INFORMATION FOR HEALTH PROFESSIONALS
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Each 5mL ampoule of ORTHOCLONE OKT*3 Sterile Solution contains 5 mg (1mg/mL) of muromonab-CD3 in a clear colourless solution which may contain a few fine translucent protein particles. Each ampoule 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.
ORTHOCLONE OKT*3 (muromonab-CD3) Sterile Solution is a murine monoclonal antibody to the T3 (CD3) antigen of human T-cells which functions as an immunosuppressant.
ORTHOCLONE OKT*3 reverses graft rejection, most probably by blocking the function of all T-cells which play a major role in acute renal rejection. ORTHOCLONE OKT*3 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. Binding of ORTHOCLONE OKT*3 to T lymphocytes results in early activation of T-cells, which leads to cytokine release, while later blocking T-cell functions. After termination of ORTHOCLONE OKT*3 therapy, T-cell function usually returns to normal within one week. In in vitro cytolytic assays, ORTHOCLONE OKT*3 blocks both the generation and function of effector cells.
In vivo, ORTHOCLONE OKT*3 reacts with most peripheral blood T-cells and T-cells in body tissues, but has not been found to react with other haematopoietic 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 ORTHOCLONE OKT*3 . This decrease in the number of CD3 positive T-cells results from the specific interaction between ORTHOCLONE OKT*3 and CD3 antigen on the surface of all T lymphocytes. T-cell activation results in the release of numerous cytokines/lymphokines, which are felt to be responsible for many of the acute clinical manifestations seen following ORTHOCLONE OKT*3 administration. Between days two and seven, increasing numbers of circulating CD4 positive and CD8 positive cells have been observed in patients although CD3 positive cells are not detectable. The presence of these CD4 and CD8 positive cells has not been found to affect the clinical course of the patient. CD3 positive cells reappear rapidly and reach pre-treatment levels within a week after termination of ORTHOCLONE OKT*3 therapy. Increasing numbers of CD3 positive cells have been observed in some patients during the second week of ORTHOCLONE OKT*3 therapy, possibly as a result of the development of neutralising antibodies to ORTHOCLONE OKT*3 .
Clinical experience has shown that the dose, duration, and type of immunosuppressive medications used in combination with ORTHOCLONE OKT*3 may affect both the incidence and magnitude of the host antibody response. Furthermore, immunosuppressive agents used concomitantly with ORTHOCLONE OKT*3 (i.e. steroids, azathioprine, prednisone, or cyclosporin) have altered the time course of anti-mouse antibody development and the specificity of the antibodies formed (i.e. idiotypic, isotypic, allotypic).
Antibodies to ORTHOCLONE OKT*3 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 towards the end of the second week of treatment in 3% (n=86) of the patients.
Following administration of ORTHOCLONE OKT*3 in vivo, leucocytes have been observed in cerebrospinal and peritoneal fluids. The mechanism for this effect is not completely understood, but might be related to the release of cytokines altering membrane permeability.
Serum levels of ORTHOCLONE OKT*3 are measurable using an enzyme-linked immunosorbent assay (ELISA). During treatment with 5 mg per day for 14 days, mean serum trough levels of the drug rose over the first three days and then averaged 0.9 mcg/mL on days 3 to 14. In paediatric patients, trough serum OKT*3 concentrations measured daily during treatment with ORTHOCONE OKT*3 revealed increased levels.
Subsequent experience has demonstrated that circulating serum levels ≥800 ng/mL of ORTHOCLONE OKT*3 block the function of cytotoxic T-cells in vitro and in vivo. In patients retreated with ORTHOCLONE OKT*3 (with and without anti-mouse antibodies), the serum OKT*3 levels rose more slowly than during initial use and did not exceed 800 ng/mL until the seventh day of retreatment. Patients retreated with ORTHOCLONE OKT*3 also tended to have a slower clearance of CD3 positive cells from the peripheral circulation .
ORTHOCLONE OKT*3 is indicated for the treatment of acute allograft rejection in renal, hepatic and cardiac transplant patients.
The dosage of other immunosuppressive agents used in conjunction with ORTHOCLONE OKT*3 should be lowered to minimal levels.
The recommended dose is 5 mg per day in a single (bolus) intravenous injection for 10 to 14 days. For acute renal rejection, treatment should begin upon diagnosis. For steroid-resistant hepatic and cardiac allograft rejection treatment should begin when the treating physician deems a rejection still present despite an adequate course of corticosteroid therapy.
Administer ORTHOCLONE OKT*3 as an intravenous bolus in less than one minute. Do not administer with other drug solutions.
Safety and effectiveness in children have not been established in company sponsored trials. Published literature has reported the use of ORTHOCLONE OKT*3 in infants and children. The initial recommended dose is 2.5 mg per day in children weighing less than 30kg and 5 mg in children weighing greater than 30kg, in a single bolus intravenous injection for 10 to 14 days. Daily increases in ORTHOCLONE OKT*3 doses (i.e. by 2.5 mg increments) may be required to achieve depletion of CD3 positive cells (<25 cells/mm³) and ensure therapeutic OKT*3 serum concentrations ≥800 ng/mL. Paediatric liver allograft patients may require augmentation of the ORTHOCLONE OKT*3 dose. For acute renal and hepatic rejection, treatment should begin upon diagnosis.
Prior to administration of ORTHOCLONE OKT*3 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 showing no evidence of heart failure or fluid overload, and a weight restriction of < 3% above the patient's minimum weight should be placed on the patient in the week prior to injection. Prior to treatment with ORTHOCLONE OKT*3, the patients anti-mouse antibody titre should be determined.
Patients should be monitored closely for 48 hours after the first dose is administered.
Intravenous methylprednisolone sodium succinate 8.0 mg/kg given 1-4 hours prior to the first dose of ORTHOCLONE OKT*3 is strongly recommended to decrease the incidence and severity of reactions to the first dose, which have been attributed to the ORTHOCLONE OKT*3 mediated Cytokine Release Syndrome.
Paracetamol and antihistamines can be given concomitantly with ORTHOCLONE OKT*3 to reduce early reactions. Patient temperature should not exceed 37.8°C (100°F) at the time of first ORTHOCLONE OKT*3 administration.
ORTHOCLONE OKT*3 should not be used in patients who:
Only physicians experienced in immunosuppressive therapy and management of transplant patients should use ORTHOCLONE OKT*3 (muromonab-CD3).
Patients receiving ORTHOCLONE OKT*3 should be managed in facilities equipped and staffed for cardio-pulmonary resuscitation.
Associated with the administration of the first few doses of ORTHOCLONE OKT*3, patients have developed an acute clinical syndrome [i.e. Cytokine Release Syndrome (CRS)] 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 central nervous system manifestations.
The syndrome typically begins approximately 30-60 minutes after administration of a dose of ORTHOCLONE OKT*3 (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 OKT*3, 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 CRS may include: high (often spiking, up to 41.7°C) fever, chills/rigors, headache, tremor, nausea/vomiting, diarrhoea, abdominal pain, malaise, muscle/joint aches and pains, and generalised weakness. Less frequently reported adverse experiences include: minor dermatological reactions (e.g. rash, pruritus, etc) and a spectrum of often serious occasionally fatal, cardiorespiratory and neuro-psychiatric adverse experiences.
Cardiorespiratory findings may include: dyspnoea/shortness of breath, bronchospasm/ wheezing, tachypnoea, respiratory arrest/failure/distress, cardiovascular collapse, cardiac arrest, angina/myocardial infarction, chest pain/tightness, tachycardia, hypertension, haemodynamic instability, hypotension including profound shock, heart failure, pulmonary oedema (cardiogenic and non-cardiogenic), adult respiratory distress syndrome, hypoxaemia, apnoea, and arrhythmias.
Severe pulmonary oedema has occurred in patients with volume (fluid) overload and in those who appeared to be euvolaemic. The pathogenesis of pulmonary oedema 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 ORTHOCLONE OKT*3 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 OKT*3.
Patients at risk of more serious complications from CRS may include those with the following conditions: unstable angina, recent myocardial infarction or symptomatic ischaemic heart disease; heart failure of any aetiology; pulmonary oedema of any aetiology; any form of chronic obstructive pulmonary disease; intravascular volume overload or depletion of any aetiology (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. Every effort should be made to correct or stabilise background conditions prior to the initiation of therapy.
Prior to administration of ORTHOCLONE OKT*3 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 showing no evidence of heart failure or fluid overload, and a weight restriction of < 3% above the patient's minimum weight during the week prior to injection. Prior to treatment with ORTHOCLONE OKT*3 , the patients anti-mouse antibody titre should be determined.
Anaphylactic or anaphylactoid reactions may occur following administration of ORTHOCLONE OKT*3 .
Serious and occasionally fatal, immediate (usually within 10 minutes) hypersensitivity (anaphylactic) reactions have been reported in patients treated with ORTHOCLONE OKT* 3. Manifestations of anaphylaxis may appear similar to manifestations of the Cytokine Release Syndrome. 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 to cytokine release.
Acute hypersensitivity reactions may be characterized by: cardiovascular collapse, cardiorespiratory arrest, loss of consciousness, hypotension, pulmonary oedema especially in patients with volume overload, seizures, coma, tachycardia, pruritis, urticaria, tingling, angioedema including laryngeal, pharyngeal or facial oedema, dyspnoea, bronchospasm, and airway obstruction.
Serious allergic events, including anaphylactic or anaphylactoid reactions, have been reported in patients re-exposed to ORTHOCLONE OKT*3 subsequent to their initial course of therapy. Pretreatment with antihistamines and/or steroids may not reliably prevent anaphylaxis in this setting. Possible allergic hazards from retreatment should be weighed against expected therapeutic benefits and alternatives.
It may be very difficult, even impossible, to distinguish between an acute hypersensitivity reaction (e.g. anaphylaxis, angiooedema, etc.) and the Cytokine Release Syndrome. Potentially serious signs and symptoms having an immediate onset (usually within 10 minutes) following administration of ORTHOCLONE OKT*3 are more likely due to acute hypersensitivity, in this case discontinue the medicine immediately. If hypersensitivity is suspected, do not resume therapy or re-expose the patient to ORTHOCLONE OKT*3 . Clinical manifestations beginning approximately 30 to 60 minutes (or later) following administration of ORTHOCLONE OKT*3, are more likely cytokine-mediated.
Seizures, encephalopathy, cerebral oedema/herniation, aseptic meningitis, and headache have been reported, even following the first dose of therapy with ORTHOCLONE OKT*3, 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/uraemia, fever, infection, a precipitous fall in serum calcium, fluid overload, hypertension, hypoglycaemia, history of seizures, and electrolyte imbalances or those who are taking a medication concomitantly that may, by itself, cause seizures. Seizures have been reported in approximately 0.2% of patients treated with ORTHOCLONE OKT*3 (n=40,000).
Signs and symptoms of the aseptic meningitis syndrome described in association with the use of ORTHOCLONE OKT*3 have included: fever, headache, meningismus (stiff neck), and photophobia. In a post-marketing survey involving 214 renal transplant patients, the incidence of this syndrome was 6%. Fever (89%), headache (44%), neck stiffness (14%), and photophobia (10%) were the most commonly reported symptoms; a combination of these four symptoms occurred in 5% of patients. Diagnosis is confirmed by cerebrospinal fluid (CSF) analysis demonstrating leucocytosis with pleocytosis, elevated protein and normal or decreased glucose, with negative viral, bacterial, and fungal cultures.
Approximately one-third of the patients with a diagnosis of aseptic meningitis had co-existing 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, auditory/visual hallucinations, psychosis (delirium, paranoia), mood changes (eg. mania, agitation, combativeness, etc.), diffuse hypotonus, hyperreflexia, myoclonus, 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 oedema (and other signs of increased vascular permeability (e.g. otitis media, nasal and ear stuffiness, etc.) has been seen in patients treated with ORTHOCLONE OKT*3 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, uraemia, etc.); with underlying vascular diseases; or who are receiving a medication concomitantly that may, by itself, affect the central nervous system.
Signs or symptoms of encephalopathy, meningitis, seizures, and cerebral oedema, 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. A few cases of fatal cerebral oedema with or without herniation have been reported. All patients, and in particular children, must be carefully evaluated for excessive fluid retention and hypertension before the initiation of ORTHOCLONE OKT*3 therapy. Close monitoring for neuropsychiatric symptoms must be observed during the first 24 hours following the first ORTHOCLONE OKT*3 injection. Treatment should be stopped if symptoms compatible with cerebral oedema are observed. Irreversible sequelae associated with serious CNS events (e.g. blindness, deafness, paralysis) have been reported rarely.
Infections: ORTHOCLONE OKT*3 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 infections and 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, culture or biopsy should be done as soon as possible, appropriate anti-infective therapy instituted, and if possible, immunosuppressive therapy reduced or discontinued.
When using combinations of immunosuppressive agents, the dose of each agent, including ORTHOCLONE OKT*3, 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 ORTHOCLONE OKT*3, which produce profound impairment of cell-mediated immunity, further increase the risk of infection, especially with the Herpes viruses (Herpes simplex virus (HSV), Cytomegalovirus (CMV), Epstein-Barr virus (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.
As a result of depressed cell-mediated immunity, organ transplant patients have an increased risk of developing malignancies, especially lymphoproliferative disorders (LPD), squamous cell carcinomas of the skin and lip, and sarcomas. In immunosuppressed patients, T-cell cytotoxicity is impaired, allowing transformation and proliferation of EBV-infected B lymphocytes. Transformed B lymphocytes are thought to initiate the oncogenic process that ultimately culminates in the development of most post-transplant lymphoproliferative disorders.
A recent study examined the incidence of non-Hodgkin's lymphoma (NHL) in approximately 100,000 recipients of kidney, heart or liver transplants. There was an increased risk of NHL compared to the general population. This risk was highest in the first year of therapy and was higher in patients undergoing heart or liver transplants than in patients undergoing kidney transplants. In renal transplant patients undergoing treatment of rejection, the incidence of NHL was higher in patients receiving OKT3 and ATG/ALG together compared to patients receiving OKT3 or ATG/ALG alone.
The relative risk of neoplastic events in patients being treated with ORTHOCLONE OKT*3, compared to other immunosuppressive agents has not been determined.
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 showing no evidence of heart failure or fluid overload and a weight restriction of ≤ 3% above the patient's minimum weight placed during the week prior to injection. Prior to treatment with ORTHOCLONE OKT*3, the patients anti-mouse antibody titre should be determined.
Fever: If the temperature of the patient exceeds 37.8°C, it should be lowered by antipyretics before administration of each dose of ORTHOCLONE OKT*3 . The possibility of infection should be evaluated.
ORTHOCLONE OKT*3 is a mouse (immunoglobulin) protein that induces human anti-mouse antibody (HAMA) production (ie sensitisation) in most patients following exposure. Dependent on the HAMA titre, ORTHOCLONE OKT*3 has been used to reverse subsequent rejection episodes in patients without detectable or with weakly positive (≤1:100) antibody titres. Higher antibody titres (> 1:100) may preclude successful use of ORTHOCLONE OKT*3 . If an antibody titre ≥ 1:1000 is detected therapy should not be attempted.
Adult patients receiving ORTHOCLONE OKT*3 for initial use should be monitored periodically to ensure adequate plasma OKT*3 levels (>800 ng/mL) or T-cell clearance (CD3 positive T-cells <25 cells/mm3). For paediatric patients, both plasma OKT*3 levels (>800 ng/mL) and CD3 positive T-cells (CD3 positive T-cells <25 cells/mm3) should be monitored daily. Caution should be used if retreatment is considered. Anticipated reuse of ORTHOCLONE OKT*3 requires monitoring prior to therapy to determine the HAMA titre. If reuse is deemed appropriate, daily immunologic monitoring is recommended. Reduced T-cell clearance or impaired ability to maintain adequate OKT*3 levels provides the basis for adjusting ORTHOCLONE OKT*3 dosage or for discontinuing therapy.
As with other immunosuppressive therapies, arterial or venous and capillary thromboses of allografts and other vascular beds (e.g. heart, lungs, brain, bowel, etc.) have been reported in patients with ORTHOCLONE OKT*3. The decision to use ORTHOCLONE OKT*3 in patients with a history of thrombotic events or underlying vascular disease should take into consideration the risks of thrombosis. Concomitant use of prophylactic anti-thrombotic interventions (e.g. mini-dose heparin, etc.) should be considered.
As with many potent drugs, periodic assessment of organ system functions should be performed during treatment with ORTHOCLONE OKT*3 .
The following tests should be monitored prior to and during ORTHOCLONE OKT*3 therapy:
For use of ORTHOCLONE OKT*3, one of the following immunological tests should be monitored during ORTHOCLONE OKT*3 therapy:
For paediatric patients, both plasma OKT*3 levels ( ≥800 ng/mL) and target CD3 positive cells (<25 cells/mm³) should be monitored daily.
Prior to retreatment with ORTHOCLONE OKT*3 Testing for human mouse antibody titres is strongly recommended :
Retreatment requires daily monitoring of either plasma OKT*3 levels or clearance of CD3 positive T-cells for adult patients, and monitoring of both tests for paediatric patients to achieve the same targets described above for initial use.
No adequate controlled studies have been conducted in children. Published literature has reported the successful use of ORTHOCLONE OKT*3 in infants and children with rejection reversal results similar to those observed in adults .
Close attention should be given to body fluid homeostasis in small children during the first 48 hours of ORTHOCLONE OKT*3 therapy. Gastrointestinal fluid loss due to diarrhoea and/or vomiting may be significant when treating small children and may require parenteral hydration.
Signs and symptoms of encephalopathy, meningitis, seizures and cerebral oedema 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. A few cases of fatal cerebral oedema with or without herniation have been reported. All patients, and in particular children, must be carefully evaluated for excessive fluid retention and hypertension before the initiation of ORTHOCLONE OKT*3 therapy. Close monitoring for neuro-psychiatric symptoms must be observed for each twenty four (24) hour period following administration of each of the first few doses of ORTHOCLONE OKT*3. Treatment should be stopped if symptoms comparable with cerebal oedema are observed. Irreversible sequelae associated with serious CNS events (e.g. blindness, deafness, paralysis) have been reported rarely.
Because meningitis is a frequent infection encountered in paediatric allograft recipients, and the immunosuppression associated with transplantation increases the risk of opportunistic infection, the development of meningeal irritation during ORTHOCLONE OKT*3 therapy must be properly diagnosed with lumbar puncture to rule out an infectious aetiology.
It is unknown whether there may be significant long-term effects on the developing brains of children (e.g. cognitive defects, neurodevelopmental language difficulties in infants under one year of age) related to the occurrence of seizures, high fever, CNS infections, aseptic meningitis, etc. following treatment with ORTHOCLONE OKT*3.
Paediatric allograft recipients are reported to be significantly immunosuppressed for a prolonged period of time and, therefore, require close monitoring post-therapy for opportunistic infections.
In the paediatric 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 children have not been infected by herpes viruses (e.g. EBV, CMV, HSV) prior to transplantation and, therefore, are more susceptible to developing primary infections from the grafted organ and/or blood products. Patients with primary EBV infection may be at a higher risk for the development of EBV-associated lymphoproliferative disorders (LPD), a source of significant concern for the paediatric population. There is some data to support an association between the development of LPD at the time of active EBV infection and ORTHOCLONE OKT*3 administration in paediatric liver allograft recipients.
Paediatric patients may be at an increased risk of intravascular graft thrombosis. Possible reasons may include: small arteries and veins of young donor organs, different surgical and vascular anastomotic techniques required for small organs, young recipient age, prior lack of dialysis, etc. The possible role of ORTHOCLONE OKT*3 in altering haemostasis has not been determined.
ORTHOCLONE OKT*3 is contraindicated in women who are pregnant or suspected to be pregnant, and in those who are breast feeding. Animal reproductive studies have not been conducted with ORTHOCLONE OKT*3.
The adverse effect profile for ORTHOCLONE OKT*3 is similar for adult and paediatric populations.
In controlled clinical trials for treatment of acute renal allograft rejection, patients treated with ORTHOCLONE OKT*3 plus concomitant low-dose immunosuppressive therapy (primarily azathioprine and corticosteroids) were observed to have an increased incidence of adverse experiences during the first two days of treatment, as compared with the group of patients receiving azathioprine and high-dose steroid therapy. During this period the majority of patients experienced pyrexia (90%), of which 19% were 40.0°C or above, and chills (59%). In addition, other adverse experiences occurring in 8% or more of the patients during the first two days of ORTHOCLONE OKT*3 therapy included: dyspnoea (21%), nausea (19%), vomiting (19%), chest pain (14%), diarrhoea (14%), tremor (13%), wheezing (13%), headache (11%), tachycardia (10%), rigor (8%), and hypertension (8%). A similar spectrum of clinical manifestations has been observed in open clinical studies and in post-marketing experience involving patients treated with ORTHOCLONE OKT*3 for rejection following renal, cardiac, and hepatic transplantation.
Additional serious and occasionally fatal cardiorespiratory manifestations have been reported following any of the first few doses.
In the acute renal allograft rejection trials, potentially fatal pulmonary oedema has been reported following the first two doses in less than 2% of the patients treated with ORTHOCLONE OKT*3. Pulmonary oedema was usually associated with fluid overload. However, post-marketing experience revealed that pulmonary oedema 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).
In the controlled randomised renal rejection trial conducted during the precyclosporine era, the most common infections during ORTHOCLONE OKT*3 therapy were due to Herpes simplex (27% ) and Cytomegalovirus (19% ). Other severe and life-threatening infections were Staphylococcus epidermidis (4.8%), Pneumocystis carinii (3.1%), Legionella (1.6%), Cryptococcus (1.6%), Serratia (1.6%) and gram negative bacteria (1.6%). The incidence of infections were similar in patients treated with ORTHOCLONE OKT*3 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 ORTHOCLONE OKT*3 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 rejection refractory to conventional treatment, the most common infections reported in the ORTHOCLONE OKT*3 group during the first 45 days of the study were Herpes 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 severe or life threatening infections were reported during this period.
In a retrospective analysis of paediatric patients treated for acute hepatic rejection, the most common infections reported in patients treated with ORTHOCLONE OKT*3 therapy were due to bacterial infections (47.1%), fungal infections (20.7%), Cytomegalovirus (18.8%), Herpes simplex (15%), Adenovirus (7.5%), and Epstein-Barr virus (7.5%). The overall rates of viral, fungal, and bacterial infections were similar in patients treated with ORTHOCLONE OKT*3 (n=53) and in patients whose rejection was treated with steroids alone (n=27). In another study of 149 paediatric liver allograft patients where 59 episodes of steroid-resistant rejection were treated with ORTHOCLONE OKT*3, the incidence of systemic cytomegalovirus disease was the only serious infectious complication that was significantly different between patients receiving and not receiving ORTHOCLONE OKT*3.
In a retrospective study of paediatric patients treated for steroid-resistant renal rejection, no significant difference in infectious complications was noted between patients receiving ORTHOCLONE OKT*3 (n=23) and patients whose rejection was treated with antithymocyte globulin (ATG)(n=26).
Clinically significant infections (e.g. pneumonia, sepsis, etc.) due to the following pathogens have been reported:
Clostridium species (including perfringens), Corynebacterium, Enterococcus, Enterobacter aerogenes, Escherichia coli, Klebsiella species, Lactobacillus, Legionella, Listeria monocytogenes, Mycobacteria species, Nocardia asteroides, Proteus species, Providencia species, Pseudomonas aeruginosa, Serratia species, Staphylococcus species, Streptococcus species, Yersinia enterocolitica, and other gram-negative bacteria.
Aspergillus, Candida, Cryptococcal, Dermatophytes.
Pneumocystis carinii, Toxoplasma gondii.
Cytomegalovirus (CMV), Epstein-Barr virus (EBV), Herpes simplex virus (HSV), Hepatitis viruses, Varicella zoster virus (VZV), Adenovirus, Enterovirus, Respiratory syncytial virus (RSV).
In patients treated with ORTHOCLONE OKT*3, post-transplant lymphoproliferative disorders (LPD) 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 disorders 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 and 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 four 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.
Reported adverse reactions resulting from the formation of antibodies to ORTHOCLONE OKT*3 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).
Other hypersensitivity reactions have included: ineffectiveness of treatment, serum sickness, arthritis, allergic interstitial nephritis, immune complex deposition resulting in glomerulonephritis, vasculitis, temporal arteritis, and eosinophilia.
Clinical adverse events irrespective of causality, 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 107°F), chills/rigors, flu-like syndrome, fatigue/malaise, generalized weakness, anorexia.
Cardiovascular: cardiac arrest, hypotension/shock, heart failure, cardiovascular collapse, angina/myocardial infarction, tachycardia, bradycardia, haemodynamic instability, hypertension, left ventricular dysfunction, arrhythmias, chest pain/tightness.
Respiratory: respiratory arrest, adult respiratory distress syndrome (ARDS), respiratory failure, pulmonary oedema (cardiogenic or noncardiogenic), apnoea, dyspnoea, bronchospasm, wheezing, shortness of breath, hypoxemia, tachypnoea/hyperventilation, abnormal chest sounds, pneumonia/pneumonitis (bacterial, viral, P.carinii, etc.).
Dermatologic: rash, Stevens-Johnson syndrome, urticaria, pruritus, erythema, flushing, diaphoresis.
Gastrointestinal: diarrhoea, nausea/vomiting, abdominal pain, bowel infarction, gastrointestinal haemorrhage.
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 haemolytic anemia.
Hepatobiliary: increases in transaminases (SGOT, SGPT, etc.), hepato/splenomegaly or hepatitis, usually secondary to viral infection or lymphoma.
Neuro-Psychiatric: seizures, status epilepticus, lethargy/stupor/coma, encephalopathy, psychotic reactions (delirium), encephalitis, meningitis, cerebral oedema/ herniation, cerebritis, 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/plegia, transient ischemic attack, intracranial haemorrhage.
Musculoskeletal: arthralgia, arthritis, myalgia, stiffness/aches/pains.
Special Senses: blindness, blurred vision, papilloedema, diplopia, hearing loss, otitis media, tinnitus, vertigo, Vl cranial nerve palsy, photophobia, conjunctivitis, nasal and ear stuffiness.
Renal: anuria/oliguria, azotemia, delayed graft function, renal insufficiency/renal failure, usually transient and reversible and occasionally in association with cytokine release syndrome, abnormal urinary cytology, including exfoliation of damaged lymphocytes, collecting duct cells, and cellular casts.
Usage of concomitant medications (azathioprine, corticosteroids, cyclosporin) may have contributed to the neuropsychiatric, infectious, nephrotoxic, thrombotic, and/or neoplastic events reported in patients treated with ORTHOCLONE OKT*3. In addition, the use of indomethacin in patients simultaneously receiving therapy with ORTHOCLONE OKT*3 may increase the incidence and severity of encephalopathic and other CNS adverse events.
Symptoms of overdosage with ORTHOCLONE OKT*3 may include hyperthermia, severe chills, myalgia, vomiting, diarrhoea, oedema and oliguria. In the event of acute overdosage with ORTHOCLONE OKT*3 the patient should be carefully observed and given symptomatic and supportive treatment.
Store in refrigerator at 2°C to 8°C (36°F to 46°F). Exposure to light should be minimised. Do not freeze or shake.
Prescription Medicine.
ORTHOCLONE OKT*3 Sterile Solution is supplied in 5mL ampoules containing 5 mg of muromonab-CD3
There are 5 ampoules to a folding carton.
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 in the human T-cell surface which is essential for T-cell functions.
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 Leucocyte Differentiation Antigens.
Janssen-Cilag Pty Ltd
P O Box 9222
Newmarket, Auckland
NEW ZEALAND
Ph: (09) 524 5012
Fax: (09) 523 1646
28 July 2004