Carboplatin 10 Mg/Ml Concentrate For Solution 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
1 ml of concentrate for solution for infusion contains 10 mg 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 the full list of excipients see section 6.1.
3. PHARMACEUTICAL FORM Concentrate for solution for infusion.
A clear, colourless solution free from visible particles. pH- 5.0 to 7.0
Osmolality: 200 - 300 mOsm/kg
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
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]
|
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/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.
The safety measures for dangerous substances are to be complied with for 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.
Patient with renal impairment:
Patients with creatinine clearance values of less than 60 ml/min are at greater risk to develop severe myelosuppression.
The frequency of severe leukopenia, neutropenia, or thrombocytopenia has been maintained at about 25% with the following dosage recommendations:
250 mg/m2 I.V. 200 mg/m2 I.V.
41-59 ml/min 16-40 ml/min
Insufficient data exist on the use of carboplatin injection in patients with creatinine clearance of 15 ml/min or less to permit a recommendation for treatment.
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.
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.
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 patient:
In patients of more than 65 years of age, adjustment of the carboplatin dose to the general condition and renal function is necessary during the first and the subsequent therapeutic courses.
Paediatric population:
There is insufficient information available to recommend a dosage in the paediatric population.
Method of administration
Precautions to be taken before handling or administering the medicinal product.
For instructions on dilution of the medicinal product before administration, see section 6.6.
The safety measures for dangerous substances are to be complied with 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.
4.3 Contraindications
Carboplatin is contra-indicated 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 (creatinine clearance < 30 ml/min), unless in the judgement of the physician and patient, the possible benefits of treatment outweights the risks.
- concomitant use with yellow fever vaccine (see section 4.5.)
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.
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.
Diagnostic and treatment facilities should be readily available for management of therapy and possible complications.
Haematological toxicity
Carboplatin Infusion courses should not be repeated more frequently than monthly under normal circumstancesLeukopenia, 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/mm3 and the platelet count is at least 100,000 cells/mm3.
Anaemia is frequent and cumulative requiring very rarely a transfusion.
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 injection combination therapy with other myelosuppressive forms of treatment must be planned very carefully with respect to dosages an timing in order to minimize additive effects.
Supportive transfusional therapy may be required in patients who suffer severe myelosuppression.
Hepatic and/or renal insufficiency
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. 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).
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 Posology and method of administration and 4.4 hematological toxicity.
Impairment of renal function is more likely in patients who have previously experienced nephrotoxicity as a result of cisplatin therapy.
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).
Patients should be observed carefully for possible allergic reactions.
The occurrenceand severity and of toxicity is likely to be greater in patients who have received extensive prior treatment for their disease, have poor performance status and are advanced in years. Renal function parameters should be assessed prior to, during and after carboplatin therapy.
Neurotoxicity
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.
Ototoxicity
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.
Geriatric Use:
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).
Live vaccinations
Administration of live or live-attenuated vaccines in patients immune compromised 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.
Aluminium containing equipment should not be used during preparation and administration of carboplatin (see section 6.2). Aluminum reacts with carboplatin injection causing precipitate formation and/or loss of potency.
4.5 Interaction with other medicinal products and other forms of interaction
When combining carboplatin with other myelosuppressive compounds (or radiation therapy, 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.
Concomitant use contraindicated
- Yellow fever vaccine: risk of generalised vaccinal disease mortal ((see section 4.3.).
Concomitant use not recommended (see section 4.4)
- 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 exist (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 lose of efficacy of the cytotoxic drug due to increased hepatic metabolism by phenytoin.
- 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.
Concomitant use to be taken into consideration
- Chelating agents - decreasing effect of carboplation
- Cyclosporin (and by extrapolation tacrolimus and sirolimus): Excessive immunosuppression with risk of lymphoproliferation.
- Aminoglycosides: The concomitant use of carboplatine with aminoglycosides antibiotics should be taken into account due to the cumulative nephrotoxicity
and ear toxicity, particulary in patient with severe renal impairment.
- Loop diuretics: The concomitant use of carboplatine with loop diuretic should be taken into account due to the cumulative nephrotoxicity and ear toxicity.
- 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 VKA, to increase frequency of the control of the INR monitoring. Caution and more frequent INR monitoring is recommended at
concomitant treatment of warfarin with Carboplatin, as increased INR has been reported.
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.
4.6 Fertility, pregnancy and lactation
Pregnancy
Carboplatin injection can cause fetal harm when administered to a pregnant woman. Carboplatin injection has been shown to be embryotoxic and teratogenic in rats receiving the drug during organogenesis (see section 5.3.). No controlled studies in pregnant women have been conducted.
The safe use of carboplatin during pregnancy has not been established: Studies in animals have shown reproductive toxicity Carboplatin has been shown to be an embryo toxin and teratogen in rats and mutagenic in vivo and in vitro.
Breast-feeding:
It is not known whether carboplatin injection is excreted in human milk.
If treatment becomes necessary during the lactation period, breastfeeding must be stopped.
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.
Women with child-bearing potential
Women with child-bearing potential should be advised to avoid becoming pregnant. Carboplatin must not be used in pregnant women or women of childbearing potential who might become pregnant unless the potential benefits to the mother outweigh the possible risks to the foetus. 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.
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 must 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* |
|
Blood and lymphatic system disorders |
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 |
|
Nervous System Disorders |
Common |
Neuropathy peripheral, paraesthesia, decrease of osteotendinous reflexes, sensory disturbance, |
|
Not known |
Cerebrovascular accident* | |
|
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 | |
|
Skin and Subcutaneous Tissue Disorders |
Common |
Alopecia, skin disorder |
|
Not known |
Urticaria, rash, erythema, pruritus | |
|
Musculoskeletal, Connective Tissue and Bone 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 | |
|
Investigations |
Very Common |
Creatinine renal clearance decreased, blood urea increased, blood alkaline phosphatase increased, aspartate aminotransferase increased, liver funtion test abnormal, blood sodium decreased, blood potassium decreased, blood calcium |
|
Common |
Blood bilirubin increased, blood creatinine increased, blood uric acid |
* Fatal in <1%, fatal cardiovascular events in <1% included cardiac failure, embolism, and
cerebrovascular accident combined.
Neoplasms benign, malignant and unspecified (including cysts and polyps)
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).
Blood and lymphatic system disorders
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/mm3 in 18% of patients, and leukopenia with WBC counts below 2,000/mm3 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.
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.
Immune system disorders
Allergic Reactions:
Anaphylactic-type reactions, sometimes fatal, may occur most often in the minutes following injection of the product: facial oedema, dyspnoea, tachycardia, low blood pressure, urticaria, anaphylactic shock, bronchospasm (see section 4.4)
These reactions are similar to those observed after administration of other platinum containing compounds and should be managed with appropriate supportive therapy.
Metabolism and nutrition disorders
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.
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 (ie, 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.
Eye disorders
Visual disturbances, and rare loss of vision, including transient sight loss, have been reported 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
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.
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.
Respiratory, thoracic and mediastinal disorders
In addition to Interstitial lung disease, pulmonary fibrosis should be considered if a pulmonary hypersensitivity state is excluded.
Gastrointestinal disorders
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.
Nausea and vomiting are generally delayed until 6 to 12 hours after administration of carboplatin
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.
Hepatobiliary disorders
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.
Rare: Cases of an acute, fulminant liver cell necrosis occurred after high-dosed administration of carboplatin.
Renal and urinary disorders
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.
Other undesirable effects:
Alopecia, fever and chills, mucositis, asthenia, malaise as well as dysgeusia have occasionally been observed.
Isolated cases of haemolytic-uraemic syndrome have been reported.
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.
4.9 Overdose
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/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.
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 and auditory 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: other antineoplastic agents, platinum compounds, ATC code: LO1XA02
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 (see section 4.2, 4.4 and 5.2).
5.2 Pharmacokinetic properties
Following administration of carboplatin in man, linear relationships exist 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 of half-lives of free ultra-filterable 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 clearances 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 (see section 4.2 and 4.4).. 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.
Toxicity studies have shown that extravasal administration of carboplatin causes tissue necrosis.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Water for Injections
6.2 Incompatibilities
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 IV administration sets containing aluminium parts that may come into contact with carboplatin should not be used for preparation or administration of carboplatin.
6.3 Shelf life
Unopened:
2 years
After dilution
Chemical and physical in-use stability has been demonstrated after dilution in Glucose 5 % for 96 hours at 20C to 80 C and 200C to 250C.
Chemical and physical in-use stability has been demonstrated after dilution in Sodium Chloride 0.9% for 24 hours at 20C to 80C and 8 hours 200C to 250C.
From a microbiological point of view however, 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 °C to 8 °C, unless dilution has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage
Store below 25°C. Keep vial in the outer carton in order to protect from light.
For storage conditions of the diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
5 ml/15 ml/45 ml/60 ml concentrate for solution in a colourless Ph Eur. Type I glass vial with flurotec rubber closure with green/blue/red and yellow aluminium flip-off seal for each presentation. Each vial may be shrink wrapped and may/may not be packed in plastic container Pack size:
1 vial
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
This product is for single use only. Any unused infusion solution should be discarded. Instruction for dilution
The product must be diluted prior to infusion, with 5 % Glucose for Injection or 0.9 % Sodium Chloride for Injection, to concentrates as low as 0.5 mg/ml (500 micrograms/ml).
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, face mask and protective clothes 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.
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
Fresenius Kabi Oncology Plc.
Lion Court, Farnham Road, Bordon,
Hampshire, GU350NF United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 18727/0025
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
05/03/2012
10 DATE OF REVISION OF THE TEXT
29/09/2013