KEMOCARB Concentrate for solution for infusion Ref.[50351] Active ingredients: Carboplatin

Myelosuppression as a result of carboplatin treatment is closely related to the renal clearance of the drug. Therefore, in patients with 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 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.

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 minimize 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.

Infrequent allergic reactions to carboplatin have been reported, e.g. erythematous rash, fever with no apparent cause or pruritus. Rarely anaphylaxis, angioedema 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 therapy, including antihistamines, adrenaline and/or glucocorticoids.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

Cases of RPLS have been reported in patients receiving carboplatin in combination chemotherapy. RPLS is a rare, reversible after treatment discontinuation, rapidly evolving neurological condition, which can include seizure, hypertension, headache, confusion, blindness, and other visual and neurological disturbances. Diagnosis of RPLS is based upon confirmation by brain imaging, preferably MRI.

Haematologic toxicity

Bone marrow suppression is the dose limiting toxicity of Carboplatin. Thrombocytopenia with platelet counts below 50,000/mm³ occurs in 25% of the patients; neutropenia with granulocyte counts below 1,000/mm³ occurs in 16% of the patients, leucopenia with WBC counts below 2,000/ mm 3 occurs in 15% of the patients. The nadir usually occurs about day 21 in patients receiving single agent therapy. By day 28, 90% of patients have platelet counts above 100,00/mm³, 74% have neutrophil counts above 2,000/mm³; 67% have leukocyte counts above 4,000/mm³. Marrow suppression is usually more severe in patients with impaired kidney function. Patients with poor performance status have also experienced a higher incidence of severe leucopenia and thrombocytopenia. Anemia with haemoglobin less than 11 g/dl occurs in majority of the patients who start therapy with a baseline above the value. The incidence of anemia increases with increasing exposure to carboplatin. Transfusions may be required in some patients treated with carboplatin. Bone marrow depression may be more severe when carboplatin is combined with other bone marrow suppressing drugs or with radiotherapy.

Gastrointestinal toxicity

Vomiting occurs in about 65% of the patients and in about one third of these patients, it is severe. Nausea alone occurs in an additional 10-15% of patients. Both nausea and vomiting usually cease within 24 hours of treatment and are often responsive to antiemetic measures. Emesis was increased when carboplatin was used in combination with other emetogenic compound. Other gastrointestinal effects observed frequently were pain, in 17% of the patients; diarrhea, in 6% and constipation, also in 6%.

Neurologic toxicity

Peripheral neuropathies have been observed in small number of patients receiving carboplatin with mild paresthesia occurring most frequently. Patients older than 65 years have an increased risk for peripheral neuropathies. Clinical ototoxicity and other sensory abnormalities such as visual disturbances and change in taste occur rarely. Central nervous system symptoms have been reported in fewer patients and appear to be most often related to the use of antiemetics. Although the overall incidence of peripheral neurologic side effects induced by carboplatin is low, prolonged treatment may result in cumulative neurotoxicity.

Nephrotoxicity

Development of abnormal renal function test results is uncommon with carboplatin. Creatinine clearance has proven to be the most sensitive measure of kidney function in patients receiving carboplatin, and it appears to be the most useful test for correlating drug clearance and bone marrow suppression.

Hepatic toxicity

Abnormalities of liver function tests (usually mild to moderate) have been reported with carboplatin in about one-third of the patients with normal baseline values. The alkaline phosphatase level is increased more frequently than SGOT, SGPT or total bilirubin. The majority of these abnormalities regress spontaneously during the course of treatment.

Electrolyte changes

Decreases in serum electrolytes (sodium, magnesium, potassium and calcium) have been reported after treatment with carboplatin but have not been reported to be severe enough to cause the appearance of clinical signs or symptoms. Cases of hyponatraemia have been reported. Haemolytic uraemic syndrome has been reported rarely.

Allergic reactions

Hypersensitivity to Carboplatin develops only in a small number of patients and consists of rash, urticaria, erythema, pruritus and rarely bronchospasm and hypotension. These reactions are successfully managed with standard epinephrine, corticosteroid and antihistamine therapy.

Others

Pain and asthenia occur most frequently. Alopecia, cardiovascular, respiratory, genitourinary and mucosal side effects occur only in small number of patients. Use of higher than recommended dose of carboplatin has been associated with loss of vision.

Carboplatin should only be administered 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 management of therapy and possible complications.

Peripheral blood counts and renal function tests should be monitored closely. Blood counts should be performed prior to commencement of carboplatin therapy, and at weekly intervals thereafter. This will monitor toxicity and help determine the nadir and recovery of haematological parameters and assist in subsequent dosage adjustments. 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 initial therapy. If levels fall below 2000 cells/mm³ or platelets less than 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 reductions recommended for subsequent treatment.

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 programme might overcome such an effect, but dosage reduction or discontinuation of therapy is required in the presence of severe alteration in renal function test. Impairment of renal function is more likely in patients who have previously experienced nephrotoxicity as a result of cisplatin therapy. Neurological evaluation and an assessment of hearing should be performed on a regular basis. Neurotoxicity, such as paraesthesia, decreased deep tendon reflexes, and ototoxicity are more likely seen in patients previously treated with cisplatin.

Aluminium containing equipment should not be used during preparation and administration of carboplatin.

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.

Concurrent therapy with nephrotoxic or ototoxic drugs such as aminoglycosides, vancomycin, capreomycin and diuretics may increase or exacerbate toxicity due to carboplatin induced changes in renal clearance.

Combination therapy with other myelosuppressive agents may require dose changes or rescheduling of doses in order to minimize the additive myelosuppressive effects.

Incompatibilities

It is important not to use needles or other equipment that contain aluminium while preparing or administering Kemocarb.

Pregnancy category D.

Carboplatin may cause fetal harm when administered to a pregnant woman. Carboplatin has been shown to be embryotoxic and teratogenic in rats. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the foetus. Women of child bearing potential should be advised to avoid becoming pregnant.

It is not known whether carboplatin is excreted in human milk. Because there is a possibility of toxicity in nursing infants secondary to carboplatin treatment of the mother, it is recommended that breast feeding be discontinued if the mother is being treated with carboplatin.