992/BERLEX
`
`Betaseron-Cont.
`
`r------~6. Hold the syringe with the needle
`pointing upward.
`7. TiP. the syringe gently until any air
`bubbles that formed rise to the top of
`the barrel of the syringe.
`
`rj~,-.-.
`• > -.
`/;
`/ ·} \.1
`\I \
`)
`ir.-'
`1 ",
`; 8. Carefully push in the plunger to
`··
`/
`//
`t "..
`eject ONLY THE AIR through the
`' - - - - - - - needle.
`
`9. Remove the needle/syringe from the viaL
`10~~~Ci.£ the needle on the syringe.
`NOTE: The injection should be administered immediately
`after mixing (if the injection is delayed, refrigerate the so·
`lution and inJect it within 3 hours). Do not freeze.
`11. Throw away_ unused portion of the solution remaining in
`the -Vlal.
`
`GIVING THE INJECTION
`Subcutaneous (under the skin) self-administration
`1. Choose an area for injection (see diagrams for areas); use
`a different area each day.
`• Abdomen-Areas 1 and 3
`• Thighs- Areas 2 and 4
`• Back of Arms-Areas 5 and 7
`• Buttocks-Areas 6 and 8
`NOTE: Do not use any areas in which you feel lumps,
`bumps, firm knots, or pain. Do not use any area in which the
`skin is discolored, depressed, scabbed, or has broken open.
`Talk to your doctor or healthcare professional about these or
`any other unusual conditions that you find.
`·
`Hold the syringe like a pencil or dart.
`2. Use an alcohol wipe to clean the skin at the injection site;
`let it air dry.
`~~-
`3. Thr~-~ the wipe.
`4. Uncap the needle.
`.---------,5. Gently ~_!! the skin together
`around the site (to lift it up a bit).
`
`6. Resting your wrist on the skin near
`the site, stick the needle straight into
`the skin ata· 90" angle with a quick,
`firm motion.
`
`.----------, 7. !Eject the drug by using a slow,
`steadypush (push the plunger all the
`way in until the syringe is empty).
`
`.,
`'(.
`
`8. Hold a swab on the injection site.
`RemoVe the needle from the skin.
`
`9. Gently massage the injection site
`with a dry cotton ball or gauze.
`10. !_~ow awa_1 the 1 mL syringe in the disposal unit.
`
`INJECTION SITE
`Picking an injection site
`Betaseron® (Interferon beta·lh) should be injected into sub(cid:173)
`cutaneous tissue (into the fat layer between the skin and
`the muscles beneath). The best areas for injection are where
`the skin is loose and soft (flabby), away from joints, nerves_,
`bones, and other important structures.
`Each day of injection you can choose an injection site from
`the upper, middle, or lower section of an area shown in the
`accompanying diagrams. It is a good idea to know where
`your injection will be given befo~ you prepare your syringe.
`If there are any sites that are difficult for you to reach, you
`can ask your support person (or someone who has been
`trained to give injections) to help you.
`Rotating injection sites
`Each day of. injection you can choose an injection site from
`the upper, middle, or lower section of an area shown in the
`accompanying diagrams.
`To help prevent injection site reactions, you need to select a
`site in an area different from the area where you last in(cid:173)
`jected yourself. You should not choose the same area for two
`injections in a row. Keeping a record of your injections will
`help make sure you rotate areas.
`On the accompanying diagrams of the body, the areas of in(cid:173)
`jection are numbered 1 through 8. Each area may be divided
`into three sections-upper, middle, and lower. If self-admin(cid:173)
`istering Betaseron, areas 1 through 4 may be the most con(cid:173)
`venient. Use the 8 areas in the following sequence:
`• Your first 8 injections should be in a site in the upper sec~
`tion of each area (Rotation 1);
`• The next 8 injections should be in a site in the middle sec-
`tion of each area (RotAtion 2);
`·
`• And the next 8 should be in a site in the lower section of
`each area (Rotation 3).
`By following this schedule, you will carne back. to your first
`injection site after 24 injections (48 days). If there are any
`sites that are difficult for you to reach, you can ask your
`
`support person, or someone who has been trained to give
`injections, to help you.
`
`~) Ei!D BD
`""""'
`leHAbdmnl!ll
`(lt!.111)a!Jout2"on
`lcft~Ol o1 nal'!:l)
`
`(up(lllrtlack
`Milton)
`
`llilDJI
`Right Arm
`(upfler.bac~
`portrr~·)
`
`UP"' UPPf:R
`MID-= MIDDLE
`LOW-=- LOWER
`
`FRONT
`
`BACK
`
`ROTATION 1
`
`ROTATION2
`
`ROTATION 3
`
`{InJections 1-8)
`
`(Injections 9-16)
`
`{lnJeCtrons 17-24)
`
`Upper Area 1
`
`Upper Area 2
`
`Upper Area 3
`
`Upper Area 4
`
`Upper Area 5
`
`Upper Area 6
`
`Upper Area 7
`
`Upper Area 8
`
`Middle Area 1
`
`Middle Area 2
`
`Middle Area 3
`
`Middle Area 4
`
`M1ddle Area 5
`
`Mrddle Area 6
`
`Middle Area 7
`
`Mrddle Area 8
`
`Lower Area 1
`
`Lower Area 2
`
`Lower Area 3
`
`Lower Area 4
`
`Lower Area 5
`
`Lower Area 6
`
`Lower Area 7
`
`Lower Area 8 '
`
`Manufactured by:
`CHIRON Corporation
`Emeryville, CA 94608
`U.S. License No. 1106
`Distributed by:
`BERLEX Laboratories
`Richmond, CA 94804
`All rights reserved.
`©1993 Berlex Laboratories
`Part Number L-1171.3
`Revision date 12/97
`Shown in Product Identification Guide, page 308
`
`CAM PATH®
`(Aiemtuzumab)
`
`WARNING
`Cam path should be administered under the supervision
`of a physician experienced in the use of antineoplastic
`therapy.
`• Hematologic Tox~ Serious and, in rare itlstances
`fatal, pancYtopenia/marrow hypoplasia1 autoimmune
`:•idiopathic thrombocytopenia, and autoimmune hemo(cid:173)
`lytic 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 pan(cid:173)
`cytopenia.
`• Infusion Reaction: Cam path can result in serious in(cid:173)
`fuSTOi-irea"Ctioll8.""Patients should be carefully moni(cid:173)
`tored during infusions and Campath discontinued if
`indicated. (See DOSAGE AND ADMINISTRATION.J
`Gradual escalation to the recommended mainte(cid:173)
`nance dose is required at the initiation of therapy and
`after interruption of therapy for 7 or more days.
`• Infections, Opportunistic Infections: Serious, some(cid:173)
`times fatal bacterial, viral, fungal, and protozoan in(cid:173)
`fections have been reported in patients receiving
`Cam path therapy. Prophylaxis directed against Pneu(cid:173)
`mocystis carinii pneumonia (PCP) and herpes virus
`infections has been shown to decrease, but not elimi(cid:173)
`nate, the occurrence of these infections.
`
`·
`
`Campath® (Alemtuzmnab) is a recombinant DNA-derived
`humanized monoclonal antibody (Campath-lH) that is di(cid:173)
`rected against the 21-28 kD cell surface glycoprotein, CDS2.
`
`Information will be superseded by supplements and subsequent editions
`
`PHYSICIANS' DESK REFERENCE®
`
`CD52 is expressed on the surface of normal and malignant
`B and T lymphocytes, NK cells, rnonocytes, macrophages,
`and
`tissues of the male reproductive system. The
`Campath-lH antibody is an lgG1 kappa with human vari(cid:173)
`able framework and constant regions, and COID:plementati.(cid:173)
`ty-determining regions from a murine (rat) monoclonal anti(cid:173)
`body <Campath-lG). The Campath-111 antibody has an ap(cid:173)
`proximate molecular weight"of 150 kD.
`Campath is produced in mammalian cell (Chinese hamster
`ovary) suspension culture in a medium cont~ining neomy(cid:173)
`cin .. Neomycin is not detectable in the final product.
`Campath is a sterile, clear, colorless, isotonic p_H 6.8-7.4 so(cid:173)
`lution 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 m_onobasic potassium phosphate, 0.3 mg polysorbatP
`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 ly~­
`phocytes, a majority of monocytes, macrophages, and NK
`cells, and a subpopulation Of granulocytes. Analysis of
`samples collected from multiple volunteers has not identi(cid:173)
`fied CD52 expression on erythrocytes or hematopoetic stem
`cells. The proposed mechanism of action is antibody-depen·
`dent lysis of leukemic cells following cell surface binding.
`Campatp-1H Fab binding wa~ observed in lymphoid tissues
`and the mononuclear phagocyte system. A proportion of
`bone marrow cells, including some CD34 + ce11s, eXpress
`variable levels of CD52. Significant binding was also ob(cid:173)
`served in the skin and male reproductive tract (epididymis,
`sperm, seminal vesicle). Mature spermatozoa stain for
`CD52, but neither spermatogenic cells nor immature sper(cid:173)
`matozoa show evidence of staining.
`Human Pharmacokinetics:
`The pharmacokinetic profile of Alemtuzlimab 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 infusi~ns over a range of doses, the
`maximum serum concentration (Cmnx) and the area under
`the curve (AUC) showed relative dose proportionality. The
`overall average half-life (t,,.) over the dosing interval was
`about 12 days. The pharmacokinetic profile of Campath ad(cid:173)
`ministered as a 30 mg iritravenous infusion tht"ee tinies per
`week was evaluated in CLL patients. Peak and trough lev(cid:173)
`els of Cam path rose during the first few weeks of treatment,
`and appeared to approach steady state by approximately
`week 6, although there was marked inter-patient variabil(cid:173)
`ity. The rise in serum Campath concentration corresponded
`with the reduction in malignant lymphocytosis.
`
`CLINICAL STUDIES
`The safety and efficacy ofCampath were.evaluated in a mul(cid:173)
`ticenter, 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 fl.udarabine. Fludarabine failure
`was defined as lack of an objective partial (PR) or complete
`(CR} response to at least one fludarabine-containing regi(cid:173)
`men, progressive disease (PD) while on fiudarabine treat(cid:173)
`ment. or relapse within6 months of the last dose offludara(cid:173)
`bine. Patients were gradually escalated to a maintenance
`dose of Cam path 30 mg intravenously three times per week
`for 4 to 12 weeks. Patients rec<~ived premedication prior to
`infusion and anti-Pneumocystis carinii and anti-herpes pro(cid:173)
`phylaxis while on treatment and for at least 2 months after
`the last dose of Cam path.
`'1Wo 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 previ(cid:173)
`ously treated with fludarabine or other chemotherapies. In
`Studies 2 and 3, the maintenance dose of Campath was 30
`m.g 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 amelio(cid:173)
`rate infusional reactions and anti~Pneumocystis carinii and
`anti-herpes prophylaxis were optional.
`Objective tumor response rates and duration of response
`were determined using t~e NCI Working Group Response
`Criteria (1996). A comparison of patient characteristics and
`the resultf'> for each of these studies is summarized in Table
`1. Time to event parameters, except for duration of re(cid:173)
`sponse, are calculated from initiation of Campath therapy.
`Duration of response is calculated from the onset of the re(cid:173)
`sponse.
`[See table at bottom of next page)
`
`INDICATIONS AND USAGE
`Cam path 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 fiudara(cid:173)
`bine therapy. Determination of the effectiveness of Cam path
`is based on overall response rates. (See CLINICAL STUD(cid:173)
`IES.) Comparative, randomized trials demonstrating in(cid:173)
`creased 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 sys~
`temic infections, underlying immunodeficiency (e.g., sero-
`
`Ex. 2024-0001
`
`

`
`PRODUCT INFORMATION
`
`positive for HIV), or known Type I hypersensitivity or ana(cid:173)
`phylactic reactions to Campath or to any one of its compo(cid:173)
`nents.
`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 infnsion-related events, patients should be premedi(cid:173)
`cated 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 dis(cid:173)
`ease and in patients on antihypertensive medication. If
`therapy is interrupted for 7 or more days, Campath should
`be reinstituted with gradual dose escalation. (See AD(cid:173)
`VERSE EVENTS and DOSAGE AND ADMINISTRATION.)
`Immunosuppression/Opportunistic Infections:
`Cam path induces profound lymphopenia. A variety of oppor(cid:173)
`tunistic infections have been reported in patients receiving
`Cam path therapy (see ADVERSE EVENTS, Infections). If a
`serious infection occurs, Campath therapy should be inter(cid:173)
`rupted and may be reinitiated following the resolution of
`the infection.
`Anti-infective prophylaxis is recommended upon initiation
`oftherapy and for a minimum of2 months following the last
`dose of Campath or until CD4·~ counts are ~ 200 cells/p.L.
`The median
`time
`to
`recovery of CD4 + counts
`to
`? 200/J.IL was 2 months, however, full recovery (to baseline)
`of CD4 + and CDS+ counts may take more than 12 months.
`(See BOXED WARNING and DOSAGE AND ADMINIS·
`TRATION.)
`Because of the potential for Graft versus Host Disease
`(GVHD) in severely lymphopenic patients, irradiation of
`any blood products administered prior to recovery from lym(cid:173)
`phopenia is recommended.
`Hematologic Toxicity:
`Severe, prolonged, and in rare instances fatal, myelosup(cid:173)
`pression has occurred in patients with leukemia and lym(cid:173)
`phoma receiving Campath. Bone marrow aplasia and hypo(cid:173)
`plasia were observed in the clinical studies at the recom(cid:173)
`mended dose. The
`incidence of these complications
`increased with doses above the recommended dose. In addi(cid:173)
`tion, severe and fatal autoimmune anemia and thrombocy(cid:173)
`topenia 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 ally patient with evidence of au~
`toimmune hematologic toxicity. Following resolution of
`transient, non~immune myelosuppression, Campath may be
`reinitiated with caution. (See DOSAGE AND ADMINIS·
`TRATION.) There is no information on the safety of re·
`sumption of Cam path in patients with autoimmune cytope(cid:173)
`nias or marrow aplasia. (See ADVERSE REACTIONS.)
`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
`;;, 200 cells/pL. (See WARNINGS and ADYERSE REAC(cid:173)
`TIONS.)
`Drug/Laboratory Interactions:
`No formal drug interaction studies have been performed
`with Cam path. An immun-e response to Cam path may inter(cid:173)
`fere with subsequent diagnostic serum tests that utilize an(cid:173)
`tibodies.
`
`Immunization:
`Patients who have recently received Campath, should not
`be immunized with live viral vaccines, due to their immu~
`nosuj:Jpression. The ·safety of immunization with live viral
`vaccines fol1owing Campath therapy has not been studied.
`The ability to generate a primary or anamnestic humoral
`response to any vaccine following Cam path therapy has not
`been ~tudied.
`lmmunogenicity:
`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 influ(cid:173)
`enced by several additional factors including sample han(cid:173)
`dling, concomitant medkations 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 Cam path may have allergic or hypersensitivity reactions
`to other monoclonal antibodies.
`Carcinogenesis, Mutagenesis, Impairment of FertilitY:
`No long-term studies in animals have been performed toes(cid:173)
`tablish the carcinogenic or mutagenic potential of Cam path,
`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 Cam path can affect re(cid:173)
`productive 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 lympho·
`cyte depletion. Campath should be given to a pregnant
`woman only if clearly needed.
`Nursing Mothers:
`Excretion of Cam path in human breast milk has not been
`studied. Because many drugs including human IgG are ex·
`creted in human milk, breast-feeding should be discontin(cid:173)
`ued 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:
`·
`Ofthe 149 patients with B·CLL enrolled in the three clini(cid:173)
`cal 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 pa(cid:173)
`tients with B~CLL enrolled in studies of Cam path as a sin(cid:173)
`gle agent administered at a maintenance dose of 30 mg in(cid:173)
`travenously 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
`
`Table 1: Summary of Patient Population and Outcomes
`
`Median Age in Years (Range)
`
`Study 1
`{N = 931
`
`66 {32-68)
`
`Median Number of Prior Regimens (Range)
`
`3 {2-7)
`
`Prior Therapies:
`Alkylating Agents
`Fludarabine
`
`Disease Characteristics:
`Rai Stage III/IV Disease
`B~Symptoms
`
`Overall Response Rate
`(95% Confidence Interval)
`Complete Response
`Partial Response
`
`Median Duration of Response (months)
`{95% Confidence Interval}
`
`Median Time to Response (months)
`(95% Confidence Interval)
`
`Progression-Free Survival (months)
`(95% Confidence Interval]
`
`100%
`100%
`
`76%
`42%
`
`33%
`{23%, 43%)
`2%
`31%
`
`7
`{5, 8)
`
`2
`{1, 21
`
`4
`{3, 5)
`
`Study 2
`{N = 32)
`
`57 {46-75)
`
`·3 {1-10)
`
`100%
`34%
`
`72%
`31%
`
`21%
`{8%, 33%)
`0%
`21%
`
`7
`{5, 23)
`
`4
`{1, 5)
`
`5
`{3, 7)
`
`Study 3
`{N = 24)
`
`62 {44-77)
`
`3 {1-8)
`
`92%
`100%
`
`71%
`21%
`
`29%
`(11%,47%)
`0%
`29%
`
`11
`{6,19)
`
`4
`{2, 4)
`
`7
`{3, 9)
`
`BERLEX/993
`
`available for Study 1 (93 patients), therefore the narrative
`description of certain events, noted below, is based on this
`study.
`lnfusion~Related Adverse Events:
`Infusion-related adverse events resulted in discontinuation
`of Cam path therapy in 6% of the patients enrolled in Study
`L The most commonly reported infusion~related. adverse
`events on this study included rigors in 89% of patients,
`drug~related fever in 83%, nausea in 4 7%, vomiting in 33%,
`and hypotension in 15%. Other frequently reported infu~
`sion~related events include, rash in 30% of patients, .fatigue
`in 22%, urticaria in 22%, dyspnea in 17%, pruritis in 14%,
`headache in 13%, and diarrhea in 13%. Similar types of ad~
`verse events were reported on the supporting studies (see
`Table 2). Acute infusion-related events were most common
`during the first week of therapy. Antihistamines, acetami(cid:173)
`nophen, antiemetics, meperidine, and corticosteroids as
`well as incremental dose escalation were used to prevent or
`ameliorate infusion-reiated events. (See WARNINGS and
`DOSAGE.AND ADMINISTRATION.)
`Infections:
`On Study 1, all patients were required to receive anti-her·
`pes and anti·PCP prophylaxis (see DOSAGE AND ADMIN(cid:173)
`ISTRATION) and were followed for infections for 6 months.
`Forty (43%) of93 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 fe·
`brile neutropenia (ANC :s; 500/pL) 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 op(cid:173)
`portunistic 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 discontin(cid:173)
`ued PCP prophylaxis.
`On Studies 2 and 3 in which anti-herpes and anti-PCP pro(cid:173)
`phylaxis was optional, 37 (66%) patients had 47 infections
`while or after receiving Cam path 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 multifo(cid:173)
`cal leukoencephalopathy.
`Hematologic Adverse Events:
`~~!.'!.~~P!:.!lla!Mag~~!!: Campath therapy was
`permanently discontinued in six (6%) patients due to pan(cid:173)
`cytopenia/marrow hypoplasia. Two (2%) cases of pancytope(cid:173)
`nia/marrow hypoplasia were fatal.
`Anemia: Forty-four (47%) patients had one or more epi(cid:173)
`sodes of new onset NCI-CTC Grade 3 or4 anemia. Sixty-two
`(67%) patients required RBC transfusions. In addition,
`erythropoietin use was reported in nineteen (20%) patients.
`Autoimmune hemolytic anemia secondary to Cam path ther(cid:173)
`apy was reported in 1% of patients,_ Positive Coombs test
`without hemolysis was reported in 2% (See BOXED WARN·
`ING.)
`Neutropenia: Sixty-five (70%) patients had one or more
`episodes ofNCI-CTC Grade 3 or 4 neutropenia. Median du(cid:173)
`ration of Grade 3 or 4 neutropenia was 28 days (range:
`2-165 days). (See Infections.)
`Thromb~nia: 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 daysl. Thirty-five (38%) patients required platelet
`transfusions for management of thrombocytopenia. Autoim(cid:173)
`mune thrombocytopenia was reported in 2% of patients
`with one fatal case of Campath-related autoimmune throm(cid:173)
`bocytopenia. (See BOXED WARNING.)
`~l?.QP~nia: The median CD4+ count at 4 weeks after
`initiation 'Of Cam path therapy was 2 (two)/J..IL, at 2 months
`after discontinuation of Campath therapy, 207/J.lL, and 6
`months after discontinuation, 470/J.lL. The pattern of
`change in median CDS+ lymphocyte counts was similar to
`that of CD4 + cells. In some patients treated with Cam path,
`
`Continued on next page
`
`Information on the Berlex products appearing here is based on
`the most current information available at the time of
`publication closing, Further information for these and other
`products may be obtained from the Professional Services/
`Product Information Departments, Berlex Laboratories,
`340 Changebridge Road, Pine Brook, New Jersey 07058.
`1·BBB·BERLEX·4. Information on Campath and Fludara may be
`obtained from Berlex Laboratories, 15049 San Pablo Avenue,
`Richmond, California 94804-0099. 1·888-BERLEX·4.
`
`Consult 2 0 0 2 PDR® supplements and future editions for revisions
`
`Ex. 2024-0002
`
`

`
`994/BERLEX
`
`PHYSICIANS' DESK REFERENCE®
`
`Campath-Cont.
`
`Resistance Mechanism Disorders
`
`CD4 • and CDS •
`lymphocyte counts had not returned to
`baseline levels at longer than 1 year post therapy.
`
`Sepsis
`
`Herpes Simplex
`
`Table 2: Adverse Events in >5% of the B-Cll Study
`Population During Treatment or Within 30 Days (N = 149)
`
`Moniliasis
`
`Adverse Event:
`
`Body As A Whole
`
`Rigors
`
`Fever
`
`Fatigue
`
`Pain. Skeletal Pain
`
`Anorexia
`
`Asthenia
`
`Edema, Peripheral Edema
`
`Back Pain
`
`Chest Pain
`
`Malaise
`
`Temperature Change Sensation
`
`Infection {other viral or unidentified)
`
`Respiratory System Disorders
`
`Dyspnea
`
`Cough
`
`Bronchitis, Pneumonitis
`
`Pneumonia
`
`Pharyngitis
`
`Bronchospasm
`
`Rhinitis
`
`Skin & Appendage Disorders
`
`Rash, Maculopapular Rash,
`Erythematous Rash
`
`Urticaria
`
`Prurrtus
`
`Sweating increased
`
`B·CLL STUDIES
`IN= 149)
`
`ANY
`Grade
`(o/o)
`
`Grade 3
`or4
`(o/o)
`
`16
`
`19
`
`5
`
`2
`
`3
`
`4
`
`1
`
`3
`
`1
`
`1
`
`86
`
`85
`
`34
`
`24
`
`20
`
`13
`
`13
`
`10
`
`10
`
`9
`
`5
`
`15
`
`11
`
`8
`
`7
`
`26
`
`25
`
`21
`
`t6
`
`12
`
`9
`
`7
`
`40
`
`30
`
`24
`
`19
`
`10
`
`1
`
`1
`
`1
`
`9
`
`2
`
`13
`
`10
`
`-
`
`2
`-
`
`3
`
`5
`
`1
`
`1
`
`Platelet, Bleeding, and Clotting Disord"~"-' coagulation
`disorder, disseminated intravascular coagulation, hema-
`toma, pulmonary embolism, thrombocythemia
`~!!!_atric ~§.~ders: confusion, hallucinations, nervous-
`ness, abnormal thinking, apathy
`Whi~e Cel~d RES Disorders~ agranulocytosis, aplasia,
`decreas_ed haptoglobin, lymphadenopathy, marrow depres-
`sian
`Red Blood Cell Disorders: hemolysis, hemolytic anemia,
`splenic infarction, splenomegaly
`~productiv~_Y-stem Disorders: cervical dysplasia
`Resistance Mechanism Disorders: abscess, bacterial infec-
`tion, HerPes zoster infection, Pneumocystis carinii infection,
`otitis media, Tuberculosis infection, viral infection
`Respiratory Systm:n Disorders: asthma, bronchitis, chronic
`obstructive pulmonary disease, hemoptysis, hypox~a, pleu-
`r,a.l:effusion pleurisy, pneumothorax, pulmonary edema, pul-
`ntl;l~a-ry fibrosis, pulmonary infiltrat\on, respiratory depres-
`sion~ :respiratory insufficiency, siilusitis, strider~ throat
`~tness
`,
`S m ~nd Appendages Disorders::.· angio;edema, bullous
`eruption, cellulitis, purpuric rash
`Special Senses Disorde..!2..:
`taste less
`Urinary S~~m Disorders: abnormal renal function, acute
`renal failure, anuria, facial edema., hematuria, toxic neph-
`ropathy ureteric obstruction, urinary retention, urinary
`tract infection
`Vascl~~Extrac~~iac) _Q~rders: -cerebral hemon·hage,
`cerebrovascular disorder, deep vein.- thrombosis, increased
`capillary fragility, intracranial hemorrhage, phlebitis, suba-
`rachnoid hemorrhage, thrombophlehims
`~~!!.Disorders: endophthalmit.<s
`OVERDOSAGE
`Initial doses of Cam path 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 cumula-
`tive weekly dose greater than 90 mg should not be admin-
`istered 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 overdos-
`age. Treatment consists of drug discontinuatiqn and sup-
`portive therapy.
`
`DOSAGE AND ADMINISTRATION
`Cam path should be administered under the supervision of a
`physician experienced in the use of antineoplastic therapy.
`Dosing Schedule and Administration:
`Cam path therapy should be initiated at a dose of 3 mg ad-
`ministered 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 ::s:: Grade 2), the daily
`dose should be escalated to 10 mg and_ continued until tal-
`erated. When the 10 mg dose is tolerated, the mainteriance
`dose of Cam path 30 mg may be jnitiated. The maintenance
`dose of Cam path is 30 mg/day administered three times per
`week on alternate days (i.e., Monday, Wednesday, and Fri-
`day) 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 pancytope-
`nia. (See BOXED WARNING.) Campath should be adniinis·
`tered intravenously only. 'rhe infusion should be adminis-
`tered 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 premedi-
`eaton used in clinical studies was diphenhydramine 50 mg
`and acetaminophen 650 mg administered 30 minutes prior
`
`Serious adverse events:
`The following serious adverse events, defined as events
`which result in death, requiring or prolonging hospitaliza·
`tion, requiring medical intervention to prevent hospitaliza-
`tion, or malignancy, were reported in at least one patient
`tre.ated on studies where Campath was used as a sitlgle
`agent (and are not reported in Table 2). These studies were
`conducted in patients with lymphocytic leukemia and lym-
`phoma (N = 745) and in patients with non-malignant dis-
`eases (N = 152) such as rheumatoid arthritis, 'Solid· organ
`transplant, or multiple sclerosis.
`Bodl All A Whole: allergic reactions, anaphylactoid reac-
`tion, ascites, hypovolemia, influenza-like syndrome, inouth
`edema, neutropenic fever, syncope
`Cardiovascular Disorders: cardiac failure, cyanosis, atrial
`fibrillation; cardiac arrest, ventricular arrhythmia, ventric-
`ular tachycardia, angina pectoris, coronary artery disorder,
`myocardial infarction, pericarditis
`Central and Peripheral Nervous Sys~m ~~~ders: abnor-
`mal gait, aphasia, coma, grand mal convulsions, paralysis,
`meningitis
`Endocrine Disorders: hyperthyroidism
`Gastrointestinal S;ys'iem Disorders: duodenal ulcer, esoph-
`agitis, gingivitis, gastroenteritis, GI hemorrhage, hematem-
`esis, ?emorrhoids, intestinal obstruction, intestinal perfora-
`tion, melena, paralytic ileus, peptic ulcer, pseudomembra-
`no us
`colitis,
`colitis,
`pancreatitis,
`peritonitis,
`hyperbilirubinemia, hepatic failure, hepatocellular damage,
`hypoalbuminemia, biliary pain
`£lea~ and Vestibular Disord~rs: decreased hearing
`Metabolic and NutritiOnal Disorders: acidosis, aggravated
`diabetes mellitus, dehydratio~Uid overload, hyperglyce-
`mia, hyperkalemia, hypokalemia, hypoglycemia, hyponatre-
`mia, increased alkaline phosphatase, respifatory alkalosis
`Musculoskeletal S~stem Disorders~ arthritis or worsening
`arthritis, arthropathy, bone fracture, myositis, muscle a