6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Cytopenias [see Warnings and Precautions (5.1)] Infusion Reactions [see Warnings and Precautions (5.2)] Immunosuppression/Infections [see Warnings and Precautions (5.3)] The most common adverse reactions with CAMPATH are: infusion reactions (pyrexia, chills, hypotension, urticaria, nausea, rash, tachycardia, dyspnea), cytopenias (neutropenia, lymphopenia, thrombocytopenia, anemia), infections (CMV viremia, CMV infection, other infections), gastrointestinal symptoms (nausea, emesis, abdominal pain), and neurological symptoms (insomnia, anxiety). The most common serious adverse reactions are cytopenias, infusion reactions, and immunosuppression/infections. Most common adverse reactions (≥10%): cytopenias, infusion reactions, cytomegalovirus (CMV) and other infections, nausea, emesis, diarrhea, and insomnia. (6) To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation at 1-877-4-CAMPATH (1-877-422-6728) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to CAMPATH in 296 patients with CLL of whom 147 were previously untreated and 149 received at least 2 prior chemotherapy regimens. The median duration of exposure was 11.7 weeks for previously untreated patients and 8 weeks for previously treated patients. Lymphopenia Severe lymphopenia and a rapid and sustained decrease in lymphocyte subsets occurred in previously untreated and previously treated patients following administration of CAMPATH. In previously untreated patients, the median CD4+ was 0 cells/μL at one month after treatment and 238 cells/μL [25%–75% interquartile range 115 to 418 cells/μL at 6 months post treatment [see Warnings and Precautions (5.3)]. Neutropenia In previously untreated patients, the incidence of Grade 3 or 4 neutropenia was 42% with a median time to onset of 31 days and a median duration of 37 days. In previously treated patients, the incidence of Grade 3 or 4 neutropenia was 64% with a median duration of 28 days. Ten percent of previously untreated patients and 17% of previously treated patients received granulocyte colony stimulating factors. Anemia In previously untreated patients, the incidence of Grade 3 or 4 anemia was 12% with a median time to onset of 31 days and a median duration of 8 days. In previously treated patients, the incidence of Grade 3 or 4 anemia was 38%. Seventeen percent of previously untreated patients and 66% of previously treated patients received either erythropoiesis stimulating agents, transfusions or both. Thrombocytopenia In previously untreated patients, the incidence of Grade 3 or 4 thrombocytopenia was 14% with a median time to onset of 9 days and a median duration of 14 days. In previously treated patients, the incidence of Grade 3 or 4 thrombocytopenia was 52% with a median duration of 21 days. Autoimmune thrombocytopenia was reported in 2% of previously treated patients with one fatality. Infusion Reactions Infusion reactions, which included pyrexia, chills, hypotension, urticaria, and dyspnea, were common. Grade 3 and 4 pyrexia and/or chills occurred in approximately 10% of previously untreated patients and in approximately 35% of previously treated patients. The occurrence of infusion reactions was greatest during the initial week of treatment and decreased with subsequent doses of CAMPATH. All patients were pretreated with antipyretics and antihistamines; additionally, 43% of previously untreated patients received glucocorticoid pre-treatment. Infections In the study of previously untreated patients, patients were tested weekly for CMV using a PCR assay from initiation through completion of therapy, and every 2 weeks for the first 2 months following therapy. CMV infection occurred in 16% (23/147) of previously untreated patients; approximately one-third of these infections were serious or life threatening. In studies of previously treated patients in which routine CMV surveillance was not required, CMV infection was documented in 6% (9/149) of patients; nearly all of these infections were serious or life threatening. Other infections were reported in approximately 50% of patients across all studies. Grade 3 to 5 sepsis ranged from 3% to 10% across studies and was higher in previously treated patients. Grade 3 to 4 febrile neutropenia ranged from 5% to 10% across studies and was higher in previously treated patients. Infection-related fatalities occurred in 2% of previously untreated patients and 16% of previously treated patients. There were 198 episodes of other infection in 109 previously untreated patients; 16% were bacterial, 7% were fungal, 4% were other viral, and in 73% the organism was not identified. Cardiac Cardiac dysrhythmias occurred in approximately 14% of previously untreated patients. The majority were tachycardias and were temporally associated with infusion; dysrhythmias were Grade 3 or 4 in 1% of patients. Previously Untreated Patients Table 1 contains selected adverse reactions observed in 294 patients randomized (1:1) to receive CAMPATH or chlorambucil as first line therapy for B-CLL. CAMPATH was administered at a dose of 30 mg intravenously three times weekly for up to 12 weeks. The median duration of therapy was 11.7 weeks with a median weekly dose of 82 mg (25–75% interquartile range: 69–90 mg). Table 1: Per Patient Incidence of SelectedAdverse reactions occurring at a higher relative frequency in the CAMPATH arm Adverse Reactions in Treatment Naive B-CLL Patients CAMPATH (n=147) Chlorambucil (n=147) All GradesNCI CTC version 2.0 for adverse reactions; NCI CTCAE version 3.0 for laboratory values % Grades 3–4 % All Grades % Grades 3–4 % Blood and Lymphatic System Disorders Lymphopenia 97 97 9 1 Neutropenia 77 42 51 26 Anemia 76 13 54 18 Thrombocytopenia 71 13 70 14 General Disorders and Administration Site Conditions Pyrexia 69 10 11 1 Chills 53 3 1 0 Infections and Infestations CMV viremiaCMV viremia (without evidence of symptoms) includes both cases of single PCR positive test results and of confirmed CMV viremia (≥2 occasions in consecutive samples 1 week apart). For the latter, ganciclovir (or equivalent) was initiated per protocol. 55 4 8 0 CMV infection 16 5 0 0 Other infections 74 21 65 10 Skin and Subcutaneous Tissue Disorders Urticaria 16 2 1 0 Rash 13 1 4 0 Erythema 4 0 1 0 Vascular Disorders Hypotension 16 1 0 0 Hypertension 14 5 2 1 Nervous System Disorders Headache 14 1 8 0 Tremor 3 0 1 0 Respiratory, Thoracic and Mediastinal Disorders Dyspnea 14 4 7 3 Gastrointestinal Disorders Diarrhea 10 1 4 0 Psychiatric Disorders Insomnia 10 0 3 0 Anxiety 8 0 1 0 Cardiac Disorders Tachycardia 10 0 1 0 Previously Treated Patients Additional safety information was obtained from 3 single arm studies of 149 previously treated patients with CLL administered 30 mg CAMPATH intravenously three times weekly for 4 to 12 weeks (median cumulative dose 673 mg [range 2–1106 mg]; median duration of therapy 8.0 weeks). Adverse reactions in these studies not listed in Table 1 that occurred at an incidence rate of >5% were fatigue, nausea, emesis, musculoskeletal pain, anorexia, dysesthesia, mucositis, and bronchospasm. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Using an ELISA assay, anti-human antibodies (HAHA) were detected in 11 of 133 (8.3%) previously untreated patients. In addition, two patients were weakly positive for neutralizing activity. Limited data suggest that the anti-CAMPATH antibodies did not adversely affect tumor response. Four of 211 (1.9%) previously treated patients were found to have antibodies to CAMPATH following treatment. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to CAMPATH with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post approval use of alemtuzumab. 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. Fatal infusion reactions Cardiovascular: congestive heart failure, cardiomyopathy, decreased ejection fraction (some patients had been previously treated with cardiotoxic agents). Gastrointestinal: Acute acalculous cholecystitis Immune disorders: Goodpasture's syndrome, Graves' disease, aplastic anemia, Guillain Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, serum sickness, fatal transfusion associated graft versus host disease. Infections: Epstein-Barr virus (EBV) including EBV-associated lymphoproliferative disorder, progressive multifocal leukoencephalopathy (PML), reactivation of latent viruses. Metabolic: tumor lysis syndrome. Neurologic: optic neuropathy.