Action And Clinical Pharmacology: Carboplatin has biochemical properties similar to that of cisplatin, thus producing predominantly interstrand DNA crosslinks. In patients with creatinine clearances of 60 mL/min or greater given carboplatin at doses of 300 to 500 mg/m the plasma concentrations of carboplatin decay in a biphasic manner with mean alpha and beta half-lives of 1.6 h and 3 h, respectively. The total body clearance, apparent volume of distribution, and mean residence time for carboplatin are 73 mL/min, 16 L, and 3.5 h, respectively. The Cmax value and area under the plasma concentration versus time curve from zero to infinity increase linearly with dose. Therefore, over the range of doses studied, carboplatin exhibits linear, dose-independent pharmacokinetics in patients with creatinine clearances ³60 mL/min.
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 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 and is slowly eliminated with a minimum half-life of 5 days.
The major route of elimination of carboplatin is renal excretion. Patients with creatinine clearances of about 60 mL/min or greater excrete 70% of the dose of carboplatin in the urine with most of this occurring within 12 to 16 hours. All of the platinum in 24 h urine is present as carboplatin, and only 3 to 5% of the dose is excreted between 24 and 96 hours. Total body and renal clearances of free ultrafilterable platinum correlate with the rate of glomerular filtration, but not tubular secretion.
In patients with creatinine clearances of less than 60 mL/min, carboplatin renal and total body clearances decrease with decreases in creatinine clearance. Doses of carboplatin, therefore, should be reduced in patients with creatinine clearance.
Indications And Clinical Uses: For the treatment of advanced ovarian carcinoma of epithelial origin in: first line therapy or second line therapy, after other treatments have failed.
Contra-Indications: Preexisting severe renal impairment. Do not employ carboplatin in severely myelosuppressed patients and/or in patients with bleeding tumoral localizations. Patients with a history of severe allergic reactions to carboplatin, other platinum containing compounds, or mannitol.
Manufacturers’ Warnings In Clinical States: Carboplatin is a potent drug and should be used only by physicians experienced with cancer chemotherapeutic drugs. 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 is dose dependent and dose limiting and closely related to renal clearance of carboplatin. Patients with abnormal kidney function or receiving concomitant therapy with other drugs with nephrotoxic potential are likely to experience more severe and prolonged myelotoxicity. Myelosuppression may also be more severe and prolonged in patients with extensive prior treatment (in particular with cisplatin) poor performance status and above 65 years of age. Initial dosages in these groups should be appropriately reduced (see Dosage) and renal function parameters should be carefully assessed before and during therapy. Carboplatin courses should not be repeated more frequently than monthly under normal circumstances. Thrombocytopenia, leukopenia and anemia occur after administration of carboplatin. Frequent monitoring of peripheral blood counts is recommended throughout and following therapy (see Precautions). Administration of carboplatin in combination with other myelosuppressive compounds must be planned very carefully with respect to dosages and timing in order to minimize additive effects. Supportive transfusional therapy might be required in patients who suffer severe myelosuppression, particularly in patients receiving prolonged therapy, since anemia is cumulative.
Its carcinogenic potential has not been studied, but compounds with similar mechanisms of action and mutagenicity have been reported to be carcinogenic.
Pregnancy: Carboplatin can cause fetal harm when administered to a pregnant woman. Carboplatin has been shown to be embryotoxic and teratogenic in rats as well as mutagenic in several experimental systems. No controlled studies in pregnant women have been conducted. 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 fetus. Women with child-bearing potential should be advised to avoid becoming pregnant.
Although carboplatin has limited nephrotoxic potential, concomitant treatment with aminoglycosides has resulted in episodes of increased renal and audiologic toxicity.
As with other platinum compounds, allergic reactions to carboplatin have been reported. These may occur within minutes of administration and should be managed with appropriate supportive therapy.
Visual disturbances, including loss of vision, have been reported rarely after the use of carboplatin, 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. Very high dosages of carboplatin (up to 5 times the single agent recommended dose or more) have resulted in severe abnormalities in hepatic and renal function.
Carboplatin can induce nausea and vomiting, which can be more severe in previously treated patients (in particular in patients previously pretreated with cisplatin).
Although peripheral neurologic toxicity is generally rare and mild, its incidence is increased in patients older than 65 years and/or in patients previously treated with cisplatin.
Precautions: Peripheral blood counts, renal and hepatic function tests should be monitored closely. Blood counts are recommended at the beginning of the therapy and weekly to assess hematologic nadir for subsequent dose adjustments. Leukopenia and thrombocytopenia are at their lowest levels between days 14 and 28 and 14 and 21, respectively, after initial therapy. Should the white blood cell count fall below 2 000 cells/mmor the platelet count fall below 50 000 cells/mm consideration should be given to discontinuation of carboplatin treatment until bone marrow recovery, which usually occurs in 5 to 6 weeks.
Renal toxicity is usually not dose-limiting in patients receiving carboplatin nor does it require preventive measures such as high-volume fluid hydration or forced diuresis. Nevertheless, increasing blood urea or serum creatinine levels can occur in about 6 to 14% of the patients. Renal function impairment, as defined by a decrease in the creatinine clearance below 60 mL/min, may be observed in about 27% of the patients. 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 program might overcome such effect. Dosage reduction or discontinuation of therapy is required in the presence of severe alteration of renal function.
Neurotoxicity is usually limited to paresthesias and decreased deep tendon reflexes. The frequency and intensity of this side effect increase in patients previously treated with cisplatin. Thus neurologic evaluations should be performed on a regular basis.
After reconstitution, carboplatin is physically incompatible with any i.v. set, needle and syringe containing aluminum. An interaction will occur between aluminum and platinum from carboplatin causing a black precipitate which is visible in the solution (see Reconstituted Solutions).
Children: Safety and effectiveness in children have not been established.
Lactation: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from carboplatin, nursing should be discontinued.
Drug Interactions: The use of carboplatin with nephrotoxic compounds is not recommended.
Hematologic: Myelosuppression is the dose-limiting toxicity of carboplatin. In patients with normal baseline values, thrombocytopenia with platelet counts below 50 000/mmoccurs in 25% of patients, neutropenia with granulocyte counts below 1 000/mmin 18% of patients, and leukopenia with WBC counts below 2 000/mmin 14% of patients. The nadir usually occurs on day 21 (on day 15 in patients receiving carboplatin in combination). By day 28, recovery of platelet counts above 100 000/mmoccurs in 90% of patients, recovery of neutrophils above 2 000/mmoccurs in 74% and recovery of leukocytes above 4 000/mmoccurs in 67% of patients.
Thrombocytopenia, neutropenia, and leukopenia are 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 Paraplatin or Paraplatin-AQ, respectively. These complications have led to death in less than 1% of patients.
Anemia with hemoglobin values below 11 g/dL has been observed in 71% of patients with normal baseline values. The incidence of anemia is increased with increasing exposure to carboplatin. Transfusional support has been administered to 26% of patients given carboplatin. Myelosuppression can be worsened by combination of carboplatin with other myelosuppressive compounds or other forms of treatment.
Gastrointestinal: Vomiting occurs in 64% of patients, and nausea in an additional 15%. About one-third of patients who vomit suffer severe emesis. Previously treated patients (in particular patients previously treated with cisplatin) appear to be more prone to vomiting. Nausea and/or vomiting usually disappear within 24 hours after treatment and are usually responsive to (and are prevented by) antiemetic medication. It appears that a prolonged administration time for carboplatin (by continuous infusion or in daily doses administered over 5 consecutive days) can induce less vomiting than the single dose schedule. Emesis is increased when carboplatin is given in combination with other emetogenic compounds. Other gastrointestinal side effects consist of pain, in 17% of patients; diarrhea, in 6% and constipation, in 6% of patients. The actual contribution of carboplatin to these observations is unclear.
Neurologic: Peripheral neuropathies have occurred in 4% of patients administered carboplatin and are evidenced mainly by paresthesias. Patients older than 65 years and patients previously treated with cisplatin, as well as those receiving prolonged treatment with carboplatin, appear to be at increased risk of developing peripheral neuropathies. In one-half of the patients who have pre-existing, cisplatin-induced peripheral neurotoxicity, there is no further worsening of symptoms during therapy with carboplatin. Subclinical decrease in hearing acuity, consisting of high-frequency (4 000-8 000 Hz) hearing loss as determined by audiogram, has been reported in 15% of patients. Clinical ototoxicity, manifested in the majority of cases by tinnitus, and other sensory disturbances (including visual disturbances and taste modifications) have affected only 1% of patients. 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. Central nervous symptoms have been reported in 5% of patients and appear frequently to be related to the use of antiemetics.
Although the overall incidence of neurologic side effects seems to be increased in patients receiving carboplatin in combination, this may be related to longer cumulative exposure.
Renal: When given in usual doses, development of abnormal renal function has been uncommon, despite the fact that carboplatin 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 of the patients. Creatinine clearance has proven to be the most sensitive parameter of kidney function in patients receiving carboplatin and is useful in correlating drug clearance with myelosuppression. Twenty-seven percent of patients who have a baseline value of 60 mL/min or greater, experience a reduction in creatinine clearance during carboplatin therapy.
Serum Electrolytes: Decreases in serum sodium, potassium, calcium and magnesium occur in 29%, 20%, 22% and 29% of patients respectively. Electrolyte supplementation was not routinely administered together with carboplatin. Combination chemotherapy has not increased the incidence of these electrolyte changes.
Several cases of early hyponatremia have been reported. While the contribution of carboplatin is not clear in light of other contributory factors (diuresis, respiratory dysfunction, malignancy, etc.) the possibility of hyponatremia should be considered especially for patients with other risk factors, such as concurrent diuretic therapy. Sodium replacement or free water restriction generally reversed the hyponatremia.
Hepatic: Modification of liver function in patients with normal baseline values is observed and includes elevation of total bilirubin in 5%, AST in 15% and alkaline phosphatase in 24% of patients. These modifications usually are mild and are reversible in about one-half of the patients. The role of tumor progression in the liver in these patients is unclear. In a limited series of patients receiving very high dosages of carboplatin and autologous bone marrow transplantation, severe elevation of liver function tests has occurred.
Allergy: Hypersensitivity to carboplatin has been reported in 2% of patients. These allergic reactions, comparable in characteristics and outcome to what has been reported in the case of other platinum-containing compounds (rash, urticaria, erythema, fever with no apparent cause, pruritus, rarely bronchospasm and hypotension). Anaphylactic-type reactions have occurred within minutes of administration. Hypersensitivity reactions have been successfully treated with standard epinephrine, corticosteroid and antihistamine therapy.
Other: Respiratory, cardiovascular, mucosal, genitourinary, cutaneous and musculoskeletal side effects have occurred in 5% or less of patients. Fever and chills without evidence of infection or allergic reaction has occurred in 2% of patients. Although death occurred because of cardiovascular events (cardiac failure, embolism, cerebrovascular accident) in less than 1% of patients, it is unclear whether this was related to chemotherapy rather than general patient conditions.
Among miscellaneous side effects, asthenia (8%) and alopecia (3%) were the most frequent. Their incidence is greatly increased in patients receiving carboplatin in combination. Hemolytic-uremic syndrome has been reported rarely.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: No overdosage occurred during clinical trials, but should it occur, symptomatic measures should be taken to sustain the patient through any period of toxicity that might occur. The anticipated complications would be related to myelosuppression as well as impairment of renal and hepatic function. Use of higher than recommended doses of carboplatin has been associated with loss of vision (see Warnings).
Dosage And Administration: Needles or i.v. sets containing aluminum parts that may come in contact with carboplatin should not be used for preparation or administration. Aluminum reacts with carboplatin causing precipitate formation and/or loss of potency.
After reconstitution, use carboplatin by the i.v. route only. The recommended dosage in previously untreated adult patients with normal kidney function is 400 mg/mas a single i.v. dose administered by a short-term (15 to 60 minutes) infusion. Do not repeat therapy until 4 weeks after the previous carboplatin course and/or until the neutrophil count is at least 2 000 cells/mmand the platelet count is at least 100 000 cells/mm
Reduction of the initial dosage by 20 to 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). For patients aged 65 and over, dosage adjustment, initially or subsequently, may be necessary depending on the physical condition of the patient.
Determination of the hematologic nadir by weekly blood counts during the initial courses of treatment with carboplatin is recommended for dosage adjustments for subsequent courses of therapy.
Impaired Renal Function: The optimal use of carboplatin in patients presenting with impaired renal function requires adequate dosage adjustments and frequent monitoring of both hematologic nadirs and renal function.
Patients with creatinine clearance values below 60 mL/min are at increased risk of severe myelosuppression. The incidence of severe leukopenia, neutropenia, or thrombocytopenia has been maintained at about 25% with the following dosages: 250 mg/mi.v. on day 1 in patients with baseline creatinine clearance values between 41 to 59 mL/min; 200 mg/mi.v. on day 1 in patients with baseline creatinine clearance values between 16 to 40 mL/min.
Insufficient data exist on the use of carboplatin 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 desired myelosuppressive effect.
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.
Reconstituted Solution: Carboplatin may be further diluted with 5% Dextrose in water or 0.9% sodium chloride to concentrations as low as 0.5 mg/mL (500 µg/mL).
The reconstituted solution must be used i.v. only and should be administered by short-term (15 to 60 minutes) i.v. infusion.
Parenteral Products: I.V. needles, syringes or sets having aluminum components should not be employed in preparation or administration of carboplatin solution. An interaction will occur between aluminum and platinum from carboplatin causing a black precipitate which is visible in the reconstituted solution.
Stability and Storage of Solutions: When reconstituted or diluted as directed, carboplatin solution are stable for 8 hours at room temperature. Since no antibacterial preservatives are contained in the present formulation, it is recommended that any carboplatin solution remaining after 8 hours from reconstitution be discarded.
Handling and Disposal: Preparation of carboplatin should be done in a vertical laminar flow hood (Biological Safety Cabinet – Class II).
Personnel preparing carboplatin should wear PVC gloves, safety glasses, disposable gowns and masks.
All needles, syringes, vials and other materials which have come in contact with carboplatin should be segregated and incinerated at 1 000Â°C or more. Sealed containers may explode. Intact vials should be returned to the manufacturer for destruction. Proper precautions should be taken in packaging these materials for transport.
Personnel regularly involved in the preparation and handling of carboplatin should have bi-annual blood examinations.
Availability And Storage: Each mL contains: carboplatin 10 mg. Nonmedicinal ingredients: water for injection. Clear glass vials of 5, 15 and 45 mL. Store between 15 and 25°C and protect from light.
PARAPLATIN-AQ Bristol Carboplatin Antineoplastic
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