Alemtuzumab

CAMPATH is indicated as a single agent for the treatment of B-cell chronic lymphocytic leukemia (B-CLL). CAMPATH is a CD52-directed cytolytic antibody indicated as a single agent for the treatment of B-cell chronic lymphocytic leukemia (B-CLL). ( 1 )

Injection: 30 mg/1 mL as a clear, colorless solution in single-dose vial Injection: 30 mg/1 mL single-dose vial ( 3 )

None. None ( 4 )

Cytopenias : Obtain complete blood counts (CBC) and platelet counts at weekly intervals during therapy and CD4 counts after therapy until recovery to ≥200 cells/µL. Withhold for severe cytopenias. Discontinue for autoimmune or severe hematologic adverse reactions. ( 2.2 , 5.1 ) Immunosuppression/Infections : CAMPATH induces severe and prolonged lymphopenia and increases risk of infection. If a serious infection occurs, withhold treatment until infection resolves. ( 5.3 ) Immunization : Do not administer live viral vaccines to patients who have recently received CAMPATH. ( 5.4 )

5.1 Cytopenias Severe, including fatal, autoimmune anemia and thrombocytopenia, and prolonged myelosuppression have been reported in patients receiving CAMPATH. In addition, hemolytic anemia, pure red cell aplasia, bone marrow aplasia, and hypoplasia have been reported after treatment with CAMPATH at the recommended dose. Single doses of CAMPATH greater than 30 mg or cumulative doses greater than 90 mg per week increase the incidence of pancytopenia. Withhold CAMPATH for severe cytopenias (except lymphopenia). Discontinue for autoimmune cytopenias or recurrent/persistent severe cytopenias (except lymphopenia) [see Dosage and Administration (2.3) ] . No data exist on the safety of CAMPATH resumption in patients with autoimmune cytopenias or marrow aplasia [see Adverse Reactions (6.1) ] . Obtain complete blood counts (CBC) at weekly intervals during CAMPATH therapy and more frequently if worsening anemia, neutropenia, or thrombocytopenia occurs. Assess CD4+ counts after treatment until recovery to ≥200 cells/µL [see Dosage and Administration (2.3) and Adverse Reactions (6) ] .

5.2 Infusion-Related Reactions Adverse reactions occurring during or shortly after CAMPATH infusion include pyrexia, chills/rigors, nausea, hypotension, urticaria, dyspnea, rash, emesis, and bronchospasm [see Adverse Reactions (6.1) ] . In clinical trials, the frequency of infusion-related reactions was highest in the first week of treatment. Monitor for the signs and symptoms listed above and withhold infusion for Grade 3 or 4 infusion-related reactions. The following serious, including fatal, infusion-related reactions have been identified in postmarketing reports: syncope, pulmonary infiltrates, acute respiratory distress syndrome (ARDS), respiratory arrest, cardiac arrhythmias, myocardial infarction, acute cardiac insufficiency, cardiac arrest, angioedema, and anaphylactoid shock. Initiate CAMPATH according to the recommended dose-escalation scheme [see Dosage and Administration (2.1) ] . Premedicate patients with an antihistamine and acetaminophen prior to each dose. Institute appropriate medical management (e.g., glucocorticoids, epinephrine, meperidine) for infusion-related reactions as needed [see Dosage and Administration (2.2) ] . If therapy is interrupted for 7 or more days, reinstitute CAMPATH with gradual dose escalation [see Dosage and Administration (2.1) ].

5.3 Immunosuppression/Infections CAMPATH treatment results in severe and prolonged lymphopenia with a concomitant increased incidence of opportunistic infections [see Adverse Reactions (6.1) ] . Administer PCP and herpes viral prophylaxis during treatment with CAMPATH and for a minimum of 2 months after completion of CAMPATH or until the CD4+ count is ≥200 cells/µL, whichever occurs later [see Dosage and Administration (2.2) ] . Prophylaxis does not eliminate these infections. Routinely monitor patients for CMV infection during treatment with CAMPATH and for at least 2 months following completion of CAMPATH. Withhold CAMPATH for serious infections and during antiviral treatment for CMV infection or confirmed CMV viremia (defined as polymerase chain reaction [PCR] positive CMV in ≥2 consecutive samples obtained 1 week apart). Initiate therapeutic ganciclovir (or equivalent) for CMV infection or confirmed CMV viremia. Epstein-Barr virus (EBV) infection, including severe and fatal EBV-associated hepatitis, has been reported in patients who received CAMPATH. Monitor for sign and symptoms of EBV infections. Withhold CAMPATH for EBV reactivation or severe infection. Administer only irradiated blood products to avoid transfusion associated Graft versus Host Disease (TAGVHD), unless emergent circumstances dictate immediate transfusion. In patients who received CAMPATH as initial therapy, recovery of CD4+ counts to ≥200 cells/µL occurred by 6 months following completion of CAMPATH; however, at 2 months post treatment, the median was 183 cells/µL. In previously treated patients who received CAMPATH, the median time to recovery of CD4+ counts to ≥200 cells/µL was 2 months; however, full recovery (to baseline) of CD4+ and CD8+ counts may take more than 12 months [see Adverse Reactions (6) ] .

5.4 Immunization The safety of immunization with live viral vaccines following CAMPATH therapy has not been studied. Do not administer live viral vaccines to patients or infants born to patients receiving CAMPATH. The ability to generate an immune response to any vaccine following CAMPATH therapy has not been studied.

The following clinically significant adverse reactions are discussed in greater detail in other sections of the label: Cytopenias [see Warnings and Precautions (5.1) ] Infusion-Related Reactions [see Warnings and Precautions (5.2) ] Immunosuppression/Infections [see Warnings and Precautions (5.3) ] Most common adverse reactions (≥10%): cytopenias, infusion-related 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. The most common adverse reactions with CAMPATH are: infusion-related 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-related reactions, and immunosuppression/infections. 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-Related Reactions Infusion-related 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-related 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 Selected Adverse 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 Grades NCI 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 viremia CMV 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. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. […]

No formal drug interaction studies have been performed with CAMPATH.

Pregnancy : May cause fetal harm. ( 8.1 ) Lactation : Advise not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Based on findings from animal studies, CAMPATH may cause fetal harm when administered to a pregnant woman. Available data from published cohort studies in pregnant women are insufficient to establish a CAMPATH-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Alemtuzumab was embryolethal in pregnant huCD52 transgenic mice when administered during organogenesis (see Data ) . Human IgG antibodies are known to cross the placental barrier; therefore, CAMPATH may be transmitted from the mother to the developing fetus. Advise women of the potential risk to the fetus. Infants born to pregnant women treated with CAMPATH may be at increased risk of infection (see Clinical Considerations ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal adverse reactions Monoclonal antibodies are transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Consider the risks and benefits of administering live or live-attenuated vaccines to infants exposed to CAMPATH in utero [see Warnings and Precautions (5.3 , 5.4) ] . Data Animal data When alemtuzumab was administered to pregnant huCD52 transgenic mice during organogenesis (gestation days [GD] 6–10 or GD 11–15) at intravenous doses of 3 or 10 mg/kg, no teratogenic effects were observed. However, there was an increase in embryolethality (increased postimplantation loss and the number of dams with all fetuses dead or resorbed) in pregnant animals dosed during GD 11–15. In a separate study in pregnant huCD52 transgenic mice, administration of alemtuzumab during organogenesis (GD 6–10 or GD 11–15) at intravenous doses of 3 or 10 mg/kg, decreases in B-lymphocyte and T-lymphocyte populations were observed in the offspring at both doses tested. In pregnant huCD52 transgenic mice administered alemtuzumab at intravenous doses of 3 or 10 mg/kg/day throughout gestation and lactation, there was an increase in pup deaths during the lactation period at 10 mg/kg. Decreases in T-lymphocyte and B-lymphocyte populations and in antibody response were observed in offspring at both doses tested.

8.2 Lactation Risk Summary There are no data on the presence of alemtuzumab in human milk, effects on milk production, or the breastfed child. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to alemtuzumab are unknown. Alemtuzumab was detected in the milk of lactating huCD52 transgenic mice administered alemtuzumab (see Data ) . Maternal IgG is known to be present in human milk and when a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential for serious adverse reactions from CAMPATH in a breastfed child, including reduced lymphocyte counts, advise lactating women not to breastfeed during treatment with CAMPATH and for at least 3 months following the last dose. Data Alemtuzumab was detected in the milk of lactating huCD52 transgenic mice following intravenous administration of alemtuzumab at a dose of 10 mg/kg on postpartum days 8–12. Serum levels of alemtuzumab were similar in lactating mice and offspring on postpartum day 13 and were associated with evidence of pharmacological activity (decrease in lymphocyte counts) in the offspring.

8.3 Females and Males of Reproductive Potential CAMPATH may cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1) ] . Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential prior to initiating CAMPATH therapy. Contraception Females Advise female patients of reproductive potential to use effective contraception during treatment with CAMPATH and for at least 3 months after the last dose. Infertility Based on findings from animal studies, alemtuzumab may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1) ]. The reversibility of the effect on fertility is unknown.

8.4 Pediatric Use Safety and effectiveness of CAMPATH have not been established in pediatric patients.

8.5 Geriatric Use Of 147 previously untreated B-CLL patients treated with CAMPATH, 35% were ≥ age 65 and 4% were ≥ age 75. Of 149 previously treated patients with B-CLL, 44% were ≥65 years of age and 10% were ≥75 years of age. Clinical studies of CAMPATH did not include sufficient number of subjects age 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

CAMPATH binds to CD52, an antigen present on the surface of B and T lymphocytes, a majority of monocytes, macrophages, NK cells, and a subpopulation of granulocytes. A proportion of bone marrow cells, including some CD34+ cells, express variable levels of CD52. The proposed mechanism of action is antibody-dependent cellular-mediated lysis following cell surface binding of CAMPATH to the leukemic cells.