Oxaliplatin: Package Insert and Label Information

OXALIPLATIN- oxaliplatin injection, solution, concentrate
Teva Parenteral Medicines, Inc.

WARNING: ANAPHYLACTIC REACTIONS

Anaphylactic reactions to oxaliplatin have been reported, and may occur within minutes of oxaliplatin administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms of anaphylaxis [see Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

Oxaliplatin Injection, used in combination with infusional 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.

2 DOSAGE AND ADMINISTRATION

Administer Oxaliplatin Injection under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.

2.1 Dosage

Administer Oxaliplatin Injection in combination with 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: Oxaliplatin Injection 85 mg/m2 intravenous infusion in 250 to 500 mL 5% Dextrose Injection and leucovorin 200 mg/m2 intravenous infusion in 5% Dextrose Injection both given over 120 minutes at the same time in separate bags using a Y-line, followed by fluorouracil 400 mg/m2 intravenous bolus given over 2 to 4 minutes, followed by fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection (recommended) as a 22-hour continuous infusion.

Day 2: Leucovorin 200 mg/m2 intravenous infusion over 120 minutes, followed by fluorouracil 400 mg/m2 intravenous bolus given over 2 to 4 minutes, followed by fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection (recommended) as a 22-hour continuous infusion.

Figure 1

Figure 1
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The administration of Oxaliplatin Injection does not require prehydration. Premedication with antiemetics, including 5-HT3 blockers with or without dexamethasone, is recommended.

For information on fluorouracil and leucovorin, see the respective package inserts.

2.2 Dose Modification Recommendations

Prior to subsequent therapy cycles, evaluate patients for clinical toxicities and recommended laboratory tests [see Warnings and Precautions ( 5.9) ]. Prolongation of infusion time for Oxaliplatin Injection from 2 hours to 6 hours may mitigate acute toxicities. The infusion times for 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 [see Warnings and Precautions ( 5.2)].

For patients who experience persistent Grade 2 neurosensory events that do not resolve, consider a dose reduction of Oxaliplatin Injection to 75 mg/m2. For patients with persistent Grade 3 neurosensory events, consider discontinuing therapy. The infusional fluorouracil/leucovorin regimen need not be altered.

A dose reduction of Oxaliplatin Injection to 75 mg/m2 and infusional 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 febrile neutropenia, or Grade 3/4 thrombocytopenia. Delay the next dose 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 [see Warnings and Precautions ( 5.2)]. Other toxicities were graded by the NCI CTC, Version 2.0.

For patients who experience persistent Grade 2 neurosensory events that do not resolve, consider a dose reduction of Oxaliplatin Injection to 65 mg/m2. For patients with persistent Grade 3 neurosensory events, consider discontinuing therapy. The fluorouracil/leucovorin regimen need not be altered.

A dose reduction of Oxaliplatin Injection to 65 mg/m2 and 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 febrile neutropenia, or Grade 3/4 thrombocytopenia. Delay the next dose 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 Oxaliplatin Injection is 85 mg/m2. In patients with severe renal impairment, the recommended Oxaliplatin Injection dose is 65 mg/m2 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

2.3 Preparation of Infusion Solution

Oxaliplatin Injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

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 to 500 mL of 5% Dextrose Injection.

After dilution with 250 to 500 mL of 5% Dextrose Injection, the shelf life is 6 hours at room temperature [20°C to 25°C (68°F to 77°F)] or up to 24 hours under refrigeration [2°C to 8°C (36°F to 46°F)]. After final dilution, protection from light is not required.

Oxaliplatin Injection is incompatible in solution with alkaline medications or media (such as basic solutions of 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 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 Oxaliplatin Injection should not be used for the preparation or mixing of the drug. Aluminum has been reported to cause degradation of platinum compounds.

Discard unused portion.

3 DOSAGE FORMS AND STRENGTHS

Injection: 50 mg/10 mL (5 mg/mL) and 100 mg/20 mL (5 mg/mL) as a sterile, preservative-free, aqueous solution in single-dose vials.

4 CONTRAINDICATIONS

Oxaliplatin Injection should not be administered to patients with a history of known allergy to oxaliplatin or other platinum compounds [see Warnings and Precautions ( 5.1)].

5 WARNINGS AND PRECAUTIONS

5.1 Allergic Reactions

Grade 3/4 hypersensitivity, including anaphylactic/anaphylactoid reactions, to oxaliplatin has been observed in 2% to 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 [see Contraindications (4)]. Drug-related deaths associated with platinum compounds from anaphylaxis have been reported.

5.2 Neurologic Toxicity

Neuropathy

Oxaliplatin 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 oxaliplatin with 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 oxaliplatin with fluorouracil/leucovorin combination arm was 6.

An acute syndrome of pharyngolaryngeal dysesthesia seen in 1% to 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 oxaliplatin 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 oxaliplatin with 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 oxaliplatin.

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:

Table 1: NCI CTC Grading for Neuropathy in Adjuvant Patients
Grade Definition

Grade 0

No change or none

Grade 1

Mild paresthesias, loss of deep tendon reflexes

Grade 2

Mild or moderate objective sensory loss, moderate paresthesias

Grade 3

Severe objective sensory loss or paresthesias that interfere with function

Grade 4

Not applicable

Peripheral sensory neuropathy was reported in adjuvant patients treated with the oxaliplatin 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 (see below).

Table 2: Grading Scale for Paresthesias/Dysesthesias in Advanced Colorectal Cancer Patients
Grade Definition

Grade 1

Resolved and did not interfere with functioning

Grade 2

Interfered with function but not daily activities

Grade 3

Pain or functional impairment that interfered with daily activities

Grade 4

Persistent impairment that is disabling or life-threatening

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 [see Adverse Reactions (6.2)]. Diagnosis of RPLS is based upon confirmation by brain imaging.

5.3 Severe Neutropenia

Grade 3 or 4 neutropenia occurred in 41 to 44% of patients with colorectal cancer treated with oxaliplatin in combination with flurouracil (FU) and leucovorin compared to 5% with FU plus leucovorin alone. Sepsis, neutropenic sepsis and septic shock have been reported in patients treated with oxaliplatin, including fatal outcomes [see Adverse Reactions ( 6.1)].

Delay Oxaliplatin Injection until neutrophils are ≥ 1.5 x 109 /L. Withhold Oxaliplatin Injection for sepsis or septic shock. Reduce the dose of Oxaliplatin Injection after recovery from Grade 4 neutropenia or febrile neutropenia [see Dosage and Administration ( 2.2)].

5.4 Pulmonary Toxicity

Oxaliplatin 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 oxaliplatin plus infusional fluorouracil/leucovorin arm compared to 4.5% (any grade) and no Grade 3 and 0.1% Grade 4 events in the infusional fluorouracil/leucovorin alone arm in adjuvant colon cancer patients. In this study, one patient died from eosinophilic pneumonia in the oxaliplatin combination arm. The combined incidence of cough, dyspnea and hypoxia was 43% (any grade) and 7% (Grade 3 and 4) in the oxaliplatin plus fluorouracil/leucovorin arm compared to 32% (any grade) and 5% (Grade 3 and 4) in the irinotecan plus 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, Oxaliplatin Injection should be discontinued until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.

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