APPROVED PACKAGE INSERT P&U CISPLATIN CSV RANGE

Transcription

1 Approved PI: 24 Aug 2012 Page 1 of 12 APPROVED PACKAGE INSERT P&U CISPLATIN CSV RANGE SCHEDULING STATUS: S4 PROPRIETARY NAME (and dosage form): P&U CISPLATIN CSV 10 mg/10 ml INJECTION P&U CISPLATIN CSV 50 mg/50 ml INJECTION P&U CISPLATIN CSV 100 mg/100 ml INJECTION COMPOSITION: Each 1 ml contains 1,0 mg cisplatin. PHARMACOLOGICAL CLASSIFICATION: A 26 Cytostatic agents PHARMACOLOGICAL ACTION: CISPLATIN is a platinum co-ordination compound with antitumour properties. The platinum complexes can react with DNA forming both interstrand and intrastrand DNA cross links. In addition to its reactivity with DNA, CISPLATIN can react with other nucleophiles, such as sulfhydryl groups of proteins. There is no phase specificity in the action of CISPLATIN on the cell cycle. With rapid intravenous administration the medicine has an initial half-life in plasma of minutes; concentrations decline subsequently with a half-life of hours. More than

2 Approved PI: 24 Aug 2012 Page 2 of % of the platinum in the blood is bound to plasma proteins. High concentrations of CISPLATIN are found in the kidney, liver, intestine and testes, but there is poor penetration into the central nervous system. INDICATIONS: P&U CISPLATIN CSV is indicated for advanced, non-seminomatous testicular cancer in combination therapy with bleomycin and vinblastine. Carcinoma of the ovary, particularly when used with cyclophosphamide or doxyrubicin. Cancers of the bladder, head and neck, endometrium, small cell carcinoma of the lung, lymphomas and some neoplasms of childhood. CONTRA-INDICATIONS: Hypersensitivity to P&U CISPLATIN CSV or any other platinum containing product. P&U CISPLATIN CSV is contra-indicated in renal or hearing impairment or bone marrow depression. Pregnancy and lactation (See Pregnancy and Lactation). The use of live vaccines is contra-indicated in patients receiving P&U CISPLATIN CSV. WARNINGS: P&U CISPLATIN CSV should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available. Peripheral blood counts must be monitored closely. Blood counts, at the beginning of therapy and weekly, to assess haematological nadir for dose adjustment are recommended.

3 Approved PI: 24 Aug 2012 Page 3 of 12 Neurological evaluations should also be performed prior to initiation and at periodic intervals during therapy. Treatment should be stopped if signs of peripheral neuropathies, including optic neuritis, papilloedema, cerebral blindness and seizures develop. Because of cumulative nephrotoxicity, creatinine clearance and serum creatinine concentrations and blood urea should be measured prior to initiation of therapy and before each course of P&U CISPLATIN CSV to detect renal toxicity. Since ototoxicity is cumulative, an audiometric test must be performed prior to each dose. The concomitant use of other nephrotoxic or ototoxic medicines should be avoided. Because of the possibility of carcinogenicity and mutagenicity, patients of child bearing age or conceiving potential must exercise non-hormonal conception control. INTERACTIONS: P&U CISPLATIN CSV is mostly used in combination with antineoplastic medicines having similar cytotoxic effects. In these circumstances additive toxicity is likely to occur. Other known drug interactions are reported below: Nephrotoxic medicines: Aminoglycoside antibiotics, when given concurrently or within1-2 weeks after P&U CISPLATIN CSV administration, may potentiate its nephrotoxic effects. Furosemide, ethacrinic acid, hydralazine and propanolol may increase nephrotoxicity. Concomitant use of other potentially nephrotoxic medicines (e.g. amphotericin B) is not recommended during P&U CISPLATIN CSV therapy. Ototoxic medicines: Concurrent and/or sequential administration of ototoxic medicines such as aminoglycoside antibiotics or loop diuretics may increase the potential of P&U CISPLATIN CSV to cause ototoxicity, especially in the presence of renal impairment.

4 Approved PI: 24 Aug 2012 Page 4 of 12 Antihistamines, buclizine, cyclizine, loxapine, meclizine, phenothiazines, thioxanthenes or trimethobenzamide may mask the symptoms of ototoxicity. Renally excreted medicines: P&U CISPLATIN CSV may alter the renal elimination of bleomycin and methotrexate (possibly as a result of cisplatin-induced nephrotoxicity) and enhance their toxicity. Anticonvulsant agents: In patients receiving P&U CISPLATIN CSV and phenytoin, serum concentrations of the latter may be decreased, possibly as a result of decreased absorption and/or increased metabolism. In these patients, serum levels of phenytoin should be monitored and dosage adjustments made as necessary. Antigout agents: P&U CISPLATIN CSV may raise the concentration of blood uric acid. Thus, in patients concurrently receiving antigout agents such as allopurinol, colchicine, probenecid or sulfinpyrazone, dosage adjustment of these medicines may be necessary to control hyperuricemia and gout. Combinations of the following medications may also interact with P&U CISPLATIN CSV, the reaction is dose dependent: Blood dyscrasia causing medications, bone marrow depressants (particularly adriamycin) or radiotherapy and killed virus vaccines. The use of live vaccines is contra-indicated in these patients. P&U CISPLATIN CSV is rapidly degraded by bisulphite or metabisulphate and admixtures with preparations containing these as preservatives may result in loss of activity. Mixtures with sodium bicarbonate, potassium chloride and/or etoposide may cause precipitation of P&U CISPLATIN CSV. Stability of P&U CISPLATIN CSV when mixed with fluorouracil is limited. PREGNANCY AND LACTATION:

5 Approved PI: 24 Aug 2012 Page 5 of 12 The safety of P&U CISPLATIN CSV in pregnancy has not been established. P&U CISPLATIN CSV can cross the placental barrier. P&U CISPLATIN CSV has been shown to be teratogenic, embryotoxic and carcinogenic in mice. Therefore P&U CISPLATIN CSV is contraindicated for use in pregnant women (See Contraindications). Males undergoing P&U CISPLATIN CSV treatment should use barrier contraceptive measures. Breast-feeding is not recommended during therapy. DOSAGE AND DIRECTIONS FOR USE: The physician should in all cases be familiar with the current literature before choosing a specific dosage. P&U CISPLATIN CSV is given by intravenous infusion not more frequently than every 3 to 4 weeks. It is usually given as a single dose of 50 to 120 mg per m 2 bodysurface or in a dose of 15 to 20 mg per m 2 daily for 5 days. Subsequent doses should be adjusted according to the nadir of the white-blood cell and platelet counts or before renal function approaches normal. Auditory acuity must also be within normal limits. Lower doses may be required when P&U CISPLATIN CSV is given as part of a combination regimen and may range from 20 mg per m 2 upwards every 3 to 4 weeks. In order to prevent renal toxicity, hydration of the patient is recommended by infusion of 1 to 2 litres of suitable fluid containing 37,5g mannitol for intravenous infusion for 8 to12 hours before administration of P&U CISPLATIN CSV. Adequate hydration and urinary output must be maintained before and for 24 hours after administration. Concurrent furosemide may also be used provided that salt and water depletion are avoided. Any solution not used must be discarded. Dosage adjustments are needed in cases of impaired renal function, elderly patients or use in combination with other myelosuppressive agents.

6 Approved PI: 24 Aug 2012 Page 6 of 12 Note: P&U CISPLATIN CSV is incompatible with aluminium; do not use needles, intravenous sets or equipment containing aluminium for administration since an interaction may occur and a black precipitate will form. Guidelines for handling of antineoplastic agents must be followed. Cautious and proper disposal of needles, syringes, containers and unused medication must be done. SIDE-EFFECTS AND SPECIAL PRECAUTIONS: Many of the adverse effects of P&U CISPLATIN CSV are an extension of their therapeutic action, which is not selective for malignant cells, but affects all rapidly-dividing cells. In consequence, adverse effects may be expected where normal cell division is fairly rapid, e.g. the bone marrow, lymphoreticular tissue, gastro-intestinal mucosa, skin and gonads, as well as in the foetus. Serious toxic effects on the kidneys, bone-marrow and ears, occur. These effects are generally dose related and cumulative, and may require dose adjustment. Blood and lymphatic system disorders: Very Common: Leukopenia, thrombocytopenia, anaemia Anaemia, leucopenia, thrombocytopenia is the result of dose related and reversible myelosuppression. With leucopenia and thrombocytopenia, the leukocyte and platelet counts reach a nadir between 18 and 23 days after a dose, with recovery within 39 days. Coombs positive haemolytic anaemia has also been reported. There have been rare reports of acute myelogenous leukemias and myelodysplastic syndromes arising in patients who have been treated with P&U CISPLATIN CSV, mostly when given in combination with other potentially leukemogenic agents. Renal and urinary disorders:

7 Approved PI: 24 Aug 2012 Page 7 of 12 Very common: Acute Renal toxicity Frequency unknown: Renal failure Damage to the renal tubules may be evident during the second week after a dose of P&U CISPLATIN CSV. It is generally dose related and cumulative, but may become irreversible at high doses or with repeated treatments and is occasionally fatal. Intensive hydration may ameliorate nephrotoxic effects. Electrolyte disturbances, particularly hypomagnesemia and hypocalcemia may occur, possibly as a result of renal tubular damage. The destruction of large numbers of cells during therapy and the consequent release of breakdown products may also lead to problems with hyperuricaemia and acute renal failure due to uric acid nephropathy. High or repeated P&U CISPLATIN CSV doses can increase the severity and duration of renal impairment and may produce irreversible renal insufficiency. Renal failure has been reported following intraperitoneal instillation of the medicine. The concomitant use of other nephrotoxic components should be avoided. Gastrointestinal disorders: Very common: Nausea, vomiting Frequency unknown: Gingival platinum line Severe nausea and vomiting occur in most patients 1 to 4 hours after a dose and may persist for up to a week. It may be treated or prevented by antiemetic medication. The severity of these symptoms may be reduced by dividing the total dose per cycle into smaller doses given once daily for five days (See Dosage and Directions for Use). Reported toxicity includes gingival platinum line. Immune system disorders: Common: Anaphylactic reaction

8 Approved PI: 24 Aug 2012 Page 8 of 12 An allergic reaction can occur within minutes of administration and includes dizziness or fainting, fast heartbeat, swelling of face and wheezing and should be treated with supportive therapy. Anaphylactic reactions can occur and supportive treatment should be available. Metabolism and nutrition disorders: Very common: Hypomagnesaemia, hyponatraemia Common: Hypocalcemia Frequency unknown: Hypokalaemia, hyperuricaemia P&U CISPLATIN CSV may cause serious electrolyte disturbances, mainly represented by hypomagnesaemia, hypocalcaemia and hypokalaemia, and associated with renal tubular dysfunction. Hypomagnesaemia and/or hypocalcaemia may become symptomatic, with muscle irritability or cramps, clonus, tremor, carpopedal spasm, and/or tetany. Other reported toxicities are hyperuricaemia, hyponatraemia and syndrome of inappropriate antidiuretic hormone (SIADH). Nervous system disorders: Common: Peripheral neuropathies, cerebrovascular accident Frequency unknown: Autonomic neuropathy, seizures, slurred speech, loss of taste, memory loss Peripheral neuropathies occur infrequently with usual doses of P&U CISPLATIN CSV. These are generally sensory in nature (e.g. paraesthesia of the upper and lower extremities) but can also include motor difficulties, reduced flexes and leg weakness. Autonomic neuropathy, seizures, slurred speech, loss of taste and memory loss have also been reported. These neuropathies usually appear after prolonged therapy, but have also developed after a single drug dose. Peripheral neuropathy may be reversible in some patients; however, it has been

9 Approved PI: 24 Aug 2012 Page 9 of 12 partially or completely reversible in others following discontinuance of P&U CISPLATIN CSV therapy. Central neurotoxicity includes focal encephalopathy, seizures, aphasia and cortical blindness. Cerebrovascular accident has been reported in patients treated with P&U CISPLATIN CSV. Eye disorders: Frequency unknown: Papilloedema, cortical blindness, optic neuritis These events may be reversible after withdrawal of the medicine. Ear and labyrinth disorders: Common: Tinnitus Unilateral or bilateral tinnitus, with or without hearing loss, occurs in about 10% of P&U CISPLATIN CSV-treated patients and is usually reversible. The damage to the hearing system appears to be dose-related and cumulative, and it is reported more frequently in very young and very old patients. Vestibular toxicity can occur. Cardiac disorders: Common: Cardiovascular abnormalities Respiratory, thoracic and mediastinal disorders: Frequency unknown: Pulmonary toxicity Pulmonary toxicity has been reported in patients treated with cisplatin in combination with bleomycin or 5-fluorouracil. Hepatobiliary disorders: Frequency unknown: Serum AST level elevation, serum ALT level elevations Skin and subcutaneous tissue disorders: Very common: Mild alopecia Frequency unknown: Urticarial or maculopapular skin rash, skin necrosis

10 Approved PI: 24 Aug 2012 Page 10 of 12 Musculoskeletal and connective tissue disorders: Frequency unknown: Myalgia Reproductive system and breast disorders: Very common: Azoospermia Frequency unknown: Impairment of spermatogenesis P&U CISPLATIN CSV can affect male fertility. Although the impairment of spermatogenesis can be reversible, males undergoing P&U CISPLATIN CSV treatment should be warned about the possible adverse effects on male infertility. General disorders and administration site conditions: In addition, P&U CISPLATIN CSV is an irritant or vesicant, and produces local pain, irritation, and inflammation at the administration site; extravasation may lead to ulceration and necrosis. Stomatitis secretion and loss of appetite has also been reported. Special Precautions: Bone marrow function: Peripheral blood counts should be monitored frequently in patients receiving P&U CISPLATIN CSV. Although the haematologic toxicity is usually moderate and reversible, severe thrombocytopenia and leukopenia may occur. In patients who develop thrombocytopenia special precautions are recommended: care in performing invasive procedures; search for signs of bleeding or bruising; test of urine, stools and emesis for occult blood; avoiding aspirin and other NSAIDs. Patients who develop leukopenia should be observed carefully for signs of infection and might require antibiotic support and blood product transfusions. CNS Functions: P&U CISPLATIN CSV is known to induce neurotoxicity; therefore neurologic examination is warranted in patients receiving a cisplatin-containing treatment. Since

11 Approved PI: 24 Aug 2012 Page 11 of 12 neurotoxicity may result in irreversible damage, it is recommended to discontinue therapy with P&U CISPLATIN CSV when neurologic toxic signs or symptoms become apparent. Immunosuppressant effects/increased susceptibility to infections: Administration of live or liveattenuated vaccines in patients immunocompromised by chemotherapeutic agents including P&U CISPLATIN CSV, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving P&U CISPLATIN CSV. Killed or inactivated vaccines may be administered; however the response to such vaccines may be diminished. KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT: See "Side-effects and Special Precautions". Treatment should be symptomatic and supportive. IDENTIFICATION: Clear, colourless to pale yellow liquid, free from particles. PRESENTATION: P&U CISPLATIN CSV 10 mg/10 ml INJECTION: Cartons with either 1 x 10 ml or 5 x 10 ml single dose plastic vials, each containing 1 mg CISPLATIN per ml solution. P&U CISPLATIN CSV 50 mg/50 ml INJECTION: A single dose plastic vial containing 1 mg CISPLATIN per ml solution. P&U CISPLATIN CSV 100 mg/100 ml INJECTION: A single dose plastic vial containing 1 mg CISPLATIN per ml solution. STORAGE INSTRUCTIONS:

12 Approved PI: 24 Aug 2012 Page 12 of 12 Store at room temperature below 25 0 C. Do not refrigerate. Protect from light. Any unused portion must be discarded. Keep out of reach of children. REGISTRATION NUMBERS: P&U CISPLATIN CSV 10 mg/10 ml INJECTION: 30/26/0328 P&U CISPLATIN CSV 50 mg/50 ml INJECTION: 30/26/0329 P&U CISPLATIN CSV 100 mg/100 ml INJECTION: 30/26/0330 NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION: Pfizer Laboratories (Pty) Ltd 85 Bute Lane Sandton 2196 South Africa DATE OF PUBLICATION OF THIS PACKAGE INSERT: 3 June 2011