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CARBOPLATIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Carboplatin is a platinum coordination compound that has antineoplastic activity. It binds to DNA base pairs, forming inter- and intra-strand crosslinks, leading to DNA strand breaks.

Specific Substances

    1) Carboplatine
    2) Carboplatino
    3) Carboplatinum
    4) CBDCA
    5) JM-8
    6) Karboplatiini
    7) Karboplatin
    8) Karboplatina
    9) NSC-241240
    10) CAS 41575-94-4
    1.2.1) MOLECULAR FORMULA
    1) C6H12N2O4Pt

Available Forms Sources

    A) FORMS
    1) Carboplatin is available in the United States as 50 mg, 150 mg, and 450 mg IV powder for solution (Prod Info PARAPLATIN(R) IV injection, 2010) and 50 mg/5 mL, 150 mg/15 mL, and 450 mg/45 mL (10 mg/mL) aqueous solution in multidose amber glass vials (Prod Info carboplatin intravenous injection, 2008).
    B) USES
    1) Carboplatin is approved in the United States for the treatment of advanced ovarian carcinoma (Prod Info PARAPLATIN(R) IV injection, 2010). It has also been used to treat leukemia, lymphoma, and cancers of the lung, head and neck, breast, and cervix.

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: Carboplatin is approved in the United States for the treatment of advanced ovarian carcinoma. It has also been used to treat leukemia, lymphoma, and cancers of the lung, head and neck, breast, and cervix.
    B) PHARMACOLOGY: Carboplatin, like cisplatin, is a platinum coordination compound that has antineoplastic activity. It binds to DNA base pairs, forming inter- and intra-strand crosslinks leading to DNA strand breaks and inhibiting DNA synthesis.
    C) TOXICOLOGY: The disruption of DNA synthesis affects rapidly dividing cells first; myelosuppression is the dose-limiting toxicity. In addition, pretreated patients with carboplatin are at greater risk of bone marrow suppression than naive patients. Hypersensitivity reactions may be observed in patients treated after several cycles of chemotherapy with carboplatin.
    D) EPIDEMIOLOGY: Inadvertent iatrogenic overdose is very rare, but has occurred.
    E) WITH THERAPEUTIC USE
    1) COMMON: Nausea and vomiting, bone marrow suppression, renal insufficiency, electrolyte abnormalities (eg, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia), and neurotoxicity (peripheral neuropathy, mostly sensorineuronal). OTHER EFFECTS: Diarrhea, constipation, rash, ototoxicity, hypersensitivity reaction, transient elevation of liver enzymes. Extravasation and necrosis have been reported in patients receiving carboplatin.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea and vomiting, and less often diarrhea, may develop within hours. Transient renal insufficiency, mucositis, hyponatremia, hypokalemia, hypomagnesemia, and hypocalcemia may develop within days. Myelosuppression develops within the first two weeks. Nadir occurs in about 21 to 28 days, but may be earlier after an overdose.
    2) SEVERE TOXICITY: Severe mucositis, diarrhea, and myelosuppression have been reported after large overdoses. Ototoxicity (ie, tinnitus, high-frequency deafness), and peripheral neuropathy (mostly sensorineuronal) may develop. Cortical blindness has been reported rarely following high doses.
    0.2.20) REPRODUCTIVE
    A) Carboplatin is classified as FDA pregnancy category D. One pregnancy identified in a systematic review that involved the use of carboplatin resulted in the birth of 1 heathy newborn. In 2 case reports, healthy infants were delivered after the mothers had received carboplatin during pregnancy (case 1, at 27 and 30 weeks; case 2, at 20 weeks). The teratogenic potential of chemotherapeutic agents is difficult to assess because of the relatively small number of reports, variation in dosages, routes of administration, timing of administration with respect to gestational age, and the variety of combinations of drugs administered. In animal studies, there was evidence of embryotoxicity and teratogenicity.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of carboplatin in humans. However, carcinogenicity has been reported with compounds that have mutagenicity profiles and similar mechanisms of action as carboplatin. There have been reports of secondary malignancies associated with combination therapy.

Laboratory Monitoring

    A) Monitor vital signs and mental status, and perform repeated neurological examination.
    B) Carboplatin plasma concentrations are not clinically useful or readily available.
    C) Closely monitor renal function, electrolytes, liver enzymes, and urine output.
    D) Monitor CBC with differential daily until nadir has clearly been reached and marrow recovery has begun. Nadir occurs in about 21 to 28 days, but may be earlier after an overdose.
    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) Monitor visual acuity and hearing. Obtain baseline ophthalmologic evaluation and audiogram and repeat as necessary.

Treatment Overview

    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    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 to 1 to 3 mL/kg/hr. Avoid nephrotoxic drugs. Treat persistent nausea and vomiting with several antiemetics of different classes. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Aggressive IV fluid resuscitation with normal saline 3 to 6 L per day. Target urine output to 1 to 3 mL/kg/hr. Avoid nephrotoxic drugs. Emergent hemodialysis should be performed as early as possible in any patient with a significant overdose. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia. Patients with severe neutropenia should be in protective isolation. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia, or hemorrhage. Severe nausea and vomiting may respond to a combination of agents from different drug classes.
    C) INTRATHECAL INJECTION
    1) Inadvertent intrathecal injection has not been reported with carboplatin. The following information is derived from experience with other antineoplastics. After an overdose, keep the patient upright and immediately drain at least 20 mL of 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 saline). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 24 hours). Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.
    D) DECONTAMINATION
    1) Activated charcoal is not helpful as overdose most often occurs inadvertently by the IV route. For dermal exposures, clean skin with soap and water, and for eye exposures, flush with water.
    E) AIRWAY MANAGEMENT
    1) Endotracheal intubation and mechanical ventilation may be required in patients with significant encephalopathy (agitation, delirium).
    F) ANTIDOTE
    1) None.
    G) 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.
    H) 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).
    I) 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.
    J) NAUSEA AND VOMITING
    1) Treat severe nausea and vomiting with agents from several different classes. For example: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol).
    K) STOMATITIS/MUCOSITIS
    1) In one study, all grade stomatitis (onset: day 11; range 1 to 35 days; duration: 15 days; range 4 to 46 days) developed in 93% of patients with AML after receiving idarubicin, etoposide, and carboplatin. Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics. Patients with mucositis and moderate xerostomia may receive sialagogues (eg, sugarless candy/mints, pilocarpine/cevimeline, or bethanechol) and topical fluorides to stimulate salivary gland function. Consider prophylactic antiviral and antifungal agents to prevent infections. Topical oral antimicrobial mouthwashes, rinses, pastilles, or lozenges may be used to decrease the risk of infection. Palifermin is indicated to reduce the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. In patients with carboplatin overdose, administer palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.
    L) PERIPHERAL NEUROPATHY
    1) Peripheral neurotoxicity should be anticipated in overdose. Monitor and treat symptoms as indicated.
    M) 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. One source recommended applying warm packs. Another source recommended cold compresses for 15 to 20 minutes at least 4 times daily. 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.
    N) HYPERSENSITIVITY REACTION
    1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    O) ENHANCED ELIMINATION
    1) Carboplatin has a small volume of distribution and low protein binding; it is readily removed by hemodialysis. Emergent hemodialysis should be performed as early as possible in any patient with a significant overdose.
    P) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management.
    2) ADMISSION CRITERIA: Patients with carboplatin overdose need to be admitted, as toxicity develops over several days. Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    3) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with carboplatin overdose. Consult a nephrologist for emergent dialysis. In addition, consultation with an infectious diseases physician with expertise in the management of neutropenic patients with infections is strongly recommended.
    4) TRANSFER CRITERIA: Patients with large overdoses may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    Q) PITFALLS
    1) Symptoms of overdose are similar to reported side effects of the medication. Early symptoms of overdose may be delayed or not evident (ie, particularly myelosuppression), so reliable follow-up is imperative. Patients taking carboplatin may have severe comorbidities and may be receiving other drugs that may produce synergistic effects (ie, myelosuppression, neurotoxicity).
    R) PHARMACOKINETICS
    1) Carboplatin is not bound to plasma proteins, however, the platinum from degraded carboplatin irreversibly binds to plasma proteins and is slowly eliminated with an approximate half-life of 5 days. Vd, 16 L. Renal excretion: Approximately 60% to 80%, as measured by total platinum. Carboplatin is primarily excreted by glomerular filtration. Within 12 hours, approximately 65% of the dose in the urine is excreted by a patient with creatinine clearance of approximately 60 mL/min. Elimination half-life: 1 to 6 hours.
    S) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression or peripheral neuropathy.

Range Of Toxicity

    A) TOXICITY: Expect toxicity in therapeutic dose. CHILDREN: In a 3-year-old girl, administration of a cumulative dose of 4938 mg/m(2) instead of 1913 mg/m(2) resulted in grade IV mucositis, febrile neutropenia and grade II diarrhea. In a 4-year-old boy, the administration of 3939 mg/m(2)/course of carboplatin instead of 1719 mg/m(2)/course led to ototoxicity and renal insufficiency.
    B) THERAPEUTIC DOSE: ADULTS: 360 mg/m(2) IV on day 1 every 4 weeks OR dose based on the Calvert formula, with a target AUC of 4 to 6 mg/mL x min; total dose (mg) = target (AUC) x (GFR +25). CHILDREN: Safety and efficacy have not been established in pediatric patients. In several pediatric studies, high-dose carboplatin (up to 750 mg/m(2)) was administered alone or in combination with other chemotherapeutic agents in children. The dose-limiting toxicity was myelosuppression.

Clinical Effects

Summary Of Exposure

    A) USES: Carboplatin is approved in the United States for the treatment of advanced ovarian carcinoma. It has also been used to treat leukemia, lymphoma, and cancers of the lung, head and neck, breast, and cervix.
    B) PHARMACOLOGY: Carboplatin, like cisplatin, is a platinum coordination compound that has antineoplastic activity. It binds to DNA base pairs, forming inter- and intra-strand crosslinks leading to DNA strand breaks and inhibiting DNA synthesis.
    C) TOXICOLOGY: The disruption of DNA synthesis affects rapidly dividing cells first; myelosuppression is the dose-limiting toxicity. In addition, pretreated patients with carboplatin are at greater risk of bone marrow suppression than naive patients. Hypersensitivity reactions may be observed in patients treated after several cycles of chemotherapy with carboplatin.
    D) EPIDEMIOLOGY: Inadvertent iatrogenic overdose is very rare, but has occurred.
    E) WITH THERAPEUTIC USE
    1) COMMON: Nausea and vomiting, bone marrow suppression, renal insufficiency, electrolyte abnormalities (eg, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia), and neurotoxicity (peripheral neuropathy, mostly sensorineuronal). OTHER EFFECTS: Diarrhea, constipation, rash, ototoxicity, hypersensitivity reaction, transient elevation of liver enzymes. Extravasation and necrosis have been reported in patients receiving carboplatin.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea and vomiting, and less often diarrhea, may develop within hours. Transient renal insufficiency, mucositis, hyponatremia, hypokalemia, hypomagnesemia, and hypocalcemia may develop within days. Myelosuppression develops within the first two weeks. Nadir occurs in about 21 to 28 days, but may be earlier after an overdose.
    2) SEVERE TOXICITY: Severe mucositis, diarrhea, and myelosuppression have been reported after large overdoses. Ototoxicity (ie, tinnitus, high-frequency deafness), and peripheral neuropathy (mostly sensorineuronal) may develop. Cortical blindness has been reported rarely following high doses.

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) VISION LOSS
    a) Clinical cortical blindness developed in 2 patients after treatment with high-dose (800 to 1200 mg/m(2)) carboplatin. Both patients had a history of impaired renal function prior to carboplatin administration (O'Brien et al, 1992).
    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) Tinnitus and subclinical audiogram alterations have been reported in 1% of patients (Prod Info PARAPLATIN(R) IV injection, 2010).
    2) Hearing loss appears to be cumulative with increasing dose. Clinically significant hearing loss usually does not occur with conventional dosing (Gore et al, 1987; Kennedy et al, 1990).
    3) In a phase I study, 10 patients had pre-existing mild to moderate hearing loss, but only one patient's hearing deteriorated after receiving 4 courses of carboplatin (median cumulative dose of 1,470 mg/m(2)). Three patients showed abnormal audiograms, with a high frequency loss, after a median cumulative dose of 1,320 mg/m(2) (Leyvraz et al, 1985).
    B) WITH POISONING/EXPOSURE
    1) Studies using higher doses suggest that ototoxicity may become dose-limiting (Woloschuk et al, 1988).
    a) Ototoxicity was associated with high doses of carboplatin 1200 and 1600 mg/m(2). Patients complained of short-term tinnitus and hearing loss (Gore et al, 1987).
    2) In a phase I/II study of 21 patients with advanced ovarian cancer, grade 2 and 3 ototoxicity was dose-limiting and developed in 86% of patients following carboplatin 1800 mg/m(2) (Wandt et al, 1999)
    3) PEDIATRIC: In one phase I study, 12 children (3 to 17 years of age) received high-dose carboplatin (target total AUC 20 to 30 mg/mL x min; total doses range, 715 to 2550 mg) administered as a daily 60-min infusion, repeated on 5 consecutive days. Hearing loss developed in 3 patients who were previously treated with cisplatin (Rubie et al, 2003).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypertension was reported in patients receiving carboplatin during postmarketing surveillance (Prod Info PARAPLATIN(R) IV injection, 2010).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) In clinical trials, peripheral neuropathy developed in 4% of patients receiving carboplatin. The incidence of neuropathy increased to 10% in those over 65 years of age and in patients previously treated with cisplatin (Prod Info PARAPLATIN(R) IV injection, 2010; Gore et al, 1987a; Heinzlef et al, 1998).
    b) In 2 prospective, randomized, controlled trials of 553 previously treated patients, peripheral neuropathies and central neurotoxicity developed in 6% and 5% of patients treated with single-agent carboplatin, respectively (Prod Info PARAPLATIN(R) IV injection, 2010).
    c) In a review of data from 710 patients from 23 different Phase II and III trials, peripheral neuropathy occurred in only 6% of patients (25 of 428) receiving carboplatin (Canetta et al, 1985a).
    2) WITH POISONING/EXPOSURE
    a) Paresthesias, ataxia, distal motor deficits, diminished sense of vibration, light touch, pinprick, and joint position, absent deep tendon reflexes, and difficulty in walking have been reported with high-dose carboplatin regimens (Gore et al, 1987; Heinzlef et al, 1998a).
    B) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) Severe headaches, in conjunction with bilateral vision loss, developed in 2 patients following high-dose administration of carboplatin, 800 to 1200 mg/m(2). Both patients had impaired renal function prior to carboplatin administration, which could contribute to the toxicity of carboplatin (O'Brien et al, 1992).
    b) In one study, 3 patients complained of malaise associated with headache that lasted 5 to 7 days and occurred at doses of 1200 mg/m(2) or more of carboplatin (Gore et al, 1987a).
    C) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) In 2 prospective, randomized, controlled trials of 553 previously treated patients, asthenia developed in 11% of patients treated with single-agent carboplatin (Prod Info PARAPLATIN(R) IV injection, 2010).
    D) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Generalized CNS toxicity was reported in 5% of patients, but was mostly related to the use of antiemetics (Prod Info Paraplatin(R), carboplatin, 1998).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) In 2 prospective, randomized, controlled trials of 553 previously treated patients, nausea and vomiting developed in 92% of patients treated with single-agent carboplatin (Prod Info PARAPLATIN(R) IV injection, 2010).
    2) WITH POISONING/EXPOSURE
    a) PEDIATRIC: In one clinical trial of 15 children (7 months to 16 years of age) with malignant solid tumors, most patients experienced vomiting (mild, grade I or II) a few hours after receiving carboplatin (560 mg/m(2) IV every 4 weeks). Severe vomiting developed in 3 patients (Doz et al, 1990).
    B) STOMATITIS
    1) WITH THERAPEUTIC USE
    a) Stomatitis has been reported in patients receiving carboplatin (Prod Info PARAPLATIN(R) IV injection, 2010).
    b) COMBINATION THERAPY: In an open-label, uncontrolled Phase II clinical trial (n=43), all grade stomatitis (onset: day 11; range 1 to 35 days; duration: 15 days; range 4 to 46 days) developed in 40 (93%) patients with AML after receiving idarubicin, etoposide, and carboplatin (1000 to 1500 mg/m(2)) (Bow et al, 1998).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORTS: Grade IV mucositis was reported in two children with neuroblastoma after receiving excessive doses (2,639 mg/course vs. the intended 1,152 mg/course in one; and 930 mg for one day vs. the intended 360.3 mg/day) of carboplatin as part of a preoperative chemotherapy protocol (Liem et al, 2003).
    C) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In clinical trials, diarrhea developed in 6% of patients treated with carboplatin (Prod Info PARAPLATIN(R) IV injection, 2010).
    2) WITH POISONING/EXPOSURE
    a) In one study, diarrhea was common in patients treated with carboplatin 1600 mg/m(2) (Gore et al, 1987).
    b) CASE REPORTS: Grade II diarrhea was reported in two children after receiving excessive doses of carboplatin as part of a preoperative chemotherapy protocol for stem cell transplant for neuroblastoma. One child received 2,639 mg/course instead of the intended 1,152 mg/course of carboplatin; the other child received 930 mg instead of 360.3 mg for one day(Liem et al, 2003).
    D) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) In clinical trials, constipation developed in 6% of patients treated with carboplatin (Prod Info PARAPLATIN(R) IV injection, 2010).
    2) WITH POISONING/EXPOSURE
    a) Constipation was reported in patients receiving high-dose carboplatin (800 to 1600 mg/m(2)) (Gore et al, 1987).
    E) ENTEROCOLITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Neutropenic enterocolitis with intestinal perforation was reported with an antineoplastic regimen including carboplatin in a patient undergoing autologous bone marrow transplantation (Mehta et al, 1992).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC LIVER DISEASE
    1) WITH THERAPEUTIC USE
    a) Elevated alkaline phosphatase (24%; 37% of pretreated patients), SGOT (15%; 19% of pretreated patients), and total serum bilirubin (5%; 5% of pretreated patients) have been reported in patients with normal baseline values. Approximately one-half of these cases were mild and reversible (Prod Info PARAPLATIN(R) IV injection, 2010).
    b) CASE REPORT: An 18-year-old man developed severe thrombocytopenia and liver necrosis after receiving carboplatin 270 mg/m(2)/day for 5 days. He died 10 days after the last dose of carboplatin. The autopsy findings of hemorrhage into the myocardium and centrilobular liver necrosis suggest that carboplatin-induced thrombocytopenia contributed directly to the hepatotoxicity (Hruban et al, 1991).
    2) WITH POISONING/EXPOSURE
    a) Severe elevation of liver enzymes has been reported in patients receiving high doses of carboplatin (more than 4 times the recommended dose) (Prod Info PARAPLATIN(R) IV injection, 2010).
    b) Hepatotoxicity (greater than WHO II) has been reported in patients receiving high-dose carboplatin (1500 to 2000 mg/m(2)) (Beyer et al, 1992).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) TOXIC NEPHROPATHY
    1) WITH THERAPEUTIC USE
    a) Carboplatin is less nephrotoxic than cisplatin. Incidence of increased serum creatinine is 6% and BUN is 14%. Most abnormalities are mild and reversible (Prod Info PARAPLATIN(R) IV injection, 2010).
    b) In 2 prospective, randomized, controlled trials of 553 previously treated patients, serum creatinine elevations developed in 10% of patients treated with single-agent carboplatin; 22% of patients developed elevated BUN (Prod Info PARAPLATIN(R) IV injection, 2010).
    c) Reduced glomerular filtration rates and increased renal tubular loss of magnesium, observed as low serum magnesium levels, were reported in children after receiving chemotherapy with carboplatin. The nephrotoxicity persisted up to 2 years after completion of carboplatin treatment (English et al, 1999).
    2) WITH POISONING/EXPOSURE
    a) High-dose (800 to 1600 mg/m(2)) carboplatin lead to transient decreases in renal function but recovery occurred in most patients (Hardy et al, 1990; Gore et al, 1987).
    b) PEDIATRIC: In one clinical trial of 15 children (7 months to 16 years of age) with malignant solid tumors, high-dose carboplatin (560 mg/m(2) IV every 4 weeks) lead to decreases in creatinine clearance in 7 patients, but the decreased creatinine clearance values were still within normal range (Doz et al, 1990).
    B) ACUTE RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 57-year-old woman with stage 1C ovarian carcinoma underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy and received paclitaxel and carboplatin therapy one month later. One day following the administration, the patient developed frank hematuria, flank pain, and a decreased urine output. An intravenous pyelogram (IVP) showed early obstruction and intraureteral blood clots. Following diuresis, all effects resolved without the use of fibrinolytics or anticoagulants. A repeat IVP indicated a complete resolution of the blockages (Agraharkar et al, 1998).
    b) Two cases of acute nonoliguric renal failure were reported with intraperitoneal administration of carboplatin. Both patients were pretreated with cisplatin (McDonald et al, 1991).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A fatal case of acute renal failure occurred after a myeloablative regimen consisting of carboplatin 750 mg/m(2) over 3 days prior to a bone marrow transplant procedure. The patient had compromised renal function due to prior nephrectomy and cisplatin therapy. The baseline creatinine clearance was 45 to 49 mL/min and decreased 62% 1 to 8 days after carboplatin treatment (Mulder et al, 1988).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) Myelosuppression is the dose-limiting toxicity of carboplatin. It is usually characterized by thrombocytopenia, leukopenia, neutropenia, and/or anemia. Although usually reversible, these hematological effects have resulted in infectious or hemorrhagic complications in 5% of patients on carboplatin therapy. Nadir occurs in about 21 to 28 days (Prod Info PARAPLATIN(R) IV injection, 2010; Woloschuk et al, 1988; Ozols et al, 1985; Leyvraz et al, 1985a; Canetta et al, 1985).
    b) COMBINATION THERAPY: In an open-label, uncontrolled Phase II clinical trial of patients (n=43) with AML receiving idarubicin, etoposide, and carboplatin (1000 to 1500 mg/m(2) over 5 days), the median duration of severe neutropenia (defined by an absolute neutrophil count of less than 0.5 x 10(9)/L) was 23 days. The median time to bone marrow recovery was 27 days (Bow et al, 1998).
    c) RISK FACTORS: The risk of severe myelosuppression is increased in patients who have previously received cisplatin and/or radiation therapy. Other risk factors include combination therapy with other myelosuppressive agents, low initial blood cell counts, increasing age, renal impairment, poor performance status, or extensive prior chemotherapy (Prod Info PARAPLATIN(R) IV injection, 2010; Woloschuk et al, 1988; Ozols et al, 1985; Leyvraz et al, 1985a; Canetta et al, 1985).
    2) WITH POISONING/EXPOSURE
    a) Bone marrow suppression should be expected following an overdose (Prod Info PARAPLATIN(R) IV injection, 2010).
    B) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) In clinical trials, thrombocytopenia developed in 25% (35% in patients with pretreated ovarian cancer) of patients receiving carboplatin. A nadir occurs in 21 days (Prod Info PARAPLATIN(R) IV injection, 2010).
    b) In 2 prospective, randomized, controlled trials of 553 previously treated patients, thrombocytopenia with platelet counts below 100,000/mm(3) and 50,000/mm(3) developed in 62% and 35% of patients treated with single-agent carboplatin, respectively. Platelet counts above 100,000/mm(3) were observed in 90% of patients by day 28 (Prod Info PARAPLATIN(R) IV injection, 2010).
    c) Severe thrombocytopenia (less than 25,000 cells/mm(3)) was reported in 5% of patients (Woloschuk et al, 1988).
    d) In one study, thrombocytopenia occurred in 32% (195 of 612) of patients on carboplatin therapy. However, bleeding occurred only in 6% of 710 patients. Transfusions were required in 21% of patients (146 of 710) (Canetta et al, 1985a).
    e) CASE REPORT: An 18-year-old man developed severe thrombocytopenia and liver necrosis after receiving carboplatin 270 mg/m(2)/day for 5 days. He died 10 days after the last dose of carboplatin. The autopsy findings of hemorrhage into the myocardium and centrilobular liver necrosis suggest that carboplatin-induced thrombocytopenia contributed directly to the hepatotoxicity (Hruban et al, 1991).
    2) WITH POISONING/EXPOSURE
    a) Following high-dose IV carboplatin 800 mg/m(2) continuous infusion over 48 hours, the median nadir platelet count was 6500/mm(3) (range, 1000 to 356,000). The median duration of thrombocytopenia was 5 days (range, 1 to 28 days) (Ozols et al, 1987).
    b) In a phase I/II study of 21 patients with advanced ovarian cancer, the maximum tolerated dose of sequential carboplatin was 1600 mg/m(2). Thrombocytopenia (median duration, 0 to 3.5 days; range, 0 to 12 days) and leukopenia (median duration, 4 to 7 days; range, 0 to 15 days) developed in patients receiving high-dose carboplatin (1600 mg/m(2) or 1800 mg/m(2)) (Wandt et al, 1999)
    c) PEDIATRIC: In one phase I study, 12 children (3 to 17 years of age) received high-dose carboplatin (target total AUC 20 to 30 mg/mL x min; total doses range, 715 to 2550 mg) administered as a daily 60-min infusion, repeated on 5 consecutive days. All patients developed grade 4 neutropenia and thrombocytopenia, lasting up to 32 days (average 7 days) (Rubie et al, 2003).
    d) PEDIATRIC: In one clinical trial of 15 children (7 months to 16 years of age) with malignant solid tumors, 11 patients developed severe thrombocytopenia after receiving several courses of carboplatin (560 mg/m(2) IV every 4 weeks). Platelet transfusion was required in 3 patients (Doz et al, 1990).
    C) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) In clinical trials, leukopenia developed in 15% of patients treated with carboplatin and in 26% of patients pretreated for ovarian cancer (Prod Info PARAPLATIN(R) IV injection, 2010).
    b) In 2 prospective, randomized, controlled trials of 553 previously treated patients, leukopenia with leukocyte counts below 4000 cells/mm(3) and 2000 cells/mm(3) developed in 85% and 26% of patients treated with single-agent carboplatin, respectively (Prod Info PARAPLATIN(R) IV injection, 2010).
    c) In phase II or phase III studies, leukopenia developed in approximately 50% of all patients receiving carboplatin as a single agent (Canetta et al, 1985).
    2) WITH POISONING/EXPOSURE
    a) In a phase I/II study of 21 patients with advanced ovarian cancer, the maximum tolerated dose of sequential carboplatin was 1600 mg/m(2). Thrombocytopenia (median duration, 0 to 3.5 days; range, 0 to 12 days) and leukopenia (median duration, 4 to 7 days; range, 0 to 15 days) developed in patients receiving high-dose carboplatin (1600 mg/m(2) or 1800 mg/m(2)) (Wandt et al, 1999)
    b) PEDIATRIC: In one clinical trial of 15 children (7 months to 16 years of age) with malignant solid tumors, 5 patients developed severe leukopenia for less than 7 days after receiving 5 courses of carboplatin (560 mg/m(2) IV every 4 weeks) (Doz et al, 1990).
    D) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) In clinical trials, neutropenia developed in 16% of patients treated with carboplatin and 21% of patients pretreated for ovarian cancer (Prod Info PARAPLATIN(R) IV injection, 2010).
    b) In 2 prospective, randomized, controlled trials of 553 previously treated patients, neutropenia with neutrophil counts below 2000 cells/mm(3) and 1000 cells/mm(3) developed in 67% and 21% of patients treated with single-agent carboplatin, respectively (Prod Info PARAPLATIN(R) IV injection, 2010).
    c) COMBINATION THERAPY: In an open-label, uncontrolled Phase II clinical trial of patients (n=43) with AML receiving idarubicin, etoposide, and carboplatin (1000 to 1500 mg/m(2) over 5 days), the median duration of severe neutropenia (defined by an absolute neutrophil count of less than 0.5 x 10(9)/L) was 23 days. The median time to bone marrow recovery was 27 days (Bow et al, 1998).
    2) WITH POISONING/EXPOSURE
    a) PEDIATRIC: In one phase I study, 12 children (3 to 17 years of age) received high-dose carboplatin (target total AUC 20 to 30 mg/mL x min; total doses range, 715 to 2550 mg) administered as a daily 60-min infusion, repeated on 5 consecutive days. All patients developed grade 4 neutropenia and thrombocytopenia, lasting up to 32 days (average 7 days) (Rubie et al, 2003).
    b) CASE REPORTS: Febrile neutropenia developed in 2 children with neuroblastoma following inadvertent excessive doses of carboplatin, as part of a preoperative chemotherapy protocol, prior to stem cell transplant. The intended dose was 1,152 mg/course vs. 2,639 mg/course (actual dose administered) for one child, and 930 mg was given for one day vs. the intended 360.3 mg dose in the other child. The overdose effect appeared similar to therapeutic use (Liem et al, 2003).
    E) ANEMIA
    1) WITH THERAPEUTIC USE
    a) In 2 prospective, randomized, controlled trials of 553 previously treated patients, anemia with hemoglobin counts below 11 g/dL and 8 g/dL developed in 90% and 21% of patients treated with single-agent carboplatin, respectively. Transfusion was required in 44% of these patients (Prod Info PARAPLATIN(R) IV injection, 2010).
    b) In clinical trials, anemia occurred in 59% (320 of 543) of evaluable patients on carboplatin therapy. However, serious bleeding occurred only in 6% of 710 patients on carboplatin therapy. Transfusions were reported in 21% of patients (146 of 710) on carboplatin therapy (Canetta et al, 1985a).
    2) WITH POISONING/EXPOSURE
    a) PEDIATRIC: In one clinical trial of 15 children (7 months to 16 years of age) with malignant solid tumors, 3 patients developed severe anemia, requiring red blood cell transfusions, after receiving several courses of carboplatin (560 mg/m(2) IV every 4 weeks) (Doz et al, 1990).
    F) HEMOLYTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A fatal case of carboplatin-related thrombotic microangiopathic hemolytic anemia is reported. Progressive brainstem dysfunction culminated in coma and respiratory arrest. Pathologic examination revealed microvascular thrombosis in the heart, kidney, and brain (Walker et al, 1989).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) MACULOPAPULAR ERUPTION
    1) WITH THERAPEUTIC USE
    a) Ten patients developed pruritic maculopapular rash after receiving high-dose carboplatin in combination with other chemotherapy agents. This rash started on the extremities and progressed to involve the trunk and face (Beyer et al, 1992).
    B) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) Alopecia has been reported in patients receiving single-agent carboplatin (Prod Info PARAPLATIN(R) IV injection, 2010).
    2) WITH POISONING/EXPOSURE
    a) Alopecia occurred in patients following high-dose carboplatin administration of 800 to 1600 mg/m(2) (Gore et al, 1987a).
    C) INJECTION SITE REACTION
    1) WITH THERAPEUTIC USE
    a) Injection site reactions, including redness, swelling, and pain have been reported in patients receiving carboplatin (Prod Info PARAPLATIN(R) IV injection, 2010).
    D) EXTRAVASATION
    1) WITH THERAPEUTIC USE
    a) Extravasation and necrosis have been reported in patients receiving carboplatin (Prod Info PARAPLATIN(R) IV injection, 2010).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) Anaphylactic-like reactions to carboplatin have occurred in patients with prior exposure to carboplatin or cisplatin. Bronchoconstriction, facial flushing, hypotension, shortness of breath, erythema, and pruritus have been associated with hypersensitivity reactions (Tonkin et al, 1993; Windom et al, 1992; Weidmann et al, 1994).

Reproductive

    3.20.1) SUMMARY
    A) Carboplatin is classified as FDA pregnancy category D. One pregnancy identified in a systematic review that involved the use of carboplatin resulted in the birth of 1 heathy newborn. In 2 case reports, healthy infants were delivered after the mothers had received carboplatin during pregnancy (case 1, at 27 and 30 weeks; case 2, at 20 weeks). The teratogenic potential of chemotherapeutic agents is difficult to assess because of the relatively small number of reports, variation in dosages, routes of administration, timing of administration with respect to gestational age, and the variety of combinations of drugs administered. In animal studies, there was evidence of embryotoxicity and teratogenicity.
    3.20.2) TERATOGENICITY
    A) EMBRYO/FETAL RISK
    1) The teratogenic potential of chemotherapeutic agents is difficult to assess because of the relatively small number of reports, variation in dosages, routes of administration, timing of administration with respect to gestational age, and the variety of combinations of drugs administered. Although fetal exposure to chemotherapy throughout all trimesters of pregnancy has been reported to not induce abnormalities, there is no assurance that deleterious fetal effects will not occur. Exposure during the first trimester is still considered by most practitioners as the critical trimester for abnormal fetal development (Glantz, 1994).
    B) ANIMAL STUDIES
    1) There was evidence of teratogenicity when animals were exposed to carboplatin (Prod Info carboplatin intravenous injection, 2014) at days 6 to 9 of gestation (Kai et al, 1989).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified carboplatin as FDA pregnancy category D (Prod Info carboplatin intravenous injection, 2014).
    2) Avoid use of carboplatin in pregnant women (Prod Info carboplatin intravenous injection, 2014).
    B) LACK OF EFFECT
    1) A systematic review identified 1 pregnancy specific to the administration of carboplatin, which was given in combination with paclitaxel. This pregnancy resulted in the birth of 1 live newborn who was healthy at a 48-month follow-up (Zagouri et al, 2013).
    2) Stage 3 epithelial ovarian cancer was diagnosed in the second trimester of gestation and successfully treated with carboplatin with preservation of the pregnancy. Follow-up more than 18 months later found the baby girl developing normally (Picone et al, 2004).
    3) 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 therapy, carboplatin was substituted for cisplatin, and therapy was continued. At 36 weeks, a grossly normal 3600-g infant was delivered. Growth, neurologic findings, hematologic parameters, and renal function were normal at 12 months of age (Henderson et al, 1993).
    C) ANIMAL STUDIES
    1) There was evidence of embryotoxicity when animals were exposed to carboplatin (Prod Info carboplatin intravenous injection, 2014) at days 6 to 9 of gestation (Kai et al, 1989).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is unknown whether carboplatin is excreted in human milk. Due to the potential for carboplatin toxicity in nursing infants, discontinue breastfeeding while receiving carboplatin (Prod Info carboplatin intravenous injection, 2014).
    2) CASE REPORT: Both carboplatin and paclitaxel were found in the breast milk of a 40-year-old lactating woman following adjuvant chemotherapy treatment. The patient was administered 6 weekly doses of IV carboplatin 233 mg (AUC, 1.5) and IV paclitaxel 56.1 mg (30 mg/m(2)) approximately 30 minutes apart. Both carboplatin and paclitaxel were detected in breast milk samples collected during the sixth chemotherapy session. Carboplatin had a relative infant dose of 2% of the maternal dose and continued to be measurable after 316 hours, while paclitaxel had a relative infant dose of 16.7% and was measurable for at least 172 hours. The possible transfer of metabolites were not measured (Griffin et al, 2012).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects on fertility from exposure to this agent.

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of carboplatin in humans. However, carcinogenicity has been reported with compounds that have mutagenicity profiles and similar mechanisms of action as carboplatin. There have been reports of secondary malignancies associated with combination therapy.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, the manufacturer does not report any carcinogenic potential of carboplatin. However, carcinogenicity has been reported with compounds that have mutagenicity profiles and similar mechanisms of action as carboplatin (Prod Info PARAPLATIN(R) IV injection, 2010).
    B) SECONDARY MALIGNANCIES
    1) There have been reports of secondary malignancies associated with combination therapy (Prod Info PARAPLATIN(R) IV injection, 2010).

Genotoxicity

    A) There was evidence of mutagenicity in vivo and in vitro (Prod Info PARAPLATIN(R) IV injection, 2010).
    B) Carboplatin has been reported to cause DNA repair, DNA damage, DNA inhibition, mutations, sex chromosome loss and nondisjunction, sister chromatid exchange, gene conversion, and mitotic recombination (Calvert et al, 1993).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status, and perform repeated neurological examination.
    B) Carboplatin plasma concentrations are not clinically useful or readily available.
    C) Closely monitor renal function, electrolytes, liver enzymes, and urine output.
    D) Monitor CBC with differential daily until nadir has clearly been reached and marrow recovery has begun. Nadir occurs in about 21 to 28 days, but may be earlier after an overdose.
    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) Monitor visual acuity and hearing. Obtain baseline ophthalmologic evaluation and audiogram and repeat as necessary.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Closely monitor renal function, electrolytes, liver enzymes, and urine output.
    B) HEMATOLOGIC
    1) Monitor CBC with differential daily until nadir has clearly been reached and marrow recovery has begun. Nadir occurs in about 21 to 28 days (Prod Info PARAPLATIN(R) IV injection, 2010; Woloschuk et al, 1988; Ozols et al, 1985; Leyvraz et al, 1985a; Canetta et al, 1985), but may be earlier after an overdose.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor vital signs and mental status, and perform repeated neurological examination.
    b) 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.
    c) Monitor visual acuity and hearing. Obtain baseline ophthalmologic evaluation and audiogram and repeat as necessary.

Methods

    A) SPECTROSCOPY/SPECTROMETRY
    1) Free or total platinum in plasma and tissues has been determined by flame-less atomic absorption spectometry (Baselt, 2000).
    B) CHROMATOGRAPHY
    1) High-performance liquid chromatographic procedures have been developed for the analysis of carboplatin in human plasma and urine (Gaver & Deeb, 1986). The lower limit of quantification was 1.0 mcg/mL plasma and 5.0 mcg/mL urine.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with carboplatin overdose need to be admitted, as toxicity develops over several days. Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no data to support home management.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with carboplatin overdose. Consult a nephrologist for emergent dialysis. In addition, consultation with an infectious diseases physician with expertise in the management of neutropenic patients with infections is strongly recommended.
    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.

Monitoring

    A) Monitor vital signs and mental status, and perform repeated neurological examination.
    B) Carboplatin plasma concentrations are not clinically useful or readily available.
    C) Closely monitor renal function, electrolytes, liver enzymes, and urine output.
    D) Monitor CBC with differential daily until nadir has clearly been reached and marrow recovery has begun. Nadir occurs in about 21 to 28 days, but may be earlier after an overdose.
    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) Monitor visual acuity and hearing. Obtain baseline ophthalmologic evaluation and audiogram and repeat as necessary.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Activated charcoal is not helpful as overdose most often occurs inadvertently by the IV route. For dermal exposures, clean skin with soap and water, and for eye exposures, flush with water.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment should include recommendations listed in the PARENTERAL EXPOSURE section when appropriate.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Carboplatin has a small volume of distribution and low protein binding (Gaver et al, 1988a); it is readily removed by hemodialysis. Emergent hemodialysis should be performed as early as possible in any patient with a significant overdose.
    2) Late dialysis is unlikely to be effective as the platinum metabolite is irreversibly bound to plasma proteins (Prod Info PARAPLATIN(R) IV injection, 2010).
    3) Carboplatin is removed efficiently by hemodialysis. In one study, the clearance of carboplatin due to hemodialysis was 88 to 139 mL/min in a 17-year-old patient with relapsed Wilms' tumor. This clearance approached the plasma flow through the hemodialysis apparatus (140 mL/min) (English et al, 1996).
    B) PLASMAPHERESIS
    1) There are no clinical reports using plasmapheresis in carboplatin overdose. Plasmapheresis is not likely to be as effective as in cisplatin because carboplatin is less protein bound. In a case of massive cisplatin overdose (480 mg), plasma platinum levels decreased during plasmapheresis, which was initiated 12 days after overdose. When plasmapheresis was discontinued from days 16 to 20, plasma platinum levels increased, with associated worsening of symptoms (nausea, vomiting, worsening vision). Plasma platinum levels decreased again and symptoms improved when plasmapheresis was reinstituted on days 21 to 28 (Chu et al, 1993). These observations notwithstanding, plasmapheresis is not recommended.
    C) PERITONEAL DIALYSIS
    1) Carboplatin was not removed by peritoneal dialysis in a 4-year-old girl with relapsed Wilms' tumor (English et al, 1996). Accordingly, peritoneal dialysis is not recommended.

Range Of Toxicity

Summary

    A) TOXICITY: Expect toxicity in therapeutic dose. CHILDREN: In a 3-year-old girl, administration of a cumulative dose of 4938 mg/m(2) instead of 1913 mg/m(2) resulted in grade IV mucositis, febrile neutropenia and grade II diarrhea. In a 4-year-old boy, the administration of 3939 mg/m(2)/course of carboplatin instead of 1719 mg/m(2)/course led to ototoxicity and renal insufficiency.
    B) THERAPEUTIC DOSE: ADULTS: 360 mg/m(2) IV on day 1 every 4 weeks OR dose based on the Calvert formula, with a target AUC of 4 to 6 mg/mL x min; total dose (mg) = target (AUC) x (GFR +25). CHILDREN: Safety and efficacy have not been established in pediatric patients. In several pediatric studies, high-dose carboplatin (up to 750 mg/m(2)) was administered alone or in combination with other chemotherapeutic agents in children. The dose-limiting toxicity was myelosuppression.

Therapeutic Dose

    7.2.1) ADULT
    A) SINGLE AGENT THERAPY: 360 mg/m(2) IV on day 1 every 4 weeks OR dose based on the Calvert formula, with a target AUC of 4 to 6 mg/mL x min; total dose (mg) = target (AUC) x (GFR +25) (Prod Info carboplatin intravenous injection, 2014)
    B) IN COMBINATION WITH OTHER AGENTS: 300 mg/m(2) on day 1 every 4 weeks for 6 cycles OR dose based on the Calvert formula, with a target AUC of 4 to 6 mg/mL x min; total dose (mg) = target (AUC) x (GFR +25). Carboplatin dose is given in combination with cyclophosphamide 600 mg/m(2) IV on day 1 every 4 weeks for 6 cycles (Prod Info carboplatin intravenous injection, 2014).
    C) DOSING GUIDELINE
    1) Dose based on ACTUAL GFR measurements: Total Dose (mg) = target (AUC) x (GFR + 25) (US Food and Drug Administration, 2010)
    2) Dose based on ESTIMATED GFR obtained from serum creatinine measured by IDMS: Total Maximum Dose (mg) = target (AUC) x 150 mL/min (US Food and Drug Administration, 2010)
    3) GFR capped at 125 mL/min for patients with normal renal function if estimated from serum creatinine measured by Isotope Dilution Mass Spectrometry (IDMS) (US Food and Drug Administration, 2010).
    a) IDMS = a method of serum creatinine (SCr) measurement which tends to underestimate SCr when the values are low (eg, approximately 0.7 mg/dL) resulting in an overestimation of the GFR in patients with normal renal function, which could lead to overdosing and drug-related toxicity.
    b) Total Maximum Dose (mg) = target (AUC) x 150 mL/min
    1) Target AUC of 6 = the maximum dose is 6 x 150 = 900 mg
    2) Target AUC of 5 = the maximum dose is 5 x 150 = 750 mg
    3) Target AUC of 4 = the maximum dose is 4 x 150 = 600 mg
    7.2.2) PEDIATRIC
    A) Safety and efficacy have not been established the pediatric or adolescent population (Prod Info carboplatin intravenous injection, 2014; Prod Info PARAPLATIN(R) IV injection, 2010).
    B) In several pediatric studies, high-dose carboplatin (up to 750 mg/m(2)) was administered alone or in combination with other chemotherapeutic agents to children. The dose-limiting toxicity was myelosuppression (Thomas et al, 2000; Friedman et al, 2000; Kung et al, 1999; Frascella et al, 1996; Doz et al, 1990; Foster et al, 1985).

Minimum Lethal Exposure

    A) A minimum lethal dose has not been reported in the literature.

Maximum Tolerated Exposure

    A) ADULT
    1) In one study, 31 women with advanced cancer (29 of them with ovarian cancer) were initially treated with cyclophosphamide supported by filgrastim. Peripheral blood progenitor cells (PBPC) were collected, and escalating doses of carboplatin were administered every 14 days, 500 mg/m(2)/course, 800 mg/m(2)/course (over 2 days), and either 1000 or 1200 mg/m(2)/course (over 2 days). Ototoxicity was dose limiting at 1200 mg. All of these patients received PBPC infusion following each course of carboplatin (Fennelly et al, 1994). . Without PBPC support, it is likely that these doses would have caused lethal marrow suppression in some patients.
    2) In another study, 21 women with advanced ovarian cancer were given filgrastim and peripheral blood progenitor cells (PBPC) were collected. They were then treated with a single cycle of cyclophosphamide, followed by PBPC infusion. Following this they were treated with two cycles of carboplatin 1600 or 1800 mg/m(2) over 72 hours, and a final cycle of carboplatin 1600 mg/m(2) over 72 hours along with etoposide and melphalan. PBPC were collected prior to each course of therapy and reinfused after each course of therapy (Wandt et al, 1999). Without PBPC support, it is likely that these doses would have caused lethal marrow suppression in some patients.
    B) PEDIATRIC
    1) In one study, the maximum tolerated dose in children with solid tumors was 210 mg/m(2)/week for 4 weeks. At this dose, nausea and vomiting were observed in greater than 80% of the courses (Bacha et al, 1986).
    2) In several pediatric studies, high-dose carboplatin (up to 750 mg/m(2)) was administered alone or in combination with other chemotherapeutic agents to children. The dose-limiting toxicity was myelosuppression (Thomas et al, 2000; Friedman et al, 2000; Kung et al, 1999; Frascella et al, 1996; Doz et al, 1990; Foster et al, 1985).
    3) In one phase I study, 12 children (3 to 17 years of age) received high-dose carboplatin (target total AUC 20 to 30 mg/mL x min; total doses range, 715 to 2550 mg) administered as a daily 60-minute infusion, repeated on 5 consecutive days. All patients developed grade 4 neutropenia and thrombocytopenia, lasting up to 32 days (average 7 days). Hearing loss developed in 3 patients who were previously treated with cisplatin (Rubie et al, 2003).
    4) CASE REPORTS: Overdose effects (i.e., neutropenia, diarrhea, mucositis, etc) reported in two young children were similar to adverse effects observed with therapeutic carboplatin use. The children received inadvertent excessive carboplatin doses of 2,639 mg/course vs. the intended 1,152 mg/course in one case, and 930 mg for one day vs. the intended 360.3 mg/day in the other (Liem et al, 2003).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) Based on studies, a target AUC of 4 to 6 mg/mL x min can provide the most appropriate dose range in previously treated patients (Prod Info PARAPLATIN(R) IV injection, 2010).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Carboplatin, like cisplatin, is a platinum coordination compound that has antineoplastic activity. This effect is cell-cycle nonspecific. Carboplatin binds to DNA base pairs, forming inter- and intra-strand crosslinks, and leading to DNA strand breaks and inhibiting DNA synthesis (Prod Info PARAPLATIN(R) IV injection, 2010; Micetich et al, 1985; Harrap, 1985; Rosenberg, 1978).

Toxicologic Mechanism

    A) The disruption of DNA synthesis affects rapidly dividing cells first; myelosuppression is the dose-limiting toxicity. In addition, pretreated patients with carboplatin are at greater risk of bone marrow suppression than naive patients (Prod Info PARAPLATIN(R) IV injection, 2010; Woloschuk et al, 1988; Ozols et al, 1985; Leyvraz et al, 1985a; Canetta et al, 1985).

Physicochemical

Physical Characteristics

    A) Carboplatin is a crystalline powder that is soluble in water at a rate of approximately 14 mg/mL and is virtually insoluble in ethanol, acetone, and dimethylacetamide (Prod Info PARAPLATIN(R) IV injection, 2010).

Ph

    A) 5 to 7 (1% solution) (Prod Info PARAPLATIN(R) IV injection, 2010)

Molecular Weight

    A) 371.25 (Prod Info PARAPLATIN(R) IV injection, 2010)

References

General Bibliography

    1) Addiego JE, Ridgway D, & Bleyer WA: The acute management of intrathecal methotrexate overdose: pharmacologic rationale and guidelines. J Pediatr 1981; 98(5):825-828.
    2) Agraharkar M, Nerenstone S, & Palmisano J: Carboplatin-related hematuria and acute renal failure. Am J Kid Dis 1998; 32 :1-4.
    3) Anon: ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm 1990; 47:1033-1048.
    4) Anon: ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm 1990a; 47:1033-1049.
    5) Anon: OSHA work-practice guidelines for personnel dealing with cytotoxic (antineoplastic) drugs. Am J Hosp Pharm 1986; 43:1193-1204.
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