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CISplatin

Medically reviewed by Drugs.com. Last updated on Jul 2, 2019.

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); 200 mg/200 mL (200 mL)

Solution, Intravenous [preservative free]:

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

Solution Reconstituted, Intravenous [preservative free]:

Generic: 50 mg (1 ea)

Pharmacologic Category

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

Pharmacology

Cisplatin 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: 11 to 12 L/m2

Metabolism

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

Excretion

Cisplatin: Urine (13% to 17% within 1 hour); Platinum: Urine (35% to 51%)

Half-Life Elimination

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

Adults: Cisplatin: 20 to 30 minutes; Platinum: ≥5 days

Protein Binding

Plasma platinum: >90%

Use: Labeled Indications

Bladder cancer, advanced: Treatment of advanced bladder cancer

Ovarian cancer, advanced: Treatment of advanced ovarian cancer

Testicular cancer, advanced: Treatment of advanced testicular cancer

Off Label Uses

Anal carcinoma, squamous cell, metastatic

Data from a retrospective study support the use of cisplatin (in combination with continuous infusion fluorouracil) in the treatment of metastatic squamous cell anal carcinoma [Eng 2014].

Breast cancer (triple-negative)

Data from a small study support the use of cisplatin (as a single agent) in the neoadjuvant treatment of triple-negative breast cancer [Silver 2010].

Cervical cancer

Data from phase III randomized trials support the use of cisplatin (in combination with fluorouracil and radiation) in the management of patients with cervical cancer [Morris 1999], [Peters 2000], [Whitney 1999].

Endometrial carcinoma, recurrent, metastatic, or high-risk

Data from a phase III clinical trial in patients with recurrent, metastatic, or high-risk endometrial carcinoma, support the use of cisplatin (in combination with doxorubicin ± paclitaxel) for the treatment of this condition [Fleming 2004].

Esophageal cancer

Data from a large, randomized, phase III trial support the use of cisplatin in combination with epirubicin and fluorouracil (ECF regimen) pre- and postoperatively for the management of adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus [Cunningham 2006].

Another large phase III trial (REAL-2) investigated whether fluorouracil could be replaced by capecitabine, and cisplatin could be replaced by oxaliplatin, in the ECF regimen for the treatment of esophagogastric cancers; data from the two-by-two design showed that capecitabine and oxaliplatin were inferior to fluorouracil and cisplatin, respectively (in combination with epirubicin) [Cunningham 2008].

Two large phase III trials illustrated that cisplatin in combination with docetaxel and fluorouracil is effective in the treatment of gastric and gastroesophageal cancer [Ajani 2007], [Van Cutsem 2006]. Additionally, data from a small phase III trial (CALGB 9781) supports the use of cisplatin (in combination with fluorouracil and radiation) as preoperative therapy for esophageal cancer [Tepper 2008].

Gastric cancer

Data from a large, randomized, phase III trial support the use of cisplatin in combination with epirubicin and fluorouracil (ECF regimen) pre- and postoperatively for the management of adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus [Cunningham 2006].

Another large phase III trial (REAL-2) investigated whether fluorouracil could be replaced by capecitabine, and cisplatin could be replaced by oxaliplatin, in the ECF regimen for the treatment of esophagogastric cancers; data from the two-by-two design showed that capecitabine and oxaliplatin were inferior to fluorouracil and cisplatin, respectively (in combination with epirubicin) [Cunningham 2008].

Two large phase III trials illustrated that cisplatin in combination with docetaxel and fluorouracil is effective in the treatment of gastric and gastroesophageal cancer [Ajani 2007], [Van Cutsem 2006]. Additionally, data from a small phase III trial (CALGB 9781) supports the use of cisplatin (in combination with fluorouracil and radiation) as preoperative therapy for esophageal cancer [Tepper 2008].

Gestational trophoblastic neoplasia (high-risk)

Data from studies in patients with high-risk metastatic gestational trophoblastic neoplasia support the use of cisplatin (in combination with etoposide, methotrexate, leucovorin, and dactinomycin, [EMA-EP regimen or EP-EMA regimen]) in the treatment of high-risk disease [Ghaemmaghami 2004], [Newlands 2000].

Head and neck cancer (locally advanced disease)

Data from large randomized phase III trials support the use of cisplatin in combination with radiation [Bernier 2004], [Cooper 2004] or in combination with docetaxel and fluorouracil followed by chemoradiation [Posner 2007] for the treatment of locally advanced head and neck cancer. In addition, another large phase III trial combining cisplatin with docetaxel and fluorouracil demonstrated efficacy in patients with unresectable disease [Vermorken 2007].

Head and neck cancer (metastatic disease)

Cisplatin (in combination with fluorouracil and cetuximab) demonstrated efficacy in a large phase III randomized trial of patients with recurrent or metastatic head and neck cancer [Vermorken 2008].

Hepatobiliary cancer (advanced)

Data from a large randomized phase III study support the use of cisplatin (in combination with gemcitabine) in the treatment of unresectable, recurrent, or metastatic biliary tract cancers, including cholangiocarcinoma, gallbladder cancer, or ampullary carcinoma [Valle 2010].

Hodgkin lymphoma

Data from phase II studies support the use of cisplatin in combination with dexamethasone and cytarabine (DHAP regimen) or in combination with etoposide, methylprednisolone and cytarabine (ESHAP regimen) for the treatment of relapsed/refractory Hodgkin lymphoma [Aparicio 1999], [Josting 2002].

Malignant pleural mesothelioma

Data from a large randomized phase III trial support the use of cisplatin in combination with pemetrexed for the treatment of malignant pleural mesothelioma [Vogelzang 2003]. Data from two additional phase II studies support the use of cisplatin in combination with gemcitabine for management of this disease state [Nowak 2002], [van Haarst 2002].

Multiple myeloma

Data from large randomized phase III trials support the use of cisplatin (in combination with bortezomib, dexamethasone, thalidomide, doxorubicin, cyclophosphamide, and etoposide) as induction therapy for the management of multiple myeloma [Lee 2003], [Pineda-Roman 2008].

Non-Hodgkin lymphoma, relapsed/refractory

Data from phase II studies support the use of cisplatin in combination with dexamethasone and cytarabine (DHAP regimen) or in combination with etoposide, methylprednisolone and cytarabine (ESHAP regimen) for the treatment of relapsed/refractory Hodgkin lymphoma [Velasquez 1988], [Velasquez 1994].

Non-small cell lung cancer

Data from multiple large randomized phase III trials have demonstrated the efficacy of cisplatin-based chemotherapy regimens for the treatment of non-small cell lung cancer [Arriagada 2004], [Comella 2000], [Kelly 2001], [Ohe 2007], [Scagliotti 2008], [Wozniak 1998].

Osteosarcoma

Data from a large international randomized trial support the use of cisplatin (in combination with doxorubicin and methotrexate) as both neoadjuvant and adjuvant treatment in patients with resectable osteosarcoma [Marina 2015], [Whelan 2015].

Penile cancer (metastatic)

Data from a small phase II study support the use of neoadjuvant chemotherapy (cisplatin, paclitaxel, and ifosfamide) in patients with penile cancer who have bulky regional lymph node metastases [Pagliaro 2010].

Small cell lung cancer (extensive-stage disease)

Data from large randomized phase III trials support the use of cisplatin in combination with etoposide [Ihde 1994], [Lara 2009] or irinotecan [Lara 2009] for the treatment of extensive stage small cell lung cancer.

Based on American Society of Clinical Oncology Guidelines for Treatment of Small-Cell Lung Cancer, platinum-based therapy in combination with either etoposide or irinotecan is recommended over other chemotherapy regimens for extensive stage disease [Rudin 2015].

Small cell lung cancer (limited-stage disease)

Data from a large randomized phase III trial support the combination of cisplatin and etoposide with concurrent radiotherapy in the management of limited stage small cell lung cancer [Turrisi 1999].

Based on American Society of Clinical Oncology Guidelines for Treatment of Small-Cell Lung Cancer, platinum-based therapy in combination with either etoposide or irinotecan is recommended over other chemotherapy regimens for limited stage disease [Rudin 2015].

Thymomas (advanced or metastatic)

Data from phase II trials support the use of cisplatin in combination with vincristine, cyclophosphamide, and doxorubicin [Fornasiero 1991] or in combination with doxorubicin and cyclophosphamide [Loehrer 1994] for the treatment of advanced thymomas. Data from another study support the use of cisplatin (in combination with etoposide) for the treatment of recurrent or metastatic malignant thymoma [Giaccone 1996].

Additional Off-Label Uses

Central nervous system tumors; Melanoma (metastatic); Neuroendocrine tumors; Pancreatic cancer (advanced); Primary CNS lymphoma; Prostate cancer; Unknown primary cancers

Contraindications

Severe hypersensitivity to cisplatin or any component of the formulation

Dosing: Adult

Note: Administer appropriate pretreatment hydration and maintain adequate hydration and urinary output for 24 hours following cisplatin administration. Cisplatin is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Hesketh 2017; Roila 2016). Cisplatin doses exceeding 100 mg/m2 per treatment course are rarely used and should be verified with the prescriber.

Anal carcinoma, squamous cell, metastatic (off-label use): IV: 75 mg/m2 on day 1 every 4 weeks (in combination with continuous infusion fluorouracil) (Eng 2014).

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

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).

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 (advanced disease): 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)

Gestational trophoblastic neoplasia, high-risk metastatic disease (off-label use): IV:

EMA-EP regimen:60 to 80 mg/m2 on day 8 every 2 weeks (in combination with etoposide, methotrexate, leucovorin, and dactinomycin); continue for 2 to 4 treatment cycles after a normal hCG level (Ghaemmaghami 2004)

EP-EMA regimen: EP: 25 mg/m2/dose over 4 hours each for 3 consecutive doses on day 1 (in combination with etoposide), alternating weekly with EMA (etoposide, methotrexate, leucovorin, and dactinomycin) (Newlands 2000)

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

Locally-advanced disease: 100 mg/m2 on day 1 every 3 weeks for 3 doses (with concurrent radiation) (Bernier 2004; Cooper 2004) or 75 mg/m2 on day 1 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 on day 1 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 on day 1 every 3 weeks (in combination with fluorouracil and cetuximab) until disease progression or unacceptable toxicity or a maximum of 6 cycles (Vermorken 2008)

Hepatobiliary cancer, advanced (off-label use): IV: 25 mg/m2 over 2 hours on days 1 and 8; repeat cycle every 3 weeks (in combination with gemcitabine) for 4 to 8 cycles (Valle 2010)

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 every 3 weeks (in combination with pemetrexed) (Vogelzang 2003) or 100 mg/m2 on day 1 every 4 weeks (in combination with gemcitabine) (Nowak 2002) or 80 mg/m2 on day 1 every 3 weeks (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 (off-label use): IV:

DHAP regimen (for DLBCL): 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): IV: Adults ≤40 years of age: 60 mg/m2/day (over 4 hours) for 2 days (total of 120 mg/m2/cycle) of weeks 1 and 6 (neoadjuvant therapy) and then 60 mg/m2/day (over 4 hours) for 2 days (total of 120 mg/m2/cycle) of weeks 12 and 17 (adjuvant therapy) in combination with methotrexate, leucovorin, and doxorubicin (Marina 2015; Whelan 2015)

Ovarian cancer, advanced: IV: 75 to 100 mg/m2 once every 3 to 4 weeks or (off-label combination) 75 mg/m2 every 3 weeks (in combination with paclitaxel) (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)

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 (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)

Testicular cancer, advanced: IV: 20 mg/m2 once daily 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)

Thymomas, advanced or metastatic (off-label use): IV:

CAP regimen: 50 mg/m2 over at least 1 hour on day 1 every 3 weeks for up to 8 cycles (in combination with cyclophosphamide and doxorubicin) (Loehrer 1994)

ADOC regimen: 50 mg/m2 on day 1 every 3 weeks (in combination with doxorubicin, vincristine, and cyclophosphamide) (Fornasiero 1991)

PE regimen: 60 mg/m2 over 1 hour on day 1 every 3 weeks (in combination with etoposide) (Giaccone 1996)

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

Note: Dosing and frequency may vary by protocol and/or treatment phase; refer to specific protocol. Cisplatin is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Basch 2011; Dupuis 2011; Roila 2010).

TO PREVENT POSSIBLE OVERDOSE, VERIFY ANY CISPLATIN DOSE EXCEEDING 100 mg/m2 PER COURSE (eg, every 3 to 4 week cycle). Pretreatment hydration is recommended.

Germ cell tumors: Limited data available:

Cushing 2004:

Infants: IV: 0.7 mg/kg on days 1 to 5 of a 21-day cycle (in combination with bleomycin and etoposide)

Children and Adolescents: IV: 20 mg/m2 on days 1 to 5 of a 21-day cycle (in combination with bleomycin and etoposide)

Pinkerton 1986: Children and Adolescents: IV: 100 mg/m2on day 1 of a 21-day cycle (in combination with bleomycin and vinblastine or etoposide)

Lopes 2016: Children and Adolescents:

Intermediate risk: PE regimen: IV: 35 mg/m2 on days 1, 2, and 3 of a 21-day cycle for 3 cycles (weeks 1, 4, and 7) in combination with etoposide; a fourth cycle may be considered depending on response

High risk: PEI regimen: IV: 35 mg/m2 on days 1, 2, and 3 of a 21-day cycle for 4 cycles (weeks 1, 4, 7, and 11) in combination with etoposide and ifosfamide; a fifth or sixth cycle may be considered depending on response

Hepatoblastoma: Limited data available: IV:

Continuous IV infusion:

Infants and Children <10 kg: PLADO regimen: 2.7 mg/kg/day continuous infusion over 24 hours on day 1 of a 21-day cycle in combination with doxorubicin for 4 to 6 cycles (Pritchard 2000)

Children ≥10 kg and Adolescents:

Monotherapy: Standard risk: 80 mg/m2/day continuous infusion over 24 hours every 2 weeks on day 1

Combination therapy: PLADO regimen: 80 mg/m2/day continuous infusion over 24 hours on day 1 of a 21-day cycle in combination with doxorubicin (Perilongo 2004; Perilongo 2009; Pritchard 2000) or doxorubicin and sorafenib (Schmid 2012)

Intermittent infusion (over 6 hours):

Infants and Children <10 kg: 3 mg/kg over 6 hours on day 1 of a 21-day cycle for 4 to 8 cycles in combination with vincristine and fluorouracil or continuous infusion doxorubicin (Douglass 1993; Malogolowkin 2008; Ortega 2000)

Children ≥10 kg and Adolescents: 90 mg/m2 over 6 hours on day 1 of a 21-day cycle for 4 to 8 cycles in combination with vincristine and fluorouracil or continuous infusion doxorubicin (Douglass 1993; Malogolowkin 2008; Ortega 2000)

Medulloblastoma: Limited data available: Children ≥3 years and Adolescents: IV: 75 mg/m2 every 6 weeks on either day 0 in combination with vincristine and cyclophosphamide or day 1 in combination with lomustine and vincristine of each chemotherapy cycle for 8 cycles (Packer 2006; Packer 2013)

Medulloblastoma/PNET, relapsed or refractory: Very limited data available: Children and Adolescents: IV: 60 mg/m2 on day 0 every 4 weeks (in combination with irinotecan, vincristine, cyclophosphamide, and etoposide) (Kim 2013)

Neuroblastoma, high-risk: Limited data available: Infants, Children, and Adolescents: IV: 50 mg/m2 on days 0 to 3 of a 21-day cycle in combination with etoposide (cycles 3 and 5) (Kreisman 2013; Naranjo 2011) or 50 mg/m2 on days 1 to 4 in combination with etoposide (cycles 3, 5, and 7) (Kushner 1994)

Osteosarcoma: Limited data available: Children and Adolescents: IV: 60 mg/m2/day for 2 days at weeks 2, 7, 25, and 28 (neoadjuvant) or weeks 5, 10, 25, and 28 (adjuvant) in combination with doxorubicin (Goorin 2003) or 120 mg/m2/day at weeks 0, 5, 12, and 17 in combination with doxorubicin (Meyers 2005)

Dosing: Adjustment for Toxicity

Consider alternative treatments or dose reductions for toxicities.

Hematologic toxicity: May require treatment interruption and/or dosage reduction.

Hypersensitivity: Discontinue cisplatin immediately (and manage appropriately) for severe hypersensitivity reactions; do not rechallenge with cisplatin in patients with a history of severe hypersensitivity reactions.

Neurotoxicity: Consider discontinuing cisplatin if symptomatic grade 3 or 4 peripheral neuropathy develops.

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

Do not use needles or IV administration sets that contain aluminum for cisplatin preparation or administration; aluminum may react with cisplatin resulting in precipitate formation and loss of potency.

Lyophilized powder: Reconstitute each 50 mg vial with 50 mL SWFI, resulting in a reconstituted concentration of 1 mg/mL. Dilute for infusion in 1 to 2 L of a compatible IV solution (with or without mannitol 37.5 g).

Solution: Prior to infusion, dilute in NS, D51/2NS or D5NS. Do NOT dilute in D5W. The manufacturer recommends dilution in up to 2 liters.

Administration

Cisplatin is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Hesketh 2017; Roila 2016). Administer appropriate pretreatment hydration and maintain adequate hydration and urinary output for 24 hours following cisplatin administration.

IV: Cisplatin has been infused over 30 minutes to 4 hours, at a rate of 1 mg/minute, or as a continuous infusion (off-label rates); 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, diuretics, and (for combination regimens) the administration sequence.

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).

Dietary Considerations

Some products may contain sodium.

Storage

Lyophilized powder: Store intact vials at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Store in original carton prior to reconstitution to protect from light. The reconstituted solution is stable for 20 hours at 20°C to 25°C (68°F to 77°F); do not refrigerate. Solution removed from amber vial should be protected from light if not used within 6 hours.

Solution: 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 in D51/4NS, D51/2NS, D5NS, 1/4NS, 1/3NS, 1/2NS, or NS, cisplatin 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

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

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

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. 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

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. 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

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

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

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

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

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

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

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

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. Consider therapy modification

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%, postmarketing, and/or case reports: Alopecia (mild), ageusia, anaphylaxis, autonomic neuropathy, bradycardia (Schlumbrecht 2015), bronchoconstriction, cardiac arrhythmia, cardiac failure, cerebral arteritis, cerebrovascular accident, dehydration, diarrhea, dysgeusia (Rehwaldt 2009), extravasation, heart block, hemolytic anemia (acute), hemolytic-uremic syndrome, hiccups, hypercholesterolemia, hyperuricemia, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, hypotension, increased serum amylase, ischemic heart disease, leukoencephalopathy, Lhermitte's sign, mesenteric ischemia (acute; Morgan 2011), myocardial infarction, neutropenic enterocolitis (Furonaka 2005), optic neuritis, pancreatitis (Trivedi 2005), papilledema, peripheral ischemia (acute), phlebitis (Tokuda 2015), reversible posterior leukoencephalopathy syndrome, seizure, SIADH, skin rash, tachycardia, tetany, thrombosis (aortic; Fernandes 2011), thrombotic thrombocytopenic purpura, vasospasm (acute arterial; Morgan 2011), vision color changes, vision loss

ALERT: U.S. Boxed Warning

Myelosuppression:

Cisplatin can cause severe myelosuppression with fatalities due to infections. Monitor blood counts accordingly. Interruption of therapy may be required.

Nausea and vomiting:

Cisplatin can cause severe nausea and vomiting. Use highly effective antiemetic premedication.

Nephrotoxicity:

Cisplatin can cause severe renal toxicity, including acute renal failure. Severe renal toxicities are dose-related and cumulative. Ensure adequate hydration and monitor renal function and electrolytes. Consider dose reductions or alternative treatments in patients with renal impairment.

Peripheral neuropathy:

Cisplatin can cause dose-related peripheral neuropathy that becomes more severe with repeated courses of the drug.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [US Boxed Warning]: Cisplatin may cause severe myelosuppression; fatalities due to infection (secondary to myelosuppression) have been reported. Monitor blood counts (prior to cisplatin initiation, prior to each subsequent treatment course, and as clinically indicated). May require treatment interruption. Fever has been reported in patients with neutropenia. Monitor closely for signs/symptoms of infection (during and after cisplatin treatment). Geriatric patients may be at higher risk for hematologic toxicity. Hematologic toxicity may require dosage modification.

• 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. Monitor infusion site during administration. Local soft tissue toxicity has been reported following cisplatin extravasation; the severity of the local tissue toxicity appears to be related to the cisplatin concentration. Cisplatin infusion solutions at a concentration >0.5 mg/mL may result in tissue cellulitis, fibrosis, necrosis, pain, edema, and erythema.

• Gastrointestinal toxicity: [US Boxed Warning]: Cisplatin can cause severe nausea and vomiting; use highly effective antiemetic premedication. Cisplatin is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011; Hesketh 2017; Paw Chow Sing 2019; Roila 2016). Nausea and vomiting are dose-related and may be immediate and/or delayed, usually lasting up to 72 hours, although may persist for up to 1 week. Diarrhea may also occur.

• Hypersensitivity: Cisplatin may cause severe hypersensitivity reactions, including anaphylaxis (some fatal). Manifestations of hypersensitivity include facial edema, wheezing, tachycardia, and hypotension. Hypersensitivity reactions have occurred within minutes of administration (in patients with prior cisplatin exposure). Monitor for hypersensitivity reactions. Ensure supportive equipment and medications for management of severe hypersensitivity reactions are available. Discontinue cisplatin immediately (and manage appropriately) for severe hypersensitivity reactions. Do not rechallenge with cisplatin in patients with a history of severe hypersensitivity reactions. Cross-reactivity between platinum-based antineoplastic agents has been reported; severe hypersensitivity reactions have recurred following rechallenge with a different platinum agent (case reports).

• Nephrotoxicity: [US Boxed Warning]: Cisplatin can cause severe renal toxicity, including acute renal failure. Severe renal toxicities are dose-related and cumulative. Ensure adequate hydration (before, during, and following cisplatin administration); monitor renal function and electrolytes. Consider dose reductions or alternative treatments in patients with renal impairment. Acute renal failure may be prolonged and severe with repeat cisplatin courses. The onset of nephrotoxicity usually begins during the second week following a cisplatin dose. Patients with renal impairment at baseline, geriatric patients, those taking other nephrotoxic medications and/or patients who are not well hydrated may be at higher risk for nephrotoxicity. Monitor serum creatinine, blood urea nitrogen, creatinine clearance, and serum electrolytes (calcium, magnesium, potassium, and sodium) prior to treatment initiation and as clinically indicated. Magnesium supplementation may be indicated. According to clinical treatment guidelines, consider alternate treatments or cisplatin dose reductions for patients with baseline renal impairment or who develop significantly reduced creatinine clearance during cisplatin treatment.

• Neurotoxicity: [US Boxed Warning]: Cisplatin may cause dose-related peripheral neuropathy that becomes more severe with repeated cisplatin courses. Neurotoxicity has been reported following a single cisplatin dose. Neuropathy may be delayed, with an onset occurring 3 to 8 weeks after the last cisplatin dose. Neuropathy manifestations include paresthesias with a stocking-glove distribution, areflexia, and loss of proprioception and vibratory sensation. Neuropathy may progress following cisplatin discontinuation. In some patients, peripheral neuropathy may be irreversible. Perform a neurological examination prior to cisplatin initiation, as appropriate during therapy, and following completion of cisplatin therapy. Consider discontinuing cisplatin if symptomatic peripheral neuropathy develops. Geriatric patients may be more susceptible to peripheral neuropathy. Seizures, loss of motor function, loss of taste, leukoencephalopathy, and posterior reversible leukoencephalopathy syndrome (PRES [formerly RPLS]) have also been described.

• Ocular toxicity: Optic neuritis, papilledema, and cortical blindness have been reported in patients receiving standard recommended cisplatin doses. Blurred vision and altered color perception have been reported after the use of regimens with higher or more frequent cisplatin doses. Altered color perception manifests as a loss of color discrimination, particularly in the blue-yellow axis and irregular retinal pigmentation of the macular area on fundoscopic exam. Improvement and/or total recovery usually occurs following cisplatin discontinuation, although may be delayed.

• Ototoxicity: Cisplatin may cause cumulative and severe ototoxicity. Ototoxicity is manifested by tinnitus, high frequency (4,000 to 8,000 Hz) hearing loss, and/or decreased ability to hear normal conversational tones. Ototoxicity may occur during or after treatment; may be unilateral or bilateral. Deafness following the initial cisplatin dose has been reported. Vestibular toxicity has also been reported. Ototoxic effects may be more severe and/or detrimental in pediatric patients, particularly those <5 years of age. The prevalence of hearing loss in pediatric patients is estimated to be 40% to 60%. Additional risk factors for ototoxicity include simultaneous cranial irradiation, treatment with other ototoxic medications, and/or renal impairment. Consider audiometric and vestibular testing, particularly in all pediatric patients receiving cisplatin. 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). In a randomized phase III study in pediatric patients with hepatoblastoma (standard risk) receiving cisplatin, a single dose of sodium thiosulfate (STS) was administered following each cisplatin dose; compared to a control group that did not receive STS, patients in the group receiving STS had a lower incidence of hearing loss and similar 3-year event-free survival and overall survival (Brock 2018).

• Secondary malignancies: Secondary malignancies, including acute leukemias, have been reported with cisplatin, usually when used in combination with other chemotherapy agents.

• Tumor lysis syndrome: Hyperuricemia has been reported with cisplatin; consider antihyperuricemic therapy to reduce uric acid levels.

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 hematologic toxicity, infections, nephrotoxicity, and/or peripheral neuropathy.

Other warnings/precautions:

• Medication safety: Doses >100 mg/m2/cycle (once every 3 to 4 weeks) are rare; verify with the prescriber. At the approved dose, cisplatin should not be administered more frequently than once every 3 to 4 weeks. 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.

Monitoring Parameters

Monitor blood counts (prior to cisplatin initiation, prior to each subsequent treatment course, and as clinically indicated). Monitor serum creatinine, blood urea nitrogen, creatinine clearance, and serum electrolytes (calcium, magnesium, potassium, and sodium) prior to treatment initiation and as clinically indicated. Consider audiometric and vestibular testing, particularly in all pediatric patients receiving cisplatin (pediatric patients should receive audiometric testing at baseline, prior to each dose, and for several years after discontinuing therapy). Monitor for hypersensitivity reactions. Monitor for signs/symptoms of infection (during and after cisplatin treatment), neuropathy, ocular toxicity, and secondary malignancies. Monitor infusion site during administration.

Pregnancy Considerations

Cisplatin has been reported to cross the human placenta. Cisplatin may cause fetal harm if administered to a pregnant female.

Females of reproductive potential should use effective contraception during treatment and for 14 months after the last cisplatin dose. Verify pregnancy status prior to treatment initiation in females of reproductive potential. Male patients with female partners of reproductive potential should use effective contraception during treatment and for 11 months after the last cisplatin dose.

Cisplatin has been associated with cumulative dose-dependent ovarian failure, premature menopause, impairment of spermatogenesis (oligospermia, azoospermia; possibly irreversible). and reduced female and male fertility.

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 hair loss, lack of appetite, nausea, vomiting, or diarrhea. Have patient report immediately to prescriber signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), hearing impairment, tinnitus, severe loss of strength and energy, burning or numbness feeling, severe dizziness, passing out, tachycardia, vision changes, or severe injection site redness, burning, pain, edema, 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 health care 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.

Further information

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