of adverse reactions reported is based on a cumulative database of 1,893 patients receiving single agent

carboplatin injection and post-marketing experience.

The list is presented by system organ class, MedDRA preferred term, and frequency using the following frequency categories:

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

rare (< 1/10,000), not known (cannot be estimated from the available data).

System Organ Class

Frequency

MedDRA Term

Neoplasms, benign and malignant

(including cysts and polyps)

Not known

Treatment related secondary

Malignancy

Infections and infestations

Common

Infections*

Not known

Pneumonia

Blood and lymphatic system

Very common

Thrombocytopenia, neutropenia, leukopenia, anaemia

Common

Haemorrhage*

Not known

Bone marrow failure, febrile neutropenia,

hemolytic-uraemic syndrome

Immune system disorders

Common

Hypersensitivity, anaphylactoid type reaction

Metabolism and nutrition

disorders

Not known

Dehydration, anorexia, hyponatraemia, tumor lysis

syndrome

Nervous system disorders

Common

Neuropathy peripheral, paraesthesia, decrease of

osteotendinous reflexes, sensory disturbance, dysgeusia

Not known

Cerebrovascular accident*, Reversible Posterior

Leukoencephalopathy Syndrome (RPLS)

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Eye disorders

Common

Visual disturbance, rare cases of loss of vision

Ear and labyrinth disorders

Common

Ototoxicity

Cardiac disorders

Common

Cardiovascular disorder*

Not known

Cardiac failure*

Vascular disorders

Not known

Embolism*, hypertension, hypotension

Respiratory, thoracic and

mediastinal disorders

Common

Respiratory disorder, interstitial lung disease,

bronchospasm

Gastrointestinal disorders

Very common

Vomiting, nausea, abdominal pain

Common

Diarrhoea, constipation, mucous

membrane disorder

Not known

Stomatitis, pancreatitis

Skin and subcutaneous tissue

disorders

Common

Alopecia, skin disorder

Not known

Urticaria, rash, erythema, pruritus

Musculoskeletal and connective

tissue disorders

Common

Musculoskeletal disorder

Renal and urinary disorders

Common

Urogenital disorder

General disorders and administration site conditions

Common

Asthenia

Not known

Injection site necrosis, injection site reaction, injection

site extravasation, injection site erythema, malaise

Investigation

Very common

Creatinine renal celarance

decreased, blood urea increased,

blood alkaline phosphatase

increased, aspartate

aminotransferase increased, liver

function test abnormal, blood sodium decreased, blood

potassium decreased, blood calcium decreased, blood

magnesium decreased.

Common

Blood bilirubin increased, blood

creatinine increased, blood uric acid increased

* Fatal in < 1%, fatal cardiovascular events in <1% included cardiac failure, embolism, and cerebrovascular accident combined.

based on post-marketing experience.

Description of selected adverse reactions

Haematologic:

Myelosuppression is the dose-limiting toxicity of carboplatin injection. In patients with normal baseline values,

thrombocytopenia with platelet counts below 50,000/mm

occurs in 25% of patients, neutropenia with granulocyte counts

below 1,000/mm

in 18% of patients, and leukopenia with WBC counts below 2,000/mm

in 14% of patients. The nadir usually

occurs on day 21. Myelosuppression can be worsened by combination of carboplatin injection with other myelosuppressive

compounds or forms of treatment.

Myelotoxicity is more severe in previously treated patients, in particular in patients previously treated with cisplatin and in

patients with impaired kidney function. Patients with poor performance status have also experienced increased leukopenia and

thrombocytopenia. These effects, although usually reversible, have resulted in infectious and hemorrhagic complications in 4%

and 5% of patients given carboplatin injection, respectively. These complications have led to death in less than 1% of patients.

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Anaemia with haemoglobin values below 8 g/dl has been observed in 15% of patients with normal baseline values. The

incidence of anaemia is increased with increasing exposure to carboplatin injection.

Gastrointestinal:

Vomiting occurs in 65% of patients, in one-third of whom it is severe. Nausea occurs in an additional 15%. Previously treated

patients (in particular patients previously treated with cisplatin) appear to be more prone to vomiting. These effects usually

disappear within 24 hours after treatment and are generally responsive to or prevented by antiemetic medication. Vomiting is

more likely when carboplatin injection is given in combination with other emetogenic compounds.

The other gastro-intestinal complaints corresponded to pain in 8% of patients, diarrhoea, and constipation in 6% of patients.

Neurologic:

Peripheral neuropathy (mainly paresthesias and decrease of osteotendinous reflexes) has occurred in 4% of patients

administered carboplatin injection. Patients older than 65 years and patients previously treated with cisplatin, as well as those

receiving prolonged treatment with carboplatin injection, appear to be at increased risk.

Clinically significant sensory disturbances (i.e. visual disturbances and taste modifications) have occurred in 1% of patients.

The overall frequency of neurologic side effects seems to be increased in patients receiving carboplatin injection in

combination. This may also be related to longer cumulative exposure.

Ototoxicity:

Auditory defects out of the speech range with impairments in the high-frequency range (4,000-8,000 Hz) were found in serial

audiometric investigations with a frequency of 15%. Very rare cases of hypoacusia have been reported.

In patients with a hearing organ predamaged due to cisplatin, a further exacerbation in the hearing function sometimes occurs

during treatment with carboplatin.

Renal:

When given in usual doses, development of abnormal renal function has been uncommon, despite the fact that carboplatin

injection has been administered without high-volume fluid hydration and/or forced diuresis. Elevation of serum creatinine

occurs in 6% of patients, elevation of blood urea nitrogen in 14%, and of uric acid in 5% of patients. These are usually mild and

are reversible in about one-half the patients. Creatinine clearance has proven to be the most sensitive renal function measure

in patients receiving carboplatin injection. Twenty-seven percent (27%) of patients who have a baseline value of 60 ml/min or

greater, experience a reduction in creatinine clearance during carboplatin injection therapy.

Electrolytes:

Decreases in serum sodium, potassium, calcium, and magnesium occur in 29%, 20%, 22%, and 29% of patients, respectively. In

particular, cases of early hyponatraemia have been reported. The electrolyte losses are minor and mostly take a course without

any clinical symptoms.

Hepatic:

Modification of liver function in patients with normal baseline values was observed, including elevation of total bilirubin in 5%,

SGOT in 15%, and alkaline phosphatase in 24% of patients. These modifications were generally mild and reversible in about

one-half the patients. In a limited series of patients receiving very high dosages of carboplatin injection and autologous bone

marrow transplantation, severe elevation of liver function tests has occurred.

Cases of an acute, fulminant liver cell necrosis occurred after high-dosed administration of carboplatin.

Allergic Reactions:

Anaphylactic-type reactions, sometimes fatal, may occur in the minutes following injection of the product: facial oedema,

dyspnoea, tachycardia, low blood pressure, urticaria, anaphylactic shock, bronchospasm.

Other undesirable effects:

Secondary acute malignancies after cytostatic combination therapies containing carboplatin have been reported.

Alopecia, fever and chills, mucositis, asthenia, malaise as well as dysgeusia have occasionally been observed.

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In isolated cases, a haemolytic-uraemic syndrome occurred.

Isolated cases of cardiovascular incidents (cardiac insufficiency, embolism) as well as isolated cases of cerebrovascular accidents

have been reported.

Cases of hypertension have been reported.

Local reactions:

Reactions at the site of injection (burning, pain, reddening, swelling, urticaria, necrosis in connection with extravasation) have

been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued

monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected

adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517.

Website: http://www.hpra.ie/; E-mail: medsafety@hpra.ie.

4.9 Overdose

Symptoms of overdose

Carboplatin was administered in Phase I studies at a dosage of up to 1600 mg/m

i.v. per course. At this dosage,

life--threatening haematological side effects with granulocytopenia, thrombocytopenia and anaemia were observed. The

granulocyte, thrombocyte and haemoglobin nadir were observed between days 9-25 (median: days 12-17). The granulocytes

had reached values of ≥ 500/µl after 8-14 days (median: 11) and the thrombocytes values of ≥ 25.000/microlitre after 3-8 days

(median: 7).

The following non-haematological side effects also occurred: renal function disturbances with a 50% drop in the glomerular

filtration rate, neuropathy, ototoxicity, sight loss, hyperbilirubinaemia, mucositis, diarrhoea, nausea and vomiting with

headache, alopecia, erythema, and severe infection. In the majority of cases, hearing disturbances were transient and reversible.

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Treatment of Overdose

There is no known antidote for carboplatin over dosage. The anticipated complications of over dosage would be related to

myelosuppression as well as impairment of hepatic and renal function. Bone marrow transplantation and transfusions

(thrombocytes, blood) can be effective measures of managing haematological side effects.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, Platinum compounds

ATC code: L01X A02

Carboplatin is an antineoplastic agent. Its activity has been demonstrated against several murine and human cell lines.

Carboplatin exhibited comparable activity to cisplatin against a wide range of tumours regardless of implant site. Alkaline

elution techniques and DNA binding studies have demonstrated the qualitatively similar modes of action of Carboplatin and

cisplatin.

Carboplatin, like cisplatin, induces changes in the superhelical conformation of DNA, which is consistent with a DNA shortening

effect.

Paediatric patients: safety and efficacy in children have not been established.

5.2 Pharmacokinetic properties

Following administration of carboplatin in man, linear relationships exist between dose and plasma concentrations of total and

free ultrafilterable platinum. The area under the plasma concentration versus time curve for total platinum also shows a linear

relationship with the dose when creatinine clearance ≥ 60 ml/min.

Repeated dosing during four consecutive days did not produce an accumulation of platinum in plasma. After a 1-hour infusion

(20-520 mg/m

), plasma levels of total platinum and free (ultrafilterable) platinum decay biphasically following first order

kinetics. For free platinum, the initial phase (t alpha) half life is approximately 90 minutes and the later phase (t beta) half life

approximately 6 hours. All free platinum is in the form of carboplatin in the first 4 hours after administration. Protein binding of

carboplatin reaches 85-89% within 24 hours of administration, although during the first 4 hours, only up to 29% of the dose is

protein bound. Carboplatin is excreted primarily in the urine, with recovery of approximately 65% of the administered platinum

within 24 hours. Most of the drug is excreted in the first 6 hours.

Approximately 32% of a given dose of carboplatin is excreted unchanged. Total body and renal clearances of free ultrafilterable

platinum correlate with the rate of glomerular filtration but not tubular secretion. Patients with poor renal function may require

dosage adjustments due to altered pharmacokinetics of carboplatin.

Carboplatin clearance has been reported to vary by 3- to 4- fold in paediatric patients. As for adult patients, literature data

suggest that renal function may contribute to the variation in carboplatin clearance.

5.3 Preclinical safety data

Carboplatin has been shown to be embryotoxic and teratogenic in rats. It is mutagenic in vivo and in vitro and although the

carcinogenic potential of Carboplatin has not been studied, compounds with similar mechanisms of action and mutagenicity

have been reported to be carcinogenic.

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6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Mannitol

Water for injections

6.2 Incompatibilities

Carboplatin may interact with aluminium to form a black precipitate. Needles, syringes, catheters or intravenous administration

sets that contain aluminium parts which may come into contact with carboplatin, should not be used for the preparation or

administration of the drug. Stainless steel types SS304 and SS316 have been found to be compatible with carboplatin.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 4.2.

6.3 Shelf life

Unopened:

2 years.

After dilution:

Carboplatin-Teva may be diluted under aseptic conditions with water for injection, 0.9% sodium chloride Injection or 5%

dextrose injection. From a microbiological point of view, the product should be used immediately. If not used immediately,

in-use storage times and conditions prior to use are the responsibility of the user and would not be longer than 24 hours at

2°C to 8°C.

Since the formulations of carboplatin do not contain preservatives, it is recommended that any solution remaining after this

time should be discarded.

6.4 Special precautions for storage

Do not store above 25°C.

Keep vial in the outer carton.

6.5 Nature and contents of container

Carboplatin-Teva is available in-

Amber glass vials, USP type I of 5ml, 15ml, 45ml or 60ml capacity. Rubber closures 20mm. Nature of Elastomer: chlorobutyl,

siliconized grey.

Each vial is packed in an individual carton.

Pack sizes are 5ml, 15ml, 45ml or 60 ml containers.

6.6 Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal

product and other handling of the product

Dilution:

Carboplatin-Teva may be diluted under aseptic conditions to the required strength with Water for Injection, 5% Dextrose

Injection, or 0.9% Sodium Chloride Injection, to concentrations as low as 0.5 mg/ml.

Carboplatin-Teva does not contain any antimicrobial preservation; it is intended for single-dose administration only. Following

dilution, carboplatin solution must be refrigerated at 2-8°C. Any solution remaining after 24 hours must be discarded.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration,

whenever solution and container permit.

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Needles or intravenous sets containing aluminium parts that may come in contact with carboplatin should not be used for

preparation or administration. Aluminium reacts with carboplatin causing precipitate formation and/or loss of potency.

The safety measures for dangerous substances are to be complied with during preparation and administration. Preparation

must be carried out by personnel who have been trained in the safe use while wearing protective gloves, face mask and

protective clothes.

As with all cytotoxic preparations, the following special precautions should be taken for safe handling and disposal:

1. Trained personnel only should dilute the drug. Pregnant staff should not be involved in its handling.

2. Preparation of the drug should be performed in a designated area, ideally in a vertical laminar flow hood (Biological Safety

Cabinet - Class II). The work surface should be covered with disposable plastic-backed absorbent paper.

3. Adequate protective clothing should be worn, i.e. PVC gloves, safety glasses, disposable gowns and masks. In the event of

contact with the eyes, wash with copious amounts of water or saline.

4. Luer-Lock fittings should be used on all syringes and sets. The possible formation of aerosols may be reduced by using

large-bore needles and venting needles.

5. All unused material, needles, syringes, vials and other items which have come into contact with cytotoxic drugs should be

segregated, placed in double-sealed polyethylene bags and incinerated at 1000

C or more. Excreta should be similarly treated.

Liquid waste should be flushed away with copious amounts of water.

6. In the event of spillage, trained personnel wearing appropriate personal protective equipment as outlined above, should

mop the spilled material with a spill kit or sponge kept in the area for that purpose. Rinse the area with copious amounts of

water. Put all solutions and sponges into a designated suitable high risk waste disposal bag and then seal it.

For single use only. Discard any remaining solution appropriately.

The solution should be inspected visually for particulate matter and discolouration prior to administration. The solution should

only be used if it is clear and free from particles.

7 MARKETING AUTHORISATION HOLDER

Teva Pharma B.V.

Swansweg 5

2031GA Haarlem

Netherlands

8 MARKETING AUTHORISATION NUMBER

PA0749/004/001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 09 March 2001

Date of last renewal: 09 March 2006

10 DATE OF REVISION OF THE TEXT

May 2017

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