Alemtuzumab

Pronunciation

(ay lem TU zoo mab)

U.S. Brand Names

Campath®

Synonyms

Campath-1H; DNA-derived Humanized Monoclonal Antibody; Humanized IgG1 Anti-CD52 Monoclonal Antibody

Generic Available

Use

Treatment of B-cell chronic lymphocytic leukemia (B-CLL)

Use - Unlabeled/Investigational

Treatment of refractory T-cell prolymphocytic leukemia (T-PLL); rheumatoid arthritis; graft versus host disease; multiple myeloma

Pregnancy Risk Factor

Pregnancy Implications

Human IgG is known to cross the placental barrier; therefore, alemtuzumab may also cross the barrier and cause fetal B- and T-lymphocyte depletion. Well-controlled human trials have not been done. Use during pregnancy only if the benefit to the mother outweighs the potential risk to the fetus.

Lactation

Excretion in breast milk unknown/contraindicated

Contraindications

Known type 1 hypersensitivity or anaphylactic reaction to alemtuzumab or any component of the formulation; hypersensitivity to another monoclonal antibody; active systemic infections; underlying immunodeficiency (eg, seropositive for HIV); single doses >30 mg or cumulative doses >90 mg/week; administration by I.V. push or bolus

Warnings/Precautions

Should only be used by physicians experienced in antineoplastic therapy. Serious infections may occur. Prophylactic therapy against PCP pneumonia and herpes viral infections is recommended upon initiation of therapy and for at least 2 months following last dose or until CD4⁺ counts

200 cells/

L. CD4⁺ and CD8⁺ lymphocyte counts may not return to baseline levels for more than 1 year. Premedication with an antihistamine and acetaminophen prior to dosing recommended; may prevent or ameliorate infusion-related reactions. Antiemetics, meperidine, and corticosteroids have also been used. Gradual escalation to the recommended maintenance dose is required at initiation and after interruption of therapy for

7 days to minimize infusion-related reactions. Irradiation of any blood products administered during lymphopenia is recommended to prevent graft versus host disease. Severe, prolonged myelosuppression, autoimmune anemia, and autoimmune thrombocytopenia have occurred. Doses >90 mg/week are associated with an increased incidence of pancytopenia. Median duration of neutropenia is 21 days; median duration of thrombocytopenia is 21 days. Discontinue therapy during serious infection, serious hematologic or other serious toxicity until the event resolves. Permanently discontinue if autoimmune anemia or autoimmune thrombocytopenia occurs. Patients should not be immunized with live, viral vaccines during or recently after treatment. The ability to respond to any vaccine following therapy is unknown. Patients who develop hypersensitivity reactions to alemtuzumab may have reactions to other monoclonal antibodies. Women of childbearing potential and men of reproductive potential should use effective contraceptive methods during treatment and for a minimum of 6 months following therapy. Safety and efficacy have not been established in pediatric patients.

Adverse Reactions

>10%:

Cardiovascular: Hypotension (15% to 32%, infusion-related), peripheral edema (13%), hypertension (11%), tachycardia/SVT (11%)

Central nervous system: Drug-related fever (83%, infusion-related), fatigue (22% to 34%, infusion-related), headache (13% to 24%), dysthesias (15%), dizziness (12%), neutropenic fever (10%)

Dermatologic: Rash (30% to 40%, infusion-related), urticaria (22% to 30%, infusion-related), pruritus (14% to 24%, infusion-related)

Gastrointestinal: Nausea (47% to 54%), vomiting (33% to 41%), anorexia (20%), diarrhea (13% to 22%), stomatitis/mucositis (14%), abdominal pain (11%)

Hematologic: Lymphopenia, severe neutropenia (64% to 70%); severe anemia (38% to 47%) and severe thrombocytopenia (50% to 52%) may be prolonged and dose-limiting

Neuromuscular & skeletal: Rigors (89%, infusion-related), skeletal muscle pain (24%), weakness (13%), myalgia (11%)

Respiratory: Dyspnea (17% to 26%, infusion-related), cough (25%), bronchitis/pneumonitis (21%), pharyngitis (12%)

Miscellaneous: Infection (43% including sepsis, pneumonia, opportunistic infection; received PCP pneumonia and herpes prophylaxis); diaphoresis (19%)

1% to 10%:

Cardiovascular: Chest pain (10%)

Central nervous system: Insomnia (10%), malaise (9%), depression (7%), temperature change sensation (5%), somnolence (5%)

Dermatologic: Purpura (8%)

Gastrointestinal: Dyspepsia (10%), constipation (9%)

Hematologic: Pancytopenia/marrow hypoplasia (6%), positive Coombs' test without hemolysis (2%), autoimmune thrombocytopenia (2%), antibodies to alemtuzumab (2%), autoimmune hemolytic anemia (1%)

Neuromuscular & skeletal: Back pain (10%), tremor (7%)

Respiratory: Bronchospasm (9%), epistaxis (7%), rhinitis (7%)

<1%: Abnormal gait, abnormal thinking, acidosis, acute renal failure, agranulocytosis, alkaline phosphatase elevation, allergic reactions, anaphylactoid reactions, angina pectoris, angioedema, anuria, apathy, aphasia, arthritis, arthritis exacerbation, arthropathy, ascites, asthma, biliary pain, bone fracture, bone marrow aplasia, bronchitis, bullous eruption, capillary fragility, cardiac arrest, cardiac failure, cellulitis, cerebral hemorrhage, cerebrovascular disorder, cervical dysplasia, coagulation abnormality, colitis, coma, confusion, COPD, decreased haptoglobin, deep vein thrombosis, dehydration, diabetes mellitus exacerbation, disseminated intravascular coagulation, duodenal ulcer, endophthalmitis, esophagitis, facial edema, fluid overload, gingivitis, gastroenteritis, gastrointestinal hemorrhage, hallucinations, hearing loss, hematemesis, hematoma, hematuria, hemolysis, hemolytic anemia, hemoptysis, hemorrhoids, hepatic failure, hepatocellular damage, hyperbilirubinemia, hyperglycemia, hyperkalemia, hyperthyroidism, hypoalbuminemia, hypoglycemia, hyponatremia, hypovolemia, hypoxia, influenza-like syndrome, interstitial pneumonitis, intestinal obstruction, intestinal perforation, intracranial hemorrhage, lymphadenopathy, malignant lymphoma, malignant testicular neoplasm, marrow depression, melena, meningitis, mouth edema, MI, myositis, muscle atrophy, muscle weakness, nervousness, osteomyelitis, pancreatitis, paralysis, paralytic ileus, paroxysmal nocturnal hemoglobinuria-like monocytes, peptic ulcer, pericarditis, peritonitis, plasma cell dyscrasia, phlebitis, pleural effusion, pleurisy, pneumothorax, polymyositis, progressive multifocal leukoencephalopathy, prostate cancer, pseudomembranous colitis, pulmonary edema, pulmonary embolism, pulmonary fibrosis, pulmonary infiltration, purpuric rash, renal dysfunction, respiratory alkalosis, respiratory depression, respiratory insufficiency, secondary leukemia, seizure (grand mal), sinusitis, splenic infarction, splenomegaly, squamous cell carcinoma, stridor, subarachnoid hemorrhage, syncope, taste loss, toxic nephropathy, transformation to aggressive lymphoma, transformation to prolymphocytic leukemia, thrombocythemia, thrombophlebitis, throat tightness, ureteric obstruction, urinary retention, ventricular arrhythmia, ventricular tachycardia

Overdosage/Toxicology

Symptoms are likely to be extensions of adverse events (may include respiratory distress, bronchospasm, anuria). Tumor lysis syndrome has been associated with accidental overdose. Treatment is symptom-directed and supportive.

Stability

Prior to dilution, store at 2°C to 8°C (36°F to 46°F). Do not freeze; protect from direct sunlight. Throw away solution that has been frozen. Do not shake prior to use. Withdraw dose into a syringe. Inject into 100 mL NS or D5W. Gently invert bag to mix solution. Following dilution, use within 8 hours. Store at room temperature or refrigerate; protect from light. Medications should not be added to the solution or simultaneously infused through the same I.V. line.

Compatibility

Medications should not be added to the solution or simultaneously infused through the same I.V. line.

Mechanism of Action

Recombinant monoclonal antibody binds to CD52, a nonmodulating antigen present on the surface of B and T lymphocytes, a majority of monocytes, macrophages, NK cells and a subpopulation of granulocytes. After binding to CD52⁺ cells, an antibody-dependent lysis occurs.

Pharmacodynamics/Kinetics

Distribution: Vd: 0.18 L/kg

Metabolism: Clearance decreases with repeated dosing (due to loss of CD52 receptors in periphery), resulting in a sevenfold increase in AUC.

Half-life elimination: Initial: 11 hours; 6 days following repeated dosing

Dosage

Note: Dose escalation is required; usually accomplished in 3-7 days. Do not exceed single doses >30 mg or cumulative doses >90 mg/week. Premedicate with diphenhydramine and acetaminophen 30 minutes before initiation of infusion. Start anti-infective prophylaxis. Discontinue therapy during serious infection, serious hematologic or other serious toxicity until the event resolves. Permanently discontinue if evidence of autoimmune anemia or autoimmune thrombocytopenia occurs.

I.V. infusion: Adults: B-CLL: Note: A similar dosing regimen has been successfully administered subcutaneously (Lundin, 2002):

Initial: 3 mg/day as a 2-hour infusion; increase to 10 mg/day, then to 30 mg/day as tolerated

Maintenance: 30 mg/day 3 times/week on alternate days for up to 12 weeks

Dosage adjustment for hematologic toxicity (severe neutropenia or thrombocytopenia, not autoimmune):

First occurrence: ANC <250/ L and/or platelet count 25,000/ L: Hold therapy; resume at same dose when ANC 500/ L and platelet count 50,000/ L. If delay between dosing is 7 days, restart at 3 mg/day and escalate as tolerated.

Second occurrence: ANC <250/ L and/or platelet count 25,000/ L: Hold therapy; resume at 10 mg/day when ANC 500/ L and platelet count 50,000/ L. If delay between dosing is 7 days, restart at 3 mg/day and escalate as tolerated.

Third occurrence: ANC <250/ L and/or platelet count 25,000/ L: Permanently discontinue therapy

Patients with a baseline ANC 500/ L and/or a baseline platelet count 25,000/ L at initiation of therapy: If ANC and/or platelet counts decreased to 50% of the baseline value, hold therapy. When ANC and/or platelet count return to baseline, resume therapy. If delay between dosing is 7 days, restart at 3 mg/day and escalate as tolerated.

Administration

Administer by I.V. infusion only over 2 hours. Premedicate with diphenhydramine and acetaminophen 30 minutes before initiation of infusion. Start anti-infective prophylaxis. Other drugs should not be added to or simultaneously infused through the same I.V. line. Do not give I.V. bolus or push.

Monitoring Parameters

Vital signs; carefully monitor BP especially in patient with ischemic heart disease or on antihypertensive medications; CBC and platelets weekly (more frequent monitoring needed if any hematologic abnormality occurs); signs and symptoms of infection; CD4⁺ lymphocyte counts. Monitor closely for infusion reactions (including hypotension, rigors, fever, shortness of breath, bronchospasm, chills, and/or rash).

Test Interactions

May interfere with diagnostic serum tests that utilize antibodies.

Patient Education

This medication can only be administered I.V.; during infusion, you will be closely monitored. You will need frequent laboratory tests during course of therapy. Do not use any prescription or OTC medications unless approved by your prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake, and nutrition (small, frequent meals will help). You may experience abdominal pain, mouth sores, nausea, or vomiting (small, frequent meals, good mouth care with soft toothbrush or swabs, sucking lozenges or chewing gum, and avoidance of spicy or salty foods may help). Report unresolved GI problems, persistent fever, chills, muscle pain, skin rash, unusual bleeding or bruising, signs of infection (mouth sores, sore throat, white plaques in mouth or perianal area, burning on urination); swelling of extremities; respiratory difficulty; chest pain or palpitations; or other persistent adverse reactions. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Stomatitis and mucositis.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

Fatigue is common; may cause dizziness, depression, insomnia

Mental Health: Effects on Psychiatric Treatment

Hypotension is common; concurrent use with psychotropics may produce additive hypotensive effects; monitor. Nausea, vomiting, and diarrhea are common; may be additive when used with SSRIs; monitor. Neutropenia is common; use caution with clozapine and carbamazepine.

Oncology: Emetic Potential

Moderate (30% to 60%)

Oncology: Vesicant

Dosage Forms

[DSC] = Discontinued product

Injection, solution [ampul]: 10 mg/mL (3 mL)

Injection, solution [vial]: 30 mg/mL (1 mL) [DSC]

References

Dearden CE, Matutes E, and Catovsky D, "Alemtuzumab in T-Cell Malignancies," Med Oncol , 2002, 19(Suppl):27-32.

Dumont FJ, "CAMPATH (Alemtuzumab) for the Treatment of Chronic Lymphocytic Leukemia and Beyond," Expert Rev Anticancer Ther , 2002, 2(1):23-35.

Ferrajoli A, O'Brien S, and Keating MJ, "Alemtuzumab: A Novel Monoclonal Antibody," Expert Opin Biol Ther , 2001, 1(6):1059-65.

Hale G, "Alemtuzumab in Stem Cell Transplantation," Med Oncol , 2002, 19(Suppl):33-47.

Kennedy B and Hillmen P, "Immunological Effects and Safe Administration of Alemtuzumab (MabCampath) in Advanced B-cLL," Med Oncol , 2002, 19(Suppl):49-55.

Lundin J, Kimby E, Bjorkholm M, et al, "Phase II Trial of Subcutaneous Anti-CD52 Monoclonal Antibody Alemtuzumab (Campath-1H) as First-line Treatment for Patients With B-cell Chronic Lymphocytic Leukemia (B-CLL)," Blood , 2002, 100(3):768-73.

Lundin J, Osterborg A, Brittinger G, et al, "CAMPATH-1H Monoclonal Antibody in Therapy for Previously Treated Low-Grade Non-Hodgkin's Lymphomas: A Phase II Multicenter Study. European Study Group of CAMPATH-1H Treatment in Low-Grade Non-Hodgkin's Lymphoma," J Clin Oncol , 1998, 16(10):3257-63.

Osterborg A, Dyer MJ, Bunjes D, et al, "Phase II Multicenter Study of Human CD52 Antibody in Previously Treated Chronic Lymphocytic Leukemia. European Study Group of CAMPATH-1H Treatment in Chronic Lymphocytic Leukemia," J Clin Oncol , 1997, 15(4):1567-74.

Osterborg A, Fassas AS, Anagnostopoulos A, et al, "Humanifed CD52 Monoclonal Antibody Campath-1H as First-Line Treatment in Chronic Lymphocytic Leukaemia, Br J Haematol , 1996, 93(1):151-3.

Osterborg A, Mellstedt H, and Keating M, "Clinical Effects of Alemtuzumab (Campath-1H) in B-cell Chronic Lymphocytic Leukemia," Med Oncol , 2002, 19(Suppl):21-6.

Rai K and Hallek M, "Future Prospects for Alemtuzumab (MabCampath)," Med Oncol , 2002, 19(Suppl):57-63.

International Brand Names

Mabcambath® (AT, CH, DE, DK, ES, FI, FR, GB, IL, IT, NO, PL); Mabcampath® (BE, GB, SE)

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