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Navelbine

Safety Overview for Navelbine (vinorelbine tartrate)

Summary

Data in the following table are based on the experience of 365 patients enrolled in three clinical studies of IV Navelbine in NSCLC (143 patients) and advanced breast cancer (222 patients).[1,2,3,4] Patients in each study received 30 mg/square m weekly of IV Navelbine.


Incidence of Adverse Events in 365 Patients Receiving Single-Agent Navelbine [a,b]

Safety Table One

Safety Table Two

a None of the reported toxicities were influenced by age. Grade based on modified criteria from the National Cancer Institute.
b None of the patients with NSCLC were previously treated with chemotherapy.The majority of patients with advanced breast cancer were previously treated with chemotherapy.
c Incidence of paresthesia plus hypesthesia

The following descriptive information regarding adverse events associated with the use of Navelbine refers to all patients (NSCLC and breast cancer) summarized in the table above.

Hematologic
Reversible granulocytopenia is the major dose-limiting toxicity reported with Navelbine. It is not cumulative over time. Granulocyte nadirs occur 7 to 10 days after the dose and usually recover within the following 7 to 14 days. Hospitalization for fever and/or sepsis while granulocytopenic is reported in 9% of patients. Septic deaths are reported in approximately 1% of patients. Prophylactic hematologic growth factors have not been routinely used with Navelbine. Mild to moderate anemia is common (grade III-IV anemia is uncommon). Few patients require transfusion. Thrombocytopenia is rare. Mild to moderate thrombocytosis is observed but it is not associated with coagulopathies.

Neurologic
Mild to moderate peripheral neuropathy manifested by paresthesia and hypesthesia are the most frequently reported neurologic toxicities. Loss of deep tendon reflexes may represent cumulative toxicity and have occurred in 5% of patients. Neurotoxicity may be reversible upon discontinuation of Navelbine. Tumor pain and jaw pain have been reported with Navelbine, as with other vinca alkaloids. Grade III-IV peripheral neuropathy is reported in 1% of patients.

Gastrointestinal
Mild to moderate nausea and vomiting occur in 44% of patients; severe nausea is infrequent (<2%). Prophylactic administration of antiemetics has not been routine in patients treated with single-agent Navelbine. Due to the low incidence of severe nausea and vomiting with single-agent Navelbine, the use of serotonin antagonists is generally not required. Nausea and vomiting have responded to standard antiemetic treatment. Constipation occurs in approximately 35% of patients, with paralytic ileus occurring in <2%. Diarrhea, anorexia and stomatitis are usually mild or moderate and are reported in <20% of patients.

Injection Site Reactions
Navelbine, like other vinca alkaloids, is a moderate vesicant. Injection site reactions, including erythema, pain at the injection site and vein discoloration are reported in approximately one-third of patients; 2% are severe. Chemical phlebitis, characterized by erythema and tenderness over the palpable length of the infused vein, is reported. Venous pain can be minimized by administering Navelbine over 6 to 10 minutes and by flushing the vein with at least 75 to 125 mL of intravenous fluid after the infusion of Navelbine is completed.

Alopecia
Alopecia is reported in 12% of patients and is usually mild and reversible.

Cardiovascular
Chest pain is reported in approximately 6% of patients treated with IV Navelbine. Most reports of chest pain are in patients with either a history of cardiovascular disease or tumor within the chest. There are rare reports of myocardial infarction in patients with a history of severe cardiovascular disease.

Pulmonary
Shortness of breath is reported in approximately 6% of patients (severe in 2%). Interstitial pulmonary changes have been documented in a few patients. Navelbine, like vindesine and vinblastine, may produce acute and sub-acute pulmonary reactions. The acute reaction may be allergic in character, and occurs within a few hours of administration. Sub-acute pulmonary reactions may be characterized by dyspnea, cough, hypoxemia, and interstitial infiltrates on chest x-ray. Chest radiation therapy may increase the likelihood or severity of such pulmonary reactions. Corticosteroid therapy has produced significant improvement in some patients, and two such patients have been successfully rechallenged with Navelbine. These adverse events may also require treatment with supplemental oxygen and bronchodilators, particularly when there is pre-existing pulmonary dysfunction.

Serum Chemistry Studies
Transient elevations in liver enzymes without clinical symptoms have been observed. A few patients with NSCLC have developed syndrome of inappropriate anti-diuretic hormone (SIADH) secretion. This syndrome is commonly associated with lung cancer, and has been previously reported with the use of other vinca alkaloids and cisplatin.


References

1. Data on file, Glaxo Wellcome Inc. (THRS/92/0026).
2. Data on file, Glaxo Wellcome Inc. (THRS/92/0035/01).
3. Data on file, Glaxo Wellcome Inc. (THRS/92/0042/01).
4. Data on file, Glaxo Wellcome Inc. (THZZ/94/0626).


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