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adverse reactions
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Myelosuppression [see Warnings and Precautions (5.1 ) ] Hepatic Toxicity [see Warning and Precautions (5.2) ] Severe Constipation and Bowel Obstruction [see Warnings and Precautions (5.3) ] Extravasation Tissue Injury [see Wa rnings and Precautions (5.4 ) ] Neurologic Toxicity [see Warnings and Precautions (5.5) ] Pulmonary Toxicity and Respiratory Failure [see Warnings and Precautions (5.6) ) ] Most common adverse reactions (incidence ≥ 20%) are leukopenia, neutropenia, anemia, increased aspartate aminotransferase, nausea, vomiting, constipation, asthenia, injection site reaction, and peripheral neuropathy ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pierre Fabre Pharmaceuticals at 1- 855-PFPHARM (1-855-737-4276) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 NAVELBINE as a single agent administered at a dose of 30 mg/m2 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 NAVELBINE. The patients were aged 32 to 79 (median 61 years), 71% were male, 91% White, 48% had adenocarcinoma histology. The data also reflect exposure to NAVELBINE in 222 patients with previously treated advanced breast cancer who received a median of 10 doses of NAVELBINE. NAVELBINE 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 NAVELBINE 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 NAVELBINE experienced at least one dose reduction due to an adverse reaction. Thirteen percent of patients discontinued NAVELBINE due to adverse reactions. The most frequent adverse reactions leading to NAVELBINE discontinuation were asthenia, dyspnea, nausea, constipation, anorexia, myasthenia and fever. Table 1: Hematologic Adverse Reactions Experienced in > 5% of Patients Receiving NAVELBINE*†: All patients (n=365) (%) NSCLC (n= 143) (%) Laboratory 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 Anemia < 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 NAVELBINE*†: All grades Grades 3+4 All Patients (%) NSCLC (%) All Patients (%) NSCLC (%) Laboratory 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. †Patients with NSCLC had not received prior chemotherapy. The majority of the remaining patients had received prior chemotherapy. ‡ Incidence of paresthesia plus hypesthesia. Myelosuppression: In clinical trials, Grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 69%, 9% and 1%, respectively of patients receiving single-agent NAVELBINE. 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 NAVELBINE. Injection site reactions: 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 NAVELBINE treated patients reported in a randomized trial comparing the combination of NAVELBINE 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 NAVELBINE 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 NAVELBINE plus cisplatin arm (82%) compared to the cisplatin alone arm (5%). Four patients in the NAVELBINE 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 NAVELBINE, and 3 from febrile neutropenia. Table 3: Adverse Reactions Experienced by > 10% of Patients on NAVELBINE plus Cisplatin versus Single-Agent Cisplatin* NAVELBINE 25mg/m 2 plus Cisplatin 100mg/m 2 Cisplatin 100 mg/m 2 (N=212) (n=210) All Grades (%) Grades 3+4 (%) All Grades (%) Grades 3+4 (%) Laboratory 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 impaired 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 Phlebitis/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 NAVELBINE treated patients reported in a randomized trial of NAVELBINE plus cisplatin, vindesine plus cisplatin and NAVELBINE as a single agent in patients with stage III or IV NSCLC who had not received prior chemotherapy. A total of 604 patients received either NAVELBINE 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 NAVELBINE 30mg/m 2 every week (N=204). Patients randomized to NAVELBINE plus cisplatin received a median of 15 weeks of treatment, vindesine plus cisplatin 12 weeks and NAVELBINE received 13 weeks. Grade 3 and 4 neutropenia was significantly greater in the NAVELBINE plus cisplatin arm (78%) compared to vindesine plus cisplatin (48%) and NAVELBINE as a single agent (53%). Neurotoxicity, including peripheral neuropathy and constipation, was reported in 44% (Grade 3-4, 7%) of the patients receiving NAVELBINE plus cisplatin, 58% (Grade 3-4, 17%) of the patients receiving vindesine and cisplatin and 44% (Grade 3-4, 8.5%) of the patients receiving NAVELBINE as a single agent. Study discontinuation due to an adverse reaction was required in 27, 22 and 10% of the patients randomized to NAVELBINE plus cisplatin, vindesine plus cisplatin and cisplatin alone arms, respectively. Table 4: Adverse Reactions Experienced by > 10 % of Patients from a Comparative Trial of NAVELBINE Plus Cisplatin versus Vindesine Plus Cisplatin versus Single Agent NAVELBINE* NAVELBINE /Cisplatin† Vindesine/Cisplatin† NAVELBINE § All Grades (%) Grades 3+4 (%) All Grades (%) Grades 3+4 (%) All Grades (%) Grades 3+4 (%) Laboratory 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 Diarrhea 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 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of NAVELBINE. 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), palmar-plantar erythrodysesthesia syndrome 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