Alemtuzumab (3522)
[ uh-lem-tooz'-uh-mab ]
| Ingredients: |
Alemtuzumab |
| Indications: |
Leukemia, chronic lymphocytic |
| Pregnancy Category: |
C |
| FDA Approved: |
2001- 05- 01 |
| Classes: |
Antineoplastics, monoclonal antibodies; Monoclonal antibodies; WHO Formulary |
| HCFA Jcodes: |
J9010 |
| Brand Names: |
Campath
-
US
;
MabCampath
-
EUROPE; Israel, Singapore
;
|
| DEA schedules: |
(none)
|
| Cost of therapy: |
$3,076.50
(
Chronic Lymphocytic Leukemia ;
Campath ;
30 mg/3 ml ampules ;
10 mg/day intial therapy ;
5 day supply
)
$66,452.40
(
Chronic Lymphocytic Leukemia ;
Campath ;
30 mg/3 ml ampules ;
90 mg/week maintenance therapy ;
84 day supply
)
|
BOXED WARNING
|
| |
- Alemtuzumab should be administered under the supervision of a physician experienced in the use of antineoplastic therapy.
-
- Hematologic Toxicity: Serious and, in rare instances fatal, pancytopenia/ marrow hypoplasia, autoimmune idiopathic thrombocytopenia, and autoimmune
hemolytic anemia have occurred in patients receiving alemtuzumab therapy. Single doses of alemtuzumab greater than 30 mg or cumulative doses greater than 90 mg/ week should not be administered because
these doses are associated with a higher incidence of pancytopenia.
- Infusion Reactions: Campath can result in serious infusion reactions. Patients should be carefully monitored during infusions and alemtuzumab
discontinued if indicated. (See DOSAGE AND ADMINISTRATION .) Gradual escalation to the recommended maintenance dose is required at the initiation of therapy and after interruption of
therapy for 7 or more days.
- Infections, Opportunistic Infections: Serious, sometimes fatal bacterial, viral, fungal, and protozoan infections have been reported in patients receiving alemtuzumab
therapy. Prophylaxis directed against Pneumocystis carinii pneumonia (PCP) and herpes virus infections has been shown to decrease, but not eliminate, the occurrence of these infections.
|
|
DESCRIPTION
|
| |
Campath (alemtuzumab) is a recombinant DNA- derived humanized monoclonal antibody (Campath- 1H) that is directed against the
21- 28 kD cell surface glycoprotein, CD52. CD52 is expressed on the surface of normal and malignant B and T lymphocytes, NK
cells, monocytes, macrophages, and tissues of the male reproductive system. The Campath- 1H antibody is an IgG1 kappa with
human variable framework and constant regions, and complementarity- determining regions from a 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 a medium containing neomycin. Neomycin
is not detectable in the final product. Campath is a sterile, clear, colorless, isotonic pH 6.8- 7.4 solution for injection.
Each single use ampoule of Campath contains 30 mg alemtuzumab, 24.0 mg sodium chloride, 3.5 mg dibasic sodium phosphate, 0.6
mg potassium chloride, 0.6 mg monobasic potassium phosphate, 0.3 mg polysorbate 80, and 0.056 mg disodium edetate. No preservatives
are added.
|
CLINICAL PHARMACOLOGY
|
| |
General
|
| |
Alemtuzumab binds to CD52, a non- modulating antigen that is present on the surface of essentially all B and T lymphocytes,
a majority of monocytes, macrophages, and NK cells, and a subpopulation of granulocytes. Analysis of samples collected from
multiple volunteers has not identified CD52 expression on erythrocytes or hematopoetic stem cells. The proposed mechanism
of action is antibody- dependent lysis of leukemic cells following cell surface binding. Campath- 1H Fab binding was observed
in lymphoid tissues and the mononuclear phagocyte system. A proportion of bone marrow cells, including some CD34+cells, express variable levels of CD52. Significant binding was also observed in the skin and male reproductive tract (epididymis,
sperm, seminal vesicle). Mature spermatozoa stain for CD52, but neither spermatogenic cells nor immature spermatozoa show
evidence of staining.
|
Human Pharmacokinetics
|
| |
The pharmacokinetic profile of Alemtuzumab was studied in a multicenter rising- dose trial in non- Hodgkin's lymphoma (NHL)
and chronic lymphocytic leukemia (CLL). Alemtuzumab was administered once weekly for a maximum of 12 weeks. Following intravenous
(IV) infusions over a range of doses, the maximum serum concentration (Cmax ) and the area under the curve (AUC) showed relative dose proportionality. The overall average half- life (T½ ) over the dosing interval was about 12 days. The pharmacokinetic profile of alemtuzumab administered as a 30 mg IV infusion
3 times/ week was evaluated in CLL patients. Peak and trough levels of alemtuzumab rose during the first few weeks of treatment,
and appeared to approach steady state by approximately week 6, although there was marked inter- patient variability. The rise
in serum alemtuzumab concentration corresponded with the reduction in malignant lymphocytosis.
|
|
CLINICAL STUDIES
|
| |
The safety and efficacy of alemtuzumab were evaluated in a multicenter, open- label, noncomparative study (Study 1) of 93
patients with B- cell chronic lymphocytic leukemia (B- CLL) who had been previously treated with alkylating agents and had
failed treatment with fludarabine. Fludarabine failure was defined as lack of an objective partial (PR) or complete (CR) response
to at least one fludarabine- containing regimen, progressive disease (PD) while on fludarabine treatment, or relapse within
6 months of the last dose of fludarabine. Patients were gradually escalated to a maintenance dose of alemtuzumab 30 mg intravenously
3 times/ week for 4- 12 weeks. Patients received premedication prior to infusion and anti- Pneumocystis carinii and anti- herpes prophylaxis while on treatment and for at least 2 months after the last dose of alemtuzumab.
Two supportive, multicenter, open- label, noncomparative studies of alemtuzumab enrolled a total of 56 patients with B- CLL
(Studies 2 and 3). These patients had been previously treated with fludarabine or other chemotherapies. In Studies 2 and 3,
the maintenance dose of alemtuzumab was 30 mg 3 times/ week with treatment cycles of 8 and 6 weeks respectively. A slightly
different dose escalation scheme was used in these trials. Premedication to ameliorate infusional reactions and anti- Pneumocystis carinii and anti- herpes prophylaxis were optional.
Objective tumor response rates and duration of response were determined using the NCI Working Group Response Criteria (1996).
A comparison of patient characteristics and the results for each of these studies is summarized in TABLE 1 . Time to event parameters, except for duration of response, are calculated from initiation of alemtuzumab therapy. Duration
of response is calculated from the onset of the response.
| TABLE 1
Summary of Patient Population and Outcomes
|
| |
|
Study 1 |
Study 2 |
Study 3 |
| |
|
(n=93) |
(n=32) |
(n=24) |
| Median Age in Years (range) |
66 (32- 68) |
57 (46- 75) |
62 (44- 77) |
| Median Number of Prior Regimens (range) |
3 (2- 7) |
3 (1- 10) |
3 (1- 8) |
| Prior Therapies: |
|
|
|
| |
Alkylating agents |
100% |
100% |
92% |
| |
Fludarabine |
100% |
34% |
100% |
| Disease Characteristics: |
|
|
|
| |
Rai Stage III/ IV Disease |
76% |
72% |
71% |
| |
B- Symptoms |
42% |
31% |
21% |
| Overall Response Rate |
33% |
21% |
29% |
| (95% Confidence Interval) |
(23%, 43%) |
(8%, 33%) |
(11%, 47%) |
| |
Complete response |
2% |
0% |
0% |
| |
Partial response |
31% |
21% |
29% |
| Median Duration of Response (months) |
7 |
7 |
11 |
| (95% Confidence Interval) |
(5, 8) |
(5, 23) |
(6, 19) |
| Median Time to Response (months) |
2 |
4 |
4 |
| (95% Confidence Interval) |
(1, 2) |
(1, 5) |
(2, 4) |
| Progression- Free Survival (months) |
4 |
5 |
7 |
| (95% Confidence Interval) |
(3, 5) |
(3, 7) |
(3, 9) |
|
|
INDICATIONS AND USAGE
|
| |
Alemtuzumab is indicated for the treatment of B- cell chronic lymphocytic leukemia (B- CLL) in patients who have been treated
with alkylating agents and who have failed fludarabine therapy. Determination of the effectiveness of alemtuzumab is based
on overall response rates. (See CLINICAL STUDIES .) Comparative, randomized trials demonstrating increased survival or clinical benefits such as improvement in disease- related
symptoms have not yet been conducted.
|
CONTRAINDICATIONS
|
| |
Alemtuzumab is contraindicated in patients who have active systemic infections, underlying immunodeficiency ( e.g., seropositive for HIV), or known Type I hypersensitivity or anaphylactic reactions to alemtuzumab or to any one of its components.
|
WARNINGS
|
| |
See BOXED WARNING .
Infusion-Related Events
|
| |
Alemtuzumab has been associated with infusion- related events including hypotension, rigors, fever, shortness of breath, bronchospasm,
chills, and/ or rash. In order to ameliorate or avoid infusion- related events, patients should be premedicated with an oral
antihistamine and acetaminophen prior to dosing and monitored closely for infusion- related adverse events. In addition, alemtuzumab
should be initiated at a low dose with gradual escalation to the effective dose. Careful monitoring of blood pressure and
hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive
medications. If therapy is interrupted for 7 or more days, alemtuzumab should be reinstituted with gradual dose escalation.
(See ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION .)
|
Immunosuppression/Opportunistic Infections
|
| |
Alemtuzumab induces profound lymphopenia. A variety of opportunistic infections have been reported in patients receiving alemtuzumab
therapy (see ADVERSE REACTIONS, Infections ). If a serious infection occurs, alemtuzumab therapy should be interrupted and may be reinitiated following the resolution
of the infection.
Anti- infective prophylaxis is recommended upon initiation of therapy and for a minimum of 2 months following the last dose
of alemtuzumab or until CD4+counts are ≥200 cells/ μl. The median time to recovery of CD4+counts to ≥200/ μl was 2 months, however, full recovery (to baseline) of CD4+and CD8+counts may take more than 12 months. (See BOXED WARNING and DOSAGE AND ADMINISTRATION .)
Because of the potential for Graft versus Host Disease (GVHD) in severely lymphopenic patients, irradiation of any blood products
administered prior to recovery from lymphopenia is recommended.
|
Hematologic Toxicity
|
| |
Severe, prolonged, and in rare instances fatal, myelosuppression has occurred in patients with leukemia and lymphoma receiving
alemtuzumab. Bone marrow aplasia and hypoplasia were observed in the clinical studies at the recommended dose. The incidence
of these complications increased with doses above the recommended dose. In addition, severe and fatal autoimmune anemia and
thrombocytopenia were observed in patients with CLL. Alemtuzumab should be discontinued for severe hematologic toxicity (see TABLE 3 ) or in any patient with evidence of autoimmune hematologic toxicity. Following resolution of transient, non- immune myelosuppression,
alemtuzumab may be reinitiated with caution. (See DOSAGE AND ADMINISTRATION .) There is no information on the safety of resumption of alemtuzumab in patients with autoimmune cytopenias or marrow aplasia.
(See ADVERSE REACTIONS .)
|
|
PRECAUTIONS
|
| |
Laboratory Monitoring
|
| |
Complete blood counts (CBC) and platelet counts should be obtained at weekly intervals during alemtuzumab therapy and more
frequently if worsening anemia, neutropenia, or thrombocytopenia is observed on therapy. CD4+counts should be assessed after treatment until recovery to ≥200 cells/ μl. (See WARNINGS and ADVERSE REACTIONS .)
|
Drug/Laboratory Interactions
|
| |
No formal drug interaction studies have been performed with alemtuzumab. An immune response to alemtuzumab may interfere with
subsequent diagnostic serum tests that utilize antibodies.
|
Immunization
|
| |
Patients who have recently received alemtuzumab, should not be immunized with live viral vaccines, due to their immunosuppression.
The safety of immunization with live viral vaccines following alemtuzumab therapy has not been studied. The ability to generate
a primary or anamnestic humoral response to any vaccine following alemtuzumab therapy has not been studied.
|
Immunogenicity
|
| |
Four (1.9%) of 211 patients evaluated for development of an immune response were found to have antibodies to alemtuzumab.
The data reflect the percentage of patients whose test results were considered positive for antibody to alemtuzumab in a kinetic
enzyme immunoassay, and are highly dependent on the sensitivity and specificity of the assay. The observed incidence of antibody
positivity may be influenced by several additional factors including sample handling, concomitant medications and underlying
disease. For these reasons, comparison of the incidence of antibodies to alemtuzumab with the incidence of antibodies to other
products may be misleading. Patients who develop hypersensitivity to alemtuzumab may have allergic or hypersensitivity reactions
to other monoclonal antibodies.
|
Carcinogenesis, Mutagenesis, and Impairment of Fertility
|
| |
No long- term studies in animals have been performed to establish the carcinogenic or mutagenic potential of alemtuzumab,
or to determine its effects on fertility in males or females. Women of childbearing potential and men of reproductive potential
should use effective contraceptive methods during treatment and for a minimum of 6 months following alemtuzumab therapy.
|
Pregnancy Category C
|
| |
Animal reproduction studies have not been conducted with alemtuzumab. It is not known whether alemtuzumab can affect reproductive
capacity or cause fetal harm when administered to a pregnant woman. However, human IgG is known to cross the placental barrier
and therefore alemtuzumab may cross the placental barrier and cause fetal B and T lymphocyte depletion. Alemtuzumab should
be given to a pregnant woman only if clearly needed.
|
Nursing Mothers
|
| |
Excretion of alemtuzumab in human breast milk has not been studied. Because many drugs including human IgG are excreted in
human milk, breast- feeding should be discontinued during treatment and for at least 3 months following the last dose of alemtuzumab.
|
Pediatric Use
|
| |
The safety and effectiveness of alemtuzumab in children have not been established.
|
Geriatric Use
|
| |
Of the 149 patients with B- CLL enrolled in the three clinical studies, 66 (44%) were 65 and over, while 15 (10%) were 75
and over. Substantial differences in safety and efficacy related to age were not observed; however the size of the database
is not sufficient to exclude important differences.
|
|
ADVERSE REACTIONS
|
| |
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 adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse
events that appear to be related to drug use and for approximating rates.
Safety data, except where indicated, are based on 149 patients with B- CLL enrolled in studies of alemtuzumab as a single
agent administered at a maintenance dose of 30 mg intravenously 3 times weekly for 4- 12 weeks. TABLE 2 lists adverse events including severe or life threatening (NCI- CTC Grade 3 or 4) adverse events reported in >5% of the patients.
More detailed information and follow- up were available for Study 1 (93 patients), therefore the narrative description of
certain events, noted below, is based on this study.
Infusion-Related Adverse Events
|
| |
Infusion- related adverse events resulted in discontinuation of alemtuzumab therapy in 6% of the patients enrolled in Study
1. The most commonly reported infusion- related adverse events on this study included rigors in 89% of patients, drug- related
fever in 83%, nausea in 47%, vomiting in 33%, and hypotension in 15%. Other frequently reported infusion- related events include,
rash in 30% of patients, fatigue in 22%, urticaria in 22%, dyspnea in 17%, pruritus in 14%, headache in 13%, and diarrhea
in 13%. Similar types of adverse events were reported on the supporting studies (see TABLE 2 ). Acute infusion- related events were most common during the first week of therapy. Antihistamines, acetaminophen, antiemetics,
meperidine, and corticosteroids as well as incremental dose escalation were used to prevent or ameliorate infusion- related
events. (See WARNINGS and DOSAGE AND ADMINISTRATION .)
|
Infections
|
| |
On Study 1, all patients were required to receive anti- herpes and anti- PCP prophylaxis (see DOSAGE AND ADMINISTRATION ) and were followed for infections for 6 months. Forty (43%) of 93 patients experienced 59 infections (1 or more infections/
patient) related to alemtuzumab during treatment or within 6 months of the last dose. Of these, 34 (37%) patients experienced
42 infections that were of Grade 3 or 4 severity; 11 (18%) were fatal. Fifty- five percent (55%) of the Grade 3 or 4 infections
occurred during treatment or within 30 days of last dose. In addition 1 or more episodes of febrile neutropenia (ANC ≤500
cells/ μl were reported in 10% of patients.
The following types of infections were reported in Study 1: Grade 3 or 4 sepsis in 12% of patients with 1 fatality, Grade 3 or 4 pneumonia in 15% with 5 fatalities, and opportunistic
infections in 17% with 4 fatalities. Candida infections were reported in 5% of patients; CMV infections in 8% (4% of Grade
3 or 4 severity); Aspergillosis in 2% with fatal Aspergillosis in 1%; fatal Mucormycosis in 2%; fatal Cryptococcal pneumonia
in 1%; Listeria monocytogenes meningitis in 1%; disseminated Herpes zoster in 1%; Grade 3 Herpes simplex in 2%; and Torulopsis pneumonia in 1%. PCP pneumonia occurred in one (1%) patient who discontinued PCP prophylaxis.
On Studies 2 and 3 in which anti- herpes and anti- PCP prophylaxis was optional, 37 (66%) patients had 47 infections while
or after receiving alemtuzumab therapy. In addition to the opportunistic infections reported above, the following types of
related events were observed on these studies: interstitial pneumonitis of unknown etiology and progressive multifocal leukoencephalopathy.
|
Hematologic Adverse Events
|
| |
Pancytopenia/Marrow Hypoplasia
|
| |
Alemtuzumab therapy was permanently discontinued in six (6%) patients due to pancytopenia/ marrow hypoplasia. Two (2%) cases
of pancytopenia/ marrow hypoplasia were fatal.
|
Anemia
|
| |
Forty- four (47%) patients had 1 or more episodes of new onset NCI- CTC Grade 3 or 4 anemia. Sixty- two (67%) patients required
RBC transfusions. In addition, erythropoietin use was reported in nineteen (20%) patients. Autoimmune hemolytic anemia secondary
to alemtuzumab therapy was reported in 1% of patients. Positive Coombs test without hemolysis was reported in 2%. (See BOXED WARNING .)
|
Neutropenia
|
| |
Sixty- five (70%) patients had 1 or more episodes of NCI- CTC Grade 3 or 4 neutropenia. Median duration of Grade 3 or 4 neutropenia
was 28 days (range: 2- 165 days). (See Infections .)
|
Thrombocytopenia
|
| |
Forty- eight (52%) patients had 1 or more episodes of new onset Grade 3 or 4 thrombocytopenia. Median duration of thrombocytopenia
was 21 days (range: 2- 165 days). Thirty- five (38%) patients required platelet transfusions for management of thrombocytopenia.
Autoimmune thrombocytopenia was reported in 2% of patients with 1 fatal case of alemtuzumab- related autoimmune thrombocytopenia.
(See BOXED WARNING .)
|
Lymphopenia
|
| |
The median CD4+count at 4 weeks after initiation of alemtuzumab therapy was 2/ μl, at 2 months after discontinuation of alemtuzumab therapy,
207/ μl, and 6 months after discontinuation, 470/ μl. The pattern of change in median CD8+lymphocyte counts was similar to that of CD4+cells. In some patients treated with alemtuzumab, CD4+and CD8+lymphocyte counts had not returned to baseline levels at longer than 1 year post therapy.
|
|
| TABLE 2
Adverse Events in >5% of the B- CLL Study Population During Treatment or Within 30 Days (n=149)
|
| |
|
B- CLL Studies |
| |
|
(n=149) |
| Adverse Event |
ANY Grade |
Grade 3 or 4 |
| Body as a Whole
|
| |
Rigors |
86% |
16% |
| |
Fever |
85% |
19% |
| |
Fatigue |
34% |
5% |
| |
Pain, skeletal pain |
24% |
2% |
| |
Anorexia |
20% |
3% |
| |
Asthenia |
13% |
4% |
| |
Edema, peripheral edema |
13% |
1% |
| |
Back pain |
10% |
3% |
| |
Chest pain |
10% |
1% |
| |
Malaise |
9% |
1% |
| |
Temperature change sensation |
5% |
— |
| Cardiovascular Disorders, General
|
| |
Hypotension |
32% |
5% |
| |
Hypertension |
11% |
2% |
| Heart Rate & Rhythm Disorders
|
| |
Tachycardia, SVT |
11% |
3% |
| Central & Peripheral Nervous System Disorders
|
| |
Headache |
24% |
1% |
| |
Dysthesias |
15% |
— |
| |
Dizziness |
12% |
1% |
| |
Tremor |
7% |
— |
| Gastrointestinal Disorders
|
| |
Nausea |
54% |
2% |
| |
Vomiting |
41% |
4% |
| |
Diarrhea |
22% |
1% |
| |
Stomatitis, ulcerative stomatitis, mucositis |
14% |
1% |
| |
Abdominal pain |
11% |
2% |
| |
Dyspepsia |
10% |
— |
| |
Constipation |
9% |
1% |
| Hematologic Disorders
|
| |
WBC Disorders: Neutropenia |
85% |
64% |
| |
RBC Disorders: Anemia |
80% |
38% |
| |
Pancytopenia |
5% |
3% |
| Platelet, Bleeding & Clotting Disorders
|
| |
Thrombocytopenia |
72% |
50% |
| |
Purpura |
8% |
— |
| |
Epistaxis |
7% |
1% |
| Musculoskeletal Disorders
|
| |
Myalgias |
11% |
— |
| Psychiatric Disorders
|
| |
Insomnia |
10% |
— |
| |
Depression |
7% |
1% |
| |
Somnolence |
5% |
1% |
| Resistance Mechanism Disorders
|
| |
Sepsis |
15% |
10% |
| |
Herpes simplex |
11% |
1% |
| |
Moniliasis |
8% |
1% |
| |
Infection (other viral or unidentified) |
7% |
1% |
| Respiratory System Disorders
|
| |
Dyspnea |
26% |
9% |
| |
Cough |
25% |
2% |
| |
Bronchitis, pneumonitis |
21% |
13% |
| |
Pneumonia |
16% |
10% |
| |
Pharyngitis |
12% |
— |
| |
Bronchospasm |
9% |
2% |
| |
Rhinitis |
7% |
— |
| Skin & Appendage Disorders
|
| |
Rash, maculopapular rash, erythematous rash |
40% |
3% |
| |
Urticaria |
30% |
5% |
| |
Pruritus |
24% |
1% |
| |
Sweating increased |
19% |
1% |
|
Serious Adverse Events
|
| |
The following serious adverse events, defined as events which result in death, requiring or prolonging hospitalization, requiring
medical intervention to prevent hospitalization, or malignancy, were reported in at least 1 patient treated on studies where
alemtuzumab was used as a single agent (and are not reported in TABLE 2 ). These studies were conducted in patients with lymphocytic leukemia and lymphoma (n=745) and in patients with non- malignant
diseases (n=152) such as rheumatoid arthritis, solid organ transplant, or multiple sclerosis.
- Body as a Whole: Allergic reactions, anaphylactoid reaction, ascites, hypovolemia, influenza- like syndrome, mouth edema, neutropenic fever,
syncope.
- Cardiovascular Disorders: Cardiac failure, cyanosis, atrial fibrillation, cardiac arrest, ventricular arrhythmia, ventricular tachycardia, angina pectoris,
coronary artery disorder, myocardial infarction, pericarditis.
- Central and Peripheral Nervous System Disorders: Abnormal gait, aphasia, coma, grand mal convulsions, paralysis, meningitis.
- Endocrine Disorders: Hyperthyroidism.
- Gastrointestinal System Disorders: Duodenal ulcer, esophagitis, gingivitis, gastroenteritis, GI hemorrhage, hematemesis, hemorrhoids, intestinal obstruction,
intestinal perforation, melena, paralytic ileus, peptic ulcer, pseudomembranous colitis, colitis, pancreatitis, peritonitis,
hyperbilirubinemia, hepatic failure, hepatocellular damage, hypoalbuminemia, biliary pain.
- Hearing and Vestibular Disorders: Decreased hearing.
- Metabolic and Nutritional Disorders: Acidosis, aggravated diabetes mellitus, dehydration, fluid overload, hyperglycemia, hyperkalemia, hypokalemia, hypoglycemia,
hyponatremia, increased alkaline phosphatase, respiratory alkalosis.
- Musculoskeletal System Disorders: Arthritis or worsening arthritis, arthropathy, bone fracture, myositis, muscle atrophy, muscle weakness, osteomyelitis, polymyositis.
- Neoplasms: Malignant lymphoma, malignant testicular neoplasm, prostatic cancer, plasma cell dyscrasia, secondary leukemia, squamous cell
carcinoma, transformation to aggressive lymphoma, transformation to prolymphocytic leukemia.
- Platelet, Bleeding, and Clotting Disorders: Coagulation disorder, disseminated intravascular coagulation, hematoma, pulmonary embolism, thrombocythemia.
- Psychiatric Disorders: Confusion, hallucinations, nervousness, abnormal thinking, apathy.
- White Cell and RES Disorders: Agranulocytosis, aplasia, decreased haptoglobin, lymphadenopathy, marrow depression.
- Red Blood Cell Disorders: Hemolysis, hemolytic anemia, splenic infarction, splenomegaly.
- Reproductive System Disorders: Cervical dysplasia.
- Resistance Mechanism Disorders: Abscess, bacterial infection, Herpes zoster infection, Pneumocystis carinii infection, otitis media, Tuberculosis infection, viral infection.
- Respiratory System Disorders: Asthma, bronchitis, chronic obstructive pulmonary disease, hemoptysis, hypoxia, pleural effusion, pleurisy, pneumothorax,
pulmonary edema, pulmonary fibrosis, pulmonary infiltration, respiratory depression, respiratory insufficiency, sinusitis,
stridor, throat tightness.
- Skin and Appendages Disorders: Angioedema, bullous eruption, cellulitis, purpuric rash.
- Special Senses Disorders: Taste loss.
- Urinary System Disorders: Abnormal renal function, acute renal failure, anuria, facial edema, hematuria, toxic nephropathy, ureteric obstruction, urinary
retention, urinary tract infection.
- Vascular (extracardiac) Disorders: Cerebral hemorrhage, cerebrovascular disorder, deep vein thrombosis, increased capillary fragility, intracranial hemorrhage,
phlebitis, subarachnoid hemorrhage, thrombophlebitis.
- Vision Disorders: Endophthalmitis.
|
|
OVERDOSAGE
|
| |
Initial doses of alemtuzumab of greater than 3 mg are not well- tolerated. One (1) patient who received 80 mg as an initial
dose by IV infusion experienced acute bronchospasm, cough, and shortness of breath, followed by anuria and death. A review
of the case suggested that tumor lysis syndrome may have played a role.
Single doses of alemtuzumab greater than 30 mg or a cumulative weekly dose greater than 90 mg should not be administered as
higher doses have been associated with a higher incidence of pancytopenia. (See BOXED WARNING and DOSAGE AND ADMINISTRATION .)
There is no known specific antidote for alemtuzumab overdosage. Treatment consists of drug discontinuation and supportive
therapy.
|
DOSAGE AND ADMINISTRATION
|
| |
Alemtuzumab should be administered under the supervision of a physician experienced in the use of antineoplastic therapy.
Dosing Schedule and Administration
|
| |
Alemtuzumab therapy should be initiated at a dose of 3 mg administered as a 2 hour IV infusion daily. (See ADVERSE REACTIONS .) When the alemtuzumab 3 mg daily dose is tolerated ( e.g., infusion- related toxicities are ≤Grade 2), the daily dose should be escalated to 10 mg and continued until tolerated. When
the 10 mg dose is tolerated, the maintenance dose of alemtuzumab 30 mg may be initiated. The maintenance dose of alemtuzumab
is 30 mg/ day administered 3 times/ week on alternate days ( i.e., Monday, Wednesday, and Friday) for up to 12 weeks. In most patients, escalation to 30 mg can be accomplished in 3- 7 days. Dose escalation to the recommended maintenance dose of 30 mg administered 3 times/ week is required. Single doses of alemtuzumab
greater than 30 mg or cumulative weekly doses of greater than 90 mg should not be administered since higher doses are associated
with an increased incidence of pancytopenia. (See BOXED WARNING .) Alemtuzumab should be administered intravenously only. The infusion should be administered over a 2 hour period. DO NOT ADMINISTER AS AN IV PUSH OR BOLUS.
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Recommended Concomitant Medications
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Premedication should be given prior to the first dose, at dose escalations, and as clinically indicated. The premedication
used in clinical studies was diphenhydramine 50 mg and acetaminophen 650 mg administered 30 minutes prior to alemtuzumab infusion.
In cases where severe infusion- related events occur, treatment with hydrocortisone 200 mg was used in decreasing the infusion-
related events.
Patients should receive anti- infective prophylaxis to minimize the risks of serious opportunistic infections. (See BOXED WARNING .) The anti- infective regimen used on Study 1 consisted of trimethoprim/ sulfamethoxazole DS twice daily (bid) 3 times/ week
and famciclovir or equivalent 250 mg twice a day (bid) upon initiation of alemtuzumab therapy. Prophylaxis should be continued
for 2 months after completion of alemtuzumab therapy or until the CD4+count is ≥200 cells/ μl, whichever occurs later.
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Dose Modification and Reinitiation of Therapy
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Alemtuzumab therapy should be discontinued during serious infection, serious hematologic toxicity, or other serious toxicity
until the event resolves. (See WARNINGS .) Alemtuzumab therapy should be permanently discontinued if evidence of autoimmune anemia or thrombocytopenia appears. TABLE 3 includes recommendations for dose modification for severe neutropenia or thrombocytopenia.
| TABLE 3
Dose Modification and Reinitiation of Therapy for Hematologic Toxicity
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| Hematologic Toxicity |
Dose Modification and Reinitiation of Therapy |
| For first occurrence of ANC <250/ μl and/ or platelet count ≤25, 000/ μl |
Withhold alemtuzumab therapy. When ANC ≥500/ μl and platelet count ≥50, 000/ μl, resume alemtuzumab therapy at same dose.
If delay between dosing is ≥7 days, initiate therapy at alemtuzumab 3 mg and escalate to 10 mg and then to 30 mg as tolerated.
|
| For second occurrence of ANC <250/ μl and/ or platelet count ≤25, 000/ μl |
Withhold alemtuzumab therapy. When ANC ≥500/ μl and platelet count ≥50, 000/ μl, resume alemtuzumab therapy at 10 mg. If delay between dosing is ≥7 days, initiate therapy at alemtuzumab 3 mg and escalate to 10 mg only.
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| For third occurrence of ANC <250/ μl and/ or platelet count ≤25, 000/ μl |
Discontinue alemtuzumab therapy permanently. |
| For a decrease of ANC and/ or platelet count to ≤50% of the baseline value in patients initiating therapy with a baseline
ANC ≤500/ μl and/ or a baseline platelet count ≤25, 000/ μl
|
Withhold alemtuzumab therapy. When ANC and/ or platelet count return to baseline value(s), resume alemtuzumab therapy. If
the delay between dosing ≥7 days, initiate therapy at alemtuzumab 3 mg and escalate to 10 mg and then to 30 mg as tolerated.
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Incompatibilities
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No incompatibilities between alemtuzumab and polyvinylchloride (PVC) bags, PVC or polyethylene- lined PVC administration sets,
or low- protein binding filters have been observed. No data are available concerning the incompatibility of alemtuzumab with
other drug substances. Other drug substances should not be added or simultaneously infused through the same IV line.
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HOW SUPPLIED
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Campath (alemtuzumab) is supplied in single- use clear glass ampoules containing 30 mg of alemtuzumab in 3 ml of solution.
Storage: Campath should be stored at 2- 8°C (36- 46°F). Do not freeze. DISCARD IF AMPOULE HAS BEEN FROZEN. Protect from direct sunlight.
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PRODUCT IDENTIFICATION
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None Available |
PRODUCT LISTING - EQUIVALENTS NOT AVAILABLE
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| injection - intravenous - 10 mg/ ml -
|
| 3.0 ml x 3.0 |
$5537.70 |
Campath
Berlex Laboratories
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50419035510 |
| 3.0 ml x 12.0 |
$19372.50 |
Campath
Berlex Laboratories
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50419035512 |
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