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Cisplatin

Pronunciation

Pronunciation: SIS-plat-in
Class: Platinum coordination complex

Trade Names

Platinol AQ
- Solution for injection 1 mg/mL
- Powder for injection 1 mg/mL

Pharmacology

The antitumor effect of cisplatin has been correlated with binding to DNA, production of intrastrand crosslinks, and formation of DNA adducts.

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Distribution

Vd is about 11 to 12 L/m 2 (steady state). Platinum is 90% protein bound. Cisplatin is excreted in breast milk.

Elimination

The t ½ is about 20 to 30 min (cisplatin) and at least 5 days (platinum-albumin complexes). Cl is about 15 to 16 L/h/m 2 . Renal Cl is 50 to 62 mL/min/m 2 . Cisplatin is 90% excreted in urine and less than 10% removed by biliary excretion.

Indications and Usage

Metastatic testicular or ovarian tumors, advanced bladder cancer.

Unlabeled Uses

Squamous cell carcinoma of the head and neck and of the cervix; lung carcinomas, osteogenic sarcoma, brain tumors; advanced esophageal, adrenal cortex, breast, endometrial, and liver carcinoma, bone marrow transplantation.

Contraindications

Pre-existing renal impairment; myelosuppression; hearing impairment; history of allergic reactions to cisplatin or other platinum-containing compounds.

Dosage and Administration

Metastatic Testicular Tumors
Adults

IV Cisplatin 20 mg/m 2 /day IV for 5 days every 3 wk for 3 courses (combination regimen). Single doses of cisplatin up to 120 mg/m 2 in combination with other antineoplastics have been used.

Metastatic Ovarian Tumors (Cyclophosphamide Combination Therapy)
Adults

IV Cisplatin 75 to 100 mg/m 2 once every 4 wk. Cyclophosphamide 600 mg/m 2 once every 4 wk (day 1).

Metastatic Ovarian Tumors (Single Agent Therapy)
Adults

IV Administer as a single agent of 100 mg/m 2 IV/cycle once every 4 wk.

Advanced Bladder Cancer
Adults

IV Administer as a single agent. Give 50 to 70 mg/m 2 once every 3 to 4 wk, depending on prior radiation therapy or chemotherapy. For heavily pretreated patients, give an initial dose of 50 mg/m 2 /cycle repeated every 4 wk.

Repeat Courses
Adults

IV Do not give a repeat course until serum creatinine is below 1.5 mg/dL or BUN is below 25 mg/dL or until circulating blood elements are at an acceptable level (platelets at least 100,000/mm 3 , WBC at least 4,000/mm 3 ). Do not give subsequent doses until an audiometric analysis indicates that auditory acuity is within normal limits.

Renal Impairment
Adults

IV The manufacturer does not recommend the use of cisplatin in patients with renal impairment. Some clinicians recommend not giving cisplatin to patients with a Ccr below 30 mL/min.

General Advice

  • If not protected from light, reconstituted cisplatin solution is stable for 6 h at room temperature.
  • Cisplatin degrades and forms a black precipitate on contact with aluminum. Although needles and administration sets rarely contain aluminum, consider this interaction if a black precipitate is observed.
  • Reconstitute powder with 50 mL of sterile Water for Injection or Bacteriostatic Water for Injection for a final concentration of 1 mg/mL. The resulting solution should be clear and colorless.
  • Skin reactions associated with accidental exposure may occur. Use gloves. If solution contacts skin or mucosa, wash immediately and thoroughly with soap and water and flush mucosa with water.
  • The manufacturer recommends further dilution in 2 L of solution containing 37.5 g mannitol, using dextrose 5% with sodium chloride 0.45%. More concentrated solutions, up to a max concentration of 0.7 mg/mL have been used. Cisplatin (up to 200 mg) may also be diluted in 500 mL of sodium chloride 0.9% with 12.5 to 25 g mannitol.
  • The administration of cisplatin using a 6- to 8-h infusion with IV hydration and mannitol has been used to reduce nephrotoxicity.
  • Delayed emesis typically occurs 24 to 72 h after cisplatin administration. Severity may be reduced by administration of a prophylactic regimen of dexamethasone in combination with metaclopramide or prochlorperazine. Begin prophylactic therapy 16 to 24 h after cisplatin administration and continue for a total of 4 days. Add additional antiemetics if breakthrough nausea and vomiting occur.

Storage/Stability

  • Store at 59° to 77°F. Protect unopened container from light. Do not refrigerate. The cisplatin remaining in the amber vial following initial entry is stable for 28 days protected from light or for 7 days under fluorescent room light.
  • Cisplatin powder reconstituted with Bacteriostatic Water for Injection is chemically stable for 3 days at room temperature with protection from light.
  • Cisplatin and fluorouracil admixtures are stable in normal saline 0.9% for 1 h.

Drug Interactions

Aminoglycosides

Potentiation of nephrotoxicity is possible.

Lithium

Cisplatin may transiently decrease lithium serum levels.

Loop diuretics (eg, furosemide)

Potentiation of ototoxicity is possible.

Paclitaxel

Paclitaxel clearance decreases when cisplatin is given immediately prior to paclitaxel, resulting in increased hematologic toxicity.

Phenytoin

Cisplatin may decrease absorption or increase metabolism, resulting in lower serum levels of phenytoin.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

MI; cerebrovascular accident; cerebral arteritis; thrombotic microangiopathy.

CNS

Peripheral sensory neuropathy with a glove-and-stocking distribution.

GI

Nausea; vomiting; anorexia; transient LFT elevations.

Hematologic

Bone marrow suppression.

Hypersensitivity

Anaphylactic reaction.

Metabolic

Hypomagnesemia; hypocalcemia; hypokalemia; SIADH.

Renal

Dose-related and cumulative renal tubular damage.

Special Senses

Tinnitus; high frequency hearing loss.

Precautions

Warnings

Overdose/confusion with carboplatin

Doses above 100 mg/m 2 /cycle once every 3 to 4 wk rarely used. Avoid confusion with carboplatin or prescribing practices that fail to differentiate daily doses from total dose per cycle.

GI

Marked nausea and vomiting occur in almost all patients and are occasionally so severe that the drug must be discontinued.

Hematologic

Myelosuppression occurs in 25% to 30% of patients. Leukopenia and thrombocytopenia are more pronounced at doses above 50 mg/m 2 . Anemia (decrease of 2 g hemoglobin/dL) occur at the same frequency and with the same timing as leukopenia and thrombocytopenia.

Hypersensitivity

Anaphylactic-like reactions have occurred.

Ototoxicity

Has occurred in no more than 31% of patients given a single dose of 50 mg/m 2 . It is manifested by tinnitus or loss of high frequency hearing, and occasionally deafness. May be pronounced in children.

Renal toxicity

Dose-related and cumulative renal insufficiency is the major dose-limiting toxicity. This is manifested by elevations in BUN and creatinine, serum uric acid, or a decrease in Ccr. Renal toxicity becomes more severe and prolonged with repeated courses; therefore, renal function must return to normal before another dose can be given. Amifostine can be used to reduce renal toxicity in patients with advanced ovarian cancer receiving repeated doses of cisplatin.


Pregnancy

Category D .

Lactation

Reported to be found in breast milk. Do not breast-feed.

Children

Safety and efficacy not established.

Electrolyte disturbances

Hypomagnesemia, hypocalcemia, hyponatremia, hypokalemia, and hypophosphatemia have occurred and are probably related to renal tubular damage.

Extravasation risk

Local irritation or phlebitis may occur. Refer to your institution specific protocol.

Hepatotoxicity

Transient elevations of liver enzymes, especially AST, as well as bilirubin have been reported.

High/Cumulative doses

Muscle cramps, defined as localized painful, involuntary skeletal muscle contractions of sudden onset and short duration, have occurred.

Hyperuricemia

Occurs at about the same frequency as increase in BUN and serum creatinine. It is more pronounced after doses above 50 mg/m 2 . Monitor serum uric acid. Minimize effects with hydration, urinary alkalinization, and allopurinol.

Neuropathies

Neurotoxicity, usually characterized by peripheral neuropathy, have occurred. Severe neuropathies have occurred in patients receiving higher doses of cisplatin or greater dose frequencies than those recommended, or after prolonged therapy. Discontinue therapy when symptoms are observed.

Ophthalmic effects

Optic neuritis, papilledema, and cerebral blindness have occurred infrequently in patients receiving recommended cisplatin doses.

Vascular toxicities

These events are rare and coincident with the use of cisplatin in combination with other antineoplastic agents. These events may include MI, cerebrovascular accident, thrombotic microangiopathy, or cerebral arteritis.

Overdosage

Symptoms

Kidney failure, liver failure, deafness, ocular toxicity, significant myelosuppression, intractable nausea and vomiting, neuritis, death.

Patient Information

  • Advise patient, family, or caregiver that medication will be prepared and administered by health care provider in a health care setting.
  • Advise patient, family, or caregiver that medication may be used in combination with other agents to achieve maximum benefit possible.
  • Review dosing schedule with patient, family, or caregiver.
  • Advise patient, family, or caregiver to immediately report any of the following to health care provider: rash; hives; difficulty breathing; fever, chills or other signs of infection; sores in mouth; unusual bleeding or bruising.
  • Advise patient, family, or caregiver to report any of the following to health care provider: persistent nausea, vomiting or appetite loss; persistent or worsening general body weakness; changes in hearing or ringing in the ears; dizziness or feeling of whirling motion; abnormal skin sensations; any other unexplained sensation; pain, redness or swelling at injection site.

Copyright © 2009 Wolters Kluwer Health.

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