Cisplasan

Cisplasan

cisplatin

Manufacturer:

Sanbe
Full Prescribing Info
Contents
Cisplatin.
Description
Each mL injection contains: Cisplatin 1 mg.
Action
Pharmacology: Cisplatin is a heavy metal complex containing a central atom of platinum surrounded by two chloride atoms and two ammonia molecules in the cis positions. It is an anti-cancer drug with biochemical properties similar to bi-functional alkylating agents producing inter-strand and intra-strand cross links in DNA; It is cell-cycle non-specific. After a single i.v. dose, Cisplatin concentrates in liver, kidney and large and small intestines.
It has poor penetration into the CNS. More than 90% of the drug is bound to plasma protein.
The distribution half-life ranges from 58 to 73 hours.
Cisplatin excreted primarily in the urine, although urinary excretion is incomplete with only 27 to 43% of the dose being excreted within the first 5 days post-dose.
Indications/Uses
CISPLASAN is indicated as palliative therapy either alone or in combination with other approved chemotherapeutic against and in patients who have already received appropriate surgical and/or radio therapeutic procedures in the management of metastatic testicular tumors or metastatic ovarian tumors and advanced bladder cancer.
Dosage/Direction for Use
Do not use needles or i.v. sets containing aluminium parts because Al reacts with CISPLASAN. Causing precipitate formation and a loss of potency.
Prehydration therapy: A prehydration therapy is required 8-12 hours before the CISPLASAN administration. This consist of 1-2 L physiological saline solution per m2 body surface area (BSA) per infusion over at least 2-3 hours.
Cisplatin administration: Short-term infusion: i.v. Infusion over 15 minutes. The CISPLASAN dose to be administered is given immediately following an i.v. administration of 62.5 mL 20% mannitol solution.
Long-term infusion: i.v. Infusion over 1-8 hours. The CISPLASAN dose to be administered is diluted with 1- 2 L physiological saline solution.
The solution can contain 50 g glucose and 18.75 g mannitol/L.
Dosages of monochemotherapy: 50-120 mg CISPLASAN per m2 BSA at 3-4 weeks intervals; or 50 mg CISPLASAN per m2 BSA on day 1 and 8 at 3-4 weeks intervals; or 15-20 mg CISPLASAN per m2 BSA on day 1-5 at 3-4 weeks intervals. CISPLASAN is generally administered in chemotherapeutics combinations in which the dose is accordingly reduced.
Post hydration therapy: Adequate fluids must be given during the period after the CISPLASAN administration, i.e. in the (6-12) 24 hours following the drug administration (this consist of 2-31 physiological saline solution/m2 BSA together with a 5% glucose solution at a ratio 1:1.5). The urine volume during the post hydration should be at least 100-200 mL/h. A forced diuresis must be induced in the case of inadequate excretion.
Forced diuresis: For patients who have received proper prehydration and posthydration therapy and CISPLASAN doses below 60 mg/m2 BSA, and who have normal renal function, the administration of mannitol to induce a diuresis can be replaced by careful balancing and weight control. Mannitol must be administered when the retention ≥ 1000 mL.
For CISPLASAN doses above 60 mg/m2 BSA, mannitol administration (8 g/m2) BSA is obligatory immediately prior to the first CISPLASAN administration. Only after the onset of a minimal diuresis of 250 mL within 30 minutes may the CISPLASAN administration be started.
During the therapy with CISPLASAN, attention must be paid to electrolyte losses, namely losses of potassium, magnesium, and calcium and an appropriate replacement therapy must be carried out as required. An adequate antiemetic therapy best with serotonin-receptor antagonist with or without dexamethasone, is to be carried out as required. Larger fluid losses, resulting from vomiting or diarrhea are to be replaced.
Various therapy regimens recommended the following dose reductions for patients with impaired renal failure: Serum creatinine ≤ 2 mg/dL: No reduction in the CISPLASAN dose, some therapy regimens recommend a dose reduction of a 50% of the standard dose already in the serum creatinine range 1.5-2 mg/dL. The clinical benefits and risks must be assessed here individually. It is particularly important to also differentiate between the benefit-risk relationship of a CISPLASAN administration in patients with healthy kidneys by whom renal function impairment are observed after CISPLASAN administration, and the benefits and risks involved with such a treatment in patients with preexisting renal impairment.
Serum creatinine ≥ 2 mg/dL: Stop the CISPLASAN therapy until the serum creatinine is again ≤ 2 mg/dL. If the recovery phase until reaching this value takes longer than 6 weeks, then an alternative treatment with an other cytostatic agent is to be started. CISPLASAN administrated as an intravenous infusion.
As with other potentially toxic compounds, handle the solution of CISPLASAN with caution. Accidental exposure to CISPLASAN may cause skin reaction. The use of gloves is recommended. If CISPLASAN powder or solution contact with skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water.
Overdosage
In the event of an overdosage, the described side effects are more intense. As a rule, bone marrow toxicity predominates. An overdose is potentially lethal and leads to the following symptoms, among other: Liver failure, deafness, ocular toxicity (including retinal detachment), incontrollable vomiting or retching and/or neuritis. A direct influence on the respirator center with life-threatening impaired ventilation and acid-base imbalances is possible with an overdose (≥ 200 mg/m2 BSA) due to the crossing of the blood-brain barrier.
Therapeutic measures for overdose: There is not known specific antidote against Cisplatin. The immediate, emergency measures to be taken in the event of severe intolerance reactions consist of withdrawing the therapy immediately, symptomatic treatment and shock therapy if required.
The following individual counter measures are recommended: Renal function impairment: The frequency and severity of renal function impairments can be substantially reduced through adequate hydration before and after the administration (see Dosage & Administration). Modulators, such as Sodium thiosulphate can be applied to reduce the nephrotoxic effect of Cisplatin.
Hyperuricaemia: Elevated serum uric acid levels can be lowered by administering Allopurinol.
Plasma electrolyte losses: Clinically relevant electrolyte losses (mostly sodium, magnesium and calcium) can be compensated by appropriate electrolyte replacement therapy.
Anaphylactic reactions: Symptomatic treatment, e.g. with sympathomimetics, corticoids and antihistamines.
Dialysis: Over 90% of the Cisplatin administered is bound to plasma proteins 2 hours after the administration. Due to the rapid protein binding, Cisplatin is dialyzable only in the first 2 hours after the administration. Approximately 8% of the administered dose can be removed from the plasma via dialysis immediately after administration.
Contraindications
Preexisting renal impairment, Myelosupressed patients, Hearing impairment, Hypersensitivity to Cisplatin or other platinum containing compounds.
Special Precautions
Administer Cisplatin under the supervision of qualified physician experienced in the use of anti-cancer agents.
Cisplatin procedures cumulative renal toxicity which is severe and potentiated by aminoglicoside antibiotics. Therefore, measure the serum creatinine, BUN, creatinine clearance, and Mg, K, and Ca levels prior to initiating therapy, and prior to each subsequent course. At the recommended dosage, do not give this drug more frequently than once every 3-4 weeks.
Since the ototoxicity of Cisplatin is also cumulative, perform audiometric testing prior to initiating therapy and prior to each subsequent dose of drug.
Cisplatin also causes dose-related myelosuppression. Peripheral blood counts should be monitored weekly.
Anaphylactic-like reactions to Cisplatin have occurred in patients with prior exposure to this drug, and have been alleviated by administration of Epinephrine, corticosteroids and antihistamines.
Cisplatin may cause severe neuropathies and these may be irreversible in some patients. Neurologic examination should be performed regularly.
Liver function should also be monitored periodically; elevated SGOT may occur.
Safe use in human pregnancy has not established. In mice, Cisplatin is teratogenic and embryotoxic.
Adverse Reactions
Nephrotoxicity: This adverse reaction is dose related and cumulative to renal insufficiency associated with renal tubular damages by the major dose-limiting toxicity of Cisplatin. A single dose of 50 mg/m2 has caused renal toxicity in 28-36% of patients. Elevations in BUN and creatinine, serum uric acid and/or a decrease in creatinine clearance are first note during the second week after the dose. Renal function must return to normal before another dose of Cisplatin can be given.
Ototoxicity: Ototoxicity is manifested by tinnitus and/or hearing loss in the high frequency range. Decreased ability to hear normal conversational tones may occur occasionally. Hearing loss can be unilateral or bilateral. A single dose of 50 mg/m2 has caused ototoxicity in up to 31% of patients. Cisplatin induced ototoxicity is a cumulative, may be more severe in children, and it is unclear whether reversible or not.
Hematologic: Dose-related myelosuppression occurs in 25-30% of patients. The lowest platelet and leukocyte counts occur between days 18 to 23 (ranges 7.5 to 45). Most patients recover by day 39 (range 13 to 62). Anemia (decrease of > 2 g Hb/100 mL) occurs at approximately the same frequency and with the same timing as leucopenia and thrombocytopenia.
Gastrointestinal: Marked nausea and vomiting occur in almost all patients, and are occasionally so severe that the drug must be discontinued. Nausea and vomiting usually begin within 1- 4 hours after treatment and last up to 24 hours. Various degrees of nausea and anorexia may persist up to one week after treatment.
Neurotoxicity: This reaction has occurred in some patients. It is usually manifested by peripheral neuropathies and rarely by optic neuritis, papilledema, cerebral blindness, loss of appetite and seizures. Cisplatin induced neuropathies may occur after prolonged therapy (4-7 months), but may also occur after a single dose. The drug should not be continued when the symptoms are first observed. Improvement and/or total recovery usually occurs. In some patients, however peripheral neuropathy may be irreversible.
Anaphylactic-like reactions: The reaction has been occasionally reported in patients previously exposed to Cisplatin. The reactions consist of facial edema, wheezing tachycardia and hypotension within a few minute of drug administration.
Disturbances of serum electrolyte: Hypocalcemia, hypokalemia and hypophosphatemia have occurred and probably related to renal tubular damage. Tetany has occasionally accompanied hypocalcemia and hypomagnesemia. Discontinuation usually restores the serum electrolyte levels to normal.
Hyperuricemia: Hyperuricemia occurs at approximately the same frequent as the increased in BUN and serum creatinine. It peaks between 3 to 5 days after the dose. Allopurinol therapy effectively reduces uric acid levels.
Other toxicities which rarely occurred are cardiac abnormalities, anorexia and elevated SGOT.
Drug Interactions
An increased bone marrow toxicity must be expected when combined with other myelosuppressants or therapeutic measures such as radiotherapy. Nephrotoxic and ototoxic substances (e.g. Aminoglycoside, Amphotericine-β) must not be administered concomitantly with Cisplatin since an increased nephrotoxicity and ototoxicity is to be expected also in this case.
Chelating agents such as Penicillamine should not be administered concomitantly with Cisplatin since the combination lowers the efficacy of Cisplatin.
Due to a possibly reduced renal excretion, substances which are eliminated primarily via the kidneys among other cytostatic agents such as Bleomycin and Methotrexate should only be administered with special care during or after the treatment with cisplatin.
A randomized study of advanced ovarian cancer showed that simultaneous administration of Pyridoxine and Hexamethylamine negatively influenced the therapeutic response.
A Raynaud's phenomenon can occur when Cisplatin is combined with Bleomycin or Vinblastine. Concomitant treatment with anti-convulsants can result in their plasma concentrations dropping to the subtherapeutics range (adjust dose is require).
The combination of Cisplatin and Docetaxel caused neuropathy, which was more pronounced than that of the single agents at similar dosage.
Cisplatin exerts and immunosuppressive effect: vaccinations with live vaccines should be avoided in patients on Cisplatin therapy.
Please keep in mind that this information can also apply to drugs taken a short-time ago.
Storage
Store below 25°C, away from light. Do not freeze.
ATC Classification
L01XA01 - cisplatin ; Belongs to the class of platinum-containing antineoplastic agents. Used in the treatment of cancer.
Presentation/Packing
Inj (vial) 1 mg/mL x 50 mL x 1's.
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