Alemtuzumab

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# Black Box Warning

# Overview
Alemtuzumab is a monoclonal antibody that is FDA approved for the treatment of B-cell chronic lymphocytic leukemia (B-CLL). There is a Black Box Warning for this drug as shown here.  Common adverse reactions include cytopenias, infusion reactions, cytomegalovirus (CMV) and other infections, nausea, diarrhea and insomnia.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
Alemtuzumab is indicated as a single agent for the treatment of B-cell chronic lymphocytic leukemia (B-CLL).

### Dosage
- Gradually escalate to the maximum recommended single dose of 30 mg.
- Escalation Strategy:
- Administer 3 mg daily until infusion reactions are  grade 2.
- Then administer 10 mg daily until infusion 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.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Alemtuzumab in adult patients.

### NonGuideline-Supported Use
- Autoimmune disease - Cytopenia
- Malignant tumor of lymphoid hemopoietic and related tissue
- Relapsed or refractory primary cutaneous T-cell lymphoma
- Prophylaxis of renal transplant rejection
- T-cell prolymphocytic leukemia

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
Safety and efficacy not established in pediatric patients

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Alemtuzumab in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Alemtuzumab in pediatric patients.

# Contraindications
None

# Warnings

### Cytopenias
Severe, including fatal, autoimmune anemia and thrombocytopenia, and prolonged myelosuppression have been reported in patients receiving alemtuzumab.
In addition, hemolytic anemia, pure red cell aplasia, bone marrow aplasia, and hypoplasia have been reported after treatment with alemtuzumab at the recommended dose. Single doses of alemtuzumab greater than 30 mg or cumulative doses greater than 90 mg per week increase the incidence of pancytopenia.
Withhold alemtuzumab for severe cytopenias (except lymphopenia). Discontinue for autoimmune cytopenias or recurrent/persistent severe cytopenias (except lymphopenia). No data exist on the safety of alemtuzumab resumption in patients with autoimmune cytopenias or marrow aplasia.

### Infusion Reactions
Adverse reactions occurring during or shortly after alemtuzumab infusion include pyrexia, chills/rigors, nausea, hypotension, urticaria, dyspnea, rash, emesis, and bronchospasm.  In clinical trials, the frequency of infusion 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 reactions.
The following serious, including fatal, infusion reactions have been identified in post-marketing 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 alemtuzumab according to the recommended dose-escalation scheme. Premedicate patients with an antihistamine and acetaminophen prior to dosing. Institute medical management (e.g., glucocorticoids, epinephrine, meperidine) for infusion reactions as needed. If therapy is interrupted for 7 or more days, reinstitute alemtuzumab with gradual dose escalation.

### Immunosuppression/Infections
Alemtuzumab treatment results in severe and prolonged lymphopenia with a concomitant increased incidence of opportunistic infections. Administer PCP and herpes viral prophylaxis during alemtuzumab therapy and for a minimum of 2 months after completion of alemtuzumab or until the CD4+ count is  200 cells/L, whichever occurs later. Prophylaxis does not eliminate these infections.
Routinely monitor patients for CMV infection during alemtuzumab treatment and for at least 2 months following completion of treatment. Withhold alemtuzumab 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.
Administer only irradiated blood products to avoid transfusion associated Graft versus Host Disease (TAGVHD), unless emergent circumstances dictate immediate transfusion.
In patients receiving alemtuzumab as initial therapy, recovery of CD4+ counts to  200 cells/L occurred by 6 months post-treatment; however at 2 months post-treatment, the median was 183 cells/L. In previously treated patients receiving alemtuzumab, the median time to recovery of CD4+ counts to  200 cells/L was 2 months; however, full recovery (to baseline) of CD4+ and CD8+ counts may take more than 12 months.

### Laboratory Monitoring
Obtain complete blood counts (CBC) at weekly intervals during alemtuzumab therapy and more frequently if worsening anemia, neutropenia, or thrombocytopenia occurs. Assess CD4+ counts after treatment until recovery to  200 cells/L.

### Immunization
The safety of immunization with live viral vaccines following alemtuzumab therapy has not been studied. Do not administer live viral vaccines to patients who have recently received alemtuzumab. The ability to generate an immune response to any vaccine following alemtuzumab therapy has not been studied.

# Adverse Reactions

## 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 alemtuzumab 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 alemtuzumab. In previously untreated patients, the median CD4+ was 0 cells/L at one month after treatment and 238 cells/L 25-75% interquartile range 115 to 418 cells/L at 6 months post-treatment.
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 alemtuzumab. 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 - 5 sepsis ranged from 3% to 10% across studies and was higher in previously treated patients. Grade 3 - 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 alemtuzumab or chlorambucil as first line therapy for B-CLL. alemtuzumab 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 mg  90 mg).

### Previously Treated Patients
Additional safety information was obtained from 3 single arm studies of 149 previously treated patients with CLL administered 30 mg alemtuzumab intravenously three times weekly for 4 to 12 weeks (median cumulative dose 673 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.

## Postmarketing Experience
The following adverse reactions were 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 alemtuzumab exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors:
- Seriousness of the reaction,
- Reported frequency of the reaction, or
- Strength of causal connection to alemtuzumab

### Fatal infusion reactions
syncope, pulmonary infiltrates, acute respiratory distress syndrome (ARDS), respiratory arrest, cardiac arrhythmias, myocardial infarction, acute cardiac insufficiency, cardiac arrest, angioedema, and anaphylactoid shock.

### Cardiovascular
Congestive heart failure, cardiomyopathy, decreased ejection fraction (some patients had been previously treated with cardiotoxic agents).

### Immune disorders
Goodpasture's syndrome, Graves' disease, aplastic anemia, Guillain Barre 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), re-activation of latent viruses.

### Metabolic
Tumor lysis syndrome

### Neurologic
Optic neuropathy

# Drug Interactions
No formal drug interaction studies have been performed with alemtuzumab.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): C
Animal reproduction studies have not been conducted with alemtuzumab. IgG antibodies, such as alemtuzumab, can cross the placental barrier. It is not known whether alemtuzumab can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. alemtuzumab should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS): B2
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Alemtuzumab in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Alemtuzumab during labor and delivery.

### Nursing Mothers
Excretion of alemtuzumab in human breast milk has not been studied; it is not known whether this drug is excreted in human milk. IgG antibodies, such as alemtuzumab, can be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from alemtuzumab, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the elimination half-life of alemtuzumab and the importance of the drug to the mother.

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

### Geriatic Use
Of 147 previously untreated B-CLL patients treated with alemtuzumab, 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 alemtuzumab 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.

### Gender
There is no FDA guidance on the use of Alemtuzumab with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Alemtuzumab with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Alemtuzumab in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Alemtuzumab in patients with hepatic impairment.

### Females of Reproductive Potential and Males
No long-term studies in animals have been performed to establish the effects on fertility in males or females.

### Immunocompromised Patients
There is no FDA guidance one the use of Alemtuzumab in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Intravenous

### Monitoring
There is limited information regarding Alemtuzumab Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Alemtuzumab and IV administrations.

# Overdosage
Across all clinical experience, the reported maximum single dose received was 90 mg. Bone marrow aplasia, infections, or severe infusions reactions occurred in patients who received a dose higher than recommended.
One patient received an 80 mg dose by IV infusion and experienced acute bronchospasm, cough, and dyspnea, followed by anuria and death. Another patient received two 90 mg doses by IV infusion one day apart during the second week of treatment and experienced a rapid onset of bone marrow aplasia.
There is no known specific antidote for alemtuzumab overdosage. Treatment consists of drug discontinuation and supportive therapy.

# Pharmacology

## Mechanism of Action
alemtuzumab 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 alemtuzumab to the leukemic cells.

## Structure
There is limited information regarding Alemtuzumab Structure in the drug label.

## Pharmacodynamics

### Cardiac Electrophysiology
The effect of multiple doses of alemtuzumab (12 mg/day for 5 days) on the QTc interval was evaluated in a 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. A mean increase in heart rate of 22 to 26 beats/min was observed for at least 2 hours following the initial infusion of alemtuzumab. This increase in heart rate was not observed with subsequent doses.

## Pharmacokinetics
Alemtuzumab pharmacokinetics were characterized in a study of 30 previously treated B-CLL patients in whom alemtuzumab was administered at the recommended dose and schedule. alemtuzumab pharmacokinetics displayed nonlinear elimination kinetics. After 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). Systemic clearance decreased with repeated administration due to decreased receptor-mediated clearance (i.e., loss of CD52 receptors in the periphery). After 12 weeks of dosing, patients exhibited a seven-fold increase in mean AUC. Mean half-life was 11 hours (range 2 to 32 hours) after the first 30 mg dose and was 6 days (range 1 to 14 days) after the last 30 mg dose.
Comparisons of AUC in patients  65 years (n=6) versus patients < 65 years (n=15) suggested that no dose adjustments are necessary for age. Comparisons of AUC in female patients (n=4) versus male patients (n=17) suggested that no dose adjustments are necessary for gender.
The pharmacokinetics of alemtuzumab in pediatric patients have not been studied. The effects of renal or hepatic impairment on the pharmacokinetics of alemtuzumab have not been studied.

## Nonclinical Toxicology
No long-term studies in animals have been performed to establish the carcinogenic or mutagenic potential of alemtuzumab.

# Clinical Studies

### Previously Untreated B-CLL Patients
alemtuzumab 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 alemtuzumab 30 mg IV 3 times/week for a maximum of 12 weeks or chlorambucil 40 mg/m2 PO once every 28 days, for a maximum of 12 cycles.
Of the 297 patients randomized, the median age was 60 years, 72% were male, 99% were Caucasian, 96% had a WHO performance status 0-1, 23% had maximum lymph node diameter  5cm, 34% were Rai Stage III/IV, and 8% were treated in the U.S.
Patients randomized to receive alemtuzumab 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 alemtuzumab and chlorambucil arms, respectively. The Kaplan-Meier curve for PFS is shown in FIGURE 1.

### Previously Treated B-CLL Patients
alemtuzumab 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 alemtuzumab, 30 mg intravenously, three 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.

# How Supplied
Alemtuzumab is supplied in 30 mg/1 mL single use vial
- Each carton contains three alemtuzumab vials (NDC 58468-0357-3) or one alemtuzumab vial (NDC 58468-0357-1).

## Storage
Store at 2-8C (36-46F).

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Cytopenias: Advise patients to report any signs or symptoms such as bleeding, easy bruising, petechiae or purpura, pallor, weakness or fatigue.
- Infusion Reactions: Advise patients of the signs and symptoms of infusion reactions and of the need to take premedications as prescribed.
- Infections: Advise 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.
- Advise patients that irradiation of blood products is required.
- Advise patients that they should not be immunized with live viral vaccines if they have recently been treated with alemtuzumab.
- Advise male and female patients with reproductive potential to use effective contraceptive methods during treatment and for a minimum of 6 months following alemtuzumab therapy.

# Precautions with Alcohol
Alcohol-Alemtuzumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Campath 
- Lemtrada

# Look-Alike Drug Names
There is limited information regarding Alemtuzumab Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price