INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
ORTHOCLONE®

WARNINGS Only physicians experienced in immunosuppressive therapy and management of renal, cardiac and hepatic transplant patients should use ORTHOCLONE. Serious and occasionally life-threatening systemic, cardio-vascular, and central nervous system reactions have been reported following administration of ORTHOCLONE. Patients receiving ORTHOCLONE should be managed in facilities equipped and staffed for cardio-pulmonary resuscitation.

PROPRIETARY NAME
(and dosage form):

ORTHOCLONE^®

DESCRIPTIVE NAME OF MEDICINE
Biochemically purified murine (mouse) monoclonal T3 antibody (muromonab-CD3).

REGISTRATION NUMBER
T/30.2/32

PHARMACOLOGICAL CLASSIFICATION
A.30.2 - Antibodies

SCHEDULING STATUS
Schedule 4.

COMPOSITION
Each 5 mL ampoule of ORTHCLONE sterile solution contains 5 mg (1 mg/mL) of muromonab-CD3 in a clear, colourless, buffered solution (pH 7,0 ± 0,5).

IDENTIFICATION
ORTHOCLONE is a clear colourless solution which may contain a few fine translucent protein particles.

PHARMACOLOGICAL ACTION OF THE MEDICINE
ORTHOCLONE (muromonab-CD3 human T cell blocker) sterile solution is a murine monoclonal antibody to the T3 (CD3) antigen of human T cells, (for intravenous use). The antibody is a biochemically purified IgG_2a immunoglobulin with a heavy chain of approximately 50 000 daltons and a light chain of approximately 25 000 daltons. Because it is a monoclonal antibody preparation, ORTHOCLONE sterile solution is a homogenous reproducible product with consistent, measurable reactivity to human T cells.
ORTHOCLONE reverses graft rejection most probably by blocking the function of all T cells which play a major role in acute rejection. ORTHOCLONE 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 to T lymphocytes results in early activation of T cells, which leads to cytokine release. ORTHOCLONE later blocks all known T cell functions. After termination of ORTHOCLONE therapy, T cell function usually returns to normal within one week. In vivo it reacts with most peripheral blood T cells, and T cells in body tissues, but has not been found to react with other haemopoietic elements or other tissues of the body.
In all patients studied, a rapid and concomitant decrease in the number of circulating CD2 positive, CD3 positive, CD4 positive and CD8 positive T cells was observed within minutes after the administration of ORTHOCLONE. This decrease in the number of CD3 positive T cells results from the specific interaction between ORTHOCLONE and the 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 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 have not been found to affect reversal of rejection. CD3 positive cells reappear rapidly and reach pre-treatment levels within a week after termination of ORTHOCLONE therapy. Increasing numbers of CD3 positive cells have been observed in some patients during the second week of ORTHOCLONE therapy, possibly as a result of the development of neutralizing antibodies to ORTHOCLONE, which in turn block its ability to bind to the CD3 antigen on T lymphocytes.
The dose, duration and type of immunosuppresive medications used in combination with ORTHOCLONE may affect both the incidence and magnitude of the host antibody response.
Immunosuppressive agents used concomitantly with ORTHOCLONE (i.e. steroids azathioprine, prednisone, or cyclosporine) have altered the time course of antimurine antibody development and the specificity of the antibodies formed (i.e. idiotypic, isotypic, allotypic).
Antibodies to ORTHOCLONE have been observed in patients receiving low doses of prednisone, and azathioprine during ORTHOCLONE therapy, occurring with an incidence of 21% for IgM 86% for IgG and 29% for IgE. The mean time of appearance of IgG antibodies was 20 ± 2 days (mean ± SD). Early IgG antibodies appeared towards the end of the second week of treatment in some of the patients.
Following administration of ORTHOCLONE in vivo, leukocytes have been observed in cerebrospinal and peritoneal fluids. The mechanism for this effect is not understood but might be related to the release of cytokines altering membrane permeability.
Serum levels of ORTHOCLONE are measurable using an enzyme-linked immunosorbent assay (ELISA). During treatment with 5 mg per day for 14 days, mean serum trough levels of ORTHOCLONE rose over the first three days and then averaged 0,9 µg/mL on days 3 –14. Circulating serum levels greater than 0,8 µg/mL of ORTHOCLONE blocks the function of cytotoxic T cells in vitro and in vivo.
In patients retreated with ORTHOCLONE (with and without antimurine antibodies), the serum levels rose more slowly than during initial use and did not exceed 0,8 µg/mL until the seventh day of treatment. Patients retreated with ORTHOCLONE also tend to have a slower clearance of CD3 positive cells from the peripheral circulation.

INDICATIONS
ORTHOCLONE is indicated for the reversal of acute allograft rejection in renal, cardiac and hepatic transplant patients.

CONTRA-INDICATIONS
ORTHOCLONE should not be given to patients who:

–	are sensitive to this product or other products of murine origin.
–	have antimurine antibody titres > 1:1000.
–	are in (uncompensated) heart failure or in fluid overload as evidenced by chest X-rays or a greater than three percent weight gain within the week prior to planned ORTHOCLONE administration.
–	have a history of seizures or are predisposed to seizures.

ORTHOCLONE therapy is contra-indicated in pregnancy, suspected pregnancy and lactation.

WARNINGS
ORTHOCLONE should be administered by physicians experienced in immunosuppressive therapy and management of renal, cardiac and hepatic transplant patients.
Reactions to the first dose of ORTHOCLONE may occur. Serious and occasionally life-threatening systemic, cardio-vascular, and central nervous system reactions have been reported following administration of ORTHOCLONE.
Therapy should therefore be initiated in facilities equipped and staffed for cardio-pulmonary resuscitation.
This formulation of ORTHOCLONE contains polysorbate 80 and should only be used in vivo as indicated.

DOSAGE AND DIRECTIONS FOR USE
The recommended dose of ORTHOCLONE for the treatment of acute renal, hepatic, and cardiac allograft rejection is 5 mg per day by IV push for 10 to 14 days. Treatment should begin once acute rejection is diagnosed.
Intravenous methylprednisolone sodium succinate: 8,0 mg/kg given 1- 4 hours prior to the first dose of ORTHOCLONE administration is strongly recommended to decrease the incidence and severity of reactions to the first dose. Similar precaution should be taken in the case of resumption of therapy and following a treatment hiatus.
Paracetamol and antihistamines given concomitantly with ORTHOCLONE may help to reduce early reactions.
When using combinations of immunosuppressive agents, the dose of each agent, including ORTHOCLONE, 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.

ADMINISTRATION INSTRUCTIONS
Parenteral products should be inspected visually for particulate matter and discolouration, prior to administration whenever solution and container permit. Because ORTHOCLONE is a protein solution, it may develop a few fine translucent particles.
No bacteriostatic agent is present in this product; adherence to aseptic technique is advised. Once the ampoule is opened, use immediately and discard the unused portion.
Prepare ORTHOCLONE for injection by drawing solution into a syringe through a low protein-binding 0,2 or 0,22 µm filter. Discard filter and attach needle for IV bolus injection.
Administer ORTHOCLONE as an IV bolus in less than one minute. Do not administer by intravenous infusion or in conjunction with other solutions of medicines.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
SIDE-EFFECTS
Cytokine Release Syndrome (CRS): is a clinical syndrome mostly experienced in patients following the first few doses of ORTHOCLONE. Symptoms diminish with successive doses but may reappear with increasing the amount of a dose or resuming treatment after a hiatus.
Symptoms range from frequently reported mild "flu-like" symptoms to less frequently reported severe "shock-like" reactions (which may include cardiovascular and central nervous system manifestations).
Symptoms include fever, chills, headache, tremor, nausea/vomiting, diarrhoea, abdominal pain, malaise and muscle/joint aches and pains, and generalized weakness. Less frequently reported but seroius and occasionally fatal adverse events include cardio-respiratory events (dyspnea, shortness of breath, bronchospasm/wheezing, tachypnea, 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, adult respiratory distress syndrome, hypoxemia, apnoea and arrhythmias) and neuro-psychiatric events.
Severe pulmonary oedema has occurred in patients with fluid overload and in those who appeared to be euvolemic.
During the first 1 to 3 days of ORTHOCLONE 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 function 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.
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 oedema 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. Every effort should be made to correct or stabilize background conditions prior to the initiation of therapy.
Neuro-psychiatric events: include headache, seizures, aseptic meningitis, encephalopathy and cerebral oedema/herniation.
Seizures, which have been occasionally serious and life-threatening, (i.e. accompanied by cardiorespiratory arrest), 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 medication concomitantly that may, by itself cause seizures. Seizures have rarely been reported in patients treated with ORTHOCLONE.
Symptoms of aseptic meningitis include fever, headache, stiff neck and photophobia. A combination of the above 4 symptoms have occurred in some patients. The cerebrospinal fluid in evaluable patients showed leucocytosis, elevated protein and normal or decreased glucose, with negative viral, bacterial and fungal cultures.
MOST PATIENTS WITH ASEPTIC MENINGITIS HAD A BENIGN COURSE AND RECOVERED, BUT INFECTION MUST BE CONSIDERED IN THE DIFFERENTIAL DIAGNOSIS OF AN IMMUNOSUPPRESSED TRANSPLANT PATIENT WITH ANY SIGNS OR SYMPTOMS OF MENINGITIS.
Manifestations of encephalopathy may include impaired cognition, confusion, obtundation, altered mental status, auditory/visual hallucinations, psychosis - delirium, paranoia, mood changes - mania, agitation 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 co-existing aseptic meningitis and vice versa.
Cerebral oedema and other signs of increased permeability (otitis media, nasal and ear stuffiness) have been reported.
The following neurological events have rarely been reported: irreversible blindness, impaired vision, quadri-or paraparesis/plegia, cerebrovascular accident, aphasia, transient ischemic attacks, subarachnoid haemorrhage, palsy of the VI cranial nerve, and hearing loss.
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 herniations subsequent to cerebral oedema have been reported. All patients, and in particular children, must be carefully evaluated for excessive fluid retention and hypertension before the initiation of ORTHOCLONE therapy. Close monitoring for neuro-psychiatric symptoms must be observed during the first twenty four (24) hours following the first ORTHOCLONE injection. Irreversible sequelae associated with serious CNS events (e.g. blindness, deafness, paralysis) have been reported rarely.
Post-therapy encephalopathy, meningitis, CNS lymphoproliferative disorders and infection have been reported but association of these events with ORTHOCLONE treatment is unclear.
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 neurological 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 (CNS).
Serious and occasionally fatal, immediate (usually within 10 minutes) hypersensitivity (anaphylactic) reactions have been reported in patients treated with ORTHOCLONE.
Manifestations of anaphylaxis may appear similar to manifestations of CRS (described above). Reactions attributed to hypersensitivity have been reported less frequently than those attributed to cytokine release.
Other hypersensitivity reactions reported include mild, self-limited rash and pruritus, urticaria, ineffectiveness of treatment, serum sickness, arthritis, allergic interstitial nephritis, immune complex deposition resulting in glomerulonephritis, vasculitis, and temporal arteritis, and eosinophilia.
Infections and neoplasias: (serious and sometimes fatal) have been reported in association with all immunosuppressive therapies.
Infections: The addition of ORTHOCLONE to immunosuppressive therapeutic regimens augments the degree of immunosuppression thus increasing the risk and severity of infectious complications.
During the first month post-transplant, patients are at risk for infections present prior to transplant and infections conveyed by the donor organ as well as the usual post-operative urinary tract, intravenous line-related, wound, or pulmonary infections due to bacterial pathogens.
Approximately 1 to 6 months post-transplant, patients are at risk for viral infections which produce serious systemic disease (e.g. pneumonia, sepsis which may occur with any microorganisms) and which increase the overall state of immunosuppression.
Multiple or intensive courses of ORTHOCLONE (or any other anti-T cell antibody preparation), which produce profound impairment of cell-mediated immunity, further increase the risk of infection, especially with the Herpes viruses (HSV, CMV, EBV) and fungi.
Reactivation (1 to 4 months post-transplant) of EBV and CMV has been reported including the following syndromes: fever of unknown origin, pneumonia, viraemia, hepatitis, liver/renal dysfunction, gastritis or gastrointestinal ulcerations, pancreatitis, chorioretinitis, leucopenia and thrombocytopenia.
When administration of ORTHOCLONE (or any other anti-T cell antibody preparation) 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 (primary or reactivated) may play an important role in the development of post-transplant neoplasias.
Neoplasia: As a result of depressed cell mediated immunity, organ transplant patients have an increased risk of developing malignancies as evidenced by the occurrence of lymphoproliferative disorders, lymphomas and skin cancers. Lymphoproliferative disorders reported ranged from lymphadenopathy or benign polyclonal B cell hyperplasias to malignant and often fatal monoclonal B cell lymphomas.
Approximately 1/3 of lymphoproliferations are benign and 2/3 malignant.
Classifications of lymphomas include: B cell, large cell, polyclonal, non-Hodgkin's, lymphocytic, T cell and Burkitt's. Malignant lymphomas have been reported to develop soon after transplantation (majority within 4 months post-treatment), many of which were rapidly progressive, widely disseminated at diagnosis and fatal. Skin carcinomas have included: basal cell, squamous cell, Kaposi's sarcoma, melanoma, and keratoacanthoma.
The long term risk of neoplastic events in patients treated with ORTHOCLONE has not been determined.
Intravascular thrombosis: (arterial/venous thromboses) of allografts and other vascular beds (e.g. heart, lungs, brain, bowel, etc.) have been reported in patients treated with ORTHOCLONE.
Haematopoietic effects including: pancytopaenia, aplastic anaemia, neutropaenia, leukopaenia, leucocytosis, thrombocytopenia, lymphopaenia and disturbances of coagulation have been reported in patients treated with ORTHOCLONE.

PRECAUTIONS
Prior to treatment with ORTHOCLONE:
Fluid status: 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, including a clear chest x-ray and weight restriction of < 3% above the patient's minimum weight during the week prior to injection.
Fever: If the patient's temperature exceeds 37,8°C, it should be lowered by antipyretics before ORTHOCLONE administration. The possibility of infection should be evaluated.
Blood tests: Periodic assessment of organ system functions (renal, hepatic and hematopoietic) should be performed prior to and during ORTHOCLONE treatment.
The effect of ORTHOCLONE on circulating T cells expressing the CD3 antigen should be monitored during treatment by an in vitro assay.
Patients receiving ORTHOCLONE for initial use should be monitored periodically to ensure adequate plasma ORTHOCLONE levels > 0.800 µg/mL or T cell clearance, CD3 positive T cells < 25 cells/mm³.
Prior to retreatment: ORTHOCLONE is a heterologous protein and can induce detectable antibodies in patients following exposure. Only limited data are available regarding retreatment with ORTHOCLONE. The presence of antibodies to ORTHOCLONE could limit its efficacy following readministration and possibly cause serious adverse reactions.
Testing for human antimurine antibody titres is strongly recommended prior to retreatment. A titre > 1:100 may preclude successful retreatment, a titre > 1:1000 is a contraindication for use.
Retreatment: Caution should be used if retreatment is considered with daily monitoring of either plasma ORTHOCLONE levels or clearance of CD3 positive T cells to achieve the same targets described for initial use.

Information for Patients:
Patients should be informed of the expected first-dose ORTHOCLONE effects, which are markedly reduced on successive days of ORTHOCLONE treatment.

Paediatric use:
Safety and effectiveness in children have not been established. No adequate and well-controlled studies have been conducted in children.
Signs and symptoms of encephalopathy, meningitis, seizures and cerebral oedema 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 herniations subsequent to cerebral oedema have been reported. All patients, and in particular children, must be carefully evaluated for excessive fluid retention and hypertension before the initiation, of ORTHOCLONE therapy. Close monitoring for neuro-psychiatric symptoms must be observed during the frist twenty four (24) hours following the first ORTHOCLONE injection. Irreversible sequelae associated with serious CNS events (e.g. blindness, deafness, paralysis) have been reported.
Paediatric recipients are reported to be significantly immunosuppressed for a prolonged period of time and hence require close monitoring post-therapy for opportunistic infections, particularly varicella (VZV), which poses an infectious complication unique to this population.
Gastrointestinal fluid loss secondary to diarrhoea and/or vomiting resulting from 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 (e.g. neurodevelopmental language difficulties in infants under 1 year of age) related to the occurrence of seizures, high fever, CNS infections, aseptic meningitis, etc. following ORTHOCLONE treatment.
When administration of ORTHOCLONE is deemed necessary, more vigilant and frequent monitoring than in adults, is requred.
Drug interactions:
Other medications/substances should not be added or infused simultaneously through the same intravenous line.
If the same intravenous line is used for sequential infusion of different drugs, the line should be flushed with saline before and after infusion of ORTHOCLONE.
Concomitant medications (azathioprine, corticosteroids, cyclosporine) may have contributed to the neuro-psychiatric, infectious, nephrotoxic, thrombotic and/or neoplastic events reported in patients treated with ORTHOCLONE.
The use of indomethacin in patients receiving ORTHOCLONE may have contributed to some encephalopathic and other CNS adverse events.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
The maximum amount of ORTHOCLONE that can be administered in single or multiple doses has not been determined.
Treatment should be symptomatic and supportive.

PRESENTATION
ORTHOCLONE is supplied in cartons containing 5 x 5 mL ampoules.

STORAGE INSTRUCTIONS
Store in a refrigerator 2 to 8°C.
DO NOT FREEZE OR SHAKE.
Keep out of reach of children.

NAME AND BUSINESS ADDRESS OF THE APPLICANT
JANSSEN-CILAG
JANSSEN PHARMACEUTICA (PTY) LTD
(Reg. No. 80/11122/07)
15th Road, HALFWAY HOUSE 1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT
December 1992
                        Code No.: 023422
                        97J
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