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adverse reactions
6 ADVERSE REACTIONS Most common adverse reactions (incidence ≥ 20%) are neutropenia, anemia, liver enzyme elevation, nausea, vomiting, asthenia, constipation, injection site reaction, and peripheral neuropathy ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following serious adverse reactions, which may include fatalities, are discussed in greater detail in other sections of the label: • Myelosuppression [ see Warnings and Precautions (5.1) ] • Pulmonary Toxicity and Respiratory Failure [ see Warnings and Precautions (5.6) ] • Constipation and Bowel Obstruction [ see Warnings and Precautions (5.3) ] • Extravasation Tissue Injury [ see Warnings and Precautions (5.4) ] • Neurologic Toxicity [ see Warnings and Precautions (5.5) ] • Hepatic Toxicity [ see Warnings and Precautions (5.2) ] 6.1 Clinical Trials Experience Because clinical trials are conducted under varying designs and in different patient populations, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice. Single Agent The data below reflect exposure to Vinorelbine Injection as a single agent administered at a dose of 30 mg/m 2 on a weekly basis to 365 patients enrolled in 3 controlled studies for metastatic NSCLC and advanced breast cancer. The population included 143 previously untreated metastatic NSCLC patients (Study 3) who received a median of 8 doses of Vinorelbine Injection. The patients were aged 32 to 79 (median 61 years), 71% were male, 91% Caucasian, 48% had adenocarcinoma histology. The data also reflect exposure to Vinorelbine Injection in 222 patients with previously treated advanced breast cancer who received a median of 10 doses of Vinorelbine Injection. Vinorelbine Injection is not indicated for the treatment of breast cancer. Selected adverse reactions reported in these studies are provided in Tables 1 and 2. The most common adverse reactions (≥ 20%) of single agent Vinorelbine Injection were leukopenia, neutropenia, anemia, Aspartate aminotransferase (AST) elevation, nausea, vomiting, constipation, asthenia, injection site reaction, and peripheral neuropathy. The most common (≥ 5%) Grade 3 or 4 adverse reactions were neutropenia, leukopenia, anemia, increased total bilirubin, AST elevation, injection site reaction and asthenia. Approximately 49% of NSCLC patients treated with Vinorelbine Injection experienced at least one dose reduction due to an adverse reaction. Thirteen percent of patients discontinued Vinorelbine Injection due to adverse reactions. The most frequent adverse reactions leading to Vinorelbine Injection discontinuation were asthenia, dyspnea, nausea, constipation, anorexia, myasthenia and fever. Table 1: Hematologic Adverse Reactions Experienced in > 5% of Patients Receiving Vinorelbine Injection*†: Laboratory All patients (n=365) NSCLC (n=143) Hematologic Neutropenia < 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% Anaemia < 11 g/dl 83% 77% < 8 g/dl 9% 1% Hospitalizations due to neutropenic complications 9% 8% * Grade based on modified criteria from the National Cancer Institute version 1. †Patients with NSCLC had not received prior chemotherapy. The majority of the remaining patients had received prior chemotherapy. Table 2: Non-hematologic Adverse Reactions Experienced in ≥ 5% of Patients Receiving Vinorelbine Injection*†: Laboratory All grades Grades 3+4 All Patients NSCLC All Patients NSCLC Hepatic AST increased (n=346) 67% 54% 6% 3% bilirubin increased (n=351) 13% 9% 7% 5% Clinical Nausea 44% 34% 2% 1% Asthenia 36% 27% 7% 5% Constipation 35% 29% 3% 2% Injection Site reaction 28% 38% 2% 5% Injection site pain 16% 13% 2% 1% Neuropathy Peripheral ‡ 25% 20% <2% 1% Vomiting 20% 15% 2% 1% Diarrhea 17% 13% 1% 1% Alopecia 12% 12% ≤1% 1% Phlebitis 7% 10% <1% 1% Dyspnea 7% 3% 3% 2% * Grade based on modified criteria from the National Cancer Institute version 1. ‡ Incidence of paresthesia plus hypesthesia. †Patients with NSCLC had not received prior chemotherapy. The majority of the remaining patients received prior chemotherapy. Myelosuppression : In clinical trials, Grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 69%, 9% and 1%, respectively of patients receiving single-agent Vinorelbine Injection. Neutropenia is the major dose-limiting toxicity. Neurotoxicity : Neurotoxicity was most commonly manifested as constipation, paresthesia, hypersthesia, and hyporeflexia. Grade 3 and 4 neuropathy was observed in 1% of the patients receiving single-agent Vinorelbine Injection. Injection sitereactions: Injection site reactions, including erythema, pain at injection site, and vein discoloration, occurred in approximately one third of patients; 5% were severe. Phlebitis (chemical phlebitis) along the vein proximal to the site of injection was reported in 10% of patients. Cardiovascular toxicity: Chest pain occurred in 5% of patients; myocardial infarction occurred in less than 0.1% of patients. Pulmonary Toxicity and Respiratory Failure: Dyspnea (shortness of breath) was reported in 3% of patients; it was severe in 2%. Interstitial pulmonary changes were documented. Other: Hemorrhagic cystitis and the syndrome of inappropriate ADH secretion were each reported in <1% of patients. In Combination with Cisplatin Table 3 presents the incidence of selected adverse reactions, occurring in ≥ 10% of Vinorelbine Injection treated patients reported in a randomized trial comparing the combination of Vinorelbine Injection 25 mg/m 2 administered every week of each 28-day cycle and cisplatin 100 mg/m 2 administered on day 1 of each 28-day cycle versus cisplatin alone at the same dose and schedule in patients with previously untreated NSCLC (Study 1). Patients randomized to Vinorelbine Injection plus cisplatin received a median of 3 cycles of treatment and those randomized to cisplatin alone received a median of 2 cycles of treatment. Thirty-Five percent of the eligible patients in the combination arm required treatment discontinuation due to an adverse reaction compared to 19% in the cisplatin alone arm. The incidence of Grade 3 and 4 neutropenia was significantly higher in the Vinorelbine Injection plus cisplatin arm (82%) compared to the cisplatin alone arm (5%). Four patients in the Vinorelbine Injection plus cisplatin arm died of neutropenic sepsis. Seven additional deaths were reported in the combination arm: 2 from cardiac ischemia, 1 cerebrovascular accident, 1 multisystem failure due to an overdose of Vinorelbine Injection, and 3 from febrile neutropenia. Table3:Adverse Reactions Experienced by ≥ 10% of Patients on Vinorelbine Injection plus Cisplatin versus Single-Agent Cisplatin* Laboratory Vinorelbine Injection 25mg/m² plus Cisplatin 100 mg/m² (n=212) Cisplatin 100mg/m² (n=210) All Grades Grades 3+4 All Grades Grades 3+4 Hematologic Neutropenia 89% 82% 26% 5% Anemia 89% 24% 72% <8% Leukopenia 88% 58% 31% <1% Thrombocytopenia 29% 5% 21% <2% Febrile neutropenia N/A* 11% N/A* 0% Renal Blood Creatinine increased 37% 4% 28% <5% Clinical Malaise/Fatigue/Lethargy 67% 12% 49% 8% Vomiting 60% 13% 60% 14% Nausea 58% 14% 57% 12% Decreased apetite 46% 0% 37% 0% Constipation 35% 3% 16% 1% Alopecia 34% 0% 14% 0% Weight decreased 34% 1% 21% <1% Fever without infection 20% 2% 4% 0% Hearing imparied 18% 4% 18% <4% Injection site reaction 17% <1% 1% 0% Diarrhea 17% <3% 11% <2% Paraesthesia 17% <1% 10% <1% Taste alterations 17% 0% 15% 0% Peripheral numbness 11% 2% 7% <1% Myalgia/Arthralgia 12% <1% 3% <1% Phelbitis/Thrombosis/Embolism 10% 3% <1% <1% Weakness 12% <3% 7% 2% Infection 11% <6% <1% <1% Respiratory tract infection 10% <5% 3% 3% * Graded according to the standard SWOG criteria version 1. *Categorical toxicity grade not specified Table 4 presents the incidence of selected adverse reactions, occurring in ≥ 10% of Vinorelbine Injection treated patients reported in a randomized trial of Vinorelbine Injection plus cisplatin, vindesine plus cisplatin and Vinorelbine Injection alone in patients with stage III or IV NSCLC who had not received prior chemotherapy. A total of 604 patients received either Vinorelbine Injection 30 mg/m 2 every week plus cisplatin 120 mg/m 2 on Day 1 and Day 29, then every 6 weeks thereafter (N=207), vindesine 3 mg/m 2 for 6 weeks, then every other week thereafter plus cisplatin 120 mg/m 2 on Days 1 and Day 29, then every 6 weeks thereafter (N=193) or Vinorelbine Injection 30 mg/m 2 every week (N=204). Patients randomized to Vinorelbine Injection plus cisplatin received a median of 15 weeks of treatment, vindesine plus cisplatin 12 weeks and Vinorelbine Injection received 13 weeks. Study discontinuation due to an adverse reaction was required in 27, 22 and 10% of the patients randomized to Vinorelbine Injection plus cisplatin, vindesine plus cisplatin and cisplatin alone arms, respectively. Grade 3 and 4 neutropenia was significantly greater in the Vinorelbine Injection plus cisplatin arm (78%) compared to vindesine plus cisplatin (48%) and Vinorelbine Injection alone (53%). Neurotoxicity, including peripheral neuropathy and constipation was reported in 44% (Grades 3‑4, 7%) of the patients receiving Vinorelbine Injection plus cisplatin, 58% (Grades 3-4, 17%) of the patients receiving vindesine and cisplatin and 44% (Grades 3-4, 8.5%) of the patients receiving Vinorelbine Injection alone. Table 4: Adverse Reactions Experienced by ≥ 10 % of Patients from a Comparative Trial of Vinorelbine Injection Plus Cisplatin versus Vindesine Plus Cisplatin versus Single-Agent Vinorelbine Injection* Laboratory Vinorelbine Injection/Cisplatin † Vindesine/Cisplatin ‡ Vinorelbine Injection § All Grades Grades 3+4 All Grades Grades 3+4 All Grades Grades 3+4 Hematologic Neutropenia 95% 78% 79% 48% 85% 53% Leukopenia 94% 57% 82% 27% 83% 32% Thrombocytopenia 15% 4% 10% 3.5% 3% 0% Renal Blood Creatinine increased ¦ 46% N/A 37% N/A 13% N/A Clinical Nausea/Vomiting 74% 30% 72% 25% 31% 2% Alopecia 51% 7.5% 56% 14% 30% 2% Neurotoxicity¶ 44% 7% 58% 17% 44% 8.5% Diarrhoea 25% 1.5% 24% 1% 12% 0.5% Injection Site Reaction 17% 2.5% 7% 0% 22% 2% Ototoxicity 10% 2% 14% 1% 1% 0% * Grade based on criteria from the World Health Organization (WHO). † n=194 to 207; all patients receiving Vinorelbine Injection /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 Vinorelbine Injection with laboratory and non laboratory data. ¦ Categorical toxicity grade not specified. ¶ Neurotoxicity includes peripheral neuropathy and constipation. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Vinorelbine Injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Infections and infestations: pneumonia Immune system disorders: anaphylactic reaction, pruritus, urticaria, angioedema Nervous system disorders: loss of deep tendon reflexes, muscular weakness, gait disturbance, headache Ear and labyrinth disorders: vestibular disorder, hearing impaired Cardiac disorders: tachycardia Respiratory disorders: pulmonary edema Vascular disorders: pulmonary embolism, deep vein thrombosis, hypertension, hypotension, flushing, vasodilatation Gastrointestinal disorders: mucosal inflammation, dysphagia, pancreatitis Skin disorders: generalized cutaneous reactions (rash) Musculoskeletal and connective tissue disorders: jaw pain, myalgia, arthralgia General disorders and administration site conditions: injection site rash, urticaria, blistering, sloughing of skin Injury, poisoning and procedural complications: radiation recall phenomenon, dermatitis, esophagitis Laboratory abnormalities: electrolyte imbalance including hyponatremia Other: tumor pain, back pain, abdominal pain