Action And Clinical Pharmacology: Carboplatin is a synthetic analogue of cisplatin. Like cisplatin, carboplatin interferes with DNA intrastrand and interstrand crosslinks in cells exposed to the drug. DNA reactivity has been correlated with cytotoxicity.
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.
Repeated dosing during 4 consecutive days did not produce an accumulation of platinum in plasma.
Following administration of carboplatin, reported values for the terminal elimination half-lives of free ultrafilterable platinum and carboplatin in man were 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 the 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.
Excretion of carboplatin is by glomerular filtration. Patients with poor renal function have a higher area under curve (AUC) for total platinum and a reduction in dosage is recommended (see Dosage).
Indications And Clinical Uses: For the treatment of ovarian cancer of epithelial origin in first line therapy and in second line therapy after other treatments have failed.
Contra-Indications: Severe myelosuppression.
Pre-existing severe renal impairment. Dosage adjustment may allow use in the presence of mild renal impairment (see Dosage).
History of severe allergic reactions to carboplatin, or other platinum-containing compounds. Patients allergic to mannitol may be given carboplatin injection.
Manufacturers’ Warnings In Clinical States: Caution: Carboplatin is a potent drug and should be used only by physicians experienced with cancer chemotherapeutic drugs (see Precautions). Blood counts as well as renal and hepatic function tests must be done regularly. Discontinue the drug if abnormal depression of bone marrow or abnormal renal or hepatic function is seen.
Myelosuppression as a result of carboplatin treatment is closely related to the renal clearance of the drug. Therefore in patients who have abnormal renal function or who are receiving concomitant therapy with nephrotoxic drugs, myelosuppression especially thrombocytopenia, may be more severe and prolonged.
The occurrence, severity and protraction of myelotoxicity is likely to be greater in patients who have received extensive prior treatment for their disease, have poor performance status and who are more than 65 years of age.
Renal function parameters should be assessed prior to, during and after therapy. Thrombocytopenia, leukopenia and anemia occur after administration of carboplatin. Peripheral blood counts (including platelets, white blood cells and hemoglobin) should be monitored frequently during and after therapy. Combination therapy with other myelosuppressive drugs may require modification of dosage and/or frequency of administration in order to minimize additive effects. Supportive transfusional therapy may be required in patients who suffer severe myelosuppression.
Carboplatin courses should not be repeated more frequently than monthly in most circumstances, in order to ensure that the nadir in blood counts has occurred and that there has been recovery to a satisfactory level.
Precautions: General: Carboplatin should only be administered to patients under the supervision of a qualified physician who is experienced in the use of chemotherapeutic agents. Diagnostic and treatment facilities should be readily available for appropriate management of therapy and possible complications.
Peripheral blood counts and renal function should be monitored closely. Blood counts should be performed prior to commencement of carboplatin therapy and weekly to assess hematologic nadir for subsequent dose adjustments. Lowest levels in white cells and platelets are seen between days 14 and 28, and days 14 and 21 respectively after initial therapy. A greater reduction in platelets is seen in patients who have received extensive myelosuppressive chemotherapy than in untreated patients. White blood cell counts less than 2 000 cells/mmor platelets less than 50 000 cells/mmmay necessitate postponement of carboplatin therapy until bone marrow recovery is evident, usually within 5 to 6 weeks.
Dosage reduction or discontinuation may be necessary in the case of severe alteration of renal function tests.
Renal toxicity is not usually dose-limiting. Pretreatment and post-treatment hydration is not necessary. However about 25% of patients show decreases in creatinine clearance below 60 mL/min. and, less frequently, rises in serum creatinine and blood urea nitrogen may be seen in patients who have previously experienced nephrotoxicity as a result of cisplatin therapy.
Neurotoxicity, such as parasthesias and decreased deep tendon reflexes, and ototoxicity are more likely to be seen in patients who have received cisplatin previously to carboplatin therapy or who are undergoing combination therapy with other neurotoxic drugs such as vincristine. Neurological evaluations and an assessment of hearing should be performed prior to therapy and on a regular basis thereafter.
Conception Control: Carboplatin is mutagenic in in vitro tests. It is recommended that patients with child bearing or conceiving potential who are receiving carboplatin, exercise adequate conception control.
Pregnancy: Carboplatin produces embryotoxicity and teratogenicity in rats. Safe use of carboplatin in human pregnancy has not been established and its use in pregnancy is not recommended.
Lactation: It is not known whether carboplatin is excreted in breast milk. To avoid possible harmful effects in the infant, breast feeding is not advised during carboplatin therapy.
Geriatrics: For patients aged 65 and over, dosage adjustment, initially or subsequently, may be necessary, depending on the patient’s physical status.
Patients with Impaired Renal Function: The optimal use of carboplatin in patients presenting with impaired renal function requires adequate dosage adjustments and frequent monitoring of both hematological nadirs and renal function.
Children: Sufficient use of carboplatin in pediatrics has not occurred to allow specific dosage recommendations to be made.
Interactions : Needles, syringes, catheters or i.v. administration sets that contain aluminum parts which may come in contact with carboplatin should not be used for preparation or administration of Carboplatin Injection. Carboplatin may interact with aluminum to form a black precipitate.
Concurrent therapy with nephrotoxic drugs may increase or exacerbate toxicity due to carboplatin-induced changes in renal clearance.
Combination therapy with other myelosuppressive drugs may necessitate changes in the dose or frequency of administration of carboplatin in order to minimize additive myelosuppressive effects.
Adverse Reactions: Myelosuppression is the dose-limiting toxicity of carboplatin. It is usually reversible and is not cumulative when carboplatin is used as a single agent and at the recommended dosage regimens. Adverse reactions which have been observed include: Hematologic: leukopenia 55%, thrombocytopenia 32%, anemia 59%, bleeding 6%, infection 4%. Transfusional support has been required in about one-fifth of patients.
Gastrointestinal: nausea and vomiting 53%, nausea only 25%, diarrhea 6%, constipation 3%. Nausea and vomiting usually occur 6 to 12 hours after administration of carboplatin and disappear within 24 hours. It is readily controlled (or may be prevented) by antiemetic medication.
Renal: decrease in creatinine clearance 25%, increases in uric acid 25%, blood urea nitrogen 16% and serum creatinine 7%.
Serum Electrolytes: decreases in serum magnesium 37%, potassium 16% and calcium 5%. These changes have not caused clinical symptoms.
Neurological: peripheral neuropathy 6%, dysgeusia
Ototoxicity: subclinical decrease in hearing acuity as determined by audiogram in the high frequency (4 000 to 8 000 Hz) range, 15%, clinical ototoxicity usually manifested as tinnitus 1%. In patients who developed hearing loss as a result of cisplatin therapy, the impairment may persist or worsen after completion of therapy.
Hepatic: Increases in alkaline phosphatase 36%, AST 15%, ALT 16%, total bilirubin 4%. Increases in liver enzymes have been transient in the majority of cases.
Allergic Reactions: In less than 2% of patients, reactions similar to those seen after cisplatin have been observed, erythematous rash, fever and pruritus. However no cross-reactivity between cisplatin and carboplatin was seen.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: No cases of overdosage of carboplatin are known. Should it occur, the patient may need to be sustained through complications relating to myelosuppression, renal and hepatic impairment. From reports in which doses up to 1 600 mg/mwere used, patients were said to feel extremely unwell and developed diarrhea and alopecia.
Dosage And Administration: Adults: The recommended dose of carboplatin in previously untreated adults with normal renal function is 400 mg/mgiven as a single i.v. infusion over 15 to 60 minutes. Therapy should not be repeated until 4 weeks after the previous carboplatin course.
Initial dosage should be reduced 20 to 25% in patients with risk factors such as previous myelosuppressive therapy and poor performance status. Initial and subsequent dose reduction may be required in elderly patients, depending upon their physical status.
Determination of hematologic nadir by weekly blood counts during initial courses is recommended for future dosage adjustment and scheduling of carboplatin.
Patients with Impaired Renal Function: Hematological nadir and renal function should be closely monitored.
Children: Specific dosage recommendations cannot be made due to insufficient use in pediatrics.
Stability and Storage: Store between 15 and 25°C, protected from light.
Dilution for I.V. Infusion: Vials of carboplatin may be further diluted with 5% Dextrose Injection or 0.9% Sodium Chloride Injection to give solutions containing approximately 0.3, 0.5 and 2 mg/mL carboplatin.
Diluted solutions are stable for 24 hours in glass or plastic containers, in light and dark storage conditions. Discard unused portion after 24 hours.
Dilutions prepared as directed with 5% Dextrose Injection or 0.9% Sodium Chloride Injection are stable for 48 hours under refrigeration from the time of initial reconstitution, after which time the unused portion should be discarded.
Special Instructions for Handling and Disposal: Carboplatin should be prepared for administration by professionals who have been trained in the safe use of cytotoxic drugs.
The personnel carrying out these procedures should be adequately protected with clothing, gloves, masks and eye protection.
Personnel regularly involved in the preparation and handling of carboplatin should have bi-annual blood examinations.
In the event of contact with the skin or eyes, the affected area should be washed with copious amounts of water or normal saline.
A bland cream may be used to treat the transient stinging of skin. Medical advice should be sought if the eyes are affected.
In the event of spillage, personnel wearing protective clothing should sponge up the spilled material. The area should be rinsed twice with water, and all solutions, and contaminated clothing and sponges put into a plastic bag and sealed. The bag should be disposed of as below.
Syringes, containers, absorbent materials, solution and any other material which has come into contact with carboplatin should be placed in a thick plastic bag or other impervious container and incinerated at 1 000°C. Tightly sealed containers may explode.
Availability And Storage: Each mL of sterile aqueous solution contains: carboplatin 10 mg. Preservative-free. Single dose vials of 50 mg in 5 mL, 150 mg in 15 mL and 450 mg in 45 mL.
CARBOPLATIN INJECTION Faulding Antineoplastic