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|Alemtuzumab

Alemtuzumab

Trade Names:
Campath
- Sterile, preservative-free solution for injection 30 mg/ mL

Mechanism of Action

Pharmacology

Alemtuzumab is a recombinant DNA-derived humanized monoclonal antibody. Alemtuzumab binds to CD52, a nonmodulating antigen that is present on the surface of essentially all B- and T-lymphocytes, a majority of monocyte, macrophages, NK cells, and a subpopulation of granulocytes. The proposed mechanism of action is antibody-dependent lysis of leukemic cells following cell surface binding.

Pharmacokinetics

Distribution

Vd at steady state is about 0.18 L/kg.

Elimination

Displays nonlinear elimination kinetics. Systemic Cl decreases with repeated administration because of decreased receptor-mediated Cl (loss of CD52 receptors in the periphery). Mean t _½ was 11 h after first dose and 6 days after 12 wk of therapy.

Indications and Usage

Treatment of B-cell chronic lymphocytic leukemia in patients who have been treated with alkylating agents and who have failed fludarabine therapy.

Contraindications

Allergic to alemtuzumab or any of its components; patients with active systemic infections; patients with underlying immunodeficiency.

Dosage and Administration

IV 3 mg/dose daily until tolerated. Increase to 10 mg/dose IV daily until tolerated, then switch to maintenance regimen. Dose escalation to the maintenance dose is required. Most patients start maintenance regimen within 3 to 7 days of initiating therapy.

IV 30 mg/dose, given 3 times weekly for up to 12 wk. Give doses on alternate days, with 1 day between doses (such as Monday, Wednesday, and Friday). Gradually increase to the recommended maintenance dose when initiating therapy or when therapy is interrupted for at least 7 days. To reduce the risk of pancytopenia, avoid giving single doses that are more than 30 mg or cumulative doses more than 90 mg/week.

Diphenhydramine 50 mg and acetaminophen 650 mg 30 min prior to infusion (give prior to first dose, at dose escalations, and as clinically indicated). Also initiate anti-infective prophylaxis: trimethoprim/sulfamethoxazole double strength twice daily 3 times a wk and famciclovir 250 mg twice daily at start of therapy and continue for 2 mo after last dose or when CD4 ⁺ count is at least 200 cells/mL, whichever occurs later.

Discontinue alemtuzumab if any severe infection, profound hematologic toxicity, or other serious toxicity occurs. Resume treatment after event resolves. If therapy is interrupted for 7 or more days, reinstitute alemtuzumab with gradual dose escalation. Permanently discontinue therapy if autoimmune anemia or thrombocytopenia is evident.

IV First occurrence: Delay therapy until ANC at least 500 and platelet count at least 50,000. If therapy is delayed less than 7 days, resume therapy at same dose. If delayed 7 days or more, resume therapy at 3 mg, increasing to 10 and 30 mg as tolerated. Second occurrence: Delay therapy until ANC at least 500 and platelet count at least 50,000. If therapy is delayed less than 7 days, resume therapy at 10 mg. If delayed 7 days or more, resume therapy at 3 mg and increase to 10 mg (maximum) as tolerated. Third occurrence: Permanently discontinue therapy.

IV Delay therapy until ANC and platelet count return to baseline. If therapy is delayed less than 7 days, resume therapy at same dose. If delayed 7 days or more, resume therapy at 3 mg, increasing to 10 and 30 mg as tolerated.

General Advice

• For IV infusion only. Not for intradermal, subcutaneous, IM, IV push or bolus, or intra-arterial administration. Do not shake vial prior to use.
• Withdraw necessary amount of alemtuzumab from vial into syringe (0.1 mL for 3 mg dose; 0.33 mL for 10 mg dose; 1 mL for 30 mg dose) and inject into 100 mL sterile sodium chloride 0.9% or D5W. Gently invert bag to mix solution.
• Administer infusion solution within 8 h after dilution.
• Administer infusion solution over a 2-h period.
• If severe infusion-related reaction occurs, treat with hydrocortisone 200 mg.
• Do not add or simultaneously infuse other drug substances through same IV line.
• Do not use if solution is discolored, cloudy, or contains particulate matter.
• Discard any unused solution. Do not save unused solution for future use.

Storage/Stability

Store vials in refrigerator (36° to 46°F). Protect from direct sunlight and freezing. Discard if vial has been frozen. Diluted infusion solution may be stored for up to 8 h at controlled room temperature (59° to 86°F) or refrigerated. Protect from light.

Drug Interactions

None well documented.

Laboratory Test Interactions

An immune response to alemtuzumab may interfere with subsequent diagnostic serum tests that utilize antibodies.

Adverse Reactions

Cardiovascular

Hypotension (32%); hypertension, tachycardia/supraventricular tachycardia (11%); angina pectoris; atrial fibrillation; cardiac arrest; cardiac failure; cerebral hemorrhage; cerebrovascular disorder; coronary artery disorder; cyanosis; deep vein thrombosis; increased capillary fragility; intracranial hemorrhage; MI; pericarditis; pulmonary embolism; subarachnoid hemorrhage; syncope; thrombophlebitis; ventricular arrhythmia; ventricular tachycardia.

CNS

Fatigue (34%); headache (24%); dysesthesia (15%); asthenia (13%); dizziness (12%); insomnia (10%); malaise (9%); depression, tremor (7%); somnolence (5%); abnormal gait; abnormal thinking; apathy; aphasia; coma; confusion; grand mal convulsions; hallucinations; meningitis; nervousness; paralysis.

Dermatologic

Rash/maculopapular/erythematous (40%); urticaria (30%); pruritus (24%); increased sweating (19%); angioedema; bullous eruption; cellulitis; purpuric rash.

EENT

Decreased hearing; endophthalmitis; otitis media, taste loss, throat tightness; optic neuropathy (postmarketing).

GI

Nausea (54%); vomiting (41%); diarrhea (22%); anorexia (20%); stomatitis/ulcerative stomatitis/mucositis (14%); abdominal pain (11%); dyspepsia (10%); constipation (9%); biliary pain; colitis; duodenal ulcer; esophagitis; gastroenteritis; GI hemorrhage; gingivitis; hematemesis; hemorrhoids; hypoalbuminemia; intestinal obstruction; intestinal perforation; melena; pancreatitis; paralytic ileus; peptic ulcer; peritonitis; pseudomembranous colitis.

Endocrine

Hyperthyroidism.

Genitourinary

Abnormal renal function; acute renal failure; anuria; cervical dysplasia; facial edema; hematuria; toxic nephropathy; ureteric obstruction; urinary retention; UTI.

Hepatic

Hepatic failure; hepatocellular damage; hyperbilirubinemia.

Hematologic-Lymphatic

WBC disorders/neutropenia (85%); RBC disorder/anemia (80%); thrombocytopenia (72%); purpura (8%); epistaxis (7%); pancytopenia (5%); agranulocytosis; aplasia; coagulation disorder; decreased haptoglobin; disseminated intravascular coagulation; hematoma; hemolysis; hemolytic anemia; lymphadenopathy; lymphopenia; marrow depression; splenic infarction; splenomegaly; thrombocythemia.

Metabolic-Nutritional

Acidosis; aggravated diabetes mellitus; dehydration; fluid overload; hyperglycemia; hyperkalemia; hypoglycemia; hypokalemia; hyponatremia; increased alkaline phosphatase; respiratory alkalosis.

Musculoskeletal

Rigors (86%); skeletal pain (24%); myalgias (11%); back pain (10%); arthritis; arthropathy; bone fracture; exacerbation of arthritis; muscle atrophy; muscle weakness; myositis; osteomyelitis; polymyositis.

Respiratory

Dyspnea (26%); cough (25%); bronchitis/pneumonitis (21%); pneumonia (16%); pharyngitis (12%); bronchospasm (9%); rhinitis (7%); asthma; bronchitis; COPD; hemoptysis; hypoxia; pleural effusion; pleurisy; pneumothorax; pulmonary edema; pulmonary fibrosis; pulmonary infiltration; respiratory depression; respiratory insufficiency; sinusitis; stridor.

Miscellaneous

Fever (85%); sepsis (15%); edema/peripheral edema (13%); herpes simplex (11%); chest pain (10%); moniliasis (8%); infection (7%); sensation of temperature change (5%); infusion-related reactions (eg, rigors [89%]; drug-related fever [83%]; nausea [47%]; vomiting [33%]; rash [30%]; fatigue, urticaria [22%]; dyspnea [17%]; hypotension [15%]; pruritus [14%]; diarrhea, headache [13%]); abscess; allergic reactions; anaphylactoid reaction; ascites; bacterial infection; herpes zoster infection; hypovolemia; influenza-like syndrome; malignant lymphoma; malignant testicular neoplasms; mouth edema; neutropenic fever; Pseudomonas carinii infection; plasma cell dyscrasias; prostatic cancer; secondary leukemia; squamous cell carcinoma; transformation to aggressive lymphoma; transformation to prolymphocyte leukemia; tuberculosis infection; viral infection; ARDS, cardiac arrest and arrhythmias, Goodpasture syndrome, Graves disease, Guillain-Barr syndrome, MI, pulmonary infiltrates, respiratory arrest, serum sickness, syncope, tumor lysis syndrome (postmarketing).

Precautions

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy in children not established.

Hypersensitivity

Discontinue further therapy if the patient experiences anaphylaxis. Patients who are hypersensitive to alemtuzumab may react to other monoclonal antibodies.

CV

Use additional caution in patients with ischemic heart disease or patients receiving antihypertensive medications.

Immunization

Do not immunize patients who recently received alemtuzumab with live viral vaccines.

Immunosuppression

Alemtuzumab may cause profound immunosuppression and increased risk of infection during treatment and up to 12 mo afterward.

Lymphopenia

Patients with profound lymphopenia are at risk for graft-vs-host disease when nonirradiated blood products are given. Administration of irradiated blood products is recommended.

Opportunistic infections

To minimize risks of serious opportunistic infections, give anti-infective prophylaxis during and for 2 mo after completion of alemtuzumab therapy, or until CD4 count is at least 200 cells/mcL, which ever occurs later.

Overdosage

Symptoms

Acute bronchospasm, cough, shortness of breath, followed by anuria and death.

Patient Information

• Advise patient or caregiver that alemtuzumab will be prepared and administered by health care professionals in a health care setting.
• Advise patient that additional medications to prevent infections and infusion-related reactions may be ordered and to take exactly as prescribed.
• Advise family or caregiver to report any of the following to health care provider: fever, sore throat, changes in heart rhythm, chest pain, chills, persistent nausea, vomiting, diarrhea, fainting, rash, hives, itching, any sign of infection, unexplained shortness of breath or difficulty breathing, mouth sores, bleeding or unusual bruising, any other unusual or unexplained feelings or symptoms.
• Advise patient that medication may cause drowsiness or dizziness and not to drive or perform other activities requiring mental alertness or coordination until tolerance is determined.
• Caution patient not to receive live viral vaccines during treatment with, or within several months after completing therapy with, alemtuzumab.
• Advise women of childbearing potential and men of reproductive potential to use effective contraception during and for at least 6 mo following treatment.
• Instruct women not to breast-feed during treatment and for at least 3 mo following the last dose of alemtuzumab.