Cisplatin

Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: (SP-4-2)-Diamminedichloroplatinum
Molecular Formula: Cl₂H₆N₂Pt
CAS Number: 15663-27-1
Brands: Platinol-AQ

• Experience of Supervising Clinician


• 
  

  Use under supervision of a qualified clinician experienced in therapy with antineoplastic agents.¹ Use only when adequate treatment facilities for appropriate management of therapy and complications are available.¹

  
  

• Dose-Related Toxicities


• 
  

  Risk of dose-related toxicities, including myelosuppression, nausea, vomiting, and cumulative, severe renal toxicity.¹ Dosages >100 mg/m²/cycle once every 3–4 weeks rarely used.¹

  
  

• Ototoxicity


• 
  

  Risk of ototoxicity; more pronounced in children.¹ Manifestations include tinnitus, loss of high frequency hearing, decreased hearing acuity, and, occasionally, deafness.^{1 276 287 288 289 290 291 292 358}

  
  

• Anaphylaxis


• 
  

  Risk of anaphylactoid reactions (e.g., facial edema, bronchoconstriction, wheezing, tachycardia, hypotension); may occur within minutes following administration.¹ (See Anaphylactoid Reactions under Cautions.) IV epinephrine, corticosteroids, and antihistamines have been effectively employed to alleviate symptoms.¹

  
  

• Potential Medication Errors


• 
  

  Avoid accidental, potentially fatal, overdosage due to confusion with carboplatin (Paraplatin)^{1 419 420 421 422} or due to failure to differentiate daily dosages from total dosage per cycle.¹ Cisplatin dosages >100 mg/m²/cycle once every 3–4 weeks rarely used.¹

  
  

Introduction

Antineoplastic agent; platinum-containing compound.^{1 7 13}

Uses for Cisplatin

Testicular Cancer

Adjunct to other antineoplastic agents for the treatment of metastatic testicular tumors (including nonseminomatous testicular carcinoma, seminoma testis, and extragonadal germ-cell tumors) in patients who have already received appropriate surgery and/or radiation therapy.^{1 63 403}

For induction of remissions, a regimen of cisplatin, bleomycin, and vinblastine (with or without other antineoplastic agents) has been used.^{64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 403}

For treatment of disseminated disease, a regimen of cisplatin, bleomycin, and etoposide has been used.^{63 335 403 406 407 408 409 410 411 412}

Regimen consisting of cisplatin, ifosfamide with mesna, and either vinblastine or etoposide considered standard initial salvage (i.e., second-line) regimen in patients with recurrent disease.^{63 403 507}

Ovarian Cancer

Used alone or in combination therapy for the treatment of ovarian cancer.^{1 509}

Platinum-based therapy has been used for adjuvant treatment following surgery in early-stage ovarian epithelial cancer†.⁵⁰⁹

For initial (first-line) treatment of advanced ovarian epithelial cancer, combination chemotherapy with a platinum-containing agent (e.g., cisplatin, carboplatin) and paclitaxel currently is preferred regimen.^{63 509} Carboplatin is as effective as but less toxic than cisplatin when used in combination with either paclitaxel^{757 758} or cyclophosphamide; ^{521 522} therefore, carboplatin in combination with paclitaxel currently is a preferred regimen for initial treatment of advanced ovarian epithelial cancer.^{63 509} Regimen consisting of cisplatin and paclitaxel is superior to regimen consisting of cisplatin and cyclophosphamide.^{509 517 641}

Second-line therapy for the treatment of advanced epithelial ovarian cancer when retreatment is indicated in patients with platinum-sensitive disease who relapse.^{1 489 509} However, carboplatin monotherapy preferred to cisplatin monotherapy by some clinicians due to its more favorable toxicity profile.^{489 509} Nonplatinum-based monotherapy regimens (e.g., paclitaxel) generally preferred for retreatment of platinum-resistant disease.^{489 509 512 514}

For the adjuvant therapy of ovarian germ-cell tumors, combination chemotherapy with cisplatin, bleomycin, and etoposide currently is regimen of choice.^{63 415 582}

Bladder Cancer

Used alone or in combination therapy for the treatment of muscle-invasive and advanced bladder cancer that is no longer amenable to surgery and/or radiation therapy.^{1 584 585 587 591 605 606}

For adjuvant treatment of muscle-invasive bladder cancer, regimens consisting of cisplatin, methotrexate, and vinblastine with or without doxorubicin (abbreviated as M-VAC or CMV, respectively) currently is used.^{591 605 606}

For palliative treatment of advanced or metastatic bladder cancer, M-VAC, CMV, or, alternatively, a regimen consisting of cisplatin and gemcitabine currently is used.^{63 134 556 584 585 626}

Head and Neck Cancer

Adjunct to fluorouracil or paclitaxel for the palliative treatment of recurrent or metastatic head and neck cancer†.^{63 527 673 674} Regimen consisting of cisplatin, methotrexate, bleomycin, and vincristine also has been used.⁶⁷⁵

Cervical Cancer

Used alone^{63 685 687} or in combination therapy^{63 684 686 687 688} as an adjunct to radiation therapy for the treatment of invasive cervical cancer† (FIGO stages IB2 through IVA^{684 685 687 688} or FIGO stage IA2, IB, or IIA with poor prognostic factors).^{683 684 685 686 687 688 690 697}

Component of various combination chemotherapeutic regimens (e.g., bleomycin, cisplatin, and ifosfamide [BIP]; bleomycin, cisplatin, mitomycin, and vincristine [BOMP]) for the treatment of metastatic or recurrent cervical cancer†.^{63 177 179 180 181}

Non-small Cell Lung Cancer

Component of various chemotherapeutic regimens for advanced non-small cell lung cancer†.^{63 529 665}

Currently preferred regimens include the combination of cisplatin with another agent, such as paclitaxel,^{63 187 529 665 666} vinorelbine,^{63 529 665 667} gemcitabine,^{63 187 529 669 670} or docetaxel.^{187 529}

Small Cell Lung Cancer

Adjunct to other antineoplastic agents for the treatment of small cell lung cancer†.^{63 533}

Regimens consisting of cisplatin and etoposide or irinotecan currently considered preferred regimens.^{63 515 533}

Malignant Pleural Mesothelioma

Used in combination with pemetrexed for the treatment of malignant pleural mesothelioma in patients not eligible for surgery.^{63 679}

Monotherapy^{202 203 679 680} or as adjunct to other antineoplastic agents (e.g., doxorubicin, gemcitabine, mitomycin)^{63 204 681} for the palliative treatment of advanced malignant pleural mesothelioma†.^{202 203 204 679 680 681}

Esophageal Cancer

Monotherapy^{569 576 644} or as adjunct to other antineoplastic agents^{63 568 569 570 576 644} for the treatment of localized or advanced esophageal cancer†.

For treatment of localized, resectable esophageal cancer, some experts recommend combined modality treatment with combination chemotherapy (e.g., cisplatin and fluorouracil) and concurrent radiation therapy with or without surgery.^{361 568 572}

For palliative treatment of metastatic (local or distant) disease or recurrent or locally advanced disease not amenable to surgery or radiation therapy,^{63 568 570 576 644} combination therapy with cisplatin and fluorouracil is considered regimen of choice.^{63 568 644}

Brain Tumors

Adjunct for the treatment of astrocytic tumors†, such as anaplastic astrocytoma and glioblastoma multiforme.⁶³

Used in combination with lomustine and vincristine as adjuvant therapy following surgical resection and radiation therapy for the treatment of medulloblastoma†.^{63 546}

Monotherapy or in combination chemotherapy regimens (e.g., cisplatin and etoposide) as salvage therapy for recurrent oligodendroglioma†.^{63 213}

Adjunct to etoposide for the treatment of intracranial germ cell tumors†.^{63 214 545}

Neuroblastoma

Component of combination therapy for high-risk neuroblastoma†.^{63 541}

In patients with intermediate-risk tumors or some patients with low-risk tumors, combination chemotherapy with moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide is used in conjunction with surgery (with or without radiation therapy).⁵⁴¹ In patients with high-risk tumors, aggressive chemotherapy using higher doses of these drugs and additional drugs (e.g., ifosfamide, high-dose cisplatin, vincristine) is used.⁵⁴¹

Cisplatin Dosage and Administration

General

• 
  

  Consult specialized references for procedures for proper handling and disposal of antineoplastics.¹

  
  


• 
  

  Consider pretreatment with antiemetics (e.g., selective inhibitors of type 3 [5-HT₃] serotonergic receptors)^{440 441 445 446 449 450 451 452 453 454 455 456 457 459 460 461 462 466 468} or combination antiemetic therapy (e.g., 5-HT₃ receptor antagonist and corticosteroid) to prevent nausea and vomiting,.^{446 451 452 455 456 462 464 466 468 469 470}

  
  

Hydration

• 
  

  Hydrate with 1–2 L IV fluid 8–12 hours prior to administration.^{1 67 245 252 344} Maintain adequate hydration and urinary output during and for 24 hours after administration to minimize nephrotoxicity.^{1 243 245 251 256 343 344}

  
  


• 
  

  In adults, IV fluids usually administered alone or with mannitol and/or furosemide to achieve a diuresis of 150–400 mL/hour (during and for at least 4–6 hours after administration of cisplatin)^{245 251 252 256 343 344} or ≥100–200 mL/hour (for the next 18–24 hours^{65 251 252 343 344} or until vomiting stops and oral fluids are tolerated).³⁴³

  
  


• 
  

  Potassium chloride (e.g., 10–20 mEq/L) often added to IV fluids to replace losses and prevent deficiencies.^{245 259 344}

  
  

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV infusion.¹

Aluminum displaces platinum from cisplatin molecule,^{10 11 12} causing formation of a black precipitate^{1 10 11 12} and loss of potency;^{1 12} do not use needles or IV administration sets that contain aluminum parts for preparation or administration.¹

Handle cautiously (e.g., use gloves); avoid exposure during handling and preparation of IV solution.¹ If skin or mucosal contact occurs, immediately and thoroughly wash skin with soap and water and flush mucosa with water.¹

Dilution

Dilute preservative-free solution with 2 L of 5% dextrose and 0.33 or 0.45% sodium chloride injection containing 18.75 g of mannitol/L (i.e., 37.5 g in 2 L).¹ Do not dilute with 5% dextrose injection.¹

If not used within 6 hours, protect from light.¹

Rate of Administration

Manufacturer recommends administering dose by IV infusion over 6–8 hours.¹

Has been administered over 15 minutes to 2 hours with minimal adverse renal effects.^{65 243 247 252 256 257 258 261} Continuous 24-hour³⁸ or 5-day^{263 264 265} IV infusions also have been used.

Rapid IV injection (e.g., over 1–5 minutes)^{25 27 259 290} associated with increased risk of nephrotoxicity²⁴³ or ototoxicity.²⁹⁰

Dosage

Contact prescriber if prescribed dose >100 mg/m²/cycle.¹ (Cisplatin dosages exceeding 100 mg/m²/cycle once every 3–4 weeks are rarely used.)¹ Inadvertent substitution of cisplatin for carboplatin can result in potentially fatal overdosage.^{419 420 421 422} (See Boxed Warning.)

Do not administer repeat course until S_cr <1.5 mg/dL and/or BUN <25 mg/dL, platelet count ≥100,000/mm³, and leukocyte count ≥4000/mm³, and unless auditory acuity is within normal limits.¹

Consult published protocols for dosages of other chemotherapeutic agents and alternative cisplatin dosages, the method and sequence of administration, and duration of therapy.

Adults

Testicular Cancer

IV

20 mg/m² daily for 5 consecutive days every 3 weeks for 3 or 4 courses of therapy.^{1 64 65 66 67 68 69 70 71 72 73 335 408} 3 cycles of therapy are sufficient for favorable-prognosis germ cell tumors.^{85 86}

Ovarian Cancer

IV

Combination chemotherapy with paclitaxel: 75 mg/m² once every 3 weeks.^{361 517}

Combination chemotherapy with cyclophosphamide: 50–100 mg/m² once every 3–4 weeks.^{1 361} Administer cisplatin and cyclophosphamide sequentially.¹

Monotherapy: Manufacturer recommends 100 mg/m² once every 4 weeks.¹ Some experts recommend 50–100 mg/m² once every 3 weeks;³⁶¹ dosages of 30–120 mg/m² once every 3–4 weeks have been used.^{97 98 101 102 103 104 105 383}

Bladder Cancer

IV

50–70 mg/m² once every 3–4 weeks, depending on extent of prior radiation therapy and/or chemotherapy.¹

In extensively pretreated patients, 50 mg/m² once every 4 weeks.¹

Head and Neck Cancer†

IV

Monotherapy: 80–120 mg/m² once every 3 weeks^{38 143 144 147 149} or 50 mg/m² on the first and eighth days of every 4 weeks.^{143 148}

Combination chemotherapy: 50–120 mg/m²; frequency of administration depends on the specific regimen employed (consult specialized references).^{144 146 149 150 151 152 154 155 157 158 160 161 162 163 164 165 166 167 168 169 170}

Cervical Cancer†

Invasive Cervical Cancer†

IV

Monotherapy: 40 mg/m² once weekly has been administered concurrently with radiation therapy up to a maximum of 6 doses.^{685 687}

Combination chemotherapy (e.g., with fluorouracil): 50–75 mg/m² has been administered concurrently with radiation therapy according to various dosage schedules.^{684 686 687}

Metastatic or Recurrent Cervical Cancer†

IV

50 mg/m² once every 3 weeks up to a maximum of 6 courses.^{175 178 180 181} Higher dosages (e.g., 100 mg/m² once every 3 weeks) produce higher response rates but also increased toxicity.¹⁷⁵

Non-small Cell Lung Cancer†

IV

75–100 mg/m² once every 3–4 weeks.^{666 667 669 670}

Esophageal Cancer†

IV

Monotherapy: 50–120 mg/m² once every 3–4 weeks.⁵⁷⁶

Combination chemotherapy: 75–100 mg/m² once every 3–4 weeks.^{361 570 572 576}

Prescribing Limits

Adults

Do not administer cycle more frequently than once every 3–4 weeks.¹

Contact prescriber if prescribed dose >100 mg/m²/cycle.¹ (Cisplatin dosages exceeding 100 mg/m²/per cycle once every 3–4 weeks are rarely used.)¹

Consider that renal toxicity becomes more severe with repeated courses of cisplatin.¹

Cervical Cancer†

Invasive cervical cancer: Maximum 6 doses.^{685 687}

Metastatic or recurrent cervical cancer: Maximum 6 courses.^{175 178 180 181}

Special Populations

Geriatric Patients

Careful dosage selection and monitoring of renal function recommended due to possible age-related decrease in renal function.^{1 756}

Cautions for Cisplatin

Contraindications

• 
  

  Patients with preexisting renal impairment, myelosuppression, or hearing impairment.¹

  
  


• 
  

  Known hypersensitivity to cisplatin or other platinum-containing compounds or any ingredient in the formulation.¹

  
  

Warnings/Precautions

Warnings

Renal Effects

Risk of dose-related (cumulative), severe nephrotoxicity^{1 243 244 245 246} (manifested as increased S_cr, BUN, serum uric acid concentrations, and/or decreased Cl_cr^{1 243 244 245 246} and GFR);^{247 339} nephrotoxicity more common and severe than with carboplatin.^{440 493 521 522 542 549 566}

Nephrotoxicity generally occurs during second week following initiation of therapy;^{1 246} may occur within several days following administration of high-dose regimens.²⁴⁶ (See Clinical/Laboratory Monitoring under Cautions.)

High^{13 243 244 245} or repeated doses^{1 13 390} can increase severity^{1 13 244 390} and duration^{1 244} of renal impairment. Recovery generally occurs within 2–4 weeks after administration of cisplatin,^{244 246 256} but renal insufficiency may be irreversible (sometimes fatal).^{13 243 244 245}

Maintain adequate hydration and urinary output during and for 24 hours after administration of cisplatin to minimize nephrotoxicity.^{1 243 245 251 256 343 344} (See Hydration under Dosage and Administration.)

Nervous System Effects

Risk of neurotoxicity, usually characterized by severe neuropathy (e.g., paresthesia, areflexia, loss of proprioception and vibratory sensation)^{1 101 276 297 298 299 300 301 302 303 304 444} in patients receiving higher single or cumulative doses, prolonged therapy (4–7 months),^{1 276 297 298 299 300 301 302 303 304 486 488} or greater dose frequency than recommended.¹ Neurotoxicity more severe and occurs more frequently than with carboplatin.^{440 493 521 522}

Perform neurologic examination regularly.¹ If manifestations of neuropathy occur, discontinue cisplatin immediately; neuropathy may worsen even after discontinuance.^{1 297 488} Peripheral neuropathy may be irreversible in some patients.^{1 297}

Possible motor (especially gait) difficulties,^{101 276 297 299 300 302 472} reduced or absent deep-tendon reflexes,^{101 297 298 300 304} leg weakness,^{300 301} or loss of motor function.¹ Muscle cramps reported, particularly in patients receiving high cumulative dose and at advanced symptomatic stage of peripheral neuropathy.¹

Loss of taste, seizures, Lhermite's sign, dorsal column myelopathy, and autonomic neuropathy reported.¹

Otic Effects

Risk of dose-related, cumulative ototoxicity.¹ (See Boxed Warning.) Hearing loss can be unilateral or bilateral and becomes more frequent and severe with repeated doses;¹ may occasionally require dosage reduction or discontinuance of therapy.^{276 290 358} (See Clinical/Laboratory Monitoring under Cautions.)

Risk of vestibular ototoxicity^{1 295 296} (manifested as vertigo²⁹⁵ ) or vestibular dysfunction.²⁹⁶

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals.^{1 347 360 367 368} Avoid pregnancy during therapy.¹ If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.^{1 347 360}

Carcinogenic Effects

Malignancies (e.g., leukemia, renal fibrosarcoma) reported in rats.¹ Bladder cancer reported in at least 1 patient, but causal relationship not established.^{330 331} Acute leukemia rarely reported in humans; in such cases, cisplatin generally was given in combination with other leukemogenic agents and/or radiation.^{1 331 478 479 480 481}

Sensitivity Reactions

Anaphylactoid Reactions

Anaphylactoid reactions reported.¹ (See Boxed Warning.) Anaphylactoid reactions usually have occurred only after multiple cycles (e.g., at least 5 doses),^{245 312 313 440} but also can occur after the initial dose.⁴⁴⁰ Observe patients carefully; supportive equipment and medication should be available for immediate use.¹

Major Toxicities

Hematologic Effects

Risk of cumulative myelosuppression (manifested as leukopenia, thrombocytopenia, and anemia).^{1 13 276} Leukopenia and thrombocytopenia are dose-related.^{1 276} Anemia not clearly dose-related but may be severe, possibly requiring transfusions.^{97 245 393}

Myelosuppression may be more severe in patients previously treated with other antineoplastic agents or radiation therapy.^{245 276} Myelosuppression less pronounced than with carboplatin.^{440 495 496 521 522 551}

Nadir in circulating platelets, leukocytes, and hemoglobin occurs 18–23 days (range: 7.2–45 days) following single dose; levels return to pretreatment values in most patients within 39 days (range: 13–62 days).^{1 440} (See Clinical/Laboratory Monitoring under Cautions.)

Fever and infection reported in patients with neutropenia.¹

Hemolytic anemia reported.¹ Repeat course may result in increased hemolysis; carefully weigh benefit of therapy versus risk.¹

GI Effects

Marked nausea and vomiting reported in virtually all patients;^{1 276 440 441 442 445 446 447 448 449 450 462 468 469 470} occasionally may require discontinuance of therapy.^{1 276 468}

Increased incidence and severity in females, in young patients, following administration of high doses or by rapid infusion, and/or following concomitant administration with other emetogenic drugs (e.g., doxorubicin); patients with history of chronic heavy alcohol use may experience less frequent and severe emetogenic effects.^{440 450 462 468}

Nausea and vomiting generally begin within 1–6 (usually 2–3) hours after administration of cisplatin; persist for up to 24 hours or longer.^{1 101 276 440 441 462} Average of 10–12 vomiting episodes reported within first 24 hours after initial dose.^{440 462 468} Various degrees of nausea, vomiting, and anorexia may persist for up to 5–10 days.^{1 101 259 276}

Delayed nausea and vomiting (beginning or persisting ≥24 hours following chemotherapy) has occurred in patients who had attained complete emetic control on the day of cisplatin therapy.^{1 440 441 445 449 450 451 458 459 462 468}

Cardiovascular and Cerebrovascular Effects

Bradycardia,³¹⁶ left bundle-branch block,²⁷⁶ ST-T-wave changes with CHF,²⁷⁶ postural hypotension,²⁷⁶ MI, cerebrovascular accident, thrombotic microangiopathy, or cerebral arteritis reported rarely.¹

Electrolyte Disturbances

Hypomagnesemia,^{1 251 268 269 270 271 272 273 342 390} hypocalcemia,^{1 268 269 271 342 390} hypokalemia,^{1 271} hypophosphatemia,^{1 271} and hyponatremia^{1 274 342} reported. SIADH reported.¹

Manifestations of hypomagnesemia and/or hypocalcemia include muscle irritability²⁶⁸ or cramps,²⁷⁰ clonus,²⁷¹ tremor,²⁷⁰ carpopedal spasm,^{269 271} and/or tetany.^{1 269 271}

Electrolyte disturbances may occur within several days after administration of initial dose;^{268 269 342} hypomagnesemia usually develops within 3–4 weeks^{268 269 270 273} and appears to increase in severity with progressive courses of treatment.³⁹⁰ (See Clinical/Laboratory Monitoring under Cautions.)

Normal serum electrolyte concentrations generally restored by administration (usually parenteral)^{268 269 270 271 390} of appropriate supplemental electrolytes and drug discontinuance.^{1 268 269 270 271}

Metabolic Effects

Hyperuricemia (resulting from drug-induced nephrotoxicity²⁵⁶ ) reported;^{1 126 256} more pronounced with doses >50 mg/m².¹ Peak uric acid concentrations generally occur 3–5 days after administration of drug.¹

Allopurinol effectively reduces uric acid concentrations.^{1 256}

Ocular Effects

Optic neuritis^{1 298 304 314} (principally retrobulbar),^{298 314} papilledema,^{1 314} and cerebral (cortical) blindness^{1 48 315 471} reported infrequently. Corticosteroids, with or without mannitol, have been used; however, efficacy of such treatment not established.¹

Blurred vision and altered color perception reported following administration of higher dosages or greater dosing frequencies.¹

Hepatic Effects

Mild and transient elevations of serum AST (SGOT),^{1 276} ALT (SGPT),²⁷⁶ and bilirubin¹ reported. (See Clinical/Laboratory Monitoring under Cautions.)

Local Effects

Soft tissue toxicity (e.g., severe cellulitis with residual fibrosis,^{322 482} and full-thickness skin necrosis^{323 482} ) reported following extravasation of drug.^{1 482}

Infusion of solutions with concentration >0.5 mg/mL may result in tissue cellulitis, fibrosis, and necrosis.¹

General Precautions

Clinical/Laboratory Monitoring

Monitor S_cr, BUN, Cl_cr, and serum magnesium, sodium, potassium, and calcium concentrations prior to initiating therapy and prior to each subsequent course.¹ Do not administer repeat dose until S_cr <1.5 mg/dL and/or BUN <25 mg/dL.¹ (See Dosage under Dosage and Administration.)

Monitor peripheral blood counts weekly.¹

Perform neurologic examination regularly.¹

Monitor liver function periodically.¹

Perform audiometric testing prior to initiating therapy and prior to each subsequent dose.¹