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
Each ml of concentrate for solution for infusion contains 10mg carboplatin. Each 5ml vial contains 50mg carboplatin.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Concentrate for solution for infusion.
Clear, colourless or almost colourless solution.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Carboplatin is indicated for the treatment of:
1. Advanced ovarian carcinoma of epithelial origin in:
(a) first line therapy
(b) second line therapy, after other treatments have failed.
2. Small cell carcinoma of the lung.
4.2. Posology and method of administration
Method of administration
Carboplatin injection should be used by the intravenous route only. Dosage and Administration:
Carboplatin should be used by the intravenous route only. The recommended dose of carboplatin injection in previously untreated adult patients with normal kidney function is 400 mg/m2 as a single intravenous dose administered by a 15 to 60 minute infusion.
Alternatively, the Calvert formula shown below may be used to determine dosage:
Dose (mg) = target AUC (mg/ml x min) x [GFR ml/min + 25]
|
Target AUC |
Planned chemotherapy |
Patient treatment status |
|
5-7 mg/ml.min |
Single agent carboplatin |
Previously untreated |
|
4-6 mg/ml.min |
Single agent carboplatin |
Previously treated |
|
4-6 mg/ml.min |
Carboplatin plus cyclophosphamide |
Previously untreated |
Note: With the Calvert formula, the total dose of carboplatin is calculated in mg, not mg/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 non-tolerable side effects.
Therapy should not be repeated until four 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.
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 injection is recommended for future dosage adjustment for subsequent courses of therapy.
Needles or intravenous sets containing aluminium parts that may come in contact with carboplatin injection should not be used for preparation or administration. Aluminium reacts with carboplatin injection causing precipitate formation and/or loss of potency.
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.
Impaired renal function
Patients with creatinine clearance values below 60 ml/min are at increased risk of severe myelosuppression. The frequency of severe leukopenia, neutropenia, or thrombocytopenia has been maintained at about 25% with the following dosage recommendations:
Baseline Creatinine Clearance Initial Dose (Day 1)
41-59 mL/min 250 mg/m2 IV.
16-40 mL/min 200 mg/m2 I.V.
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.
Paediatric population:
There is insufficient information available to recommend a dosage in the paediatric population.
Elderly patients:
In patients of more than 65 years of age, adjustment of the carboplatin dose to the general condition is necessary during the first and the subsequent therapeutic courses.
Dilution & Reconstitution:
The product must be diluted prior to infusion, see section 6.6.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
Carboplatin injection is contraindicated in: • Hypersensitivity to carboplatin or other platinum containing compounds.
•Patients with pre-existing severe renal impairment (creatinine clearance < 30 mL/min), unless in the judgement of the physician and patient, the possible benefits of treatment outweigh the risks.^Patients with severe myelosuppression.^Patients with bleeding tumours.^Concomitant use with yellow fever vaccine (see section 4.5.)Dosage adjustment may allow use in the presence of mild renal impairment (see section 4.2)
4.4. Special warnings and precautions for use
Warnings:
Carboplatin should be administered by individuals 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.
The occurrence, severity and protraction of toxicity is likely to be greater in patients who have received extensive prior treatment with the drug for their disease or with cisplatin, have poor performance status and are advanced in years. 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. Initial carboplatin 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.
Peripheral blood counts (including platelets, white blood cells and haemoglobin) should be followed during and after therapy. Combination therapy with other myelosuppressive drugs may require modification of dosage/timing of schedules in order to minimise additive effects.
Carboplatin courses should not, in general, be repeated more frequently than every 4 weeks in order to ensure that the nadir in blood counts has occurred and there has been recovery to a satisfactory level.
Hematologic Toxicity
Leukopenia, neutropenia, and thrombocytopenia are dose dependent and dose-limiting. Peripheral blood counts should be monitored during carboplatin injection treatment frequently and, in case of toxicity, until recovery is achieved. Median day of nadir is day 21 in patients receiving single agent carboplatin injection and day 15 in patients receiving carboplatin injection in combination with other chemotherapeutic agents. In general, single intermittent courses of carboplatin injection should not be repeated until leukocyte, neutrophil, and platelet counts have returned to normal. 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 intial therapy. 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 then postponement of carboplatin therapy until bone marrow recovery is evident, should be considered. This recovery usually takes 5 to 6 weeks. Transfusions may be necessary and dosage resuctions recommended for subsequent treatment.
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 and timing in order to minimize additive effects. Supportive transfusional therapy may be required in patients who suffer severe myelosuppression.
Carboplatin can cause nausea and vomiting. Premedication with antiemetics has been reported to be useful in reducing the incidence and intensity of these effects.
Renal Toxicity
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).
The incidence and severity of nephrotoxicity may increase in patients who have impaired kidney function before carboplatin treatment. Impairment of renal function is also more likely in patients who have previously experienced nephrotoxicity as a result of cisplatin therapy. Although no clinical evidence on compounding nephrotoxicity has been accumulated, it is recommended not to combine carboplatin with aminoglycosides or other nephrotoxic compounds.
Allergic Reactions
As with other platinum-based drugs, allergic reactions appearing most often during perfusion may occur and necessitate discontinuation of the perfusion and an appropriate symptomatic treatment. Cross reactions, sometimes fatal, have been reported with all the platinum compounds (see section 4.3 and section 4.8), 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) must also be initiated in such cases.
The carcinogenic potential of carboplatin has not been studied but compounds with similar mechanisms of action and mutagenicity have been reported to be carcinogenic.
Safety and effectiveness of carboplatin administration in children are not proven.
Precautions:
Peripheral blood counts and renal and hepatic 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. The drug should be discontinued if abnormal depression of the bone marrow or abnormal renal or hepatic function is seen.
Neurologic Toxicity:
Although peripheral neurologic toxicity is generally common and mild, limited to paresthesia and decrease of osteotendinous reflexes, its frequency is increased in patients older than 65 years and/or in patients previously treated with cisplatin. Monitoring and neurological examinations should be carried
out at regular intervals. Neurological evaluation and an assessment of hearing should be performed on a regular basis, especially in patients receiving high dose carboplatin.
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. Neurotoxicity, such as paraesthesia, decreased deep tendon reflexes, and ototoxicity are more likely seen in patients previously treated with other platinum treatments and other ototoxic agents.
Geriatric Use:
In studies involving combination therapy with carboplatin an 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).
Other:
Auditory defects have been reported during carboplatin therapy. Ototoxicity may be more pronounced in children and is more likely seen in patients previously treated with cisplatin. Cases of hearing loss with a delayed onset have been reported in paediatric patients. A long-term audiometric followup in this population is recommended. Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including carboplatin, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving carboplatin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Aluminium-containing equipment should not be used during preparation and administration of carboplatin (see section 4.5)
4.5. Interaction with other medicinal products and other forms of interaction
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.
Due to the increase of thrombotic risk in case of tumoral diseases, the use of anticoagulative treatment is frequent. The high intra-individual variability of the coagulabilty during diseases, and the eventuality of interaction between
oral anticoagulants and anticancer chemotherapy, require, if it is decided to treat the patient with oral anticoagulants, to increase frequency of the control of the INR monitoring if a patient is treated with oral anticoagulants
Concomitant use contraindicated
- Yellow fever vaccine: risk of generalised vaccinal disease mortal ((see section 4.3.).
Concomitant use not recommended
- Live attenuated vaccines (except yellow fever): risk of systemic, possible fatal disease. This risk is increased in subjects who are already immunosuppressed by their underlying disease.
Use an inactivated vaccine where this 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.
Concomitant use to take into consideration
- Cyclosporin (and by extrapolation tacrolimus and sirolimus): Excessive immunosuppression with risk of lymphoproliferation.
- Concurrent therapy with nephrotoxic or ototoxic drugs such as aminoglycosides, vancomycin, capreomycin and diuretics, may increase or exacerbate toxicity, particularly in renal failure patients, due to carboplatin induced changes in renal clearance.
- Aminoglycosides: The concomitant use of carboplatin with aminoglycosides antibiotics should be taken into account due to the cumulative nephrotoxicity and ear toxicity, particularly in renal failure patient.
- Loop diuretics: The concomitant use of carboplatin with loop diuretic should be taken into account due to the cumulative nephrotoxicity and ear toxicity.
- Combination therapy with other myelosuppressive agents may require dose changes or rescheduling of doses in order to minimise the additive myelosuppressive effects.
4.6 Fertility, pregnancy and lactation
Pregnancy
Carboplatin injection can cause foetal harm when administered to a pregnant woman. Carboplatin injection has been shown to be embryotoxic and teratogenic in rats receiving the drug during organogenesis. No controlled studies in pregnant women have been conducted. If this drug is use during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the foetus. Women with child-bearing potential should be advised to avoid becoming pregnant.
For women who are pregnant or become pregnant during therapy, genetic counselling should be provided.
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.
Gonadal suppression resulting in amenorrhoea 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.
Breast-feeding
It is not known whether carboplatin is excreted in human milk. If treatment becomes necessary during the lactation period, breastfeeding must be stopped (See section 4.3).
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed. However, Carboplatin may cause nausea, vomiting, vision abnormalities and ototoxicity; therefore, patients should be warned on the potential effect of these events on the ability to drive or to use machines.
4.8. Undesirable effects
The frequency of adverse reactions reported is based on a cumulative database of 1,893 patients receiving single agent carboplatin injection and post-marketing experience.
The list is presented by system organ class, MedDRA preferred term, and frequency using the following frequency categories:
Very common (>1/10)
Common (>1/100,<1/10)
Uncommon (>1/1,000, <1/100)
Rare (>1/10,000, <1/1,000)
Very rare (<1/10,000), and 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, dysgeusia |
|
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 erythema, malaise | |
|
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 decreased, blood magnesium decreased. |
|
Common |
Blood bilirubin increased, blood creatinine | |
* Fatal in <1%, fatal cardiovascular events in <1% included cardiac failure, embolism, and cerebrovascular accident combined.
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/mm in 14% of patients. The nadir usually occurs on day 21. Myelosuppression can be worsened by combination of carboplatin injection with other myelosuppressive compounds or forms of treatment.
Myelotoxicity is more severe in previously treated patients, in particular in patients previously treated with cisplatin and in patients with impaired kidney function. Patients with poor performance status have also experienced increased leukopenia and thrombocytopenia. These effects, although usually reversible, have resulted in infectious and hemorrhagic complications in 4% and 5% of patients given carboplatin injection, respectively. These complications have led to death in less than 1% of patients.
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.
Neoplasms, benign, malignant and unspecified (including cysts and
p°!yps)
Secondary acute malignancies after cytostatic combination therapies containing carboplatin have been reported.
Respiratory, thoracic and mediastinal disorders
Pulmonary fibrosis has been reported very rarely, 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
Vomiting occurs in 65% of patients, in one-third of whom it is severe.
Nausea occurs in an additional 15%. Previously treated patients (in particular patients previously treated with cisplatin) appear to be more prone to vomiting. These effects usually disappear within 24 hours after treatment and are generally responsive to or prevented by antiemetic medication. Vomiting is more likely when carboplatin injection is given in combination with other emetogenic compounds.
The other gastro-intestinal complaints corresponded to pain in 8% of patients, diarrhoea, and constipation in 6 % of patients. Cramps have also been reported.
Nervous system disorders
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. Parasthesias present prior to treatment, especially if caused by cisplatin, may persist or worsen during carboplatin therapy (see section 4.4)
Eye disorders
Visual disturbances, including sight loss, are usually associated with high dose therapy in renally impaired patients.
Ear and labyrinth disorders:
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.
Tinnitus was also commonly reported. Hearing loss as a result of cisplatin therapy may give rise to persistent or worsening symptoms. 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 common with other ototoxic agents, clinically significant hearing loss has been reported to occur in paediatric patients when carboplatin is administered.
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. Impairment of renal function is more likely in patients who have previously experienced nephrotoxicity as a result of cisplatin therapy.
Investigations
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.
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.
Cases of an acute, fulminant liver cell necrosis occurred after high-dosed administration of carboplatin.
Immune system disorders
Anaphylactic-type reactions, sometimes fatal, may occur in the minutes following injection of the product: facial oedema, dyspnoea, tachycardia, low blood pressure, urticaria, anaphylactic shock, bronchospasm.
Fever with no apparent cause has also been reported.
Skin and subcutaneous tissue disorders:
Erythematous rash, fever and pruritis have been observed. These were reactions similar to those seen after cisplatin therapy but in a few cases no cross-reactivity was present.
Cardiac disorders
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.
General disorders and administration site conditions
Reactions at the site of injection (burning, pain, reddening, swelling, urticaria, necrosis in connection with extravasation) have been reported.
Fever, chills and mucositis have occasionally been observed.
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.
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.
Treatment of overdose
There is no known antidote for carboplatin injection over dosage. The anticipated complications of over dosage would be related to myelosuppression as well as impairment of hepatic and renal and auditory function. Reports of doses up to 1600mg/m2 indicate patients feeling extremely ill with diarrhoea and alopecia developing. Use of higher than recommended doses of carboplatin injection has been associated with loss of vision (see section 4.4).Bone marrow transplantation and transfusions (thrombocytes, blood) can be effective measures of managing haematological side effects.
5.1 Pharmacodynamic properties
ATC code: Antineoplastic agent LO1X AO2
Carboplatin is an antineoplastic agent. Its activity has been demonstrated against several murine and human cell lines.
Carboplatin exhibited comparable activity to cisplatin against a wide range of tumours regardless of implant site.
Alkaline elution techniques and DNA binding studies have demonstrated the qualitatively similar modes of action of carboplatin and cisplatin. Carboplatin, like cisplatin, induces changes in the superhelical conformation of DNA which is consistent with a “DNA shortening effect”.
Paediatric patients: safety and efficacy in children have not been established.
5.2 Pharmacokinetic properties
Carboplatin has biochemical properties similar to those of cisplatin, thus producing predominantly interstrand and intrastrand DNA crosslinks. 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 exceeds 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 ultrafilterable 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 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. 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. (See para. 4.6, Pregnancy and Lactation.) 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.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Water for injections.
6.2 Incompatibilities
Needles or intravenous 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
2 years (unopened).
After dilution:
24 hours under refrigeration (2 - 8°C).
6.4 Special precautions for storage
Do not store above 25 °C. Do not store in a refrigerator. Store containers in the original carton. Protect from light.
After dilution (see section 6.6.):
Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C for solutions with a final concentration of carboplatin 0.4 mg/ml or 2.0 mg/ml after dilution of the carboplatin 10 mg/ml with 5% Glucose Injection BP, or 0.9% Sodium Chloride Injection BP.
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 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.
6.5 Nature and contents of container
Clear vials of hydrolytic Type I glass, packed in a carton.
Vials are closed with a fluororesin coated bromobutyl rubber stopper with an aluminium crimp cap with a polypropylene flip-off lid.
Packs of 1 vial containing 50 mg/5ml of carboplatin.
6.6 Special precautions for disposal
This product is for single dose use only.
Solutions should only be used if clear and particle free.
Disposal:
Any unused product or waste material should be disposed of in accordance with local requirements.
Dilution:
The product must be diluted before use. It may be diluted with 5% Glucose Injection BP, or 0.9% Sodium Chloride Injection BP, to concentrations from 2.0 mg/ml to as low as 0.4 mg/ml (400 micrograms/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.
7 MARKETING AUTHORISATION HOLDER
Fannin (UK) Limited 42-46 Booth Drive Park Farm South Wellingborough Northamptonshire NN8 6GT UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 20417/0013
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
27/05/2011
10 DATE OF REVISION OF THE TEXT
31/03/2016