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阿仑单抗Campath(欧洲商品名;卡帕什MabCampath)

——Campath——FDA批准治疗B细胞性慢性淋巴细胞性白血病新药。(美国Millennium制药)

2004-04-28 05:41:06  作者:  来源:新特药房药讯  浏览次数:289  文字大小:【】【】【

Campath(MabCampath)——人源化单克隆抗体  
Campath(欧洲商品名:MabCampath)是第一个对烷化剂或福达华治疗无效的患者仍具有显着疗效的药物。根据一项国际II期临床研究结果显示,经其它药物治疗复发或难治的CLL患者用Campath治疗后?可使其生存期显着延长1倍以上。
目前,有关专家正致力于研究该药的新用法及联合用药,如研究与福达华等联合应用的疗效。
         
Campath是CD52抗体,可与表面携带CD52抗原的细胞相结合从而启动细胞破坏过程。通过这一方式,Campath可以清除外周血、骨髓及其它累及器官的淋巴细胞。由于T淋巴细胞同样携带CD52抗原,Campath已被成功地应用于前T细胞性白血病(T-PLL)及外周T细胞淋巴瘤的治疗。作为对福达华的补充,Campath在非清髓性移植中也发挥着重要作用。目前,已有越来越多的肿瘤专家在早期治疗中选择Campath。

Campath® (ALEMTUZUMAB)
Package Insert
Campath® (ALEMTUZUMAB)
Millennium and ILEX Partners, LP

▲MabCampath; 为第一及现时唯一一种被美国药物及食物管理局准许使用在B细胞型 CLL 的新的药物。
▲MabCampath;是一种单克隆抗体,能有效对化疗没有效用的病人产生疗效。
▲MabCampath; 的原理是针对CD52抗原,这种抗原主要分布在B及T细胞的表面。
▲MabCampath® 由于是一种抗体,会在淋巴细胞表面与CD 52抗原结合,并会引导身体的免疫系统破坏及吞噬在血液及骨髓结合后的细胞。

Campath should be administered under the supervisionofaphysician experienced in the use of antineoplastic therapy.

HematologicToxicity:Seriousand,inrareinstancesfatal,

pancytopenia/marrowhypoplasia,autoimmuneidiopathicthrombocytopenia,and autoimmune hemolytic anemia have occurred in patients receiving Campath therapy. Single doses of Campath greater than 30 mg or cumulative doses greater than 90 mg per week should not be administered because these doses are associated with a higher incidence of pancytopenia.

Infusion Reactions: Campath canresultinseriousinfusionreactions. Patients should be carefully monitored during infusions and Campath discontinued if indicated. (SeeDOSAGEANDADMINISTRATION.) 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 Campath 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.

Campath® (ALEMTUZUMAB)

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 ofthemalereproductive 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). Campath was administered once weekly for a maximum of 12 weeks. Following intravenous 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 (t1/2) over the dosing interval was about 12 days. The pharmacokinetic profile of Campath administered as a 30 mg intravenous infusion three times per week was evaluated in CLL patients. Peak and trough levels of Campath 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 Campath concentration corresponded with the reduction in malignant lymphocytosis.

CLINICAL STUDIES

The safety and efficacy of Campath 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 Campath 30 mg intravenously three times per week for 4 to 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 Campath.

Two supportive, multicenter, open-label, noncomparative studies of Campath 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 Campath was 30 mg three times per 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 Campath therapy. Duration of response is calculated from the onset of the response. Table 1: Summary of Patient Population and Outcomes Study 1

(N=93)
Study 2

(N=32)
Study 3

(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

Fludarabine
100%

100%
100%

34%
92%

100%

Disease Characteristics:
Rai Stage III/IV Disease

B-Symptoms
76%

42%
72%

31%
71%

21%

Overall Response Rate
(95% Confidence Interval)

Complete Response

Partial Response
33%

(23%, 43%)

2%

31%
21%

(8%, 33%)

0%

21%
29%

(11%, 47%)

0%

29%

Median Duration of Response (months)
(95% Confidence Interval)
7

(5, 8)
7

(5, 23)
11

(6, 19)
Median Time to Response (months)
(95% Confidence Interval)
2
(1, 2)
4
(1, 5)
4
(2, 4)
Progression-Free Survival (months)
(95% Confidence Interval)
4

(3, 5)
5

(3, 7)
7

(3, 9)

INDICATIONS AND USAGE

Campath 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 Campath 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

Campath 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 Campath or to any one of its components.

Return to Table of Contents

WARNINGS (See BOXED WARNING.)

Infusion-Related Events:

Campath 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, Campath 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, Campath should be reinstituted with gradual dose escalation. (See ADVERSE EVENTS and DOSAGE AND ADMINISTRATION.)

Immunosuppression/Opportunistic Infections:

Campath induces profound lymphopenia. A variety of opportunistic infections have been reported in patients receiving Campath therapy (see ADVERSE EVENTS, Infections). If a serious infection occurs, Campath 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 Campath or until CD4+ counts are ³ 200 cells/mL. The median time to recovery of CD4+ counts to ³ 200/mL 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 Campath. Bone marrow aplasia and hypoplasia were observed in the clinical studies at the recommended dose. The incidence of these complications increased with doses above therecommended dose. In addition, severe and fatal autoimmune anemia and thrombocytopenia were observed in patients with CLL. Campath should be discontinued for severe hematologic toxicity (see Table 3 Dose Modification and Reinitiation of Therapy for Hematologic Toxicity) or in any patient with evidence of autoimmune hematologic toxicity. Following resolution of transient, non-immune myelosuppression, Campath may be reinitiated with caution. (See DOSAGE AND ADMINISTRATION.) There is no information on the safety of resumption of Campath in patients with autoimmune cytopenias or marrow aplasia.(SeeADVERSEREACTIONS.)

PRECAUTIONS

Laboratory Monitoring:

Complete blood counts (CBC) and platelet counts should be obtained at weekly intervals during Campath therapy and more frequently if worsening anemia, neutropenia, or thrombocytopenia is observed on therapy. CD4+ counts should be assessed after treatment until recovery to ³ 200 cells/mL. (See WARNINGS and ADVERSE REACTIONS.)

Drug/Laboratory Interactions:

No formal drug interaction studies have been performed with Campath. An immune response to Campath may interfere with subsequent diagnostic serum tests that utilize antibodies.

Immunization:

Patients who have recently received Campath, should not be immunized with live viral vaccines, due to their immunosuppression. The safety of immunization with live viral vaccines following Campath therapy has not been studied. The ability to generate a primary or anamnestic humoral response to any vaccine following Campath 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 Campath. The data reflect the percentage of patients whose test results were considered positive for antibody to Campath 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 Campath with the incidence of antibodies to other products may be misleading. Patients who develop hypersensitivity to Campath may have allergic or hypersensitivity reactions to other monoclonal antibodies.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

No long-term studies in animals have been performed to establish the carcinogenic or mutagenic potential of Campath, 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 Campath therapy.

Pregnancy Category C:

Animal reproduction studies have not been conducted with Campath. It is not known whether Campath 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 Campath may cross the placental barrier and cause fetal B and T lymphocyte depletion. Campath should be given to a pregnant woman only if clearly needed.

Nursing Mothers: Excretion of Campath 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 Campath.

Pediatric Use: The safety and effectiveness of Campath 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 Campath as a single agent administered at a maintenance dose of 30 mg intravenously three times weekly for 4 to 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 Campath 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 mostcommon 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 (one or more infections per patient) related to Campath 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 of the Grade 3 or 4 infections occurred during treatment or within 30 days of last dose. In addition one or more episodes of febrile neutropenia (ANC £ 500 cells/mL 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 one fatality, Grade 3 or 4 pneumonia in 15% with five fatalities, and opportunistic infections in 17% with four 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 Campath 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: Campath 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 one 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 Campath 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 one 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 one 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 one fatal case of Campath-related autoimmune thrombocytopenia. (See BOXED WARNING.)

Lymphopenia: The median CD4+ count at 4 weeks after initiation of Campath therapy was 2 (two)/mL, at 2 months after discontinuation of Campath therapy, 207/mL, and 6 months after discontinuation, 470/mL. The pattern of change in median CD8+ lymphocyte counts was similar to that of CD4+ cells. In some patients treated with Campath, 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) Adverse Event: B-CLL STUDIES (N = 149)

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 one patient treated on studies where Campath 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

eaction,ascites,hypovolemia,influenzalikesyndrome,mouthedema,neutropenic fever, syncope Cardiovascular Disorders: cardiac failure, cyanosis, atrial fibrillation, cardiac arrest, ventricular arrhythmia,ventricular tachycardia, angina pectoris, coronary arterydisorder,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, paralyticileus,pepticulcer,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
Return to Table of Contents OVERDOSAGE Initial doses of Campath of greater than 3 mg are not well-tolerated. One 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 Campath 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 Campath overdosage. Treatment consists of drug discontinuation and supportive therapy.
Return to Table of Contents DOSAGE AND ADMINISTRATION Campath should be administered under the supervision of a physician experienced in the use of antineoplastic therapy.
Dosing Schedule and Administration: Campath therapy should be initiated at a dose of 3 mg administered as a 2 hour IV infusion daily. (See ADVERSE EVENTS.) When the Campath 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 Campath 30 mg may be initiated.

The maintenance dose of Campath is 30 mg/day administered three times per 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 three times per week is required. Single doses of Campath 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.) Campath should be administered intravenously only.

The infusion should be administered over a 2 hour period. DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS.
Recommended Concomitant Medications:
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 Campath 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) three times per week and famciclovir or equivalent 250 mg twice a day (BID) upon initiation of Campath therapy. Prophylaxis should be continued for 2 months after completion of Campath therapy or until the CD4+ count is ³ 200 cells/mL,whichever occurs later.
Dose Modification and Reinitiation of Therapy: Campath therapy should be discontinued during serious infection, serious hematologic toxicity, or other serious toxicity until the event resolves. (See WARNINGS.) Campath therapy should be permanently discontinued if evidence of autoimmune anemia or thrombocytopenia appears. Table 3 includes recommendations for dose modification forsevereneutropeniaorthrombocytopenia.

Table 3: Dose Modification and Reinitiation of Therapy for Hematologic Toxicity Hematologic Toxicity Dose Modification and Reinitiation of Therapy For first occurrence of ANC < 250/mL and/or platelet count £ 25,000/mL Withhold Campath therapy. When ANC ³ 500/mL and platelet count ³ 50,000/mL, resume Campath therapy at same dose. If delay between dosing is ³ 7 days, initiate therapy at Campath 3 mg and escalate to 10 mg and then to 30 mg as tolerated.
For second occurrence of ANC < 250/mL and/or platelet count £ 25,000/mL Withhold Campath therapy. When ANC ³ 500/mL and platelet count ³ 50,000/mL, resume Campath therapy at 10 mg. If delay between dosing is ³ 7 days, initiate therapy at Campath 3 mg and escalate to 10 mg only.
For third occurrence of ANC < 250/mL and/or platelet count £ 25,000/mL Discontinue Campath 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/mL and/or a baseline platelet count £ 25,000/mL Withhold Campath therapy. When ANC and/or platelet count return to baseline value(s), resume Campath therapy. If the delay between dosing ³ 7 days, initiate therapy at Campath 3 mg and escalate to 10 mg and then to 30 mg as tolerated.
Preparation for Administration:
Parenteral drug products should be inspected for visible particulate matter and discoloration prior to administration. If particulate matter is present or the solution is discolored, the vial should not be used. DO NOT SHAKE AMPOULE PRIOR TO USE. As with all parenteral drug products, aseptic technique should be used during the preparation and administration of Campath. Withdraw the necessary amount of Campath from the ampoule into a syringe. Filter with a sterile, low-protein binding, non-fiber releasing 5 mm filter prior to dilution.
Inject 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 and any unused drug product.
Campath contains no antimicrobial preservative. Campath should be used within 8 hours after dilution. Campath solutions may be stored at room temperature (15-30°C) or refrigerated. Campath solutions should be protected from light.
Incompatibilities:
No incompatibilities between Campath 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 Campath with other drug substances. Other drug substances should not be added or simultaneously infused through the same intravenous line.
Return to Table of Contents HOW SUPPLIED Campath (Alemtuzumab) is supplied in single-use clear glass ampoules containing 30 mg of Alemtuzumab in 3 mL of solution. Each box contains either three Campath ampoules (NDC 50419-355-10) or 12 Campath ampoules (NDC 50419-355-12).
Campath should be stored at 2-8°C (36-46°F). Do not freeze. DISCARD IF AMPOULE HAS BEEN FROZEN. Protect from direct sunlight.
Rx only.
U.S. Patents: 5,545,403; 5,545,405; 5,654,403; 5,846,534 Other patents pending
Manufactured by: Millennium and ILEX Partners, LP Cambridge, MA 02142
Distributed by: Berlex Laboratories, Richmond, CA 94804 Issued: May 2001
Last Updated: 8/30/2001
Date created: September 26, 2003

【一】其它名称:
Campath、Mabcampath,坎帕斯
【二】来源:
利用基因重组及单克隆抗体技术生产的人源性抗CD52单克隆抗体。
【三】药物机制:
本品是CD52单抗,与表达CD52的细胞结合后,可以通过抗体领带的溶解作用破坏白血病细胞。CD52表达于所有B细胞、T中国医学健康网细胞、NK细胞、多数单核巨噬细胞、部分粒细胞表面,而红细胞和造血干细胞不表达。皮肤细胞和男性生殖器(附睾、精子、精襄)细胞也表达CD52。成熟精子表达CD52,但是精原细胞和不成熟精子不表达。
【四】药代动力学:
慢性淋巴细胞白血病(CLL)患者每周静脉输液3次,每次30mg,治疗6周后,达到稳态血药浓度。最大血药浓度(Cmax)和曲线下面积(AUC)与用药剂量有关。平均半衰期(T1/2)为12天。本品存在较大的个体差异。随着治疗中恶性淋巴细胞数降低,本品血药浓度会有调高。
【五】药物相互作用:
尚无正式有关本品与其它药物间相互作用的研究报道。
【六】适应证:
本品为抗细胞表面CD52抗原的单克隆抗体,FDA批准此药用于治疗对烷化剂和氟达拉滨耐药的进展期CLL。此外,已进行的临床研究还包括非霍奇金淋巴瘤(NHL)、多发性硬化症及其它自身免疫性疾病、实体器官移植及骨髓移植后移植抗宿主病(GVHD)等。
【七】单药有效率:
治疗烷化剂和氟达拉滨耐药的进展期CLL单药有效率为21%-33%。
【八】剂型:
每支(3ml)Campath含有30mg
Alemtuzumab,24.0mg氯化钠,3.5mg磷酸氢二钠,0.6mg氯化钾,0.6mg磷酸二氢钾,0.3mg polysorbate
80,0.056mg依地酸二钠。不含防腐剂。
【九】剂量:
 起始剂量:3mg/d,静脉输液持续2小时。如患者可以耐受,剂量可增加至10mg/d,如还可以耐受,加量至30mg,隔日用药,每周3次,持续12周。(建议每次剂量不超过30mg,或者每周累积剂量不超过90mg).
【十】给药途径:
本品只能静脉点滴,不能静脉注射或者静脉冲击给药。
【十一】配伍:
尚无相关资料。
【十二】禁忌证:
全身活动性感染、免疫缺陷症(如HIV血清学检查阳性)、已知对本品中Campath和其它添加成分有I型超每反应和过敏史的患者。
【十三】不良反应:
1.输液相关副作用:寒战、发热、恶心、呕吐、低血压、皮疹、乏力、荨麻疹、呼吸困难、瘙痒、头痛、腹泻。
2.全身副作用:发热、乏力、疼痛、衰弱、水肿、脓血症、单纯疱疹、念珠菌病、病毒感染和其它病原菌感染。
3.血液系统:全血减少、骨髓增生低下、贫血、中性粒细胞减少、血小板减少、淋巴细胞减少、紫癜。
4.循环系统:低血压、高血压、心律失常(心动过速)。
5.中枢和外周神经系统痢疾:头痛眩晕、颤抖。6.消化系统:食欲不振、呕吐、腹泻、胃炎、溃疡性口炎、粘膜炎、腹痛、消化不良、便秘。
7.肌肉骨骼:肌痛、骨痛、背痛、胸痛。
8.精神病变:失眠、抑郁、嗜睡。
9.呼吸系统:呼吸困难、咳嗽、支气管炎、肺炎、咽炎、鼻炎、支气管痉挛。
10.皮肤病变:皮疹、斑丘疹、红斑疹、多汗。
【十四】临床应用规程:
1.用药前检测血常规、肝肾功能、血压、心电图、免疫功能。
2.静脉输液30分钟前予以苯海拉明50mg和对乙酰氨基酚650mg预防和减轻输液反应。如果出现严重输液反应,予以氢化可的松200mg.
3.用药前予以磺胺类药物和法昔洛韦及类似药物预防感染,直至停药后2个月或者CD4+细胞达到200000000/l以上。
4.每周检查外周血全血细胞计数,如果出现中性粒细胞减少、血小板减少则需增加检查频次。定基检测CD4+细胞直至达到200000000/l以上。
5.首次出现ANC<250000000/l以上,和/或血小板≤25000000000/L.则需要停药,直至ANC≥500000000/L.和血小板≥50000000000/L。重新用药时,停药时间在7天之内者,剂量同停药前;如停药时间超过7天,则从3mg起用,渐渐加量至10mg,30mg。
6.如果第二次出现ANC<250000000/L,和/或血小板≤25000000000/L,则需要停药,直至ANC≥500000000/L.和血小板≥50000000000/L。重新用药时,停药时间在7天之内者,剂量为10mg/d;如停药时间超过7天,则从3mg/d起用,并只能加量至10mg/d.
7.如果第三次出现ANC<250000000/L,和/或血小板≤25000000000/L,则永久停药。
8.如果患者用药前ANC<500000000/L,和/或血小板≤25000000000/L,则于ANC和/或血小板减少至用药前50%以下时停药。在ANC和/或血小板调高至用药前水平时,重新开始用药。如果停药时间超过7天,则从3mg起用,渐渐加量至10mg/30mg.
9.使用时100ml0.9%无菌生理盐水或者5%葡萄糖稀释,轻轻颠倒混匀。丢掉用过的注射器和剩余药品。每次输液持续时间2小时以上。
【十五】贮存:
原药2-8℃(36-46℃)避光保存,严禁冻存。稀释后室温(15-30℃)避光保存,8小时内使用。

Campath(卡帕什MabCampath)说明

【原产地英文商品名】CAMPATH-30mg/ml/Vial,3Vials/Bo
【原产地英文药品名称】ALEMTUZUMAB
【中文参考商品】卡帕什-30毫克/毫升/瓶, 3瓶/盒
【中文参考药品】阿仑单抗
【临床试验期】完成
【中文适应病症】慢性淋巴β细胞白血球
【中文适应病症】非白血性白血病
【中文适应病症】白血病
【中文适应病症】癌症 

责任编辑:


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