Navelbine
SIDE EFFECTS
The pattern of adverse reactions is similar whether NAVELBINE is used as a single agent or in combination. Adverse reactions from studies with single-agent and combination use of NAVELBINE are summarized in Tables 2-4.
Single-Agent NAVELBINE
Data in the following table are based on the experience of 365 patients (143 patients with NSCLC; 222 patients with advanced breast cancer) treated with IV NAVELBINE as a single agent in 3 clinical studies. The dosing schedule in each study was 30 mg/m2 NAVELBINE on a weekly basis.
| Table 2. Summary of Adverse Events in 365 Patients Receiving Single-Agent NAVELBINE* | |||
| All Patients (n = 365) | NSCLC (n = 143) | ||
| <2,000 cells/mm3 <500 cells/mm3 | 90% 36% | 80% 29% | |
| <4,000 cells/mm3 <1,000 cells/mm3 | 92% 15% | 81% 12% | |
| Thrombocytopenia | <100,000 cells/mm3 <50,000 cells/mm3 | 5% 1% | 4% 1% |
| <11 g/dL <8 g/dL | 83% 9% | 77% 1% | |
| Hospitalizations due to granulocytopenic complications | 9% | 8% | |
| Adverse Event | All Grades | Grade 3 | Grade 4 | |||
| All Patients | NSCLC | All Patients | NSCLC | All Patients | NSCLC | |
| Clinical Chemistry Elevations | ||||||
| Total Bilirubin (n = 351) | 13% | 9% | 4% | 3% | 3% | 2% |
| SGOT (n = 346) | 67% | 54% | 5% | 2% | 1% | 1% |
| General | ||||||
| 36% | 27% | 7% | 5% | 0% | 0% | |
| Injection Site Reactions | 28% | 38% | 2% | 5% | 0% | 0% |
| Injection Site Pain | 16% | 13% | 2% | 1% | 0% | 0% |
| 7% | 10% | <1% | 1% | 0% | 0% | |
| Digestive | ||||||
| 44% | 34% | 2% | 1% | 0% | 0% | |
| Vomiting | 20% | 15% | 2% | 1% | 0% | 0% |
| 35% | 29% | 3% | 2% | 0% | 0% | |
| 17% | 13% | 1% | 1% | 0% | 0% | |
| 25% | 20% | 1% | 1% | <1% | 0% | |
| 7% | 3% | 2% | 2% | 1% | 0% | |
| 12% | 12% | ≤1% | 1% | 0% | 0% | |
| * None of the reported toxicities were influenced by age. Grade based on modified criteria from the National Cancer Institute. | ||||||
| † Patients with NSCLC had not received prior chemotherapy. The majority of the remaining Patients had received prior chemotherapy. | ||||||
| ‡ Incidence of paresthesia plus hypesthesia. | ||||||
Hematologic
Granulocytopenia is the major dose-limiting toxicity with NAVELBINE. Dose adjustments are required for hematologic toxicity and hepatic insufficiency (see DOSAGE AND ADMINISTRATION). Granulocytopenia was generally reversible and not cumulative over time. Granulocyte nadirs occurred 7 to 10 days after the dose, with granulocyte recovery usually within the following 7 to 14 days. Granulocytopenia resulted in hospitalizations for fever and/or sepsis in 8% of patients. Septic deaths occurred in approximately 1% of patients. Prophylactic hematologic growth factors have not been routinely used with NAVELBINE. If medically necessary, growth factors may be administered at recommended doses no earlier than 24 hours after the administration of cytotoxic chemotherapy. Growth factors should not be administered in the period 24 hours before the administration of chemotherapy.
Whole blood and/or packed red blood cells were administered to 18% of patients who received NAVELBINE.
Neurologic
Loss of deep tendon reflexes occurred in less than 5% of patients. The development of severe peripheral neuropathy was infrequent (1%) and generally reversible.
Like other anticancer vinca alkaloids, NAVELBINE is a moderate vesicant. Injection site reactions, including erythema, pain at injection site, and vein discoloration, occurred in approximately one third of patients; 5% were severe. Chemical phlebitis along the vein proximal to the site of injection was reported in 10% of patients.
Prophylactic administration of antiemetics was not 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.
Hepatic
Transient elevations of liver enzymes were reported without clinical symptoms.
Chest pain was reported in 5% of patients. Most reports of chest pain were in patients who had either a history of cardiovascular disease or tumor within the chest. There have been rare reports of myocardial infarction.
Shortness of breath was reported in 3% of patients; it was severe in 2% (see WARNINGS). Interstitial pulmonary changes were documented.
Other
Fatigue occurred in 27% of patients. It was usually mild or moderate but tended to increase with cumulative dosing.
Other toxicities that have been reported in less than 5% of patients include jaw pain, myalgia, arthralgia, and rash. Hemorrhagic cystitis and the syndrome of inappropriate ADH secretion were each reported in <1% of patients.
Combination Use
Adverse events for combination use are summarized in Tables 3 and 4.
NAVELBINE in Combination with Cisplatin:
NAVELBINE plus Cisplatin versus Single-Agent Cisplatin (Table 3):
Myelosuppression was the predominant toxicity in patients receiving combination therapy, Grade 3 and 4 granulocytopenia of 82% compared to 5% in the single-agent cisplatin arm. Fever and/or sepsis related to granulocytopenia occurred in 11% of patients on NAVELBINE and cisplatin compared to 0% on the cisplatin arm.
Four patients on the combination died of granulocytopenia-related sepsis. During this study, the use of granulocyte colony-stimulating factor ([G-CSF] filgrastim) was permitted, but not mandated, after the first course of treatment for patients who experienced Grade 3 or 4 granulocytopenia (≤1,000 cells/mm3) or in those who developed neutropenic fever between cycles of chemotherapy. Beginning 24 hours after completion of chemotherapy, G-CSF was started at a dose of 5 mcg/kg/day and continued until the total granulocyte count was >1,000 cells/mm3 on 2 successive determinations. G-CSF was not administered on the day of treatment.
Grade 3 and 4 anemia occurred more frequently in the combination arm compared to control, 24% vs. 8%, respectively. Thrombocytopenia occurred in 6% of patients treated with NAVELBINE plus cisplatin compared to 2% of patients treated with cisplatin.
The incidence of severe non-hematologic toxicity was similar among the patients in both treatment groups. Patients receiving NAVELBINE plus cisplatin compared to single-agent cisplatin experienced more Grade 3 and/or 4 peripheral numbness (2% vs. <1%), phlebitis/thrombosis/embolism (3% vs. <1%), and infection (6% vs. <1%). Grade 3-4 constipation and/or ileus occurred in 3% of patients treated with combination therapy and in 1% of patients treated with cisplatin.
Seven deaths were reported on the combination arm; 2 were related to cardiac ischemia, 1 massive cerebrovascular accident, 1 multisystem failure due to an overdose of NAVELBINE, and 3 from febrile neutropenia. One death, secondary to respiratory infection unrelated to granulocytopenia, occurred with single-agent cisplatin.
NAVELBINE plus Cisplatin versus Vindesine plus Cisplatin versus Single-Agent NAVELBINE (Table 4): Myelosuppression, specifically Grade 3 and 4 granulocytopenia, was significantly greater with the combination of NAVELBINE plus cisplatin (79%) than with either single-agent NAVELBINE (53%) or vindesine plus cisplatin (48%), P<0.0001. Hospitalization due to documented sepsis occurred in 4.4% of patients treated with NAVELBINE plus cisplatin, 2% of patients treated with vindesine and cisplatin, and 4% of patients treated with single-agent NAVELBINE. Grade 3 and 4 thrombocytopenia was infrequent in patients receiving combination chemotherapy and no events were reported with single-agent NAVELBINE.
The incidence of Grade 3 and/or 4 nausea and vomiting, alopecia, and renal toxicity were reported more frequently in the cisplatin-containing combinations compared to single-agent NAVELBINE. Severe local reactions occurred in 2% of patients treated with combinations containing NAVELBINE; none were observed in the vindesine plus cisplatin arm. Grade 3 and 4 neurotoxicity was significantly more frequent in patients receiving vindesine plus cisplatin (17%) compared to NAVELBINE plus cisplatin (7%) and single-agent NAVELBINE (9%) (P<0.005). Cisplatin did not appear to increase the incidence of neurotoxicity observed with single-agent NAVELBINE.
| Table 3. Selected Adverse Events From a Comparative Trial of NAVELBINE Plus Cisplatin versus Single-Agent Cisplatin* | ||||||
| Adverse Event | NAVELBINE 25 mg/m2 plus Cisplatin 100 mg/m2 (n = 212) | Cisplatin 100 mg/m2 (n = 210) | ||||
| All Grades | Grade 3 | Grade 4 | All Grades | Grade 3 | Grade 4 | |
| Granulocytopenia | 89% | 22% | 60% | 26% | 4% | 1% |
| Anemia | 88% | 21% | 3% | 72% | 7% | <1% |
| Leukopenia | 88% | 39% | 19% | 31% | <1% | 0% |
| Thrombocytopenia | 29% | 4% | 1% | 21% | 1% | <1% |
| Febrile Neutropenia | N/A | N/A | 11% | N/A | N/A | 0% |
| Hepatic | ||||||
| Elevated transaminase | 1% | 0% | 0% | <1% | <1% | 0% |
| Renal | ||||||
| Elevated creatinine | 37% | 2% | 2% | 28% | 4% | <1% |
| Non-Laboratory | ||||||
| Malaise/fatigue/lethargy | 67% | 12% | 0% | 49% | 8% | 0% |
| Vomiting | 60% | 7% | 6% | 60% | 10% | 4% |
| Nausea | 58% | 14% | 0% | 57% | 12% | 0% |
| 46% | 0% | 0% | 37% | 0% | 0% | |
| Constipation | 35% | 3% | 0% | 16% | 1% | 0% |
| Alopecia | 34% | 0% | 0% | 14% | 0% | 0% |
| 34% | 1% | 0% | 21% | <1% | 0% | |
| Fever without infection | 20% | 2% | 0% | 4% | 0% | 0% |
| Hearing | 18% | 4% | 0% | 18% | 3% | <1% |
| Local (injection site reactions) | 17% | <1% | 0% | 1% | 0% | 0% |
| Diarrhea | 17% | 2% | <1% | 11% | 1% | <1% |
| Paresthesias | 17% | <1% | 0% | 10% | <1% | 0% |
| Taste alterations | 17% | 0% | 0% | 15% | 0% | 0% |
| Peripheral numbness | 11% | 2% | 0% | 7% | <1% | 0% |
| Myalgia/arthralgia | 12% | <1% | 0% | 3% | <1% | 0% |
| Phlebitis/thrombosis/embolism | 10% | 3% | 0% | <1% | 0% | <1% |
| Weakness | 12% | 2% | <1% | 7% | 2% | 0% |
| Dizziness/vertigo | 9% | <1% | 0% | 3% | <1% | 0% |
| Infection | 11% | 5% | <1% | <1% | <1% | 0% |
| Respiratory infection | 10% | 4% | <1% | 3% | 3% | 0% |
| *Graded according to the standard SWOG criteria. | ||||||
| Table 4. Selected Adverse Events From a Comparative Trial of NAVELBINE Plus Cisplatin versus Vindesine Plus Cisplatin versus Single-Agent NAVELBINE* | |||||||||
| Adverse Event | NAVELBINE/Cisplatin | Vindesine/Cisplatin | NAVELBINE§ | ||||||
| All Grades | Grade 3 | Grade 4 | All Grades | Grade 3 | Grade 4 | All Grades | Grade 3 | Grade 4 | |
| Bone Marrow | |||||||||
| Neutropenia | 95% | 20% | 58% | 79% | 26% | 22% | 85% | 25% | 28% |
| Leukopenia | 94% | 40% | 17% | 82% | 24% | 3% | 83% | 26% | 6% |
| Thrombocytopenia | 15% | 3% | 1% | 10% | 3% | 0.5% | 3% | 0% | 0% |
| Febrile Neutropenia | N/A | N/A | 4% | N/A | N/A | 2% | N/A | N/A | 4% |
| Hepatic | |||||||||
| Elevated bilirubin¦ | 6% | N/A | N/A | 5% | N/A | N/A | 5% | N/A | N/A |
| Renal | |||||||||
| Elevated creatinine¦ | 46% | N/A | N/A | 37% | N/A | N/A | 13% | N/A | N/A |
| Non-Laboratory | |||||||||
| Nausea/vomiting | 74% | 27% | 3% | 72% | 24% | 1% | 31% | 1% | 1% |
| Alopecia | 51% | 7% | 0.5% | 56% | 14% | 0% | 30% | 2% | 0% |
| Ototoxicity | 10% | 1% | 1% | 14% | 1% | 0% | 1% | 0% | 0% |
| Local reactions | 17% | 2% | 0.5% | 7% | 0% | 0% | 22% | 2% | 0% |
| Diarrhea | 25% | 1.5% | 0% | 24% | 1% | 0% | 12% | 0% | 0.5% |
| Neurotoxicity¶ | 44% | 7% | 0% | 58% | 16% | 1% | 44% | 8% | 0.5% |
| *Grade based on criteria from the World Health Organization (WHO). | |||||||||
| † n = 194 to 207; all patients receiving NAVELBINE/cisplatin with laboratory and non-laboratory data. | |||||||||
| †n = 173 to 192; all patients receiving vindesine/cisplatin with laboratory and non-laboratory data. | |||||||||
| §n = 165 to 201; all patients receiving NAVELBINE with laboratory and non-laboratory data. | |||||||||
| †?Categorical toxicity grade not specified. | |||||||||
| ¶Neurotoxicity includes peripheral neuropathy and constipation. | |||||||||
Observed During Clinical Practice
In addition to the adverse events reported from clinical trials, the following events have been identified during post-approval use of NAVELBINE. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to NAVELBINE.
Body as a Whole: Systemic allergic reactions reported as anaphylaxis, pruritus, urticaria, and angioedema; flushing; and radiation recall events such as dermatitis and esophagitis (see PRECAUTIONS) have been reported.
Hematologic: Thromboembolic events, including pulmonary embolus and deep venous thrombosis, have been reported primarily in seriously ill and debilitated patients with known predisposing risk factors for these events.
Neurologic: Peripheral neurotoxicities such as, but not limited to, muscle weakness and disturbance of gait, have been observed in patients with and without prior symptoms. There may be increased potential for neurotoxicity in patients with pre-existing neuropathy, regardless of etiology, who receive NAVELBINE. Vestibular and auditory deficits have been observed with NAVELBINE, usually when used in combination with cisplatin.
Skin: Injection site reactions, including localized rash and urticaria, blister formation, and skin sloughing have been observed in clinical practice. Some of these reactions may be delayed in appearance.
Gastrointestinal: Dysphagia, mucositis, and pancreatitis have been reported.
Cardiovascular: Hypertension, hypotension, vasodilation, tachycardia, and pulmonary edema have been reported.
Pulmonary: Pneumonia has been reported.
Musculoskeletal: Headache has been reported, with and without other musculoskeletal aches and pains.
Other: Pain in tumor-containing tissue, back pain, and abdominal pain have been reported. Electrolyte abnormalities, including hyponatremia with or without the syndrome of inappropriate ADH secretion, have been reported in seriously ill and debilitated patients.
Combination Use: Patients with prior exposure to paclitaxel and who have demonstrated neuropathy should be monitored closely for new or worsening neuropathy. Patients who have experienced neuropathy with previous drug regimens should be monitored for symptoms of neuropathy while receiving NAVELBINE. NAVELBINE may result in radiosensitizing effects with prior or concomitant radiation therapy (see PRECAUTIONS).
DRUG INTERACTIONS
Acute pulmonary reactions have been reported with NAVELBINE and other anticancer vinca alkaloids used in conjunction with mitomycin. Although the pharmacokinetics of vinorelbine are not influenced by the concurrent administration of cisplatin, the incidence of granulocytopenia with NAVELBINE used in combination with cisplatin is significantly higher than with single-agent NAVELBINE. Patients who receive NAVELBINE and paclitaxel, either concomitantly or sequentially, should be monitored for signs and symptoms of neuropathy. Administration of NAVELBINE to patients with prior or concomitant radiation therapy may result in radiosensitizing effects.
Caution should be exercised in patients concurrently taking drugs known to inhibit drug metabolism by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily, or in patients with hepatic dysfunction. Concurrent administration of vinorelbine tartrate with an inhibitor of this metabolic pathway may cause an earlier onset and/or an increased severity of side effects.
Generic Name: Vinorelbine Tartrate
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