ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. 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)] 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.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 prior chemotherapy regimens. The median duration of exposure was 11.7 weeks for previously untreated patients and 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.. LymphopeniaSevere lymphopenia and 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 cells/uL at one month after treatment and 238 cells/uL [25%-75% interquartile range 115 to 418 cells/uL at months post treatment [see Warnings and Precautions (5.3)].. NeutropeniaIn previously untreated patients, the incidence of Grade or neutropenia was 42% with median time to onset of 31 days and median duration of 37 days. In previously treated patients, the incidence of Grade or neutropenia was 64% with median duration of 28 days. Ten percent of previously untreated patients and 17% of previously treated patients received granulocyte colony stimulating factors.. AnemiaIn previously untreated patients, the incidence of Grade or anemia was 12% with median time to onset of 31 days and median duration of days. In previously treated patients, the incidence of Grade or anemia was 38%. Seventeen percent of previously untreated patients and 66% of previously treated patients received either erythropoiesis stimulating agents, transfusions or both.. ThrombocytopeniaIn previously untreated patients, the incidence of Grade or thrombocytopenia was 14% with median time to onset of days and median duration of 14 days. In previously treated patients, the incidence of Grade or thrombocytopenia was 52% with median duration of 21 days. Autoimmune thrombocytopenia was reported in 2% of previously treated patients with one fatality.. Infusion-Related ReactionsInfusion-related reactions, which included pyrexia, chills, hypotension, urticaria, and dyspnea, were common. Grade and 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.. InfectionsIn the study of previously untreated patients, patients were tested weekly for CMV using PCR assay from initiation through completion of therapy, and every weeks for the first 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 to sepsis ranged from 3% to 10% across studies and was higher in previously treated patients. Grade to 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.. CardiacCardiac dysrhythmias occurred in approximately 14% of previously untreated patients. The majority were tachycardias and were temporally associated with infusion; dysrhythmias were Grade or in 1% of patients.. Previously Untreated PatientsTable 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 dose of 30 mg intravenously three times weekly for up to 12 weeks. The median duration of therapy was 11.7 weeks with median weekly dose of 82 mg (25%-75% interquartile range: 69-90 mg).Table 1: Per Patient Incidence of SelectedAdverse reactions occurring at higher relative frequency in the CAMPATH arm Adverse Reactions in Treatment Naive B-CLL PatientsCAMPATH (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 DisordersLymphopenia979791Neutropenia77425126Anemia76135418Thrombocytopenia71137014General Disorders and Administration Site ConditionsPyrexia6910111Chills53310Infections and InfestationsCMV 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 week apart). For the latter, ganciclovir (or equivalent) was initiated per protocol. 55480CMV infection16500Other infections74216510Skin and Subcutaneous Tissue DisordersUrticaria16210Rash13140Erythema4010Vascular DisordersHypotension16100Hypertension14521Nervous System DisordersHeadache14180Tremor3010Respiratory, Thoracic and Mediastinal DisordersDyspnea14473Gastrointestinal DisordersDiarrhea10140Psychiatric DisordersInsomnia10030Anxiety8010Cardiac DisordersTachycardia10010. Previously Treated PatientsAdditional safety information was obtained from single arm studies of 149 previously treated patients with CLL administered 30 mg CAMPATH intravenously three times weekly for 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 that occurred at an incidence rate of >5% were fatigue, nausea, emesis, musculoskeletal pain, anorexia, dysesthesia, mucositis, and bronchospasm.. 6.2Immunogenicity. 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. 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 with the incidence of antibodies to other alemtuzumab products may be misleading.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.. 6.3Postmarketing Experience. CAMPATHThe following adverse reactions have been identified during postapproval use of CAMPATH. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.General Disorders and Administration Site Conditions: Fatal infusion-related reactions.Cardiovascular Disorders: Congestive heart failure, cardiomyopathy, decreased ejection fraction (some patients had been previously treated with cardiotoxic agents).Cerebrovascular Disorders: Cervicocephalic arterial dissection, stroke, including hemorrhagic and ischemic stroke.Gastrointestinal Disorders: Acute acalculous cholecystitis.Immune System Disorders: Goodpastures syndrome, Graves disease, aplastic anemia, Guillain Barre syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, serum sickness, fatal transfusion associated graft versus host disease, hemophagocytic lymphohistiocytosis (HLH).Infections: Epstein-Barr virus (EBV) infection, progressive multifocal leukoencephalopathy (PML), reactivation of latent viruses.Metabolism and Nutrition Disorders: Tumor lysis syndrome.Neoplasms: EBV-associated lymphoproliferative disorder.Nervous System Disorders: Optic neuropathy.Renal and Urinary Disorders: Glomerular nephropathies.. Other Alemtuzumab ProductsThe following adverse reactions have been identified during postapproval use of another alemtuzumab product. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Endocrine Disorders: Hypothyroidism, hyperthyroidism, and thyroiditis.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Cardiac ElectrophysiologyThe effect of multiple doses of alemtuzumab (12 mg/day for days) on the QTc interval was evaluated in single-arm study in 53 patients without malignancy. No large changes in the mean QTc interval (i.e., >20 ms) were detected in the study. mean increase in heart rate of 22 to 26 beats/min was observed for at least hours following the initial infusion of alemtuzumab. This increase in heart rate was not observed with subsequent doses.

BOXED WARNING SECTION.

WARNING: CYTOPENIAS, INFUSION-RELATED REACTIONS, AND INFECTIONS. WARNING: CYTOPENIAS, INFUSION-RELATED REACTIONS, AND INFECTIONSSee full prescribing information for complete boxed warning.Serious, including fatal, cytopenias, infusion-related reactions, and infections can occur (5.1-5.3).Limit doses to 30 mg (single) and 90 mg (cumulative weekly); higher doses increase risk of pancytopenia. (2.1)Escalate dose gradually and monitor patients during infusion. Withhold therapy for Grade or infusion-related reactions. (5.2)Administer prophylaxis against Pneumocystis jirovecii pneumonia (PCP) and herpes virus infections. (2.2, 5.3). Limit doses to 30 mg (single) and 90 mg (cumulative weekly); higher doses increase risk of pancytopenia. (2.1). Escalate dose gradually and monitor patients during infusion. Withhold therapy for Grade or infusion-related reactions. (5.2). Administer prophylaxis against Pneumocystis jirovecii pneumonia (PCP) and herpes virus infections. (2.2, 5.3). Cytopenias: Serious, including fatal, pancytopenia/marrow hypoplasia, autoimmune idiopathic thrombocytopenia, and autoimmune hemolytic anemia can occur in patients receiving CAMPATH. Single doses of CAMPATH greater than 30 mg or cumulative doses greater than 90 mg per week increase the incidence of pancytopenia [see Warnings and Precautions (5.1)].. Infusion-Related Reactions: CAMPATH administration can result in serious, including fatal, infusion-related reactions. Carefully monitor patients during infusions and withhold CAMPATH for Grade or infusion-related reactions. Gradually escalate CAMPATH to the recommended dose at the initiation of therapy and after interruption of therapy for or more days [see Dosage and Administration (2.1) and Warnings and Precautions (5.2)].. Immunosuppression/Infections: Serious, including fatal, bacterial, viral, fungal, and protozoan infections can occur in patients receiving CAMPATH. Administer prophylaxis against Pneumocystis jirovecii pneumonia (PCP) and herpes virus infections [see Dosage and Administration (2.2) and Warnings and Precautions (5.3)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Studies to assess the carcinogenic or genotoxic potential of CAMPATH have not been conducted.In fertility studies, alemtuzumab (3 or 10 mg/kg intravenously) was administered to huCD52 transgenic male mice on consecutive days prior to cohabitation with untreated wild-type females. No effect on fertility or reproductive performance was observed. However, adverse effects on sperm parameters (including abnormal morphology [detached/no head] and reduced total count and motility) were observed at both doses tested.When alemtuzumab (3 or 10 mg/kg intravenously) was administered to huCD52 transgenic female mice for consecutive days prior to cohabitation with untreated wild-type males, there was decrease in the average number of corpora lutea and implantation sites and an increase in postimplantation loss, resulting in fewer viable embryos at the higher dose tested.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. CAMPATH binds to CD52, an antigen present on the surface of and lymphocytes, majority of monocytes, macrophages, NK cells, and subpopulation of granulocytes. 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.. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyThe effect of multiple doses of alemtuzumab (12 mg/day for days) on the QTc interval was evaluated in single-arm study in 53 patients without malignancy. No large changes in the mean QTc interval (i.e., >20 ms) were detected in the study. mean increase in heart rate of 22 to 26 beats/min was observed for at least hours following the initial infusion of alemtuzumab. This increase in heart rate was not observed with subsequent doses.. 12.3 Pharmacokinetics. CAMPATH pharmacokinetics were characterized in study of 30 previously treated B-CLL patients in whom CAMPATH was administered at the recommended dose and schedule. After 12 weeks of dosing, patients exhibited 7-fold increase in mean AUC.. DistributionAfter the last 30 mg dose, the mean volume of distribution at steady-state was 0.18 L/kg (range 0.1 to 0.4 L/kg).. EliminationCAMPATH pharmacokinetics displayed nonlinear elimination kinetics. Systemic clearance decreased with repeated administration due to decreased receptor-mediated clearance (i.e., loss of CD52 receptors in the periphery). Mean half-life was 11 hours (range to 32 hours) after the first 30 mg dose and was days (range to 14 days) after the last 30 mg dose.. Specific PopulationsThe effects of renal or hepatic impairment on the pharmacokinetics of CAMPATH have not been studied.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Previously Untreated B-CLL Patients. CAMPATH was evaluated in an open-label, randomized (1:1) active-controlled study in previously untreated patients with B-CLL, Rai Stage I-IV, with evidence of progressive disease requiring therapy. Patients received either CAMPATH 30 mg intravenously times per week for maximum of 12 weeks or chlorambucil 40 mg/m2 orally once every 28 days for maximum of 12 cycles.Of the 297 patients randomized, the median age was 60 years, 72% were male, 99% were Caucasian, 96% had WHO performance status 0-1, 23% had maximum lymph node diameter >=5 cm, 34% were Rai Stage III/IV, and 8% were treated in the U.S.Patients randomized to receive CAMPATH experienced longer progression free survival (PFS) compared to those randomized to receive chlorambucil (median PFS 14.6 months vs. 11.7 months, respectively). The overall response rates were 83% and 55% (p <0.0001) and the complete response rates were 24% and 2% (p <0.0001) for CAMPATH and chlorambucil arms, respectively. The Kaplan-Meier curve for PFS is shown in Figure 1.Figure 1: Progression Free Survival in Previously Untreated B-CLL PatientsLog-rank test adjusted for Rai Stage (I-II vs. III-IV). Figure 1. 14.2Previously Treated B-CLL Patients. CAMPATH was evaluated in three multicenter, open-label, single-arm studies of 149 patients with B-CLL previously treated with alkylating agents, fludarabine, or other chemotherapies. Patients were treated with the recommended dose of CAMPATH 30 mg intravenously times per week for up to 12 weeks. Partial response rates of 21% to 31% and complete response rates of 0% to 2% were observed.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Alemtuzumab, CD52-directed cytolytic antibody, is recombinant DNA-derived humanized monoclonal antibody (CAMPATH-1H). CAMPATH-1H is an IgG1 kappa antibody with human variable framework and constant regions, and complementarity-determining regions from murine (rat) monoclonal antibody (CAMPATH-1G). The CAMPATH-1H antibody has an approximate molecular weight of 150 kD. CAMPATH is produced in mammalian cell (Chinese hamster ovary) suspension culture in medium containing neomycin. Neomycin is not detectable in the final product.CAMPATH (alemtuzumab) injection is sterile, clear, colorless, isotonic solution (pH 6.8-7.4) in single-dose vial for intravenous use. Each single-dose vial of CAMPATH contains 30 mg alemtuzumab, 8.0 mg sodium chloride, 1.44 mg dibasic sodium phosphate, 0.2 mg potassium chloride, 0.2 mg monobasic potassium phosphate, 0.1 mg polysorbate 80, and 0.0187 mg disodium edetate dihydrate. No preservatives are added.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Administer as an intravenous infusion over hours. (2.1)Escalate to recommended dose of 30 mg/day three times per week for 12 weeks. (2.1)Premedicate with oral antihistamine and acetaminophen. (2.2). Administer as an intravenous infusion over hours. (2.1). Escalate to recommended dose of 30 mg/day three times per week for 12 weeks. (2.1). Premedicate with oral antihistamine and acetaminophen. (2.2). 2.1Dosing Schedule and Administration. Administer as an intravenous infusion over hours. Do not administer as intravenous push or bolus. Recommended Dosing RegimenGradually escalate to the maximum recommended single dose of 30 mg. Escalation is required at initiation of dosing or if dosing is held >=7 days during treatment. Escalation to 30 mg ordinarily can be accomplished in to days.Escalation Strategy:-Administer mg daily until infusion-related reactions are <= Grade [see Adverse Reactions (6.1)].-Then administer 10 mg daily until infusion-related reactions are <= Grade 2.-Then administer 30 mg/day three times per week on alternate days (e.g., Mon-Wed-Fri). The total duration of therapy, including dose escalation, is 12 weeks. Single doses of greater than 30 mg or cumulative doses greater than 90 mg per week increase the incidence of pancytopenia.. Administer as an intravenous infusion over hours. Do not administer as intravenous push or bolus. Recommended Dosing RegimenGradually escalate to the maximum recommended single dose of 30 mg. Escalation is required at initiation of dosing or if dosing is held >=7 days during treatment. Escalation to 30 mg ordinarily can be accomplished in to days.Escalation Strategy:-Administer mg daily until infusion-related reactions are <= Grade [see Adverse Reactions (6.1)].-Then administer 10 mg daily until infusion-related reactions are <= Grade 2.-Then administer 30 mg/day three times per week on alternate days (e.g., Mon-Wed-Fri). The total duration of therapy, including dose escalation, is 12 weeks. Gradually escalate to the maximum recommended single dose of 30 mg. Escalation is required at initiation of dosing or if dosing is held >=7 days during treatment. Escalation to 30 mg ordinarily can be accomplished in to days.. Escalation Strategy:-Administer mg daily until infusion-related reactions are <= Grade [see Adverse Reactions (6.1)].-Then administer 10 mg daily until infusion-related reactions are <= Grade 2.-Then administer 30 mg/day three times per week on alternate days (e.g., Mon-Wed-Fri). The total duration of therapy, including dose escalation, is 12 weeks. -Administer mg daily until infusion-related reactions are <= Grade [see Adverse Reactions (6.1)].. -Then administer 10 mg daily until infusion-related reactions are <= Grade 2.. -Then administer 30 mg/day three times per week on alternate days (e.g., Mon-Wed-Fri). The total duration of therapy, including dose escalation, is 12 weeks.. Single doses of greater than 30 mg or cumulative doses greater than 90 mg per week increase the incidence of pancytopenia.. 2.2Recommended Concomitant Medications Premedicate with diphenhydramine (50 mg) and acetaminophen (500-1000 mg) 30 minutes prior to first infusion and each dose escalation. Institute appropriate medical management (e.g., glucocorticoids, epinephrine, meperidine) for infusion-related reactions as needed [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].Administer trimethoprim/sulfamethoxazole double strength (DS) twice daily times per week (or equivalent) as Pneumocystis jirovecii pneumonia (PCP) prophylaxis.Administer famciclovir 250 mg BID or equivalent as herpetic prophylaxis.Continue PCP and herpes viral prophylaxis for minimum of months after completion of CAMPATH or until the CD4+ count is >=200 cells/uL, whichever occurs later [see Warnings and Precautions (5.3)].. Premedicate with diphenhydramine (50 mg) and acetaminophen (500-1000 mg) 30 minutes prior to first infusion and each dose escalation. Institute appropriate medical management (e.g., glucocorticoids, epinephrine, meperidine) for infusion-related reactions as needed [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].. Administer trimethoprim/sulfamethoxazole double strength (DS) twice daily times per week (or equivalent) as Pneumocystis jirovecii pneumonia (PCP) prophylaxis.. Administer famciclovir 250 mg BID or equivalent as herpetic prophylaxis.. 2.3Dosage Modification. Withhold CAMPATH during serious infection or other serious adverse reactions until resolution.Discontinue CAMPATH for autoimmune anemia or autoimmune thrombocytopenia.There are no dose modifications recommended for lymphopenia.Dose Modification for Neutropenia or Thrombocytopenia [see Warnings and Precautions (5.1)]Hematologic ValuesDosage ModificationIf the delay between dosing is >=7 days, initiate therapy at CAMPATH mg and escalate to 10 mg and then to 30 mg as tolerated [see Dosage and Administration (2.1)]. ANC <250/uL and/or platelet count <=25,000/uL For first occurrence:Withhold CAMPATH therapy. Resume CAMPATH at 30 mg when ANC >=500/uL and platelet count >=50,000/uL. For second occurrence:Withhold CAMPATH therapy. Resume CAMPATH at 10 mg when ANC >=500/uL and platelet count >=50,000/uL. For third occurrence:Discontinue CAMPATH therapy.>=50% decrease from baseline in patients initiating therapy with baseline ANC <=250/uL and/or baseline platelet count <=25,000/uL For first occurrence:Withhold CAMPATH therapy. Resume CAMPATH at 30 mg upon return to baseline value(s). For second occurrence:Withhold CAMPATH therapy. Resume CAMPATH at 10 mg upon return to baseline value(s). For third occurrence:Discontinue CAMPATH therapy.. Withhold CAMPATH during serious infection or other serious adverse reactions until resolution.. Discontinue CAMPATH for autoimmune anemia or autoimmune thrombocytopenia.. There are no dose modifications recommended for lymphopenia.. 2.4Preparation and Administration. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. If particulate matter is present or the solution is discolored, discard the vial. DO NOT SHAKE VIAL.Use aseptic technique during the preparation and administration of CAMPATH. Withdraw the necessary amount of CAMPATH from the vial into syringe.To prepare the mg dose, withdraw 0.1 mL into 1 mL syringe calibrated in increments of 0.01 mL.To prepare the 10 mg dose, withdraw 0.33 mL into 1 mL syringe calibrated in increments of 0.01 mL.To prepare the 30 mg dose, withdraw mL in either 1 mL or mL syringe calibrated in 0.1 mL increments.Inject syringe contents into 100 mL sterile 0.9% Sodium Chloride USP or 5% Dextrose in Water USP. Gently invert the bag to mix the solution. Discard syringe.The vial contains no preservatives and is intended for single use only. DISCARD VIAL including any unused portion after withdrawal of dose.Use within hours after dilution. Store diluted CAMPATH at room temperature between 15C to 30C (59F to 86F) or refrigerated at 2C to 8C (36F to 46F). Protect from light.. To prepare the mg dose, withdraw 0.1 mL into 1 mL syringe calibrated in increments of 0.01 mL.. To prepare the 10 mg dose, withdraw 0.33 mL into 1 mL syringe calibrated in increments of 0.01 mL.. To prepare the 30 mg dose, withdraw mL in either 1 mL or mL syringe calibrated in 0.1 mL increments.. 2.5Incompatibilities. CAMPATH is compatible with polyvinylchloride (PVC) bags and PVC or polyethylene-lined PVC administration sets. Do not add or simultaneously infuse other drug substances through the same intravenous line.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection: 30 mg/1 mL as clear, colorless solution in single-dose vial. Injection: 30 mg/1 mL single-dose vial (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. No formal drug interaction studies have been performed with CAMPATH.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3Females and Males of Reproductive Potential. CAMPATH may cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].. Pregnancy TestingPregnancy testing is recommended for females of reproductive potential prior to initiating CAMPATH therapy. Contraception. FemalesAdvise female patients of reproductive potential to use effective contraception during treatment with CAMPATH and for at least months after the last dose.. InfertilityBased 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.

GERIATRIC USE SECTION.

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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. CAMPATH (alemtuzumab) is supplied in clear glass single-dose vial containing 30 mg of alemtuzumab in mL of solution. Each carton contains three CAMPATH vials (NDC 58468-0357-3) or one CAMPATH vial (NDC 58468-0357-1).. Store CAMPATH at 2C to 8C (36F to 46F). Do not freeze. If accidentally frozen, thaw at 2C to 8C before administration. Protect from direct sunlight.

INDICATIONS & USAGE SECTION.

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

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. CytopeniasAdvise patients to report any signs or symptoms such as bleeding, easy bruising, petechiae or purpura, pallor, weakness or fatigue [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].. Infusion-Related ReactionsAdvise patients of the signs and symptoms of infusion-related reactions and of the need to take premedications as prescribed [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].. Immunosuppression/InfectionsAdvise patients to immediately report symptoms of infection (e.g., pyrexia) and to take prophylactic anti-infectives for PCP (trimethoprim/sulfamethoxazole DS or equivalent) and for herpes virus (famciclovir or equivalent) as prescribed [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].Advise patients that irradiation of blood products is required [see Warnings and Precautions (5.3)]. ImmunizationAdvise patients that they should not be immunized with live viral vaccines if they have recently been treated with CAMPATH. Advise females with infants exposed to CAMPATH in utero to inform the pediatrician of the exposure [see Warnings and Precautions (5.4)].. Embryo-Fetal ToxicityAdvise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females to inform their healthcare provider of known or suspected pregnancy [see Use in Specific Populations (8.1, 8.3)].Advise female patients of reproductive potential to use effective contraception during treatment with CAMPATH and for months after the final dose [see Use in Specific Populations (8.1, 8.3)].. LactationAdvise females not to breastfeed during treatment with CAMPATH and for months after the final dose [see Use in Specific Populations (8.2)].. InfertilityAdvise females and males of reproductive potential that CAMPATH may impair fertility [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].. Glomerular NephropathiesAdvise patients on signs and symptoms of glomerular nephropathies that may occur months to years after receiving CAMPATH [see Adverse Reactions (6.2)].

LACTATION SECTION.

8.2Lactation. Risk SummaryThere 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 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 breastfed child, including reduced lymphocyte counts, advise lactating women not to breastfeed during treatment with CAMPATH and for at least months following the last dose.. DataAlemtuzumab was detected in the milk of lactating huCD52 transgenic mice following intravenous administration of alemtuzumab at 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.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. CAMPATH binds to CD52, an antigen present on the surface of and lymphocytes, majority of monocytes, macrophages, NK cells, and subpopulation of granulocytes. 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Studies to assess the carcinogenic or genotoxic potential of CAMPATH have not been conducted.In fertility studies, alemtuzumab (3 or 10 mg/kg intravenously) was administered to huCD52 transgenic male mice on consecutive days prior to cohabitation with untreated wild-type females. No effect on fertility or reproductive performance was observed. However, adverse effects on sperm parameters (including abnormal morphology [detached/no head] and reduced total count and motility) were observed at both doses tested.When alemtuzumab (3 or 10 mg/kg intravenously) was administered to huCD52 transgenic female mice for consecutive days prior to cohabitation with untreated wild-type males, there was decrease in the average number of corpora lutea and implantation sites and an increase in postimplantation loss, resulting in fewer viable embryos at the higher dose tested.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Across all clinical experience, the reported maximum single dose received was 90 mg. Bone marrow aplasia, infections, or severe infusion-related reactions occurred in patients who received dose higher than recommended.One patient who received an 80 mg dose intravenously experienced acute bronchospasm, cough, and dyspnea, followed by anuria and death. Another patient received two 90 mg doses intravenously one day apart during the second week of treatment and experienced rapid onset of bone marrow aplasia.There is no known specific antidote for CAMPATH overdosage. Discontinue CAMPATH and provide supportive therapy.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 1 Vial Carton. NDC 58468-0357-1 Rx onlyCampath(R) alemtuzumab Injection30 mg/mLFor Intravenous Infusion After DilutionSterile No U.S. Standard of PotencyOne single-dose vial Discard unused portionSANOFI GENZYME. PRINCIPAL DISPLAY PANEL 1 Vial Carton.

PEDIATRIC USE SECTION.

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

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. CAMPATH pharmacokinetics were characterized in study of 30 previously treated B-CLL patients in whom CAMPATH was administered at the recommended dose and schedule. After 12 weeks of dosing, patients exhibited 7-fold increase in mean AUC.. DistributionAfter the last 30 mg dose, the mean volume of distribution at steady-state was 0.18 L/kg (range 0.1 to 0.4 L/kg).. EliminationCAMPATH pharmacokinetics displayed nonlinear elimination kinetics. Systemic clearance decreased with repeated administration due to decreased receptor-mediated clearance (i.e., loss of CD52 receptors in the periphery). Mean half-life was 11 hours (range to 32 hours) after the first 30 mg dose and was days (range to 14 days) after the last 30 mg dose.. Specific PopulationsThe effects of renal or hepatic impairment on the pharmacokinetics of CAMPATH have not been studied.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on findings from animal studies, CAMPATH may cause fetal harm when administered to pregnant woman. Available data from published cohort studies in pregnant women are insufficient to establish 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 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 reactionsMonoclonal 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 dataWhen alemtuzumab was administered to pregnant huCD52 transgenic mice during organogenesis (gestation days [GD] 6-10 or GD 11-15) at intravenous doses of 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 separate study in pregnant huCD52 transgenic mice, administration of alemtuzumab during organogenesis (GD 6-10 or GD 11-15) at intravenous doses of 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 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.

SPL UNCLASSIFIED SECTION.

Cytopenias: Serious, including fatal, pancytopenia/marrow hypoplasia, autoimmune idiopathic thrombocytopenia, and autoimmune hemolytic anemia can occur in patients receiving CAMPATH. Single doses of CAMPATH greater than 30 mg or cumulative doses greater than 90 mg per week increase the incidence of pancytopenia [see Warnings and Precautions (5.1)].

STORAGE AND HANDLING SECTION.

Store CAMPATH at 2C to 8C (36F to 46F). Do not freeze. If accidentally frozen, thaw at 2C to 8C before administration. Protect from direct sunlight.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: May cause fetal harm. (8.1)Lactation: Advise not to breastfeed. (8.2). Pregnancy: May cause fetal harm. (8.1). Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on findings from animal studies, CAMPATH may cause fetal harm when administered to pregnant woman. Available data from published cohort studies in pregnant women are insufficient to establish 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 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 reactionsMonoclonal 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 dataWhen alemtuzumab was administered to pregnant huCD52 transgenic mice during organogenesis (gestation days [GD] 6-10 or GD 11-15) at intravenous doses of 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 separate study in pregnant huCD52 transgenic mice, administration of alemtuzumab during organogenesis (GD 6-10 or GD 11-15) at intravenous doses of 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 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.. 8.2Lactation. Risk SummaryThere 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 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 breastfed child, including reduced lymphocyte counts, advise lactating women not to breastfeed during treatment with CAMPATH and for at least months following the last dose.. DataAlemtuzumab was detected in the milk of lactating huCD52 transgenic mice following intravenous administration of alemtuzumab at 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.. 8.3Females and Males of Reproductive Potential. CAMPATH may cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].. Pregnancy TestingPregnancy testing is recommended for females of reproductive potential prior to initiating CAMPATH therapy. Contraception. FemalesAdvise female patients of reproductive potential to use effective contraception during treatment with CAMPATH and for at least months after the last dose.. InfertilityBased 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 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Cytopenias: Obtain complete blood counts (CBC) and platelet counts at weekly intervals during therapy and CD4 counts after therapy until recovery to >=200 cells/uL. 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 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). Cytopenias: Obtain complete blood counts (CBC) and platelet counts at weekly intervals during therapy and CD4 counts after therapy until recovery to >=200 cells/uL. 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 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). 5.1Cytopenias. 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/uL [see Dosage and Administration (2.3) and Adverse Reactions (6)].. 5.2Infusion-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 or 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 or more days, reinstitute CAMPATH with gradual dose escalation [see Dosage and Administration (2.1)].. 5.3Immunosuppression/Infections. CAMPATH treatment results in severe and prolonged lymphopenia with concomitant increased incidence of opportunistic infections [see Adverse Reactions (6.1)]. Administer PCP and herpes viral prophylaxis during treatment with CAMPATH and for minimum of months after completion of CAMPATH or until the CD4+ count is >=200 cells/uL, 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 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 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/uL occurred by months following completion of CAMPATH; however, at months post treatment, the median was 183 cells/uL. In previously treated patients who received CAMPATH, the median time to recovery of CD4+ counts to >=200 cells/uL was months; however, full recovery (to baseline) of CD4+ and CD8+ counts may take more than 12 months [see Adverse Reactions (6)].. 5.4Immunization. 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.