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WARNINGS SEE BOXED WARNING Cytokine Release Syndrome Most patients develop an acute clinical syndrome [i.e., Cytokine Release Syndrome (CRS)] that has been attributed to the release of cytokines by activated lymphocytes or monocytes and is temporally associated with the administration of the first few doses of ORTHOCLONE OKT ® 3 (particularly, 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-threatening shock-like reaction, which may include serious cardiovascular and central nervous system manifestations. The syndrome typically begins approximately 30 to 60 minutes 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. Increasing the amount of ORTHOCLONE OKT3 or resuming treatment after a hiatus may result in a reappearance of the CRS. Common clinical manifestations of CRS may include: high fever (often spiking, up to 107°F), chills/rigors, headache, tremor, nausea/vomiting, diarrhea, abdominal pain, malaise, muscle/joint aches and pains, and generalized weakness. Less frequently reported adverse experiences include: minor dermatologic reactions (e.g., rash, pruritus, etc.) and a spectrum of often serious, occasionally fatal, cardiorespiratory and central nervous system adverse experiences. Cardiorespiratory findings may include: dyspnea, shortness of breath, bronchospasm/wheezing, tachypnea, respiratory arrest/failure/distress, cardiovascular collapse, cardiac arrest, angina/myocardial infarction, chest pain/tightness, tachycardia (including ventricular), hypertension, hemodynamic instability, hypotension including profound shock, heart failure, pulmonary edema (cardiogenic and non-cardiogenic), adult respiratory distress syndrome, hypoxemia, apnea, and arrhythmias. (See: BOXED WARNING ; PRECAUTIONS ; 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 restrictions. In subsequent trials and in post-marketing experience, 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 therapy, some patients have experienced an acute and transient decline in the glomerular filtration rate (GFR) and diminished 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 delayed renal allograft function. Similarly, transient elevations 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 angina; recent myocardial infarction or symptomatic ischemic heart disease; heart failure of any etiology; pulmonary edema of any etiology; any form of chronic obstructive pulmonary disease; intravascular volume overload or depletion of any etiology (e.g., excessive dialysis, recent intensive diuresis, blood loss, etc.); cerebrovascular disease; patients with advanced symptomatic vascular disease or neuropathy; 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 patient's volume (fluid) status and a chest X-ray should be assessed to rule out volume overload, uncontrolled hypertension, 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 increased serum levels of cytokines (e.g., TNF-α, IL-2, IL-6, IFN-γ) that peak between 1 and 4 hours following administration of ORTHOCLONE OKT3. The serum levels of cytokines and the manifestations of CRS may be reduced by pretreatment with 8 mg/kg of methylprednisolone (i.e., high-dose steroids), given 1 to 4 hours prior to administration of the first dose of ORTHOCLONE OKT3, and by closely following recommendations for dosage and treatment duration. (See: DOSAGE AND ADMINISTRATION .) It is not known if corticosteroid pretreatment decreases organ damage and sequelae associated with CRS. For example, increased 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 Release Syndrome occur, intensive treatment including oxygen, intravenous fluids, corticosteroids, pressor amines, antihistamines, intubation, etc., may be required. Central Nervous System Events Seizures, encephalopathy, cerebral edema, aseptic meningitis, and headache have been reported, even following the first dose, during therapy with ORTHOCLONE OKT ® 3. Seizures, some accompanied by loss of consciousness or cardiorespiratory arrest, or death, have occurred independently or in conjunction with any of the neurologic syndromes described below. A few cases of fatal cerebral herniations subsequent to cerebral edema have been reported. All patients, particularly pediatric patients, must be carefully evaluated for fluid retention and hypertension before the initiation of ORTHOCLONE OKT3 therapy. Close monitoring for neurologic symptoms must be performed during the first twenty - four (24) hours following each of the first few doses of ORTHOCLONE OKT3 injection. Patients should be closely monitored for convulsions and manifestations of encephalopathy, including: impaired cognition, confusion, obtundation, altered mental status, disorientation, auditory/visual hallucinations, psychosis (delirium, paranoia), mood changes (e.g., mania, agitation, combativeness, etc.), diffuse hypotonus, hyperreflexia, myoclonus, tremor, asterixis, involuntary movements, major motor seizures, lethargy/stupor/coma, and diffuse weakness. Approximately one-third of patients with a diagnosis of encephalopathy may have had coexisting aseptic meningitis syndrome. Signs and symptoms of the aseptic meningitis syndrome described in association with the use of ORTHOCLONE OKT3 have included: fever, headache, meningismus (stiff neck), and photophobia. Diagnosis is confirmed by cerebrospinal fluid (CSF) analysis demonstrating leukocytosis with pleocytosis, elevated protein and normal or decreased glucose, with negative viral, bacterial, and fungal cultures. The possibility of infection should be evaluated in any immunosuppressed transplant patient 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 subsequent to its completion or discontinuation. However, because meningitis is a frequent infection encountered in pediatric allograft recipients, and the immunosuppression associated with transplantation increases the risk of opportunistic infection, pediatric patients with signs or symptoms suggestive of meningeal irritation while receiving ORTHOCLONE OKT3 should have lumbar punctures performed to rule out an infectious etiology. (See: PRECAUTIONS: Pediatric Use .) Signs or symptoms of encephalopathy, meningitis, seizures, and cerebral edema, with or without headache, typically have been reversible. Headache, aseptic meningitis, seizures, and less severe forms of encephalopathy resolved in most patients despite continued treatment with ORTHOCLONE OKT3. However, some events resulted in permanent neurologic impairment. The following additional central nervous system events have each been reported: irreversible blindness, impaired vision, quadri-or paraparesis/plegia, cerebrovascular accident (hemiparesis/plegia), aphasia, transient ischemic attack, subarachnoid hemorrhage, palsy of the VI cranial nerve, hearing decrease, and deafness. Patients who may be at greater risk for CNS adverse experiences include those: with known or suspected CNS disorders (e.g., history of seizure disorder, etc.); with cerebrovascular disease (small or large vessel); with conditions having associated neurologic problems (e.g., head trauma, uremia, infection, fluid and electrolyte disturbance, etc.); with underlying vascular diseases; or who are receiving a medication concomitantly that may, by itself, affect the central nervous system. (See: WARNINGS , PRECAUTIONS and ADVERSE 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 (described above). It may be impossible to determine the mechanism responsible for any systemic reaction(s). Reactions attributed to hypersensitivity have been reported less frequently than those attributed to cytokine release. Acute hypersensitivity reactions may be characterized by: cardiovascular collapse, cardiorespiratory arrest, loss of consciousness, hypotension/shock, tachycardia, tingling, angioedema (including laryngeal, pharyngeal, or facial edema), airway obstruction, bronchospasm, dyspnea, urticaria, and pruritus. Serious allergic events, including anaphylactic or anaphylactoid reactions, have been reported in patients re-exposed to ORTHOCLONE OKT3 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 ORTHOCLONE OKT3, it is particularly important that epinephrine and other emergency life-support equipment should be immediately available. If hypersensitivity is suspected, discontinue the drug immediately; do not resume therapy or re-expose the patient to ORTHOCLONE OKT3 . Serious acute hypersensitivity reactions may require emergency treatment with 0.3 mL to 0.5 mL aqueous epinephrine (1:1000 dilution) subcutaneously and other resuscitative measures including oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated. (See: PRECAUTIONS: Cytokine Release Syndrome vs. Anaphylactic Reactions ; ADVERSE EVENTS: Hypersensitivity Reactions .) Consequences of Immunosuppression Serious and sometimes fatal infections and neoplasias have been reported in association with all immunosuppressive therapies, including those regimens containing ORTHOCLONE OKT ® 3. Infections ORTHOCLONE OKT3 is usually added to immunosuppressive therapeutic regimens, thereby augmenting 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 transplant, perhaps exacerbated by post-transplant immunosuppression; (2) infection conveyed by the donor organ; and (3) the usual post-operative urinary tract, intravenous line related, 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.] which produce serious systemic disease and which also increase the overall state of immunosuppression. Reactivation (1 to 4 months post-transplant) of EBV and CMV has been reported. When administration of an anti-lymphocyte antibody, including ORTHOCLONE OKT3, is followed by an immunosuppressive regimen including cyclosporine, there is an increased risk of reactivating CMV and impaired ability to limit its proliferation, resulting in symptomatic and disseminated disease. EBV infection, either primary or reactivated, may play an important role in the development of post-transplant lymphoproliferative disorders. (See: WARNINGS and ADVERSE EVENTS: Neoplasia .) In the pediatric transplant population, viral infections often include pathogens uncommon in adults, such as varicella zoster virus (VZV), adenovirus, and respiratory syncytial virus (RSV). A large proportion of pediatric patients have not been infected with the herpes viruses prior to transplantation and, therefore, are susceptible to developing primary infections from the grafted organ and/or blood products. Geriatric patients may have a reduced capability to overcome infections during intense immunosuppression. There is no information on the use of OKT3 in geriatric patients. In an age-stratification analysis, no overall difference in the safety of OKT3 was noted between older (51 to 64 years) and younger (≤30 years) patients. Caution should be used when prescribing immunosuppressive agents to elderly patients. Anti-infective prophylaxis may reduce the morbidity associated with certain potential pathogens and should be considered for pediatric and other high-risk patients. Judicious use of immunosuppressive drugs, including type, dosage, and duration, may limit the risk and seriousness of some opportunistic infections. It is also possible to reduce the risk of serious CMV or EBV infection by avoiding transplantation of a CMV-seropositive (donor) and/or EBV-seropositive (donor) organ into a seronegative patient. Neoplasia As a result of depressed cell-mediated immunity from immunosuppressive agents, organ transplant patients have an increased risk of developing malignancies. This risk is evidenced almost exclusively by the occurrence of lymphoproliferative disorders, squamous cell carcinomas of the skin and lip, and sarcomas. In immunosuppressed patients, T cell cytotoxicity is impaired allowing for transformation and proliferation of EBV-infected B lymphocytes. Transformed B lymphocytes are thought to initiate oncogenesis, which ultimately culminates in the development of most post-transplant lymphoproliferative disorders. Patients, especially pediatric patients, with primary EBV infection may be at a higher risk for the development of EBV-associated lymphoproliferative disorders. Data support an association between the development of lymphoproliferative disorders at the time of active EBV infection and ORTHOCLONE OKT3 administration in pediatric liver allograft recipients. (See: ADVERSE EVENTS, Infections , Neoplasia .) Following the initiation of ORTHOCLONE OKT3 therapy, patients should be continuously monitored for evidence of lymphoproliferative disorders through physical examination and histological evaluation of any suspect lymphoid tissue. Close surveillance is advised, since early detection with subsequent reduction of total immunosuppression may result in regression of some of these lymphoproliferative disorders. Since the potential for the development of lymphoproliferative disorders is related to the duration and extent (intensity) of total immunosuppression, physicians are advised: to adhere to the recommended dosage and duration of ORTHOCLONE OKT3 therapy; to limit the number of courses of ORTHOCLONE OKT3 and other anti- T lymphocyte antibody preparations administered within a short period of time; and, if appropriate, to reduce the dosage(s) of immunosuppressive drugs used concomitantly to the lowest level compatible with an effective therapeutic response. (See: DOSAGE AND ADMINISTRATION .) A recent study examined the incidence of non-Hodgkin's lymphoma (NHL) among 45,000 kidney transplant recipients and over 7,500 heart transplant recipients. This study suggested that all transplant patients, regardless of the immunosuppressive regimen employed, are at increased risk of NHL over the general population. The relative risk was highest among those receiving the most aggressive regimens. The long-term risk of neoplastic events in patients being treated with ORTHOCLONE OKT3 has not been determined.