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OXALIPLATIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Oxaliplatin is a platinum-containing antineoplastic agent.

Specific Substances

    1) Oxalatoplatin
    2) Oxalatoplatinum
    3) PR-54780
    4) 1-OHP
    5) L-OHP
    6) 1670 RB
    7) RP-54780
    1.2.1) MOLECULAR FORMULA
    1) C8-H14-N2-O4-Pt (Prod Info ELOXATIN(R) intravenous injection, 2008)

Available Forms Sources

    A) FORMS
    1) Available as 50 mg or 100 mg in a powder for infusion following reconstitution, and as a 5 mg/mL solution for infusion in 50 mg, 100 mg, and 200 mg single-use vials (Prod Info ELOXATIN IV injection, 2008).
    B) USES
    1) Oxaliplatin is indicated as adjuvant therapy of stage III colon cancer and for treatment of advanced colorectal cancer, and is given in combination with 5-fluorouracil and leucovorin (Prod Info ELOXATIN IV injection, 2008).

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: Oxaliplatin is an anticancer agent most commonly used in combination with 5-fluorouracil and leucovorin for adjuvant therapy of stage III colon cancer and for treatment of advanced colorectal cancer.
    B) PHARMACOLOGY: Oxaliplatin binds to DNA bases, forming inter- and intra-strand crosslinks, that 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. Most often reported are nausea (64%), vomiting (37%), diarrhea (46%), anorexia (20%), myelosuppression, and peripheral neuropathies (mostly sensorineuronal). Two types of peripheral neuropathies may occur: an acute reversible peripheral neuropathy (56% of patients) that occurs within 2 hours to 2 days of dosing, resolves within 14 days, and can recur with continued dosing, and a persistent (greater than 14 days) peripheral neuropathy (48% of patients). Peripheral neuropathy is generally the dose-limiting effect. Hypersensitivity reactions may be observed in patients treated with more than 5 cycles of oxaliplatin therapy.
    F) WITH POISONING/EXPOSURE
    1) Immediate effects (hours to days) include severe nausea and vomiting, diarrhea, dyspnea, wheezing, laryngospasm, and paresthesias. Bone marrow suppression commonly occurs following overdose as a delayed effect (days to a week or more). Bradycardia, renal failure, and respiratory failure are less often observed.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Fever has been reported in adult and pediatric patients following oxaliplatin monotherapy.
    0.2.20) REPRODUCTIVE
    A) Oxaliplatin is classified as FDA pregnancy category D. Oxaliplatin administration to rats has resulted in increased early resorptions, decreased fetal weight, and delayed ossification.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no human data were available to assess the potential carcinogenic activity of oxaliplatin.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Oxaliplatin plasma levels are not clinically useful or readily available.
    C) Monitor renal function and hepatic enzymes.
    D) Monitor daily CBC with differential to detect bone marrow depression.
    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) Closely monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
    G) Monitor chest radiographs in patients with pulmonary symptoms.
    H) Nerve conduction studies may be useful to evaluate neuropathy.

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. Severe nausea and vomiting may respond to a combination of agents from different drug classes. Administer granulocyte colony stimulating factor (filgrastim or sargramostim).
    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 granulocyte colony stimulating factor (filgrastim or sargramostim). Patients with severe neutropenia should be placed in protective isolation. Platelet and red cell transfusions may be necessary. Severe nausea and vomiting may respond to a combination of agents from different drug classes. .
    C) DECONTAMINATION
    1) GI decontamination is not indicated as oxaliplatin is administered intravenously.
    2) Wash exposed skin with soap and water, irrigate exposed eyes with water or normal saline.
    D) AIRWAY MANAGEMENT
    1) Consider orotracheal intubation in patients with significant encephalopathy (ie, agitation, delirium) or respiratory failure.
    E) ANTIDOTE
    1) There is no antidote for oxaliplatin overdose.
    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) NAUSEA AND VOMITING
    1) 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.
    J) INTRATHECAL INJECTION
    1) No clinical reports available, information derived from experience with other antineoplastics. 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). Fresh frozen plasma (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 oxaliplatin. Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.
    K) ENHANCED ELIMINATION
    1) Hemodialysis is unlikely to be of benefit due to the high protein binding and large volume of distribution of oxaliplatin. Plasma pheresis or plasma exchange might theoretically be of benefit if performed shortly after overdose, but there are no published overdose cases where these methods have been used.
    L) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management. Patients with oxaliplatin overdose need to be admitted.
    2) ADMISSION 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, medical toxicologist, and/or a poison center for assistance in managing patients with oxaliplatin overdose.
    4) TRANSFER CRITERIA: Patients with large overdoses may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    M) 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.
    N) PHARMACOKINETICS
    1) Protein binding is greater than 95%. Volume of distribution is 440 liters following a single 2-hour infusion of 85 mg/m(2). Metabolism is rapid and extensive via nonenzymatic biotransformation. Elimination is mainly by the renal route (approximately 54% platinum is eliminated 5 days after oxaliplatin infusion). Terminal elimination half-life of platinum can range from 9 to 16 days.
    O) DIFFERENTIAL DIAGNOSIS
    1) Differential diagnosis includes other chemotherapeutic agents.

Range Of Toxicity

    A) TOXICITY: Expect toxicity with therapeutic doses. Adult patients have developed toxicity, but recovered following doses of 360 mg to 700 mg. A 7-year-old child experienced severe toxicity (myelosuppression, gastrointestinal symptoms, and neurotoxicity) after receiving 800 mg oxaliplatin but survived. Death has been reported in one patient after receiving 500 mg.
    B) THERAPEUTIC DOSE: ADULT: 85 mg/m(2) IV in 250 to 500 mL D5W over 120 minutes every 2 weeks as combination therapy. PEDIATRIC: Safety and efficacy have not been established. Phase I and II trials were conducted, involving pediatric patients (ages 7 months to 22 years) with solid tumors who received oxaliplatin doses ranging from 40 mg/m(2) to 160 mg/m(2) on day 1 of the cycle every 3 to 4 weeks, for a maximum of 6 to 17 cycles. Pediatric patients 12-months-old or younger received 4.3 mg/kg of oxaliplatin.

Clinical Effects

Summary Of Exposure

    A) USES: Oxaliplatin is an anticancer agent most commonly used in combination with 5-fluorouracil and leucovorin for adjuvant therapy of stage III colon cancer and for treatment of advanced colorectal cancer.
    B) PHARMACOLOGY: Oxaliplatin binds to DNA bases, forming inter- and intra-strand crosslinks, that 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. Most often reported are nausea (64%), vomiting (37%), diarrhea (46%), anorexia (20%), myelosuppression, and peripheral neuropathies (mostly sensorineuronal). Two types of peripheral neuropathies may occur: an acute reversible peripheral neuropathy (56% of patients) that occurs within 2 hours to 2 days of dosing, resolves within 14 days, and can recur with continued dosing, and a persistent (greater than 14 days) peripheral neuropathy (48% of patients). Peripheral neuropathy is generally the dose-limiting effect. Hypersensitivity reactions may be observed in patients treated with more than 5 cycles of oxaliplatin therapy.
    F) WITH POISONING/EXPOSURE
    1) Immediate effects (hours to days) include severe nausea and vomiting, diarrhea, dyspnea, wheezing, laryngospasm, and paresthesias. Bone marrow suppression commonly occurs following overdose as a delayed effect (days to a week or more). Bradycardia, renal failure, and respiratory failure are less often observed.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fever has been reported in adult and pediatric patients following oxaliplatin monotherapy.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) FEVER
    a) In a North American, multicenter, randomized, three-arm, controlled study comparing 5-fluorouracil/leucovorin (5-FU/LV), oxaliplatin monotherapy, and oxaliplatin in combination with 5-FU/LV for advanced colorectal cancer that was previously treated, fever occurred in 23% of patients treated with 5-FU/LV (n=142), 25% of patients treated with oxaliplatin monotherapy (n=153) and 29% of patients treated with oxaliplatin plus 5-FU/LV (n=150) (Prod Info ELOXATIN IV injection, 2008).
    b) In an international, multicenter, randomized study comparing combination adjuvant therapy of oxaliplatin and 5-fluorouracil/leucovorin (5-FU/LV) to 5-FU/LV alone for stage II or III colon cancer, fever occurred in 27% of patients treated with oxaliplatin plus 5-FU/LV (n=1108) for 6 months (ie, 12 cycles) and in 12% of patients treated with 5-FU/LV alone (n=1111) (Prod Info ELOXATIN IV injection, 2008).
    c) In a Phase II study, fever occurred in 40% of pediatric patients (n=15) between 7 months and 22 years of age who had solid tumors and were treated with oxaliplatin 90 mg/m(2) IV (Prod Info ELOXATIN IV injection, 2008).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A patient who inadvertently received 500 mg oxaliplatin (instead of carboplatin) developed dyspnea, wheezing, paresthesia, vomiting and chest pain on the day of administration. She subsequently developed respiratory failure and severe bradycardia that did not respond to resuscitation (Prod Info ELOXATIN IV injection, 2008).
    B) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) In a North American, multicenter, randomized, three-arm, controlled study comparing 5-fluorouracil/leucovorin (5-FU/LV), oxaliplatin monotherapy, and oxaliplatin in combination with 5-FU/LV for advanced colorectal cancer that was previously treated, the incidence of tachycardia was 2% to less than 5% in patients treated with oxaliplatin plus 5-FU/LV (Prod Info ELOXATIN IV injection, 2008).
    C) EDEMA
    1) WITH THERAPEUTIC USE
    a) In a North American, multicenter, randomized, three-arm, controlled study evaluating 5-fluorouracil/leucovorin (5-FU/LV), oxaliplatin monotherapy, and oxaliplatin in combination with 5-FU/LV for advanced colorectal cancer that was previously treated, edema occurred in 13% of patients treated with 5-FU/LV (n=142), 10% of patients treated with oxaliplatin monotherapy (n=153), and 15% of patients treated with oxaliplatin plus 5-FU/LV (n=150). Additionally, grade 3 or 4 edema was experienced by 1% of patients in all 3 arms (Prod Info ELOXATIN IV injection, 2008).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY FAILURE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A patient who inadvertently received 500 mg oxaliplatin instead of carboplatin developed dyspnea, wheezing, paresthesia, vomiting and chest pain the day of administration. She subsequently developed respiratory failure and bradycardia that did not respond to resuscitative measures (Prod Info ELOXATIN IV injection, 2008).
    B) BRONCHOSPASM
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Bronchospasm and laryngeal stridor were reported in a 7-year-old child who inadvertently received 800 mg of oxaliplatin instead of the prescribed 80 mg during the third chemotherapy cycle for treatment of a paravertebral Schwannoma . The patient recovered following cessation of oxaliplatin and administration of epinephrine, hydrocortisone, and chlorpheniramine (Soloni et al, 2009).
    C) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) In clinical trials of oxaliplatin as a single agent and in combination with other chemotherapeutic agents, cough and dyspnea were commonly reported (Prod Info ELOXATIN IV injection, 2008).
    D) PNEUMONITIS
    1) WITH THERAPEUTIC USE
    a) Two case reports described fatal pneumonitis in a 73-year-old female and a 71-year-old male following adjuvant treatment of colorectal cancer with oxaliplatin in combination with 5-fluorouracil/leucovorin (5-FU/LV) (ArevaloLobera et al, 2008).
    1) In the first case, the patient, who underwent segmental resection, received no supplemental treatment. Four months later, she presented with complaints of chest pain. A resection of the upper right lobe of the lung revealed metastases. Subsequently, chemotherapeutic treatment was initiated with the FOLFOX-4 regimen. Following cycle 4, the patient developed chest pain, dry cough and dyspnea with moderate effort. A CT scan revealed pulmonary fibrosis. Although she was treated with oxygen therapy, corticosteroids, diuretics, and broad-spectrum antibiotic therapy, she showed no clinical improvement. An infectious etiology and further lung metastases were subsequently ruled out and despite continued treatment, the patient experienced worsening respiratory insufficiency resulting in her death. Autopsy revealed an adult respiratory distress syndrome and mild right pleural effusion with no lung metastases (ArevaloLobera et al, 2008).
    2) In the second case, the patient, who had a history of mild COPD, and Wegener disease with lung involvement and axonal polyneuropathy for which he was treated with segmentectomy of the left lower lobe and cyclophosphamide for 4 years, had been asymptomatic. Four years later, the patient presented to the emergency room noting a change in bowel habits that had been occurring over the previous 3 months. He was diagnosed with intestinal occlusion. A stenosing neoplasm was found during emergency surgery and removed by sigmoidectomy. Adjuvant treatment using FOLFOX-4 regimen was initiated a month later. The patient had received 4 treatment cycles when he began experiencing dyspnea with minimal effort, dry cough, severe fatigue, and arthromyalgia. Chest x-rays and arterial blood gases revealed bilateral interstitial and alveolar infiltrates and respiratory insufficiency, respectively. As a result, the patient was admitted to the hospital and initiated on oxygen therapy, corticosteroids, and broad-spectrum antibiotics. Due to lack of clinical response, he was transferred to intensive care and required assisted ventilation. Because his condition could have potentially been a reactivation of Wegener disease, high-dose corticosteroids, cyclophosphamide, and immunoglobulins were started. Despite clinical and radiographic treatment, the patient eventually died. Autopsy revealed bilateral bronchopneumonia, acute lung damage with fibrosis and interstitial inflammatory infiltrate (ArevaloLobera et al, 2008).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) Oxaliplatin is associated with two types of peripheral neuropathies, acute and persistent, as well as pharyngolaryngeal dysesthesia (Prod Info ELOXATIN IV injection, 2008).
    b) Peripheral sensory neuropathies are dose-related, cumulative, aggravated by cold exposure, and often dose-limiting (Becouarn et al, 1998; de Gramont et al, 1997a; Chollet et al, 1996a; Degardin et al, 1996; Levi et al, 1994).
    c) Acute Neuropathy
    1) Fifty-six percent of patients receiving oxaliplatin/5-fluorouracil/leucovorin developed acute sensory neuropathy. Acute neuropathy has an onset within hours to one or two days, resolves within 2 weeks, and frequently recurs with further dosing. Symptoms include transient paresthesia, dysesthesia, and hypoesthesia in the hands, feet, perioral area, or throat. Jaw spasm, abnormal tongue sensation, dysarthria, eye pain, and a feeling of chest pressure have also been observed. Exposure to cold temperatures or cold objects (eg, ice for mucositis prophylaxis) can precipitate or exacerbate these symptoms (Prod Info ELOXATIN IV injection, 2008).
    2) In chronomodulated or constant infusion (single-agent or combined with 5-fluorouracil plus leucovorin), onset is near the end of 5-day oxaliplatin infusion regimen. Dysesthesias consisting of cold-induced sensation of electric discharges in fingertips or toes and hypoesthesia gradually extending to whole fingers/footplant have been observed. Effects usually subside over 1 to 2 weeks; persistence for 2 to 12 months have been reported after several courses (Levi et al, 1997; Levi et al, 1995a; Levi et al, 1993; Levi et al, 1992; Caussanel et al, 1990). In a combination study with 5-fluorouracil plus leucovorin, there was a 31% incidence with constant-rate infusion and 16% with chronotherapy (Levi et al, 1997).
    3) During short infusion regimens (eg, 1 to 6 hours monthly) paresthesias (lips/extremities) have been observed with doses greater than 100 mg/m(2) and persisted for several days. Development of sensory neuropathy after repeat courses was associated with sensory ataxia and dysesthesia (limbs, mouth, throat) with a progressive increase in duration/intensity. Effects have persisted up to 6 months (de Gramont et al, 1997a; Degardin et al, 1996; McKeage, 1995; Tuxen & Hansen, 1994; Weiss & Christian, 1993a; Extra et al, 1990).
    d) Persistent Neuropathy
    1) Forty-eight percent of patients receiving oxaliplatin/5-fluorouracil/leucovorin developed persistent neuropathy. Persistent neuropathy lasts longer than 2 weeks and is characterized by paresthesia, dysesthesias, hypoesthesias, and possibly proprioception that can interfere with activities of daily living. This type of neuropathy can occur without any prior acute neuropathy. The symptoms may improve with the discontinuation of oxaliplatin (Prod Info ELOXATIN IV injection, 2008).
    2) During short infusion regimens (eg, 1 to 6 hours monthly) paresthesias (lips/extremities) have been observed with doses greater than 100 mg/m(2) and persisted for several days. Development of sensory neuropathy after repeat courses was associated with sensory ataxia and dysesthesia (limbs, mouth, throat) with a progressive increase in duration/intensity. Effects have persisted up to 6 months (de Gramont et al, 1997a; Degardin et al, 1996; McKeage, 1995; Tuxen & Hansen, 1994; Weiss & Christian, 1993a; Extra et al, 1990).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Two patients who received oxaliplatin 500 mg and 650 mg instead of carboplatin developed paresthesia. Another patient received 700 mg oxaliplatin and developed rapid onset of dysesthesia. A fourth patient developed paresthesia after receiving 360 mg oxaliplatin instead of the prescribed 120 mg (Prod Info ELOXATIN IV injection, 2008).
    b) CASE REPORT: A 64-year-old woman developed grade 2 peripheral neuropathy for 5 days after receiving 500 mg oxaliplatin; she recovered (Munoz et al, 2006).
    c) CASE REPORT: A 7-year-old child developed hyporeactivity, dizziness, horizontal nystagmus, lower limb weakness, and hyperextension of the right foot after inadvertently receiving 800 mg of oxaliplatin instead of the prescribed 80 mg during the third chemotherapy cycle for treatment of a paravertebral Schwannoma. A CT scan and a brain/spinal MRI were negative and the patient gradually improved over the next 3 weeks and was discharged; however, she continued to experience localized lower limb tingling for another 3 weeks following discharge (Soloni et al, 2009).
    B) DYSESTHESIA
    1) WITH THERAPEUTIC USE
    a) Pharyngolaryngeal dysesthesia, characterized by subjective sensations of dysphagia and dyspnea with or without any laryngospasm or bronchospasm, has been reported in 1% to 2% of patients receiving oxaliplatin (Prod Info ELOXATIN IV injection, 2008; Barhamand, 2003).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 64-year-old woman experienced mild pharyngolaryngeal dysesthesia after inadvertently receiving 500 mg of oxaliplatin instead of the prescribed 236 mg (Munoz et al, 2006).
    C) FATIGUE
    1) WITH THERAPEUTIC USE
    a) In a North American, multicenter, randomized, three-arm, controlled study comparing 5-fluorouracil/leucovorin (5-FU/LV), oxaliplatin monotherapy, and oxaliplatin in combination with 5-FU/LV for advanced colorectal cancer that was previously treated, fatigue occurred in 52% of patients treated with 5-FU/LV (n=142), 61% of patients treated with oxaliplatin monotherapy (n=153) and 68% of patients treated with oxaliplatin plus 5-FU/LV (n=150) (Prod Info ELOXATIN IV injection, 2008).
    b) In an international, multicenter, randomized study comparing combination adjuvant therapy of oxaliplatin and 5-fluorouracil/leucovorin (5-FU/LV) to 5-FU/LV alone for stage II or III colon cancer, fatigue occurred in 44% of patients treated with oxaliplatin plus 5-FU/LV (n=1108) for 6 months (ie, 12 cycles) and in 38% of patients treated with 5-FU/LV alone (n=1111) (Prod Info ELOXATIN IV injection, 2008).
    D) TRANSIENT CEREBRAL ISCHEMIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 68-year-old male developed a transient ischemic attack (TIA) following the administration of oxaliplatin for metastatic colon adenocarcinoma. The patient was receiving oral capecitabine 1.5 gm twice daily for 14 days of a 21 day cycle in combination with IV oxaliplatin 210 mg every 3 weeks. During his second cycle of therapy, the patient developed a sudden onset of dysphasia and motor neurone weakness of his upper right limb. The patient was a former smoker, had controlled hypertension, and no history of cerebrovascular disease. Testing revealed nothing abnormal. Over the following 3 days, his neurological symptoms resolved. Oxaliplatin was suspected to be a possible cause of his TIA. His oxaliplatin dose was reduced to 150 mg with a slower infusion rate over 12 hours. Treatment was continued for 7 more cycles without further issue, however, 8 months following therapy, the patient developed widespread progressive disease and died (Azad & Tan, 2009).
    E) BARBER'S CHAIR SIGN
    1) WITH THERAPEUTIC USE
    a) Five of 150 consecutive patients with colorectal cancer developed Lhermitte's phenomenon (electrical sensation running down the back and into the limbs) after receiving oxaliplatin therapy. Patients were administered regimens containing either a single oxaliplatin dose of 85 mg/m(2) or 100 mg/m(2). A complete medical history, neurological examination, MRI of the brain and spinal cord, spinal assessment, neurotoxicity grading and conventional nerve studies were conducted for each patient. Patients were without structural or functional spinal cord damage. Nerve conduction studies found severe sensory neuropathy along with progressive changes in sensory excitability throughout treatment. The 5 patients who developed Lhermitte's phenomenon had a mean cumulative dose of oxaliplatin 777 mg/m(2) to 945 mg/m(2) (range 574 mg/m(2) to 1,100 mg/m(2)); and showed a significant reduction in refractoriness from the beginning of treatment (18.2%; 95% confidence interval (CI), 11.3% to 25%) to -0.3% (95% CI -9% to 8.5%) at mid-treatment which was further reduced to -14.4% (95% CI -20.5% to -8.4%) by late treatment compared to -2.7% (95% CI -7.6% to 2.2%; p=0.013) in patients who did not develop Lhermitte's phenomenon (n=20) with a mean cumulative oxaliplatin dose of 791 mg/m(2) to 871 mg/m(2) at completion of treatment (Park et al, 2009).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) The incidence of nausea and vomiting was 35% to 90% with short infusions and 40% to 60% with single-agent chronotherapy/constant infusions (Chollet et al, 1996a; Levi et al, 1993; Christian, 1992a; Extra et al, 1990; Caussanel et al, 1990) More often grade 3 with short infusions (Extra et al, 1990).
    b) In a North American, multicenter, randomized, three-arm, controlled study comparing 5-fluorouracil/leucovorin (5-FU/LV), oxaliplatin monotherapy, and oxaliplatin in combination with 5-FU/LV for advanced colorectal cancer that was previously treated, nausea occurred in 59% of patients treated with 5-FU/LV (n=142), 64% of patients treated with oxaliplatin monotherapy (n=153) and 65% of patients treated with oxaliplatin plus 5-FU/LV (n=150) (Prod Info ELOXATIN IV injection, 2008).
    c) In a North American, multicenter, randomized, three-arm, controlled study comparing 5-fluorouracil/leucovorin (5-FU/LV), oxaliplatin monotherapy, and oxaliplatin in combination with 5-FU/LV for advanced colorectal cancer that was previously treated, vomiting occurred in 27% of patients treated with 5-FU/LV (n=142), 37% of patients treated with oxaliplatin monotherapy (n=153) and 40% of patients treated with oxaliplatin plus 5-FU/LV (n=150). Additionally, grade 3 or 4 vomiting occurred in 4%, 4%, and 9% of patients in the 5-FU/LV, oxaliplatin monotherapy, and the oxaliplatin plus 5-FU/LV arms, respectively (Prod Info ELOXATIN IV injection, 2008).
    2) WITH POISONING/EXPOSURE
    a) Profuse vomiting developed in two patients who inadvertently received 500 mg and 650 mg of oxaliplatin instead of carboplatin (Prod Info ELOXATIN IV injection, 2008).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) The incidence of diarrhea was 17% to 25% with short infusions and 10% to 42% with single-agent chronotherapy (Chollet et al, 1996; Levi et al, 1993a; Caussanel et al, 1990a). The incidence of grade 3/4 diarrhea was 6 of 105 single-agent chronotherapy courses in one study (Levi et al, 1993a).
    b) In a North American, multicenter, randomized, three-arm, controlled study comparing 5-fluorouracil/leucovorin (5-FU/LV), oxaliplatin monotherapy, and oxaliplatin in combination with 5-FU/LV for advanced colorectal cancer that was previously treated, diarrhea occurred in 44% of patients treated with 5-FU/LV (n=142), 46% of patients treated with oxaliplatin monotherapy (n=153) and 67% of patients treated with oxaliplatin plus 5-FU/LV (n=150) (Prod Info ELOXATIN IV injection, 2008).
    c) The incidence of grade 3/4 diarrhea was reported in 29% of patients (per course) with chronotherapy compared to constant-rate infusion (Levi et al, 1997).
    2) WITH POISONING/EXPOSURE
    a) Diarrhea is an anticipated event following overdose (Prod Info ELOXATIN IV injection, 2008).
    b) CASE REPORT: A 64-year-old woman developed grade 2 diarrhea after receiving 500 mg oxaliplatin (Munoz et al, 2006).
    c) CASE REPORT: Vomiting, diarrhea, and severe abdominal pain were reported in a 7-year-old child, who inadvertently received 800 mg of oxaliplatin instead of the prescribed 80 mg during the third chemotherapy cycle for treatment of a paravertebral Schwannoma. She then developed constipation from 3 to 6 weeks after exposure (Soloni et al, 2009).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) In an international, multicenter, randomized study comparing combination adjuvant therapy of oxaliplatin in combination and 5-fluorouracil/leucovorin (5-FU/LV) to 5-FU/LV alone for stage II or III colon cancer, abdominal pain occurred in 18% of patients treated with oxaliplatin plus 5-FU/LV (n=1108) for 6 months (ie, 12 cycles) compared to 17% in patients treated with 5-FU/LV alone (Prod Info ELOXATIN IV injection, 2008).
    b) In a North American, multicenter, open-label, randomized, controlled study evaluating oxaliplatin in combination with 5- fluorouracil/leucovorin (5-FU/LV) or irinotecan as therapy for locally advanced or metastatic colorectal cancer that was previously untreated, abdominal pain occurred in 29% of patients treated with oxaliplatin plus 5-FU/LV (n=259) and 39% of patients treated with oxaliplatin plus irinotecan (n=258) (Prod Info ELOXATIN IV injection, 2008).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Vomiting, diarrhea, and severe abdominal pain were reported in a 7-year-old child, who inadvertently received 800 mg of oxaliplatin instead of the prescribed 80 mg during the third chemotherapy cycle for treatment of a paravertebral Schwannoma (Soloni et al, 2009).
    D) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) In an international, multicenter, randomized study evaluating combination adjuvant therapy of oxaliplatin and 5-fluorouracil/leucovorin (5-FU/LV) to 5-FU/LV alone for stage II or III colon cancer, constipation occurred in 22% of patients treated with oxaliplatin plus 5-FU/LV (n=1108) for 6 months (ie, 12 cycles) compared to 19% of patients treated with 5-FU/LV alone (n=1111) (Prod Info ELOXATIN IV injection, 2008).
    b) In a North American, multicenter, open-label, randomized, controlled study evaluating oxaliplatin in combination with 5- fluorouracil/leucovorin (5-FU/LV) or irinotecan as therapy for locally advanced or metastatic colorectal cancer that was previously untreated, constipation occurred in 32% of patients treated with oxaliplatin plus 5-FU/LV (n=259) and 21% of patients treated with oxaliplatin plus irinotecan (n=258) (Prod Info ELOXATIN IV injection, 2008).
    E) STOMATITIS
    1) WITH THERAPEUTIC USE
    a) In an international, multicenter, randomized study comparing combination adjuvant therapy of oxaliplatin and 5-fluorouracil/leucovorin (5-FU/LV) to 5-FU/LV alone for stage II or III colon cancer, stomatitis occurred in 42% of patients treated with oxaliplatin plus 5-FU/LV (n=1108) for 6 months (ie, 12 cycles) and in 40% of patients treated with 5-FU/LV alone (n=1111) (Prod Info ELOXATIN IV injection, 2008).
    b) In a North American, multicenter, open-label, randomized, controlled study evaluating oxaliplatin in combination with 5- fluorouracil/leucovorin (5-FU/LV) or irinotecan as therapy for locally advanced or metastatic colorectal cancer that was previously untreated, stomatitis occurred in 38% of patients treated with oxaliplatin plus 5-FU/LV (n=259) and 19% of patients treated with oxaliplatin plus irinotecan (n=258) (Prod Info ELOXATIN IV injection, 2008).
    F) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) In a North American, multicenter, randomized, three-arm, controlled study comparing 5-fluorouracil/leucovorin (5-FU/LV), oxaliplatin monotherapy, and oxaliplatin in combination with 5-FU/LV for advanced colorectal cancer that was previously treated, anorexia occurred in 20% of patients treated with 5-FU/LV (n=142), 20% of patients treated with oxaliplatin monotherapy (n=153) and 29% of patients treated with oxaliplatin plus 5-FU/LV (n=150) (Prod Info ELOXATIN IV injection, 2008).
    b) In an international, multicenter, randomized study comparing combination adjuvant therapy of oxaliplatin and 5-fluorouracil/leucovorin (5-FU/LV) to 5-FU/LV alone for stage II or III colon cancer, anorexia occurred in 13% of patients treated with oxaliplatin plus 5-FU/LV (n=1108) for 6 months (ie, 12 cycles) and in 8% of patients treated with 5-FU/LV alone (n=1111) (Prod Info ELOXATIN IV injection, 2008).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ABNORMAL BILIRUBIN LEVEL
    1) WITH THERAPEUTIC USE
    a) In a North American, multicenter, randomized, three-arm, controlled study comparing 5-fluorouracil/leucovorin (5-FU/LV), oxaliplatin monotherapy, and oxaliplatin in combination with 5-FU/LV for advanced colorectal cancer that was previously treated, bilirubinaemia occurred in 22% of patients treated with 5-FU/LV (n=142), 13% of patients treated with oxaliplatin monotherapy (n=153) and 13% of patients treated with oxaliplatin plus 5-FU/LV (n=150) (Prod Info ELOXATIN IV injection, 2008).
    b) In a North American, multicenter, open-label, randomized, controlled study evaluating oxaliplatin in combination with 5- fluorouracil/leucovorin (5-FU/LV) or irinotecan as therapy for locally advanced or metastatic colorectal cancer that was previously untreated, abnormal bilirubin levels occurred in 6% of patients treated with oxaliplatin plus 5-FU/LV (n=259) and 3% of patients treated with oxaliplatin plus irinotecan (n=258) (Prod Info ELOXATIN IV injection, 2008).
    B) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) In an international, multicenter, randomized study comparing combination adjuvant therapy of oxaliplatin and 5-fluorouracil/leucovorin (5-FU/LV) to 5-FU/LV alone for stage II or III colon cancer, increases in hepatic transaminases and alkaline phosphatase occurred in 57% of patients treated with oxaliplatin plus 5-FU/LV (n=1108) for 6 months (ie, 12 cycles) and in 34% of patients treated with 5-FU/LV alone (n=1111) (Prod Info ELOXATIN IV injection, 2008).
    C) PORTAL HYPERTENSION
    1) WITH THERAPEUTIC USE
    a) A case series described 6 patients (37 to 69 years of age, 3 women and 3 men) with stage 3 or 4 colorectal cancer (CRC) who developed noncirrhotic portal hypertension following extended oxaliplatin-based chemotherapy. Baseline laboratory testing of total bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, prothrombin time, and albumin were all within normal limits. Prior to oxaliplatin, platelet count for 5 of the 6 cases ranged from 192,000 cells/mm(3) to 367,000 cells/mm(3) (value not available for patient 6). At least one month after the last dose of chemotherapy, the range was 53,000 cells/mm(3) to 128,000 cells/mm(3) (value not available for patient 2). The mean cumulative dose was 1913 mg administered for a median of 12 cycles over 6 months with the exception of one patient. Patient 2 received 15 cycles over approximately 21 months as he experienced multiple treatment delays due to neuropathy and thrombocytopenia. Complications of profound splenomegaly, persistent thrombocytopenia, varices, or ascites were observed in each case. In one case, the patient showed evidence of pericardial calcification, which can result in elevated portal pressure. In another case the patients chronically used alcohol, resulting in cirrhotic changes. However, in 4 of the 6 cases presented, no other apparent causes of risk were present. In each case, oxaliplatin-induced hepatic sinusoidal injury was noted as the common factor for the development of noncirrhotic portal hypertension (Slade et al, 2009).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Mild renal failure was reported in a 7-year-old child who inadvertently received 800 mg of oxaliplatin instead of the prescribed 80 mg during the third chemotherapy cycle for treatment of a paravertebral Schwannoma (Soloni et al, 2009).
    B) PROXIMAL RENAL TUBULAR ACIDOSIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 66-year-old male developed severe proximal renal tubular acidosis following treatment with oxaliplatin for colon cancer. The patient presented with a 10 day history of anxiety, lethargy, headache, and altered mental state following his sixth cycle of chemotherapy with 5-fluorouracil and oxaliplatin (140 mg/m(2) every 21 days). On admission, he had fever and dehydration. Laboratory results showed severe hypokalemia (potassium level, 3 mmol/L) and hyperchloremic metabolic acidosis (chloride level, 122 mmol/L; bicarbonate level, 10 mmol/L; serum pH, 7.09) with a normal anion gap of 11. A urinalysis revealed bicarbonaturia (bicarbonate level, 55 mmol/24 hr), aminoaciduria (ammonium ions, 128), proteinuria (urine dipstick test positive) but no glycosuria (urine dipstick test negative). Of note, the patient had normal plasma bicarbonates level following his second chemotherapy cycle. Chemotherapy was discontinued and the patient received both IV and oral alkali treatment which resulted in a normalization of his plasma pH and bicarbonate levels. Additionally, he had a serum pH of 7.41 and serum bicarbonate level of 23 mmol/L six months later (Negro et al, 2010).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) In a North American, multicenter, randomized, three-arm, controlled study comparing 5-fluorouracil/leucovorin (5-FU/LV), oxaliplatin monotherapy, and oxaliplatin in combination with 5-FU/LV for advanced colorectal cancer that was previously treated, neutropenia occurred in 25% of patients treated with 5-FU/LV (n=142), 7% of patients treated with oxaliplatin monotherapy (n=153) and 73% of patients treated with oxaliplatin plus 5-FU/LV (n=150) (Prod Info ELOXATIN IV injection, 2008).
    b) In an international, multicenter, randomized study comparing combination adjuvant therapy of oxaliplatin and 5-fluorouracil/leucovorin (5-FU/LV) to 5-FU/LV alone for stage II or III colon cancer, neutropenia occurred in 79% of patients treated with oxaliplatin plus 5-FU/LV (n=1108) for 6 months (ie, 12 cycles) compared to 40% associated with 5-FU/LV alone (n=1111) (Prod Info ELOXATIN IV injection, 2008).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 64-year-old woman developed neutropenia (1900/mcL) and thrombocytopenia (72,000/mcL) after receiving 500 mg oxaliplatin (Munoz et al, 2006).
    B) ANEMIA
    1) WITH THERAPEUTIC USE
    a) In a North American, multicenter, randomized, three-arm, controlled study comparing 5-fluorouracil/leucovorin (5-FU/LV), oxaliplatin monotherapy, and oxaliplatin in combination with 5-FU/LV for advanced colorectal cancer that was previously treated, anemia occurred in 68% of patients treated with 5-FU/LV (n=142), 64% of patients treated with oxaliplatin monotherapy (n=153) and 81% of patients treated with oxaliplatin plus 5-FU/LV (n=150). Additionally, grade 3 or 4 anemia occurred in 2%, 1% and 2% of patients in the 5-FU/LV, oxaliplatin monotherapy and the oxaliplatin plus 5-FU/LV arms, respectively (Prod Info ELOXATIN IV injection, 2008).
    b) In an international, multicenter, randomized study comparing combination adjuvant therapy of oxaliplatin and 5-fluorouracil/leucovorin (5-FU/LV) to 5-FU/LV alone for stage II or III colon cancer, anemia occurred in 76% of patients treated with oxaliplatin plus 5-FU/LV (n=1108) for 6 months (ie, 12 cycles) compared to 67% associated with 5-FU/LV alone (n=1111). Additionally, grade 3 or 4 anemia occurred in 1% of patients in the oxaliplatin plus 5-FU/LV arm and in less than 1% in the 5-FU/LV arm (Prod Info ELOXATIN IV injection, 2008).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Anemia and severe thrombocytopenia were reported in a 7-year-old child who inadvertently received 800 mg of oxaliplatin instead of the prescribed 80 mg during the third chemotherapy cycle for treatment of a paravertebral Schwannoma . The patient's condition improved with supportive care, including platelet transfusions, although the patient's platelet count never returned to normal (Soloni et al, 2009).
    C) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) In a North American, multicenter, randomized, three-arm, controlled study comparing 5-fluorouracil/leucovorin (5-FU/LV), oxaliplatin monotherapy, or oxaliplatin in combination with 5-FU/LV for advanced colorectal cancer that was previously treated, thrombocytopenia occurred in 20% of patients treated with 5-FU/LV (n=142), 30% of patients treated with oxaliplatin monotherapy (n=153), and 64% of patients treated with oxaliplatin plus 5-FU/LV (n=150). Additionally, grade 3 or 4 thrombocytopenia occurred in 0%, 3% and 4% of patients in the 5-FU/LV, oxaliplatin monotherapy and the oxaliplatin plus 5-FU/LV arms, respectively (Prod Info ELOXATIN IV injection, 2008).
    b) A case report described fatal thrombocytopenia in a 64-year-old man who had been receiving oxaliplatin in combination with fluorouracil/leucovorin (FU/LV) for metastatic colon cancer. After the patient had been treated with oxaliplatin and 24-hour infusion of FU/LV for 8 months, CT scan indicated complete response and chemotherapy was stopped. However, salvage chemotherapy with the same regimen was resumed 15 months later when a liver tumor recurred and new lung metastases developed. Over the course of treatment, he experienced 5 episodes of grade 1 to 2 hypersensitivity reactions during infusion and mild hemoptysis with courses 22 and 23. Upon admission for course 24, baseline hemogram showed normal hemoglobin, platelet, and leukocyte values. At 1 hour after oxaliplatin infusion initiation, the patient experienced acute back soreness without cutaneous symptoms or hemoptysis. Subsequently, infusion time was prolonged and symptoms subsided. The following evening, however, he developed hematemesis and pupils became anisocoric. Soon after becoming lethargic, he went into a coma. CT scan showed a large intracerebral hematoma of the left frontal lobe. A follow-up hemogram indicated a decreased platelet count (4000 microL) with little change in leukocyte count and a normal INR. A haptoglobin level of less than 18 mg/dL (normal range: 30 to 179 mg/dL) and a strongly positive direct antiglobulin test suggested a possible concomitant intravascular hemolytic anemia and an immune-related process. Subsequently, aggressive platelet transfusion was initiated. However, the patient remained in a deep coma and died 6 days later (Shao & Hong, 2008).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A patient who inadvertently received two 130 mg/m(2) doses of oxaliplatin in a 24-hour period developed thrombocytopenia (platelets less than 25,000/mm3) without bleeding, which resolved (Prod Info ELOXATIN IV injection, 2008).
    b) CASE REPORT: Anemia and severe thrombocytopenia were reported in a 7-year-old child who inadvertently received 800 mg of oxaliplatin instead of the prescribed 80 mg during the third chemotherapy cycle for treatment of a paravertebral Schwannoma . The patient's condition improved with supportive care, including platelet transfusions, although the patient's platelet count never returned to normal (Soloni et al, 2009).
    c) CASE REPORT: A 64-year-old woman developed neutropenia (1900/mcL) and thrombocytopenia (72,000/mcL) after receiving 500 mg oxaliplatin (Munoz et al, 2006).
    D) HEMOLYTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 66-year-old woman developed hemolytic anemia after treatment with oxaliplatin (Desrame et al, 1999).
    E) THROMBOEMBOLIC DISORDER
    1) WITH THERAPEUTIC USE
    a) In a North American, multicenter, randomized, three-arm, controlled study comparing 5-fluorouracil/leucovorin (5-FU/LV), oxaliplatin monotherapy, and oxaliplatin in combination with 5-FU/LV for advanced colorectal cancer that was previously treated, thromboembolism occurred in 4% of patients treated with 5-FU/LV (n=142), 2% of patients treated with oxaliplatin monotherapy (n=153) and 9% of patients treated with oxaliplatin plus 5-FU/LV (n=150). Additionally, grade 3 or 4 thromboembolism occurred 2%, 1%, and 8% of patients in the 5-FU/LV, oxaliplatin monotherapy, and the oxaliplatin plus 5-FU/LV arms, respectively (Prod Info ELOXATIN IV injection, 2008).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) In several phase I and phase II trials of oxaliplatin use, alopecia was an uncommon or absent adverse effect of the drug (Becouarn et al, 1998; Levi et al, 1993; Extra et al, 1990; Caussanel et al, 1990).
    b) In a North American, multicenter, randomized, three-arm, controlled study comparing 5-fluorouracil/leucovorin (5-FU/LV), oxaliplatin monotherapy, and oxaliplatin in combination with 5-FU/LV for advanced colorectal cancer that was previously treated, alopecia occurred in 3% of patients treated with 5-FU/LV (n=142), 3% of patients treated with oxaliplatin monotherapy (n=153) and 7% of patients treated with oxaliplatin plus 5-FU/LV (n=150) (Prod Info ELOXATIN IV injection, 2008).
    B) RADIATION RECALL SYNDROME
    1) WITH THERAPEUTIC USE
    a) A case report described a radiation-recall-type skin reaction in a 50-year-old man 3 days after commencing an oxaliplatin-based chemotherapy regimen which was started 8 days after concomitant chemoradiotherapy with oxaliplatin alone. One year after an anterior resection for a T4N2 sigmoid carcinoma and adjuvant chemotherapy with fluorouracil (5-FU) and folinic acid monthly for 6 months, the patient was found to have metastases in an inguinal lymph node, an abdominal wall mass, a liver lesion, and multiple para-aortic lymph node and pelvic nodules. He received 4 courses of oxaliplatin, 5-FU, and folinic acid every 2 weeks as palliative chemotherapy. He then received 2 cycles of reduced-dose oxaliplatin during radiotherapy of the inguinal node, the abdominal wall lesion, and the pelvic lesions (total of 41.4 Gray in 23 fractions over 35 days). Dry desquamation and erythema developed over the irradiated field and resolved within a week of completion of radiotherapy. The same oxaliplatin-based regimen was started 8 days after completion of radiotherapy and 3 days later a severe skin reaction with wet desquamation developed in the area of the previous radiation field. Chemotherapy was discontinued, the patient was treated with aqueous cream and fucidin ointment, and the skin reaction resolved after 2 weeks. The skin reaction did not recur with the last cycle of 5-FU and folinic acid without oxaliplatin (Chan et al, 2001).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) BACKACHE
    1) WITH THERAPEUTIC USE
    a) In a North American, multicenter, randomized, three-arm, controlled study comparing 5-fluorouracil/leucovorin (5-FU/LV), oxaliplatin monotherapy, and oxaliplatin in combination with 5-FU/LV for advanced colorectal cancer that was previously treated, back pain occurred in 16% of patients treated with 5-FU/LV (n=142), 11% of patients treated with oxaliplatin monotherapy (n=153) and 19% of patients treated with oxaliplatin plus 5-FU/LV (n=150) (Prod Info ELOXATIN IV injection, 2008).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) Severe anaphylactic reactions (SAR), consisting of hypotension, hypertensive crisis, bronchospasm, pruritus, sweating, dizziness, and edema, have been reported following oxaliplatin therapy. In 4 patients, who developed SAR, the onset of symptoms occurred 5 to 50 minutes after beginning oxaliplatin infusion and all patients recovered within 20 hours following supportive care. All of the patients had received several cycles of oxaliplatin treatment before SAR had occurred, suggesting a sensitization process (Lee et al, 2007).
    b) Two cases of anaphylaxis were reported following the administration of oxaliplatin for colon adenocarcinoma with liver metastases. The first case involved a 63-year-old male who complained of painful, diffuse burning and pruritus, visual disturbances, and facial and lingual edema during his sixth oxaliplatin infusion (100 milligrams per square meter (mg/m(2)). Severe hypotension and tachycardia were also observed. Symptoms resolved within minutes after methylprednisolone and epinephrine injections (Medioni et al, 1999). In the second case, a 55-year-old male experienced profuse sweating, hypertension, and tachycardia 30 minutes after completing his sixth infusion of oxaliplatin 100 mg/m(2). Symptoms resolved approximately 1 hour after stopping the infusion and administering supplemental oxygen and fluids. Both patients were also receiving 5-fluorouracil and folinic acid (Larzilliere et al, 1999).
    c) Five cases of severe anaphylaxis associated with oxaliplatin were observed at one center. All of these events developed after the patients had received multiple cycles (5 to 12) of oxaliplatin 100 mg/m(2) every 2 weeks. These patients exhibited symptoms such as reduced systolic blood pressure, flushing, sweating, dizziness, burning sensations, headache, tachycardia, and respiratory distress. The one patient whose case was detailed in this published report was managed with intravenous dexamethasone, epinephrine, and oxygen, resulting in complete recovery 9 hours later. This patient also developed symptoms upon rechallenge with an eighth oxaliplatin cycle, and the agent was definitively withdrawn thereafter (Markman, 2003; Tournigand et al, 1998). A cutaneous rash without shock has been reported (Becouarn et al, 1998).

Reproductive

    3.20.1) SUMMARY
    A) Oxaliplatin is classified as FDA pregnancy category D. Oxaliplatin administration to rats has resulted in increased early resorptions, decreased fetal weight, and delayed ossification.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Oxaliplatin is classified by the manufacturer as FDA pregnancy category D (Prod Info ELOXATIN(R) intravenous injection, 2008).
    B) LACK OF EFFECT
    1) Twin neonates exposed to 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) from week 13 of gestation through delivery were born with no evidence of teratogenicity or intrauterine growth retardation and remained developmentally normal at their 2-year follow up. A 26-year-old woman diagnosed with metastatic colorectal cancer in week 10 of pregnancy received 10 courses of a full-dose biweekly modified FOLFOX-6 regimen (oxaliplatin 85 mg/m(2) 2-hour infusion with leucovorin 400 mg/m(2), then 5-FU 400 mg/m(2) bolus and 5-FU 2400 mg/m(2) 46-hour infusion). The last FOLFOX exposure occurred 15 days before delivery at 33 weeks via cesarean section; the fraternal twins both had birth weights of about 2200 g and had one-minute Apgar scores of 10 (Jeppesen & Osterlind, 2011).
    C) ANIMAL STUDIES
    1) RATS: Oxaliplatin administration to pregnant rats at doses of less than one-tenth the recommended human dose (based on body surface area) during gestation days 6 to 16 resulted in increased early resorptions. Oxaliplatin administration to pregnant rats during gestation days 6 to 10 produced a decrease in fetal weights and delayed ossification (Prod Info ELOXATIN(R) intravenous injection, 2008).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is not known whether oxaliplatin is excreted in human breast milk (Prod Info ELOXATIN(R) intravenous injection, 2008).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Visual abnormalities, including reversible (after discontinuation) transient visual loss has been reported in patients treated with oxaliplatin (Prod Info ELOXATIN(R) intravenous injection, 2008).
    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) CASE REPORT: A 70-year-old female with stage 3 rectal adenocarcinoma developed unilateral hearing loss immediately following the first oxaliplatin infusion. Immediately following the infusion, the patient reported severe pain in her left arm, face, and jaw; difficulty opening and closing her mouth; and hearing loss in her left ear. Except for hearing loss, all other issues resolved within 24 hr. An audiogram performed 2 wk later showed markedly severe, flat loss of hearing in her left ear. No obvious cause for hearing loss was found on MRI, electronystagmography, and auditory brainstem response testing; however, an electrocochleography revealed the ototoxicity was caused by cochlear dysfunction. Repeat audiometry at 5 months after the oxaliplatin infusion showed no improvement in the severe left ear hearing loss, and clinically insignificant improvement was noted at 9 months after the oxaliplatin infusion. The patient reported only minimal improvement in hearing at 2 yr postinfusion (Malhotra et al, 2010).
    3.4.6) THROAT
    A) WITH POISONING/EXPOSURE
    1) LARYNGOSPASM: A patient inadvertently received 360 mg oxaliplatin infused over 1 hour instead of the prescribed 120 mg and, following the completion of the infusion, laryngospasm developed. The laryngospasm resolved within 30 minutes after onset (Prod Info ELOXATIN IV injection, 2008).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no human data were available to assess the potential carcinogenic activity of oxaliplatin.
    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, no long-term animal data were available to assess the potential carcinogenic activity of oxaliplatin (Prod Info ELOXATIN(R) intravenous injection, 2008).

Genotoxicity

    A) Mutagenicity was negative in bacteria (Ames test) but positive in in vitro mammalian cells (L5178Y mouse lymphoma assay). Clastogenicity was demonstrated in both in vivo (mouse bone marrow micronucleus assay) and in vitro (chromosome aberration in human lymphocytes) tests (Prod Info ELOXATIN(R) intravenous injection, 2008).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Oxaliplatin plasma levels are not clinically useful or readily available.
    C) Monitor renal function and hepatic enzymes.
    D) Monitor daily CBC with differential to detect bone marrow depression.
    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) Closely monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
    G) Monitor chest radiographs in patients with pulmonary symptoms.
    H) Nerve conduction studies may be useful to evaluate neuropathy.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor renal function and hepatic enzymes.
    2) Closely monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
    3) Oxaliplatin plasma levels are not clinically useful or readily available.
    B) HEMATOLOGIC
    1) Monitor daily CBC with differential to detect bone marrow depression. Be aware of infectious complications, especially in patients with leukopenia/agranulocytosis.
    2) Monitor for bleeding, thrombocytopenia is frequently observed.
    4.1.4) OTHER
    A) OTHER
    1) Monitor vital signs and mental status.
    2) Nerve conduction studies may be useful to evaluate neuropathy.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Chest x-ray may be helpful in evaluating pulmonary infiltrates in symptomatic patients.

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 oxaliplatin overdose need to be admitted.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult an oncologist, medical toxicologist, and/or a poison center for assistance in managing patients with oxaliplatin 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) Oxaliplatin plasma levels are not clinically useful or readily available.
    C) Monitor renal function and hepatic enzymes.
    D) Monitor daily CBC with differential to detect bone marrow depression.
    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) Closely monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
    G) Monitor chest radiographs in patients with pulmonary symptoms.
    H) Nerve conduction studies may be useful to evaluate neuropathy.

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) SUMMARY
    1) Hemodialysis is unlikely to be of benefit due to high protein binding and large volume of distribution of oxaliplatin.
    2) Plasma pheresis or plasma exchange might theoretically be of benefit if performed shortly after overdose (ie before distribution), but there are no published overdose cases where these methods have been used.

Abstracts

Case Reports

    A) ADULT
    1) The manufacturer describes 5 cases of oxaliplatin overdose (Prod Info ELOXATIN IV injection, 2008):
    a) A patient who received two 130 mg/m(2) doses over 24 hours developed thrombocytopenia (platelets less than 25,000/mm3) without bleeding and recovered.
    b) A patient who received 500 mg oxaliplatin instead of carboplatin developed dyspnea, wheezing, paresthesia, vomiting and chest pain the day of administration, and subsequently developed respiratory failure and bradycardia that was not responsive to resuscitation.
    c) Another patient received 650 mg oxaliplatin instead of carboplatin and developed dyspnea, wheezing, paresthesia and vomiting but recovered.
    d) Another patient developed rapid onset of dysesthesia after receiving 700 mg oxaliplatin. Care included intravenous hydration, electrolyte replacement, and platelet transfusion, and the patient recovered by 15 days after overdose.
    e) The fifth overdose involved a patient who received 360 mg oxaliplatin as a 1-hour infusion instead of the prescribed 120 mg. After the 1-hour infusion was finished, the patient experienced vomiting, laryngospasm, and paresthesia. The laryngospasm resolved within 30 minutes following onset; however, the paresthesia continued to persist one hour later.

Range Of Toxicity

Summary

    A) TOXICITY: Expect toxicity with therapeutic doses. Adult patients have developed toxicity, but recovered following doses of 360 mg to 700 mg. A 7-year-old child experienced severe toxicity (myelosuppression, gastrointestinal symptoms, and neurotoxicity) after receiving 800 mg oxaliplatin but survived. Death has been reported in one patient after receiving 500 mg.
    B) THERAPEUTIC DOSE: ADULT: 85 mg/m(2) IV in 250 to 500 mL D5W over 120 minutes every 2 weeks as combination therapy. PEDIATRIC: Safety and efficacy have not been established. Phase I and II trials were conducted, involving pediatric patients (ages 7 months to 22 years) with solid tumors who received oxaliplatin doses ranging from 40 mg/m(2) to 160 mg/m(2) on day 1 of the cycle every 3 to 4 weeks, for a maximum of 6 to 17 cycles. Pediatric patients 12-months-old or younger received 4.3 mg/kg of oxaliplatin.

Therapeutic Dose

    7.2.1) ADULT
    A) In combination with 5-fluorouracil and leucovorin, the recommended dose of oxaliplatin is 85 mg/m(2) IV in 250 to 500 mL D5W over 120 minutes every 2 weeks; the dose may need to be reduced (65 mg/m(2) or 75 mg/m(2)) as needed (Prod Info oxaliplatin intravenous injection, 2013).
    7.2.2) PEDIATRIC
    A) The safety and efficacy in pediatric patients have not been established (Prod Info oxaliplatin intravenous injection, 2013).
    B) PEDIATRIC CLINICAL TRIALS: Phase I and II trials were conducted, involving pediatric patients (ages 7 months to 22 years) with solid tumors who received oxaliplatin doses ranging from 40 mg/m(2) to 160 mg/m(2) on day 1 of the cycle every 3 to 4 weeks, for a maximum of 6 to 17 cycles. Pediatric patients weighing less than 10 kg or 12-months-old or younger received 4.3 mg/kg of oxaliplatin. No significant responses to the tumors were observed, and the dose-limiting toxicity at the highest doses (160 mg/m(2)) was sensory neuropathy. Other adverse effects included anemia (37% to 65%), neutropenia (58%), and thrombocytopenia (37% to 65%) (Prod Info oxaliplatin intravenous injection, 2013).

Minimum Lethal Exposure

    A) A patient who received 500 mg of oxaliplatin probably due to an anaphylactic reaction (Soloni et al, 2009; Prod Info ELOXATIN IV injection, 2008). She developed dyspnea, wheezing, vomiting, chest pain and paresthesia the day of administration followed by respiratory depression and bradycardia that did not respond to resuscitation (Prod Info ELOXATIN IV injection, 2008).

Maximum Tolerated Exposure

    A) The manufacturer reports 4 cases of survival following oxaliplatin overdose. A patient who received 260 mg/m(2) over 24 hours developed thrombocytopenia but recovered. Another patient received 650 mg and developed dyspnea, wheezing, paresthesia and vomiting but survived. A patient who received 700 mg developed rapid onset dysesthesia but recovered. The fourth case involved a patient who inadvertently received 360 mg oxaliplatin as a 1-hour infusion instead of the prescribed 120 mg, and subsequently developed vomiting, laryngospasm, and paresthesia. The laryngospasm resolved within 30 minutes after onset; however, paresthesia continued to persist 1 hour later (Prod Info ELOXATIN IV injection, 2008).
    B) CASE REPORT/CHILD: A 7-year-old child experienced severe lower limb pain, abdominal pain, respiratory distress, vomiting, diarrhea, severe thrombocytopenia, mild anemia, mild renal failure, and neurological symptoms (ie, hyporeactivity, dizziness, horizontal nystagmus, lower limb weakness, and hyperextension of the right foot) after inadvertently receiving 800 mg of oxaliplatin instead of the prescribed 80 mg during the third chemotherapy cycle for treatment of a paravertebral malignant Schwannoma. The patient's condition improved with supportive care and she was discharged 20 days after exposure; however, localized lower limb tingling and constipation developed and continued for 3 more weeks (Soloni et al, 2009).
    C) CASE REPORT/ADULT: A 64-year-old woman developed peripheral neuropathy, diarrhea, thrombocytopenia, and neutropenia after receiving 500 mg oxaliplatin; she was treated with aggressive hydration and furosemide and recovered (Munoz et al, 2006).
    D) PEDIATRIC CLINICAL TRIALS: Phase I and II trials were conducted, involving pediatric patients (ages 7 months to 22 years) with solid tumors who received oxaliplatin doses ranging from 40 mg/m(2) to 160 mg/m(2) on day 1 of the cycle every 3 to 4 weeks, for a maximum of 6 to 17 cycles. Pediatric patients 12-months-old or younger received 4.3 mg/kg of oxaliplatin. No significant response to the tumors were observed, and the dose-limiting toxicity at the highest doses (160 mg/m(2)) was sensory neuropathy. Other adverse effects included anemia (40% to 65%), neutropenia (58%), and thrombocytopenia (40% to 65%) (Prod Info ELOXATIN IV injection, 2008).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 19800 mcg/kg (RTECS, 2006)
    B) LD50- (INTRAPERITONEAL)RAT:
    1) 14300 mcg/kg (RTECS, 2006)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Although the exact mechanism of oxaliplatin remains unclear, the cytotoxicity of platinum compounds is thought to result from inhibition of DNA synthesis. Intrastrand platinum DNA adducts, the main cytotoxic lesions, are formed by cross-linking activated platinum species and specific base sequences, notably 2 adjacent guanine residues or 2 adjacent guanine-adenine bases (Culy et al, 2000).
    B) Cisplatin analogue (diaminocyclohexane complex) (Weiss & Christian, 1993; Christian, 1992; Scanlon et al, 1991).
    C) Preclinical antitumor activity: similar to/greater than cisplatin; minimal/no cross-resistance with cisplatin/carboplatin in some in vitro/in vivo studies; cisplatin cross-resistance less likely with oxaliplatin than with carboplatin. Synergy with: 5-fluorouracil/leucovorin (L1210 leukemia); cisplatin (KB/A2780 human cancer lines); carboplatin (L1210). In vitro activity against colorectal carcinoma cell lines (including cisplatin-resistant) (de Gramont et al, 1997; Chollet et al, 1996; Levi et al, 1995; Meropol et al, 1995; Weiss & Christian, 1993).

Physicochemical

Physical Characteristics

    A) Slightly soluble in water at 6 mg/mL, very slightly soluble in methanol, and practically insoluble in ethanol and acetone (Prod Info ELOXATIN(R) intravenous injection, 2008).

Molecular Weight

    A) 397.3 (Prod Info ELOXATIN(R) intravenous injection, 2008)

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