Oxaliplatin

Pronunciation

Pronunciation: ox-AL-i-PLA-tin
Class: Platinum coordination complex, Antineoplastic agent

Trade Names

Eloxatin
- Injection, solution, concentrate 5 mg/mL

Oxaliplatin
- Injection, lyophilized powder for solution 50 mg
- Injection, lyophilized powder for solution 100 mg

Pharmacology

The cytotoxic effect of oxaliplatin has been correlated with formation of inter- and intrastrand DNA crosslinks that inhibit DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific.

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Pharmacokinetics

Absorption

Following a 2-h infusion, C max was 0.814 mcg/mL.

Distribution

Following a 2-h infusion, Vd is 440 L and approximately 15% of administered platinum is present in the systemic circulation; the remaining 85% is rapidly distributed into tissues and eliminated in the urine. Plasma protein binding (albumin and gamma globulins) is irreversible and greater than 90%. Platinum also binds irreversibly and accumulates approximately 2-fold in erythrocytes.

Metabolism

Rapid and extensive nonenzymatic biotransformation.

Elimination

Renal excretion is major route of platinum elimination (54% of platinum eliminated in urine; approximately 2% excreted in feces). Plasma Cl is 10 to 17 L/h and correlates with glomerular filtration rate.

Special Populations

Renal Function Impairment

AUC of platinum increases as renal function decreases: 60% increase with mild (CrCl 50 to 80 mL/min), 140% increase with moderate (CrCl 30 to less than 50 mL/min), and 190% increase with severe (CrCl less than 30 mL/min) renal impairment.

Elderly

No effect of age on the ultrafilterable platinum has been observed.

Children

Mean C max is 0.75 mcg/mL, AUC 0-48 is 7.52 mcg•h/mL and AUC inf is 8.83 mcg•h/mL at 85 mg/m 2 oxaliplatin. Mean Cl is 4.7 L/h.

Gender

There was no significant effect of gender on the Cl of ultrafiltrable platinum.

Indications and Usage

Adjuvant treatment of stage III colon cancer in combination with infusional 5-fluorouracil/leucovorin in patients who have undergone complete resection of the primary tumor; in combination with infusional 5-fluorouracil/leucovorin for the treatment of advanced colorectal cancer.

Unlabeled Uses

Treatment of relapsed or refractory non-Hodgkin lymphoma; treatment of advanced ovarian cancer.

Contraindications

Known allergy to oxaliplatin or other platinum compounds.

Dosage and Administration

Adjuvant Therapy for Stage III Colon Cancer
Adults

IV Recommended dose schedule given every 2 wk for 12 cycles (6 mo) according to the following dosing for patients with advanced colorectal cancer.

Advanced Colorectal Cancer
Adults Recommended dose schedule given every 2 wk Day 1

IV Oxaliplatin 85 mg/m 2 IV infusion and leucovorin 200 mg/m 2 IV infusion in dextrose 5% in water, both given over 120 min at the same time in separate bags using a Y-line, followed by 5-fluorouracil 400 mg/m 2 IV bolus given over 2 to 4 min, followed by 5-fluorouracil 600 mg/m 2 IV infusion in dextrose 5% in water 500 mL (recommended) as a 22-h continuous infusion.

Day 2

IV Leucovorin 200 mg/m 2 IV infusion over 120 min, followed by 5-fluorouracil 400 mg/m 2 IV bolus given over 2 to 4 min, followed by 5-fluorouracil 600 mg/m 2 IV infusion in dextrose 5% in water 500 mL (recommended) as a 22-h continuous infusion. Treatment is recommended until disease progression or unacceptable toxicity.

Dose Modification

Prior to subsequent therapy cycles, evaluate patients for clinical toxicities and laboratory tests. Prolongation of infusion time for oxaliplatin from 2 to 6 h may mitigate acute toxicities. The infusion times for infusional 5-fluorouracil and leucovorin do not need to be changed.

Dose Modification in Patients With Stage III Colon Cancer
Adults

IV Reduce oxaliplatin dose to 75 mg/m 2 in patients who experience persistent grade 2 neurosensory events that do not resolve. Discontinue oxaliplatin in patients who experience persistent grade 3 neurosensory events. The infusional 5-fluorouracil/leucovorin regimen need not be altered. Reduce oxaliplatin dose to 75 mg/m 2 and infusional 5-fluorouracil to 300 mg/m 2 bolus and 500 mg/m 2 22-h infusion for patients after recovery from grade 3/4 GI toxicities, grade 4 neutropenia, or grade 3/4 thrombocytopenia. Delay next dose until neutrophils are 1,500/mm 3 or more and platelets are at least 75,000/mm 3 .

Dose Modification in Patients With Advanced Colorectal Cancer
Adults

IV Reduce oxaliplatin dose to 65 mg/m 2 in patients who experience persistent grade 2 neurosensory events that do not resolve. Discontinue oxaliplatin in patients who experience persistent grade 3 neurosensory events. The infusional 5-fluorouracil/leucovorin regimen need not be altered. Reduce oxaliplatin dose to 65 mg/m 2 and infusional 5-fluorouracil to 300 mg/m 2 bolus and 500 mg/m 2 22-h infusion for patients after recovery from grade 3/4 GI toxicities, grade 4 neutropenia, or grade 3/4 thrombocytopenia. Delay next dose until neutrophils are 1,500/mm 3 or more and platelets are 75,000/mm 3 or more.

General Advice

  • For IV infusion only. Not for intradermal, subcutaneous, IM, or intra-arterial administration.
  • Follow institutional and National Institutes of Health procedures for handling, administration, and disposal of anticancer drugs. Wear appropriate protective equipment when preparing and administering oxaliplatin.
  • Use of gloves is recommended. If oxaliplatin solution comes in contact with the skin, wash the skin immediately with soap and water. If oxaliplatin solution contacts a mucous membrane, flush thoroughly with water.
  • Dilute prescribed dose of oxaliplatin solution in 250 to 500 mL of dextrose 5% injection.
  • Reconstitute oxaliplatin powder with 10 mL (for the 50 mg vial) or 20 mL (for the 100 mg vial) of water for injection or dextrose 5% injection. The reconstituted solution must be further diluted in an infusion solution of 250 to 500 mL of dextrose 5% injection.
  • Do not use needles or IV administration sets containing aluminum parts that could come in contact with oxaliplatin during preparation or administration. Aluminum can cause degradation of platinum compounds.
  • Do not dilute with sodium chloride injection or other chloride-containing solutions.
  • Do not mix with alkaline medications or media (eg, basic solutions of 5-fluorouracil), or administer simultaneously through same infusion line. Flush infusion line with dextrose 5% in water prior to administration of any concomitant medications.
  • Do not administer if solution is discolored or cloudy, or if it contains particulate matter.
  • Premedicate with antiemetics (eg, 5-HT 3 blockers with or without dexamethasone) as ordered.

Storage/Stability

Solution

Store vials at 59° to 86°F. Do not freeze; protect from light (keep in original outer carton). Solution diluted in dextrose 5% in water is stable for up to 6 h at 68° to 77°F or up to 24 h under refrigeration (36° to 46°F). Protection from light is not required after final dilution.

Powder

Store unreconstituted vials at 59° and 86°F. After reconstitution in the original vial, the solution may be stored for up to 24 h at 36° to 46°F. After final dilution with 250 to 500 mL of dextrose 5% injection, the shelf life is 6 h at 68° to 77°F or up to 24 h at 36° to 46°F. Oxaliplatin is not light-sensitive.

Drug Interactions

Anticoagulants (eg, warfarin)

Prolongation of PT and INR has been reported. Monitor coagulation parameters and adjust the anticoagulant dose as needed.

5-Fluorouracil

No pharmacokinetic interaction between oxaliplatin 85 mg/m 2 and 5-fluorouracil/leucovorin has been observed in patients treated every 2 wk. Increases of 5-fluorouracil/leucovorin plasma concentrations by approximately 20% have been observed with oxaliplatin 130 mg/m 2 every 3 wk.

Nephrotoxic drugs (eg, gentamicin)

Because platinum-containing agents (eg, oxaliplatin) are eliminated primarily through the kidney, Cl of these products may be decreased by coadministration of potentially nephrotoxic compounds. However, this has not been studied.

Adverse Reactions

Adverse reaction are reported for oxaliplatin plus infusional 5-fluorouracil/leucovorin.

Cardiovascular

Thromboembolism (9%); thrombosis (6%); hypotension (5%); hypertension, syncope, tachycardia (2% to 5%).

CNS

Overall peripheral sensory neuropathy (92%); neuropathy (82%); paresthesias (77%); fatigue (70%); headache (17%); dizziness, insomnia (13%); neurosensory (12%); depression (9%); anxiety, dysphasia, neuralgia (5%); ataxia, hot flashes, nervousness, somnolence, vertigo (2% to less than 5%); convulsion, cranial nerve palsies, dysarthria, fasciculations, Lhermitte sign, loss of deep tendon reflexes (postmarketing).

Dermatologic

Alopecia (38%); skin disorder (32%); hand-foot syndrome, rash (11%); flushing (10%); dry skin, pruritus (6%); sweating (5%); pigmentation changes, purpura, urticaria (2% to less than 5%).

EENT

Pharyngolaryngeal dysesthesias (38%); epistaxis (16%); rhinitis (15%); conjunctivitis, pharyngitis, tearing (9%); abnormal lacrimation (7%); abnormal vision (5%); deafness, decreased visual acuity, optic neuritis, transient vision loss, visual field disturbances (postmarketing).

GI

Nausea (74%); diarrhea (67%); vomiting (47%); stomatitis (42%); anorexia (35%); abdominal pain (33%); constipation (32%); dyspepsia, taste perversion (14%); flatulence (9%); mucositis (7%); dysphagia, dry mouth, gastroesophageal reflux, hiccups (5%); ascites, enlarged abdomen, gingivitis, hemorrhoids, intestinal obstruction, melena, proctitis, rectal bleeding, rectal pain, tenesmus (2% to less than 5%); colitis, ileus, intestinal obstruction, pancreatitis, severe vomiting/diarrhea resulting in hypokalemia (postmarketing).

Genitourinary

Dysuria, hematuria (6%); urinary frequency (5%); abnormal micturition frequency, urinary incontinence, vaginal hemorrhage (2% to less than 5%); acute interstitial nephritis, acute renal failure, acute tubular necrosis (postmarketing).

Hematologic-Lymphatic

Leukopenia (85%); anemia, neutropenia (81%); thrombocytopenia (77%); febrile neutropenia, lymphopenia (6%); hemolytic uremic syndrome, immunoallergic hemolytic anemia, immunoallergic thrombocytopenia, prolongation of PT and INR in patients receiving anticoagulants (postmarketing).

Hepatic

Perisinusoidal fibrosis, veno-occlusive disease of the liver (postmarketing).

Hypersensitivity

Hypersensitivity (12%); allergic reactions (10%); anaphylactic shock, angioedema (postmarketing).

Lab Tests

Increased transaminases (57%); increased alkaline phosphatase (42%); bilirubinemia (20%); elevated creatine (5% to 10%).

Local

Injection-site reactions (11%); extravasation.

Metabolic-Nutritional

Increased alkaline phosphate (42%); edema (15%); hyperglycemia (14%); hypokalemia, weight loss (11%); peripheral edema, weight increase (10%); dehydration (9%); hypoalbuminemia, hyponatremia (8%); hypocalcemia (7%); metabolic acidosis (postmarketing).

Musculoskeletal

Back pain (19%); myalgia (14%); arthralgia (10%); rigors (8%); ataxia, bone pain, involuntary muscle contractions, muscle weakness (2% to less than 5%).

Respiratory

Cough (35%); dyspnea (20%); upper respiratory tract infection (10%); hemoptysis, hypoxia, pneumonia, pneumonitis (2% to less than 5%); interstitial lung disease, pulmonary fibrosis (postmarketing).

Miscellaneous

Fever (29%); infection (25%); pain (15%); chest pain, sensory disturbance (8%); catheter infections, nail changes (2% to less than 5%); secondary malignancy.

Precautions

Warnings

Anaphylactic-like reactions have been reported and may occur within minutes of administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms.


Monitor

Monitor WBC with differential, Hgb, platelet count, and blood chemistries (ALT, AST, bilirubin, and creatinine) before each cycle.


Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

The incidence of diarrhea, dehydration, fatigue, hypokalemia, leukopenia, and syncope were higher in patients 65 years of age and older.

Hypersensitivity

Grade 3/4 hypersensitivity, including anaphylactic/anaphylactoid reactions, may occur and can be fatal.

Renal Function

Use with caution in patients with renal impairment.

Hepatotoxicity

Elevated transaminases and alkaline phosphatase may occur. Consider hepatic vascular disorders in case of abnormal LFT results or portal hypertension that cannot be explained by liver metastases.

Neuropathy

Two types of neuropathy may occur: an acute, primarily peripheral sensory neuropathy that occurs within hours or 1 to 2 days of dosing, resolves within 14 days, and frequently recurs with further dosing; or a persistent (longer than 14 days), primarily peripheral sensory neuropathy that interferes with daily activities (eg, difficulty walking, swallowing, writing).

Pulmonary toxicity

Pulmonary fibrosis, which may be fatal, may occur. Discontinue use in case of unexplained pulmonary symptoms (eg, crackles, dyspnea, nonproductive cough, pulmonary infiltrates) until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.

Overdosage

Symptoms

Abdomen enlarged, anemia, chest pain, diarrhea, dysesthesia, dyspnea, facial muscle spasms, flatulence, grade 4 dehydration, grade 4 intestinal obstruction, grade 4 thrombocytopenia without bleeding, laryngospasm, myelosuppression, neurotoxicity, paresthesia, respiratory failure, severe bradycardia, stomatitis, vomiting, wheezing.

Patient Information

  • Explain name, action, potential benefits, and potential side effects of drug, particularly the neurologic effects, the acute reversible effects, and the persistent neurosensory toxicity. Review the treatment regimen including dosing schedule, duration of treatment, and monitoring that will be required.
  • Advise patient or caregiver that medication will be prepared and administered by a health care provider in a health care setting.
  • Instruct patient to avoid cold drinks, use of ice, and to cover exposed skin prior to exposure to cold or cold objects.
  • Instruct patient to immediately notify health care provider if any of the following occur: bleeding; chest pressure; chills, fever, or other signs of infection; difficulty breathing or unexplained shortness of breath; nonproductive cough; odd feelings in tongue; pain, tingling, burning, or numbness in hands, feet, or around the mouth or throat; rash, hives, or any other sign of allergic reaction; severe or persistent diarrhea or vomiting; signs of dehydration; sores in mouth; trouble swallowing or saying words; unusual bruising.
  • Advise patient or caregiver that hair loss is a common adverse reaction of therapy, but that this is usually reversible after therapy has been completed.
  • Caution women of childbearing potential to avoid becoming pregnant during therapy.
  • Inform patients that vision abnormalities and other neurologic symptoms that affect gait and balance may affect their ability to drive or operate machinery.

Copyright © 2009 Wolters Kluwer Health.

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