iMedi.co.uk

Carboplatin 10mg/Ml Concentrate For Infusion

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 solution contains 10 mg of carboplatin.

One vial of 5/15/45 ml solution contains 50/150/450 mg of carboplatin. For excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion.

Carboplatin 10 mg/ml concentrate for solution for infusion is a 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:

-    first line therapy

-    second line therapy, after other treatments have failed.

2.    Small cell carcinoma of the lung, in association with other hemotherapeutic agents.

4.2 Posology and method of administration

Dosage and administration

Route of administration: intravenous use.

Carboplatin should be used by the intravenous route only. The recommended dosage of Carboplatin in previously untreated adult patients with normal kidney function is 400 mg/m2 as a single i.v. dose administered by a short

term (15 to 60 minutes) infusion. 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 al 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 chemotherapy and/ or radiotherapy, or 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.

Dose recommendations by AUC:

As an alternative, the initial dose can be calculated using the Calvert formula, which takes account of renal function (glomerular filtration rate [GFR]). This reduces the risk of over- or underdosage caused by individual variations in renal function.

Calvert formula :

Dosage (mg) = (Target AUC*) x (GFR + 25)

Note : With the Calvert's formula, the total carboplatin dose is calculated in mg, not in mg/m2.

*Target AUC

Planned chemotherapy

Patient treatment status

5-7 mg/ml min

Monotherapy with carboplatin

Previously untreated

4-6 mg/ml min

Monotherapy with carboplatin

Previously treated

4-6 mg/ml min

Carboplatin plus cyclophosphamide

Previously untreated

Calvert's formula should not be used in patients who have received extensive pretreatment with the following therapy regimens:

-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 on more than one field.

Therapy with carboplatin should be discontinued in the case of an unresponsive tumour, progressive disease and/or occurrence of not tolerable side effects.

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 (over 65 years old)

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

Dilution

The product may be diluted with 5% Glucose for Injection to a concentration as low as 0.5 mg/ml (500 micrograms/ml).

4.3. Contraindications

Carboplatin is contra-indicated in patients with severe pre-existing renal impairment (creatinine clearance at or below 20 ml/minute).

Carboplatin is contra-indicated in severely myelosuppressed patients.

Carboplatin is also contra-indicated in patients with hypersensitivity to carboplatin or other platinum containing products, or to mannitol.

Carboplatin is contra-indicated in patients with bleeding tumours.

Carboplatin is contra-indicated during breast feeding.

4.4. Special warnings and precautions for use

Carboplatin should be administered by individuals experienced in the use of anti-neoplastic therapy.

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 and during therapy. Carboplatin courses should not be repeated more frequently than monthly under normal circumstances. Thombocytopenia, leucopenia 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 function impairment may be encountered with Carboplatin. Although no clinical evidence on compounding nephrotoxicity has been accumulated, it is recommended not to combine Carboplatin with aminoglycosides or other nephrotoxic compounds.

As for other platinum co-ordination compounds, allergic reactions to Carboplatin have been reported. They may occur within minutes of administration and should be managed with appropriate supportive therapy. Anaphylactic-like reactions may also occur as with other platinum coordination compounds.

In patients pre-treated with platinum containing medicinal products, the risk of allergic reactions, including anaphylaxis, is increased.

In old age, renal function may be impaired, and should be taken into account for dosage, if necessary.

Neurotoxic effects, especially in patients older than 65 years and/or those previously treated with cisplatin, have been reported.

A relationship between visual transient disturbances and too high dosages in renally impaired patients has been reported.

Safety and effectiveness of carboplatin administration in children are not

proven.

The carcinogenic potential of Carboplatin has not been studied but compounds with similar mechanisms of action and mutagenicity have been reported to be carcinogenic.

Carboplatin can have genotoxic effects. Therefore, 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.

Women should not become pregnant during treatment with carboplatin and should use an effective method of contraception.

Peripheral blood counts, renal and liver function tests and serum electrolytes should be monitored closely.

Precautions

Peripheral blood counts and renal function tests should be monitored closely. Blood counts at the beginning of the therapy and weekly to assess haematological nadir for subsequent dose adjustment are recommended. Neurological evaluations should also be performed on a regular basis.

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

Myelosuppression is worsened by therapy combining Carboplatin with other compounds that are myelosuppressive. Carboplatin combination therapy with other myelosuppressive compounds must be planned very carefully with respect to dosage and timing in order to minimise additive effects.

Patients receiving concomitant therapy with other nephrotoxic potential are likely to experience more severe and prolonged myelotoxicity. Although no clinical evidence on compounding nephrotoxicity has been accumulate, it is recommended not to combine Carboplatin with aminoglycosides or other nephrotoxic compounds.

Administration of nephrotoxic and/or ototoxic medicinal products (e.g. aminoglycosides, loop diuretics) during treatment with carboplatin may increase organ toxicity.

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.

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.

4.6. Pregnancy and lactation

Pregnancy

Carboplatin is suspected to cause serious birth defects when administered during pregnancy. Carboplatin was shown to be embryotoxic and teratogenic in rats. Carboplatin should not be used during pregnancy unless clearly necessary. The mother should be informed about the risk to the fetus. Women of child-bearing potential must use effective contraception during treatment. See also section 4.4 “Special warnings and precautions for use”.

For women who are pregnant or become pregnant during therapy, genetic counselling should be provided.

Lactation

It is unknown whether Carboplatin is excreted in human breastmilk. Due to the risk of serious adverse effects of carboplatin, breastfeeding must be discontinued during treatment with carboplatin.

4.7. Effects on ability to drive and use machines

Carboplatin may cause nausea and vomiting, indirectly impairing the ability to drive and use machines.

4.8. Undesirable effects

Incidences of adverse reactions reported hereunder 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, <1/1000)

•    Rare (>1/10,000, <1/1,000)

•    Very rare (<1/10,000) including isolated reports

Neoplasms benign and malignant (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, which 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.

-    Thrombocytopenia. 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.

-    Leucopenia. This has 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.

-    A haemoglobin decrease (< 9.5 mg/100 ml) has been observed in 48% of patients. 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. These reactions are similar to those observed after administration of other platinum-containing compounds, i.e. skin rash, urticaria, erythema, fever with no other apparent cause and pruritus.

Rare:

-    Cases of bronchospasm, hypotension, and anaphylactic shock requiring adequate treatment (epinephrine, antihistamines, corticosteroids) may occur.

Metabolism and nutrition disorders

Very common:

-    Decrease in serum electrolytes (magnesium, potassium, sodium and, rarely, 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:

-    Isolated cases of hyponatremia have been reported, but a causal connection is not proven.

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 patients above the age of 65 years or patients 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.

-    Central nervous symptoms have occasionally 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.

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:

-    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. Clinically significant hearing loss has occurred in children who received Carboplatin dosages higher than recommended and combined with other ototoxic drugs.

Cardiovascular disorders

-    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.

Gastrointestinal disorders

Very common:

-    Nausea and/or vomiting. Nausea without vomiting occurs in about a quarter of the patients receiving Carboplatin; vomiting has been reported in half of the patients and one-third of these suffer severe emesis. Nausea and vomiting usually disappear within 24 hours after treatment and are usually responsive to (and may be prevented by) antiemetic medication. Vomiting that could not be controlled by drugs was observed in only 1% of patients. A quarter of patients experiences no nausea or vomiting. Vomiting seems to occur more frequently in previously treated patients, particularly in patients pre-treated with cisplatin.

-    Painful gastro-intestinal disorders. These have occurred in 17 % of

patients.

Common:

-    Diarrhoea and constipation have occurred in 6 % and 4 % of patients, respectively.

-    Mucositis

Rare:

-    Taste alteration

-    Isolated cases of anorexia have been    reported.

Hepato-biliary disorders

Very common:

-    Abnormalities of liver function tests (usually mild to moderate). These 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 disorders

Common:

-    Alopecia

Renal and urinary disorders

Very common:

- Elevation of blood urea or serum creatinine levels. Renal toxicity is usually not dose-limiting in patients receiving Carboplatin, nor does it require preventive measures such as a high volume fluid hydration or forced diuresis. Nevertheless increasing blood urea or serum creatinine levels can occur commonly.

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 to 59 ml/ min) or severe alteration (21 - 40 ml/ min). Carboplatin is contra-indicated in patients with a glomerular filtration rate at or below 20 ml/ min.

General disorders and administration site conditions

Very common:

-    Hyperuricaemia, which is observed in about one quarter of patients. Serum levels of uric acid can be decreased by allopurinol.

-    Asthenia

Common:

-    Malaise

Uncommon:

-    Injection site reactions, such as pain, erythema, swelling, urticaria and necrosis, have been reported.

-    Fever and    chills    without    evidence of infection have occurred.

Rare:

-    Haemolytic uraemic syndrome occurred in single cases.

4.9. Overdose

Since no known antidote exists for Carboplatin, every possible measure should be undertaken to avoid an overdose.

Symptoms of intoxication

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/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 intoxication

There is no specific antidote. Symptomatic measures should be taken to sustain the patient through any period of toxicity that might occur. 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: Other antineoplastic agents, platinum compounds. ATC code: L01XA02.

Carboplatin has biochemical properties similar to that of cisplatin, thus producing predominantly interstrand and intrastrand DNA crosslinks.

Paediatric patients:

Safety and efficacy in children have not been established.

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.

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 half-life 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

In animals, symptoms of acute toxicity consisted of emesis, anorexia, adipsia, postural changes, troubled respiration and diarrhoea. Symptoms of long term toxicity included myelosuppression, depression of the immune system, necrosis of the mucosae of the gastrointestinal system, reduction in body weight , increases in the levels of enzymes of the liver and blood urea nitrogen, bleeding, bacterial infection, bronchitis, damage to the retinae, mild ototoxicity and damage to the kidneys. Carboplatin induces cytogenetic effects suggesting that it is likely to be mutagenic/carcinogenic. Reproduction and teratology: increases in toxicity to the mother and foetus were observed in a dose dependent fashion. Changes to the foetuses included alterations to the weight and length of the body, increases in the incidences and severity of abnormalities to the skeleton and internal organs. At doses higher than 4mg/kg/day, spontaneous abortion of most of the foetuses and severe deformities to the skeletons of surviving foetuses were observed.

6. PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Mannitol, Water for Injection.

6.2. Incompatibilities

This medicinal product should not be mixed with other medical products except those mentioned under 4.2. “Dilution”.

This product should not be used with aluminium-containing infusion assemblies, syringes and injection needles. The antineoplastic activity can be reduced.

6.3.


Shelf Life

18 months

After first opening/dilution Immediate and single use.

Chemical and physical in-use stability has been demonstrated for three hours at room temperature (15-25°C) and for 24 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 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.

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

Storage conditions after first opening/dilution Do not store above 25 °C.

Protect from light.

6.5 Nature and contents of container

Amber coloured glass vials, USP type I with chlorobutyl, black teflon-coated, grey stoppers with an aluminium seal covered with a polypropylene snap-cap.

Pack sizes:

Box of 1 vial of 5 ml, 15 ml and 45 ml

Boxes of 5 and 10 vials of 5 ml, 15 ml and 45 ml (each packed separately in a box, wrapped together with transparent shrink foil).

Not all pack sizes may be marketed

6.6 Special precautions for disposal

Dilution: The product may be diluted with 5% Glucose 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 three hours at room temperature (15-25°C) and for 24 hours at 2-8°C.

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.

For single use only. Any unused solution should be discarded.

Guidelines for safe handling of anti-neoplastic agents:

1    Trained personnel should handle the drug

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 1000°C. Liquid waste may be flushed with copious amounts of water.

Dilution:

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.

7.    MARKETING AUTHORISATION HOLDER

Pharmachemie B.V.

Swensweg 5 PO Box 562 2003 RN Haarlem The Netherlands

8. MARKETING AUTHORISATION NUMBER

PL 04946/0028

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

17 March 2004

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DATE OF REVISION OF THE TEXT

05/06/2009