Carboplatin 10 mg/ml concentrate for solution for infusion

1 ml of concentrate for solution for infusion contains 10mg of Carboplatin

Each 5 ml vial contains 50 mg carboplatin

Each 15 ml vial contains 150 mg carboplatin

Each 45 ml vial contains 450 mg carboplatin

Each 60 ml vial contains 600 mg carboplatin

For a full list of excipients, see section 6.1

Concentrate for solution for infusion

A clear, colourless to slightly pale yellow solution free from particles.

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.

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

Note: With the Calvert formula, the total dose of Carboplatin is calculated in mg, not mg/m². Calvert's formula should not be used in patients who have received extensive pretreatment**.

**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/mm³ 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.

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.

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.

Use in children:

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

Elderly:

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

Dilution and Reconstitution:

The product must be diluted prior to infusion, see section 6.6

Carboplatin is contraindicated in patients with:

- hypersensitivity to the active substance or to other platinum containing compounds

- breast feeding

- severe myelosuppression

- bleeding tumors

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

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 function parameters should therefore be carefully assessed before, during and after carboplatin 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 and at weekly intervals thereafter. This will monitor toxicity and help determine the nadir and recovery of haematological parameters and assist in subsequent dosage adjustments. Lowest levels of platelets are generally seen between days 14 and 21 of initial therapy. A greater reduction is seen in patients who previously received extensive myelosuppressive chemotherapy. Lowest levels of white cells occur generally between days 14 and 28 of initial therapy. If levels fall below 2000 cells/mm³ or platelets less than 100,000 cells/mm³ then postponement of carboplatin therapy until bone barrow recovery is evident, should be considered. This recovery usually takes 5 to 6 weeks. Transfusions may be necessary and dosage reductions recommended for subsequent treatment.

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. Premedication 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 cisplatin, 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).

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 seizures and may require an increase of phenytoin dosages.

The 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.

Pregnancy

The safe use of Carboplatin during pregnancy has not been established: Studies in animals have shown reproductive toxicity (see 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

Both men and women receiving carboplatin should be informed of the potential risk of adverse effects on reproduction (see Section 5.3). 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.

Most forms of chemotherapy have been associated with reduction of oogenesis and spermatogenesis and patients receiving carboplatin should be warned of this potential. Although not reported with carboplatin, this has been reported with other platinum agents. Recovery of fertility after exposure can occur but is not guaranteed.

Lactation:

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).

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

Incidences of adverse reactions reported here under are based on cumulative data obtain in a large group of patients with various pretreatment 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)

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.

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/100ml 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.

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).

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.

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.

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 uric acid 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. Impairment of renal function is more likely in patients who have previously experienced nephrotoxicity as a result of cisplatin therapy.

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.

Skin and subcutaneous tissue disorders

Common: Alopecia.

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.

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

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

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.

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). These were reactions similar to those seen after cisplatin therapy but in a few cases no cross-reactivity was present.

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.

Symptoms of overdose

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

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.

Pharmacotherapeutic group: Antineoplastic agents, Platinum compounds

ATC code: LO1X 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

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/m2), 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

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.

Water for injections

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

Carboplatin may interact with aluminium to form a black precipitate. Needles, syringes, catheters or intravenous sets containing aluminium parts that may come into contact with carboplatin should not be used for preparation or administration of carboplatin. Precipitation can lead to a reduction of the antineoplastic activity.

Unopened:

2 years

After dilution

In use: Chemical and physical in-use stability has been demonstrated for 24 hours at room temperature and 30 hours at 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 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 in controlled and validated aseptic conditions

Store below 25°C. Do not refrigerate or freeze

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

For storage conditions of the diluted medicinal product, see section 6.3

Carboplatin infusion is supplied in 5 ml/ 15 ml/ 50 ml/ 100 ml type I amber glass vial containing 5 ml/ 15 ml/ 45 ml/ 60 ml concentrate for solution respectively. Vials are closed using grey chlorobutyl rubber stopper with an aluminium flip off seal.

1 glass vial in one monocarton

5 ml vial, containing 50mg of carboplatin, 10mg/ml.

15 ml vial, containing 150 mg of carboplatin, 10mg/ml.

50 ml vial, containing 450 mg carboplatin, 10mg/ml.

100 ml vial, containing 600 mg carboplatin, 10mg/ml.

Not all pack sizes may be marketed.

This product is for single dose use only.

Contamination

In the event of contact of carboplatin with eyes or skin, wash affected area with copious amounts of water or normal saline. A bland cream may be used to treat transient stinging of skin. Medical advice should be sought if the eyes are affected.

Disposal

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

Dilution

The product must be diluted prior to infusion, with 5 % dextrose solution or 0.9 % sodium chloride solution, to concentrates as low as 0.5 mg/ml.

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.

Accord Healthcare Limited,

319 Pinner Road,

North Harrow,

Middlesex, HA1 4HF,

United Kingdom

PL 20075/0028

09-Dec-2008

28-Feb-2012