OKT3

OKT3- muromonab-cd3 injection, solution
Centocor Ortho Biotech Products, L.P.

For Intravenous Use Only

WARNING

Only physicians experienced in immunosuppressive therapy and management of solid organ transplant patients should use ORTHOCLONE OKT3 (muromonab-CD3). Patients treated with ORTHOCLONE OKT3 must be managed in a facility equipped and staffed for cardiopulmonary resuscitation and where the patient can be closely monitored for an appropriate period based on his or her health status.

Anaphylactic and anaphylactoid reactions may occur following administration of any dose or course of ORTHOCLONE OKT3. In addition, serious, occasionally life-threatening or lethal, systemic, cardiovascular, and central nervous system reactions have been reported following administration of ORTHOCLONE OKT3. These have included: pulmonary edema, especially in patients with volume overload; shock, cardiovascular collapse, cardiac or respiratory arrest, seizures, coma, cerebral edema, cerebral herniation, blindness, and paralysis. Fluid status should be carefully monitored prior to and during ORTHOCLONE OKT3 administration. Pretreatment with methylprednisolone is recommended to minimize symptoms of Cytokine Release Syndrome. (See: WARNINGS: Cytokine Release Syndrome, Central Nervous System Events, Anaphylactic Reactions; DOSAGE AND ADMINISTRATION).

DESCRIPTION

ORTHOCLONE OKT3 (muromonab-CD3) Sterile Solution is a murine monoclonal antibody to the CD3 antigen of human T cells which functions as an immunosuppressant. It is for intravenous use only. The antibody is a biochemically purified IgG2a immunoglobulin with a heavy chain of approximately 50,000 daltons and a light chain of approximately 25,000 daltons. It is directed to a glycoprotein with a molecular weight of 20,000 in the human T cell surface which is essential for T cell functions. Because it is a monoclonal antibody preparation, ORTHOCLONE OKT3 Sterile Solution is a homogeneous, reproducible antibody product with consistent, measurable reactivity to human T cells.

Each 5 mL ampule of ORTHOCLONE OKT3 Sterile Solution contains 5 mg (1 mg/mL) of muromonab-CD3 in a clear colorless solution which may contain a few fine translucent protein particles. Each ampule contains a buffered solution (pH 7.0 ± 0.5) of monobasic sodium phosphate (2.25 mg), dibasic sodium phosphate (9.0 mg), sodium chloride (43 mg), and polysorbate 80 (1.0 mg) in water for injection.

The proper name, muromonab-CD3, is derived from the descriptive term murine monoclonal antibody. The CD3 designation identifies the specificity of the antibody as the Cell Differentiation (CD) cluster 3 defined by the First International Workshop on Human Leukocyte Differentiation Antigens.

CLINICAL PHARMACOLOGY

ORTHOCLONE OKT3 reverses graft rejection, probably by blocking the function of T cells which play a major role in acute allograft rejection. OTHOCLONE OKT3 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. In in vitro cytolytic assays, ORTHOCLONE OKT3 blocks both the generation and function of effector cells. Binding of ORTHOCLONE OKT3 to T lymphocytes results in early activation of T cells, which leads to cytokine release, followed by blocking T cell functions. After termination of ORTHOCLONE OKT3 therapy, T cell function usually returns to normal within one week.

In vivo , ORTHOCLONE OKT3 reacts with most peripheral blood T cells and T cells in body tissues, but has not been found to react with other hematopoietic elements or other tissues of the body.

A rapid and concomitant decrease in the number of circulating CD3 positive cells, including those that are CD2, CD4, or CD8 positive has been observed in patients studied within minutes after the administration of ORTHOCLONE OKT3. This decrease in the number of CD3 positive T cells results from the specific interaction between ORTHOCLONE OKT3 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 OKT3 administration. (See: WARNINGS: Cytokine Release Syndrome, Central Nervous System Events.)

While CD3 positive cells are not detectable between days two and seven, increasing numbers of circulating CD2, CD4, and CD8 positive cells have been observed. The presence of these CD2, CD4, and CD8 positive cells has not been shown to affect reversal of rejection. After termination of ORTHOCLONE OKT3 therapy, CD3 positive cells reappear rapidly and reach pre-treatment levels within a week. In some patients however, increasing numbers of CD3 positive cells have been observed prior to termination of ORTHOCLONE OKT3 therapy. This reappearance of CD3 positive cells has been attributed to the development of neutralizing antibodies to ORTHOCLONE OKT3, which in turn block its ability to bind to the CD3 antigen on T lymphocytes. (See: PRECAUTIONS: Sensitization.)

Pediatric patients are known to have higher CD3 lymphocyte counts than adults. Pediatric patients receiving ORTHOCLONE OKT® 3 therapy often require progressively higher doses of ORTHOCLONE OKT3 to achieve depletion of CD3 positive cells (<25 cells/mm3) and ensure therapeutic ORTHOCLONE OKT3 serum concentrations (>800 ng/mL). (See: DOSAGE AND ADMINISTRATION; PRECAUTIONS: Laboratory Tests.)

Serum levels of ORTHOCLONE OKT3 are measurable using an enzyme-linked immunosorbent assay (ELISA). During the initial clinical trials in renal allograft rejection, in patients treated with 5 mg per day for 14 days, mean serum trough levels of the drug rose over the first three days and then averaged 900 ng/mL on days 3 to 14. Serum concentrations measured daily during treatment with ORTHOCLONE OKT3 in renal, hepatic, and cardiac allograft recipients revealed that pediatric patients less than 10 years of age have higher levels than patients 10–50 years of age. Subsequent clinical experience has demonstrated that serum levels greater than or equal to 800 ng/mL of ORTHOCLONE OKT3 blocks the function of cytotoxic T cells in vitro and in vivo. Reduced T cell clearance or low plasma ORTHOCLONE OKT3 levels provide a basis for adjusting ORTHOCLONE OKT3 dosage or for discontinuing therapy. (See: WARNINGS: Anaphylactic Reactions; PRECAUTIONS: Laboratory Tests; ADVERSE EVENTS: Hypersensitivity Reactions; DOSAGE AND ADMINISTRATION.)

Following administration of ORTHOCLONE OKT3 in vivo , leukocytes have been observed in cerebrospinal and peritoneal fluids. The mechanism for this effect is not completely understood, but probably is related to cytokines altering membrane permeability, rather than an active inflammatory process. (See: WARNINGS: Cytokine Release Syndrome, Central Nervous System Events.)

CLINICAL STUDIES

Acute Renal Rejection

In a controlled randomized clinical trial, ORTHOCLONE OKT3 was compared with conventional high-dose steroid therapy in reversing acute renal allograft rejection. In this trial, 122 evaluable patients undergoing acute rejection of cadaveric renal transplants were treated either with ORTHOCLONE OKT3 daily for a mean of 14 days, with concomitant lowering of the dosage of azathioprine and maintenance steroids (62 patients), or with conventional high-dose steroids (60 patients). ORTHOCLONE OKT3 reversed 94% of the rejections compared to a 75% reversal rate obtained with conventional high-dose steroid treatment (p=0.006). The one year Kaplan-Meier (actuarial) estimates of graft survival rates for these patients who had acute rejection were 62% and 45% for ORTHOCLONE OKT3 and steroid-treated patients, respectively (p=0.04). At two years the rates were 56% and 42%, respectively (p=0.06).

One- and two-year patient survivals were not significantly different between the two groups, being 85% and 75% for ORTHOCLONE OKT3 treated patients and 90% and 85% for steroid-treated patients.

In additional open clinical trials, the observed rate of reversal of acute renal allograft rejection was 92% (n=126) for ORTHOCLONE OKT3 therapy. ORTHOCLONE OKT3 was also effective in reversing acute renal allograft rejections in 65% (n=225) of cases where steroids and lymphocyte immune globulin preparations were contraindicated or were not successful.

The effectiveness of ORTHOCLONE OKT3 for prophylaxis of renal allograft rejection has not been established.

Acute Cardiac or Hepatic Allograft Rejection

ORTHOCLONE OKT3 was studied for use in reversing acute cardiac and hepatic allograft rejection in patients who are unresponsive to high-doses of steroids. The rate of reversal in acute cardiac allograft rejection was 90% (n = 61) and was 83% for hepatic allograft rejection (n = 124) in patients unresponsive to treatment with steroids.

Controlled randomized trials have not been conducted to evaluate the effectiveness of ORTHOCLONE OKT3 compared to conventional therapy as first line treatment for acute cardiac and hepatic allograft rejection.

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