No

Antineoplastic Agent, Alkylating Agent

Treatment of head and neck, breast, testicular, and ovarian cancer; Hodgkin's and non-Hodgkin's lymphoma; neuroblastoma; sarcomas, bladder, gastric, lung, esophageal, cervical, and prostate cancer; myeloma, melanoma, mesothelioma, small cell lung cancer, and osteosarcoma

D

Hypersensitivity to cisplatin or any other platinum-containing compounds or any component, anaphylactic-like reactions have been reported; pre-existing renal insufficiency, myelosuppression, hearing impairment

The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered. All patients should receive adequate hydration prior to and for 24 hours after cisplatin administration, with or without mannitol and/or furosemide, to ensure good urine output and decrease the chance of nephrotoxicity; reduce dosage in renal impairment. Cumulative renal toxicity may be severe; dose-related toxicities include myelosuppression, nausea, and vomiting; cumulative ototoxicity, especially pronounced in children, is manifested by tinnitus or loss of high frequency hearing and occasionally, deafness. Serum magnesium, as well as other electrolytes, should be monitored both before and within 48 hours after cisplatin therapy. Patients who are magnesium depleted should receive replacement therapy before the cisplatin is administered.

>10%:

Endocrine & metabolic: Hyperuricemia

Gastrointestinal: Cisplatin is one of the most emetogenic agents used in cancer chemotherapy; nausea and vomiting occur in 76% to 100% of patients and is dose related. Prophylactic antiemetics should always be prescribed; nausea and vomiting may last up to 1 week after therapy. Antiemetics should be included in discharge medications.

Emetic potential:

<50 mg/m²: Moderately high (60% to 90%)

greater than or equal to 50 mg/m²: High (>90%)

Time course of nausea/vomiting: Onset: 1-4 hours; Duration: 12-96 hours

Hematologic: Myelosuppressive: Mild with moderate doses, mild to moderate with high-dose therapy

WBC: Mild

Platelets: Mild

Onset (days): 10

Nadir (days): 14-23

Recovery (days): 21-39

Anemia: Can be chronic, when high dose cisplatin is given for multiple cycles which is responsive to epoetin alfa. Cisplatin has also been associated with Coombs' positive hemolytic anemia.

Neuromuscular & skeletal: Neurotoxicity: Peripheral neuropathy is dose- and duration-dependent. The mechanism is through axonal degeneration with subsequent damage to the long sensory nerves. Toxicity can first be noted at doses of 200 mg/m², with measurable toxicity at doses >350 mg/m². This process is irreversible and progressive with continued therapy. Ototoxicity occurs in 10% to 30%, and is manifested as high frequency hearing loss. Baseline audiography should be performed.

Otic: Ototoxicity (especially pronounced in children)

Renal: Nephrotoxicity: Related to elimination, protein binding, and uptake of cisplatin; two types of nephrotoxicity: acute renal failure and chronic renal insufficiency

Acute renal failure and azotemia is a dose-dependent process and can be minimized with proper administration and prophylaxis. Damage to the proximal tubules by the aquation products of cisplatin is suspected to cause the toxicity. Proper preplatinum hydration with a chloride containing intravenous fluid is believed to minimize the production of the more nephrotoxic aqua products. It is manifested as increased BUN and creatinine, oliguria, protein wasting, and potassium, calcium, and magnesium wasting.

Chronic renal dysfunction can develop in patients receiving multiple courses of cisplatin. This occurs with slow release of the platinum ion from tissues, which then accumulates in the distal tubules. Manifestations of this toxicity are varied, and can include sodium and water wasting, nephropathy, decreased Cl_cr, and magnesium wasting.

Recommendations for minimizing nephrotoxicity include:

Prepare cisplatin in saline-containing vehicles

Vigorous hydration with saline-containing intravenous fluids (125-150 mL/hour) before, during, and after cisplatin administration

Simultaneous administration of either mannitol or furosemide

Infuse dose over 24 hours

Pretreatment with amifostine

Avoid other nephrotoxic agents (aminoglycosides, amphotericin, etc)

Miscellaneous: Anaphylactic reaction occurs within minutes after administration and can be controlled with epinephrine, antihistamines, and steroids

1% to 10%:

Extravasation: May cause thrombophlebitis and tissue damage if infiltrated; may use sodium thiosulfate as antidote

Irritant chemotherapy

<1%: Bradycardia, arrhythmias, mild alopecia, SIADH, hypomagnesemia, hypocalcemia, hypokalemia, hypophosphatemia, mouth sores, elevated liver enzymes, phlebitis, optic neuritis, blurred vision, papilledema

Symptoms of overdose include severe myelosuppression, intractable nausea and vomiting, kidney and liver failure, deafness, ocular toxicity, and neuritis

No known antidote; hemodialysis appears to have little effect; treatment is supportive therapy

Decreased toxicity: Sodium thiosulfate theoretically inactivates drug systemically; has been used clinically to reduce systemic toxicity with intraperitoneal administration of cisplatin

Increased toxicity:

Ethacrynic acid has resulted in severe ototoxicity in animals

Delayed bleomycin elimination with decreased glomerular filtration rate

Store intact vials at room temperature (15°C to 25°C/59°F to 77°F); protect from light

Do not refrigerate solution - a precipitate may form. If inadvertently refrigerated, the precipitate will slowly dissolve within hours to days, when placed at room temperature. The precipitate may be dissolved without loss of potency by warming solution to 37°C/98.6°F.

Multidose (preservative-free) vials: After initial entry into the vial, solution is stable for 28 days protected from light or for at least 7 days under fluorescent room light at room temperature

Further dilution stability is dependent on the chloride ion concentration and should be mixed in solutions of NS (at least 0.3% NaCl). Further dilution in NS, D₅/0.45% NaCl or D₅/NS to a concentration of 0.05-2 mg/mL are stable for 72 hours at 4°C to 25°C in combination with mannitol; may administer 12.5-50 g mannitol/L

Do NOT administer with D₅W or other chloride-lacking solutions because nephrotoxicity increases in solutions which do not contain a chloride ion.

Aluminum-containing I.V. infusion sets and needles should NOT be used due to binding with the platinum

Incompatible with sodium bicarbonate

Standard I.V. dilution: Dose/250-1000 mL NS, D₅/NS or D₅/0.45% NaCl

Stable for 72 hours at 4°C to 25°C (in combination with mannitol)

Inhibits DNA synthesis by the formation of DNA cross-links; denatures the double helix; covalently binds to DNA bases and disrupts DNA function; may also bind to proteins; the cis-isomer is 14 times more cytotoxic than the trans-isomer; both forms cross-link DNA but cis-platinum is less easily recognized by cell enzymes and, therefore, not repaired. Cisplatin can also bind two adjacent guanines on the same strand of DNA producing intrastrand cross-linking and breakage.

Distribution: I.V.: Rapidly distributes into tissue; found in high concentrations in the kidneys, liver, ovaries, uterus, and lungs

Protein binding: >90%

Half-life: Initial: 20-30 minutes; Beta: 60 minutes; Terminal: ~24 hours; Secondary half-life: 44-73 hours

Metabolism: Undergoes nonenzymatic metabolism; the drug is inactivated (in both the cell and the bloodstream) by sulfhydryl groups; cisplatin covalently binds to glutathione and to thiosulfate

Elimination: >90% excreted in the urine and 10% in bile

I.V. (refer to individual protocols):

The manufacturer recommends that subsequent cycles should only be given when serum creatinine <1.5 mg%, WBC greater than or equal to 4,000/mm³, platelets greater than or equal to 100,000/mm³, and BUN <25.

It is recommended that a 24-hour urine creatinine clearance be checked prior to a patient's first dose of cisplatin and periodically thereafter (ie, after every 2-3 cycles of cisplatin)

Pretreatment hydration with 1-2 L of chloride-containing fluid is recommended prior to cisplatin administration; adequate hydration and urinary output (>100 mL/hour) should be maintained for 24 hours after administration

If the dose prescribed is a reduced dose, then this should be indicated on the chemotherapy order

Children: Various dosage schedules range from 30-100 mg/m² once every 2-3 weeks; may also dose similar to adult dosing

Recurrent brain tumors: 60 mg/m² once daily for 2 consecutive days every 3-4 weeks

Adults:

Advanced bladder cancer: 50-70 mg/m² every 3-4 weeks

Head and neck cancer: 100-120 mg/m² every 3-4 weeks

Testicular cancer: 10-20 mg/m²/day for 5 days repeated every 3-4 weeks

Metastatic ovarian cancer: 75-100 mg/m² every 3 weeks

Intraperitoneal: cisplatin has been administered intraperitoneal with systemic sodium thiosulfate for ovarian cancer; doses up to 90-270 mg/m² have been administered and retained for 4 hours before draining

Dosing adjustment in renal impairment:

Cl_cr 10-50 mL/minute: Administer 50% of normal dose

Cl_cr <10 mL/minute: Do not administer

Hemodialysis: Partially cleared by hemodialysis; administer dose posthemodialysis

CAPD effects: Unknown

CAVH effects: Unknown

Renal function tests (serum creatinine, BUN, Cl_cr), electrolytes (particularly magnesium, calcium, potassium); hearing test, neurologic exam (with high dose), liver function tests periodically, CBC with differential and platelet count; urine output, urinalysis

None reported

May cause myelosuppression; use caution with clozapine and carbamazepine

No information available to require special precautions

No effects or complications reported

This drug can only be given I.V. and numerous adverse side effects can occur. Maintaining adequate hydration is extremely important to help avoid kidney damage (2-3 L/day of fluids unless instructed to restrict fluid intake). Nausea and vomiting can be severe and can be delayed for up to 48 hours after infusion and last for 1 week; consult prescriber immediately for appropriate antiemetic medication. May cause hair loss (reversible). You will be susceptible to infection; avoid crowds or infectious situations (do not have any vaccinations without consulting prescriber). Report all unusual symptoms promptly to prescriber. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Do not get pregnant during or for 1 month following therapy. Male: Do not cause a female to become pregnant. Male/female: Consult prescriber for instruction on appropriate barrier contraceptive measures. This drug may cause severe fetal defects. Do not breast-feed.

Perform pretreatment hydration (see Usual Dosage); monitor for possible anaphylactoid reaction; monitor renal, hematologic, otic, and neurologic function frequently

Large extravasations (>20 mL) of concentrated solutions (>0.5 mg/mL) produce tissue necrosis. Treatment is not recommended unless a large amount of highly concentrated solution is extravasated.

Mix 4 mL of 10% sodium thiosulfate with 6 mL sterile water for injection: Inject 1-4 mL through existing I.V. line cannula. Administer 1 mL for each mL extravasated; inject S.C. if needle is removed.

Injection, aqueous: 1 mg/mL (50 mL, 100 mL)

Powder for injection: 10 mg, 50 mg

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