Muromonab administration

Although the release of a wide range of cytokines was increased after muromonab administration, tumor necrosis factor alfa and interleukin-6 were suggested to play a pivotal role, and monoclonal anti-TNF-alfa antibody administration reduced the acute chnical symptoms (15). A role for the activation of complement and neutrophils was also suggested. 

Isolated visual loss (persistent in one patient) shortly after muromonab administration is rare (SEDA-20, 340) (29). 

Anaphylactic or anaphylactoid reactions may occur following administration of any dose or course of muromonab-CD3. Serious and occasionally life-threatening systemic, cardiovascular, and CNS reactions have been reported. These have included the following Pulmonary edema, especially in patients with volume overload shock cardiovascular collapse cardiac or respiratory arrest seizures coma. Hence, a patient being treated with muromonab-CD3 must be managed in a facility equipped and staffed for cardiopulmonary resuscitation. 

Monitor Monitor patients closely for the first few doses. Methylprednisolone sodium succinate 8 mg/kg IV given 1 to 4 hours prior to muromonab-CD3 administration is strongly recommended to decrease the incidence of reactions to the first dose. Acetaminophen and antihistamines, given concomitantly, may reduce early reactions. Patient temperature should not exceed 37.8°C (100°F) prior to first administration. 

Cytokine release syndrome (CRS) Temporally associated with the administration of the first few doses of muromonab-CD3 (particularly, the first 2 to 3 doses), most P.1174... 

Prevention/Minimization - Manifestations of the CRS may be prevented or minimized by pretreatment with 8 mg/kg methylprednisolone, given 1 to 4 hours prior to administration of the first dose of muromonab-CD3 and by closely following recommendations for dosage and treatment duration. 

Pharmacokinetics A rapid decrease in T-lymphocytes is observed within a few minutes after administration of Orthoclone OKT3. The volume of distribution of muromonab CD3 is approximately 6.5 liters its half-life is 18 hours. Clinical experience has demonstrated that serum levels greater than or equal to 0.8pg/ml of muromonab CD3 blocks the function of cytotoxic T cells in vitro and in vivo. Reduced T-cell clearance or low plasma... 

Evidence suggests that giving 250 mg of methylprednisolone 6 hours prior and 1 hour prior to administration of muromonab-CD3 can decrease the incidence of cytokine release syndrome (CRS). Pentoxifylline has not been shown to attenuate CRS. Indomethacin, however, can be effective. 

In a 28-year-oId man the clinical features of aseptic meningitis were prolonged over 1 month after the administration of muromonab, and persistent severe headaches resolved only after several aspirations of cerebrospinal fluid (27). 

Ototoxicity from muromonab has been described, but the incidence is unknown (SEDA-21, 380). Audiograms performed before and 48-72 hours after administration of muromonab showed sensorineural hearing loss of at least 15 db in five of seven renal transplant patients (30). A third audiogram 2 weeks after muromonab treatment showed amelioration or complete recovery in all four of the patients who were tested. 

Hooks MA, Perlino CA, Henderson JM, MiUikan WJ Jr, Kutner MH. Prevalence of invasive cytomegalovirus disease with administration of muromonab CD-3 in patients undergoing orthotopic liver transplantation. Ann Pharmacother 1992 26(5) 617-20. 

Muromonab-CD3 (OKT3) is a murine monoclonal antibody to the CD3 receptor on mature human T cells (see Fig. 87-1). Minutes following the administration of OKT3, T-ceU concentrations decrease dramatically, as measured by CD3 levels. Cells reappear after a few days but bear no CD3 receptors. After cessation of OKT3 therapy, T-cell function normalizes in a week. ... 

Therapeutic Uses Muromonab-CD3 is indicated for treatment of acute organ transplant rejection. The recommended dose is 5 mg/day (in adults less for children) in a single intravenous bolus (<1 minute) for 10-14 days. Antibody levels increase over the first 3 days and then plateau. Circulating T cells disappear from the blood within minutes of administration and return within 1 week after cessation of therapy. Repeated use of muromonab-CD3 results in the immunization of the patient against the mouse determinants of the antibody, which can neutralize and prevent its immunosuppressive efficacy. Thus, repeated treatment with the muromonab-CD3 or other mouse monoclonal antibodies generally is contraindicated. 

Glucocorticoid administration before the injection of muromonab-CD3 considerably reduces first-dose reactions and is now standard. Volume status of patients also must be monitored carefully before therapy steroids and other premedications should be given, and a fully competent resuscitation facility must be immediately available for patients receiving their first several doses. 

In 1986, Muromonab CD-3 (OKT-3), which is a monoclonal antibody was first introduced to clinical practice, and the agent has been effective in reversing corticosteroid-resistant acute rejection in renal, liver, and cardiac transplant recipients. OKT-3 is administered only by intravenous injection and has a harmonic half-life of approximately 18 h. It binds specifically to the CD-3 complex, which is involved in antigen recognition and cell stimulation, on the surface of T lymphocytes. Immediately after administration, CD-3-positive T lymphocytes are abruptly removed from the circulation. OKT-3 may be removed by opsonization by the reticuloendothelial system when bound to T lymphocytes, or by human antimurine antibody production [230]. 

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