No

Immunosuppressant Agent

Treatment of acute allograft rejection in renal transplant patients; treatment of acute hepatic, kidney, and pancreas rejection episodes resistant to conventional treatment. Acute graft-versus-host disease following bone marrow transplantation resistant to conventional treatment.

C

Hypersensitivity to OKT3 or any murine product; patients in fluid overload or those with >3% weight gain within 1 week prior to start of mouse antibody titers >1:1000

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 less than or equal to 3% above the patient's minimum weight during the week prior to injection.

Severe pulmonary edema has occurred in patients with fluid overload.

First dose effect (flu-like symptoms, anaphylactic-type reaction): may occur within 30 minutes to 6 hours up to 24 hours after the first dose and may be minimized by using the recommended regimens.

Suggested prevention/treatment of muromonab-CD3 first-dose effects (grouped by adverse reaction):

Severe pulmonary edema

Effective prevention or palliation: Clear chest x-ray within 24 hours preinjection; weight restriction to less than or equal to 3% gain over 7 days preinjection

Supportive treatment: Prompt intubation and oxygenation, 24 hours close observation

Fever, chills

Effective prevention or palliation: 15 mg/kg methylprednisolone sodium succinate 1 hour preinjection; fever reduction to <37.8°C (100°F) 1 hour preinjection; acetaminophen (1 g orally) and diphenhydramine (50 mg orally) 1 hour preinjection

Supportive treatment: Cooling blanket, acetaminophen as needed

Respiratory effects

Effective prevention or palliation: 100 mg hydrocortisone sodium succinate 30 minutes postinjection

Supportive treatment: Additional 100 mg hydrocortisone sodium succinate as needed for wheezing; if respiratory distress, give epinephrine 1:1000 (0.3 mL S.C.)

Cardiopulmonary resuscitation may be needed. If the patient's temperature is >37.8°C, reduce before administering OKT3

>10%:

"First-dose" (cytokine release) effects: Onset: 1-3 hours after the dose; duration: 12-16 hours. Severity is mild to life-threatening. Signs and symptoms include fever, chilling, dyspnea, wheezing, chest pain, chest tightness, nausea, vomiting, and diarrhea. Hypervolemic pulmonary edema, nephrotoxicity, meningitis, and encephalopathy are possible. Reactions tend to decrease with repeated doses.

Cardiovascular: Tachycardia (including ventricular)

Central nervous system: Dizziness, faintness

Gastrointestinal: Diarrhea, nausea, vomiting

Hematologic: Transient lymphopenia

Neuromuscular & skeletal: Trembling

Respiratory: Shortness of breath

1% to 10%:

Central nervous system: Headache

Neuromuscular & skeletal: Stiff neck

Ocular: Photophobia

Respiratory: Pulmonary edema

<1%: Hypertension, hypotension, chest pain, tightness, aseptic meningitis, seizures, fatigue, confusion, coma, hallucinations, pyrexia, pruritus, rash, arthralgia, tremor, increased BUN and creatinine, dyspnea, wheezing. Sensitivity reactions: Anaphylactic-type reactions, flu-like symptoms (ie, fever, chills), infection, pancytopenia, secondary lymphoproliferative disorder or lymphoma, thrombosis of major vessels in renal allograft.

Decreased effect: Immunosuppressive drugs; it is recommended to decrease dose of azathioprine to 1 mg/kg and decrease dose of cyclosporine by 50% until 4 days prior to stopping OKT3

Refrigerate; do not shake or freeze; stable in Becton Dickinson syringe for 16 hours at room temperature or refrigeration

Reverses graft rejection by binding to T cells and interfering with their function by binding T-cell receptor-associated CD3 glycoprotein

Absorption: I.V.: Immediate

Time to steady-state: Trough level: 3-14 days; pretreatment levels are restored within 7 days after treatment is terminated

I.V. (refer to individual protocols):

Children >30 kg: 5 mg/day once daily for 7-14 days

OR

Children <12 years: 0.1 mg/kg/day once daily for 10-14 days

Children greater than or equal to 12 years and Adults: 5 mg/day once daily for 10-14 days

Hemodialysis: Molecular size of OKT3 is 150,000 daltons; not dialyzed by most standard dialyzers; however, may be dialyzed by high flux dialysis; OKT3 will be removed by plasmapheresis; administer following dialysis treatments

Peritoneal dialysis: Significant drug removal is unlikely based on physiochemical characteristics

Chest x-ray, weight gain, CBC with differential, temperature, vital signs (blood pressure, temperature, pulse, respiration); immunologic monitoring of T cells, serum levels of OKT3

OKT3 serum concentrations:

Serum level monitoring should be performed in conjunction with lymphocyte subset determinations; Trough concentration sampling best correlates with clinical outcome. Serial monitoring may provide a better early indicator of inadequate dosing during induction or rejection.

Mean serum trough levels rise during the first 3 days, then average 0.9 mcg/mL on days 3-14

Circulating levels greater than or equal to 0.8 mcg/mL block the function of cytotoxic T cells in vitro and in vivo

Several recent analysis have suggested appropriate dosage adjustments of OKT3 induction course are better determined with OKT3 serum levels versus lymphocyte subset determination; however, no prospective controlled trials have been performed to validate the equivalency of these tests in predicting clinical outcome.

Lymphocyte subset monitoring: CD3+ cells: Trough sample measurement is preferable and reagent utilized defines reference range.

OKT3-FITC: <10-50 cells/mm³ or <3% to 5%

CD3(IgG1)-FITC: similar to OKT3-FITC

Leu-4a: Higher number of CD3+ cells appears acceptable

Dosage adjustments should be made in conjunction with clinical response and based upon trends over several consecutive days

Dizziness is common; may rarely cause sedation, confusion, or hallucinations

None reported

No information available to require special precautions

No effects or complications reported

There may be a severe reaction to the first infusion of this medication. You may experience high fever, chills, difficulty breathing, or congestion. You will be closely monitored and comfort measures provided. Effects are substantially reduced with subsequent infusions. During the period of therapy and for some time after the regimen of infusions you will be susceptible to infection. People may wear masks and gloves while caring for you to protect you as much as possible from infection (avoid crowds and people with infections or contagious diseases). You may experience dizziness, faintness, or trembling (use caution until response to medication is known); nausea or vomiting (frequent small meals, frequent mouth care); sensitivity to direct sunlight (wear dark glasses, and protective clothing, use sunscreen, or avoid exposure to direct sunlight). Report chest pain or tightness; symptoms of respiratory infection, wheezing, or difficulty breathing; vision change; or muscular trembling. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to be pregnant. Do not breast-feed.

Do not administer I.M., monitor patient closely for 24 hours after the first dose; drugs and equipment for treating pulmonary edema and anaphylaxis should be on hand

Injection: 5 mg/5 mL

Hooks MA, Wade CS, and Millikan WJ Jr, "Muromonab CD-3: A Review of Its Pharmacology, Pharmacokinetics, and Clinical Use in Transplantation," Pharmacotherapy, 1991, 11(1):26-37.

Niaudet P, Murcia I, Jean G, et al, "A Comparative Trial of OKT3 and Antilymphocyte Serum in the Preventive Treatment of Rejection After Kidney Transplantation in Children," Ann Pediatr Paris, 1990, 37(2):83-5.

Todd PA and Brogden RN, "Muromonab CD3 A Review of Its Pharmacology and Therapeutic Potential," Drugs, 1989, 37(6):871-99.