Oxaliplatin

Oxaliplatin
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]

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Black Box Warning

ConditionName: See full prescribing information for complete Boxed Warning. ConditionName: Anaphylactic reactions to ELOXATIN have been reported, and may occur within minutes of ELOXATIN administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms.

Overview

Oxaliplatin is a antineoplasic agent that is FDA approved for the treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor, advanced colorectal cancer. There is a Black Box Warning for this drug as shown here. Common adverse reactions include peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue and stomatitis.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indications

• ELOXATIN, used in combination with infusional 5-fluorouracil/leucovorin, is indicated for:

• adjuvant treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor.
• treatment of advanced colorectal cancer.

Dosage

• Administer ELOXATIN in combination with 5-fluorouracil/leucovorin every 2 weeks. For advanced disease, treatment is recommended until disease progression or unacceptable toxicity. For adjuvant use, treatment is recommended for a total of 6 months (12 cycles):
• Day 1: ELOXATIN 85 mg/m2 intravenous infusion in 250–500 mL 5% Dextrose injection, USP and leucovorin 200 mg/m2 intravenous infusion in 5% Dextrose Injection, USP both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2–4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.
• Day 2: Leucovorin 200 mg/m2 intravenous infusion over 120 minutes, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2–4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.

• The administration of ELOXATIN does not require prehydration. Premedication with antiemetics, including 5-HT3 blockers with or without dexamethasone, is recommended.
• For information on 5-fluorouracil and leucovorin, see the respective package inserts.

Dose Modification Recommendations

• Prior to subsequent therapy cycles, patients should be evaluated for clinical toxicities and recommended laboratory test. Prolongation of infusion time for ELOXATIN from 2 hours to 6 hours may mitigate acute toxicities. The infusion times for 5-fluorouracil and leucovorin do not need to be changed.

Adjuvant Therapy in Patients with Stage III Colon Cancer

• Neuropathy and other toxicities were graded using the NCI CTC scale version 1.
• For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of ELOXATIN to 75 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The infusional 5-fluorouracil/leucovorin regimen need not be altered.
• A dose reduction of ELOXATIN to 75 mg/m2 and infusional 5-fluorouracil to 300 mg/m2 bolus and 500 mg/m2 22 hour infusion is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥1.5 × 109/L and platelets ≥75 × 109/L.
• Dose Modifications in Therapy in Previously Untreated and Previously Treated Patients with Advanced Colorectal Cancer
• Neuropathy was graded using a study-specific neurotoxicity scale. Other toxicities were graded by the NCI CTC, Version 2.0.
• For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of ELOXATIN to 65 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The 5-fluorouracil/leucovorin regimen need not be altered.
• A dose reduction of ELOXATIN to 65 mg/m2 and 5-fluorouracil by 20% (300 mg/m2 bolus and 500 mg/m2 22-hour infusion) is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥1.5 × 109/L and platelets ≥75 × 109/L.
• Dose Modifications in Therapy for Patients with Renal Impairment
• In patients with normal renal function or mild to moderate renal impairment, the recommended dose of ELOXATIN is 85 mg/m2. In patients with severe renal impairment, the initial recommended ELOXATIN dose should be reduced to 65 mg/m2.

Preparation of Infusion Solution

• Do not freeze and protect from light the concentrated solution.

A final dilution must never be performed with a sodium chloride solution or other chloride-containing solutions.

• The solution must be further diluted in an infusion solution of 250-500 mL of 5% Dextrose Injection, USP.
• After dilution with 250-500 mL of 5% Dextrose Injection, USP, the shelf life is 6 hours at room temperature [20-25°C (68-77°F)] or up to 24 hours under refrigeration [2-8°C (36-46°F)].
• After final dilution, protection from light is not required.
• ELOXATIN is incompatible in solution with alkaline medications or media (such as basic solutions of 5-fluorouracil) and must not be mixed with these or administered simultaneously through the same infusion line. The infusion line should be flushed with 5% Dextrose Injection, USP prior to administration of any concomitant medication.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration and discarded if present.
• Needles or intravenous administration sets containing aluminum parts that may come in contact with ELOXATIN should not be used for the preparation or mixing of the drug. Aluminum has been reported to cause degradation of platinum compounds.

DOSAGE FORMS AND STRENGTHS

• ELOXATIN is supplied in single-use vials containing 50 mg or 100 mg of oxaliplatin as a sterile, preservative-free, aqueous solution at a concentration of 5 mg/mL.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Condition1

• Developed by:

• Class of Recommendation:

• Strength of Evidence:

• Dosing Information

• Dosage

Condition2

There is limited information regarding Off-Label Guideline-Supported Use of Oxaliplatin in adult patients.

Non–Guideline-Supported Use

• Breast Cancer

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding FDA-Labeled Use of Oxaliplatin in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Oxaliplatin in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Oxaliplatin in pediatric patients.

Contraindications

• ELOXATIN should not be administered to patients with a history of known allergy to ELOXATIN or other platinum compounds

Warnings

ConditionName: See full prescribing information for complete Boxed Warning. ConditionName: Anaphylactic reactions to ELOXATIN have been reported, and may occur within minutes of ELOXATIN administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms.

Allergic Reactions

• Grade 3/4 hypersensitivity, including anaphylactic/anaphylactoid reactions, to ELOXATIN has been observed in 2–3% of colon cancer patients. These allergic reactions which can be fatal, can occur within minutes of administration and at any cycle, and were similar in nature and severity to those reported with other platinum-containing compounds, such as rash, urticaria, erythema, pruritus, and, rarely, bronchospasm and hypotension. The symptoms associated with hypersensitivity reactions reported in the previously untreated patients were urticaria, pruritus, flushing of the face, diarrhea associated with oxaliplatin infusion, shortness of breath, bronchospasm, diaphoresis, chest pains, hypotension, disorientation and syncope. These reactions are usually managed with standard epinephrine, corticosteroid, antihistamine therapy, and require discontinuation of therapy. Rechallenge is contraindicated in these patients. Drug-related deaths associated with platinum compounds from anaphylaxis have been reported.

Neurologic Toxicity

• Neuropathy
• ELOXATIN is associated with two types of neuropathy:

• An acute, reversible, primarily peripheral, sensory neuropathy that is of early onset, occurring within hours or one to two days of dosing, that resolves within 14 days, and that frequently recurs with further dosing.The symptoms may be precipitated or exacerbated by exposure to cold temperature or cold objects and they usually present as 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. The acute, reversible pattern of sensory neuropathy was observed in about 56% of study patients who received ELOXATIN with 5-fluorouracil/leucovorin. In any individual cycle acute neurotoxicity was observed in approximately 30% of patients. In adjuvant patients the median cycle of onset for grade 3 peripheral sensory neuropathy was 9 in the previously treated patients the median number of cycles administered on the ELOXATIN with 5-fluorouracil/leucovorin combination arm was 6.
• An acute syndrome of pharyngolaryngeal dysesthesia seen in 1–2% (grade 3/4) of patients previously untreated for advanced colorectal cancer, and the previously treated patients, is characterized by subjective sensations of dysphagia or dyspnea, without any laryngospasm or bronchospasm (no stridor or wheezing). Ice (mucositis prophylaxis) should be avoided during the infusion of ELOXATIN because cold temperature can exacerbate acute neurological symptoms.
• A persistent (>14 days), primarily peripheral, sensory neuropathy that is usually characterized by paresthesias, dysesthesias, hypoesthesias, but may also include deficits in proprioception that can interfere with daily activities (e.g., writing, buttoning, swallowing, and difficulty walking from impaired proprioception). These forms of neuropathy occurred in 48% of the study patients receiving ELOXATIN with 5-fluorouracil/leucovorin. Persistent neuropathy can occur without any prior acute neuropathy event. The majority of the patients (80%) who developed grade 3 persistent neuropathy progressed from prior Grade 1 or 2 events. These symptoms may improve in some patients upon discontinuation of ELOXATIN.
• In the adjuvant colon cancer trial, neuropathy was graded using a prelisted module derived from the Neuro-Sensory section of the National Cancer Institute Common Toxicity Criteria (NCI CTC) scale, Version 1, as follows:

• Peripheral sensory neuropathy was reported in adjuvant patients treated with the ELOXATIN combination with a frequency of 92% (all grades) and 13% (grade 3). At the 28-day follow-up after the last treatment cycle, 60% of all patients had any grade (Grade 1=40%, Grade 2=16%, Grade 3=5%) peripheral sensory neuropathy decreasing to 39% at 6 months follow-up (Grade 1=31%, Grade 2=7%, Grade 3=1%) and 21% at 18 months of follow-up (Grade 1=17%, Grade 2=3%, Grade 3=1%).

In the advanced colorectal cancer studies, neuropathy was graded using a study-specific neurotoxicity scale, which was different from the NCI CTC scale, Version 2.0

• Overall, neuropathy was reported in patients previously untreated for advanced colorectal cancer in 82% (all grades) and 19% (grade 3/4), and in the previously treated patients in 74% (all grades) and 7% (grade 3/4) events. Information regarding reversibility of neuropathy was not available from the trial for patients who had not been previously treated for colorectal cancer.

Reversible Posterior Leukoencephalopathy Syndrome

• Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES, Posterior Reversible Encephalopathy Syndrome) has been observed in clinical trials (< 0.1%) and postmarketing experience. Signs and symptoms of RPLS could be headache, altered mental functioning, seizures, abnormal vision from blurriness to blindness, associated or not with hypertension. Diagnosis of RPLS is based upon confirmation by brain imaging.

Pulmonary Toxicity=

• ELOXATIN has been associated with pulmonary fibrosis (<1% of study patients), which may be fatal. The combined incidence of cough and dyspnea was 7.4% (any grade) and <1% (grade 3) with no grade 4 events in the ELOXATIN plus infusional 5-fluorouracil/leucovorin arm compared to 4.5% (any grade) and no grade 3 and 0.1% grade 4 events in the infusional 5-fluorouracil/leucovorin alone arm in adjuvant colon cancer patients. In this study, one patient died from eosinophilic pneumonia in the ELOXATIN combination arm. The combined incidence of cough, dyspnea and hypoxia was 43% (any grade) and 7% (grade 3 and 4) in the ELOXATIN plus 5-fluorouracil/leucovorin arm compared to 32% (any grade) and 5% (grade 3 and 4) in the irinotecan plus 5-fluorouracil/leucovorin arm of unknown duration for patients with previously untreated colorectal cancer. In case of unexplained respiratory symptoms such as non-productive cough, dyspnea, crackles, or radiological pulmonary infiltrates, ELOXATIN should be discontinued until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.

Hepatotoxicity

• Hepatotoxicity as evidenced in the adjuvant study, by increase in transaminases (57% vs. 34%) and alkaline phosphatase (42% vs. 20%) was observed more commonly in the ELOXATIN combination arm than in the control arm. The incidence of increased bilirubin was similar on both arms. Changes noted on liver biopsies include: peliosis, nodular regenerative hyperplasia or sinusoidal alterations, perisinusoidal fibrosis, and veno-occlusive lesions. Hepatic vascular disorders should be considered, and if appropriate, should be investigated in case of abnormal liver function test results or portal hypertension, which cannot be explained by liver metastases

Recommended Laboratory Tests

• Standard monitoring of the white blood cell count with differential, hemoglobin, platelet count, and blood chemistries (including ALT, AST, bilirubin and creatinine) is recommended before each ELOXATIN cycle.
• There have been reports while on study and from post-marketing surveillance of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received ELOXATIN plus 5-fluorouracil/leucovorin while on anticoagulants. Patients receiving ELOXATIN plus 5-fluorouracil/leucovorin and requiring oral anticoagulants may require closer monitoring.

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Clinical Trial Experience of Oxaliplatin in the drug label.

Body as a Whole

Cardiovascular

Digestive

Endocrine

Hematologic and Lymphatic

Metabolic and Nutritional

Musculoskeletal

Neurologic

Respiratory

Skin and Hypersensitivy Reactions

Special Senses

Urogenital

Miscellaneous

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Oxaliplatin in the drug label.

Body as a Whole

Cardiovascular

Digestive

Endocrine

Hematologic and Lymphatic

Metabolic and Nutritional

Musculoskeletal

Neurologic

Respiratory

Skin and Hypersensitivy Reactions

Special Senses

Urogenital

Miscellaneous

Drug Interactions

• Drug

• Description

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Pregnancy Category

Pregnancy Category (AUS):

• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Oxaliplatin in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Oxaliplatin during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Oxaliplatin with respect to nursing mothers.

Pediatric Use

There is no FDA guidance on the use of Oxaliplatin with respect to pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Oxaliplatin with respect to geriatric patients.

Gender

There is no FDA guidance on the use of Oxaliplatin with respect to specific gender populations.

Race

There is no FDA guidance on the use of Oxaliplatin with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Oxaliplatin in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Oxaliplatin in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Oxaliplatin in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Oxaliplatin in patients who are immunocompromised.

Administration and Monitoring

Administration

• Oral

• Intravenous

Monitoring

There is limited information regarding Monitoring of Oxaliplatin in the drug label.

• Description

IV Compatibility

There is limited information regarding IV Compatibility of Oxaliplatin in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

• Description

Management

• Description

Chronic Overdose

There is limited information regarding Chronic Overdose of Oxaliplatin in the drug label.

Pharmacology

There is limited information regarding Oxaliplatin Pharmacology in the drug label.

Mechanism of Action

Structure

File:Oxaliplatin01.png

This image is provided by the National Library of Medicine.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Oxaliplatin in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Oxaliplatin in the drug label.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Oxaliplatin in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Oxaliplatin in the drug label.

How Supplied

Storage

There is limited information regarding Oxaliplatin Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Oxaliplatin in the drug label.

Precautions with Alcohol

• Alcohol-Oxaliplatin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• ®

Look-Alike Drug Names

• A® — B®

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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