Kemoplat

Cisplatin.

KEMOPLAT 1 mg/ml contains cisplatin, which is a heavy metal complex containing a central atom of platinum surrounded by two chloride. It is chemically a cis isomer of diammine dichloro platinum (II).
KEMOPLAT is a sterile solution of Cisplatin 0.5 mg/ml (20 ml and 100 ml pack) or 1.0 mg/ml (10 ml and 50 ml pack), sodium chloride 9 mg/ml in Water for Injection.
Cisplatin has a molecular formula PtCI₂H₆N₂, and molecular weight of 300.1.

Pharmacology: Pharmacodynamics: Mechanism of action: KEMOPLAT 1 mg/ml is an antineoplastic agent with biochemical properties similar to those of bifunctional alkylating agents. Cisplatin enter cells by diffusion and binds covalently to DNA bases and disrupts DNA function. Hydrolysis of chloride in its structure is responsible for formation of activated species of the drug, which reacts with nucleic acids and protein. KEMOPLAT exerts its action by forming both intrastrand and interstrand cross-links of complementary strands of DNA, thus inhibiting DNA synthesis. Protein and RNA synthesis are also inhibited to a lesser extent. Its antineoplastic actions are not cell-cycle specific.
Pharmacokinetics: Plasma concentrations of the parent compound, cisplatin, decay monoexponentially with a half-life of about 20 to 30 minutes following bolus administrations of 50 or 100 mg/m² doses. Monoexponential decay and plasma half-lives of about 0.5 hour are also seen following two hour or seven hour infusions of 100 mg/m². After the latter, the total-body clearances and volumes of distribution at steady state for cisplatin are about 15 to 16 L/h/m² and 11 to 12 L/m². Due to its unique chemical structure, the chlorine atoms of cisplatin are more subject to chemical displacement reactions by nucleophiles, such as water or sulfhydryl groups, than to enzyme-catalyzed metabolism. Cisplatin does not undergo the instantaneous and reversible binding to plasma proteins that is characteristic of normal drug-protein binding. However, the platinum from cisplatin, but not cisplatin itself, becomes bound to several plasma proteins including albumin, transferrin, and gamma globulin. Three hours after a bolus injection and two hours after the end of a three-hour infusion, 90% of the plasma platinum is protein bound. The complexes between albumin and the platinum from cisplatin do not dissociate to a significant extent and are slowly eliminated with a minimum half-life of five days or more. Over a dose range of 40 to 140 mg cisplatin/m² given as a bolus injection or as infusions varying in length from 1 hour to 24 hours, from 10% to about 40% of the administered platinum is excreted in the urine in 24 hours. Over five days following administration of 40 to 100 mg/m² doses given as rapid, 2 to 3 hour, or 6 to 8 hour infusions, a mean of 35% to 51% of the dosed platinum is excreted in the urine. Similar mean urinary recoveries of platinum of about 14% to 30% of the dose are found following five daily administrations of 20, 30, or 40 mg/m²/day.
The parent compound, cisplatin, is excreted in the urine and accounts for 13% to 17% of the dose excreted within one hour after administration of 50 mg/m². The mean renal clearance of cisplatin exceeds creatinine clearance and is 62 and 50 mL/min/m² following administration of 100 mg/m² as 2 hour or 6 to 7 hour infusions, respectively. The renal clearance of free platinum is nonlinear and variable and is dependent on dose, urine flow rate, and individual variability in the extent of active secretion and possible tubular reabsorption. There is a potential for accumulation of ultra filterable platinum plasma concentrations whenever cisplatin is administered on a daily basis but not when dosed on an intermittent basis.

KEMOPLAT 1 mg/ml is indicated for following indications: Metastatic Testicular Cancer: In established combination therapy with other approved chemotherapeutic agents in patients with metastatic testicular tumors who have already received appropriate surgical and/or radio therapeutic procedures.
Metastatic Ovarian Cancer: In established combination therapy with other approved chemotherapeutic agents.
KEMOPLAT 1 mg/ml is used in patients with metastatic ovarian tumors who have already received appropriate surgical and/or radio therapeutic procedures. Also as a single agent, it is indicated as secondary therapy in patients with metastatic ovarian tumors refractory to standard chemotherapy who have not previously received cisplatin therapy.
Advanced Bladder Cancer: Cisplatin is indicated as a single agent for patients with transitional cell bladder cancer, which is no longer amenable to local treatments such as surgery and/or radiotherapy.

Metastatic Testicular Cancer: The usual dose for the treatment of testicular cancer in combination with other approved chemotherapeutic agents is 20 mg/m² I.V. daily for 5 days per cycle.
Metastatic Ovarian Cancer: The usual cisplatin dose for the treatment of metastatic ovarian cancer in combination with cyclophosphamide is 75-100 mg/m² I.V. per cycle once every 4 weeks. As a single agent cisplatin should be administered as 100 mg/m²/cycle I.V. every 4 weeks.
Advanced Bladder Cancer: Cisplatin should be administered as a single agent at a dose of 50-70 mg/m² I.V. per cycle once every 3 to 4 weeks depending on the extent of prior exposure to radiation therapy and/or prior chemotherapy. For heavily pretreated patients an initial dose of 50 mg/m² per cycle repeated every four weeks is recommended.
Pre Treatment Hydration: Patients should be adequately hydrated before and for 24 hrs. after KEMOPLAT 1 mg/ml administration in order to induce diuresis and minimize nephrotoxicity. Hydration may be achieved either by I.V. infusion of 2 liters of 0.9% sodium chloride or dextrose saline (Dextrose 5% in one fifth normal saline (0.18% Sodium chloride injection)) over a 6-12 hr. period. During the last 30 minutes of the pre treatment hydration or after the hydration, 375 ml of 20% mannitol injection may be administered via a side arm drip.
Preparation of KEMOPLAT 1 mg/ml infusion: KEMOPLAT 1 mg/ml should be added to 2 liters of 0.9% sodium chloride injection or Dextrose-Saline solution.
Treatment: Following pre-hydration, KEMOPLAT 1 mg/ml infusion is administered over 1-2 hrs. A longer infusion time of 6-8 hrs may decrease gastrointestinal and renal toxicities.
Post Treatment Hydration: It is recommended that I.V. hydration should continue after treatment with administration of 2 liters 0.9% sodium chloride I.V. infusion or Dextrose-saline over a period of 6-12 hours.
Note: Since aluminum reacts with and inactivates cisplatin, it is important not to use needles or other equipment that contain aluminum while preparing or administering KEMOPLAT 1 mg/ml.

Treatment: No proven antidotes have been established for cisplatin overdosage. Hemodialysis, even when initiated 4 hours after the overdosage, appears to have little effect on removing platinum from the body because of cisplatin's rapid and high degree of protein binding. Management of overdosage should include general supportive measures to sustain the patient through any period of toxicity that may occur.

Use of KEMOPLAT 1 mg/ml is contraindicated in patients with a history of hypersensitivity to cisplatin or other platinum containing compounds.
Cisplatin should not be used in patients with preexisting renal impairment, myelosuppressed patients or patients with hearing impairment.

Cisplatin produces cumulative nephrotoxicity, which is potentiated by aminoglycoside antibiotics. The serum creatinine, BUN, creatinine clearance, and magnesium, sodium, potassium, and calcium levels should be measured prior to initiating therapy, and prior to each subsequent course. At the recommended dosage, cisplatin should not be given more frequently than once every 3 to 4 weeks.
There are reports of severe neuropathies in patients in whom regimens are employed using higher doses of cisplatin or greater dose frequencies than those recommended. These neuropathies may be irreversible and are seen as paresthesias in a stocking-glove distribution, areflexia, and loss of proprioception and vibratory sensation. Loss of motor function has also been reported.
Anaphylactic-like reactions to cisplatin have been reported. These reactions have occurred within minutes of administration to patients with prior exposure to cisplatin, and have been alleviated by administration of epinephrine, corticosteroids, and antihistamines. Since ototoxicity of cisplatin is cumulative, audiometric testing should be performed prior to initiating therapy and prior to each subsequent dose of drug.
Cisplatin is a cytotoxic anticancer drug and should be administered only by physicians experienced with cancer chemotherapeutic drugs.
Cumulative and dose related renal insufficiency is the major dose limiting toxicity of cisplatin. Renal function must return to acceptable limits before further doses are given. Other major dose related toxicities are myelosuppression, nausea and vomiting.
Ototoxicity, which may be more pronounced in children and is manifested by tinnitus, and/or loss of high frequency hearing and occasionally deafness, is significant.
Anaphylactic like reactions to cisplatin have been reported and may occur within minutes of administration. Epinephrine, steroids and antihistamines have been effectively employed to alleviate symptoms.
Exercise caution to prevent inadvertent cisplatin overdose.
Carcinogenicity and Mutagenicity: The carcinogenic effect of cisplatin was studied in BD IX rats. Cisplatin was administered i.p. to 50 BD IX rats for 3 weeks, 3 x 1 mg/kg body weight per week. Four hundred and fifty-five days after the first application, 33 animals died, 13 of them related to malignancies; 12 leukemias and 1 renal fibrosarcoma. The development of acute leukemia coincident with the use of cisplatin has rarely been reported in humans. In these reports, cisplatin was generally given in combination with other leukemogenic agents.

Pregnancy: Category D.
Cisplatin can cause fetal harm when administered to a pregnant woman. KEMOPLAT 1 mg/ml is mutagenic in bacteria and produces chromosome aberrations in animal cells in tissue culture. Safe use in pregnancy has not been established. In mice cisplatin is teratogenic and embryotoxic.
Lactation: After I.V. administration, KEMOPLAT 1 mg/ml is rapidly distributed into tissues including breast milk. To avoid possible harmful effects, it is recommended that KEMOPLAT therapy should not be initiated in lactating mothers.

Clinical use of KEMOPLAT 1 mg/ml may be limited because of number of drug induced toxic reactions, their time course and frequency generally depending upon dose schedule.
Nephrotoxicity: Cumulative and dose related renal impairment is the major dose limiting adverse reaction. Renal toxicity has been noted in 28 to 36% of patients treated with a single dose of 50 mg/m². It is first noted during the second week after a dose and is manifested by elevations in BUN and creatinine, serum uric acid and/or a decrease in creatinine clearance. Renal toxicity becomes more prolonged and severe with repeated courses of the drug. Impairment of renal function has been associated with renal tubular damage.
Ototoxicity: Ototoxicity has been observed in up to 31% of patients treated with a single dose of cisplatin 50 mg/m², and is manifested by tinnitus and/or hearing loss in the high frequency range (4,000 to 8,000 Hz). Ototoxic effects may be more severe in children receiving cisplatin. Hearing loss can be unilateral or bilateral and tends to become more frequent and severe with repeated doses. Ototoxicity may be enhanced with prior or simultaneous cranial irradiation. Careful monitoring of audiometry should be performed prior to initiation of therapy and prior to subsequent doses of cisplatin.
Hematologic: Myelosuppression occurs in 25% to 30% of patients treated with cisplatin. The nadirs in circulating platelets and leukocytes occur between days 18 to 23 (range 7.5 to 45) with most patients recovering by day 39 (range 13 to 62). Leukopenia and thrombocytopenia are more pronounced at higher doses (>50 mg/m²). Anemia (decrease of 2 g hemoglobin/100 mL) occurs at approximately the same frequency and with the same timing as leukopenia and thrombocytopenia. Fever and infection have also been reported in patients with neutropenia. In the presence of cisplatin hemolytic anemia, a further course of treatment may be accompanied by increased hemolysis and this risk should be weighed by the treating physician. The development of acute leukemia coincident with the use of cisplatin has rarely been reported in humans.
Gastrointestinal: Marked nausea and vomiting occur in almost all patients treated with cisplatin, and are occasionally so severe that the drug must be discontinued. Nausea and vomiting usually begin within 1 to 4 hours after treatment and last up to 24 hours. Diarrhea has also been reported.
OTHER TOXICITIES: Vascular toxicities coincident with the use of cisplatin in combination with other antineoplastics agents have been reported rarely. The events are clinically heterogeneous and may include myocardial infarction, cerebrovascular accident, thrombotic microangiopathy (HUS), or cerebral arteritis.
Serum Electrolyte Disturbances: Hypomagnesemia, hypocalcemia, hyponatremia, hypokalemia, and hypophosphatemia have been reported to occur in patients treated with cisplatin and are probably related to renal tubular damage. Tetany has occasionally been reported in those patients with hypocalcemia and hypomagnesemia. Generally, normal serum electrolyte levels are restored by administering supplemental electrolytes and discontinuing cisplatin. Inappropriate antidiuretic hormone syndrome has also been reported.
Hyperuricemia: Hyperuricemia has been reported to occur at approximately the same frequency as the increases in BUN and serum creatinine. It is more pronounced after doses greater than 50 mg/m², and peak levels of uric acid generally occur between 3 to 5 days after the dose. Allopurinol therapy for hyperuricemia effectively reduces uric acid levels.
Neurotoxicity: Neurotoxicity, usually characterized by peripheral neuropathies, has been reported. The neuropathies usually occur after prolonged therapy (4 to 7 months); however, neurologic symptoms have been reported to occur after a single dose. Although symptoms and signs of cisplatin neuropathy usually develop during treatment, symptoms of neuropathy may begin 3 to 8 weeks after the last dose of cisplatin, although this is rare. Cisplatin therapy should be discontinued when the symptoms are first observed.
Ocular Toxicity: Optic neuritis, papilledema, and cerebral blindness have been reported infrequently in patients receiving standard recommended doses of cisplatin. Improvement and/or total recovery usually occurs after discontinuing cisplatin. Steroids with or without mannitol have been used; however, efficacy has not been established. Blurred vision and altered color perception have been reported after the use of regimens with higher doses of cisplatin or greater dose frequencies than those recommended in the package insert. The altered color perception manifests as a loss of color discrimination, particularly in the blue-yellow axis.
Anaphylactic-like Reactions: Anaphylactic-like reactions have been occasionally reported in patients previously exposed to cisplatin. The reactions consist of facial edema, wheezing, tachycardia, and hypotension within a few minutes of drug administration. Reactions may be controlled by intravenous epinephrine with corticosteroids and/or antihistamines as indicated.
Hepatotoxicity: Transient elevations of liver enzymes, especially SGOT, as well as bilirubin, have been reported to be associated with cisplatin administration at the recommended doses.

Plasma levels of anticonvulsant agents may become subtherapeutic during cisplatin therapy. Cisplatin produces cumulative nephrotoxicity that is potentiated by aminoglycosides.

Handling and Disposal: KEMOPLAT 1 mg/ml should be handled only by persons conversant with standard practices of handling and disposal of anticancer agents.
Use of 5 % sodium hypochlorite solution is recommended as neutralizing agent in cases of spills or leak of this solution.
Remnants of the medicinal product as well as all materials contamination must be destroyed according to cytotoxic agents with due regard to current laws related to the disposal of hazardous waste.

Store at a temperature between 15°C-25°C. Protect from light. Do not refrigerate.

Cytotoxic Chemotherapy

L01XA01 - cisplatin ; Belongs to the class of platinum-containing antineoplastic agents. Used in the treatment of cancer.

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