SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Carboplatin 10 mg/ml concentrate for solution for infusion

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

One ml of concentrate contains 10 mg carboplatin.

A vial of 5 ml of concentrate contains 50 mg carboplatin.

A vial of 15 ml of concentrate contains 150 mg carboplatin.

A vial of 45 ml of concentrate contains 450 mg carboplatin.

A vial of 60 ml of concentrate contains 600 mg carboplatin.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Concentrate for solution for infusion.

Clear, colourless 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:

-    first line therapy

-    second line therapy, after other treatments have failed

2.    small cell carcinoma of the lung.

4.2    Posology and method of administration

Posology

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/m² as a single short term IV dose administered by a 15 to 60 minutes infusion.

Alternatively, the Calvert’s formula shown below may be used to determine dosage:

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

Dose (mg) = target AU<	C (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’s formula, the total dose of carboplatin is calculated in mg, not in mg/m².

Calvert’s formula should not be used in patients who have received extensive pre-treatment **.

**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

-    Radiation therapy > 4500 rad, focused on 20 x 20 cm field or 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 2000 cells/mm and the platelet count is at least 100.000 cells/ mm³.

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.

Patients with renal impairment

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 glomerular filtration rate of < 20 ml/min, carboplatin should not be administered at all.

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.

Elderly

Dosage adjustment, initially or subsequently, may be necessary, dependent on the physical conditions of the patient.

Paediatric population

As no sufficient experience of carboplatin use in children is available, no specific dosage recommendations can be given.

Method of administration

The product must be diluted prior to infusion. For instructions on dilution of the medical product before administration see section 6.6.

4.3 Contraindications

Carboplatin is contra-indicated in patients with:

-hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to other platinum containing compounds

-    breast-feeding

-    severe myelosuppression -bleeding tumours

-pre-existing severe renal impairment (with creatinine clearance of < 20 ml per minute).

4.4 Special warnings and precautions for use

Warnings:

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.

Carboplatin myelosuppression is closely related to its renal clearance. Patients with abnormal kidney function or receiving concomitant therapy with other drugs with nephrotoxic potential are likely to experience more severe and prolonged myelotoxicity. Renal functions parameters should therefore be carefully assessed before and during therapy.

Carboplatin infusion courses should not be repeated more frequently than monthly under normal circumstances. Thrombocytopenia, leukopenia and anaemia occur after administration of carboplatin. Frequent monitoring of peripheral blood counts is recommended throughout and following therapy with carboplatin. 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.

Carboplatin can cause nausea and vomiting. Pre-medication with anti-emetics has been reported to be useful in reducing the incidence and intensity of these effects.

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).

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.

Infrequent allergic reactions to carboplatin have been reported, e.g. erythematous rash, fever with no apparent cause or pruritus. Rarely anaphylaxis, angio-oedema and anaphylactoid reactions including bronchospasm, urticaria and facial oedema have occurred. These reactions are similar to those observed after administration of other platinum containing compounds and may occur within minutes. The incidence of allergic reactions may increase with previous exposure to platinum therapy; however, allergic reactions have been observed upon initial exposure to carboplatin. Patients should be observed carefully for possible allergic reactions and managed with appropriate supportive therapy, including antihistamines, adrenaline and/or glucocorticoids.

Neurological evaluation and an assessment of hearing should be performed on a regular basis, especially in patients receiving high dose carboplatin. Neurotoxicity, such as parasthesia, decreased deep tendon reflexes, and ototoxicity are more likely seen in patients previously treated with other platinum treatments and other ototoxic agents.

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.

Aluminium containing equipment should not be used during preparation and administration of carboplatin (see section 6.2).

4.5 Interaction with other medicinal products and other forms of interaction

Concurrent therapy with nephrotoxic drugs or ototoxic drugs such as amino glycoside, vancomycin, capreomycin and diuretics is not recommended, since this may lead to increased or exacerbated toxicity due to carboplatin induced changes in renal clearance of these substances.

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.

Caution should be exercised when carboplatin in used concomitantly with warfarin, as cases increased INR have been reported.

A decrease in phenytoin serum levels has been observed in case of concurrent administration of carboplatin and phenytoin. This may lead to reappearance of seizure and may require an increase of phenytoin dosages.

The concurrent administration of carboplatin and chelating agents should be avoided as it can therapeutically 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.

4.6 Fertility, pregnancy and lactation

Pregnancy

The safe use of carboplatin during pregnancy has not been established: Studies in animals have shown reproductive toxicity (see section 5.3.). Carboplatin has been shown to be an embryo toxin and teratogen in rats and mutagenic in vivo and in vitro. Carboplatin should not be used during pregnancy unless clearly indicated. If carboplatin is used during pregnancy the patient should be apprised of the potential hazard to the fetus.

Fertility

Women of childbearing potential should be advised to avoid becoming pregnant by using effective contraception during treatment and up to 6 months after therapy. For women who are pregnant or become pregnant during therapy, genetic counseling should be provided.

Carboplatin is genotoxic. Men being treated with carboplatin are advised not to father a child during and up to 6 months after treatment and to seek advice on conservation of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with carboplatin.

Breastfeeding

It is not known whether carboplatin is excreted in human milk.

Because of the possibility of harmful effects in suckling infants, breast-feeding must be discontinued if the mother is treated with carboplatin (see section 4.3).

4.7 Effects on ability to drive and use machines

Carboplatin has no or negligible influence on the ability to drive and use machines. However carboplatin may cause nausea and vomiting, indirectly impairing the ability to drive and use machines.

4.8 Undesirable effects

Incidences of adverse reactions reported here under are based on cumulative data obtained in a large group of patients with various pre-treatment prognostic features.

The following frequencies have been used:

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).

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Uncommon: Secondary malignancies (including promyelocytic leukaemia which occurred 6 years after monotherapy with carboplatin and preceding irradiation) have been reported following administration of carboplatin as a single agent or in combination therapy (causal relationship not established).

Blood and lymphatic system disorders

Very common: Myelosuppression is the dose-limiting toxicity of carboplatin. Myelosuppression may be more severe and prolonged in patients with impaired renal function, extensive prior treatment, poor performance status and age above 65. Myelosuppression is also worsened by therapy combining carboplatin with other compounds that are myelosuppressive. Myelosuppression is usually reversible and not cumulative when carboplatin is used as a single agent and at the recommended dosages and frequencies of administration.

At maximum tolerated dosages of carboplatin administered as a single agent, thrombocytopenia, with nadir platelet counts of less than 50 x 109/l, occurs in about a third of the patients. The nadir usually occurs between days 14 and 21, with recovery within 35 days from the start of therapy.

Leukopenia has also occurred in approximately 20% of patients but its recovery from the day of nadir (day 14-28) may be slower and usually occurs within 42 days from the start of therapy. Neutropenia with granulocyte counts below 1 x 109/l occurs in approximately one fifth of patients. Haemoglobin values below 9.5 mg/100 ml have been observed in 48% of patients with normal base-line values. Anaemia occurs frequently and may be cumulative. Common: Haemorrhagic complications, usually minor, have also been reported.

Uncommon: Infectious complications have occasionally been reported.

Rare: Cases of febrile neutropenia have been reported. Single cases of life-threatening infections and bleeding have occurred.

Immune system disorders

Common: Allergic reactions to carboplatin have been reported in less than 2% of patients, e.g., skin rash, urticaria, erythematous rash, and fever with no apparent cause or pruritus. These reactions are similar to those observed after administration of other platinum containing compounds and should be managed with appropriate supportive therapy.

Rare: Anaphylaxis, anaphylactic shock, angio-oedema and anaphylactoid reactions, including bronchospasm, urticaria, facial odema and facial flushing, dyspnoea, hypotension, dizziness, wheezing, and tachycardia have occurred (see section 4.4).

Metabolism and nutrition disorders

Very common'. Decreases in serum electrolytes (sodium, magnesium, potassium and calcium) have been reported after treatment with carboplatin but have not been reported to be severe enough to cause the appearance of clinical signs or symptoms.

Rare: Cases of hyponatraemia have been reported.

Nervous system disorders

Common: The incidence of peripheral neuropathies after treatment with carboplatin is 6%. In the majority of the patients neurotoxicity is limited to paraesthesia and decreased deep tendon reflexes. The frequency and intensity of this side effect increases in elderly patients and those previously treated with cisplatin. Paraesthesia present before commencing carboplatin therapy, particularly if related to prior cisplatin treatment, may persist or worsen during treatment with carboplatin (see Precautions).

Uncommon: Central nervous symptoms have been reported, however, they seem to be frequently attributed to concomitant antiemetic therapy.

Eye disorders

Rare: Transient visual disturbances, sometimes including transient sight loss, have been reported rarely with platinum therapy. This is usually associated with high dose therapy in renally impaired patients. Optic neuritis has been reported in post marketing surveillance.

Ear and labyrinth disorders

Very common: Subclinical decrease in hearing acuity, consisting of high-frequency (4000-8000 Hz) hearing loss determined by audiogram, has been reported in 15% of the patients treated with carboplatin.

Common: Clinical ototoxicity. Only 1% of patients present with clinical symptoms, manifested in the majority of cases by tinnitus. In patients who have been previously treated with cisplatin and have developed hearing loss related to such treatment, the hearing impairment may persist or worsen.

At higher than recommended doses in combination with other ototoxic agents, clinically significant hearing loss has been reported to occur in paediatric patients when carboplatin was administered.

Cardiac disorders

Very rare: Cardiovascular events (cardiac failure, embolism) as well as cerebrovascular events (apoplexy) have been reported in single cases (causal relationship with carboplatin not established). Single cases of hypertension have been reported.

Respiratory, thoracic and mediastinal disorders

Very rare: Pulmonary fibrosis manifested by tightness of the chest and dyspnoea. This should be considered if a pulmonary hypersensitivity state is excluded (see General disorders below).

Gastrointestinal disorders

Very common: Nausea without vomiting occurs in about a quarter of patients receiving carboplatin, vomiting has been reported in over half of the patients and about one-third of these suffer severe emesis. Nausea and vomiting are generally delayed until 6 to 12 hours after administration of carboplatin, usually disappear within 24 hours after treatment and are usually responsive to (and may be prevented by) anti-emetic medication. A quarter of patients experience no nausea or vomiting. Vomiting that could not be controlled by drugs was observed in only 1% of patients. Vomiting seems to occur more frequently in previously treated patients, particularly in patients pre-treated with cisplatin.

Painful gastro-intestinal disorders occurred in 17% of patients.

Common: Diarrhoea (6%), constipation (4%), mucositis.

Rare: Taste alteration. Cases of anorexia have been reported.

Hepatobiliary disorders

Very common: Abnormalities of liver function tests (usually mild to moderate) have been reported with carboplatin in about one-third of the patients with normal baseline values. The alkaline phosphatase level is increased more frequently than SGOT, SGPT or total bilirubin. The majority of these abnormalities regress spontaneously during the course of treatment.

Rare: Severe hepatic dysfunction (including acute liver necrosis) has been reported after administration of higher than recommended carboplatin dosages.

Skin and subcutaneous tissue disorders

Common: Alopecia.

Renal and urinary disorders

Very common: Renal toxicity is usually not dose-limiting in patients receiving carboplatin, nor does it require preventive measures such as high volume fluid hydration or forced diuresis. Nevertheless, increasing blood urea and blood urea nitrogen levels or serum creatinine levels can occur.

Common: Renal function impairment, as defined by a decrease in the creatinine clearance below 60 ml/min, may also be observed. The incidence and severity of nephrotoxicity may increase in patients who have impaired kidney function before carboplatin treatment.

It is not clear whether an appropriate hydration programme might overcome such an effect, but dosage reduction or discontinuation of therapy is required in the presence of moderate alteration of renal function (creatinine clearance 41-59 ml/min) or severe renal impairment (creatinine clearance 21-40 ml/min). Carboplatin is contra-indicated in patients with a creatinine clearance at or below 20 ml/min.

General disorders and administration site conditions

Very common: Hyperuricaemia is observed in about one quarter of patients. Serum levels of uric acid can be decreased by allopurinol. Asthenia. Common: Malaise, urticaria, flu-like syndrome, erythematous rash, pruritis. Uncommon: Fever and chills without evidence of infection; injection site reactions such as pain, erythema, swelling, urticaria and necrosis.

Rare: Haemolytic uraemic syndrome.

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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms of overdose

Carboplatin was administered in Phase I studies at a dosage of up to 1600mg/m² 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/pl after 8-14 days (median: 11) and the thrombocytes values of > 25.000/pl 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, erythema, and severe infection. In the majority of cases, hearing disturbances were transient and reversible.

Therapy 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 population

5.2 Pharmacokinetic properties

Following administration of carboplatin in man, linear relationship exists between dose and plasma concentrations of total and free ultra-filterable 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. Following the administration of carboplatin reported values for the terminal elimination half-lives of free ultrafilterable platinum and carboplatin in man are approximately 6 hours and 1.5 hours respectively. During the initial phase, most of the free ultra-filterable platinum is present as carboplatin. The terminal halflife for total plasma platinum is 24 hours. Approximately 87% of plasma platinum is protein bound within 24 hours following administration. Carboplatin is excreted primarily in the urine, with recovery of approximately 70% of the administered platinum within 24 hours. Most of the drug is excreted in the first 6 hours. Total body and renal clearance of free ultra-filterable platinum correlate with the rate of glomerular filtration but not tubular secretion.

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 actions and mutagenicity have been reported to be carcinogenic.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Water for injections.

6.2    Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Needles, syringes, catheters or intravenous sets containing aluminum parts that may come into contact with Carboplatin should not be used for preparation or administration of Carboplatin.

Shelf life

Unopened product:

2 years.

Diluted product:

8 hours at room temperature (15-25°C), or 24 hours under refrigeration (2-8°C)

From a microbiological point of view, the product should be used immediately. If not used immediately, in use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution / dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Do not store above 25°C. Do not refrigerate or freeze.

Keep vial in the outer carton in order to protect from light.

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

6.5. Nature and contents of container

Colourless EP Type 1 glass vials, with teflon coated grey chlorobutyl rubber stoppers sealed with an orange center flip-off aluminium seal.

Pack sizes:

Vials of 5 ml and 15 ml.

Boxes of 1, 5 and 10 vials.

Colourless EP Type 1 glass vials, with flurotec coated grey chlorobutyl rubber stoppers sealed with an orange center flip-off aluminium seal.

Pack sizes:

Vial of 45 ml.

Boxes of 1, 5 and 10 vials.

Colourless EP Type 1 glass vials, with flurotec coated grey chlorobutyl rubber stoppers sealed with a parrot green center flip-off aluminium seal.

Pack sizes:

Vial of 60 ml.

Boxes of 1, 5 and 10 vials.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling and other handling

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

Instructions for dilution

The product must be diluted prior to infusion, with 5% Glucose for Injection or 0.9% Sodium Chloride for Injection, to concentrations as low as 0.5 mg/ml (500 micrograms/ml). When diluted as directed, carboplatin is chemically and physically stable for 8 hours at room temperature (15-25°C) and for 24 hours at 2-8°C.

From a microbiological point of view, the infusion preparation should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8 °C, unless dilution has taken place under controlled and validated conditions.

The solution is to be inspected visually for particulate matter and discoloration prior to administration.

The solution should only be used if the solution is clear and free from particles. Guidelines for the safe handling of anti-neoplastic agents:

1    Carboplatin should be prepared for administration only by professionals who have been trained in the safe use of chemotherapeutic agents.

2    This should be performed in a designated area.

3    Adequate protective gloves should be worn.

4    Precautions should be taken to avoid the drug accidentally coming into contact with the eyes. In the event of contact with the eyes, wash with water and/or saline.

5    The cytotoxic preparation should not be handled by pregnant staff.

6    Adequate care and precautions should be taken in the disposal of items (syringes, needles, etc.) used to reconstitute cytotoxic drugs. Excess material and body waste may be disposed of by placing in double sealed polythene bags and incinerating at a temperature of 1,000 °C. Liquid waste may be flushed with copious amounts of water.

7    The work surface should be covered with disposable plastic-backed absorbent paper.

8    Use Luer-Lock fittings on all syringes and sets. Large bore needles are recommended to minimise pressure and the possible formation of aerosols. The latter may also be reduced by the use of a venting needle.

Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Sun Pharmaceutical Industries Europe B.V.

Polarisavenue 87 2132 JH Hoofddorp The Netherlands

8    MARKETING AUTHORISATION NUMBER(S)

PL 31750/0001

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

11/03/2010

10    DATE OF REVISION OF THE TEXT

11/07/2014