cisplatin (Rx)

>10%

Nausea (76-100%)

Vomiting (76-100%)

Nephrotoxicity (28-36%)

Ototoxicity, especially in children (31%)

Myelosuppression (25-30%)

Anaphylaxis (1-20%)

Alopecia

Frequency Not Defined

Cerebral herniation

Encephalopathy

Leukoencephalopathy and reversible posterior leukoencephalopathy syndrome

Seizure

Peripheral neuropathy (dose and duration dependent)

Diarrhea

Electrolyte changes

Hyperuricemia

Hepatotoxicity

Local tissue irritation

Blood and lymphatic system disorders: Coombs-positive hemolytic anemia. hemolytic uremic syndrome, thrombotic thrombocytopenic purpura

Cardiovascular disorders: Venous thromboembolism, arterial thromboembolism, myocardial infarction, cerebrovascular accident, thrombotic microangiopathy, cerebral arteritis, pericardial effusion, cardiac failure, ventricular dysfunction, Raynaud’s phenomenon

Eye disorders: Optic neuritis, papilledema, cortical blindness, blurred vision, color blindness, retinal pigmentation

Gastrointestinal disorders: Nausea, vomiting, anorexia, diarrhea, stomatitis, gastrointestinal perforation, pancreatitis, hiccups

General disorders: Asthenia, malaise

Hepatobiliary disorders: Elevations of aminotransferases, lactate dehydrogenase, and bilirubin; hepatic failure

Hypersensitivity: Anaphylaxis, facial edema, wheezing, tachycardia, and hypotension

Local Site Reactions: Tissue cellulitis, fibrosis, necrosis, pain, edema, and erythema

Metabolism and nutrition disorders: Hypomagnesemia, often requiring magnesium supplementation; hyperuricemia, other electrolyte abnormalities (hypocalcemia, hyponatremia, hypokalemia, and hypophosphatemia), Syndrome of Inappropriate Antidiuretic Hormone Excretion (SIADH), dehydration, tumor lysis syndrome, increased serum amylase

Musculoskeletal disorders: Muscle cramps (localized, painful, involuntary skeletal muscle contractions of sudden onset and short duration)

Nervous system disorders: Peripheral neuropathy, encephalopathy, loss of motor function, loss of taste, leukoencephalopathy, reversible posterior leukoencephalopathy syndrome, progressive multifocal leukoencephalopathy, seizures, Lhermitte’s sign, dorsal column myelopathy, autonomic neuropathy, seizures, involuntary skeletal muscle contractions, tetany (with hypocalcemia and hypomagnesemia)

Ototoxicity: Tinnitus, hearing loss, deafness, vestibular toxicity

Renal and urinary disorders: Nephrotoxicity including renal failure, renal electrolyte wasting, azotemia, decreased creatinine clearance

Respiratory disorders: Pneumonitis/interstitial lung disease, pulmonary embolism

Contraindications

Hypersensitivity to cisplatin, other platinum compounds

Severe myelosuppression, renal impairment, hearing impairment

Pregnancy, lactation

Cautions

Irritant; injection site reactions may occur during administration; local soft tissue toxicity reported following extravasation of cisplatin for injection; severity of local tissue toxicity appears to be related to concentration of drug; closely monitor infusion site during drug administration

Avoid aluminum needles/equipment

Pediatric patients, hearing impairment, neuropathy, neuromuscular disease, with neurotoxic agents, with ototoxic agents, elderly

Risk of cumulative nephrotoxicity (exacerbated by aminoglycoside antibiotics); renal toxicity becomes more prolonged and severe with repeated courses; renal function must return to normal before administering another dose

Myelosuppression occurs in 25-30%; nadirs in circulating platelets and leukocytes occur between days 18-23 (range 7.5-45) with most patients recovering by day 39; elderly may be more susceptible to myelosuppression

Development of acute leukemia secondary to therapy reported; in these reports, cisplatin for injection was generally given in combination with other leukemogenic agents

Cardiac abnormalities, hiccups, elevated serum amylase, rash, alopecia, malaise, asthenia, and dehydration have been reported

Ocular toxicity

• Optic neuritis, papilledema, and cortical blindness reported in patients receiving standard recommended doses of cisplatin for injection
• Blurred vision and altered color perception reported after use of regimens with higher doses and dose frequencies of cisplatin for injection; the altered color perception manifests as a loss of color discrimination, particularly in the blue-yellow axis and irregular retinal pigmentation of macular area on fundoscopic exam
• Improvement and/or total recovery usually occurs after discontinuing cisplatin for injection but can be delayed

Renal toxicity

• Ensure adequate hydration before, during, and after administration; measure serum creatinine, blood urea nitrogen, creatinine clearance, and serum electrolytes including magnesium prior to initiating therapy, and as clinically indicated; consider magnesium supplementation as clinically needed
• Consider alternative treatments or reduce dose for patients with baseline renal impairment or who develop significant reductions in creatinine clearance during treatment

Peripheral neuropathy

• Drug can cause dose-related peripheral neuropathy that becomes more severe with repeated courses of drug; neurologic symptoms have been reported to occur after a single dose
• Neuropathy can also have a delayed onset from 3-8 weeks after last dose of cisplatin for injection; manifestations include paresthesias in a stocking-glove distribution, areflexia, and loss of proprioception and vibratory sensation
• Neuropathy may progress further even after stopping treatment; peripheral neuropathy may be irreversible in some patients
• Perform a neurological examination before initiating therapy, at appropriate intervals during therapy, and after completion of therapy; consider discontinuation of cisplatin for injection for patients who develop symptomatic peripheral neuropathy; geriatric patients may be more susceptible to peripheral neuropathy

Nausea and vomiting

• Cisplatin for injection is a highly emetogenic antineoplastic agent; premedicate with anti-emetic agents; without antiemetic therapy, marked nausea and vomiting occur in almost all patients treated with cisplatin for injection and may be so severe that drug must be discontinued
• Nausea and vomiting may begin within 1 to 4 hr after treatment and last up to 72 hr; maximal intensity occurs 48 to 72 hours after administration
• Various degrees of vomiting, nausea, and/or anorexia may persist for up to 1 week after treatment; delayed nausea and vomiting (begins or persists 24 hours or more after chemotherapy) has occurred in patients attaining complete emetic control on day of injection therapy
• Consider use of additional anti-emetics following infusion

Myelosuppression

• Potential fatalities due to infection (secondary to myelosuppression) reported
• Perform standard hematologic tests before initiating therapy, before each subsequent course, and as clinically indicated; closely monitor patients for development of signs and symptoms of infection during and after treatment with cisplatin for injection; for patients who develop severe myelosuppression, consider dose modifications and manage according to clinical treatment guidelines

Hypersensitivity

• Therapy can cause severe hypersensitivity reactions, including anaphylaxis and death; manifestations have included facial edema, wheezing, tachycardia, hypotension; hypersensitivity reactions have occurred within minutes of administration to patients with prior exposure to cisplatin
• Severe hypersensitivity reactions require immediate discontinuation of cisplatin for injection and aggressive therapy; patients with a history of severe hypersensitivity reactions should not be rechallenged with cisplatin for injection
• Cross-reactivity between platinum-based antineoplastic agents reported; cases of severe hypersensitivity reactions have recurred after rechallenging patients with a different platinum agent

Ototoxicity

• Cisplatin for injection can cause ototoxicity, which is cumulative and may be severe; consider audiometric and vestibular function monitoring
• Ototoxic effects may be more severe and detrimental in pediatric patients receiving cisplatin for injection, particularly in patients less than 5 years of age; consider audiometric and vestibular function monitoring in all patients receiving cisplatin for injection; the prevalence of hearing loss in pediatric patients is particularly high and is estimated to be 40% to 60%
• Earlier detection of hearing loss can limit potential impact of hearing impairment on a pediatric patient’s cognitive and social development

Pregnancy

Based on human data from published literature, cisplatin can cause fetal harm when administered to pregnant women; data demonstrates transplacental transfer of cisplatin

Exposure associated with oligohydramnios, intrauterine growth restriction, and preterm birth; cases of neonatal acute respiratory distress syndrome, cytopenias, and hearing loss reported

Verify the pregnancy status of females of reproductive potential before initiating prior to initiation of cisplatin for injection

Contraception

• Females: Advise females of reproductive potential to use effective contraception during treatment and for 14 months following the last dose
• Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 11 months after the last dose

Infertility

• Females: Use associated with cumulative dose-dependent ovarian failure, premature menopause, and reduced fertility
• Males: Use associated with a cumulative dose-dependent impairment of spermatogenesis (oligospermia, azoospermia; possibly irreversible) and reduced fertility

Animal data

• Cisplatin for injection administration to animals during and after organogenesis resulted in teratogenicity; a published study in mice showed placental transfer of cisplatin increased with placenta maturation

Lactation

Limited data from published literature report the presence of drug in human milk; because of potential for serious adverse reactions in a breastfed child and because of potential for tumorigenicity, advise lactating women not to breastfeed during treatment

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Platinum coordination compound that inhibits DNA synthesis; cross-links and denatures strands of DNA; disrupts DNA function by covalently binding to DNA bases; can also produce DNA intrastrand cross-linking and breakage

Not a true alkylating agent

Pharmacokinetics

Half-life elimination (terminal): 24hr to 47 days

Protein bound: >90%

Excretion: Urine (90%); feces (10%)

Clearance: 15 L/hr/m²

Vd: 11 L/m²

IV Incompatibilities

Solution: Na-bicarb 5%, D5W(?)

Additive: fluorouracil, mesna, paclitaxel(?), thiotepa

Y-site: amifostine, amphotericin B cholesteryl-SO4, cefepime, piperacillin/tazobactam, thiotepa

IV Compatibilities

Solution: dextrose-saline, NS, 1/2NS, other saline concentrations

Additive: carboplatin, cyclophosphamide w/ etoposide, etoposide, floxuridine, floxuridine w/ leucovorin, hydroxyzine, ifosfamide, leucovorin, MgSO4, mannitol, ondansetron

Syringe: bleomycin, cyclophosphamide, doxapram, doxorubicin, droperidol, fluorouracil, furosemide, heparin, leucovorin, methotrexate, metoclopramide, mitomycin, vinblastine, vincristine

Y-site (partial list): allopurinol, aztreonam, bleomycin, chlorpromazine, cladribine, cyclophophamide, dexamethasone Na-succinate, diphenhydramine, doxorubicin, doxorubicin liposomal, etoposide phosphate, filgrastim, fludarabine, fluorouracil, furosemide, gemcitabine, granisetron, heparin, leucovorin, linezolid, lorazepam, melphalan, methotrexate, methylprednisolone Na-succinate, metoclopramide, mitomycin, morphine, ondansetron, paclitaxel, prochlorperazine edisylate, propofol, sargramostim, vinblastine, vincristine, vinorelbine

IV Preparation

Further dilution stability is dependent on chloride ion concentration & should be mixed in solutions of NS (at least 0.3% NaCl)

Further dilution in NS, D5/½NS or D5/NS to a concentration of 0.05-2 mg/mL are stable for 72 hr at 4-25°C in combination with mannitol

May administer 12.5-50 g mannitol/L

Standard dilution: dose/250-1000 mL NS, D5W/NS or D5/½NS

IV Administration

Perform pretreatment hydration

Do not use aluminum-containing needles or IV administration sets that may come in contact with carboplatin (aluminum can react causing precipitate formation & loss of potency)

Administration rate has varied from a 15-120 min infusion, 1 mg/min infusion, 6-8 hr infusion, 24 hr infusion, or per protocol

Maximum rate of infusion: 1 mg/min in patients with CHF

When administered as sequential infusions, taxane derivatives (docetaxel, paclitaxel) should be administered before platinum derivatives to limit myelosuppression & to enhance efficacy

Extravasation Management

Large extravasations (>20 mL) of concentrated solutions (>0.5 mg/mL) produce tissue necrosis

Tx is not recommended unless a large amount of highly concentrated solution is extravasated

Mix 4 mL of 10% sodium thiosulfate with 6 mL SWI; inject 1-4 mL through existing IV line cannula; administer 1 mL for each mL extravasated; inject SC if needle is removed

Storage

Store intact vials at 15-25°C (59-77°F)

Protect from light