Oxaliplatin (Page 2 of 10)

2.4 Preparation and Administration

  • Oxaliplatin Injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.1
  • Do not freeze.
  • Protect the concentrated solution from light.
  • Dilute concentrated solution with 250 to 500 mL of 5% Dextrose Injection, USP. Do not dilute with sodium chloride solution or other chloride-containing solutions.
  • Store diluted solution for no more than 6 hours at room temperature (20°C to 25°C [68°F to 77°F]) or 24 hours under refrigeration (2°C to 8°C [36°F to 46°F]). Protection from light is not required.
  • Visually inspect for particulate matter and discoloration prior to administration and discard if present.
  • Do not mix oxaliplatin injection or administer oxaliplatin injection through the same infusion line concurrently with alkaline medications or media (such as basic solutions of fluorouracil).
  • Flush the infusion line with 5% Dextrose Injection, USP prior to administration of any concomitant medication.
  • Do not use needles or intravenous administration sets containing aluminum parts for the preparation or mixing of oxaliplatin injection. Aluminum has been reported to cause degradation of platinum compounds.
  • Administer oxaliplatin injection as an intravenous infusion over 120 minutes concurrently with leucovorin over 120 minutes in separate bags.

3 DOSAGE FORMS AND STRENGTHS

Injection: 50 mg (5 mg/mL), 100 mg (5 mg/mL) or 200 mg (5 mg/mL) clear, colorless solution in a single-dose vial .

4 CONTRAINDICATIONS

Oxaliplatin Injection is contraindicated in patients with a history of a hypersensitivity reaction to oxaliplatin or other platinum-based drugs. Reactions have included anaphylaxis [see Warnings and Precautions (5.1)].

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

Serious and fatal hypersensitivity reactions, including anaphylaxis, can occur with oxaliplatin injection within minutes of administration and during any cycle. Grade 3-4 hypersensitivity reactions, including anaphylaxis, occurred in 2% to 3% of patients with colon cancer who received oxaliplatin injection. Hypersensitivity reactions, including rash, urticaria, erythema, pruritus, and, rarely, bronchospasm and hypotension, were similar in nature and severity to those reported with other platinum-based drugs.

Oxaliplatin Injection is contraindicated in patients with hypersensitivity reactions to platinum-based drugs [see Contraindications (4)]. Immediately and permanently discontinue oxaliplatin injection for hypersensitivity reactions and administer appropriate treatment for management of hypersensitivity reactions.

5.2 Peripheral Sensory Neuropathy

Oxaliplatin Injection can cause acute and delayed neuropathy. Reduce the dose or permanently discontinue oxaliplatin injection for persistent neurosensory reactions based on the severity of the adverse reaction [see Dosage and Administration (2.3)].

Acute Neuropathy

Acute neuropathy typically presents as a reversible, primarily peripheral sensory neuropathy that occurs within hours or 2 days following a dose, resolves within 14 days, and frequently recurs with further dosing. The symptoms can 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 patients who received oxaliplatin injection ATIN with fluorouracil/leucovorin. In any individual cycle, acute neuropathy occurred in approximately 30% of patients. For grade 3 peripheral sensory neuropathy, the median time to onset was 9 cycles for adjuvant treatment and 6 cycles for previously treated advanced colorectal cancer.

An acute syndrome of pharyngolaryngeal dysesthesia occurred in 1% to 2% (grade 3-4) of patients previously untreated for advanced colorectal cancer. Subjective sensations of dysphagia or dyspnea, without any laryngospasm or bronchospasm (no stridor or wheezing) occurred in patients previously treated for advanced colorectal cancer.

Avoid topical application of ice for mucositis prophylaxis or other conditions, because cold temperature can exacerbate acute neurological symptoms.

Delayed Neuropathy

Delayed neuropathy typically presents as a persistent (greater than 14 days), primarily peripheral sensory neuropathy that is usually characterized by paresthesias, dysesthesias, and 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 patients receiving oxaliplatin injection. Delayed neuropathy can occur without any prior acute neuropathy. Most patients (80%) who developed grade 3 persistent neuropathy progressed from prior grade 1 or 2 reactions. These symptoms may improve in some patients upon discontinuation of oxaliplatin injection.

Adjuvant treatment

In the adjuvant treatment trial, neuropathy was graded using NCI CTC, version 1 as summarized in Table 3.

Table 3: Grading for Neuropathy in Adjuvant Treatment Trial
Grade Definition
0 No change or none
1 Mild paresthesias, loss of deep tendon reflexes
2 Mild or moderate objective sensory loss, moderate paresthesias
3 Severe objective sensory loss or paresthesias that interfere with function
4 Not applicable

Peripheral sensory neuropathy occurred in 92% of patients (all grades), including 13% of patients (grade 3) who received oxaliplatin injection with fluorouracil/leucovorin. At the 28-day follow-up after the last treatment cycle, 60% of patients had any grade (grade 1=40%, grade 2=16%, grade 3=5%) peripheral sensory neuropathy, decreasing to 39% at 6 months of 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%).

Advanced colorectal cancer

In the advanced colorectal cancer trials, neuropathy was graded using the neurotoxicity scale summarized in Table 4.

Table 4: Grading for Neuropathy in Advanced Colorectal Cancer Trials
Grade Definition
1 Resolved and did not interfere with functioning
2 Interfered with function but not daily activities
3 Pain or functional impairment that interfered with daily activities
4 Persistent impairment that is disabling or life-threatening

Neuropathy occurred in 82% (all grades) of patients previously untreated for advanced colorectal cancer, including 19% grade 3-4; and in 74% (all grades) of patients previously treated for advanced colorectal cancer, including 7% grade 3-4.

5.3 Severe Myelosuppression

Grade 3 or 4 neutropenia occurred in 41% to 44% of patients with colorectal cancer who received oxaliplatin injection with fluorouracil/leucovorin. Sepsis, neutropenic sepsis and septic shock, including fatal outcomes, occurred in patients who received oxaliplatin injection [see Adverse Reactions (6.1, 6.2)].

Grade 3 or 4 thrombocytopenia occurred in 2% to 5% of patients with colorectal cancer who received oxaliplatin injection with fluorouracil/leucovorin.

Monitor complete blood cell count at baseline, before each subsequent cycle and as clinically indicated. Delay oxaliplatin injection until neutrophils are greater than or equal to 1.5 x 109 /L and platelets are greater than or equal to 75 × 109 /L. Withhold oxaliplatin injection for sepsis or septic shock. Dose reduce oxaliplatin injection after recovery from grade 4 neutropenia, febrile neutropenia or grade 3-4 thrombocytopenia as recommended [see Dosage and Administration (2.2)].

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