Oxaliplatin

Pronunciation

Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: [SP-4-2-(1R-trans)]-(1,2-cyclohexanediamine-N,N′)[ethanedioato(2-)-O,O′]platinum
Molecular Formula: C8H14N2O4Pt
CAS Number: 61825-94-3
Brands: Eloxatin

Warning(s)

  • Risk of anaphylactic/anaphylactoid reactions; may occur within minutes following administration.1 (See Anaphylaxis under Cautions.)

Introduction

Antineoplastic agent; platinum-containing compound.1 2

Uses for Oxaliplatin

Colorectal Cancer

Used in combination with fluorouracil and leucovorin as adjuvant therapy for stage III colon cancer following complete resection of the primary tumor.1 9 10

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Used in combination with fluorouracil and leucovorin for the treatment of advanced carcinoma of the colon or rectum.1 Evaluated as first-line therapy for unresectable colorectal cancer1 11 and as second-line therapy in patients whose disease recurred or progressed during or within 6 months following first-line therapy with fluorouracil, leucovorin, and irinotecan.1

Combination regimen of oxaliplatin, fluorouracil, and leucovorin considered one of the regimens of choice for metastatic colorectal cancer by some clinicians.b

Oxaliplatin Dosage and Administration

General

  • Administer on day 1 as part of a 2-day combination regimen.1

  • Premedication with antiemetics, including selective inhibitors of type 3 serotonergic (5-HT3) receptors (e.g., dolasetron, granisetron, ondansetron) with or without dexamethasone, recommended prior to each 2-day cycle.1

  • Hydration prior to administration not necessary.1

  • Handle cautiously (e.g., use gloves) to avoid exposure to oxaliplatin during preparation of IV solutions.1 Immediately treat accidental contact; wash skin thoroughly with soap and water or flush mucosa with copious amounts of water.1 Consult specialized references for procedures for proper handling and disposal of antineoplastics.

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV infusion.1

Flush infusion line with 5% dextrose injection prior to administration of oxaliplatin or any concomitant drug.1 7

Aluminum may cause degradation of platinum compounds; do not use needles or IV administration sets that contain aluminum parts for reconstitution or dilution.1

Administer leucovorin by IV infusion concurrently with oxaliplatin but in a separate container using a Y-type administration set.1 Administer fluorouracil by direct IV injection (over 2–4 minutes), then by IV infusion.1 Consult respective manufacturer’s prescribing information for additional information on reconstitution and administration of fluorouracil and leucovorin.1

Reconstitution

Reconstitute vial containing 50 or 100 mg of oxaliplatin powder with 10 or 20 mL, respectively, of water for injection or 5% dextrose injection to provide a solution containing 5 mg/mL.7

Must be diluted further before IV administration.1

Dilution

Reconstituted solution or commercially available concentrate (5 mg/mL) must be further diluted prior to IV administration.1

Withdraw appropriate dose of oxaliplatin and dilute in 250–500 mL of 5% dextrose injection.1

Manufacturer of oxaliplatin recommends leucovorin and fluorouracil for IV infusion be diluted with 5% dextrose injection.1

Rate of Administration

Administer oxaliplatin over 2 hours.1

Administer leucovorin over 2 hours.1

Administer fluorouracil injection over 2–4 minutes followed by an IV infusion over 22 hours.1

Dosage

Adults

Stage III Colon Cancer (Adjuvant Therapy)
IV

Administer oxaliplatin/fluorouracil/leucovorin (FOLFOX4) regimen over 2 consecutive days.1 13

On day 1, administer oxaliplatin 85 mg/m2 concurrently with leucovorin 200 mg/m2 (in separate containers) by IV infusion over 2 hours.1 Then administer fluorouracil 400 mg/m2 by IV injection over 2–4 minutes, followed by fluorouracil 600 mg/m2 by IV infusion over 22 hours.1

On day 2, administer leucovorin 200 mg/m2 by IV infusion over 2 hours.1 Then administer fluorouracil 400 mg/m2 by IV injection over 2–4 minutes, followed by fluorouracil 600 mg/m2 by IV infusion over 22 hours.1

Repeat regimen at intervals of 2 weeks for a total of 12 cycles (6 months).1 9

Alternative regimen (modified FOLFOX6): On day 1, administer oxaliplatin 85 mg/m2 concurrently with leucovorin 400 mg/m2 (in separate containers) by IV infusion over 2 hours.12 13 Then administer fluorouracil 400 mg/m2 by IV injection over 5 minutes, followed by fluorouracil 1200 mg/m2 by IV infusion daily for 2 days (i.e., 2400 mg/m2 by IV infusion over 46–48 hours [total fluorouracil dosage of 2800 mg/m2 per cycle]).12 13 Repeat regimen at intervals of 2 weeks.13

Dosage Modification for Toxicity in Stage III Colon Cancer
IV

To minimize acute toxicities, administer oxaliplatin over 6 hours; adjustment of infusion duration for fluorouracil or leucovorin not necessary.1

If persistent grade 2 adverse neurosensory effects occur, consider reducing oxaliplatin dosage to 75 mg/m2; dosage modification for fluorouracil or leucovorin not required.1 Consider drug discontinuance if persistent grade 3 neurosensory effects occur.1

In patients who have recovered from grade 3 or 4 GI toxicity (that occurred despite prophylactic treatment), grade 4 neutropenia, or grade 3 or 4 thrombocytopenia, reduce oxaliplatin dosage to 75 mg/m2 and reduce fluorouracil dosage by approximately 20% (i.e., to 300 mg/m2 by IV injection over 2–4 minutes and 500 mg/m2 by IV infusion over 22 hours).1 Do not administer next dose until neutrophil count ≥1500/mm3 and platelet count ≥75,000/mm3.1

Advanced Colorectal Cancer
IV

Administer oxaliplatin/fluorouracil/leucovorin (FOLFOX4) regimen over 2 consecutive days.1 13

On day 1, administer oxaliplatin 85 mg/m2 concurrently with leucovorin 200 mg/m2 (in separate containers) by IV infusion over 2 hours.1 Then administer fluorouracil 400 mg/m2 by IV injection over 2–4 minutes, followed by fluorouracil 600 mg/m2 by IV infusion over 22 hours.1

On day 2, administer leucovorin 200 mg/m2 by IV infusion over 2 hours.1 Then administer fluorouracil 400 mg/m2 by IV injection over 2–4 minutes, followed by fluorouracil 600 mg/m2 by IV infusion over 22 hours.1

Repeat regimen at intervals of 2 weeks.1 Continue therapy until disease progression or unacceptable toxicity occurs.1 11

Alternative regimen (modified FOLFOX6): On day 1, administer oxaliplatin 85 mg/m2 concurrently with leucovorin 400 mg/m2 (or, alternatively, leucovorin 350 mg) (in separate containers) by IV infusion over 2 hours.12 13 Then administer fluorouracil 400 mg/m2 by IV injection over 5 minutes, followed by fluorouracil 1200 mg/m2 by IV infusion daily for 2 days (i.e., 2400 mg/m2 by IV infusion over 46–48 hours [total fluorouracil dosage of 2800 mg/m2 per cycle]).12 13 Repeat regimen at intervals of 2 weeks.12 13

Dosage Modification for Toxicity in Advanced Colorectal Cancer
IV

To minimize acute toxicities, administer oxaliplatin over 6 hours; adjustment of infusion duration for fluorouracil or leucovorin not necessary.1

If persistent grade 2 adverse neurosensory effects occur, consider reducing the oxaliplatin dosage to 65 mg/m2; dosage modification for fluorouracil or leucovorin not required.1 Consider drug discontinuance if persistent grade 3 neurosensory effects occur.1

In patients who have recovered from grade 3 or 4 GI toxicity (that occurred despite prophylactic treatment), grade 4 neutropenia, or grade 3 or 4 thrombocytopenia, reduce oxaliplatin dosage to 65 mg/m2 and reduce fluorouracil dosage by approximately 20% (i.e., to 300 mg/m2 by IV injection over 2–4 minutes and 500 mg/m2 by IV infusion over 22 hours).1 Do not administer next dose until neutrophil count ≥1500/mm3 and platelet count ≥75,000/mm3.1

Special Populations

Renal Impairment

Safety and efficacy not established; use with caution.1

Geriatric Patients

No adjustment of initial dosage was necessary in geriatric patients ≥65 years of age receiving oxaliplatin in combination with fluorouracil and leucovorin as second-line therapy for advanced colorectal cancer.1

Cautions for Oxaliplatin

Contraindications

  • Known hypersensitivity to oxaliplatin, any ingredient in the formulation, or other platinum-containing compounds.1 7

Warnings/Precautions

Warnings

Anaphylaxis

Risk of anaphylactic/anaphylactoid and other hypersensitivity reactions (e.g., rash, urticaria, erythema, pruritus, flushing, infusion-associated diarrhea, dyspnea, bronchospasm, diaphoresis, hypotension, chest pain, disorientation, syncope).1 (See Boxed Warning.) Can be fatal.1 Similar in nature and severity to those associated with other platinum-containing antineoplastic agents.1 May occur within minutes following administration and during any cycle of therapy.1

If an allergic reaction occurs, institute appropriate supportive therapy.1 Epinephrine, corticosteroids, and antihistamines have been used to alleviate symptoms; discontinuance of therapy may be required.1

Other Warnings and Precautions

Use under supervision of a qualified clinician experienced in therapy with antineoplastic agents.1 Use only when adequate treatment facilities for appropriate management of therapy and complications are available.1

Consider the usual cautions, precautions, and contraindications of fluorouracil and leucovorin therapy.7

Neuropathy

Consistently associated with acute or persistent peripheral neuropathy.1 2 3 4 Duration and severity increase with increasing oxaliplatin cumulative dosage.2 7

Acute, reversible sensory neuropathy (e.g., acute transient paresthesia,1 3 dysesthesia,1 3 and hypoesthesia in hands, feet, perioral area, or throat, jaw spasm, abnormal tongue sensation, dysarthria, ocular pain, feeling of chest pressure1 ) may occur within hours1 2 or 1–2 days following oxaliplatin administration, resolves within 14 days, and frequently recurs with further administration of the drug.1 Acute neuropathy may be precipitated or exacerbated by exposure to cold temperature or cold objects;1 2 avoid ice (e.g., for mucositis prophylaxis) during oxaliplatin infusion.1

Possible acute pharyngolaryngeal dysesthesia;1 3 incidence may be reduced by prolonging duration of infusion.2 7

Persistent sensory neuropathy (e.g., paresthesias, dysesthesias, hypoesthesias, impaired proprioception)1 2 can occur without any prior acute neuropathic event and typically persists for >14 days following oxaliplatin administration;1 symptoms may improve upon discontinuance of therapy.1

Insufficient evidence to support use of any preventive strategy (e.g., intermittent [“stop and go”] oxaliplatin regimens, potential neuromodulatory agents).14

Pulmonary Toxicity

Pulmonary fibrosis (sometimes fatal) reported.1 7 If unexplained respiratory manifestations (e.g., nonproductive cough, dyspnea, crackles, radiographic evidence of pulmonary infiltrates) develop, temporarily discontinue therapy until interstitial lung disease and pulmonary fibrosis are excluded.1

Fatal eosinophilic pneumonia reported.1

Hepatic Effects

Possible elevation of ALT, AST, alkaline phosphatase, or bilirubin concentrations.1 Perform hepatic function tests (e.g., transaminases, bilirubin) prior to each cycle of therapy.1 7

Hepatic vascular conditions (e.g., peliosis hepatis, nodular regenerative hyperplasia or sinusoidal changes, perisinusoidal fibrosis, veno-occlusive lesions) reported in patients receiving oxaliplatin in combination with fluorouracil and leucovorin.1 Consider hepatic vascular toxicity in patients with abnormal liver function test results or portal hypertension that cannot be explained by metastases to the liver; investigate as clinically appropriate.1

Fetal/Neonatal Morbidity and Mortality

Possible fetal harm; teratogenicity and embryolethality demonstrated in animals.1 Avoid pregnancy during therapy.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

GI Effects

Possible grade 3 or 4 nausea, vomiting, diarrhea, or stomatitis; premedication with antiemetics recommended (see General under Dosage and Administration).1 Avoid ice (e.g., for mucositis prophylaxis) during and following IV infusion of oxaliplatin to prevent precipitation or exacerbation of acute neurologic symptoms.1 7

Thrombocytopenia and Bleeding

Possible thrombocytopenia and hemorrhage (e.g., GI bleeding, hematuria, epistaxis).1 Determine platelet count prior to each cycle of therapy.1

Possible prolongation of PT and INR with possible hemorrhage in patients receiving anticoagulant therapy; carefully monitor patients receiving concomitant oral anticoagulant therapy (e.g., warfarin).1

Neutropenia and Infectious Complications

Possible grade 3 or 4 neutropenia, febrile neutropenia, or documented infection with severe neutropenia.1

Perform WBC with differential prior to each cycle of therapy.1

Thromboembolism

Possible thromboembolic events.1

Renal Effects

Possible increased Scr.1

Perform renal function tests (e.g., Scr) prior to each cycle of therapy.1 7

Dermatologic Effects

Possible injection site reactions (e.g., erythema, swelling, pain).1 Extravasation may result in local pain and inflammation; possibly severe and may lead to complications (e.g., necrosis).1

Possible palmar-plantar erythrodysesthesia (hand-foot syndrome).1

Ocular Effects

Possible ocular effects (e.g., decreased visual acuity,1 21 visual field changes,1 21 22 optic neuritis,1 21 ocular pain,22 transient vision loss1 21 ). Effects have been reversible.1 21 22

Laboratory Monitoring

Monitor WBC with differential, platelet count, hemoglobin, and blood chemistry tests (including ALT, AST, bilirubin, and creatinine) prior to each treatment cycle.1

Closely monitor PT and INR in patients receiving oral anticoagulants concomitantly.1 (See Specific Drugs under Interactions.)

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether oxaliplatin or its metabolites are distributed into milk;1 discontinue nursing or the drug.1

Pediatric Use

Efficacy not established in children <18 years of age.1 7 No substantial antitumor activity reported in childhood solid tumors (patients 7 months to 22 years of age).1

Geriatric Use

No differences in clearance of ultrafilterable platinum compared with younger adults.1 However, increased incidence of certain adverse effects (i.e., diarrhea, dehydration, hypokalemia, granulocytopenia, leukopenia, fatigue, syncope).1 5 7

Efficacy (effect on disease-free survival) of oxaliplatin/fluorouracil/leucovorin versus fluorouracil/leucovorin as adjuvant therapy for colon cancer was inconclusive in patients ≥65 years of age (based on descriptive subset analysis of study data).1

In patients receiving oxaliplatin/fluorouracil/leucovorin as first-line therapy for advanced colorectal cancer, no differences in efficacy observed in patients ≥65 years of age compared with the overall study population.1

Renal Impairment

Safety and efficacy of the combination regimen not evaluated.1 Possible decreased clearance and increased AUC of platinum ultrafiltrate.1 Use with caution.1

Common Adverse Effects

Peripheral sensory neuropathies, fatigue, neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, mucositis, increases in ALT, AST, and alkaline phosphatase concentrations.1

Interactions for Oxaliplatin

Not metabolized by and does not inhibit CYP isoenzymes.1

Nephrotoxic Drugs

Potential pharmacokinetic interaction (decreased clearance of platinum-containing compounds); however, this interaction has not been specifically studied.1

Protein-bound Drugs

Pharmacokinetic interaction with highly protein-bound drugs unlikely; platinum displacement not observed in vitro.1 7

Drugs Affecting Hepatic Microsomal Enzymes

Pharmacokinetic interaction with drugs metabolized by CYP isoenzymes or those that induce or inhibit these isoenzymes unlikely.1 However, no studies have been conducted.1

Specific Drugs

Drug

Interaction

Comment

Anticoagulants, oral (warfarin)

Possible prolonged PT and INR; hemorrhage reported1

Close monitoring required1

Erythromycin

Platinum displacement from protein binding sites not observed in vitro1

Fluorouracil

Pharmacokinetic interaction unlikely when recommended dosages and administration schedule are used1 2

Potential pharmacokinetic interaction (increased plasma fluorouracil concentrations) when used concomitantly with oxaliplatin dosages greater than recommended (e.g., 130 mg/m2) at intervals of 3 weeks1 7

Granisetron

Platinum displacement from protein binding sites not observed in vitro1

Irinotecan

Pharmacokinetic interaction unlikely2

Paclitaxel

Platinum displacement from protein binding sites not observed in vitro1

Salicylates

Platinum displacement from protein binding sites not observed in vitro1

Topotecan

Pharmacokinetic interaction unlikely2

Valproate sodium

Platinum displacement from protein binding sites not observed in vitro1

Oxaliplatin Pharmacokinetics

Undergoes rapid and extensive nonenzymatic biotransformation to numerous platinum-containing transient reactive intermediates.1 2 Pharmacokinetic parameters generally expressed in terms of platinum-containing complexes rather than parent compound.2

Distribution

Extent

Following a 2-hour IV infusion, 85% of administered platinum is rapidly distributed into tissues or eliminated in urine; approximately 15% of administered platinum is present in systemic circulation.1

No evidence of accumulation in plasma following usual dosage;1 2 possible progressive accumulation in erythrocytes.2

Not known whether oxaliplatin or its metabolites are distributed into milk.1

Plasma Protein Binding

>90% irreversibly bound to plasma proteins (principally albumin and γ-globulins).1

Elimination

Metabolism

Undergoes rapid and extensive nonenzymatic biotransformation; no evidence of CYP-mediated metabolism in vitro.1

Elimination Route

Eliminated principally by renal excretion;1 2 renal clearance of ultrafilterable platinum appears to be directly proportional to GFR.1

Following 2-hour IV infusion, approximately 54 or 2% of platinum-containing derivatives is excreted in urine and feces, respectively, within 5 days.1

Half-life

Distribution and elimination of platinum-containing derivatives appears to be triphasic, with 2 relatively short distribution phases with half-lives of approximately 0.43 and 16.8 hours, respectively, and a long elimination phase with a half-life of approximately 391 hours.1

Stability

Storage

Parenteral

Powder for Injection

25°C (may be exposed to 15–30°C).1

Following reconstitution, store in original vial at 2–8°C; discard after 24 hours.1

Following dilution, store at 2–8°C for up to 24 hours or at room temperature (i.e., 20–25°C) for up to 6 hours.1

Concentrate for Injection

25°C (may be exposed to 15–30°C).1 Do not freeze.1

Protect concentrate from light (keep in original outer carton).1 Not necessary to protect diluted solution from light.1

Following dilution, store at 2–8°C for up to 24 hours or at room temperature (i.e., 20–25°C) for up to 6 hours.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Aluminum reportedly causes degradation of platinum compounds; do not use needles or IV administration sets that contain aluminum parts for preparation or administration.1

Parenteral

Solution Compatibility

Compatible1

Dextrose 5% in water

Incompatible1

Chloride-containing solutions

Sodium chloride 0.9%

Drug Compatibility
Y-Site CompatibilityHID

Compatible

Bumetanide

Buprenorphine HCl

Butorphanol tartrate

Calcium gluconate

Carboplatin

Chlorpromazine HCl

Cyclophosphamide

Dexamethasone sodium phosphate

Diphenhydramine HCl

Dobutamine HCl

Docetaxel

Dolasetron mesylate

Dopamine HCl

Doxorubicin HCl

Droperidol

Enalaprilat

Epirubicin HCl

Etoposide phosphate

Famotidine

Fentanyl citrate

Furosemide

Gemcitabine HCl

Granisetron HCl

Haloperidol lactate

Heparin sodium

Hydrocortisone sodium succinate

Hydromorphone HCl

Hydroxyzine HCl

Ifosfamide

Irinotecan HCl

Leucovorin calcium

Lorazepam

Magnesium sulfate

Mannitol

Meperidine HCl

Mesna

Methotrexate sodium

Methylprednisolone sodium succinate

Metoclopramide HCl

Mitoxantrone HCl

Morphine sulfate

Nalbuphine HCl

Ondansetron HCl

Paclitaxel

Palonosetron HCl

Potassium chloride

Prochlorperazine edisylate

Promethazine HCl

Ranitidine HCl

Theophylline

Topotecan HCl

Verapamil HCl

Vincristine sulfate

Vinorelbine tartrate

Incompatible

Alkaline drugs or media (e.g., basic solutions of fluorouracil)1

Diazepam

Actions

  • Antineoplastic agent;1 2 consists of a platinum atom complexed with 1,2-diaminocyclohexane (DACH) and a labile oxalate ligand.1

  • Must undergo nonenzymatic activation before antineoplastic activity occurs.1 7 In physiologic solutions, the labile oxalate ligand presumably is displaced, forming several transient reactive complexes (e.g., monoaquo DACH platinum, diaquo DACH platinum).1 2 These complexes covalently bind to specific DNA base sequences, producing intrastrand and interstrand DNA cross-links, which are thought to inhibit DNA replication and transcription.1 2

  • Cycle-phase nonspecific.1

  • Exhibits antitumor activity against colon carcinoma in vivo.1 Exhibits synergistic antiproliferative activity with fluorouracil.1 2

Advice to Patients

  • Risk of neuropathy.1 Instruct patients to avoid cold drinks and use of ice (e.g., for mucositis prophylaxis) and to cover skin prior to exposure to cold temperature or cold objects since such exposure can precipitate or exacerbate acute sensory neuropathy.1 Importance of reading manufacturer’s patient information for further instructions to minimize exposure to cold temperature or cold objects.1

  • Risk of dizziness, nausea, vomiting, visual abnormalities (e.g., transient vision loss), and other neurologic symptoms that may affect gait and balance; may affect ability to drive or operate machinery.1

  • Importance of immediately seeking medical attention if symptoms of anaphylactic/anaphylactoid reactions (e.g., swelling of the throat, difficulty breathing) occur.1

  • Importance of informing clinicians immediately if fever (particularly if associated with persistent diarrhea) or evidence of infection develops.1 Importance of informing clinicians of persistent vomiting, signs of dehydration, cough or shortness of breath, or signs of allergic reactions (e.g., rash).1

  • Importance of informing clinicians if visual changes or disturbances develop.1

  • Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed; necessity of advising women to avoid pregnancy during therapy.1 Advise pregnant women of risk to the fetus.1

  • Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Oxaliplatin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion

50 mg

Eloxatin

Sanofi-Aventis

100 mg

Eloxatin

Sanofi-Aventis

For injection concentrate, for IV infusion

5 mg/mL (50, 100, and 200 mg)

Eloxatin

Sanofi-Aventis

AHFS DI Essentials. © Copyright, 2004-2013, Selected Revisions September 4, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Sanofi-Synthelabo Inc. Eloxatin (oxaliplatin) for injection prescribing information. New York, NY; 2009 Mar.

2. Culy CR, Clemett D, Wiseman LR. Oxaliplatin: a review of its pharmacological properties and clinical efficacy in metastatic colorectal cancer and its potential in other malignancies. Drugs. 2000; 60:895-924. [PubMed 11085200]

3. de Gramont A, Figer A, Seymour M et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000 Aug;18:2938-47.

4. Giacchetti S, Perpoint B, Zidani R et al. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2000 Jan;18:136-47.

5. Tabah-Fisch I, Maindrault-Goebel F, Benavides M et al. Oxaliplatin/5FU/LV is feasible, safe and active in elderly colorectal cancer (CRC) patients. Proceedings of ASCO. 2002; Abstract No. 556.

6. Grothey A, Deschler B, Kroening H et al. Phase III study of bolus 5-fluorouracil (5-FU)/folinic acid (FA) (Mayo) vs weekly high-dose 24-h 5-FU infusion/FA + oxaliplatin (OXA) (FUFOX) in advanced colorectal cancer (ACRC). Proceedings of ASCO. 2002; Abstract No. 512.

7. Sanofi-Synthelabo, New York, NY: Personal communication.

8. Goldberg RM, Morton RF, Sargent DJ et al. Oxaliplatin or CPT-11 + 5FU/leucovorin or oxaliplatin + CPT-11 in advanced colorectal cancer (ACRC): efficacy and safety results from a North American Gastrointestinal Intergroup Study (N9741). Abstract #6 presented at Perspectives in Colorectal Cancer, a Consensus Meeting, Fourth International Conference, Barcelona, June 2002.

9. André T, Boni C, Mounedji-Boudiaf L et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004; 350:2343-51. [PubMed 15175436]

10. André T, Boni C, Navarro M et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009; 27:3109-16. [PubMed 19451431]

11. Goldberg RM, Sargent DJ, Morton RF et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004; 22:23-30. [PubMed 14665611]

12. Cheeseman SL, Joel SP, Chester JD et al. A ’modified de Gramont’ regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002; 87:393-9. [PubMed 12177775]

13. National Comprehensive Cancer Network. NCCN colon cancer practice guidelines. Version 2.2009. Available from web. Accessed 2009 Jul 13.

14. Saif MW, Reardon J. Management of oxaliplatin-induced peripheral neuropathy. Ther Clin Risk Manag. 2005; 1:249-58. [PubMed 18360567]

15. Gamelin L, Boisdron-Celle M, Delva R et al. Prevention of oxaliplatin-related neurotoxicity by calcium and magnesium infusions: a retrospective study of 161 patients receiving oxaliplatin combined with 5-Fluorouracil and leucovorin for advanced colorectal cancer. Clin Cancer Res. 2004; 10:4055-61. [PubMed 15217938]

16. Nikcevich, DA, Grothey A, Sloan JA et al. Effect of intravenous calcium and magnesium (IV CaMg) on oxaliplatin-induced sensory neuropathy (sNT) in adjuvant colon cancer: results of the phase III placebo-controlled, double-blind NCCTG trial N0347. J Clin Oncol. 2008; 26: Abstract 4009 (presented at the 2008 ASCO Annual Meeting).

17. Gamelin L, Boisdron-Celle M, Morel A et al. Oxaliplatin-related neurotoxicity: interest of calcium-magnesium infusion and no impact on its efficacy. J Clin Oncol. 2008; 26:1188-9; author reply 1189-90. [PubMed 18309961]

18. Hochster HS, Grothey A, Shplisky A et al. Effect of intravenous (IV) calcium and magnesium (Ca/Mg) versus placebo on reponse to FOLFOX + bevacizumab (BEV) in the CONcePT trial. Presented at the ASCO 2008 Gastrointestinal Cancers Symposium. From ASCO website. Abstract 280. Accessed 2009 Jul 9.

19. A phase III randomized, placebo-controlled, double-blind study of intravenous calcium/magnesium to prevent oxaliplatin-induced sensory neuropathy. From ClinicalTrials.gov registry. Accessed 2009 Jul 13.

20. CONCEPT: Phase IV, randomized, prospective, multicenter comparison of intermittent schedule of oxaliplatin combined with FOLFOX/bevacizumab vs conventional mode of administration of FOLFOX/bevacizumab + neuroprophylaxis with calcium/magnesium for optimization of first-line therapy of metastatic colorectal cancer. From ClinicalTrials.gov registry. Accessed 2009 Jul 16.

21. O’Dea D, Handy CM, Wexler A. Ocular changes with oxaliplatin. Clin J Oncol Nurs. 2006; 10:227-9. [PubMed 16708705]

22. Leonard GD, Wright MA, Quinn MG et al. Survey of oxaliplatin-associated neurotoxicity using an interview-based questionnaire in patients with metastatic colorectal cancer. BMC Cancer. 2005; 5:116. [PubMed 16168057]

b. Anon. Drugs of choice for cancer. Treatment Guidelines from the Medical Letter. 2003; 1:41-53. [PubMed 15529105]

HID. Trissel LA. Handbook on injectable drugs. 17th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2013:884-6.

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