CARBOPLATIN

Posology The recommended dose of carboplatin in previously untreated adults with normal renal function is 400 mg/m², given as a single short term intravenous infusion over 15 to 60 minutes. min Carboplatin plus cyclophosphamide Previously untreated Note: With the Calvert formula, the total dose of carboplatin is calculated in mg, not mg/m².

Therapy should not be repeated until 4 weeks after the previous carboplatin 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. Initial dosage should be reduced by 20-25% in patients with risk factors such as previous myelosuppressive therapy and/or poor performance status (ECOG-Zubrod 2 - 4 or Karnofsky below 80).

Determination of haematologic nadir by weekly blood counts during initial courses is recommended for future dosage adjustment and scheduling of carboplatin. Needles or intravenous sets containing aluminium parts that may come in contact with carboplatin should not be used for preparation or administration.

Aluminium reacts with carboplatin 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 In patients with impaired renal function, dosage of carboplatin should be reduced (refer to Calvert formula) and haematological nadirs and renal function monitored. Patients with creatinine clearance values below 60 ml/min are at increased risk of severe myelosuppression.

V. V. 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 acceptable level of myelosuppression. 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 to support a dosage recommendation in the paediatric population. Elderly population 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.

Method of administration Carboplatin should be used by the intravenous route only.

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 and unspecified (incl cysts and polyps) Not known Treatment related secondary malignancy Common Infections*Infections and infestations Not known Pneumonia Very common Thrombocytopenia, neutropenia, leukopenia, anaemia Common Haemorrhage* Blood and lymphatic system disorders Not known Bone marrow failure, febrile neutropenia, haemolytic- uraemic syndrome (HUS), haemolytic anaemia (sometimes fatal) Immune system disorders Common Hypersensitivity, anaphylactoid type reaction Metabolism and nutrition disorders Not known Dehydration, anorexia, hyponatraemia, tumour lysis syndrome Common Neuropathy peripheral, paraesthesia, decrease of osteotendinous reflexes, sensory disturbance, dysgeusia Nervous system disorders Not known Cerebrovascular accident*, encephalopathy, Reversible Posterior Leukoencephalopathy Syndrome (RPLS) Eye disorders Common Visual disturbance (incl.

rare cases of loss of vision) Ear and labyrinth disorders Common Ototoxicity Common Cardiovascular disorder*Cardiac disorders Not known Cardiac failure*, Kounis syndrome Vascular disorders Not known Embolism*, hypertension, hypotension, veno-occlusive disease (fatal) Respiratory, thoracic and mediastinal disorders Common Respiratory disorder, interstitial lung disease, bronchospasm Very common Vomiting, nausea, abdominal pain Common Diarrhoea, constipation, mucous membrane disorder Gastrointestinal disorders Not known Stomatitis, pancreatitis Common Alopecia, skin disorderSkin and subcutaneous tissue disorders Not known Urticaria, rash, erythema, pruritus Musculoskeletal and connective tissue disorders Common Musculoskeletal disorder Renal and urinary disorders Common Urogenital disorder Common AstheniaGeneral disorders and administration site conditions Not known Injection site necrosis, injection site reaction, injection site extravasation, injection site erythema, malaise Very Common Creatinine renal clearance decreased, blood urea increased, blood alkaline phosphatase increased, aspartate aminotransferase increased, liver function test abnormal, blood sodium decreased, blood potassium decreased, blood calcium decreased, blood magnesium decreased.

Investigations Common Blood bilirubin increased, blood creatinine increased, blood uric acid increased * 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/mm3 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/mm3 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 haemorrhagic complications in 4% and 5% of patients given carboplatin, 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 polyps) 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. Nausea and vomiting are generally delayed until 6 to 12 hours after administration of carboplatin, are readily controlled or prevented with antiemetics and disappear within 24 hours.

Vomiting is more likely when carboplatin injection is given in combination with other emetogenic compounds. The other gastrointestinal 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 paraesthesia 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.

e. 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.

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Warnings:

Myelosuppression 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 with the drug for their disease or with cisplatin, have poor performance status and are advanced in years.

Renal function parameters should be assessed prior to, during and after carboplatin therapy. 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.

Myelosuppressive effects may be additive to those of concomitant chemotherapy. 8). If any of these events occur, carboplatin should be discontinued. 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.

2). Hypersensitivity reactions As with other platinum-based drugs, allergic reactions appearing most often during administration may occur and necessitate discontinuation of infusion. Patients should be observed carefully and an appropriate symptomatic treatment (including antihistamines, adrenaline and/or glucocorticoids) must also be initiated in such cases.

8). 8). Kounis syndrome can develop in patients with and without cardiac risk factors, and may be presented with a combination of cardiac and allergic symptoms, or as a standalone. Coronary vasospasm may be eliminated with steroids, antihistamines in addition to spasmolytics treatment.

The vial stopper contains dry natural rubber (a derivative of latex), which may cause allergic reactions.

Precautions:

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 and hepatic function tests should be monitored closely. Blood counts should be performed prior to commencement of carboplatin therapy and at weekly intervals thereafter. The drug should be discontinued if abnormal depression of the bone marrow or abnormal renal or hepatic function is seen.

Haematologic toxicity Leukopenia, neutropenia, and thrombocytopenia are dose-dependent and dose-limiting. Peripheral blood counts should be monitored during carboplatin treatment. This will monitor toxicity and help determine the nadir and recovery of haematological parameters and assist in subsequent dosage adjustments.

Median day of nadir is day 21 in patients receiving single agent carboplatin and day 15 in patients receiving carboplatin in combination with other chemotherapeutic agents. In general, single intermittent courses of carboplatin 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 initial therapy.

If neutrophil levels fall below 2000 cells/mm3 or platelets are less than 100,000 cells/mm3 then postponement of carboplatin therapy until bone barrow 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. Anaemia is frequent and cumulative, however rarely requires a transfusion. Haemolytic anaemia with the presence of serologic drug-induced antibodies has been reported in patients treated with carboplatin.

This event can be fatal. Acute promyelocytic leukaemia and myelodysplastic syndrome (MDS) / acute myeloid leukaemia (AML) have been reported years after therapy with carboplatin and other antineoplastic treatments. Haemolytic-uraemic syndrome (HUS) Haemolytic-uraemic syndrome (HUS) is a life-threatening side effect.

Carboplatin should be discontinued at the first signs of any evidence of microangiopathic haemolytic anaemia, such as rapidly falling haemoglobin with concomitant thrombocytopenia, elevation of serum bilirubin, serum creatinine, blood urea nitrogen, or LDH.

Renal failure may not be reversible with discontinuation of therapy and dialysis may be required. Renal toxicity 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 […]

5) • patients with a history of severe allergic reaction to carboplatin or other platinum containing compounds. 2).