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Treatment of acute allograft rejection in renal transplant patients; treatment of steroid-resistant acute allograft rejection in cardiac or hepatic transplantation
Hypersensitivity to OKT3 or any murine product; patients with uncompensated heart failure or uncontrolled hypertension, in fluid overload or those with >3% weight gain within 1 week prior to start of OKT3; mouse antibody titers >1:1000; history of seizures; known or suspected pregnancy; breast-feeding
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Treatment of acute allograft rejection: IV (refer to individual protocols): 5 mg/day once daily for 10-14 days
Note: 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 ≤3% gain over 7days 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 SubQ)
Refer to adult dosing.
Refer to individual protocols.
Treatment of acute allograft rejection: IV
Children ≤30 kg: 2.5 mg/day once daily for 10-14 days
Children >30 kg: 5 mg/day once daily for 10-14 days
or
Children <12 years (off-label dosing): 0.1 mg/kg/day once daily for 10-14 days
Children ≥12 years: Refer to adult dosing.
Note: Suggested prevention/treatment of muromonab-CD3 first-dose effects (grouped by adverse reaction): Refer to adult dosing.
Removal by dialysis: 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.
Not for IM administration. Filter each dose through a low protein-binding 0.22 micron filter (Millex GV) before administration; administer IV push over <1 minute at a final concentration of 1 mg/mL
Methylprednisolone sodium succinate 15 mg/kg IV administered prior to first muromonab-CD3 administration and IV hydrocortisone sodium succinate 50-100 mg given 30 minutes after administration are strongly recommended to decrease the incidence of reactions to the first dose
Patient temperature should not exceed 37.8 � �C (100 � �F) at time of administration
Some products may contain sodium.
Refrigerate; do not freeze. Do not shake. Stable in Becton Dickinson syringe for 16 hours at room temperature or refrigeration.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Injection, solution:
Orthoclone OKT � � 3: 1 mg/mL (5 mL [DSC]) [contains polysorbate 80]
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; monitor for hypersensitivity
Note: Signs and symptoms of cytokine release syndrome (characterized by pyrexia, chills, dyspnea, nausea, vomiting, chest pain, diarrhea, tremor, wheezing, headache, tachycardia, rigor, hypertension, pulmonary edema and/or other cardiorespiratory manifestations) occurs in a significant proportion of patients following the first couple of doses of muromonab-CD3. See Warnings/Precautions. Additionally, some patients have experienced immediate hypersensitivity reactions to muromonab-CD3 (characterized by cardiovascular collapse, cardiorespiratory arrest, loss of consciousness, hypotension/shock, tachycardia, tingling, angioedema (including laryngeal, pharyngeal, or facial edema), airway obstruction, bronchospasm, dyspnea, urticaria, and/or pruritus) upon initial exposure and re-exposure.
>10%:
Cardiovascular: Tachycardia (26%), hypotension (25%), hypertension (19%), edema (12%)
Central nervous system: Pyrexia (77%), chills (43%), headache (28%)
Dermatologic: Rash (14%; erythematous 2%)
Gastrointestinal: Diarrhea (37%), nausea (32%), vomiting (25%)
Respiratory: Dyspnea (16%)
1% to 10%:
Cardiovascular: Chest pain (9%), vasodilation (7%), arrhythmia (4%), bradycardia (4%), vascular occlusion (2%)
Central nervous system: Fatigue (9%), confusion (6%), dizziness (6%), lethargy (6%), pain trunk (6%), malaise (5%), nervousness (5%), depression (3%), somnolence (2%), meningitis (1%), seizure (1%)
Dermatologic: Pruritus (7%)
Gastrointestinal: Gastrointestinal pain (7%), abdominal pain (6%), anorexia (4%)
Hematologic: Leukopenia (7%), anemia (2%), thrombocytopenia (2%), leukocytosis (1%)
Neuromuscular & skeletal: Weakness (10%), arthralgia (7%), myalgia (1%), tremor (14%)
Ocular: Photophobia (1%)
Otic: Tinnitus (1%)
Renal: Renal dysfunction (3%)
Respiratory: Abnormal chest sound (10%), hyperventilation (7%), wheezing (6%), respiratory congestion (4%), pulmonary edema (2%), hypoxia (1%), pneumonia (1%)
Miscellaneous: Diaphoresis (7%), infections (various)
<1% (Limited to important or life-threatening): ALT increased, AST increased, angina, anuria, apnea, cardiac arrest, coagulation disorder, coma, conjunctivitis, encephalopathy, epilepsy, GI hemorrhage, hallucinations, hearing decreased, heart failure, hepatitis, hypotonia, lymphadenopathy, lymphopenia, MI, mood changes, neoplasms (various), oliguria, paranoia, pneumonitis, psychosis, shock, thrombosis
Concerns related to adverse effects:
- Central nervous system events: Seizures, encephalopathy, cerebral edema, aseptic meningitis, and headache have been reported following muromonab-CD3. Contraindicated for use in patients with a history of seizures or those who are predisposed to seizures.
- Cytokine release syndrome (CRS): May occur in a significant proportion of patients following the first couple of doses of muromonab-CD3; symptoms usually begin 30-60 minutes after administration of dose and may persist for several hours; symptoms range from a mild, self-limiting "flu-like reaction " � to severe, life-threatening shock-like reaction. Signs and symptoms of CRS are characterized by pyrexia, chills, dyspnea, nausea, vomiting, chest pain, diarrhea, tremor, wheezing, headache, tachycardia, rigor, hypertension, pulmonary edema, and/or other cardiorespiratory manifestations. Patients at higher risk for serious complications include those with unstable angina, recent MI or ischemic heart disease, heart failure, pulmonary edema, COPD, intravascular volume overload or depletion, cerebrovascular disease, patients with advanced symptomatic vascular disease or neuropathy, history of seizures, and septic shock. Pretreatment with corticosteroids may decrease serum levels of cytokines and manifestations of the syndrome, but it is not known if this decreases organ damage and sequelae associated with it. Frequency and severity of this syndrome usually decreases with subsequent doses.
- Hypersensitivity/anaphylactoid reactions: [U.S. Boxed Warning]: Anaphylactic and anaphylactoid reactions may occur after administration of any dose of muromonab-CD3; acute hypersensitivity reactions may be characterized by cardiovascular collapse, cardiorespiratory arrest, loss of consciousness, shock, tachycardia, tingling, angioedema, airway obstruction, bronchospasm, dyspnea, urticaria, and pruritus. These reactions may be difficult to differentiate from the cytokine release syndrome associated with use; however, hypersensitivity reactions are more likely to occur within the first 10 minutes after administration.
- Immunosuppression: May result in an increased susceptibility to infection.
- Lymphoproliferative disorders: Risk of development of lymphoproliferative disorders (particularly of the skin) is increased. Patients should be monitored appropriately, instructed to limit exposure to sunlight/UV light, and given supportive treatment should these conditions occur.
- Pulmonary edema: Severe pulmonary edema has occurred in patients with fluid overload.
- Thrombosis: Arterial, venous, and capillary thrombosis of allografts and other vascular beds have been reported with use; use with caution in patients with history of thrombosis or underlying vascular disease.
Disease-related concerns:
- Fever: If the patients temperature is >37.8 � �C, reduce before administering OKT3.
Concurrent drug therapy issues:
- Other immunosuppressants: May result in an increased susceptibility to infection; dosage of concomitant immunosuppressants should be reduced during OKT3 therapy; cyclosporine should be decreased to 50% usual maintenance dose and maintenance therapy resumed about 4 days before stopping OKT3.
Others warnings/precautions:
- Appropriate use: 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.
- Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of a physician experienced in immunosuppressive therapy in a facility appropriate for monitoring and resuscitation. Cardiopulmonary resuscitation may be needed.
C
Reverses graft rejection by binding to T cells and interfering with their function by binding T-cell receptor-associated CD3 glycoprotein
Steady-state: Trough: 3-14 days
7 days after discontinuation
There may be a severe reaction to the first infusion of this medication. You may experience high fever, chills, respiratory difficulty, or congestion. Effects are substantially reduced with subsequent infusions. You will be susceptible to infection. You may experience dizziness, nausea, vomiting, sensitivity to direct sunlight, headache, fever, chills, rash, and diarrhea. Report chest pain or tightness, symptoms of infection, respiratory difficulty, vision change, swelling of the extremities, or weight gain.