2498/0RTHO BIOTECH
`
`Leustatin-Cont.
`
`Dose of
`LEUSTATIN
`Injection
`
`I (day) X
`0.09 mg/kg
`
`Recommended Quantity of
`Diluent
`Diluent
`
`0.9% Sodium
`Chloride
`Injection, USP
`
`500 mL
`
`24-hour
`infusion
`method
`
`To prepare a 7·day infusion: The 7 ·day infusion solution
`should only be prepared with Bacteriostatic 0.9% Sodium
`Chloride Injection, USP (0.9% benzyl alcohol preserved). In
`order to minimize the risk of microbial contamination, both
`LEUSTATIN Injection and the diluent should be passed
`through a sterile 0.22p disposable hydrophilic syringe filter
`as each solution is being introduced into the infus~on
`reservoir. First add the calculated dose of LEUSTATIN In(cid:173)
`jection (7 days X 0.09 mg/kg or mUkg) to the infusion res(cid:173)
`en•oir through the sterile filter. Then add a calculated
`amount of Bacteriostatic 0.9% Sodium Chloride Injection,
`USP (0.9% benzyl alcohol preserved) also through the filter
`to bring the total volume of the solution to 100 mL. After
`completing solution preparation, clamp off the line, discon·
`nect and discard the filter. Aseptically aspirate air bubbles
`from the reservoir as necessary using the sJiinge and a.dry
`second sterile filter or a sterile vent filter assembly. Re·
`clamp the line and discard the syringe and filter assembly.
`Infuse continuously over 7 days. Solutions prepared with
`Bacteriostatic Sodium Chloride Injection for individuals
`weighing more than 85 kg may have reduced preservative
`effectiveness due to greater dilution of the benzyl alCohol
`preservative. Admixtures for the 7-da:y infusion have dem(cid:173)
`onstrated acceptable chemical and physical stability for
`at least 7 days in the SIMS Deltec MEDICATION
`CASSETTETM Reservoirt.
`
`Dose of
`LEUSTATIN
`Injection
`
`7 (days) X
`0.09 mg/kg
`
`Recommended Quantity of
`Diluent
`Diluent
`
`q.s. to
`100 mL
`
`Bacteriostatic
`0.9% Sodium
`Chloride
`Injection, USP
`(0.9% benzyl
`alcohol)
`
`7-day
`infusion
`method
`(use sterile
`0.22p filter
`when
`preparing
`infusion
`solution)
`
`Since limited compatibili-ty data are available, adherence to
`the recommended diluEmts and ·infusion systems is ad(cid:173)
`vised. Solutions containing LEUSTATIN Injection should
`not be mixed with other intravenous drugs or additives or
`infused simultaneously via a common intravenous line,
`since compatibility testing has not been performed. Prepa(cid:173)
`rations containing benzyl alcohol should not be used in neo(cid:173)
`nates. (see WARNINGS)
`Care must be taken to assure the sterility of prepared solu(cid:173)
`tions. Once diluted, solutions: of LEUSTATIN Injection
`should be administered promptly or stored in the refrigera(cid:173)
`tor (2° to soC) for no more than 8 hours prior to start of
`admmistration. Vials of LEUSTATIN Injection are for
`single-use only. Any unused portion should be discarded in
`an appropriate manner. (see Handling and Disposal)
`Parenteral drug products should be inspected visually for
`particulate matter and discoloration prior to administra(cid:173)
`tion, whenever solution and container permit. A precipitate
`may occur during the exposure of LEUSTATIN Injection to
`low temperatures; it may be resolubilized by allowing the
`sol uti on to warm naturally to room temperature and by
`shaking vigorously. DO NOT HEAT OR. MICR.OWAVE.
`Chemical Stability of Vials:
`When stored in refrigerated conditions between 2o to soc
`(36° to 46°F) protected from light, unopened vials of
`LEUSTATIN Injection are stable until the expiration date
`indicated on the package. Freezing does not adversely affect
`the solution. If freezing occurs, thaw naturally to room tern(cid:173)
`perature. DO NOT heat or microwave. Once thawed, the
`vial of LEUSTATII'{ Injection is stable until expiry if refrig~
`erated. DO NOT refreeze. Once diluted, solutions contain(cid:173)
`ing LEUSTATIN Injection should be administered promptly
`or stored in the refrigerator (2° to SOC) for no more than S
`hours prior to administration.
`Handling and Disposal:
`The potential hazards associated with cytotoxic agents are
`well established and proper precautions should be taken
`when handling, preparing, and administering LEUSTATIN
`Injection. The use of disposable gloves and protective gar(cid:173)
`ments is recommended. If LEUSTATIN Injection contacts
`the skin or mucous membranes, wash the involved surface
`immediately wit~ copious amount~ of water. Several guide·
`
`lines on this subject have been published.12--8) .There is no
`general agreement that all of the proce.dures recommended
`in the guidelines are necessary or appropriate. Refer to your
`Institution's guidelines and all applicable state/local regula(cid:173)
`tions for disposal of cytol?xic waste.
`HOW SUPPLIED
`LEUSTATIN Injection is supplied as a sterile, preservative·
`free, isotonic solution containing 10 mg (1 mg/mL) of
`
`cladribi.R.e as 10 mL filled into a single-use clear flint glass
`20 mL vial. LEUSTATIN Injection is supplied in 10 mL
`(1 mg/mL) single-use vials (NDC 59676-2()!:01) available in
`a treatment set (case) of seven vials.
`Store refrigerated 2' to 8'C (36' to 46'F). Protect from light
`during storage.
`References:
`1. Santana VM, Mirra J, Harwood FC, et al: A phase I clin(cid:173)
`ical trial of 2-Chloro-deoxyadenosine in pediatric patients
`with acute leukemia. J. Clin. One., 9: 416 (1991).
`2. Recommendations forthe SafeHandling of Parenteral
`Antineoplastic Drugs. NIH Publication No. 83-2621. For
`sale by the Superintendent of Documents, U. S. Govern~
`ment Printing Office, Washington, D.C. 20402.
`3. AMA Council Report. Guidelines for Handling Parenteral
`Antineoplastics, JAMA, March 15 (1985).
`4. National Study Commission on Cytotoxic Exposure(cid:173)
`Recommendations for Handling Cytotoxic Agents. Avail(cid:173)
`able from Louis P. Jeffrey, Sc.D., Chairman; National
`Study Commission of Cytotoxic Exposure, Massachusetts
`College of Pharmacy and Allied Health Sciences, 179
`Longwood Avenue, Boston, Massachusetts 02115.
`5. Clinical Oncological Society of Australia: Guidelines and
`Recommendations for Safe Handling of Antineoplastic
`Agents, Med. J. Australia 1:425 (1983).
`6. Jones RB, et al. Safe Handling of Chemotherapeutic
`Agents: A Report from the Mount Sinai Medical Center.
`Ca-A Cancer Journal for Clinicians, SepllOct. 258-263
`(1983).
`7. American Society of Hospit~l Pharmacists Technical As(cid:173)
`sistance Bulletin on Handling Cytotoxic Drugs in Hospi-
`tals, Am. J. Hosp. Pharm., 42:131 (1985).
`·
`8. OSHA Work-Practice Guidelines for Personnel Dealing
`with Cytotoxic (antineoplastic) D"rugs. Am. J. Hasp.
`Pharm., 43:1193 (1986).
`CAUTION: Federal law prohibits dispensing without pre(cid:173)
`scriptiOn.
`t Viafl.ex® containers, manufactured by Baxter Healthcare
`Corporation -Code No. 2B80!3 (testing in 1991)
`t MEDICATION CASSETTETM Reservoir, manufactured
`by SIMS Deltec, Inc. - Reorder No. 602100A (tested in
`1991)
`ORTHO BIOTECH PRODUCTS, L.P
`ORTHO BIOTECH
`Raritan, New Jersey 08869
`638-10-940-7
`©OBI 1996
`Revised January 2001
`LEU-533
`Shown in Produ~t Identification Guide, page 328
`
`ORTHOCLONE OKT"3 Sterile Solution
`(muromonab-CD3l
`For Intravenous Use Only
`
`ly
`
`WARNING:
`Only physicians experienced in immunosuppressive
`therapy and management of solid organ transplant pa(cid:173)
`tients should use ORTHOCLONE OKT3 (muromonab(cid:173)
`CD3). Patients treated with ORTHOCLONE OKT3
`must be managed in a facility equipped and staffed for
`cardiopulmonary resuscitation and where the patient
`can be closely monitored for an appropriate period based
`on his or her health status.
`Anaphylactic and anaphylactoid reactions may occur
`following administration of any dose or course of
`ORTHOCLONE OKT3. In addition, serious, occasion(cid:173)
`ally life·threatening or lethal, systemic, cardiovasCular,
`and central nervous system reactions have been re(cid:173)
`ported following administration of ORTHOCLONE
`OKT3. These have included: pulmonary edema, espe(cid:173)
`cially in patients with volume overload; shock, cardio(cid:173)
`vascular collapse, cardiac or respiratory arrest, sei~
`zures, coma, cerebral edema, cerebral herniation, blind(cid:173)
`ness, and paralysis. Fluid status should be carefully
`monitored prior to and during ORTHOCLONE OKT3
`administration. Pretreatment with methylprednisolone
`is recommended to minimize symptoms of Cytok.ine Re(cid:173)
`lease Syndrome. (See: WARNINGS: Cytokine Release
`.•Syndrome, Central Nervous System Events, Anaphylac(cid:173)
`tic Reactions; DOSAGE AND ADMINISTRATION)
`
`DESCRIPTION
`ORTHOCLONE OKT3 (muromonab-CD3) Sterile Solution
`is a murine mo~oclonal antibody to the CD3 antigen of hu(cid:173)
`man T cells which functions as an immunosuppressant. It is
`for intravenous use only. The antibody is a biochemically
`purified IgG2a immunoglobulin with a heavy chain of ap~
`proximately 50,000 daltons and a· light chain of approxi(cid:173)
`mately 25,000 daltons. It is directed to a glycoprotein with a
`molecular· weight of 20,000. in the human T cell surface
`which is essential forT cell functions. Because it is a mono(cid:173)
`clonal antibody preparation, ORTHOCLONE OKT3 Sterile
`Solution is a homogeneous, reproducible antibody product
`with consistent, measurable reactivity tO human T cells.
`Each 5 mL ampule of ORTHOCLONE OKT3 Sterile Solu(cid:173)
`tion contains 5 mg·(l mg/mL) ofmuromonabMCD3 in a clear
`colorless solution which may contain a few fine translucent
`protein particles. Each ampule contains a buffered solution
`(pH 7.0 :!: 0.5) of monobasic sodium phosphate (2.25 mg),
`dibasic sodium phosphate (9.0 mg), sodium chloride (43 mg),
`and polysorbate 80 (1.0 mg) in water for injection.
`
`Information will be superseded by supplements and ·subsequent editions
`
`PHYSICIANS' DESK REFERENCE®
`
`The proper name, muromonab·CD3, is derived from the de·
`scriptive term murine monoclonal antibody. The CD3 desig(cid:173)
`nation identifies the specificity of the antibody as the Cell
`Differentiation (CD) cluster 3 defined by the First Interna(cid:173)
`tional Workshop on Human Leukocyte Differentiation Anti(cid:173)
`gens.
`CLUITCALPHARMACOLOGY
`ORTHOCLONE OKT3 re~erses graft rejection, probably by
`blocking the function ofT cells which plci.y a major role in
`acute allograft rejection. ORTHOCLONE OKT3 reacts with
`and blocks the function of a 20,000 dalton molecule (Cl?3) in
`the membrane of human T cells that has been associated in
`vitro with the antigen recognition structure ofT cells and is
`essential for Signal transduction. In in vitro cytolytic assays,
`ORTHOCLONE OKT3 blocks both the generation and func(cid:173)
`tion of effector cells. Binding of ORTHOCLONE OKT3 to T
`lymphocytes results in early activation of T cells, which
`leads to cytokine release, followed by blocking T cell func(cid:173)
`tions. After termination of ORTHOCLONE OKT3 therapy,
`T cell function usually retum.s to normal within one week.
`In vivo, ORTHOCLONE OKT3 reacts with most peripheral
`blood T cells and T cells in body tissues, but has not been
`found to react with other hematopoietic elements or other
`tissues of the body.
`A rapid and concomitant decrease in the number of circu~at­
`ing CD3 positive cells, including" those that are CD2, CD4,
`or CDS positive has been observed in patients s~udied
`within minutes after the administration of ORTHOCLONE
`OKT3. This decrease in the number of CD3 positive']' cells
`results from the specific interaction between· ORTHO(cid:173)
`CLONE OKT3 and the CD3 antigen on the surface of all T
`lymphocytes. T cell activation results in the release of nu(cid:173)
`merous cytokinesf1ymphok.ines, which are felt to be respon(cid:173)
`sible for many of the acute clinical manifestations seen fol(cid:173)
`lowing ORTHOCL()NE OKT3 administration. (See: WARN(cid:173)
`INGS: Cytokine Release Syndrome, Central Nervous
`System Events)
`,
`While CD3 positive cells are not detectable between days
`two and seven, increasing numbers of circulating CD2, CD4,
`and CDS positive cells have been observed. The presence of
`these CD2, CD4, and CD8 positive cells has not been shown
`to affect reversal of rejection. After termination ofORTHO(cid:173)
`CLONE OKT3 therapy, CD3 positive cells reappear rapidly
`and reach pre-treatment levels within a week. In some pa(cid:173)
`tients however, increasing numbers of CD3 positive cells
`have been observed prior to tP-rmination of ORTHOCLONE
`OKT3 therapy. This reappearance of CD3 posi_tive cells has
`been attributed to the development of neutralizing antibod(cid:173)
`ies to ORTHOCLONE OKT3, which in turn block its ability
`to bind to the CD3 antigen .on T lymphocytes. (See: PRE(cid:173)
`CAUTIONS: Sensitization)
`Pediab'ic patients are known to have higher CD3 lympho(cid:173)
`cyte counts than adults. Pediatric patients receiving
`ORTHOCLONE OKT"3 therapy often require progres(cid:173)
`sively higher. doses of ORTHOCLONE OKT3 to achieve de(cid:173)
`pletion of CD3 positive cells ( <~5 cells/mm3
`) and ensure
`therapeutic ORTHOCLONE OKT3 serum concentrations
`(>800 ng/mL). (See: DOSAGE AND ADMINISTRATION;
`PRECAUTIONS: Laboratory Tests)
`Serum levels of ORTHOCLONE OKT3 are measurable us(cid:173)
`ing an enzyme-linked immunosorbent assay (ELISA). Dur(cid:173)
`ing the initial clinical trials in renal allograft rejection, in
`patients treated with 5 mg per day for 14 days, mean serum
`trough levels of the drug rose over the first three days and
`then averaged 900 ng/mL on days 3 to 14. Serum concentra(cid:173)
`tions measured daily during treatment with ORTHO(cid:173)
`CLONE OKT3 in renal, hepatiC, and cardiac allograft re(cid:173)
`cipients revealed that pediatric patients less than 10 years
`of age have higher levels than patients 10-50 years of age.
`Subsequent clinical experience has demonstrated that
`serum levels greater than or equal to 800 ng/mL of ORTHO(cid:173)
`CLONE OKT3 blocks the function of cytotoxic T cells in oi(cid:173)
`tro and in vivo. Reduced T cell clearance or low plasma
`ORTHOCLONE OKT3 levels provide a basis for adjusting
`ORTHOCLONE OKT3 dosage or for discontinuing therapy.
`(See: WARNINGS: Anaphylactic Reactions; PRECAU(cid:173)
`TIONS: Laboratory Tests; ADVERSE EVENTS: Hypersen(cid:173)
`sitivity Reactions; DOSAGE AND ADMINISTRATION)
`Following administration of ORTHOCLONE OKT3 in vivo,
`Ie"ukocytes have been observed in cerebrospinal and perito(cid:173)
`neal fluids. The mechanism for this effect is not completely
`understood, but probably is related to cytokines altering
`membrane permeability, rather than an active inflamma(cid:173)
`tory process. (See: WARNINGS: Cytokine Release Syn(cid:173)
`drome, Central Nervous System Events)
`CLINICAL STUDIES
`Acu.!_e Re.E.al Re~~iOn:
`In a controlled randomized clinical trial, ORTHOCLONE
`OKT3 ·was compared with conventional high·dose steroid
`therapy in reversing acute renal allograft rejection. Iil. this
`b'ial, 122 evaluable patients undergoing acute rejection of
`cadaveric renal transplants were treated· either with
`ORTHOCLONE OKT3 daily for a mean of 14 days, with
`concomitant lowering of the dosage of azathioprine and
`maintenance steroids (62 patients), or wit~ conventional
`high-dose steroids (60 patients). ORTHOCLONE OKT3 re(cid:173)
`versed 94% of the rejections compared to a 75% reversal
`rate obtained with conventional high-dose steroid treatment
`(p=0.006). The one year Kaplan·Meier (actuarial) estimates
`of graft survival rates for these patients who had acute re(cid:173)
`jection were 62% and ·45% for ORTHOCLONE OKT3 and
`steroid-treated patients, respectively (p=0.04). At two years
`the rates were 56% and 42%, respectively (p=0.06).
`·
`
`Ex. 2022-0001
`
`

`
`PRODUCT INFORMATION
`
`ORTHO BIOTECH/2499
`
`One- and two-year patient survivals were not significantly
`different between the two groups, being 85% and 75% for
`ORTHOCLONE OKT3 treated patients and 90% and 85%
`for steroid-treated patients.
`In additional open clinical trials, the observed rate of rever(cid:173)
`sal of acu'te renal allograft rejection was 92% (n=126) for
`ORTHOCLONE OKT3 therapy. ORTHOCLONE OKT3 was
`also effective in reversing acUte renal allograft rejections in
`65% (n=225) of cases where steroids and lymphocyte im(cid:173)
`mune globulin preparations were contraindicated at were
`not successful.
`The effectiveness of ORTHOCLONE OKT3 for prophylaxis
`of renal allog-':'aft rejection has not been established.
`Acute Cardiac or Hepatic Allograft Rejection~
`ORTHOCLONE OK1,3 was studied for use in reversing
`acute cardiac and hepatic allograft rejection in patients who
`are unresponsive to high·doses of steroids. The rate of re·
`versa] in acute cardiac allograft rejection was 90% (n = 61)
`and was 83% for hepatic al1ograft rejection (n = 124) in pa·
`tients unresponsive to treatment with steroids.
`Controlled randomized trials have not been conducted to
`evaluate the effectiveness of ORTHOCLONE OKT3 com(cid:173)
`pared to conventional therapy as first line treatment for
`acute cardiac and hepatic allograft rejection·.
`INDICATIONS AND USAGE
`ORTHOCLONE OKT3 is indicated for the treatment of
`acute allograft rejection in renal transplant patients.
`ORTHOCLONE OKT3 is indicated for the treatment of ste(cid:173)
`roid·resistant acute allograft rejection in cardiac and he(cid:173)
`patic transplant patients.
`The dosage of other immunosuppressive agents used in con(cid:173)
`junction with ORTHOCLONE OKT3 should be reduced to
`the Jowest level compatible with an effective therapeutic re(cid:173)
`sponse. (See: WARNINGS and ADVERSE EVENTS: Infec(cid:173)
`tions, Neoplasia; DOSAGE AND ADMINISTRATIONl
`CONTRAINDICATIONS
`ORTHOCLONE OKT3 should not be given to patients who:
`• are hypersensitive to this or any other product of murine
`origin;
`• have anti-mouse antibody titers ~1:1000;
`• are in (uncompensated) heart failure or in fluid overload,
`as evidenced by chest X-ray or a greater than 3 percent
`weight gain within the week prior to planned ORTHO·
`CLONE OKT3 administration;
`• have uncontrolled hypertension;
`• have a history of seizures, or are predisposed to seizures;
`• are determined or suspected to be pregnant, or who are
`breast-feeding. (See: ·PRECAUTIONS: Pregnancy, Nurs(cid:173)
`ing Mothers)
`WARNINGS
`SEE BOXED WARNING
`Cytokine Release Syndrome
`Most patients develop an acute clinical syndrome [i.e., Cy(cid:173)
`tokine Release Syndrome (CRS)] that has been attributed to
`the release of cytokines by activated lymphocyteS or mono·
`cytes and is temporally associated with the administration
`of the first few doses of ORTHOCLONE OK'I"'3 (particular(cid:173)
`ly, the first two to three doses). This clinical syndrome has
`ranged from a more frequently reported mild, self-limited,
`"flu-like" illness to a less frequently reported severe, life(cid:173)
`threatening shock-like reaction, which may include serious
`cardiovascular and central nervous system manifestations.
`The syndrome typically begins approximately 30 to 60 min·
`utes after administration of a dose of ORTHOCLONE OKT3
`(but may occur later) and may persist for several hours. The
`frequency and severity of this symptom complex is usually
`greatest with the first dose. With each successive dose of
`ORTHOCLONE OKT3, both the frequency and severity of
`the Cytokine Release Syndrome tends to diminish. InCreas·
`ing the amount of ORTHOCLONE OKT3 or resuming treat(cid:173)
`ment after a hiatus may result in a reappearance of the
`CRS.
`Common clinical manifestations of CRS may include: high
`fever (often spiking, up to 107oF), chills/rigors, headache,
`tremor, nausea/vomiting, diarrhea, abdominal pain, mal(cid:173)
`aise, muscle/joint aches and pains, and generalized weak(cid:173)
`ness. Less frequently reported adverse experiences include:
`minor dermatologic reactions (e.g., rash, pruritus, etc.) and
`a spectrum of often serious, occasionally fatal, cardiorespi(cid:173)
`ratory and central nervous system adverse experiences.
`Cardiorespiratory findings may include: dyspnea, shortness
`of breath, bronchospasm/wheezing, tachypnea, respiratory
`arresUfa1lure/distress, cardiovascular collapse, cardiac ar(cid:173)
`rest, angina/myocardial infarction, chest pain/tightness,
`tachycardia (including ventricular), hypertension, hemody(cid:173)
`namic instability, hypotension including profound shock,
`heart failure, pulmonary edema (cardiogenic and non-cardi·
`ogenic), adult respiratory distress syndrome, hypoxemia,
`apnea, and arrhythmias. (See: BOXED WARNING; PRE(cid:173)
`CAUTIONS; ADVERSE EVENTS)
`In the initial studies of renal allograft rejection, potentially
`fatal, severe pulmonary edema occurred in 5% of the initial
`107 patients. Fluid overload was present before treatment
`in all of these cases. It occurred in none of the subsequent
`311 patients treated with first-dose volume/weight restric(cid:173)
`tions. In subsequent trials and in post-marketing experi·
`ence, severe pulmonary edema has occurred in patients who
`appeared to be euvolemic. The pathogenesis of pulmonary
`edema may involve all or some of the following: volume
`overload; increased pulmonary vascular permeability;
`and/or reduced left ventricular compliance/contractility.
`During the first 1 to 3 days of ORTHOCLONE OKT3 ther-
`
`apy, some patients have experienced an acute &nd transient
`decline in the glomerular filtration rate (GFR) and dimin·
`ished urine output with a resulting increase in the level of
`serum creatinine. Massive release of cytokines appears to
`lead to reversible renal functional impairment and/or de(cid:173)
`layed renal allograft function. Similarly, transient eleva(cid:173)
`tions in hepatic transaminases have been reported following
`administration of the first few doses of ORTHOCLONE
`OKT3.
`Patients at risk for more serious complications.of CRS may
`include those with the following conditions: unstable an·
`gina; recent myocardial infarction or symptomatic ischemic
`heart disease; heart failure of any etiology; pulmonary
`edema of any etiology; any form of chronic obstructive pul(cid:173)
`monary disease; intravascular volume overload or depletion
`of any etiology (e.g., excessive dialysis, recent intensive di(cid:173)
`uresis, blood loss, etc.); cerebrovascular disease; patients
`with advanced symptomatic vascular disease or neuropa·
`thy; a history of seizures; and septic shock. Efforts should be
`made to correct or stabilize background conditions prior to
`the initiation of therapy. (See: PRECAUTIONS)
`Prior to administration of ORTHOCLONE OKT3, the pa(cid:173)
`tient's volume (fluid) status and a chest x-ray should be as(cid:173)
`sessed to rule out volume overload, uncontrolled hyperten(cid:173)
`sion, or uncompensated heart failure. Patients should not
`weigh >3% above their minimum weight during the week
`prior to injection.
`The Cytokine Release Syndrome is associated with in(cid:173)
`creased serum levels of cytokines (e.g,, TNF-a, IL-2, IL-6,
`IFN -~ l that peak between 1 and 4 hours following adminis(cid:173)
`tration of ORTHOCLONE OKT3. The serum levels of cytok(cid:173)
`ines and the manifestations of CRS may be reduced by pre·
`treatment with 8 mglkg of methylprednisolone (i.e.-, high(cid:173)
`dose steroids), given 1 to 4 hours prior to administration of
`the first dose of ORTHOCLONE OKT3, and by closely fol(cid:173)
`lowing recommendations for dosage and treatment dura(cid:173)
`tion. (See: DOSAGE AND ADMINISTRATION) It is not
`known if corticosteroid pretreatment decreases organ dam(cid:173)
`age and sequelae associated with CRS. For example, in·
`creased intracranial pressure and cerebral herniation have
`occurred despite pretreatment with currently recommended
`doses and schedules of methylprednisolone.
`If any of the more serious presentations of the Cytokine Re(cid:173)
`lease Syndrome occur, inten·sive treatment including oxy·
`gen, intravenous fluids, corticosteroids, pressor amines, an·
`tihistamines, intubation, etc., may be required.
`Central Nervous System Events
`Seizures, encephalopathy, cerebral edema, aseptic meningi·
`tis, and headache have been reported, even following the
`first dose, during therapy with ORTHOCLONE OKT"3. Sei(cid:173)
`zures, some accompanied by Joss of consciousness or cardio(cid:173)
`respiratory arrest, or death, have occurred independently or
`in conjunction with any of the neurologic syndromes de·
`scribed· below.
`A few cases of fatal cerebral herniations subsequent to cer(cid:173)
`ebral edema have been rePorted. All patients, particularly
`pediatric patients, must be carefully evaluated for fluid re(cid:173)
`tention and hypertension before the initiation of ORTHO(cid:173)
`CLONE OKT3 therapy. Close monitoring for neurologic
`s~ptoms must be performed during the first twenty~four
`(24) hours following each of the first few doses of ORTHO(cid:173)
`CLONE OKT3 injection.
`Patients should be closely monitored for convulsions and
`manifestations of encephalopathy, including: .impaired cog(cid:173)
`nition, confusion, obtundation, altered mental status, dis(cid:173)
`orientation, auditory/visual hallucinations, psychosis (delir·
`ium, paranoia), mood changes (e.g., mania, agitation, com(cid:173)
`bativeness, etc.), diffuse hypotonus, hyperreflexia,
`myoclonus, tremor, asterixis, involuntary movements, ma(cid:173)
`jor motor seizures, lethargy/stupor/coma, and diffuse weak·
`ness. Approximately one-third of patients with a diagnosis
`of encephalopathy may have had coexisting aseptic menin·
`gitis syndrome.
`·
`Signs and symptoms of the aseptic meningitis syndrome de(cid:173)
`scribed in association with the use ofORTHOCLONE OKT3
`have included: fever, headache, meningismus (stiff neck),
`and photophobia. Diagnosis is confirmed by cerebrospinal
`fluid (9SF) analysis demonstrating leukocytosis with pleo(cid:173)
`cytosi~, elevated protein and normal or decreased glucose,
`with negative viral, bacterial, and fungal cultures. The pos(cid:173)
`sibility of infection should be evaluated in any immunosup(cid:173)
`pressed transplant P!itient with clinical findings suggesting
`meningitis. Approximately one· third of the patients with a
`diagnosis of aseptic meningitis had coexisting signs and
`symptoms of encephalopathy. Most patients with the aseptic
`meningitis syndrome had a benign course and recovered
`without any permanent sequelae during therapy or subse·
`quent to its completion or discontinuation. However, be(cid:173)
`cause meningitis is a frequent infection encountered in pe(cid:173)
`diatric allograft recipients, and the immunosuppression as(cid:173)
`sociated with transplantation increases the risk of
`opportunistic infection, pediatric patients with signs or
`symptoms suggestive of meningeal irritation while receiv·
`ing ORTHOCLONE OKT3 should have lumbar punctures
`performed to rule out an infectious etiology. (See: PRECAU(cid:173)
`TIONS: Pediatric Use)
`Signs or symptoms of encephalopathy, meningitis, seizures,
`and cerebral edema, with or without headache, typically
`have been reversible. Headache, aseptic meningitis, sei(cid:173)
`zures, and less severe forms of encephalopathy resolved in
`most patients despite continued treatment with ORTHO(cid:173)
`CLONE OK'f3. However, some events resulted in perma(cid:173)
`nent neurologic impairment.
`
`The following additio~al central nervous system events
`have each been reported: irreversible blindness, impaired
`vision, quadri- or paraparesis/plegia, cerebrovascular acci·
`dent (hemiparesis/plegia), aphasia, transient ischemic at·
`tack, subarachnoid hemorrhage, palsy of the VI cranial
`nerve, hearing decrease, and deafness.
`Patients who may be at greater risk for CNS adverse expe(cid:173)
`riences include those: with known or suspected CNS disor(cid:173)
`ders (e.g., history of seizure disorder, etc.); with cerebrovas(cid:173)
`cular disease (small or large vessel); with conditions having
`associated neurologic problems (e.g., head trauma, uremia,
`infection, fluid and electrolyte disturbance, etc.); with un(cid:173)
`derlying vascular diseases; or who are recei\rjng a medica(cid:173)
`tion concomitantly that may, by itself, affect the central ner(cid:173)
`vous system. (See: WARNINGS, PRECAUTIONS and AD(cid:173)
`VERSE EVENTS: Cytokine Release Syndrome)
`Anaphylactic Reactions
`Serious and occasionally fatal, immediate (usually within
`10 minutes) hypersensitivity (anaphylactic) reactions have
`been reported in patients treated with ORTHOCLONE
`OKT3. Manifestations of anaphylaxis may appear similar
`to manifestations of the Cytokine Release Syndrome (de(cid:173)
`scribed above). It may be impossible to determine the
`mechanism responsible for any systemic reaction(s). Reac(cid:173)
`tions attributed to hypersensitivity have been reported less
`frequently than those attributed to cytokine release. Acute
`hypersensitivity reactions may be characterized by: cardio(cid:173)
`vascular collapse, cardiorespiratory arrest, loss of con(cid:173)
`sciousness, hypotension/shock, tachycardia, tingling, angio(cid:173)
`edema (including laryngeal, pharyngeal, or facial edema),
`airway obstruction, bronchospasm, dyspnea, urticaria, and
`pruritus.
`Serious allergic events. including anaphylactic or anaphy(cid:173)
`lactoid reactions, have been reported in patients re-ex(cid:173)
`posed· to ORTHOCLONE OKTJ subsequent to their initial
`course of therapy. Pretreatment with antihistamines
`and/or steroids may not reliably prevent anaphylaxis in
`this setting. Possible allergic hazards of retreatment
`should be weighed against expected therapeutic benefits
`and alternatives. If a patient is retreated with ORTHO(cid:173)
`CLONE OKT3. it is particularly important that epinephrine
`and other emergency life-support equipment should be im·
`mediately available.
`If hypersensitivity is suspected, discontinue the drug im·
`mediately; do not resume therapy or re-expose the patient
`to ORTHOCLONE OKT3. Serious acute hypersensitivity re(cid:173)
`actions may require emergency treatment with 0.3 mL to
`0.5 mL aqueous epinephrine (1:1000 dilution) subcutane(cid:173)
`ously and other resuscitative measures including oxygen,
`intravenous fluids, antihistamines, corticosteroids, pressor
`amines, and airway m~nagement, as clinically indicated.
`(See: PRECAUTIONS: Cytokine Release Syndrome vs. An(cid:173)
`aphylactic Reactions; ADVERSE EVENTS: Hypersensitiv(cid:173)
`ity Reactions)
`Consequences of Immunosuppression
`Serious and sometimes fatal infections and neoplasias have
`been reported in association with all immunosuppressive
`therapies, including those regimens containing ORTHO(cid:173)
`CLONEOK'I"'3.
`Infections.- ORTHOCLONE OKT3 is usually added to im(cid:173)
`munosuppressive therapeutic regimens, thereby augment·
`ing the degree of immunosuppression. This increase in the
`total amount of immunosuppression may alter the spectrum
`of infections observed and increase the risk, the severity,
`and the morbidity of infectious complications. During the
`first month post-transplant, patients are at greatest risk for
`the following infections: (1) those present prior to .trans(cid:173)
`plant, perhaps exacerbated by post-transplant immun9sup(cid:173)
`pression; (2) infection conveyed by the donor organ; ~d (3)
`the usual post-operative urinary tract, intravenous line re(cid:173)
`lated, wound, or pulmonary infections due to bacterial
`pathogens. (See: ADVERSE EVENTS: Infections)
`Approximately one to six months post-transplant, patients
`are at risk for viral infections [e.g., cytomegalovirus (CMV),
`Epstein-Barr virus (EBV), herpes simplex virus (HSV), etc. I
`which produce serious systemic disease and which also in(cid:173)
`crease the overall state of immunosuppression.
`Reactivation (1 to 4 months post-transplant) of EBV and
`CMV has been reported. When administration of an anti(cid:173)
`lymphocyte antibody, including ORTHOCLONE OKT3,. is
`followed by an immunosuppressive regimen including cy·
`closporine, there is an increased risk of reactivating CMV
`and impaired ability to limit its proliferation, resulting in
`symptomatic and disseminated disease. EBV infection, ei(cid:173)
`ther primary or reactivated, rnay play an important role in
`the development of post. transplant lymphoproliferative dis·
`orders. (See: WARNINGS and ADVERSE EVENTS: Neopla(cid:173)
`sia)
`In the pediatric transplant population, viral infections often
`include pathogens uncommon in adults, such as varicella
`zoster virus (VZV), adenovirus, and respiratory syncytial vi(cid:173)
`rus (RSV). A large proportion of pediatric patients have not
`been infected with the herpes viruses prior to transplanta(cid:173)
`tion and, therefore, are susceptible to developing primary
`infections from the grafted organ and/or blood products.
`Anti-infective prophylaxis may reduce the morbidity associ(cid:173)
`ated with certain potential pathogens and should be consid(cid:173)
`ered for pedi