Orthoclone OKT 3 (Muromonab)





Action And Clinical Pharmacology: Muromonab-CD3 sterile solution is a murine monoclonal antibody to the T3 (CD3) antigen of human T cells which functions as an immunosuppressant. It is for i.v. use only. The antibody is a biochemically purified IgG2a immunoglobulin with a heavy chain of approximately 50 000 daltons and a light chain of approximately 25 000 daltons. It is directed to a glycoprotein with a molecular weight of 20 000 daltons in the human T cell surface which is essential for T cell functions. Because it is a monoclonal antibody preparation, muromonab-CD3 sterile solution is a homogeneous, reproducible antibody product with consistent, measurable reactivity to human T cells.

The proper name, muromonab-CD3, is derived from the descriptive term murine monoclonal antibody. The CD3 designation identifies the specificity of the antibody as the Cell Differentiation (CD) cluster 3 defined by the First International Workshop on Human Leukocyte Differentiation Antigens.

Muromonab-CD3 reverses graft rejection, most probably by blocking the function of all T cells which play a major role in acute allograft rejection. Muromonab-CD3 reacts with and blocks the function of a 20 000 dalton molecule (CD3) in the membrane of human T cells that has been associated in vitro with the antigen recognition structure of T cells and is essential for signal transduction. In in vitro cytolytic assays, muromonab-CD3 blocks both the generation and function of effector cells. It is a potent mitogen in vitro in calf serum, but this mitogenicity is markedly reduced in human serum. Muromonab-CD3 thus blocks all known T cell functions.

In vivo, muromonab-CD3 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.

In all patients studied, a rapid and concomitant decrease in the number of circulating CD3 positive, CD4 positive and CD8 positive T cells was observed within minutes after the administration of muromonab-CD3. Between days 2 and 7 increasing numbers of circulating CD4 positive and CD8 positive cells have been observed in patients, although CD3 positive cells are not detectable. CD3 positive cells reappear rapidly and reach pre-treatment levels within a week after termination of muromonab-CD3 therapy. Increasing numbers of CD3 positive cells have been observed in some patients during the second week of muromonab-CD3 therapy, possibly as a result of the development of neutralizing antibodies to muromonab-CD3.

Antibodies to muromonab-CD3 have been observed, occurring with an incidence of 21% (n=43) for IgM, 86% (n=43) for IgG and 29% (n=35) for IgE. The mean time of appearance of IgG antibodies was 20±2 (mean±SD) days. Early IgG antibodies appeared by the end of the second week of treatment in 3% (n=86) of the patients.

Serum levels of muromonab-CD3 are measurable using an enzyme-linked immunosorbent assay (ELISA). During treatment with 5 mg/day for 14 days, mean serum trough levels of muromonab-CD3 increased during the first 3 days of administration and then remained in a steady state with a mean value of 0.9 g/mL on days 3 to 14. The levels obtained during therapy have been shown to block T cell effector functions in vitro.

Following administration of muromonab-CD3 in vivo, leukocytes have been observed in cerebrospinal and peritoneal fluids. The mechanism for this effect is not understood.

Indications And Clinical Uses: For the treatment of acute renal allograft rejection, and acute cardiac and hepatic allograft rejection refractory to conventional antirejection therapy or when conventional therapy is contraindicated.

Controlled Clinical Trials: In a controlled randomized clinical trial, muromonab-CD3 was significantly more effective than conventional high dose steroid therapy in reversing acute renal allograft rejection. In this trial, 122 evaluable patients undergoing acute rejection of cadaveric renal transplants were treated either with muromonab-CD3 daily for a mean of 14 days, with concomitant lowering of the dosage of azathioprine and maintenance steroids (62 patients), or with conventional high dose steroids (60 patients). Muromonab-CD3 reversed 94% of the rejections compared to a 75% reversal rate obtained with conventional high dose steroid treatment (p=0.006). The 1 year Kaplan-Meier (actuarial) estimates of graft survival rates for these patients who had acute rejection were 62% and 45% for muromonab-CD3 and steroid treated patients, respectively (p=0.04). At 2 years the rates were 56% and 42%, respectively (p=0.06).

One- and two-year patient survivals were not significantly different between the 2 groups, being 85% and 75% for muromonab-CD3 treated patients and 90% and 85% for steroid treated patients.

Controlled randomized trials have not been conducted to evaluate the effectiveness of muromonab-CD3 compared to conventional therapy as a first-line treatment for acute cardiac and hepatic allograft rejections.

Open Clinical Trials: In open clinical trials, acute renal allograft rejection was reversed in 92% (n=126) of the patients treated with muromonab-CD3. Muromonab-CD3 also was effective in reversing acute renal, hepatic, and cardiac allograft rejections of cases where steroids and lymphocyte immune globulin preparations were contraindicated or were not successful (rescue).

The dosage of other immunosuppressive agents used in conjunction with muromonab-CD3 should be lowered to minimal levels (see Dosage).

Contra-Indications: In patients who: are hypersensitive to muromonab-CD3, any other product of mouse origin, or any other components of this product; have anti-murine antibody titres 1:1 000; are in (uncompensated) heart failure or in fluid overload, as evidenced by chest x-ray or a greater than 3% weight gain within the week prior to planned muromonab-CD3 administration; have a history of seizures or are predisposed to seizures; are pregnant or are suspected to be pregnant or who are breast-feeding (see Precautions, Pregnancy).

Manufacturers’ Warnings In Clinical States: Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should use muromonab-CD3.

Patients receiving muromonab-CD3 should be managed in facilities equipped and staffed for cardiopulmonary resuscitation.

Patients with fluid overload have developed severe pulmonary edema upon treatment with muromonab-CD3.

Cytokine Release Syndrome: Temporally associated with the administration of the first few doses of muromonab-CD3 (particularly, the first 2 or 3 doses), most patients have developed Cytokine Release Syndrome (CRS), an acute clinical syndrome, that has been attributed to the release of cytokines by activated lymphocytes or monocytes. 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 CNS manifestations.

The syndrome typically begins approximately 30 to 60 minutes after administration of a dose of muromonab-CD3 (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 muromonab-CD3, both the frequency and severity of the Cytokine Release Syndrome tends to diminish. Increasing the amount of a dose or resuming treatment after a hiatus may result in a reappearance of the CRS.

Common clinical manifestations of the Cytokine Release Syndrome may include: high (often spiking, up to 41.7°C) fever, chills/rigors, headache, tremor, nausea/vomiting, diarrhea, abdominal pain, malaise, and 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 neuropsychiatric 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, adult respiratory distress syndrome, hypoxemia, apnea, arrhythmias and pulmonary edema (cardiogenic and noncardiogenic).

Severe pulmonary edema has occurred in patients with volume (fluid) overload and in those 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 (i.e., left ventricular dysfunction).

During the first 1 to 3 days of muromonab-CD3 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 muromonab-CD3.

Patients at risk for more serious complications of the Cytokine Release Syndrome 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; intravenous vascular 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.

Prior to administration of muromonab-CD3, the patient’s volume (fluid) status should be assessed carefully. It is imperative, especially prior to the first few doses, that there be no clinical evidence of volume overload or uncompensated heart failure, including a chest x-ray free of evidence of heart failure or fluid overload within 24 hours preinjection, and weight restriction of 3% above the patient’s minimum weight during the week prior to injection. Reactions to the first dose may be minimized by using the recommended steroid regimen (see Dosage).

Management of Cytokine Release Syndrome: Manifestations of the Cytokine Release Syndrome may be prevented or minimized 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 muromonab-CD3 therapy, and by closely following recommendations for dosage and treatment duration. Since the CRS may occur following a treatment hiatus and resumption of therapy, similar precautions should be taken in such a case.

If any of the more serious presentations of the Cytokine Release Syndrome occur, intensive treatment including oxygen, i.v. fluids, corticosteroids, pressor amines, antihistamines, intubation, etc., may be required.

Anaphylatic Reactions and other Hypersensitivity Reactions: Anaphylatic or anaphylactoid reactions may occur following administration of any dose or course of muromonab-CD3 therapy.

Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions usually occurring within 10 minutes after administration have been reported in patients treated with muromonab-CD3 therapy. 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, pulmonary edema especially in patients with volume overload, seizures or coma, tachycardia, pruritus, urticaria, tingling, angioedema including laryngeal, pharyngeal or facial edema, dyspnea, bronchospasm, and airway obstruction.

Serious allergic events, including anaphylactic or anaphylactoid reactions, have been reported in patients re-exposed to muromonab-CD3 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 hypersensitivity is suspected, discontinue the drug immediately. Do not resume therapy or re-expose the patient to muromonab-CD3 therapy.

Severe Cytokine Release Syndrome Versus Anaphylactic Reactions: It may be very difficult, even impossible, to distinguish between an acute hypersensitivity reaction (e.g., anaphylaxis, angioedema, etc.) and the Cytokine Release Syndrome. Potentially serious signs and symptoms having an immediate onset (usually within 10 minutes) following administration of muromonab-CD3 are more likely due to acute hypersensitivity; discontinue the drug immediately. If hypersensitivity is suspected, do not resume therapy or re-expose the patient to muromonab-CD3. Clinical manifestations beginning approximately 30 to 60 minutes (or later) following administration of muromonab-CD3, are more likely cytokine-mediated.

Neuropsychiatric Events: Seizures, encephalopathy, cerebral edema, aseptic meningitis, and headache have been reported, even following the first dose, during therapy with muromonab-CD3, resulting in part from T-cell activation and subsequent systemic release of cytokines.

Headache is frequently seen after any of the first few doses and may occur in any of the following neurological syndromes or by itself.

Seizures, some accompanied by loss of consciousness, cardiorespiratory arrest or death, have occurred independently or in conjunction with any of the neurologic syndromes described below. Patients predisposed to seizures may include those with the following conditions: acute tubular necrosis/uremia, fever, infection, a precipitous fall in serum calcium, fluid overload, hypertension, hypoglycemia, history of seizures, and electrolyte imbalances or those who are taking a medication concomitantly that may, by itself, cause seizures.

Signs and symptoms of the aseptic meningitis syndrome described in association with the use of muromonab-CD3 therapy have included: fever, headache, meningismus (stiff neck), and photophobia. 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.

Manifestations of encephalopathy may include: 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, myclonus, tremor, asterixis, involuntary movements, major motor seizures, lethargy/stupor/coma, and diffuse weakness. Some patients with a diagnosis of encephalopathy also had symptoms of meningismus or headache.

Cerebral edema (and other signs of increased vascular permeability e.g., nasal and ear stuffiness, etc.) has been seen in patients treated with muromonab-CD3 and may accompany some of the other neurologic manifestations.

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, etc.); with underlying vascular diseases; or who are receiving a medication concomitantly that may, by itself, affect the CNS.

Signs or symptoms of encephalopathy, meningitis, seizures, and cerebral edema, with or without headache, have typically been reversible. Headache, aseptic meningitis, seizures, and less severe forms of encephalopathy resolved in most patients despite continued treatment. Irreversible sequelae associated with serious CNS events (e.g. blindness, deafness, paralysis) have been reported rarely.

Consequences of Immunosuppression: Infection/Viral-Induced Lymphoproliferative Disorders: Infections: Muromonab-CD3 is usually added to immunosuppressive therapeutic regimens, thereby augmenting the degree of immunosuppression. This increase in the total burden of immunosuppression may alter the spectrum of infections observed and increase the risk, the severity, and the potential gravity (morbidity) of infectious complications.

Patients must be observed carefully for any signs and symptoms suggesting infection or viral-induced lymphoproliferative disorders (LPD). Anti-infective prophylaxis should be considered for patients at high risk. If infection or viral-induced LPD occur, cultures should be prepared and a biopsy should be performed as soon as possible. Appropriate anti-infective therapy should be promptly instituted, and if possible, immunosuppressive therapy should be reduced or discontinued.

When using combinations of immunosuppressive agents, the dose of each agent, including muromonab-CD3, should be reduced to the lowest level compatible with an effective therapeutic response so as to reduce the potential for and severity of infections and malignant transformations.

Multiple or intensive courses of any anti-T cell antibody preparation, including muromonab-CD3, which produce profound impairment of cell-mediated immunity, further increase the risk of (opportunistic) infection, especially with the Herpes viruses (HSV, CMV, EBV) and fungi.

Anti-infective prophylaxis may reduce the morbidity associated with certain potential pathogens and should be considered for high-risk patients. 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, organ transplant patients have an increased risk of developing malignancies, especially lymphoproliferative disorders (LPD), lymphomas, and skin cancers.

The long-term risk of neoplastic events in patients being treated with muromonab-CD3 has not been determined.

This formulation of Orthoclone OKT 3 contains polysorbate 80 and must not be used for the in vitro treatment of bone marrow.

Precautions: Prior to Treatment with muromonab-CD3: Fluid Status: The patient’s volume (fluid) status should be assessed carefully. It is imperative, especially prior to the first few doses, that there be no clinical evidence of volume overload, uncontrolled hypertension or uncompensated heart failure. There should be a chest x-ray free of evidence of heart failure or fluid overload and weight restrictions of 3% above the patient’s minimum weight during the week prior to injection.

Fever: If the temperature of a patient exceeds 37.8°C, it should be lowered by antipyretics before administration of each dose of muromonab-CD3.

Sensitization: Muromonab-CD3 is a murine (immunoglobulin) protein that can induce human antimurine antibody (HAMA) production (i.e., sensitization) in some patients following exposure. Depending upon the HAMA titer, muromonab-CD3 has been used to reverse subsequent rejection episodes in patients without detectable or with weakly positive (1:100) antibody titers. Higher antibody titers (>1:100) may preclude successful reuse of muromonab-CD3. If an antibody titer 1:1 000 is detected, therapy should not be attempted.

Patients receiving muromonab-CD3 for initial use should be monitored periodically to ensure adequate plasma muromonab-CD3 levels (800 ng/mL) or T cell clearance (CD3 positive T cells
Intravascular Thrombosis: As with other immunosuppressive therapies, arterial, venous, and capillary thromboses of allografts and other vascular beds (e.g., heart, lungs, brain, bowel, etc.) have been reported in patients treated with muromonab-CD3. The decision to use muromonab-CD3 therapy in patients with a history of thrombotic events or underlying vascular disease should take into consideration the risks of thrombosis. Concomitant use of prophylactic antithrombotic interventions (e.g., mini-dose heparin, etc.) should be considered.

Use a low protein-binding 0.2 or 0.22 micrometer (m) filter to prepare the injections (see Dosage, method of administration).

Information for the Patient: Patients should be informed of the expected first dose muromonab-CD3 effects, which are markedly reduced on successive days of muromonab-CD3 treatment. Patients should also be informed regarding the potential benefits and risks of using muromonab-CD3 therapy.

Laboratory Tests: As with many potent drugs, periodic assessment of organ system functions should be performed during treatment with muromonab-CD3.

Prior to and During Muromonab-CD3 Therapy: The following tests should be monitored: Renal: BUN, serum creatinine, etc. Hepatic: transaminases, alkaline phosphatase, bilirubin. Hematopoietic: WBCs and differential, platelet count, etc. Chest x-ray: Within 24 hours before initiating muromonab-CD3 treatment, a chest x-ray should be performed to ensure that there is no evidence of heart failure or fluid overload.

For Initial Use of Muromonab-CD3: One of the following immunologic tests should be monitored during muromonab-CD3 therapy: Plasma muromonab-CD3 levels (as determined by an ELISA); target muromonab-CD3 levels should be 800 ng/mL; or quantitative T-lymphocyte surface phenotyping (CD3, CD4, CD8).

Prior to Retreatment with muromonab-CD3 therapy: Testing for human antimurine antibody titers is strongly recommended: Human antimurine antibody titers (as determined by an ELISA); a titre >1:100 may preclude successful reuse; a titer 1:1 000 is a contraindication for use.

Retreatment requires daily monitoring of either plasma muromonab-CD3 levels or clearance of CD3 positive T cells to achieve the same targets described above for initial use.

Carcinogenesis: Long-term studies have not been conducted in laboratory animals to evaluate the carcinogenic potential of muromonab-CD3 therapy.

Pregnancy and Lactation: Muromonab-CD3 is contraindicated in women who are pregnant or are suspected to be pregnant, and those who are breast feeding. Animal reproductive studies have not been conducted with muromonab-CD3. It is not known whether muromonab-CD3 can cause fetal harm when administered to a pregnant woman or whether muromonab-CD3 can affect reproduction.

Children: Safety and effectiveness in children have not been established. No adequately controlled clinical studies have been conducted in children. [Published literature has reported the use of muromonab-CD3 therapy in infants/children. Pediatric recipients are reported to be significantly immunosuppressed for a prolonged period of time and therefore, require close monitoring post-therapy for opportunistic infections, particularly varicella-zoster virus (VZV), which poses an infectious complication unique to this population. Gastrointestinal fluid loss secondary to diarrhea and/or vomiting resulting from the Cytokine Release Syndrome may be significant when treating small children and may require parenteral hydration. It is unknown whether there may be significant long-term sequelae related to the occurrence of seizures, high fever, CNS infections, aseptic meningitis, etc., following muromonab-CD3 treatment. In cases where administration of muromonab-CD3 would be deemed medically appropriate, more vigilant and frequent monitoring is required for children (especially young ones) than in adults.]

Drug Interactions: Concomitant medications (azathioprine, corticosteroids, cyclosporine) may have contributed to the neuropsychiatric, infectious, nephrotoxic, thrombotic, and/or neoplastic events reported in patients treated with muromonab-CD3.

In addition, the use of indomethacin by a few patients who were simultaneously receiving therapy with muromonab-CD3 may have contributed to some encephalopathic and other CNS adverse events (see Adverse Effects).

Adverse Reactions: The incidence of adverse experiences reported by patients in clinical trials receiving muromonab-CD3 plus concomitant low dose immunosuppressive therapy (primarily azathioprine and corticosteroids) during the first 2 days of treatment for transplant rejection, was higher than that previously reported by patients receiving conventional therapy. During this period, the majority of patients experienced pyrexia (90%) (of which 19% were 40°C or above) and chills (59%). In addition, other adverse experiences occurring in 8% or more of the patients during the first 2 days of muromonab-CD3 therapy included those listed

Similar adverse effects were observed in the additional open clinical studies.

Additional serious and occasionally fatal cardiorespiratory manifestations have been reported following any of the first few doses (see Warnings, Cytokine Release Syndrome and Adverse Effects, Adverse Events by Body System, Cardiovascular, Respiratory).

Pulmonary Edema: Potentially fatal severe pulmonary edema has been reported following the first 2 doses in less than 2% of renal transplant patients and was always associated with fluid overload. However, post-marketing experience revealed that pulmonary edema has occurred in patients who appeared to be euvolemic, presumably as a consequence of cytokine-mediated increased vascular permeability (“leaky capillaries.”) and/or reduced myocardial contractility/compliance (i.e., left ventricular dysfunction) (see Warnings, Cytokine Release Syndrome and Dosage). It is, therefore, essential that patients receiving muromonab-CD3 not be in fluid overload and remain under close medical supervision for 48 hours after the administration of the first dose. The first dose should be administered as detailed in the Dosage section.

Infections: In the controlled randomized renal rejection trial, the most common infections during the first 45 days of muromonab-CD3 therapy were due to Herpes simplex (27%) and cytomegalovirus (19%). Other severe and life threatening infections were S. epidermidis (4.8%), P. carinii (3.1%), Legionella (1.6%), Cryptococcus (1.6%), Serratia (1.6%), and gram-negative bacteria (1.6%). The incidence of infections was similar in patients treated with muromonab-CD3 and in patients treated with high dose steroids. In a clinical trial of acute hepatic rejection refractory to conventional treatment, the most common infections reported in patients treated with muromonab-CD3 during the first 45 days of the study were cytomegalovirus (15.7% of patients, of which 43% of infections were severe), fungal infections (14.9% of patients, of which 30% were severe), and Herpes simplex (7.5% of patients, of which 10% were severe). Other severe and life-threatening infections were gram-positive infections (9.0% of patients), gram-negative infections (7.5% of patients), viral infections (1.5% of patients), and Legionella (0.7% of patients). In another hepatic rejection trial the incidence of fungal infections was 34% and infections with the Herpes simplex virus was 31%.

In a clinical trial of acute cardiac rejection refractory to conventional treatment, the most common infections reported in the muromonab-CD3 group during the first 45 days of the study were Hepres simplex (5% of patients, of which 20% were severe), fungal infections (4% of patients, of which 75% were severe), and cytomegalovirus (3% of patients, of which 33% were severe). No other severe or life-threatening infections were reported during this period.

Clinically significant infections (e.g., pneumonia, sepsis, etc.) due to the following parthogens have been reported. Bacterial: Clostridium species (including perfringens), Corynebacterium, enterococcus, E. aerogenes, E. coli, Klebsiella species, Lactobacillus, Legionella, L. monocytogenes, Mycobacteria species, N. asteroides, Proteus species, Providencia species, P. aeruginosa, Serratia species, Staphylococcus species, Streptococcus species, Y. enterocolitica, and other gram-negative bacteria.

Fugal: Aspergillus, Candida, Cryptococcal, Dermatophytes.

Protoza: P. carinii, T. gondii.

Viral: cytomegalovirus (CMV), Epstein-Barr virus* (EBV), Herpes simplex virus* (HSV), Hepatitis viruses, Varicella zoster virus (VZV).

As a consequence of being a potent immunosuppressive, the incidence and severity of infections with designated pathogens, especially the Herpes family of viruses, may be increased (see Warnings, Infection/Viral-Induced Lymphoproliferative Disorders).

Neoplasia: In patients treated with muromonab-CD3, post-transplant lymphoproliferative disorders (LPD) reported have ranged from lymphadenopathy or benign polyclonal B cell hyperplasias to malignant and often fatal monoclonal B cell lymphomas. In post-marketing experience, approximately one-third of the lymphoproliferations reported were benign and two-thirds were malignant. Classification of these lymphomas has included: B cell, large cell, polyclonal, non-Hodgkin’s, lymphocytic, T cell, Burkitt’s; the majority have not been classified histologically. When malignant lymphomas have been reported, they have appeared to develop early after transplantation, the majority within the first 4 months post-treatment. Many of these have been rapidly progressive, some fulminant involving the allografted organ, widely disseminated at time of diagnosis, and fatal. Carcinomas of the skin have included: basal cell, squamous cell, Kaposi’s sarcoma, melanoma, and keratoacanthoma. Other neoplasms infrequently reported include: multiple myeloma, leukemia, carcinoma of the breast, adenocarcinoma, cholangiocarcinoma, and recurrences of pre-existing hepatoma and renal cell carcinoma.

Hypersensitivity Reactions: Reported adverse reactions resulting from the formation of antibodies to muromonab-CD3 have included antigen-antibody (immune complex) mediated syndromes and IgE-mediated reactions. Reported hypersensitivity reactions have ranged from a mild, self-limited rash or pruritus to severe, life-threatening anaphylactic reactions/shock or angioedema (including: swelling of lips, eyelids, laryngeal spasm and airway obstruction with hypoxia) (see Warnings, Anaphylactic Reactions and other Hypersensitivity Reactions).

Other hypersensitivity reactions have included: ineffectiveness of treatment, serum sickness, arthritis, allergic interstitial nephritis, immune complex deposition resulting in glomerulonephritis, vasculitis, and temporal arteritis, and eosinophilia.

Adverse Events by Body System: Clinical adverse events occurring in clinical trials and post-marketing experience are listed below by body system: Body as a Whole: fever (including, spiking temperatures as high as 41.7°C, chills/rigors, flu-like syndrome, fatigue/malaise, generalized weakness, anorexia.

Cardiovascular: cardiac arrest, hypotension/shock, heart failure, cardiovascular collapse, angina/myocardial infarction, tachycardia, bradycardia, hemodynamic instability, hypertension, left ventricular dysfunction, arrhythmias, chest pain/tightness.

Respiratory: respiratory arrest, adult respiratory distress syndrome (ARDS), respiratory failure, pulmonary edema, (cardiogenic or noncardiogenic), apnea, dyspnea, bronchospasm, wheezing, shortness of breath, hypoxemia, tachypnea/hyperventilation, abnormal chest sounds, and pneumonia/pneumonitis (bacterial, viral, P. carinii, etc.).

Dermatologic: rash, erythema multiforme, urticaria, pruritus, erythema, flushing, diaphoresis.

Gastrointestinal: diarrhea, nausea/vomiting, abdominal pain, bowel infarction, gastrointestinal hemorrhage.

Hematopoietic: pancytopenia, aplastic anemia, neutropenia, leukopenia, thrombocytopenia, lymphopenia, leukocytosis, lymphadenopathy; arterial, venous and capillary thromboses of allografts and other vascular beds (e.g., heart, lung, brain, bowel, etc.); disturbances of coagulation, including disseminated intravascular coagulation; microangiopathic hemolytic anemia.

Hepatobiliary: increases in transaminases (AST, ALT, etc.); hepato/splenomegaly or hepatitis, usually secondary to viral infection or lymphoma.

Neuropsychiatric: seizures, lethargy/stupor/coma, encephalopathy, psychotic reactions (delirium), encephalitis, meningitis, cerebral edema, headache, dizziness, tremor, aphasia, quadri- or paraparesis/plegia, obtundation, confusion, altered mental status (e.g., paranoia, etc.), impaired cognition, disorientation, auditory and visual hallucinations, agitation/combativeness, mood changes (e.g., mania, etc.), hypotonus, hyperreflexia, myoclonus, obnubilation, asterixis, involuntary movements, CNS infections, CNS malignancies, cerebrovascular accident, hemiparesis/ pelgia, transient ischemic attack, subarachnoid hemorrhage.

Musculoskeletal: arthralgia, arthritis, myalgia, stiffness/aches/pains.

Special Senses: blindness, blurred vision, diplopia, hearing loss, otitis media, tinnitus, vertigo, VI cranial nerve palsy, photophobia, conjunctivitis, nasal and ear stuffiness.

Renal: anuria/oliguria; delayed graft function; renal insufficiency/renal failure, usually transient and reversible in association with cytokine release syndrome; abnormal urinary cytology, including exfoliation of damaged lymphocytes, collecting duct cells and cellular casts.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: The maximum amount of muromonab-CD3 that can safely be administered in single or multiple doses has not been determined.

Dosage And Administration: The recommended dose of muromonab-CD3 is 5 mg as a single daily (i.v.) dose for 10 to 14 days. The diagnosis of acute allograft rejection should be made prior to administration of muromonab-CD3.

Prior to administration of muromonab-CD3, the patient’s volume status should be assessed carefully. It is imperative, especially prior to the first few doses, that there be no clinical evidence of volume overload or uncompensated heart failure, including a chest x-ray free of evidence of heart failure or fluid overload and weight restriction of 3% above the patient’s minimum weight during the week prior to injection. Prior to retreatment with muromonab-CD3, the patient’s antimurine antibody titer should be determined.

Patients should be monitored closely for 48 hours after the first dose is administered. I.V. methylprednisolone sodium succinate 8 mg/kg given 1 to 4 hours prior to muromonab-CD3 administration is strongly recommended to decrease the incidence and severity of reactions to the first dose which have been attributed to the muromonab-CD3 mediated Cytokine Release Syndrome. Acetaminophen and antihistamines can be given concomitantly with muromonab-CD3 to reduce early reactions. Patient temperature should not exceed 37.8°C at the administration of each dose of muromonab-CD3.

When using combinations of immunosuppressive agents, the dose of each agent, including muromonab-CD3, should be reduced to the lowest level compatible with an effective therapeutic response so as to reduce the potential for and severity of infections and malignant transformations.

No bacteriostatic agent is present in this product; adherence to aseptic technique is advised. Once the ampul is opened, use immediately and discard the unused portion.

Method of Administration: Muromonab-CD3 should be inspected visually for particulate matter and discoloration prior to administration. Because muromonab-CD3 is a protein solution, it may develop a few fine translucent particles which have been shown not to affect its potency. Do not shake.

Prepare muromonab-CD3 for injection by drawing 5 mL (1 mg/mL) of solution immediately prior to use into a syringe through a sterile low protein-binding 0.2 or 0.22 m filter. Discard filter and attach needle for i.v. bolus injection.

Administer muromonab-CD3 as an i.v. bolus in less than 1 minute. Do not dilute or administer by i.v. infusion or in conjunction with other drug solutions.

Availability And Storage: Each mL of clear, colorless, sterile solution (which may contain a few fine translucent protein particles) contains: muromonab-CD3 1 mg. Nonmedicinal ingredients: dibasic sodium phosphate, monobasic sodium phosphate, polysorbate 80, sodium chloride and water for injection. Ampuls of 5 mL (muromonab-CD3 5 mg). Packages of 5. Store in refrigerator at 2 to 8°C. Do not freeze or shake.

ORTHOCLONE OKT® 3 Janssen-Ortho Muromonab-CD3 Immunosuppressant

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