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CISplatin

Pronunciation

Pronunciation

(SIS pla tin)

Index Terms

  • CDDP
  • cis - DDP
  • cis - Diamminedichloroplatinum
  • cis - platinum
  • DDP
  • Platinol
  • Platinol - AQ

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous:

Generic: 50 mg/50 mL (50 mL); 100 mg/100 mL (100 mL)

Solution, Intravenous [preservative free]:

Generic: 50 mg/50 mL (50 mL); 100 mg/100 mL (100 mL); 200 mg/200 mL (200 mL)

Pharmacologic Category

  • Antineoplastic Agent, Alkylating Agent
  • Antineoplastic Agent, Platinum Analog

Pharmacology

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

IV: Rapidly into tissue; high concentrations in kidneys, liver, ovaries, uterus, and lungs

Metabolism

Nonenzymatic; inactivated (in both cell and bloodstream) by sulfhydryl groups; covalently binds to glutathione and thiosulfate

Excretion

Urine (>90%); feces (minimal)

Half-Life Elimination

Children: Free drug: 1.3 hours; Total platinum: 44 hours

Adults: Initial: 14 to 49 minutes; Beta: 0.7 to 4.6 hours; Gamma: 24 to 127 hours (O'Dwyer 2000)

Protein Binding

>90% (O'Dwyer 2000)

Use: Labeled Indications

Bladder cancer, advanced: Treatment (as a single agent) of advanced bladder cancer (transitional cell) in patients who are no longer candidates for local therapy including surgery and/or radiation therapy

Ovarian cancer, metastatic: Treatment of metastatic ovarian cancer (in combination with other chemotherapy agents) in patients who have previously received appropriate surgery and/or radiation therapy, or as a single agent for refractory tumors in patients who have not previously received cisplatin

Testicular cancer, metastatic: Treatment of metastatic testicular cancer (in combination with other chemotherapy agents) in patients who have previously received appropriate surgery and/or radiation therapy

Use: Unlabeled

Treatment of breast cancer (metastatic), central nervous system tumors, cervical cancer, endometrial cancer, esophageal cancer, gastric cancer, gestational trophoblastic disease (refractory), head and neck cancer, hepatobiliary cancer, hepatoblastoma, Hodgkin lymphoma, malignant pleural mesothelioma, melanoma (metastatic), multiple myeloma, neuroblastoma, neuroendocrine tumors, non-Hodgkin lymphoma (NHL), non-small cell lung cancer (NSCLC), osteosarcoma, pancreatic cancer (advanced), prostate cancer, small cell lung cancer (SCLC), soft tissue sarcomas, and unknown primary cancers

Contraindications

History of allergic reactions to cisplatin, other platinum-containing compounds, or any component of the formulation; preexisting renal impairment; myelosuppressed patients; hearing impairment

Dosing: Adult

VERIFY ANY CISPLATIN DOSE EXCEEDING 100 mg/m2 PER COURSE. Pretreatment hydration with 1 to 2 L of IV fluid is recommended. Cisplatin is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Basch 2011; Roila 2010).

Bladder cancer, advanced: IV: 50 to 70 mg/m2 every 3 to 4 weeks; heavily pretreated patients: 50 mg/m2 every 4 weeks

Ovarian cancer, metastatic: IV:

Single agent: 100 mg/m2 every 4 weeks

Combination therapy: 75 to 100 mg/m2 every 4 weeks or (off-label dosing) 75 mg/m2 every 3 weeks (Ozols 2003)

Intraperitoneal (off-label route): 100 mg/m2 on day 2 of a 21-day treatment cycle (in combination with IV and intraperitoneal paclitaxel) for 6 cycles (Armstrong 2006)

Testicular cancer, metastatic: IV: 20 mg/m2/day for 5 days repeated every 3 weeks (in combination with bleomycin and etoposide) (Cushing 2004; Saxman 1998)

Testicular germ cell tumor, malignant (off-label dosing): IV: 25 mg/m2 on days 2 to 5 every 3 weeks (in combination with paclitaxel and ifosfamide) for 4 cycles (Kondagunta 2005) or 20 mg/m2 on days 1 to 5 every 3 weeks (in combination with bleomycin and etoposide) for 4 cycles (Nichols 1998) or 20 mg/m2 on days 1 to 5 every 3 weeks (in combination with etoposide and ifosfamide) for 4 cycles (Nichols 1998)

Breast cancer, triple-negative (off-label use): IV: Neoadjuvant therapy (single agent): 75 mg/m2 on day 1 every 3 weeks for 4 cycles (Silver 2010). Additional data may be necessary to further define the role of cisplatin in this setting.

Cervical cancer (off-label use): IV: 75 mg/m2 on day 1 every 3 weeks (in combination with fluorouracil and radiation) for 3 cycles (Morris 1999) or 70 mg/m2 on day 1 every 3 weeks for 4 cycles (in combination with fluorouracil; cycles 1 and 2 given concurrently with radiation) (Peters 2000) or 50 mg/m2 on day 1 every 4 weeks (in combination with radiation and fluorouracil) for 2 cycles (Whitney 1999)

Endometrial carcinoma, recurrent, metastatic, or high-risk (off-label use): IV: 50 mg/m2 on day 1 every 3 weeks (in combination with doxorubicin ± paclitaxel) for 7 cycles or until disease progression or unacceptable toxicity (Fleming 2004)

Esophageal and gastric cancers (off-label uses): IV:

CF regimen: 100 mg/m2 over 30 minutes on days 1 and 29 (preoperative chemoradiation; in combination with fluorouracil) (Tepper 2008)

ECF, ECX regimens: 60 mg/m2 on day 1 every 21 days for up to 8 cycles in combination with epirubicin (E) and either fluorouracil (F) or capecitabine (X) (Cunningham 2008) or

ECF regimen: 60 mg/m2 on day 1 every 21 days for 3 preoperative and 3 postoperative cycles in combination with epirubicin and fluorouracil (Cunningham 2006)

TCF or DCF regimen: 75 mg/m2 on day 1 every 3 weeks (in combination with docetaxel and fluorouracil) until disease progression or unacceptable toxicity (Ajani 2007; Van Cutsem 2006)

Head and neck cancer (off-label use): IV:

Locally-advanced disease: 100 mg/m2 every 3 weeks for 3 doses (with concurrent radiation) (Bernier 2004; Cooper 2004) or 75 mg/m2 every 3 weeks (in combination with docetaxel and fluorouracil) for 4 cycles or until disease progression or unacceptable toxicity (if no disease progression after 4 cycles, chemotherapy was followed by radiation) (Vermorken 2007) or 100 mg/m2 every 3 weeks (in combination with docetaxel and fluorouracil) for 3 cycles or until disease progression or unacceptable toxicity (chemotherapy was followed by chemoradiation) (Posner 2007)

Metastatic disease: 100 mg/m2 every 3 weeks (in combination with fluorouracil and cetuximab) until disease progression or unacceptable toxicity or a maximum of 6 cycles (Vermorken 2008)

Hodgkin lymphoma, relapsed/refractory (off-label use): IV:

DHAP regimen: 100 mg/m2 continuous infusion over 24 hours on day 1 for 2 cycles; median duration between cycle 1 and 2 was 16 days (in combination with dexamethasone and cytarabine) (Josting 2002)

ESHAP regimen: 25 mg/m2/day on days 1 to 4 (in combination with etoposide, methylprednisolone, and cytarabine) every 3 to 4 weeks for 3 or 6 cycles (Aparicio 1999)

Malignant pleural mesothelioma (off-label use): IV: 75 mg/m2 on day 1 of each 21-day cycle (in combination with pemetrexed) (Vogelzang 2003) or 100 mg/m2 on day 1 of a 28-day cycle (in combination with gemcitabine) (Nowak 2002) or 80 mg/m2 on day 1 of a 21-day cycle (in combination with gemcitabine) (van Haarst 2002)

Multiple myeloma (off-label use): IV: VDT-PACE regimen: 10 mg/m2/day administered as a continuous infusion on days 1 to 4 of each cycle; repeat every 4 to 6 weeks (in combination with bortezomib, dexamethasone, thalidomide, doxorubicin, cyclophosphamide, and etoposide) (Lee 2003; Pineda-Roman 2008)

Non-Hodgkin lymphoma, relapsed/refractory: IV:

DHAP regimen: 100 mg/m2 continuous infusion over 24 hours on day 1 every 3 to 4 weeks for 6 to 10 cycles (in combination with dexamethasone and cytarabine) (Velasquez 1988)

ESHAP regimen: 25 mg/m2/day continuous infusion over 24 hours on days 1 to 4 every 3 to 4 weeks for 6 to 8 cycles (in combination with etoposide, methylprednisolone, and cytarabine) (Velasquez 1994)

Non-small cell lung cancer (NSCLC; off-label use): IV: Note: There are multiple cisplatin-containing regimens for the treatment of NSCLC. Listed below are several commonly used regimens:

100 mg/m2 on day 1 every 4 weeks (in combination with etoposide) for 3 to 4 cycles; (Arriagada 2004), or

100 mg/m2 on day 1 every 4 weeks (in combination with vinorelbine) (Kelly 2001; Wozniak 1998), or

100 mg/m2 on day 1 every 4 weeks (in combination with gemcitabine) (Comella 2000), or

80 mg/m2 on day 1 every 3 weeks (in combination with gemcitabine) (Ohe 2007), or

75 mg/m2 on day 1 every 3 weeks (in combination with pemetrexed) for up to 6 cycles or until disease progression or unacceptable toxicity (Scagliotti 2008)

Osteosarcoma (off-label use; combination chemotherapy): Adults < 30 years: IV: 60 mg/m2/day for 2 days on weeks 2, 7, 25, and 28 (neoadjuvant) or weeks 5, 10, 25, and 28 (adjuvant) in combination with methotrexate, leucovorin, doxorubicin, cyclophosphamide, bleomycin, and dactinomycin (Goorin 2003)

Penile cancer, metastatic (off-label use): IV: 25 mg/m2 over 2 hours on days 1, 2, and 3 every 3 to 4 weeks (in combination with paclitaxel and ifosfamide) for 4 cycles (Pagliaro 2010)

Small cell lung cancer (SCLC; off-label use): IV:

Limited-stage disease: 60 mg/m2 on day 1 every 3 weeks for 4 cycles (in combination with etoposide and concurrent radiation) (Turrisi 1999)

Extensive-stage disease: 80 mg/m2 on day 1 every 3 weeks (in combination with etoposide) for 4 cycles (Lara 2009) or a maximum of 8 cycles (Ihde 1994) or 60 mg/m2 on day 1 every 4 weeks for 4 cycles (in combination with irinotecan) (Lara 2009)

Dosing: Geriatric

Refer to adult dosing. Select dose cautiously and monitor closely in the elderly; may be more susceptible to nephrotoxicity and peripheral neuropathy.

Dosing: Pediatric

VERIFY ANY CISPLATIN DOSE EXCEEDING 100 mg/m2 PER COURSE. Pretreatment hydration is recommended. . Cisplatin is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011).

Germ cell tumors (off-label use; combination chemotherapy): IV: 20 mg/m2/day on days 1 to 5 or 100 mg/m2 on day 1 of a 21-day treatment cycle (Pinkerton 1986)

Hepatoblastoma (off-label use; combination chemotherapy): IV: 80 mg/m2 continuous infusion over 24 hours on day 1 of a 21-day treatment cycle (Pritchard 2000)

Medulloblastoma (off-label use; combination chemotherapy): IV: 75 mg/m2 on either day 0 or day 1 of each chemotherapy cycle (Packer 2006)

Neuroblastoma, high-risk (off-label use; combination chemotherapy): IV: 50 mg/m2/day on days 0 to 3 of a 21-day cycle (cycles 3 and 5) (Naranjo 2011) or 50 mg/m2/day on days 1 to 4 (cycles 3, 5, and 7) (Kushner 1994)

Osteosarcoma (off-label use; combination chemotherapy): IV: 60 mg/m2/day for 2 days on weeks 2, 7, 25, and 28 (neoadjuvant) or weeks 5, 10, 25, and 28 (adjuvant) in combination with methotrexate, leucovorin, doxorubicin, cyclophosphamide, bleomycin, and dactinomycin (Goorin 2003)

Dosing: Renal Impairment

Note: The manufacturer(s) recommend that repeat courses of cisplatin should not be given until serum creatinine is <1.5 mg/dL and/or BUN is <25 mg/dL and use is contraindicated in preexisting renal impairment. The following adjustments have been recommended.

Aronoff 2007:

CrCl 10 to 50 mL/minute: Administer 75% of dose

CrCl <10 mL/minute: Administer 50% of dose

Hemodialysis: Partially cleared by hemodialysis

Administer 50% of dose posthemodialysis

Continuous ambulatory peritoneal dialysis (CAPD): Administer 50% of dose

Continuous renal replacement therapy (CRRT): Administer 75% of dose

Janus 2010: Hemodialysis: Reduce initial dose by 50%; administer post hemodialysis or on nondialysis days.

Kintzel 1995:

CrCl 46 to 60 mL/minute: Administer 75% of dose

CrCl 31 to 45 mL/minute: Administer 50% of dose

CrCl <30 mL/minute: Consider use of alternative drug

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling. However, cisplatin undergoes nonenzymatic metabolism and predominantly renal elimination; therefore, dosage adjustment is likely not necessary.

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012).

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). Prior to infusion, dilute in NS, D51/2NS or D5NS. Do NOT dilute in D5W. The manufacturer recommends dilution in up to 2 liters. Needles or IV administration sets that contain aluminum should not be used in the preparation or administration; aluminum can react with cisplatin resulting in precipitate formation and loss of potency.

Administration

Cisplatin is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Basch 2011; Dupuis 2011; Roila 2010). Pretreatment hydration with 1 to 2 L of fluid is recommended prior to cisplatin administration; adequate post hydration and urinary output (>100 mL/hour) should be maintained for 24 hours after administration.

IV: Infuse over 6 to 8 hours (according to the manufacturer’s labeling); has also been infused (off-label rates) over 30 minutes to 3 hours, at a rate of 1 mg/minute, or as a continuous infusion; infusion rate varies by protocol (refer to specific protocol for infusion details). Do not administer as a rapid IV injection. Also refer to specific protocol for information regarding recommended concomitant hydration and diuretics.

Intraperitoneal (off-label route): Solution was prepared in warmed saline and infused as rapidly as possible through an implantable intraperitoneal catheter (Armstrong 2006).

Needles or IV administration sets that contain aluminum should not be used in the preparation or administration; aluminum may react with cisplatin resulting in precipitate formation and loss of potency.

Vesicant (at higher concentrations); ensure proper needle or catheter placement prior to and during infusion; avoid extravasation.

Extravasation management: If extravasation occurs, stop infusion immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); initiate sodium thiosulfate antidote; elevate extremity.

Sodium thiosulfate 1/6 M solution: Inject 2 mL into existing IV line for each 100 mg of cisplatin extravasated; then consider also injecting 1 mL as 0.1 mL subcutaneous injections (clockwise) around the area of extravasation, may repeat subcutaneous injections several times over the next 3 to 4 hours (Ener 2004).

Dimethyl sulfoxide (DMSO) may also be considered an option: Apply to a region covering twice the affected area every 8 hours for 7 days; begin within 10 minutes of extravasation; do not cover with a dressing (Perez Fidalgo 2012).

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Dietary Considerations

Some products may contain sodium.

Compatibility

Stable in D51/4NS, D51/2NS, D5NS, 1/4NS, 1/3NS, 1/2NS, NS; incompatible with D5W, sodium bicarbonate.

Y-site administration: Incompatible with amifostine, amphotericin B cholesteryl sulfate complex, cefepime, piperacillin/tazobactam, thiotepa.

Storage

Store intact vials at 20°C to 25°C (68°F to 77°F). Protect from light. Do not refrigerate solution (precipitate may form). According to the manufacturer, 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. When diluted for administration, stability is dependent on the chloride ion concentration.

Drug Interactions

Alpha-Lipoic Acid: May diminish the therapeutic effect of CISplatin. Monitor therapy

Aminoglycosides: CISplatin may enhance the nephrotoxic effect of Aminoglycosides. Monitor therapy

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Fosphenytoin-Phenytoin: Platinum Derivatives may decrease the serum concentration of Fosphenytoin-Phenytoin. Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Loop Diuretics: May enhance the nephrotoxic effect of CISplatin. Loop Diuretics may enhance the ototoxic effect of CISplatin. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Taxane Derivatives: Platinum Derivatives may enhance the myelosuppressive effect of Taxane Derivatives. Administer Taxane derivative before Platinum derivative when given as sequential infusions to limit toxicity. Consider therapy modification

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Topotecan: Platinum Derivatives may enhance the adverse/toxic effect of Topotecan. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Vinorelbine: CISplatin may enhance the adverse/toxic effect of Vinorelbine. Specifically, the combination may be associated with a higher risk of granulocytopenia. Monitor therapy

Adverse Reactions

>10%:

Central nervous system: Neurotoxicity (peripheral neuropathy is dose and duration dependent)

Gastrointestinal: Nausea and vomiting (76% to 100%)

Genitourinary: Nephrotoxicity (28% to 36%; acute renal failure and chronic renal insufficiency)

Hematologic & oncologic: Anemia (≤40%), leukopenia (25% to 30%; nadir: Day 18 to 23; recovery: By day 39; dose related), thrombocytopenia (25% to 30%; nadir: Day 18 to 23; recovery: By day 39; dose related)

Hepatic: Increased liver enzymes

Otic: Ototoxicity (children 40% to 60%; adults 10% to 31%; as tinnitus, high frequency hearing loss)

1% to 10%: Local: Local irritation

<1% (Limited to important or life-threatening): Alopecia (mild), ageusia, anaphylaxis, aortic thrombosis (Fernandes, 2011), autonomic neuropathy, bradycardia (Schlumbrecht, 2015), cardiac arrhythmia, cardiac failure, cerebrovascular accident, extravasation, hemolytic anemia (acute), hemolytic-uremic syndrome, hiccups, hypercholesterolemia, hyperuricemia, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, increased serum amylase, leukoencephalopathy, myocardial infarction, neutropenic enterocolitis (Furonaka, 2005), optic neuritis, pancreatitis (Trivedi, 2005), papilledema, peripheral ischemia (acute), phlebitis (Tokuda, 2014), SIADH, tachycardia, thrombotic thrombocytopenic purpura

ALERT: U.S. Boxed Warning

Experienced physician:

Cisplatin should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.

Renal toxicity:

Cumulative renal toxicity associated with cisplatin is severe. Other major dose-related toxicities are myelosuppression, nausea, and vomiting.

Ototoxicity:

Ototoxicity, which may be more pronounced in children, and is manifested by tinnitus or loss of high frequency hearing and, occasionally, deafness, is significant.

Hypersensitivity reactions:

Anaphylactic-like reactions have occurred. Facial edema, bronchoconstriction, tachycardia, and hypotension may occur within minutes of cisplatin administration. Epinephrine, corticosteroids, and antihistamines have been effectively employed to alleviate symptoms.

Medication safety:

Exercise caution to prevent inadvertent cisplatin overdose. Doses greater than 100 mg/m2/cycle once every 3 to 4 weeks are rarely used. Care must be taken to avoid inadvertent cisplatin overdose due to confusion with carboplatin or prescribing practices that fail to differentiate daily doses from total dose per cycle.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [US Boxed Warning]: Myelosuppression is a major dose-related toxicity.

• Extravasation: Cisplatin is a vesicant at higher concentrations, and an irritant at lower concentrations; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation. Local infusion site reactions may occur; monitor infusion site during administration.

• Gastrointestinal events: [US Boxed Warning]: Nausea and vomiting are dose-related toxicities. Cisplatin is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Basch, 2011; Dupuis, 2011; Roila, 2010). Nausea and vomiting are dose-related and may be immediate and/or delayed. Diarrhea may also occur.

• Hypersensitivity reactions: [US Boxed Warning]: Anaphylactic-like reactions have been reported; may include facial edema, bronchoconstriction, tachycardia, and hypotension and may occur within minutes of administration. Symptoms may be managed with epinephrine, corticosteroids, and/or antihistamines.

• Hyperuricemia: Hyperuricemia has been reported with cisplatin use, and is more pronounced with doses >50 mg/m2; consider antihyperuricemic therapy to reduce uric acid levels.

• Neurotoxicity: Severe (and possibly irreversible) neuropathies (including stocking-glove paresthesias, areflexia, and loss of proprioception/vibratory sensation) may occur with higher than recommended doses or more frequent administration; may require therapy discontinuation. Seizures, loss of motor function, loss of taste, leukoencephalopathy, and posterior reversible leukoencephalopathy syndrome (PRES [formerly RPLS]) have also been described.

• Ototoxicity: [US Boxed Warning]: Ototoxicity, which may be more pronounced in children, is manifested by tinnitus and/or loss of high frequency hearing and occasionally deafness; may be significant. Ototoxicity is cumulative and may be severe. Audiometric testing should be performed at baseline and prior to each dose. Certain genetic variations in the thiopurine S-methyltransferase (TPMT) gene may be associated with an increased risk of ototoxicity in children administered conventional cisplatin doses (Pussegoda, 2013). Controversy may exist regarding the role of TPMT variants in cisplatin ototoxicity (Ratain, 2013; Yang, 2013); the association has not been consistent across populations and studies. Children without the TPMT gene variants may still be at risk for ototoxicity. Cumulative dose, prior or concurrent exposure to other ototoxic agents (eg, aminoglycosides, carboplatin), prior cranial radiation, younger age, and type of cancer may also increase the risk for ototoxicity in children (Knight, 2005; Landier, 2014). Pediatric patients should receive audiometric testing at baseline, prior to each dose, and for several years after discontinuing therapy. An international grading scale (SIOP Boston scale) has been developed to assess ototoxicity in children (Brock, 2012).

• Renal toxicity: [US Boxed Warning]: Cumulative renal toxicity associated with cisplatin is severe. Monitor serum creatinine, blood urea nitrogen, creatinine clearance, and serum electrolytes (calcium, magnesium, potassium, and sodium) closely. According to the manufacturer’s labeling, use is contraindicated in patients with preexisting renal impairment and renal function must return to normal prior to administering subsequent cycles; some literature recommends reduced doses with renal impairment. Nephrotoxicity may be potentiated by aminoglycosides.

• Secondary malignancies: Secondary malignancies have been reported with cisplatin in combination with other chemotherapy agents.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Select dose cautiously and monitor closely in elderly patients; they may be more susceptible to nephrotoxicity and peripheral neuropathy.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• Medication safety (usual maximum dose per cycle): [US Boxed Warning]: Doses >100 mg/m2/cycle (once every 3 to 4 weeks) are rare; verify with the prescriber. Exercise caution to avoid inadvertent overdose due to potential sound-alike/look-alike confusion between CISplatin and CARBOplatin or prescribing practices that fail to differentiate daily doses from the total dose per cycle. At the approved dose, cisplatin should not be administered more frequently than once every 3 to 4 weeks.

• Experienced physician: [US Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician. Adequate diagnostic and treatment facilities and appropriate management of potential complications should be readily available.

• Hydration: Patients should receive adequate hydration, with or without diuretics, prior to and for 24 hours after administration; serum electrolytes, particularly magnesium and potassium, should be monitored and replaced as needed during and after therapy.

Monitoring Parameters

Renal function (serum creatinine, BUN, CrCl [baseline and before each cycle]); electrolytes (particularly calcium, magnesium, potassium, and sodium [baseline and before each cycle]); CBC with differential and platelet count (weekly); liver function tests (periodic); urine output, urinalysis; audiography (baseline and prior to each subsequent dose, and following treatment in children), neurologic exam (with high dose); monitor infusion site during infusion

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse effects have been observed in animal reproduction studies. Women of childbearing potential should be advised to avoid pregnancy during treatment. May case fetal harm if administered during pregnancy.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience lack of appetite. Have patient report immediately to prescriber signs of infection, signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, very bad dizziness or passing out, fast heartbeat, more thirst, seizures, feeling very tired or weak, not hungry, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, or nausea or vomiting), signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, or weight gain), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), signs of posterior reversible encephalopathy syndrome (illogical thinking, not alert, vision changes, seizures, or severe headache), hearing impairment, severe nausea, vomiting, tinnitus, bruising, bleeding, loss of strength and energy, burning or numbness feeling, angina, shortness of breath, severe dizziness, passing out, tachycardia, difficulty moving, dark urine, jaundice, or injection site pain or irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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