Carbotin IV Infusion

Carbotin Injection is indicated for the initial treatment of advanced ovarian carcinoma of epithelial origin in established combination with other approved chemotherapeutic agents. It is also indicated for the palliative treatment of patient with ovarian carcinoma recurrent after prior chemo therapy.

Carboplatin is an alkylating agent which binds covalently to DNA. It modifies the cell cycle by interfering with DNA structure and function.

Needles or intravenous sets containing aluminum parts that may come in contact with Carboplatin injection should not be used for the preparation or administration. Aluminum reacts with Carboplatin causing precipitate formation and/or loss of potency. Procedures for proper handling and disposal of anti-cancer drugs should be implemented. Several guidelines on this subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

After dilution, Carboplatin should be used by the intravenous route only. The recommended dosage of Carboplatin in previously untreated adult patients with normal kidney function is 400 mg/m2 as a single I.V. dose administered by a 15 to 60 minute infusion. Therapy should not be repeated until four weeks after the previous Carboplatin course and/or until the neutrophil count is at least 2000 cells/mm3 and the platelet count is at least 100,000 cells/mm3 . Reduction of the initial dosage by 20-25% (i.e, 300-320 mg/m2) 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 age 65 and over, dosage adjustment, initially or subsequently, may be necessary, dependent on the physical condition of
the patient.

Determination of the hematologic nadir by weekly blood count during the initial courses of treatment with Carboplatin is recommended for dosage adjustment for subsequent courses of therapy.

Carbotin should not be mixed with other drugs. The renal effects of neurotoxic compounds may be potentiated by Carbotin.

Carboplatin is contraindicated in patients with pre-existing severe renal impairment, unless in the judgement of the physician and patient, the possible benefits of treatment outweigh the risks. Carboplatin should not be employed in severely myelosuppressed patients. Carboplatin is also contraindicated in patients with a history of severe allergic reactions to Carboplatin, other platinum containing compounds, or mannitol. Carboplatin is contraindicated in patients with bleeding tumours.

Incidences of adverse reactions reported here under are based on cumulative data obtained in a large group of
patients with various pretreatment prognastic features.

Haematologic toxicity: Bone marrow suppression is the dose-limited toxicity of Carbotin. At maximum tolerated dosages of Carbotin administered as a single agent, thrombocytopenia, with platelet counts of less than 50,000/mm 3 , occurs in 25% of the patients. The nadir usually occurs between days 14 and 21, with recovery within 35 days from the start of therapy. Neutropenia with granulocyte counts below 1,000/mm 3 occurs in 18% of patients. Leucopenia, with nadir WBC counts of less than 2000/mm 3 , occurs in 14% of the patients but its recovery from the day of nadir (day 14-28) may be slower and usually occurs within 42 days from the start of therapy. Anaemia with haemoglobin values below 11 g/dL has been is observed in 71% of the patients. Myelosuppression may be more severe and prolonged in patients with impaired kidney function, extensive prior treatment, poor performance status and age above 65. Myelosuppression is also worsened by therapy combining Carbotin with other compounds that are toxic to the bone marrow. Myelosuppression is usually reversive and not cumulative when Carbotin is used as a single agent and at the recommended dosages and frequencies of administration. Infectious and haemorrhagic complications have been reported in 4% and 5% of the patients given Carbotin, respectively.

Nephrotoxicity: When given in usual doses, development of abnormal renal function has been uncommon, despite the fact that Carbotin 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 Carbotin. Twenty-seven percent of patients who have a baseline value of 60 mL/min or greater, experience a reduction in creatinine clearance during Carbotin therapy. Decreases in serum electrolytes sodium, potassium, calcium, magnesium occur in 29%, 20%, 22%, 29% of patients respectively. Spontaneous reports of early hypotension have been reported which were generally reversed by sodium replacements or free water restriction.

Gastrointestinal toxicity: Nausea without vomiting occurs in about 15% of the patients receiving Carbotin; vomiting has been reported in 65% of the patients. One-third of those patients who vomit suffer severe emesis. Nausea and vomiting usually disappear within 24 hours after treatment and are usually responsive to (and may be prevented by) antiemetic medication. Other gastrointestinal side effects consist of pain (17%); diarrhoea (6%), and constipation (6%). Anorexia has been reported from post-marketing surveillance.

Allergic reactions: Infrequent reactions to Carbotin have been reported in less than 2% of the patients. These reactions are similar to those observed after administration of other platinum-containing compounds, i.e. erythematous rash, fever with no other apparent cause, pruritus, urticaria, rarely bronchospasm and hypotension.

Hepatic Toxicity: The incidences of abnormal liver function tests in patients with normal baseline values were reported as follows: total bilirubin, 5%; SGOT, 15%; and alkaline phosphatase, 24%; (5%, 19%, and 37%, respectively, in pretreated ovarian cancer patients). These abnormalities have generally been mild and reversible in about one-half of the cases, although the role of metastatic tumor in the liver may complicate the assessment in many patients. In a limited series of patients receiving very high dosages of Carbotin and autologous bone marrow transplantation, severe abnormalities of liver function tests were reported.

Neurotoxicity: The incidence of peripheral neuropathies after treatment with Carbotin is 4%. In the majority of the patients neurotoxicity is limited to paresthesias and decreased deep tendon reflexes. The frequency and intensity of this side effect increase in patients previously treated with cisplatin. Paresthesias present before commencing Carbotin therapy, particularly if related prior cisplatin treatment, may persist or worsen during treatment with Carbotin. Central nervous symptoms have been reported in 5% of patients and often appear to be related to the use of antiemectics. The overall frequency of neurologic side effects seems to be increased in patients receiving Carbotin in combination. This may also be related to longer cumulative exposure.

Pregnancy Category D. There are no adequate and well controlled studies in pregnant women. Carboplatin has been reported to be found in human milk. It is not known whether Carboplatin is excreted in human.

Carbotin should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available. 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 haematologic nadir for subsequent dose adjustment are recommended. Neurologic evaluations should also be performed on a regular basis. The drug should be discontinued if abnormal depression of the bone marrow or abnormal renal or hepatic function is seen. Carbotin myelosuppression is closely related to its renal clearance; patients with abnormal kidney function or receiving concomitant therapy with other drugs with nephrotoxic potential are likely to experience more severe and prolonged myelotoxicity. Renal function parameters should therefore be carefully assessed before and during therapy. Carbotin courses should not be repeated more frequently than monthly under normal circumstances. Thrombocytopenia, leucopenia and anaemia which are dose dependant and dose-limiting occur after administration of Carbotin. Frequent monitoring of peripheral blood counts is recommended throughout and following the therapy with Carbotin.

Carbotin combination therapy with other myelosuppressive compounds must be planned very carefully with respect to dosages and timing in order to minimize addictive effects. Supportive transfusional therapy might be required in patients who suffer severe myelosuppression. Anemia is frequent and cumulative. Transfusional support is often needed during treatment with Carbotin, particularly in patients receiving prolonged therapy. Carbotin can cause nausea and vomiting. Premedication with antiemetics and prolongation of time of Carbotin administration by continuous infusion or over five consecutive days have been reported to be useful in reducing the incidence and intensity of these effects. Renal function impairment may be encountered with Carbotin. Although no clinical evidenceon compounding nephrotoxicity has been accumulated, it is recommended not to combine Carbotin with aminoglycosides or other nephrotoxic compounds. As for other platinum coordination compounds, allergic reactions to Carbotin have been reported. These may occur within five minutes of administration and should be managed with appropriate supportive therapy.

Cytotoxic Chemotherapy

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