Orthoclone OKT3 Side Effects
Generic Name: muromonab-cd3
Note: This document contains side effect information about muromonab-cd3. Some of the dosage forms listed on this page may not apply to the brand name Orthoclone OKT3.
For the Consumer
Applies to muromonab-cd3: intravenous solution
Along with its needed effects, muromonab-cd3 (the active ingredient contained in Orthoclone OKT3) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Because of the way that muromonab-CD3 acts on the body, there is a chance that it may cause effects that may not occur until years after the medicine is used. These delayed effects may include certain types of cancer, such as lymphomas and skin cancers. Discuss these possible effects with your doctor.
Although not all of the following side effects may occur, if they do occur, they may need medical attention.
Check with your doctor immediately if any of the following side effects occur while taking muromonab-cd3:
- Chest pain
- rapid or irregular heartbeat
- shortness of breath or wheezing
- swelling of face or throat
Check with your doctor as soon as possible if any of the following side effects occur while taking muromonab-cd3:
- dizziness or faintness
- fever and chills
- general feeling of discomfort or illness
- muscle or joint pain
- nausea and vomiting
Less Common or Rare
- black, tarry stools
- blood in urine or stools
- convulsions (seizures)
- cough or hoarseness
- hallucinations (seeing, hearing, or feeling things that are not there)
- itching or tingling
- loss of hearing or vision
- lower back or side pain
- painful or difficult urination
- pinpoint red spots on skin
- skin rash
- sores, ulcers, or white spots on the lips or in the mouth
- stiff neck
- swollen or painful glands
- tightness in the chest
- trembling and shaking of hands
- troubled breathing
- unusual sensitivity of eyes to light
- unusual bleeding or bruising
- unusual tiredness
After you stop using this medicine, it may still produce some side effects that need attention. During this period of time, check with your doctor immediately if you notice the following side effects:
- Fever and chills
For Healthcare Professionals
Applies to muromonab-cd3: intravenous solution
General side effects of muromonab CD3 include an acute clinical syndrome known as the Cytokine Release Syndrome or CRS. CRS, attributed to the release of cytokines by activated T cells, is most commonly characterized by a "flu-like" illness, including fever (spiking as high as 107 degrees Fahrenheit), chills, rigors, headache, nausea, vomiting, diarrhea, malaise, arthralgias, myalgias, and weakness. More serious, and sometimes fatal, manifestations, include pulmonary edema, hemodynamic instability, shock, respiratory arrest, and cardiac arrest.[Ref]
The CRS is associated with the first few doses of muromonab CD3. Onset of symptoms is typically within 30 to 60 minutes after the first dose. Symptoms are thought to be due to the release of cytokines, including tumor necrosis factor, gamma interferon, interleukin-2, interleukin-3, interleukin-4, interleukin-6, and granulocyte colony stimulating factor, from T cells following binding of muromonab CD3.
Pretreatment with 8 mg/kg methylprednisolone sodium succinate intravenously one to four hours before and 100 mg hydrocortisone sodium succinate 30 minutes after administration of the first dose of muromonab CD3 may reduce the severity of symptoms associated with the CRS. While data are conflicting, other agents which may be of benefit include indomethacin, heparin, pentoxifylline, and experimental anti-TNF monoclonal antibodies.
Patients at increased risk for serious complications associated with the CRS include those with unstable angina, recent myocardial infarction, symptomatic ischemic heart disease, heart failure, pulmonary edema, intravascular volume overload or depletion, cerebrovascular disease, septic shock, or a history of seizures.[Ref]
Cardiovascular side effects may be more common in patients receiving muromonab CD3 for prophylaxis of allograft rejection than in patients receiving muromonab CD3 for reversal of rejection. Tumor necrosis factor is thought to be involved in the pathogenesis of the cardiovascular side effects.
In one study involving 18 patients treated with muromonab CD3 5 mg per day for ten days for renal allograft rejection, mean systolic and diastolic blood pressures increased 20.9 and 10.8 mmHg, respectively, on day one, in nine patients. On day 2, mean systolic and diastolic pressures increased 41.7 and 19.1 mmHg, respectively, in 10 patients. Heart rate increased 23.7 beats per minute on day one but no change was noted on day two. No significant changes in blood pressure or heart rate were noted on day three. The increase in blood pressure lasted approximately two hours on day one and 11 to 13 hours on day two.
Thrombosis of allografts and other vascular beds has been reported during therapy with muromonab CD3. In one study of 93 renal allograft recipients receiving muromonab CD3 prophylactically, nine patients had intragraft thromboses within two weeks of transplantation. Elevated prothrombin fragments 1 and 2 were noted as compared to a control group. Tumor necrosis factor as well as endothelial cell activation are suspected of playing a role in the thrombotic events.[Ref]
Cardiovascular side effects have included hypertension (24% to 64%), hypotension (12% to 18%), chest pain or angina (14%), tachycardia (3% to 45%), bradycardia, and hemodynamic instability. Cardiac arrest, severe hypotension or shock, heart failure, cardiovascular collapse, left ventricular dysfunction, and arrhythmias have also been reported. In addition, thrombotic events within main graft vessels have been reported.[Ref]
Pulmonary edema, sometimes fatal, has been reported in up to 13% of patients in early studies. However, affected patients were determined to be fluid overloaded in the pretreatment period. Restrictions against use in patients who are volume overloaded as evidenced by a 3% or greater increase in body weight during the week prior to muromonab CD3 treatment has drastically reduced the occurrence of pulmonary edema; although, cases of pulmonary edema in euvolemic patients have been reported. Increased pulmonary vascular permeability and/or reduced left ventricular compliance or contractility are additional risk factors.
The mechanism may involve tumor necrosis factor-alpha as well as complement activation and pulmonary sequestration of activated granulocytes.
The use of muromonab CD3 is considered contraindicated in patients with volume overload and/or uncompensated heart failure.[Ref]
Respiratory side effects have included dyspnea, shortness of breath, bronchospasm, apnea, and tachypnea. More serious effects, including pulmonary edema (cardiogenic and noncardiogenic), respiratory distress syndrome, and respiratory failure have also been attributed to muromonab CD3 therapy and may be fatal.[Ref]
Aseptic meningitis usually presents within 72 hours following the first dose of muromonab CD3, accompanied by symptoms of fever, headache, nuchal rigidity, and photophobia. Cerebral spinal fluid findings include pleocytosis, elevated protein, and negative cultures. Symptoms typically resolve in two or three days regardless of whether or not muromonab CD3 therapy is continued.
Encephalopathy, also known as cytokine encephalopathy, may occur in up to 7% of patients and is typically characterized by confusion, hallucinations, seizures, obtundation, coma, and occasionally, blindness. Cytokine encephalopathy usually regresses without significant intervention. However, severe cases necessitate discontinuation of the drug. Permanent neurologic deficits have been reported. One study identified delayed graft function as a significant risk factor for the development of cytokine encephalopathy in patients treated prophylactically with muromonab CD3.[Ref]
Nervous system side effects have included headache and mental status changes as well as more serious sequelae including seizures, cerebritis, aseptic meningitis, and encephalopathy.[Ref]
Hematologic side effects have included pancytopenia, aplastic anemia, neutropenia, leukopenia, thrombocytopenia, lymphopenia, leukocytosis, and disturbances in coagulation. Graft vessel thromboses have also been reported.[Ref]
Elevations in prothrombin fragments 1 and 2 and von Willebrand's factor have been found following the first dose of muromonab CD3. Tumor necrosis factor-alpha appears to be the mediator of muromonab CD3-induced coagulopathy.[Ref]
Oncologic side effects, or the development of new malignancies, are of particular concern in post-transplant patients. Lymphoproliferative disorders are of the most concern. Lymphadenopathy and benign polyclonal B cell hyperplasia as well as malignant, often fatal, B cell lymphomas have been reported.[Ref]
The majority of lymphomas have been diagnosed within the first four months following transplantation, and are often rapidly progressive and disseminated at the time of diagnosis.
Muromonab CD3 is considered contraindicated in patients with a history of hypersensitivity to murine-derived products or with an anti-mouse antibody titer greater than 1:1000. Retreatment with muromonab CD3 may be associated with an increased incidence of hypersensitivity reactions and should be done with caution.[Ref]
Hypersensitivity side effects from muromonab CD3 have included rash, pruritus, angioedema, and anaphylaxis. In addition, serum sickness; immune complex deposition causing glomerulonephritis, vasculitis, and temporal arteritis; and eosinophilia have been reported.[Ref]
Reversible renal dysfunction, known as cytokine nephropathy, is characterized by transient increases in serum creatinine and blood urea nitrogen. In one study, serum creatinine increased by an average of 2.9 mg/dl and fell to prerejection levels by the end of muromonab CD3 therapy.[Ref]
Renal side effects have included a slight decline in renal function, as evidenced by a transient increase in serum creatinine and blood urea nitrogen. In addition, anuria, oliguria, delayed renal graft function, interstitial nephritis, and abnormal urinalysis have been reported.[Ref]
Gastrointestinal side effects, such as nausea/vomiting (18% to 51%) and diarrhea (21%), may be severe requiring fluid management. In addition, cases of bowel infarction and pancreatitis have been reported.[Ref]
Other side effects associated with muromonab CD3 have included blindness, anterior scleritis, blurred vision, double vision, conjunctivitis, hearing loss, vertigo, tinnitus, and VI cranial nerve palsy.[Ref]
Cytomegalovirus, Herpes simplex, and fungal infections are the most commonly encountered infections during muromonab CD3 immunosuppressive therapy. Other infections, including bacterial, viral, and protozoal, have been reported as well.
Several studies have identified an increased risk of invasive cytomegalovirus infection in recipients of CMV-positive grafts which is associated with a significant increase in morbidity and mortality.[Ref]
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2. Radhakrishnan J, Cohen DJ "Cytokine-release syndrome: general risk-factor modification-- preparation of high-risk patients for use of OKT3." Transplant Proc 25 (1993): 60-2
3. Jeyarajah DR, Thistlethwaite JR, Jr "General aspects of cytokine-release syndrome: timing and incidence of symptoms." Transplant Proc 25 (1993): 16-20
4. Shield CF II, Kahana L, Pirsch J, et al "Use of indomethacin to minimize the adverse reactions associated with orthoclone OKT3 treatment of kidney allograft rejection." Transplantation 54 (1992): 164-6
5. Todd PA, Brogden RN "Muromonab CD3. A review of its pharmacology and therapeutic potential." Drugs 37 (1989): 871-99
6. Leimenstoll G, Zabel P, Schroeder P, Schlaak M, Niedermayer W "Suppression of OKT3-induced tumor necrosis factor alpha formation by pentoxifylline in renal transplant recipients." Transplant Proc 25 (1993): 561-3
7. Chatenoud L, Ferran C, Bach JF "The anti-CD3-induced syndrome: a consequence of massive in vivo cell activation." Curr Top Microbiol Immunol 174 (1991): 121-34
8. "Product Information. Orthoclone OKT 3 (muromonab-CD3)." Ortho Pharmaceutical Corporation, Raritan, NJ.
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10. Chatenoud L "OKT3-induced cytokine-release syndrome: prevention effect of anti-tumor necrosis factor monoclonal antibody." Transplant Proc 25 (1993): 47-51
11. First MR, Schroeder TJ, Hariharan S, Weiskittel P "Reduction of the initial febrile response to OKT3 with indomethacin." Transplant Proc 25 (1993): 52-4
12. Norman DJ, Kimball JA, Barry JM "Cytokine-release syndrome: differences between high and low doses of OKT3." Transplant Proc 25 (1993): 35-8
13. Sgro C "Side-effects of a monoclonal antibody, muromonab CD3 orthoclone OKT3: bibliographic review." Toxicology 105 (1995): 23-9
14. First MR, Schroeder TJ, Hariharan S, Alexander JW, Weiskittel P "The effect of indomethacin on the febrile response following OKT3 therapy." Transplantation 53 (1992): 91-4
15. Spieker C, Zidek W, Barenbrock M, Wieneke R, Buchholz B, Rahn KH "Acute hypertension after renal allograft rejection therapy with OKT3 monoclonal antibody." J Int Med Res 19 (1991): 419-23
16. Hall KA, Dole EJ, Hunter GC, Zukoski CF, Putnam CW "Hyperpyrexia-related ventricular tachycardia during OKT3 induction therapy." Transplantation 54 (1992): 1112-3
17. Gomez E, Aguado S, Gago E, et al "Main graft vessels thromboses due to conventional-dose OKT3 in renal transplantation." Lancet 339 (1992): 1612-3
18. Abramowicz D, Pradier O, Marchant A, Florquin S, De Pauw L, Vereerstraeten P, Kinnaert P, Vanherweghem JL, Goldman M "Induction of thromboses within renal grafts by high-dose prophylactic OKT3." Lancet 339 (1992): 777-8
19. Hollenbeck M, Westhoff A, Bach D, Grabensee B, Kolvenbach R, Kniemeyer HW "Doppler sonography and renal graft vessel thromboses after OKT3 treatment." Lancet 340 (1992): 619-20
20. Costanzo-Nordin MR "Cardiopulmonary effects of OKT3: determinants of hypotension, pulmonary edema, and cardiac dysfunction." Transplant Proc 25 (1993): 21-4
21. Spieker C, Barenbrock M, Buchholz B, Heidenreich S, Zidek W "Cardiovascular effects of ATG and OKT3 in renal allograft recipients." Transplant Proc 24 (1992): 2594-5
22. Pradier O, Marchant A, Abramowicz D, De Pauw L, Vereerstraeten P, Kinnaert P, Vanherweghem JL, Capel P, Goldman M "Procoagulant effect of the OKT3 monoclonal antibody: involvement of tumor necrosis factor." Kidney Int 42 (1992): 1124-9
23. Raasveld MH, Bemelman FJ, Schellekens PT, van Diepen FN, van Dongen A, van Royen EA, Hack CE, ten Berge IJ "Complement activation during OKT3 treatment: a possible explanation for respiratory side effects." Kidney Int 43 (1993): 1140-9
24. Kehinde EO, Scriven SD, Feehally J, Veitch PS, Varty K, Bell PRF "Adverse effects of OKT3 therapy: increased risk with impaired renal function." Transplant Proc 26 (1994): 1945-7
25. Capone PM, Cohen ME "Seizures and cerebritis associated with administration of OKT3." Pediatr Neurol 7 (1991): 299-301
26. Agarwal RK, Ostaszewski ML, Feld LG, Springate JE, Moxey-Mims MM, O'Neil KM "Tumor necrosis factor and interleukin-6 in cerebrospinal fluid of a patient with recurrent adverse central nervous system events following OKT3." Transplant Proc 25 (1993): 2143-4
27. Shihab FS, Barry JM, Norman DJ "Encephalopathy following the use of OKT3 in renal allograft transplantation." Transplant Proc 25 (1993): 31-4
28. Jeffrey RF, Johnson MH, Bamford JM, Giles GR, Brownjohn AM, Will EJ "Prolonged neurological disability following OKT3 therapy for acute renal transplant rejection." Transplantation 55 (1993): 677-9
29. Shihab F, Barry JM, Bennett WM, Meyer MM, Norman DJ "Cytokine-related encephalopathy induced by OKT3: incidence and predisposing factors." Transplant Proc 25 (1993): 564-5
30. Figg WD "Aseptic meningitis associated with muromonab-CD3." DICP 25 (1991): 1395
31. Sutton JD, Prioleau MH, Wordell CJ, Francos GC "Aseptic meningitis associated with muromonab CD3 administration." DICP 23 (1989): 257-8
32. Coleman AE, Norman DJ "OKT3 Encephalopathy." Ann Neurol 28 (1990): 837
33. Joy ME, Michals ML, Canafax DM "Aseptic meningitis associated with muromonab-CD3 therapy." Clin Pharm 7 (1988): 721
34. Swinnen LJ, Costanzo-Nordin MR, Fisher SG, et al "Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac-transplant recipients." N Engl J Med 323 (1990): 1723-8
35. Rinde-Hoffman D, Cintron GB, Ferguson JE, Toole JC, Bugni WB "Lymphoproliferative disorder early after cardiac transplantation [published erratum]." Am J Cardiol 69 (1992): 844
36. Alfrey EJ, Friedman AL, Grossman RA, Perloff LJ, Naji A, Barker CF, Montone KT, Tomaszewski JE, Chmielewski C, Holland T, et al "A recent decrease in the time to development of monomorphous and polymorphous posttransplant lymphoproliferative disorder." Transplantation 54 (1992): 250-3
37. Batiuk TD, Barry JM, Bennett WM, Meyer MM, Tolzman D, Norman DJ "Incidence and type of cancer following the use of OKT3: a single center experience with 557 organ transplants." Transplant Proc 25 (1993): 1391
38. Rinde-Hoffman D, Cintron GB, Ferguson JE, Toole JC, Bugni WB "Lymphoproliferative disorder early after cardiac transplantation." Am J Cardiol 68 (1991): 1724-5
39. Abramowicz D, Crusiaux A, Goldman M "Anaphylactic shock after retreatment with OKT3 monoclonal antibody." N Engl J Med 327 (1992): 736
40. Batiuk TD, Bennett WM, Norman DJ "Cytokine nephropathy during antilymphocyte therapy." Transplant Proc 25 (1993): 27-30
41. First MR, Schroeder TJ, Hariharan S "OKT3-induced cytokine-release syndrome: renal effects (cytokine nephropathy)." Transplant Proc 25 (1993): 25-6
42. Scheinin S, Radovancevic B, Frazier OH "Acute pancreatitis complicating OKT3 administration for resistant cardiac rejection." Transplant Proc 25 (1993): 2368-9
43. Dukar O, Barr CC "Visual loss complicating OKT3 monoclonal antibody therapy." Am J Ophthalmol 115 (1993): 781-5
44. McCarthy JM, Sullivan K, Keown PA, Rollins DT "Diffuse anterior scleritis during OKT3 monoclonal antibody therapy for renal transplant rejection." Can J Ophthalmol 27 (1992): 22-4
45. Michals M, Roberts JP, Canafax D "Hearing loss associated with muromonab-CD3 therapy." Clin Pharm 7 (1988): 867-8
Some side effects may not be reported. You may report them to the FDA.