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adverse reactions
ADVERSE REACTIONS The pattern of adverse reactions is similar whether vinorelbine is used as a single agent or in combination. Adverse reactions from studies with single-agent and combination use of vinorelbine are summarized in Tables 2-4. Single-Agent Vinorelbine 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 vinorelbine as a single agent in 3 clinical studies. The dosing schedule in each study was 30 mg/m 2 vinorelbine on a weekly basis. Table 2: Summary of Adverse Events in 365 Patients Receiving Single-Agent VINORELBINE 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. : Adverse Event All Patients (n=365) NSCLC (n=143) Bone Marrow Granulocytopenia <2,000 cells/mm 3 90% 80% <500 cells/mm 3 36% 29% Leukopenia <4,000 cells/mm 3 92% 81% <1,000 cells/mm 3 15% 12% Thrombocytopenia <100,000 cells/mm 3 5% 4% <50,000 cells/mm 3 1% 1% Anemia <11 g/dL 83% 77% <8 g/dL 9% 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 Asthenia 36% 27% 7% 5% 0% 0% Injection Site Reactions 28% 38% 2% 5% 0% 0% Injection Site Pain 16% 13% 2% 1% 0% 0% Phlebitis 7% 10% <1% 1% 0% 0% Digestive Nausea 44% 34% 2% 1% 0% 0% Vomiting 20% 15% 2% 1% 0% 0% Constipation 35% 29% 3% 2% 0% 0% Diarrhea 17% 13% 1% 1% 0% 0% Peripheral Neuropathy Incidence of paresthesia plus hypesthesia 25% 20% 1% 1% <1% 0% Dyspnea 7% 3% 2% 2% 1% 0% Alopecia 12% 12% ≤1% 1% 0% 0% Hematologic Granulocytopenia is the major dose-limiting toxicity with vinorelbine. 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 vinorelbine. 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 vinorelbine. 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. Skin Like other anticancer vinca alkaloids, vinorelbine 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. Gastrointestinal Prophylactic administration of antiemetics was not routine in patients treated with single-agent vinorelbine. Due to the low incidence of severe nausea and vomiting with single-agent vinorelbine, the use of serotonin antagonists is generally not required. Hepatic Transient elevations of liver enzymes were reported without clinical symptoms. Cardiovascular 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. Pulmonary 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. Vinorelbine in Combination with Cisplatin Vinorelbine 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 vinorelbine 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/mm 3 ) 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 per day and continued until the total granulocyte count was >1,000 cells/mm 3 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 vinorelbine 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 vinorelbine 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 vinorelbine, and 3 from febrile neutropenia. One death, secondary to respiratory infection unrelated to granulocytopenia, occurred with single-agent cisplatin. Vinorelbine plus Cisplatin versus Vindesine plus Cisplatin versus Single-Agent Vinorelbine (Table 4) Myelosuppression, specifically Grade 3 and 4 granulocytopenia, was significantly greater with the combination of vinorelbine plus cisplatin (79%) than with either single-agent vinorelbine (53%) or vindesine plus cisplatin (48%), P<0.0001. Hospitalization due to documented sepsis occurred in 4.4% of patients treated with vinorelbine plus cisplatin; 2% of patients treated with vindesine and cisplatin, and 4% of patients treated with single-agent vinorelbine. Grade 3 and 4 thrombocytopenia was infrequent in patients receiving combination chemotherapy and no events were reported with single-agent vinorelbine. 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 vinorelbine. Severe local reactions occurred in 2% of patients treated with combinations containing vinorelbine; 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 vinorelbine plus cisplatin (7%) and single-agent vinorelbine (9%) (P < 0.005). Cisplatin did not appear to increase the incidence of neurotoxicity observed with single-agent vinorelbine. Table 3: Selected Adverse Events From a Comparative Trial of VINORELBINE plus Cisplatin versus Single-Agent Cisplatin Graded according to the standard SWOG criteria VINORELBINE 25mg/m 2 plus Cisplatin 100mg/m 2 (n=212) Cisplatin 100mg/m 2 (n=210) Adverse Event All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Bone Marrow 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% Anorexia 46% 0% 0% 37% 0% 0% Constipation 35% 3% 0% 16% 1% 0% Alopecia 34% 0% 0% 14% 0% 0% Weight loss 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% Table 4: Selected Adverse Events From a Comparative Trial of VINORELBINE plus Cisplatin versus Vindesine plus Cisplatin versus Single-Agent VINORELBINE Grade based on criteria from the World Health Organization (WHO). VINORELBINE /Cisplatin n=194 to 207;all patients receiving VINORELBINE/cisplatin with laboratory and non-laboratory data. Vindesine/Cisplatin n=173 to 192;all patients receiving vindesine/cisplatin with laboratory and non-laboratory data. VINORELBINE n=165 to 201;all patients receiving VINORELBINE with laboratory and non-laboratory data. Adverse Event 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 Categorical toxicity grade not specified. 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 Neurotoxicity includes peripheral neuropathy and constipation. 44% 7% 0% 58% 16% 1% 44% 8% 0.5% 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 vinorelbine. 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 vinorelbine. 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 vinorelbine. Vestibular and auditory deficits have been observed with vinorelbine, 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 vinorelbine. Vinorelbine may result in radiosensitizing effects with prior or concomitant radiation therapy (see PRECAUTIONS ).