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CISPLATIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Cisplatin is a platinum-containing antineoplastic agent.

Specific Substances

    1) CDDP
    2) Cisplatino (Spanish)
    3) cis-DDP
    4) cis-Diamminedichloroplatinum (II)
    5) cis-Platinum
    6) DDP
    7) NCI-c 55776
    8) NIOSH/RTECS TP 2450000
    9) NSC 119875
    10) Peyrone's chloride
    11) Platinum Diamminodichloride
    12) CAS 15663-27-1
    1.2.1) MOLECULAR FORMULA
    1) Pt-Cl2-H6-N2 (Prod Info cisplatin IV injection, 2008)

Available Forms Sources

    A) FORMS
    1) Available as 1 mg/mL injection in 50 mL and 100 mL multidose vials (Prod Info cisplatin intravenous injection, 2015).
    B) USES
    1) Cisplatin is indicated for combination therapy in metastatic testicular tumors, combination or as single agent therapy in metastatic ovarian tumors, and as a single agent in advanced bladder cancer (Prod Info cisplatin intravenous injection, 2015).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Cisplatin is a widely used anticancer agent. Most commonly, cisplatin is used to treat cancers of the testes, ovary, bladder, head and neck, esophagus, stomach, and lung.
    B) PHARMACOLOGY: Cisplatin binds to DNA bases, forming inter- and intra-strand crosslinks, which causes conformational changes, leading to DNA strand breaks and inhibiting DNA synthesis.
    C) TOXICOLOGY: An extension of therapeutic effects with inhibition of DNA synthesis affecting rapidly dividing cells first (eg, bone marrow, GI tract).
    D) EPIDEMIOLOGY: Inadvertent iatrogenic overdose has occurred, but is rare.
    E) WITH THERAPEUTIC USE
    1) Adverse effects are expected with therapeutic doses. Nausea, vomiting, renal insufficiency (28% to 36%), electrolyte abnormalities, and neurotoxicity (peripheral neuropathy, mostly sensorineural) are the most often reported events. Nephrotoxicity is generally the dose-limiting effect. Hypersensitivity reactions may be observed in patients treated with more than 5 cycles of cisplatin therapy.
    F) WITH POISONING/EXPOSURE
    1) Immediate effects (hours to days) include: severe nausea and vomiting and, less often, diarrhea. Early signs (within days) of toxicity are most commonly renal insufficiency and electrolyte abnormalities (hyponatremia, hypokalemia, hypomagnesemia, hypocalcemia). Ototoxicity (tinnitus, high-frequency deafness), peripheral neuropathy (mostly sensorineural), and bone marrow suppression are common, whereas retinopathy, seizures, hepatotoxicity, pancreatitis, respiratory failure, and overt encephalopathy are less often observed.
    0.2.20) REPRODUCTIVE
    A) Cisplatin is classified as FDA pregnancy category D. Normal pregnancies have been reported following cisplatin use alone and in combination with other chemotherapeutic agents. In studies with mice, cisplatin administration has demonstrated embryotoxicity and teratogenicity. In general, antineoplastic agents when given during the first trimester are believed to cause increases in the risk of congenital malformations, but when given during the second or third trimesters are believed to only increase the risk of growth retardation. Women of childbearing age should be cautioned against becoming pregnant while undergoing treatment with cisplatin.
    0.2.21) CARCINOGENICITY
    A) Acute leukemia has rarely occurred in patients treated with cisplatin, usually with other leukemogenic agents.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Cisplatin plasma levels are not clinically useful or readily available.
    C) Closely monitor renal function, hepatic enzymes, and electrolytes.
    D) Monitor daily CBC with differential to detect bone marrow depression. Nadirs in circulating platelets and leukocytes typically occur between days 18 to 23 (range 7.5 to 45), with the majority of patients recovering by day 39 (range 13 to 62).
    E) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    F) Nerve conduction studies may be useful to evaluate neuropathy and audiometry to evaluate hearing loss.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Aggressive IV fluid resuscitation with normal saline 3 to 6 L per day. Target urine output 1 to 3 mL/kg/hr. Avoid nephrotoxic drugs. Administer amifostine as soon as possible to prevent/limit nephrotoxicity (dose 910 mg/m(2) once daily as an intravenous infusion over 15 minutes). Treat nausea and vomiting with high-dose dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, promethazine or prochlorperazine), corticosteroids (eg, dexamethasone), benzodiazepines (eg, lorazepam), 5-HT3 serotonin antagonists (eg, ondansetron, dolasetron, or granisetron), and/or antipsychotics (eg, haloperidol); diphenhydramine may be required to prevent dystonic reactions from dopamine antagonists, phenothiazines, and antipsychotics. Patients with severe neutropenia should be placed in protective isolation; administer granulocyte colony stimulating factor (filgrastim or sargramostim). Platelet and red cell transfusions may be necessary.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Aggressive IV fluid resuscitation with normal saline 3 to 6 L per day. Target urine output 1 to 3 mL/kg/hr. Avoid nephrotoxic drugs. Administer amifostine as soon as possible to prevent/limit nephrotoxicity (dose 910 mg/m(2) once daily as an intravenous infusion over 15 minutes). Consider administration of sodium thiosulfate, ideally within 1 to 2 hours of overdose. In case of large overdoses, consider early plasmapheresis. Patients with severe neutropenia should be placed in protective isolation; administer granulocyte colony stimulating factor (filgrastim or sargramostim). Platelet and red cell transfusions may be necessary. Severe nausea and vomiting may respond to a combination of agents from different drug classes. Administer high-dose dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, promethazine or prochlorperazine), corticosteroids (eg, dexamethasone), benzodiazepines (eg, lorazepam), 5-HT3 serotonin antagonists (eg, ondansetron, dolasetron, or granisetron), and/or antipsychotics (eg, haloperidol); diphenhydramine may be required to prevent dystonic reactions from dopamine antagonists, phenothiazines, and antipsychotics.
    C) DECONTAMINATION
    1) PREHOSPITAL: Not helpful since overdose most often occurs by the intravenous route.
    2) HOSPITAL: Activated charcoal and/or gastric lavage are not helpful since overdose most often occurs by the intravenous route.
    D) AIRWAY MANAGEMENT
    1) Consider orotracheal intubation in patients with significant encephalopathy (ie, agitation, delirium), seizures, or respiratory failure.
    E) ANTIDOTE
    1) Amifostine reduces cisplatin-induced nephrotoxicity and neutropenia when administered prior to cisplatin, there are no studies on it's use after cisplatin overdose. However, if amifostine is being utilized as a remedy for cisplatin overdose, it should be administered as soon as possible after an overdose (dose 910 mg/m(2) once daily as an intravenous infusion over 15 minutes). Sodium thiosulfate has been prophylactically administered in patients treated with cisplatin to prevent neurotoxicity and nephrotoxicity, and has been used in several cases of overdose. While there are no controlled studies of its use in overdose, sodium thiosulfate has limited toxic effects and it should be considered after significant overdose. It should ideally be administered within 1 to 2 hours of overdose, with a loading dose of 4 g sodium thiosulfate/m(2) intravenously over 15 minutes. This can be followed by an infusion of 12 g/m(2) over 6 hours or 2.7 g/m(2) per day in 3 divided doses. The optimal duration of therapy is not known. It is not known if administration of thiosulfate and amifostine is more beneficial than administration of amifostine alone.
    F) MYELOSUPPRESSION
    1) Administer colony stimulating factors following a significant overdose as these patients are at risk for severe neutropenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.
    G) NEUTROPENIA
    1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).
    H) FEBRILE NEUTROPENIA
    1) If fever (38.3 C) develops during neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia of 7 days or more; unstable; significant comorbidities): IV monotherapy with either piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia of less than 7 days; clinically stable; no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.
    I) TOXIC NEPHROPATHY
    1) Aggressive IV fluid resuscitation with normal saline 3 to 6 L per day. Target urine output 1 to 3 mL/kg/hr. Avoid nephrotoxic drugs. For prevention of cisplatin-induced nephrotoxicity, administer amifostine. The recommended dose is 910 mg/m(2) administered once daily as an intravenous infusion, over a 15-minute period.
    J) EXTRAVASATION INJURY
    1) If extravasation occurs, stop the infusion. Disconnect the IV tubing, but leave the cannula or needle in place. Attempt to aspirate the extravasated drug from the needle or cannula. If possible, withdraw 3 to 5 mL of blood and/or fluids through the needle/cannula. Elevate the affected area. Apply ice packs for 15 to 20 minutes at least 4 times daily. Do not apply excessive cold to avoid tissue injury. Cold can cause local vasoconstriction and reduces fluid absorption. Administer analgesia for severe pain. If pain persists, there is concern for compartment syndrome, or injury is apparent, an early surgical consult should be considered. Close observation of the extravasated area is suggested. If tissue sloughing, necrosis or blistering occurs, treat as a chemical burn (ie, antiseptic dressings, silver sulfadiazine, antibiotics when applicable). Surgical or enzymatic debridement may be required. Risk of infection is increased in chemotherapy patients with reduced neutrophil count following extravasation. Consider culturing any open wounds. Monitor the site for the development of cellulitis, which may require antibiotic therapy.
    2) DIMETHYL SULFOXIDE (DMSO): Treat site with topical DMSO (for a minimum of 7 days and maximum of 14 days); however, if blistering develops, discontinue DMSO and review site.
    3) SODIUM THIOSULFATE (SODIUM HYPOSULFITE): There are no clinical reports of the use of sodium thiosulfate following cisplatin extravasation. Its use for cisplatin extravasation is based on the ability of sodium thiosulfate to inactivate cisplatin. For extravasation of large amounts (greater than 20 mL) of highly concentrated (greater than 0.5 mg/mL solutions) prepare a 0.17 moles/L solution by mixing 4 mL sodium thiosulfate 10% weight/volume with 6 mL sterile water for injection. Inject into extravasation site. Another source recommended the following dosing: inject 3 to 10 mL subQ into extravasation site.
    K) INTRATHECAL INJECTION
    1) No clinical reports are available. The following information is derived from experience with other antineoplastic drugs. Keep patient upright if possible. Immediately drain at least 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free normal saline or lactated ringers). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline or lactated ringers through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 18 to 24 hr). FFP (25 mL FFP/liter NS or LR) or albumin 5% have also been used for perfusion; may be useful because of high protein binding of cisplatin. Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.
    L) ENHANCED ELIMINATION
    1) Cisplatin is highly protein bound and can be removed by plasmapheresis. There is limited experience in the use of plasmapheresis after overdose, but it should be performed as soon as possible after significant overdose. The optimal volume, timing and duration of plasmapheresis is not known; monitor cisplatin concentrations, if possible, to guide therapy.
    M) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management. Patients with cisplatin overdose need to be admitted.
    2) OBSERVATION CRITERIA: Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), daily monitoring of CBC with differential until bone marrow suppression is resolved, and monitoring of serum electrolytes, renal function, and hepatic enzymes.
    3) CONSULT CRITERIA: Consult an oncologist, a medical toxicologist and/or a poison center for assistance in managing patients with cisplatin overdose.
    4) TRANSFER CRITERIA: Patients with large overdoses may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    N) PITFALLS
    1) Symptoms in patients may be delayed (particularly myelosuppression), so reliable follow up is imperative. Patients taking these medications may have severe co-morbidities and access to other drugs with significant toxicity.
    O) PHARMACOKINETICS
    1) Maximal plasma levels are achieved within 60 minutes following an intravenous bolus of 50 to 100 mg/m(2) of cisplatin. Protein binding is greater than 90%; CNS penetration is poor. Cisplatin is converted to inactive metabolites by non-enzymatic conjugation to sulfhydryl groups. Elimination is mainly by the renal route (greater than 90%), and is dose-dependent (apparent half-life is 1 to 28 days).
    P) TOXICOKINETICS
    1) Apparent elimination half-life may be up to 28 days in overdose.
    Q) DIFFERENTIAL DIAGNOSIS
    1) Differential diagnosis includes other chemotherapeutic agents.

Range Of Toxicity

    A) TOXICITY: Expect toxicity with therapeutic doses. Mild toxicity occurs with doses of 180 mg/m(2) or less, moderate toxicity may occur with doses of 180 to 300 mg/m(2), and severe toxicity has been reported with doses greater than 300 mg/m(2). Doses of 400 mg/m(2) are usually fatal. ADULT: Deaths have been reported with a total cisplatin dose of 640 mg over 4 days and 750 mg over 1 day. PEDIATRIC: A 3-year-old child died after receiving 400 mg/m(2).
    B) THERAPEUTIC DOSE: ADULT: 50 to 100 mg/m(2) IV as a single dose every 3 to 4 weeks. In earlier years, high-dose regimens involved using up to 200 mg/m(2) of cisplatin. PEDIATRIC: Cisplatin monotherapy, 80 mg/m(2), has been administered as a continuous 24-hr IV infusion every 14 days for 4 cycles in a clinical trial.

Clinical Effects

Summary Of Exposure

    A) USES: Cisplatin is a widely used anticancer agent. Most commonly, cisplatin is used to treat cancers of the testes, ovary, bladder, head and neck, esophagus, stomach, and lung.
    B) PHARMACOLOGY: Cisplatin binds to DNA bases, forming inter- and intra-strand crosslinks, which causes conformational changes, leading to DNA strand breaks and inhibiting DNA synthesis.
    C) TOXICOLOGY: An extension of therapeutic effects with inhibition of DNA synthesis affecting rapidly dividing cells first (eg, bone marrow, GI tract).
    D) EPIDEMIOLOGY: Inadvertent iatrogenic overdose has occurred, but is rare.
    E) WITH THERAPEUTIC USE
    1) Adverse effects are expected with therapeutic doses. Nausea, vomiting, renal insufficiency (28% to 36%), electrolyte abnormalities, and neurotoxicity (peripheral neuropathy, mostly sensorineural) are the most often reported events. Nephrotoxicity is generally the dose-limiting effect. Hypersensitivity reactions may be observed in patients treated with more than 5 cycles of cisplatin therapy.
    F) WITH POISONING/EXPOSURE
    1) Immediate effects (hours to days) include: severe nausea and vomiting and, less often, diarrhea. Early signs (within days) of toxicity are most commonly renal insufficiency and electrolyte abnormalities (hyponatremia, hypokalemia, hypomagnesemia, hypocalcemia). Ototoxicity (tinnitus, high-frequency deafness), peripheral neuropathy (mostly sensorineural), and bone marrow suppression are common, whereas retinopathy, seizures, hepatotoxicity, pancreatitis, respiratory failure, and overt encephalopathy are less often observed.

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) Loss of vision has been reported in several patients following an overdose of cisplatin (Charlier et al, 2004; Sheikh-Hamad et al, 1997; Chu et al, 1993).
    a) CASE REPORT: A patient developed PAPILLEDEMA and headache without vision disturbance. This patient also received doxorubicin.
    b) The papilledema resolved when the patient was placed on corticosteroid therapy for increased cerebrospinal fluid pressure. Papilledema was reported in a child treated with doxorubicin and cisplatin (Grant, 1986).
    2) CASE REPORT: Retrobulbar neuritis was reported in a patient. There was a reduction in vision but the optic disc was reported to be normal (Grant, 1986).
    3) Reversible ocular toxicity has been reported in patients following cisplatin overdose (Choi et al, 2002; Chu et al, 1993).
    a) CASE REPORT: Reversible loss of vision occurred in a patient following an overdose of cisplatin 480 mg (280 mg/m(2)) WITHOUT hydration. Vision returned to normal after 9 months; however, color vision remained abnormal with a blue-yellow color deficiency (Chu et al, 1993).
    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) Tinnitus and high frequency hearing loss has been reported in 30% of patients treated with 50 mg/m(2) cisplatin as a single dose. Changes secondary to cisplatin may be progressive and irreversible (Sheikh-Hamad et al, 1997; Kopelman et al, 1988; Schweitzer et al, 1986) .
    2) A high risk of ototoxicity has been associated with single, high-dose, rapid or bolus infusions. Decreased risk has been associated with lower daily doses for 5 days by slow intravenous infusion (Vermorken et al, 1983).
    a) CASE REPORT: Clinical deafness was reported in a 69-year-old man with recurrent squamous cell carcinoma of the head and neck, 2 days after completion of the second course of cisplatin, 150 mg/m(2) by intravenous infusion over 1 hour (Guthrie & Gynther, 1985).
    3) VESTIBULAR TOXICITY: Transient dizziness may occur (Prod Info cisplatin IV injection, 2008; Schweitzer et al, 1986).
    B) WITH POISONING/EXPOSURE
    1) Ototoxicity (reversible or irreversible) has been reported following cisplatin overdose (Yamada et al, 2010; Choi et al, 2002; Erdlenbruch et al, 2002; Chu et al, 1993; Schiller et al, 1989; Gebbia, 1989; Fassoulaki & Pavlou, 1989) and may occur within 2 to 7 days following overdose (Tsang et al, 2009).
    a) CASE REPORT: A 36-year-old man with testicular choriocarcinoma developed a severe, irreversible bilateral sensorineural hearing loss for which he required hearing aids following an overdosage of cisplatin (480 mg/m(2) over 4 days) during the third cycle of chemotherapy (Schiller et al, 1989).
    b) CASE REPORT: A 59-year-old woman suffered hearing impairment following an overdose of cisplatin (Fassoulaki & Pavlou, 1989).
    c) CASE REPORT: A 68-year-old woman developed permanent hearing loss 4 days after overdose with cisplatin 280 mg/m(2) without hydration (Chu et al, 1993). In a similar case, an adult developed permanent hearing loss within 3 days of an inadvertent overdose of cisplatin 750 mg; the patient died from multiorgan failure 16 days after administration (Charlier et al, 2004).
    d) CASE REPORT: A 46-year-old woman, with non-small cell lung cancer, developed severe nausea and vomiting, hearing loss, tinnitus, acute renal failure, and myelosuppression after unintentionally receiving 75 mg/m(2)/day of cisplatin for 3 days instead of the prescribed 25 mg/m(2)/day. Except for evidence of persistent subclinical renal impairment, the patient recovered following plasmapheresis for 2 days and aggressive supportive therapy (Hofmann et al, 2006).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) SUPRAVENTRICULAR TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Paroxysmal supraventricular tachycardia occurred in a 60-year-old woman following 5 days of cisplatin 20 mg/m(2) intravenously daily and etoposide 75 mg/m(2) intravenously daily.
    1) A baseline ECG performed prior to initiation of chemotherapy demonstrated a sinus rhythm with asymptomatic rare ectopic ventricular beats. There was no history of previous cardiac disease.
    2) Three weeks after this first course of cisplatin and etoposide, a second course was given. The paroxysmal supraventricular tachycardia (220 beats/minute) with abnormal conduction occurred on the second day of the 5 day regimen.
    3) The tachycardia was treated with intravenous verapamil 5 mg. There were no electrolyte abnormalities found. Cardiac toxicity has not been reported with etoposide. Hydration with cisplatin was with oral fluids (Fassio et al, 1986).
    B) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 35-year-old man with no history of cardiac abnormalities developed asymptomatic sinus bradycardia within 30 to 110 minutes of starting cisplatin infusions (25 mg/m(2) over 3 hours) during 6 consecutive cycles for treatment of relapsed Hodgkin's disease. The lowest heart rate during these episodes ranged from 32 to 42 beats/minute with normal blood pressure and serum electrolytes. Bradycardia spontaneously resolved within 90 to 180 minutes in each instance. The mechanism of this adverse effect is unknown but may involve a direct effect upon myocardial cells or the cardiac conduction system (Altundag et al, 2001).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) HYPERVENTILATION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Hyperpnea was reported on day 4 following an overdose of cisplatin in a 59-year-old woman (Fassoulaki & Pavlou, 1989).
    B) APNEA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Acute respiratory failure developed in a 59-year-old woman on day 6 following an overdose of cisplatin. She was intubated and mechanically ventilated for 2 days (Fassoulaki & Pavlou, 1989).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache may occur (Fassoulaki & Pavlou, 1989; Grant, 1986).
    B) NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) Neurotoxicity has been reported with high-dose cisplatin chemotherapy when nephrotoxicity was prevented.
    b) Cisplatin neurotoxic syndrome has been characterized by autonomic neuropathy, central extrapyramidal disorders, gait difficulties, loss or reduction of deep tendon reflexes, peripheral glove-stocking sensory neuropathy, retrobulbar neuritis, and seizures (Schweitzer et al, 1986).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 36-year-old man with testicular choriocarcinoma developed decreased hearing, thick speech, impairment of speech, impairment of taste, and numbness of the hands and feet one week after receiving an overdose of 480 mg/m(2) by continuous infusion over 4 days. On follow-up 18 months later, dysarthria, taste disturbance, and left-hand weakness had resolved (Schiller et al, 1989).
    b) CASE REPORT: A 48-year-old man developed neurotoxicity (paresthesia on lower extremities, sudden aggressive behavior, visual hallucinations) after receiving a massive cisplatin overdose (400 mg/(2) over a 4 day period) (Choi et al, 2002).
    C) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures have been reported with cisplatin therapy (Prod Info cisplatin IV injection, 2008).
    b) Occipital lobe seizures, characterized by visual hallucinations followed by a grand mal seizure in one patient and cortical blindness, ictal nystagmus, and a confusional state in two patients, have occurred following infusion in standard dosage (Kattah et al, 1987).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A patient experienced generalized seizures followed by vivid hallucinations after overdose (Chu et al, 1993).
    D) SECONDARY PERIPHERAL NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) Cisplatin therapy has been associated with the development of peripheral neuropathy (Prod Info cisplatin IV injection, 2008; Greenspan & Treat, 1988) .
    b) CASE SERIES: Three patients developed neuropathy 3 to 8 weeks after the last dose of cisplatin. The neuropathy progressed over an additional 1 to 2 months. Two of the patients improved and became asymptomatic over 8 to 27 months. The third patient died (Mollman et al, 1988).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Numbness of upper and lower extremities occurred in a 59-year-old woman following administration of a total dose of 450 mg of cisplatin over 3 days (Fassoulaki & Pavlou, 1989).
    b) CASE REPORT: A 38-year-old woman developed oliguric renal failure, hepatotoxicity, ototoxicity, peripheral neuropathy, blindness, and severe myelosuppression following a massive cisplatin overdose. Although improvement in renal function was observed after using N-acetylcysteine, she died of overwhelming Klebsiella pneumoniae sepsis, complicated by disseminated intravascular coagulation and severe leukopenia (Sheikh-Hamad et al, 1997).
    E) CLOUDED CONSCIOUSNESS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Confusion followed by loss of consciousness were reported on day 6 following an overdose of cisplatin in a 59-year-old woman (Fassoulaki & Pavlou, 1989).
    F) TOXIC ENCEPHALOPATHY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: An 84-year-old woman developed somnolence, agitation, disorientation, and distractibility following a course of cisplatin chemotherapy for adenocarcinoma of the ovary. Onset occurred approximately 7 days after therapy was begun; similar symptoms developed after rechallenge 4 months later. EEG revealed periodic lateralized epileptiform discharges, but convulsions did not develop. Treatment was discontinued with no permanent neurological deficit (Lyass et al, 1998).
    b) CASE REPORT: A 45-year-old woman with squamous cell carcinoma of the cervix developed somnolence, vision difficulties, and a severe headache after receiving 6 cycles of cisplatin (total dose of 240 mg/m(2)) combined with radiotherapy. A few hours later, the patient developed symmetrical tetraparesis and a generalized seizure. A CT scan of the brain ruled out bleeding and metastases, and blood and CSF tests were normal; however, an MRI showed several white matter lesions periventricularly and in the right occipital lobe. Following supportive treatment and cessation of chemotherapy, the patient recovered completely within one week, confirming a diagnosis of cisplatin-induced toxic leukoencephalopathy (Sterzing et al, 2007).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting onset may be delayed 24 to 120 hours following high-dose cisplatin administration (Kris et al, 1985).
    2) WITH POISONING/EXPOSURE
    a) Nausea and vomiting were reported 1 hour after an infusion delivering a total dose of cisplatin 200 mg/m(2) (Brivet et al, 1986).
    b) CASE REPORT: A 46-year-old woman, with non-small cell lung cancer, developed severe nausea and vomiting, hearing loss, tinnitus, acute renal failure, and myelosuppression after unintentionally receiving 75 mg/m(2)/day of cisplatin for 3 days instead of the prescribed 25 mg/m(2)/day. Except for evidence of persistent subclinical renal impairment, the patient recovered following plasmapheresis for 2 days and aggressive supportive therapy (Hofmann et al, 2006).
    c) CASE REPORT: A 63-year-old man, with laryngeal cancer, experienced nausea and severe vomiting after inadvertently receiving 176 mg of cisplatin daily for 3 days (total dose 528 mg) instead of the prescribed dose of 100 mg/m(2) on day 1 of his chemotherapy regimen. The vomiting persisted for 12 days despite treatment with metoclopramide and methylprednisolone (Gebbia, 1989).
    B) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) The onset of diarrhea occurred one hour after the end of an infusion that delivered a total dose of cisplatin 200 mg/m(2) (Brivet et al, 1986).
    C) THIRST FINDING
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Increased thirst was reported in a patient that received 200 mg/m(2) cisplatin by intravenous infusion (Brivet et al, 1986).
    D) TASTE SENSE ALTERED
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A metallic taste was reported in a patient that received 200 mg/m(2) cisplatin by intravenous infusion (Brivet et al, 1986).
    E) PANCREATITIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 48-year-old man developed acute pancreatitis (amylase 2874 Units/L) after receiving a massive cisplatin overdose (400 mg/m(2) over a 4 day period) (Choi et al, 2002).
    b) CASE REPORT: Acute pancreatitis (amylase 178 units/L) was reported in a 67-year-old man who inadvertently received 80 mg/m(2) for 3 consecutive days instead of the prescribed regimen of 80 mg/m(2) on day 1 of the cycle only (Yamada et al, 2010).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INJURY OF LIVER
    1) WITH THERAPEUTIC USE
    a) Liver toxicity has been reported consisting of transiently elevated alkaline phosphatase, serum bilirubin, and SGOT (Prod Info cisplatin IV injection, 2008).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Reversible hepatotoxicity occurred following a cisplatin overdose (single dose of 480 mg without hydration) (Chu et al, 1993).
    b) CASE REPORT: A 38-year-old woman developed oliguric renal failure, hepatotoxicity, ototoxicity, peripheral neuropathy, blindness, and severe myelosuppression following a massive cisplatin overdose. Although improvement in renal function was observed after using N-acetylcysteine, she died of overwhelming Klebsiella pneumoniae sepsis, complicated by disseminated intravascular coagulation and severe leukopenia (Sheikh-Hamad et al, 1997).
    c) CASE REPORT: A 48-year-old man developed reversible hepatic failure (AST 2090 International Units/L, ALT 1180 International Units/L, total bilirubin 2.61 mg/dL) and cholestasis after receiving a massive cisplatin overdose (400 mg/m(2) over a 4 day period) (Choi et al, 2002).
    d) CASE REPORT: Transient hepatic enzyme elevations occurred in a 46-year-old woman, with non-small cell lung cancer, who unintentionally received 75 mg/m(2)/day of cisplatin for 3 days instead of the prescribed dose of 25 mg/m(2)/day. The hepatic enzyme levels normalized following plasmapheresis for 2 days (Hofmann et al, 2006).
    e) CASE REPORT: Elevated hepatic transaminase concentrations (ALT 229 units/L, AST 251 units/L) were reported in a 67-year-old man who inadvertently received cisplatin 80 mg/m(2) for 3 consecutive days instead of the prescribed regimen of 80 mg/m(2) on day 1 of the cycle only (Yamada et al, 2010).
    f) CASE REPORT: A 63-year-old man, with laryngeal cancer, developed elevated serum transaminase concentrations (SGOT 220, SGPT 280) after inadvertently receiving 176 mg of cisplatin daily for 3 days (total dose 528 mg) instead of the prescribed dose of 100 mg/m(2) on day 1 of his chemotherapy regimen. The transaminase concentrations gradually normalized over a 3-week period (Gebbia, 1989).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) Acute renal failure occurred 5 days after an intravenous infusion of cisplatin 200 mg/m(2) (Brivet et al, 1986). Acute renal failure resolved in 17 days.
    b) CASE REPORT: A 36-year-old man with testicular choriocarcinoma developed acute oliguric renal failure 6 days after completion of a cisplatin infusion delivering 480 mg/m(2) over 4 days during the third cycle of chemotherapy.
    1) He required hemodialysis for one month. His serum creatine stabilized at 3.5 mg/dL with a creatinine clearance of 26 mL/min 18 months after the overdose (Schiller et al, 1989).
    c) CASE REPORT: A 68-year-old woman developed acute renal failure after overdose with cisplatin 280 mg/m(2) without hydration. By 6 months there was no recovery of renal function (Chu et al, 1993).
    d) CASE REPORT: A 38-year-old woman developed oliguric renal failure, hepatotoxicity, ototoxicity, peripheral neuropathy, blindness, and severe myelosuppression following a massive cisplatin overdose. On the 8th day after the initial cisplatin treatment, she was treated with N-acetylcysteine (first dose of 140 mg/kg body wt, followed by 70 mg/kg every 4 hours for 4 days). Although improvement in renal function was observed, she died of overwhelming Klebsiella pneumoniae sepsis, complicated by disseminated intravascular coagulation and severe leukopenia (Sheikh-Hamad et al, 1997).
    e) CASE REPORT: A 48-year-old man with laryngeal cancer developed non-oliguric renal failure (serum creatinine 4.3 mg/dL, BUN 69.7 mg/dL) after receiving a massive cisplatin overdose (100 mg/m(2) for 4 days; 400 mg/m(2) total) without intravenous prehydration. Nine cycles of plasma exchange were performed from day 5 through 19; his plasma cisplatin concentration decreased from 2,470 ng/mL to 216 ng/mL and the total bilirubin decreased to less than 2 mg/dL (Choi et al, 2002).
    f) CASE REPORT: A 14-year-old girl developed an acute renal failure (creatinine clearance of 11 mg/dL, serum creatinine concentration of 3.8 mg/dL) after receiving a massive cisplatin overdose (360 mg/m(2) instead of 120 mg/m(2)). To reverse or reduce renal toxicity, sodium thiosulfate (a loading infusion of 4 g/m(2), a maintenance dose of 2.7 g/m(2)/day in 3 doses and continued for a total of 13 days) was initiated 70 hours after completion of the cisplatin infusion. Approximately 4 weeks after cisplatin overdose, renal function was completely restored (Erdlenbruch et al, 2002).
    g) CASE REPORT: A 46-year-old woman, with non-small cell lung cancer, developed severe nausea and vomiting, hearing loss, tinnitus, acute renal failure, and myelosuppression after unintentionally receiving 75 mg/m(2)/day of cisplatin for 3 days instead of the prescribed 25 mg/m(2)/day. At admission, laboratory studies revealed serum creatinine and BUN levels of 2.6 mg/dL (normal 0.6 to 1.3) and 114 mg/dL (normal 10 to 45), respectively. Except for evidence of persistent subclinical renal impairment (glomerular filtration rate 73 mL/min/1.73 m(2) {normal 95 to 160} and BUN 47 mg/dL 271 days post-overdose), the patient recovered following plasmapheresis for 2 days and aggressive supportive therapy (Hofmann et al, 2006).
    h) CASE REPORT: A 63-year-old man, with laryngeal cancer, experienced renal toxicity (BUN 190 mg percent, serum creatinine 2.6 mg percent, creatinine clearance 20 mL/min) after inadvertently receiving 176 mg of cisplatin daily for 3 days (total dose 528 mg) instead of the prescribed dose of 100 mg/m(2) on day 1 of his chemotherapy regimen. The patient's renal dysfunction became evident on day 3, but gradually resolved by day 28 (Gebbia, 1989).
    B) TOXIC NEPHROPATHY
    1) WITH THERAPEUTIC USE
    a) Nephrotoxicity is a dose-limiting toxicity associated with cisplatin therapy. When nephrotoxicity is controlled, nausea and vomiting and neurotoxicity become the dose-limiting toxicities of cisplatin therapy (DeBroe & Wedeen, 1986).
    C) HEMOLYTIC UREMIC SYNDROME
    1) WITH THERAPEUTIC USE
    a) A 16-year-old man developed hemolytic uremic syndrome 9 months after cisplatin (150 mg/m(2) every 2 to 3 weeks) administration for osteosarcoma (Canpolat et al, 1994).
    D) RENAL TUBULAR DISORDER
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Renal tubular function was severely impaired for several weeks following cisplatin administration of 90 mg/m(2) for 5 days (total dose 450 mg/m(2)) in a 6-month-old infant.
    1) There were high daily bicarbonate losses necessitating bicarbonate replacement therapy. Serum creatinine was not elevated in this patient (Haupt et al, 1989).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Metabolic acidosis was reported 5 days following an overdose of cisplatin (200 mg/m(2)) by intravenous infusion (Brivet et al, 1986).
    B) RESPIRATORY ALKALOSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Respiratory alkalosis developed in a 59-year-old woman on day 6 following an overdose of cisplatin resulting from hyperpnea that began on day 4 (Fassoulaki & Pavlou, 1989).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) INCIDENCE: Bone marrow suppression occurs in 25% to 30% of patients receiving cisplatin therapy (Prod Info cisplatin IV injection, 2008).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Bone marrow aplasia and fever were reported 5 days after an overdose of cisplatin (200 mg/m(2)) by intravenous infusion (Brivet et al, 1986). Pancytopenia resolved in 17 days.
    b) CASE REPORT: A 68-year-old woman developed bone marrow suppression 7 days after overdose with cisplatin 280 mg/m(2) without hydration. Her blood cell counts reached their nadir by 11 days after overdose. She was treated with granulocyte-macrophage colony-stimulating factor and leukocyte and platelet counts began to recover by day 14 (Chu et al, 1993).
    c) CASE REPORT: A 38-year-old woman developed oliguric renal failure, hepatotoxicity, ototoxicity, peripheral neuropathy, blindness, and severe myelosuppression following a massive cisplatin overdose. Although improvement in renal function was observed after using N-acetylcysteine, she died of overwhelming Klebsiella pneumoniae sepsis, complicated by disseminated intravascular coagulation and severe leukopenia (Sheikh-Hamad et al, 1997).
    d) CASE REPORT: Bone marrow suppression (WBC 1700/mcL; ANC 816/mcL) was reported in a patient 7 days after receiving a massive cisplatin overdose (400 mg/m(2) over a 4-day period). He recovered after receiving GM-CSF (Choi et al, 2002).
    e) CASE REPORT: Despite treatment with G-CSF, myelosuppression (WBC less than 100/mcL) persisted for 3 weeks after a 14-year-old girl received a massive cisplatin overdose (360 mg/m(2)) (Erdlenbruch et al, 2002).
    f) CASE REPORT: A 46-year-old woman, with non-small cell lung cancer, developed severe nausea and vomiting, hearing loss, tinnitus, acute renal failure, and myelosuppression after unintentionally receiving 75 mg/m(2)/day of cisplatin for 3 days instead of the prescribed 25 mg/m(2)/day. Laboratory data revealed a leukocyte count of 0.47 g/L (normal 4.4 to 11.3), a hemoglobin level of 8.9 g/dL (normal 12 to 15.3), and a platelet count of 14 G/L (normal 140 to 440). Except for evidence of persistent subclinical renal impairment, the patient recovered following plasmapheresis for 2 days and aggressive supportive therapy (Hofmann et al, 2006).
    g) CASE REPORT: A 63-year-old man, with laryngeal cancer, developed myelosuppression after inadvertently receiving 176 mg of cisplatin daily for 3 days (total dose 528 mg) instead of the prescribed dose of 100 mg/m(2) on day 1 of his chemotherapy regimen. His platelet and white blood cell counts reached their nadir (platelet count 64,000/mcL, WBC 2,400/mcL) approximately 12 days following initiation of chemotherapy (9 days after discovery of the medication error). The platelet and WBC counts completely recovered by day 18 (Gebbia, 1989).
    B) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Cisplatin 40 mg/m(2)/day for 5 days by intravenous infusion over 4 hours produced thrombocytopenia (less than 25,000 cells/mm(3)) with a nadir of 18 days (Gandara et al, 1985).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 14-year-old girl developed thrombocytopenia (below 10,000/mcL) after receiving a massive cisplatin overdose (360 mg/m(2)). She was given several erythrocyte and platelet transfusions (Erdlenbruch et al, 2002).
    C) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Cisplatin 40 mg/m(2)/day for 5 days by intravenous infusion over 4 hours produced granulocytopenia (less than 1,500 cells/mm(3)) with a nadir at 25 days. No bleeding, peripheral neuropathy or hearing loss was observed (Gandara et al, 1985).
    D) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Coomb's test negative anemia has been reported with therapeutic doses following the 3rd and 4th course of cisplatin combination chemotherapy in 2 patients. There was no evidence of renal failure or hemolysis in either patient. Anemia presented with a severe fall in hemoglobin (Kumar & Dua, 1987).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) EXTRAVASATION INJURY
    1) WITH THERAPEUTIC USE
    a) Moderately severe cellulitis and fibrosis following an extravasation of cisplatin has been observed (Lewis & Medina, 1980).
    b) CASE REPORT: A 20 mL solution containing 15 mg of cisplatin was extravasated in the medial part of the forearm in a 57-year-old man with inoperable gastric adenocarcinoma. An infiltrated zone, with cutaneous hyperesthesia, retraction of bicep tendon, inhibiting extension of the forearm at 120 degrees, and induration of the veins infused were noted one month after the extravasation. Full recovery was reported by 2 months after the incident (Louvet et al, 1989).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) Anaphylactic-like reactions to cisplatin may occur within minutes of administration with prior exposure to the drug. Bronchoconstriction, facial edema, hypotension, and tachycardia have been associated with hypersensitivity reactions (Prod Info cisplatin IV injection, 2008).
    b) Five anaphylactoid reactions occurred in 3 patients during the evaluation of an intraperitoneal cisplatin plus hyperthermia protocol (Hebert et al, 1995). There was a correlation between high-dose cisplatin (ie, 100 mg/m(2)) with short infusion time and anaphylaxis.
    c) INTRAPERITONEAL INFUSION: A patient developed sweating, generalized erythema, pruritus, nausea, vomiting, abdominal pain, and angioedema 3 minutes into the third cycle of intraperitoneal cisplatin. The patient was a 33-year-old woman with ovarian cancer receiving consolidation therapy with paclitaxel and cisplatin. The infusion was immediately stopped. The administration of intravenous theophylline, methylprednisolone, and diphenhydramine relieved the symptoms. Intraperitoneal carboplatin replaced the cisplatin for the fourth cycle. No side effects were observed (Ozguroglu et al, 1999).

Reproductive

    3.20.1) SUMMARY
    A) Cisplatin is classified as FDA pregnancy category D. Normal pregnancies have been reported following cisplatin use alone and in combination with other chemotherapeutic agents. In studies with mice, cisplatin administration has demonstrated embryotoxicity and teratogenicity. In general, antineoplastic agents when given during the first trimester are believed to cause increases in the risk of congenital malformations, but when given during the second or third trimesters are believed to only increase the risk of growth retardation. Women of childbearing age should be cautioned against becoming pregnant while undergoing treatment with cisplatin.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) Teratogenicity has been reported during animal studies with cisplatin (Prod Info cisplatin intravenous injection, 2015).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Cisplatin is classified by the manufacturer as FDA pregnancy category D (Prod Info cisplatin intravenous injection, 2015).
    2) Do not administer this drug to a pregnant woman (Prod Info cisplatin intravenous injection, 2015).
    B) EMBRYO/FETAL RISK
    1) A systematic review, in which 24 studies and 47 pregnancies involving the use of cisplatin were identified, found that cisplatin was safe and effective to use during the second and third trimesters in the treatment of patients with cervical cancer. Cisplatin was administered either as monotherapy or in combination with bleomycin, 5-fluorouracil, paclitaxel, vincristine, or vincristine and bleomycin in these patients. The 47 pregnancies resulted in the birth of 47 live newborns (Zagouri et al, 2013).
    C) FETAL/NEONATAL ADVERSE REACTIONS
    1) In general, antineoplastic agents when given during the first trimester are believed to cause increases in the risk of congenital malformations, but when given during the second or third trimesters are believed to only increase the risk of growth retardation (Glantz, 1994; Doll et al, 1988). Depending upon the nature of the malignancy, the progression of the disease, and how advanced the gestation, chemotherapy can in some cases be deferred allowing fetal maturation to occur, and in some cases earlier-than-term delivery provides an acceptable compromise between maternal and fetal risk (Cunningham et al, 1993; Doll et al, 1988).
    2) Leukopenia, neutropenia, and bilateral hearing loss were observed in an infant born at 27 weeks gestation. The mother had been treated for 3 days with bleomycin, etoposide, and cisplatin 1 week before delivery. Leukopenia and neutropenia resolved by day 13; hearing loss may have been caused by maternal and neonatal gentamicin therapy or maternal cisplatin therapy. Etoposide was thought to have caused the neutropenia, because it is the myelosuppressive of the 3 chemotherapeutic agents given (Raffles et al, 1989).
    D) LACK OF EFFECT
    1) A 40-year-old primigravida was treated for ovarian cancer at 20 weeks gestation. The patient received initial chemotherapy of cisplatin and cyclophosphamide. After 2 courses of this therapy, carboplatin was substituted for cisplatin, and therapy was continued. At 36 weeks, a grossly normal 3600 g infant was delivered (APGAR scores of 9/9). Cisplatin-DNA adducts were found in amniotic cells and in placental tissue, but not in the infant's blood at 3 and 12 months of age. Growth, neurologic findings, hematologic parameters, and renal function were normal at 12 months of age (Henderson et al, 1993).
    E) ANIMAL STUDIES
    1) Embryotoxicity has been reported during animal studies with cisplatin (Prod Info cisplatin intravenous injection, 2015).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Cisplatin has been found in human breast milk (Prod Info cisplatin intravenous injection, 2015).
    2) Discontinue nursing or discontinue treatment with cisplatin (Prod Info cisplatin intravenous injection, 2015)
    3) CASE REPORT: A 29-year-old woman was treated with IV cisplatin 70 mg weekly for 4 cycles for treatment of adenocarcinoma of the uterine cervix. The patient also received an additional cisplatin dose. Milk samples were collected at a variety of time points starting at 4.25 hours after the first cisplatin dose and ending at 69.58 hours after administration. Platinum concentrations were quantifiable for the first 13 hours post-dose and were considered above the detection limit for up to 57 hours post-dose. At 66 and 70 hours post-dose, platinum concentration levels were no longer detectable and additional measurements were not performed. The estimated initial elimination rate constant was 0.068 hours(-1) and the calculated half-life was 10.2 hours. The platinum exposure for ingestion by an exclusively breastfed infant was 8.8 mcg +/- 1.5 mcg (range, 7.3 to 10.3 mcg) (Hays et al, 2013).
    4) CASE REPORT: A 24-year-old woman received cisplatin 30 mg/m(2) IV over 4 hours on days 1 to 5 with hyperhydration, etoposide 120 mg/m(2) on days 1, 3, and 5, and bleomycin 30 mg on days 2, 9, and 16, for treatment of an entodermal sinus tumor of the left ovary which began 6 days after a cesarean delivery at 33 weeks' gestation. Breast milk and blood collected on the third day of chemotherapy, 30 minutes before cisplatin infusion, contained platinum concentrations of 0.9 mg/L and 0.8 mg/L, respectively (De Vries et al, 1989).
    3.20.5) FERTILITY
    A) MALE FERTILITY DECREASED
    1) Azoospermia was present in 19% of conventionally-treated patients and in 47% of patients on a high-dose regimen (Petersen et al, 1994).
    a) A cumulative cisplatin dose of 600 mg/m(2) produced severe oligospermia or azoospermia in 100% of patients (Petersen et al, 1994).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Acute leukemia has rarely occurred in patients treated with cisplatin, usually with other leukemogenic agents.
    3.21.3) HUMAN STUDIES
    A) LEUKEMIA
    1) Acute leukemia has rarely occurred in patients treated with cisplatin, usually in combination with other leukemogenic agents (Prod Info cisplatin IV injection, 2008).
    3.21.4) ANIMAL STUDIES
    A) MALIGNANCY
    1) RATS: When cisplatin 1 mg/kg was given as an intraperitoneal dose 3 times per week for 3 weeks to 50 BD IX rats, 33 animals died within 455 days after the first application. Thirteen of the deaths were related to malignancies (12 cases of leukemia and 1 of renal fibrosarcoma) (Prod Info cisplatin IV injection, 2008).

Genotoxicity

    A) Mutagenicity has been demonstrated in bacteria. Chromosome aberrations have occurred in animal cells in tissue culture (Prod Info cisplatin IV injection, 2008). Cisplatin has also been reported to cause DNA repair, DNA damage, DNA inhibition, mutations, sex chromosome loss and nondisjunction, sister chromatid exchange, gene conversion, and mitotic recombination in various bacterial or human cell models ((RTECS, 1989)).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Cisplatin plasma levels are not clinically useful or readily available.
    C) Closely monitor renal function, hepatic enzymes, and electrolytes.
    D) Monitor daily CBC with differential to detect bone marrow depression. Nadirs in circulating platelets and leukocytes typically occur between days 18 to 23 (range 7.5 to 45), with the majority of patients recovering by day 39 (range 13 to 62).
    E) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    F) Nerve conduction studies may be useful to evaluate neuropathy and audiometry to evaluate hearing loss.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Closely monitor renal function, hepatic enzymes, and electrolytes (including magnesium).
    a) Monitor electrolytes for hypomagnesemia, hypocalcemia, hypokalemia, and hypophosphatemia. Should imbalance occur, correct with administration of supplemental electrolytes as is appropriate (Willox et al, 1986).
    2) Cisplatin plasma levels are not clinically useful or readily available.
    B) HEMATOLOGIC
    1) Monitor daily CBC with differential to detect bone marrow suppression.
    2) Nadirs in circulating platelets and leukocytes typically occur between days 18 to 23 (range 7.5 to 45), with the majority of patients recovering by day 39 (range 13 to 62) after therapeutic doses(Prod Info cisplatin IV injection, 2008).
    3) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor vital signs and mental status.
    b) Nerve conduction studies may be useful to evaluate neuropathy and audiometry to evaluate for hearing loss.
    c) Monitor sensory potentials especially with intra-arterial administration.
    1) Visual evoked potential and brainstem auditory evoked potential may provide early evidence of toxicity (Maiese et al, 1992).

Methods

    A) SPECTROSCOPY/SPECTROMETRY
    1) Free or total platinum in plasma, urine and tissues has been determined by flameless atomic absorption spectrometry (Erdlenbruch et al, 2002; Baselt & Cravey, 1989).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no data to support home management. Patients with cisplatin overdose need to be admitted.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with cisplatin overdose.
    6.3.2.4) PATIENT TRANSFER/PARENTERAL
    A) Patients with large overdoses may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), daily monitoring of CBC with differential until bone marrow suppression is resolved, and monitoring of serum electrolytes, renal function, and hepatic enzymes.

Monitoring

    A) Monitor vital signs and mental status.
    B) Cisplatin plasma levels are not clinically useful or readily available.
    C) Closely monitor renal function, hepatic enzymes, and electrolytes.
    D) Monitor daily CBC with differential to detect bone marrow depression. Nadirs in circulating platelets and leukocytes typically occur between days 18 to 23 (range 7.5 to 45), with the majority of patients recovering by day 39 (range 13 to 62).
    E) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    F) Nerve conduction studies may be useful to evaluate neuropathy and audiometry to evaluate hearing loss.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Not helpful since overdose most often occurs by the intravenous route.
    6.5.3) TREATMENT
    A) GENERAL TREATMENT
    1) Treatment should include recommendations listed in the PARENTERAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is unlikely to be of benefit due to the rapid and high degree of protein binding (Tsang et al, 2009; Prod Info cisplatin IV injection, 2008).
    B) PLASMAPHERESIS
    1) SUMMARY: Cisplatin is highly protein bound and can be removed by plasmapheresis. There is limited experience in the use of plasmapheresis after overdose, but it should be performed as soon as possible after significant overdose. The optimal volume, timing and duration of plasmapheresis is not known; monitor cisplatin concentrations, if possible, to guide therapy.
    2) CASE REPORT: A 46-year-old woman, with non-small cell lung cancer, developed severe nausea and vomiting, hearing loss, tinnitus, acute renal failure, and myelosuppression after unintentionally receiving 75 mg/m(2)/day of cisplatin for 3 days instead of the prescribed 25 mg/m(2)/day. Plasmapheresis was performed for 2 days, beginning 2 days after her last dose of cisplatin. Her plasma platinum level, obtained 1 hour before her first plasmapheresis treatment session, was 1.91 mg platinum per kg of plasma. During each session of plasmapheresis, 3 liters of the patient's plasma was removed and continuously substituted with 1.5 liters of a solvent-detergent treated standardized pooled human plasma and 1.5 liters of 5% human albumin. After the first treatment session, the patient's hearing loss, tinnitus, and renal failure gradually improved. Her plasma platinum level, at this time, was 0.88 mg platinum/kg plasma. After the second plasmapheresis treatment session and aggressive supportive therapy, including administration of granulocyte-colony stimulating factor and packed erythrocytes and thrombocytes for treatment of her myelosuppression, the patient completely recovered except for evidence of persistent subclinical renal impairment (Hofmann et al, 2006).
    3) CASE REPORT: A 59-year-old man, with esophageal squamous cell carcinoma, inadvertently received 100 mg/m(2) cisplatin daily for 3 days instead of the prescribed regimen of 100 mg/m(2) in 5 divided daily doses (ie, 20 mg/m(2) daily for 5 days), and subsequently developed severe nausea and vomiting, visual hallucinations, somnolence, myelosuppression, renal failure, and hepatotoxicity. On day 6 plasmapheresis was initiated, and over the course of 10 days, plasmapheresis was performed 10 times, resulting in a decrease in plasma platinum concentrations from 2979 ng/mL to 279 ng/mL. Along with supportive care and G-CSF administration, the patient gradually recovered (Jung et al, 1995).
    C) PLASMA EXCHANGE
    1) CASE REPORT: A 67-year-old man, diagnosed with stage II esophageal cancer, developed ototoxicity, non-oliguric renal failure, elevated liver enzymes, and acute pancreatitis after inadvertently receiving 80 mg/m(2) cisplatin plus 5-fluorouracil (5-FU) 800 mg/m(2) for 3 consecutive days instead of the prescribed regimen of cisplatin 80 mg/m(2) on day 1 and 5-FU 800 mg/m(2) on days 1 through 5 as postoperative adjuvant chemotherapy following an esophagectomy. After discovery of the error on day 3, hemodialysis and sodium thiosulfate treatment commenced, and plasma exchange was performed on day 5 and continued for 7 cycles through day 19. Following one hemodialysis session and administration of sodium thiosulfate, the patient's plasma cisplatin concentration was 2,350 ng/mL. Following 7 cycles of plasma exchange, his plasma cisplatin concentration decreased to 110 ng/mL. In addition to the decrease in cisplatin concentration, the patient's serum creatinine concentrations and hepatic enzyme concentrations normalized, and his hearing significantly improved (Yamada et al, 2010).
    2) CASE REPORT: Similarly, a 48-year-old man, with laryngeal cancer, developed ototoxicity, paresthesia, non-oliguric renal failure, hepatic failure, and acute pancreatitis after inadvertently receiving cisplatin 100 mg/m(2) for 4 consecutive days instead of the prescribed regimen of cisplatin 100 mg/m(2) on day 1 and 5-fluorouracil 750 mg/m(2) from days 1 to 5. The patient's initial plasma cisplatin concentration, obtained on day 5, was 2470 ng/mL. After undergoing 9 cycles of plasma exchange, from days 5 through 19, the patient's plasma cisplatin concentration decreased to 216 ng/mL. In addition to the 9 cycles of plasma exchange, the patient underwent 18 sessions of hemodialysis, resulting in complete resolution of symptoms without sequelae (Choi et al, 2002).

Abstracts

Case Reports

    A) ADULT
    1) A 41-year-old woman was administered a double dose of cisplatin (200 mg/m(2)) on the 5th day of her first course of polychemotherapy for treatment of stage III primary ovarian carcinoma. Other treatment included doxorubicin (25 mg/m(2)) and teniposide (35 mg/m(2)) on day 1, cyclophosphamide (200 mg/m(2)) and 5-fluorouracil (350 mg/m(2)) on days 2 through 4.
    a) On day 5 cisplatin 100 mg/m(2) was to be administered. Nausea and vomiting was reported one hour after the second dose of cisplatin 100 mg/m(2). Treatment with intravenous hydration of 25% mannitol and 5% dextrose was initiated immediately. The patient was transferred to ICU. She complained of headache, a metallic taste, nausea, and thirst.
    b) Hemodialysis was begun 4 hours after the end of the second dose of cisplatin. Five days post intoxication metabolic acidosis, acute renal failure, and febrile bone marrow aplasia were reported.
    c) Treatment consisted of appropriate antibiotics, hemodialysis, and transfusions. Bone marrow depression and acute renal failure resolved with the patient discharged from the ICU in good condition.
    d) A second course of chemotherapy 2 months later with cisplatin 50 mg/m(2) produced asymptomatic myelosuppression without renal failure (Brivet et al, 1986).
    2) A 36-year-old man with testicular choriocarcinoma developed decreased hearing, thick speech, impaired speech, impaired taste, and numbness of the hands and feet one week after receiving an overdose of cisplatin (480 mg/m(2) by continuous infusion over 4 days). On follow-up 18 months later, dysarthria, taste disturbance, and left-hand weakness had resolved (Schiller et al, 1989).
    3) The inadvertent administration of cisplatin 480 mg (280 mg/m(2)) WITHOUT hydration (carboplatin had been ordered) to a 68-year-old woman with ovarian cancer resulted in renal failure (she underwent kidney transplantation) and profound hearing loss. Acute toxicity consisted of severe emesis, myelosuppression, nephrotoxicity and ototoxicity, which are commonly seen with cisplatin; uncommon acute effects were central (but not peripheral) neurotoxicity (including generalized seizures and hallucinations), visual loss and reversible hepatotoxicity (Chu et al, 1993).
    B) PEDIATRIC
    1) INFANT
    a) A 6-month-old infant was erroneously administered cisplatin 90 mg/m(2) daily for 5 days in combination with standard doses of VP-16 (100 mg/m(2) for 5 days) for treatment of Stage III, localized, unresectable embryonal rhabdomyosarcoma of the shoulder.
    1) Each daily dose of cisplatin was diluted in 250 mL/m(2) of 3% hypertonic saline and administered as a one hour infusion. This infant was vigorously hydrated with 3000 mL/m(2)/day with normal saline.
    2) Vomiting began on day 2 and continued for 7 days. Diarrhea was also reported. Severe, life-threatening hematologic toxicity occurred.
    Cell LineNadir
    WBC800/mmc in 10 days
    PMNs Less than 500/mmc from 5th to 17th day
    Platelets5000/mmc on day 13 Less than 50000/mmc from 8th to 16th day

    3) Four units of platelets were transfused prophylactically during a febrile episode. Antibiotics were administered and no bleeding occurred. Hemoglobin was maintained over 10 g/L with 3 transfusions of packed red cells. Renal function was monitored daily.
    4) By the 8th day moderate hyperchloremic metabolic acidosis (pH 7.20 to 7.30) developed. Urinary bicarbonate losses were great and required bicarbonate replacement therapy. The impairment of renal tubular function continued for 3 weeks and then gradually resolved completely.
    5) Daily EEG's and peripheral nerve function measured by conduction velocity were reported normal. Four months after the overdose the patient succumbed to the disease and died from brain metastases (Haupt et al, 1989).

Range Of Toxicity

Summary

    A) TOXICITY: Expect toxicity with therapeutic doses. Mild toxicity occurs with doses of 180 mg/m(2) or less, moderate toxicity may occur with doses of 180 to 300 mg/m(2), and severe toxicity has been reported with doses greater than 300 mg/m(2). Doses of 400 mg/m(2) are usually fatal. ADULT: Deaths have been reported with a total cisplatin dose of 640 mg over 4 days and 750 mg over 1 day. PEDIATRIC: A 3-year-old child died after receiving 400 mg/m(2).
    B) THERAPEUTIC DOSE: ADULT: 50 to 100 mg/m(2) IV as a single dose every 3 to 4 weeks. In earlier years, high-dose regimens involved using up to 200 mg/m(2) of cisplatin. PEDIATRIC: Cisplatin monotherapy, 80 mg/m(2), has been administered as a continuous 24-hr IV infusion every 14 days for 4 cycles in a clinical trial.

Therapeutic Dose

    7.2.1) ADULT
    A) BLADDER CANCER, ADVANCED: As a single agent, 50 to 70 mg/m(2) IV per cycle once every 3 to 4 weeks, the frequency of administration dependent on the patient's exposure to prior chemotherapy and/or radiation (Prod Info cisplatin intravenous injection solution, 2013)
    B) OVARIAN CANCER, METASTATIC: In combination with cyclophosphamide, 75 to 100 mg/m(2) IV per cycle once every 4 weeks; as a single agent, 100 mg/m(2) IV per cycle once every 4 weeks (Prod Info cisplatin intravenous injection solution, 2013).
    C) TESTICULAR CANCER, METASTATIC: In combination with other antineoplastic agents, 20 mg/m(2) IV daily for 5 days per cycle (Prod Info cisplatin intravenous injection solution, 2013).
    D) PRETREATMENT FLUIDS: In order to reduce or prevent cisplatin toxicity, all patients should be hydrated with 1 to 2 L of fluid for 8 to 12 hours prior to the dose (Prod Info cisplatin intravenous injection solution, 2013).
    7.2.2) PEDIATRIC
    A) Safety and efficacy in the pediatric or adolescent population have not been established (Prod Info cisplatin intravenous injection solution, 2013).

Minimum Lethal Exposure

    A) SUMMARY
    1) A minimum lethal dose has not been reported in the literature.
    2) Although patients with less than 300 mg/m(2) cisplatin usually recover, cisplatin overdose greater than 400 mg/m(2) usually results in death (Choi et al, 2002).
    B) CASE REPORTS/ADULT
    1) A 38-year-old woman developed oliguric renal failure, hepatotoxicity, ototoxicity, peripheral neuropathy, blindness, and severe myelosuppression following a massive cisplatin overdose. On the 8th day after the initial cisplatin treatment, she was treated with N-acetylcysteine (first dose of 140 mg/kg body wt, followed by 70 mg/kg every 4 hours for 4 days (total dose of 640 mg over 4 days)). Although improvement in renal function was observed, she died of overwhelming Klebsiella pneumoniae sepsis, complicated by disseminated intravascular coagulation and severe leukopenia (Sheikh-Hamad et al, 1997).
    2) A 63-year-old male with recurrent lymphoma, died 16 days after inadvertent exposure to 750 mg cisplatin (intended dose was 170 mg). Although the error was noted immediately after perfusion and extra-renal dialysis cycles were begun along with N-acetylcysteine as adjuvant therapy, the patient developed ototoxicity by day 2 and severe alterations in vision by day 3. The patient was deaf and blind by day 6. The patient developed severe bone marrow suppression and septicemia and lapsed into a coma on day 11 when all therapies were discontinued, except for comfort measures until the patient's death (Charlier et al, 2004).
    C) CASE REPORT/CHILD
    1) A 3-year-old child inadvertently received 400 mg/m(2) cisplatin instead of the prescribed carboplatin and subsequently developed multiple organ failure resulting in death approximately 14 days following the overdose (Setty, Bickham, and Hord, 1996).

Maximum Tolerated Exposure

    A) Although patients with less than 300 mg/m(2) of cisplatin usually recover, cisplatin overdose greater than 400 mg/square meter usually results in death (Choi et al, 2002).
    B) Cisplatin dosages greater than 100 mg/m(2) cisplatin acutely in a controlled setting are likely to produce some toxicity, usually moderate bone marrow suppression if the patient is well hydrated and nephrotoxicity does not occur first (Legha & Dimery, 1985).
    C) Serious toxicity in adults has been reported with 180 to 480 mg/m(2) (Vila-Torres et al, 2009; Tsang et al, 2009; Schiller et al, 1989).
    D) HYDRATION: Without hydration nephrotoxicity may occur in nearly all patients at doses of at least 100 milligrams/square meter.
    1) With adequate hydration the risk of nephrotoxicity is less, the dose of cisplatin may be increased and nausea, vomiting, and neurotoxicity become the dose-limiting effects (Legha & Dimery, 1985).
    E) NONRENAL TOXICITIES of cisplatin were not prevented by administration of cisplatin in hypertonic saline in 17 previously untreated patients administered high-dose cisplatin (200 mg/m(2) in 5 divided daily doses in 250 mL of 3% saline) (Ozols et al, 1984).
    F) CASE REPORTS/ADULT
    1) A 36-year-old male with poor prognosis metastatic germ cell neoplasms was inadvertently given cisplatin 400 mg/m(2) every 8 hours (198 mg/day) by continuous infusion for 4 days during the third cycle of chemotherapy. He developed myelosuppression, nephrotoxicity, neurotoxicity, and ototoxicity. Ototoxicity was irreversible, for which he required bilateral hearing aids. At 2 years after the cisplatin overdose, the patient was still alive and computed tomographic scan revealed continued regression of his pulmonary and hepatic lesions (Schiller et al, 1989).
    2) A 48-year-old man with laryngeal cancer was successfully treated with vigorous plasma exchange (from day 5 through 19) supported by GM-CSF and broad spectrum antibiotics after receiving a massive cisplatin overdose (100 mg/m(2) for 4 days; 400 mg/m(2) total). His plasma cisplatin concentration decreased from 2,470 ng/mL to 216 ng/mL (Choi et al, 2002).
    3) A 46-year-old woman, with non-small cell lung cancer, developed severe nausea and vomiting, hearing loss, tinnitus, acute renal failure, and myelosuppression after unintentionally receiving 75 mg/m(2)/day of cisplatin for 3 days instead of the prescribed 25 mg/m(2)/day. Except for evidence of persistent subclinical renal impairment, the patient recovered following plasmapheresis for 2 days and aggressive supportive therapy (Hofmann et al, 2006).
    4) A 57-year-old man inadvertently received an intravenous cisplatin dose of 180 mg/m(2) instead of the prescribed 100 mg/m(2) for his first chemotherapy cycle, and subsequently developed delayed emesis, renal insufficiency, and ototoxicity. With supportive care, the patient improved with residual nephrotoxicity and was able to complete treatment with a 30% reduction in his cisplatin dose for the second and third treatment cycles (Vila-Torres et al, 2009).
    5) A 66-year-old man, with esophageal cancer, inadvertently received cisplatin 100 mg/m(2)/day for 4 days (a total dose of 760 mg) instead of the prescribed 100 mg/m(2) for 1 day (total dose of 190 mg), and subsequently developed renal failure followed by pancytopenia. Hemodialysis was performed; however, patient outcome was not reported (None Listed, 2004).
    G) CASE REPORTS/CHILD
    1) A 14-year-old girl developed an acute renal failure after receiving a massive cisplatin overdose (360 mg/m(2) instead of 120 mg/m(2)). To reverse or reduce renal toxicity, sodium thiosulfate was initiated 70 hours after completion of the cisplatin infusion. The filterable platinum concentration in the urine averaged 4.9 mcg/mL 6 days after starting the overdosed cisplatin administration. Approximately 4 weeks after cisplatin overdose, renal function was completely restored (Erdlenbruch et al, 2002).
    2) INFANT: A 6-month-old child inadvertently received 210 mg/m(2) cisplatin instead of the prescribed carboplatin and subsequently developed multiple organ failure complicated by a candida albicans infection (Setty, Bickham, and Hord, 1996).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) Antemortem blood concentrations of cisplatin were measured in an adult following inadvertent administration of 750 mg cisplatin (intended dose 170 mg). The concentrations were measured until day 11 when the patient became comatose and developed septicemia; all therapies were discontinued except for comfort measures. The patient died on day 16. The blood concentrations were as follows (Charlier et al, 2004):
    1) Day 1 (drawn at the end of perfusion): 8570 mcg/L
    2) Day 1 (just before dialysis): 7470 mcg/L
    3) Day 5: 3130 mcg/L
    4) Day 10: 1500 mcg/L
    1) Heart blood: 1515 mcg/L
    2) Peripheral blood: 1253 mcg/L
    3) Urine: 1038 mcg/L
    4) Bile: 501 mcg/L
    b) In 6 patients, the average total platinum concentration, 5 minutes post-administration of a cisplatin 100 mg/m(2) bolus injection was 6.2 mg/L (Baselt & Cravey, 1989).
    c) Detectable amounts of platinum were present in plasma and urine, but not unfiltered plasma 3 months after treatment with cisplatin 480 mg/m(2) given by continuous infusion over 4 days in a 36-year-old man with testicular choriocarcinoma (Schiller et al, 1989).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAMUSCULAR)MOUSE:
    a) 17900 mcg/kg ((RTECS, 2000))
    2) LD50- (INTRAPERITONEAL)MOUSE:
    a) 6600 mcg/kg ((RTECS, 2000))
    3) LD50- (INTRAMUSCULAR)RAT:
    a) 9200 mcg/kg ((RTECS, 2000))
    4) LD50- (INTRAPERITONEAL)RAT:
    a) 6400 mcg/kg ((RTECS, 2000))

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Cisplatin is an inorganic, water-soluble complex containing a central platinum atom surrounded by 2 chlorine atoms and ammonia moieties in the cis position in the horizontal plane. Only the cis-dischloro structure is active as an antitumor agent (Rozencweig et al, 1977). Cisplatin has also demonstrated immunosuppressive properties (Berenbaum, 1971; Khan & Hill, 1972; Brambilla et al, 1974) and mutagenic properties (Beck & Brubaker, 1975).

Toxicologic Mechanism

    A) Cisplatin has been classified as an alkylating agent with cell cycle nonspecific characteristics (Young & Koda-Kimble, 1988).

Physicochemical

Physical Characteristics

    A) A yellow to orange powder that is soluble in water or saline at 1 mg/mL and in dimethylformamide at 24 mg/mL. It has a melting point of 207 degrees C (Prod Info cisplatin IV injection, 2008).

Ph

    A) 3.8 to 5.9 (Prod Info cisplatin IV injection, 2008)

Molecular Weight

    A) 300.05 (Prod Info cisplatin IV injection, 2008)

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    2) Addiego JE, Ridgway D, & Bleyer WA: The acute management of intrathecal methotrexate overdose: pharmacologic rationale and guidelines. J Pediatr 1981; 98(5):825-828.
    3) Altundag O, Celik I, & Kars A: Recurrent asymptomatic bradycardia episodes after cisplatin infusion (letter). Ann Pharmacother 2001; 35:641-642.
    4) Anon: ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm 1990; 47:1033-1048.
    5) Anon: ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm 1990a; 47:1033-1049.
    6) Anon: OSHA work-practice guidelines for personnel dealing with cytotoxic (antineoplastic) drugs. Am J Hosp Pharm 1986; 43:1193-1204.
    7) Balis FM, Holcenberg JS, & Bleyer A: Clinical pharmacokinetics of commonly used anticancer drugs. Clin Pharmacokinetic 1983; 8:202-232.
    8) Banerjee A, Brotherston TM, Lamberty BG, et al: Cancer chemotherapy agent-induced perivenous extravasation injuries. Postgrad Med J 1987; 63(735):5-9.
    9) Baselt RC & Cravey RH: Disposition of Toxic Drugs and Chemicals in Man, 3rd ed, Year Book Medical Publishers, Inc, Chicago, IL, 1989, pp 698-699.
    10) Beck DJ & Brubaker RR: Mutagenic properties of cis-platinum (II) diamminodichloride in Escherichia coli. Mutat Res 1975; 27:181.
    11) Bellin MF, Jakobsen JA, Tomassin I, et al: Contrast medium extravasation injury: guidelines for prevention and management. Eur Radiol 2002; 12(11):2807-2812.
    12) Berenbaum MC: Immunosuppression by platinum diamines. Br J Cancer 1971; 25:208.
    13) Bertelli G, Gozza A, & Forno GB: Topical dimethylsulfoxide for the prevention of soft tissue injury after extravasation of vesicant cytotoxic drugs: a prospective clinical study. J Clin Oncol 1995; 13:2851-2855.
    14) Bertelli G: Prevention and management of extravasation of cytotoxic drugs. Drug Safety 1995; 12:245-255.
    15) Bertelli G: Prevention and management of extravasation of cytotoxic drugs. Drug Safety 1995a; 12:245-255.
    16) Blaney SM, Poplack DG, Godwin K, et al: Effect of body position on ventricular CSF methotrexate concentration following intralumbar administration. J Clin Oncol 1995; 13(1):177-179.
    17) Bleyer A & Alberts DS: Re: Sodium thiosulfate in cisplatin overdose by Erdlenbruch B et al., Med Pediatr Oncol 2002;38:349-352. Med Pediatr Oncol 2003; 40(6):413-414.
    18) Brambilla G, Cavanna M, & Maura A: Effect of cis-diamminedichloroplatinum (NSC-119875) on the allograft reaction in mice. Cancer Chemother Rep 1974; 58:633-636.
    19) Brivet F, Pavlovitch JM, & Gouyette A: Inefficiency of early prophylactic hemodialysis in cis-platinum overdose (Letter). Cancer Chemother Pharmacol 1986; 18:183-184.
    20) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    21) Brown AS, Hoelzer DJ, & Piercy SA: Skin necrosis from extravasation of intravenous fluids in children. Plast Reconstr Surg 1979; 64(2):145-150.
    22) Canpolat C, Pearson P, & Jaffe N: Cisplatin-associated hemolytic uremic syndrome. Cancer 1994; 74:3059-3062.
    23) Centers for Disease Control and Prevention (CDC): NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2012. Centers for Disease Control and Prevention (CDC). Atlanta, GA. 2012. Available from URL: http://www.cdc.gov/niosh/docs/2012-150/pdfs/2012-150.pdf. As accessed 2013-05-14.
    24) Chait LA & Dinner MI: Ulceration caused by cytotoxic drugs. SA Med J 1975; 49:1935-1936.
    25) Chamberlain JM, Altieri MA, & Futterman C: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care 1997; 13:92-94.
    26) Charlier C, Kintz P, Dubois N, et al: Fatal overdosage with cisplatin. J Analyt Toxicol 2004; 28:138-140.
    27) Chasse MA & Gaudet S: Safe handling of cytotoxic agents. AARN News Letter 1992; 48:14-15.
    28) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
    29) Choi J, Oh JC, & Kim KH: Successful treatment of cisplatin overdose with plasma exchange. Yonsei Med J 2002; 43(1):128-132.
    30) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    31) Chu G, Mantin R, & Shen YM: Massive cisplatin overdose by accidental substitution for carboplatin. Cancer 1993; 72:3707-3714.
    32) Cohan RH, Ellis JH, & Garner WL: Extravasation of radiographic contrast material: recognition, prevention, and treatment. Radiology 1996; 200(3):593-604.
    33) Cunningham FG, MacDonald PC, Leveno KF, et alCunningham FG, MacDonald PC, Leveno KF, et al (Eds): Williams Obstetrics, 19th. Appleton & Lange, Norwalk, CT, 1993.
    34) De Vries EGE, & Uges DRA: Excretion of platinum into breast milk (letter). Lancet 1989; 1:497.
    35) DeBroe ME & Wedeen RP: Prevention of cisplatin nephrotoxicity. Eur J Cancer Clin Oncol 1986; 22:1029-1031.
    36) DeConti RC, Toftness BR, Lange RC, et al: Clinical and pharmacological studies with cis-diamminedichloroplatinum (II). Cancer Res 1973; 33:1310-1315.
    37) Doll DC, Ringenberg QS, & Yarbro JW: Management of cancer during pregnancy. Arch Intern Med 1988; 148:2058-2064.
    38) Dorr RT & Fritz WL: Cancer Chemotherapy Handbook, Elsevier, New York, NY, 1980.
    39) Dupuis LL & Nathan PC: Options for the prevention and management of acute chemotherapy-induced nausea and vomiting in children. Paediatr Drugs 2003; 5(9):597-613.
    40) Erdlenbruch B, Pekrun A, & Schiffmann H: Accidental cisplatin overdose in a child: reversal of acute renal failure with sodium thiosulfate. Med Pediatr Oncol 2002; 38:349-352.
    41) Fassio T, Cannobbio L, & Gasparini G: Paroxysmal supraventricular tachycardia during treatment with cisplatin and etoposide combination. Oncology 1986; 43:219-220.
    42) Fassoulaki A & Pavlou H: Overdosage intoxication with cisplatin-a cause of acute respiratory failure. J Roy Soc Med 1989; 82:689.
    43) Fetoni AR, Sergi B, Ferraresi A, et al: Protective effects of alpha-tocopherol and tiopronin against cisplatin-induced ototoxicity. Acta Otolaryngol 2004; 124:421-426.
    44) Fisher MJ, Lange BJ, Needle MN, et al: Amifostine for children with medulloblastoma treated with cisplatin-based chemotherapy. Pediatr Blood Cancer 2004; 43:780-784.
    45) Freifeld AG, Bow EJ, Sepkowitz KA, et al: Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis 2011; 52(4):e56-e93.
    46) Gebbia V: Toxicity secondary to cis-diamminedichloro-platinum overdose: A case report. Int J Exp Clin Chemother 1989; 2(4):219-222.
    47) Ghirardi O, Vertechy M, Vesci L, et al: Chemotherapy-induced allodinia: neuroprotective effect of acetyl-L-carnitine. in vivo 2005; 19:631-638.
    48) Gippsland Oncology Nurses Group: Assessment, Prevention & Management Of Extravasation Of Cytotoxic Medications. GONG Cancer Care Guidelines. Gippsland Oncology Nurses Group. Gippsland, Victoria, Australia. 2010. Available from URL: http://www.gha.net.au/Uploadlibrary/393586908extravasation_guidelines0907.pdf. As accessed 2010-12-08.
    49) Glantz JC: Reproductive toxicology of alkylating agents. Obstet Gynecol 1994; 49:709-715.
    50) Gosselin S & Isbister GK: Re: Treatment of accidental intrathecal methotrexate overdose. J Natl Cancer Inst 2005; 97(8):609-610.
    51) Grant WM: Toxicology of the Eye, 3rd ed, Charles C. Thomas, Springfield, IL, 1986, pp 241.
    52) Greenspan A & Treat J: Peripheral neuropathy and low dose cisplatin. Am J Clin Oncol 1988; 11:660-662.
    53) Guthrie TH & Gynther L: Acute deafness. A complication of high-dose cisplatin. Arch Otolaryngol 1985; 111:344-345.
    54) Harris J & Dobbs LJ: Pharm J 1985; 2:289.
    55) Hartman LC, Tschetter LK, Habermann TM, et al: Granulocyte colony-stimulating factor in severe chemotherapy-induced afebrile neutropenia.. N Engl J Med 1997; 336:1776-1780.
    56) Haupt R, Perin G, & Dallorso S: Very high dose cis-platinum (450 mg/sq m) in an infant with rhabdomyosarcoma. Anticancer Res 1989; 9:427-428.
    57) Hays KE, Ryu RJ, Swisher EM, et al: Duration of cisplatin excretion in breast milk. J Hum Lact 2013; 29(4):469-472.
    58) Hebert ME, Blivin JL, & Kessler J: Anaphylactoid reactions with intraperitoneal cisplatin. Ann Pharmacother 1995; 29:260-263.
    59) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    60) Henderson CE, Elia G, Garfinkel D, et al: Platinum chemotherapy during pregnancy for serous cystadenocarcinoma of the ovary. Gynecol Oncol 1993; 49:92-94.
    61) Hensley ML, Hagerty KL, Kewalramani T, et al: American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants. J Clin Oncol 2009; 27(1):127-145.
    62) Hirosawa A, Niitani H, & Hayashibara K: Effects of sodium thiosulfate in combination therapy of cis-dichlorodiammine platinum and vindesine. Cancer Chemother Pharmacol 1989; 23:255-258.
    63) Hirsh JD & Conlon PF: Implementing guidelines for managing extravasation of antineoplastics. Am J Hosp Pharm 1983; 40:1516-1519.
    64) Hoff JV, Beatty PA, & Wade JL: Dermal necrosis from dobutamine. N Engl J Med 1979; 300:1280.
    65) Hofmann G, Bauernhofer T, Krippl P, et al: Plasmapheresis reverses all side-effects of a cisplatin overdose--a case report and treatment recommendation. BMC Cancer 2006; 6:1.
    66) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1:161.
    67) Ignoffo RJ & Friedman MA: Therapy of local toxicities caused by extravasation of cancer chemotherapeutic drugs. Cancer Treat Rev 1980; 7(1):17-27.
    68) JEF Reynolds : Martindale: The Extra Pharmacopoeia (CD-ROM Version). The Pharmaceutical Press. London, UK (Internet Version). Edition expires 1990; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    69) Jeffrey LP, Anderson RW & Fortner CL et al: Recommendations for handling cytotoxic agents. National Study Commission on Cytotoxic Exposure (Sept), 1984.
    70) Jung HK, Lee J, & Lee SN: A case of massive cisplatin overdose managed by plasmapheresis. Korean J Intern Med 1995; 10(2):150-154.
    71) Kattah JC, Potolicchio SJ Jr, & Kotz HL: Cortical blindness and occipital lobe seizures induced by cis-platinum. Neuro-ophthalmology 1987; 7:99-104.
    72) Khan A & Hill JM: Suppression of graft-versus-host reaction by cis-platinum (II) diaminochloride. Transplantation 1972; 13:55.
    73) Kondo Y, Himeno S, & Satoh M: Citrate enhances the protective effect of orally administered bismuth subnitrate against the nephrotoxicity of cis-diamminedichloroplatinum. Cancer Chemother Pharmacol 2004; 53:33-38.
    74) Kopelman J, Budnick AS, & Kramer MB: Ototoxicity of high-dose cisplatin by bolus administration in patients with advanced cancers and normal hearing. Laryngoscope 1988; 98:858-864.
    75) Kris MG, Gralla RJ, & Clark RA: Incidence, course and severity of delayed nausea and vomiting following the administration of high-dose cisplatin. J Clin Oncol 1985; 3:1379-1384.
    76) Kris MG, Hesketh PJ, Somerfield MR, et al: American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 2006; 24(18):2932-2947.
    77) Kumar L & Dua H: Cisplatin induced anaemia. NZ Med J 1987; 100:81.
    78) Larson DL: Treatment of tissue extravasation by antitumor agents. Cancer 1982; 49:1796-1799.
    79) Legha SS & Dimery IW: High-dose cisplatin administration without hypertonic saline: Observation of disabling neurotoxicity. J Clin Oncol 1985; 3:1373-1378.
    80) Lewis KP & Medina WD: Cellulitis and fibrosis due to cis-diamminedichloroplatinum (II) (platinol) infiltration. Cancer Treat Rep 1980; 64:1162-1163.
    81) Lieberman P, Nicklas R, Randolph C, et al: Anaphylaxis-a practice parameter update 2015. Ann Allergy Asthma Immunol 2015; 115(5):341-384.
    82) Lieberman P, Nicklas RA, Oppenheimer J, et al: The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010; 126(3):477-480.
    83) Loddenkemper T & Goodkin HP: Treatment of Pediatric Status Epilepticus. Curr Treat Options Neurol 2011; Epub:Epub.
    84) Loth TS & Eversmann WW Jr: Treatment methods for extravasation of chemotherapeutic agents. J Hand Surg 1986; 388-396.
    85) Louvet C, Bouleuc C, & Droz JP: Tissue complications by extravasation from cisplatin. Presse Med 1989; 18:725-726.
    86) Lyass O, Lossos A, & Hubert A: Case Report: Cisplatin-induced non-convulsive encephalopathy. Anti-Cancer Drugs 1998; 9:100-104.
    87) Lynch DJ, Key JC, & White RR: Management and prevention of infiltration and extravasation injury. Surg Clin North Am 1979; 59:939-949.
    88) Maiese K, Walker RW, & Gargan R: Intra-arterial cistlatin-associated optic and otic toxicity. Arch Neurol 1992; 49:83-86.
    89) Manno EM: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 2003; 78(4):508-518.
    90) Mariette X, Paule B, Bennet P, et al: Cisplatin and hyponatremia. Ann Intern Med 1988; 108(5):770-771.
    91) Markman M, Cleary S, & Howell SB: Nephrotoxicity of high-dose intracavitary cisplatin with intravenous thiosulfate protection. Eur J Clin Oncol 1985a; 21:1015-1018.
    92) Markman M, Cleary S, & PA-C: High-dose intracavitary cisplatin with intravenous thiosulfate. Low incidence of serious neurotoxicity. Cancer 1985b; 56:2364-2368.
    93) Meggs WJ & Hoffman RS: Fatality resulting from intraventricular vincristine administration. J Toxicol Clin Toxicol 1998; 36(3):243-246.
    94) Michelagnoli MP, Bailey CC, Wilson I, et al: Potential salvage therapy for inadvertent intrathecal administration of vincristine. Br J Haematol 1997; 99:364-367.
    95) Minakata K, Suzuki M, Nozawa H, et al: Platinum levels in various tissues of a patient who died 181 days after cisplatin overdosing determined by electrospray ionization mass spectrometry. Forensic Toxicol 2006; 24(2):83-87.
    96) Mollman JE, Hogan M, & Glover DJ: Unusual presentation of cis-platinum neuropathy. Neurology 1988; 38:488-490.
    97) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    98) National Institutes of Health Clinical Center Nursing Department: SOP: care of the patient receiving intravenous cytotoxics or biological agents. NIH. Bethesda, MDAvailable from URL: http://www.cc.nih.gov/nursing/ivctxsop.html.
    99) Nisar S & Feinfeld DA: N-acetylcysteine as Salvage Therapy in Cisplatin Nephrotoxicity. Ren Fail 2002; 24(4):529-533.
    100) None Listed: ASHP Therapeutic Guidelines on the Pharmacologic Management of Nausea and Vomiting in Adult and Pediatric Patients Receiving Chemotherapy or Radiation Therapy or Undergoing Surgery. Am J Health Syst Pharm 1999; 56(8):729-764.
    101) None Listed: Pharmaceutical drug overdose case reports: From the world literature. Toxicol Rev 2004; 23(1):59-63.
    102) Nowak RM & Macias CG : Anaphylaxis on the other front line: perspectives from the emergency department. Am J Med 2014; 127(1 Suppl):S34-S44.
    103) O'Marcaigh AS, Johnson CM, & Smithson WA: Successful treatment of intrathecal methotrexate overdose by using ventriculolumbar perfusion and trathecal instillation of carboxypeptidase G2. Mayo Clin Proc 1996; 71:161-165.
    104) Ozguroglu M, Demir G, & Demirelli F: Anaphylaxis from intraperitoneal infusion of cisplatin. Am J Clin Oncol 1999; 22(2):172-173.
    105) Ozols RF, Corden BJ, & Jacob J: High-dose cisplatin in hypertonic saline. Ann Intern Med 1984; 100:19-24.
    106) Peters BG: Technical considerations in the preparation and dispensing of chemotherapy. Top Hosp Pharm Manage 1995; 14:78-88.
    107) Petersen PM, Hansen SW, & Giwercman A: Dose-dependent impairment of testicular function in patients treated with cisplatin-based chemotherapy for germ cell cancer. Ann Oncol 1994; 5:355-358.
    108) Pfeifle CE, Howell SB, & Felthous RD: High-dose cisplatin with sodium thiosulfate protection. J Clin Oncol 1985; 3:237-244.
    109) Pisano C, Pratesi G, Laccabue D, et al: Paclitaxel and cisplatin-induced neurotoxicity: A protective role of acetyl-l-carnitine. Clin Can Res 2003; 9(15):5756-5767.
    110) Polycarpe E, Arnould L, Schmitt E, et al: Low urine osmolarity as a determinant of cisplatin-induced nephrotoxicity. Int J Cancer 2004; 111:131-137.
    111) Product Information: Allopurinol oral tablets, Allopurinol oral tablets. Watson Laboratories Inc, Corona, CA, 2006.
    112) Product Information: COMPAZINE(R) tablets, injection, suppositories, syrup, prochlorperazine tablets, injection, suppositories, syrup. GlaxoSmithKline, Research Triangle Park, NC, 2004.
    113) Product Information: Compazine(R), prochlorperazine maleate spansule. GlaxoSmithKline, Research Triangle Park, NC, 2002.
    114) Product Information: ELITEK(R) intravenous inection powder for solution, rasburicase intravenous inection powder for solution. Sanofi-Aventis U.S., Bridgewater, NJ, 2009.
    115) Product Information: ETHYOL(R) injection, amifostine injection. MedImmune Oncology,Inc, Gaithersburg, MD, 2008.
    116) Product Information: LEUKINE(R) subcutaneous, IV injection, sargramostim subcutaneous, IV injection. Bayer Healthcare, Seattle, WA, 2008.
    117) Product Information: NEUPOGEN(R) IV, subcutaneous injection, filgrastim IV, subcutaneous injection. Amgen Manufacturing, Thousand Oaks, CA, 2010.
    118) Product Information: cisplatin IV injection, cisplatin IV injection. APP Pharmaceuticals, LLC, Schaumburg, IL, 2008.
    119) Product Information: cisplatin intravenous injection solution, cisplatin intravenous injection solution. WG Critical Care, LLC (per DailyMed), Paramus, NJ, 2013.
    120) Product Information: cisplatin intravenous injection, cisplatin intravenous injection. WG Critical Care, LLC (per FDA), Paramus, NJ, 2015.
    121) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    122) Product Information: diphenhydramine HCl intravenous injection solution, intramuscular injection solution, diphenhydramine HCl intravenous injection solution, intramuscular injection solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2013.
    123) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    124) Product Information: promethazine hcl rectal suppositories, promethazine hcl rectal suppositories. Perrigo, Allegan, MI, 2007.
    125) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 1989; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    126) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 2000; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    127) Raffles A, Williams J, Costeloe K, et al: Transplacental effects of maternal cancer chemotherapy. Br J Obstet Gynaecol 1989; 96:1099-1100.
    128) Ramesh G & Reeves WB: Salicylate reduces cisplatin nephrotoxicity by inhibition of tumor necrosis factor-alpha. Kid Internat 2004; 65:490-498.
    129) Rozencweig M, von Hoff DD, Slavik M, et al: Cis-diamminedichloroplatinum (II). A new anticancer drug. Ann Intern Med 1977; 86(6):803-812.
    130) Sauerland C, Engelking C, Wickham R, et al: Vesicant extravasation part I: Mechanisms, pathogenesis, and nursing care to reduce risk. Oncol Nurs Forum 2006; 33(6):1134-1141.
    131) Sax NI: Dangerous Properties of Industrial Materials, 6th ed, Van Nostrand Reinhold Co, New York, NY, 1984, pp 2244-2245.
    132) Schiller JH, Rozental J, & Tutsch KD: Inadvertent administration of 480 mg/m(2) of cisplatin. Am J Med 1989; 86:624-625.
    133) Schweitzer VG, Dolan DF, & Abrams GE: Amelioration of cisplatin-induced ototoxicity by fosfomycin. Laryngoscope 1986; 96:948-958.
    134) Scott R, Besag FMC, & Neville BGR: Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomized trial. Lancet 1999; 353:623-626.
    135) Setty SN; Bickham P; and Hord J: Cisplatin (CDDP) substitution for carboplatin (CBDCA): an easily occurring, but preventable fatal error (Meeting abstract).. American Society of Clinical Oncology. Alexandria, VA. 1996. Available from URL: http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=29&abstractID=9600. As accessed 2010-09-23.
    136) Sheikh-Hamad D, Timmins K, & Jalali Z: Cisplatin-induced renal toxicity: possible reversal by N-acetylcysteine treatment. J Am Soc Nephrol 1997; 8:1640-1645.
    137) Smith TJ, Khatcheressian J, Lyman GH, et al: 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006; 24(19):3187-3205.
    138) Sreenath TG, Gupta P, Sharma KK, et al: Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: A randomized controlled trial. Eur J Paediatr Neurol 2009; Epub:Epub.
    139) Sterzing F, Grehn C, Dinkel J, et al: Severe reversible toxic encephalopathy induced by cisplatin in a patient with cervical carcinoma receiving combined radiochemotherapy. StrahlentherOnkol 2007; 183(9):487-489.
    140) Stillman M & Cata JP: Management of Chemotherapy-induced Peripheral Neuropathy. Curr Pain Headache Rep 2006; 10(4):279-287.
    141) Stull DM, Bilmes R, Kim H, et al: Comparison of sargramostim and filgrastim in the treatment of chemotherapy-induced neutropenia. Am J Health Syst Pharm 2005; 62(1):83-87.
    142) The University of Kansas Hospital: Guide to extravasation management in adult & pediatric patients. The University of Kansas Hospital. Kansas City, KS. 2009. Available from URL: http://www2.kumc.edu/pharmacy/guidelines/Extravasations%20diagram.pdf. As accessed 2012-09-11.
    143) Tsang RY, Al-Fayea T, & Au HJ: Cisplatin overdose: toxicities and management. Drug Saf 2009; 32(12):1109-1122.
    144) Umeki S, Watanabe M, & Yagi S: Supplemental fosfomycin and/or steroids that reduce cisplatin-induced nephrotoxicity. Am J Med Sci 1988; 295:6-10.
    145) Upton J, Mulliken JB, & Murray JE: Major intravenous extravasation injuries. Am J Surg 1979; 137(4):497-506.
    146) Upton J, Mulliken JB, & Murray JE: Major intravenous extravasation injuries. Am J Surg 1979a; 137:497-506.
    147) Vanden Hoek,TL; Morrison LJ; Shuster M; et al: Part 12: Cardiac Arrest in Special Situations 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. American Heart Association. Dallas, TX. 2010. Available from URL: http://circ.ahajournals.org/cgi/reprint/122/18_suppl_3/S829. As accessed 2010-10-21.
    148) Vermorken JB, Kapteijn TS, & Hart AA: Ototoxicity of cis-diamminedichloroplatinum (II): Influence of dose, schedule and mode of administration. Eur J Clin Oncol 1983; 19:53-58.
    149) Vila-Torres E , bert-Mari A , menar-Cubells D , et al: Cisplatin preparation error; patient management and morbidity. J Oncol Pharm Pract 2009; 15(4):249-253.
    150) Wengstrom Y, Margulies A, & European Oncology Nursing Society Task Force: European Oncology Nursing Society extravasation guidelines. Eur J Oncol Nurs 2008; 12(4):357-361.
    151) Widemann BC, Balis FM, Shalabi A, et al: Treatment of accidental intrathecal methotrexate overdose with intrathecal carboxypeptidase G2. J Nat Cancer Inst 2004; 96(20):1557-1559.
    152) Willox JC, McAllister EJ, & Sangster G: Effects of magnesium supplementation in testicular cancer patients receiving cis-platin: A randomized trial. Br J Cancer 1986; 54:19-23.
    153) Yamada Y, Ikuta Y, Nosaka K, et al: Successful treatment of Cisplatin overdose with plasma exchange. Case Report Med 2010; 2010:802312-802312.
    154) Yosowitz P, Ekland DA, & Shaw RC: Peripheral intravenous infiltration necrosis. Ann Surg 1975; 182:553-556.
    155) Young LY & Koda-Kimble MAYoung LY & Koda-Kimble MA (Eds): Applied Therapeutics The Clinical Use of Drugs, 4th. Applied Therapeutics, Inc, Vancouver, WA, 1988.
    156) Zagouri F, Sergentanis TN, Chrysikos D, et al: Platinum derivatives during pregnancy in cervical cancer: a systematic review and meta-analysis. Obstet Gynecol 2013; 121(2 Pt 1):337-343.