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LYMPHOCYTE IMMUNE GLOBULIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Lymphocyte immune globulins are immune suppressants that contain cytotoxic antibodies targeting antigens on T-lymphocytes.

Specific Substances

    A) ANTITHYMOCYTE GLOBULIN EQUINE
    1) Antilymphocyte immunoglobulin, horse
    2) Anti-thymocyte globulin equine
    3) Lymphocyte immune globulin
    4) ATC: L04AA03
    ANTITHYMOCYTE GLOBULIN RABBIT
    1) Antilymphocyte immunoglobulin, rabbit
    2) Anti-thymocyte globulin rabbit
    3) Rabbit ATG
    4) RATG - rabbit antithymocyte globulin
    5) ATC: L04AA04

Available Forms Sources

    A) FORMS
    1) ANTITHYMOCYTE GLOBULIN EQUINE
    a) Antithymocyte globulin equine is available in 5 mL ampules containing 50 mg horse gamma globulin/mL for intravenous administration (Prod Info Atgam(R) intravenous injection solution, 2014).
    2) ANTITHYMOCYTE GLOBULIN RABBIT
    a) Antithymocyte globulin rabbit is available in a 10 mL vial containing 25 mg antithymocyte globulin rabbit as a sterile, freeze-dried product for intravenous administration. Each 25 mg vial should be reconstituted with 5 mL SWFI to a concentration of 5 mg/mL (Prod Info Thymoglobulin(R) intravenous powder for injection, 2008).
    B) USES
    1) ANTITHYMOCYTE GLOBULIN EQUINE
    a) Antithymocyte globulin equine is indicated for the treatment of renal transplant rejection and as an adjunct to other immunosuppressive therapy in renal transplant rejection prophylaxis. In moderate to severe aplastic anemia, antithymocyte globulin equine is indicated in patients unsuitable for bone marrow transplant (Prod Info Atgam(R) intravenous injection solution, 2014).
    2) ANTITHYMOCYTE GLOBULIN RABBIT
    a) Antithymocyte globulin rabbit is indicated as an adjunct with other immunosuppression therapy for the treatment of renal transplant rejection (Prod Info Thymoglobulin(R) intravenous powder for injection, 2008).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Antithymocyte globulin equine is indicated for the treatment of renal transplant rejection and as an adjunct to other immunosuppressive therapy in renal transplant rejection prophylaxis. In moderate to severe aplastic anemia, antithymocyte globulin equine is indicated in patients unsuitable for bone marrow transplant. Antithymocyte globulin rabbit is indicated as an adjunct with other immunosuppression therapy for the treatment of renal transplant rejection.
    B) PHARMACOLOGY: The exact mechanism of immunosuppression is not fully understood. Antithymocyte globulins reduce the quantity of circulating T-lymphocytes, which are involved in cell-mediated and humoral immunity. Possible mechanisms include clearance of T-lymphocytes from circulation and alteration of T-lymphocyte activation, homing, and cytotoxic activities.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) The most common adverse reactions following administration of antithymocyte globulin equine or rabbit are fever, chills, thrombocytopenia, leukopenia, GI disturbances (eg, nausea, vomiting, diarrhea, abdominal pain), serum sickness due to the drug, and infection. Other effects include chest pain, hypertension, tachycardia, rash, pruritus, thyroid disorder, abnormal renal function, anaphylaxis, headache, sensory neuropathy, dyspnea, and acute lung injury.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. The signs and symptoms of an acute overdose are expected to be similar to excessive pharmacologic effects.
    0.2.20) REPRODUCTIVE
    A) Antithymocyte globulin equine and antithymocyte globulin rabbit are classified as FDA pregnancy category C. Animal reproduction data are lacking, and no studies have been conducted in pregnant or lactating women.
    0.2.21) CARCINOGENICITY
    A) Multiple myeloma and lymphomas have been reported in adult patients following therapy with equine and rabbit antithymocyte globulin, respectively.

Laboratory Monitoring

    A) Monitor vital signs, mental status, and renal function in symptomatic patients.
    B) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) Monitor CBC with differential and platelet count.
    D) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Myelosuppression has been reported. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg; filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding. For severe hypertension, nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    C) DECONTAMINATION
    1) Gastrointestinal decontamination is not recommended; administered via the parenteral route.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe respiratory distress.
    E) ANTIDOTE
    1) None.
    F) ACUTE LUNG INJURY
    1) Supplemental oxygen; PEEP and mechanical ventilation may be needed.
    G) PLASMAPHERESIS
    1) Plasmapheresis has been shown beneficial in the treatment of serum sickness secondary to antithymocyte globulin therapy.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    I) PITFALLS
    1) When managing a suspected overdose, the possibility of multidrug involvement should be considered.
    J) PHARMACOKINETICS
    1) Antithymocyte globulin equine: Tmax: Peak plasma levels are reached after 5 days of infusions of 10 mg/kg/day. Elimination half-life: about 6 days (range, 1.5 to 12 days); Antithymocyte globulin rabbit: Plasma levels persist for 2 months or longer after intravenous administration. Vd: 0.12 L/kg. Elimination half-life: about 30 days (range 14.3 to 45 days).
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression or serum sickness.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. A dose of 7000 mg antithymocyte globulin equine (7 times the recommended total dose) was administered to a renal transplant patient with no signs of acute intoxication.
    B) THERAPEUTIC DOSE: ANTITHYMOCYTE GLOBULIN EQUINE: Renal transplant rejection prophylaxis: 15 mg/kg/day IV for 14 days, then every other day for 14 more days for a total of 21 doses; 10 to 30 mg/kg/day has been used in adults. Renal transplant rejection: 10 to 15 mg/kg/day IV for 14 days, then every other day for 14 more days if needed up to 21 total doses; 10 to 30 mg/kg/day has been used in adults. Aplastic anemia: 10 to 20 mg/kg/day IV for 8 to 14 days, then every other day up to 21 total doses if needed. ANTITHYMOCYTE GLOBULIN RABBIT: Renal transplant rejection: 1.5 mg/kg/day IV for 7 to 14 days.

Clinical Effects

Summary Of Exposure

    A) USES: Antithymocyte globulin equine is indicated for the treatment of renal transplant rejection and as an adjunct to other immunosuppressive therapy in renal transplant rejection prophylaxis. In moderate to severe aplastic anemia, antithymocyte globulin equine is indicated in patients unsuitable for bone marrow transplant. Antithymocyte globulin rabbit is indicated as an adjunct with other immunosuppression therapy for the treatment of renal transplant rejection.
    B) PHARMACOLOGY: The exact mechanism of immunosuppression is not fully understood. Antithymocyte globulins reduce the quantity of circulating T-lymphocytes, which are involved in cell-mediated and humoral immunity. Possible mechanisms include clearance of T-lymphocytes from circulation and alteration of T-lymphocyte activation, homing, and cytotoxic activities.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) The most common adverse reactions following administration of antithymocyte globulin equine or rabbit are fever, chills, thrombocytopenia, leukopenia, GI disturbances (eg, nausea, vomiting, diarrhea, abdominal pain), serum sickness due to the drug, and infection. Other effects include chest pain, hypertension, tachycardia, rash, pruritus, thyroid disorder, abnormal renal function, anaphylaxis, headache, sensory neuropathy, dyspnea, and acute lung injury.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. The signs and symptoms of an acute overdose are expected to be similar to excessive pharmacologic effects.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) FEVER: Fever was reported in clinical trials of both antithymocyte globulin equine (51%) and antithymocyte globulin rabbit (63.4%) (Prod Info ATGAM(R) IV injection, 2005; Prod Info THYMOGLOBULIN(R) IV injection, 2006).
    2) CHILLS: Chills were reported in clinical trials of both antithymocyte globulin equine (16%) and antithymocyte globulin rabbit (57.3%) (Prod Info ATGAM(R) IV injection, 2005; Prod Info THYMOGLOBULIN(R) IV injection, 2006).

Heent

    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) ANTITHYMOCYTE GLOBULIN RABBIT
    a) CASE REPORT: A 26-year-old male developed sudden, almost total sensorineural hearing loss in both ears during the second day of therapy with antithymocyte globulin rabbit (300 mg/day) for acute renal transplant rejection. The patient received a total of 7 days of therapy, and hearing began to improve on the 11th day after the end of antithymocyte globulin rabbit therapy (Vural et al, 1995).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) ANTITHYMOCYTE GLOBULIN EQUINE
    1) Chest pain was reported in 5% to 10% of patients receiving antithymocyte globulin equine in postmarketing experience (Prod Info ATGAM(R) IV injection, 2005).
    B) HYPERTENSIVE DISORDER
    1) WITH THERAPEUTIC USE
    a) Hypertension was reported in clinical trials of both antithymocyte globulin equine (less than 5%) and antithymocyte globulin rabbit (36.6%) (Prod Info ATGAM(R) IV injection, 2005; Prod Info THYMOGLOBULIN(R) IV injection, 2006).
    C) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia was reported in clinical trials of both antithymocyte globulin equine (less than 5%) and antithymocyte globulin rabbit (26.8%) (Prod Info ATGAM(R) IV injection, 2005; Prod Info THYMOGLOBULIN(R) IV injection, 2006).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Dyspnea was reported in clinical trials of both antithymocyte globulin equine (5% to 10%) and antithymocyte globulin rabbit (28%) (Prod Info ATGAM(R) IV injection, 2005; Prod Info THYMOGLOBULIN(R) IV injection, 2006).
    B) ACUTE LUNG INJURY
    1) WITH THERAPEUTIC USE
    a) ANTITHYMOCYTE GLOBULIN EQUINE
    1) CASE REPORT: A 21-year-old renal transplant recipient developed acute lung injury approximately 5 hours after his second infusion of antilymphocyte globulin. Following supportive care, the patient was discharged symptom free (Dean et al, 1987).
    2) CASE REPORT: A 51-year-old cardiac transplant patient received antithymocyte globulin equine (8 mg/kg) immediately prior to transplant and therapy continued post-transplant. On post-operative day 2, the patient developed acute lung injury. Despite aggressive diuresis, the pulmonary edema worsened and noncardiogenic pulmonary edema secondary to antithymocyte globulin equine therapy was suspected. Treatment was discontinued, and a gradual resolution of symptoms was seen over the next 10 days (Murdock et al, 1987).
    3) CASE REPORT: A 57-year-old female with a history of metastatic breast cancer was diagnosed with aplastic anemia and treated with antithymocyte globulin equine (20 mg/kg/day). Approximately 3 hours following her second infusion, the patient complained of chills and fever. Her clinical status continued to deteriorate with dyspnea and hypertension consistent with acute lung injury. Despite diuresis and increased oxygen intake, the patient's condition worsened. The patient declined resuscitative measures and subsequently expired (Walton & Gualtieri, 1998).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) ANTITHYMOCYTE GLOBULIN RABBIT
    1) Headache was reported in clinical trials of antithymocyte globulin rabbit in 40.2% of patients (Prod Info THYMOGLOBULIN(R) IV injection, 2006).
    B) SENSORY NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) ANTITHYMOCYTE GLOBULIN RABBIT
    1) CASE REPORT: A 32-year-old renal transplant patient received antithymocyte globulin rabbit for acute transplant rejection and subsequently developed bilateral lower extremity neuropathy after the third dose. The patient was treated sparingly with narcotics for tingling pain on his feet. Within 2 days, the foot pain resolved and other symptoms improved over the following month (Cartwright et al, 2007).
    C) GUILLAIN-BARRé SYNDROME
    1) WITH THERAPEUTIC USE
    a) ANTITHYMOCYTE GLOBULIN EQUINE
    1) CASE REPORT: A 54-year-old female with severe aplastic anemia was treated with 5 days of antithymocyte globulin equine (15 mg/kg/day). During therapy, she developed serum sickness that was treated with hydrocortisone. Sixteen days after her treatment, the patient had lower limb weakness with absent reflexes, urinary retention, and sensory loss. The motor weakness progressed to her upper extremities over the next 24 hours, and nerve conduction studies were consistent with the diagnosis of Guillain-Barre syndrome. The patient made a slow recovery over weeks following intravenous immunoglobulin therapy (Kaya et al, 2005).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) ANTITHYMOCYTE GLOBULIN RABBIT
    1) Abdominal pain was reported in 37.8% of patients treated with antithymocyte globulin rabbit in clinical trials (Prod Info THYMOGLOBULIN(R) IV injection, 2006).
    2) WITH POISONING/EXPOSURE
    a) ANTITHYMOCYTE GLOBULIN RABBIT
    1) CASE REPORT: A 51-year-old female was treated with antithymocyte globulin rabbit at the time of kidney transplant (ordered dose of 2 mg/kg/day). The patient complained of abdominal pain consistent with appendicitis 28 hours after transplant. A laparotomy showed a normal appendix, but there was a retroperitoneal hematoma and a preperitoneal dissecting hematoma. By post-operative day 5, the patient was persistently febrile with a decreasing hematocrit and platelet count in addition to her abdominal pain. It was then discovered that the patient had received a 10 fold overdose of antithymocyte globulin rabbit on therapy days 1 and 2 (1000 mg versus 100 mg). Treatment was discontinued, and symptoms resolved by post-operative day 15 (Titiz et al, 1994).
    B) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting was reported in clinical trials of both antithymocyte globulin equine (5% to 10%) and antithymocyte globulin rabbit (36.6%) (Prod Info ATGAM(R) IV injection, 2005; Prod Info THYMOGLOBULIN(R) IV injection, 2006).
    C) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea was reported in clinical trials of both antithymocyte globulin equine (5% to 10%) and antithymocyte globulin rabbit (36.6%) (Prod Info ATGAM(R) IV injection, 2005; Prod Info THYMOGLOBULIN(R) IV injection, 2006).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RENAL FUNCTION TESTS ABNORMAL
    1) WITH THERAPEUTIC USE
    a) ANTITHYMOCYTE GLOBULIN EQUINE
    1) In postmarketing experience, abnormal renal function tests were reported in 5% to 10% of patients receiving antithymocyte globulin equine (Prod Info ATGAM(R) IV injection, 2005).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia was reported in clinical trials of both antithymocyte globulin equine (30%) and antithymocyte globulin rabbit (36.6%) (Prod Info ATGAM(R) IV injection, 2005; Prod Info THYMOGLOBULIN(R) IV injection, 2006).
    B) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia was reported in clinical trials of both antithymocyte globulin equine (14%) and antithymocyte globulin rabbit (57.3%) (Prod Info ATGAM(R) IV injection, 2005; Prod Info THYMOGLOBULIN(R) IV injection, 2006).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rash was reported in 27% of patients treated with antithymocyte globulin equine in postmarketing experience (Prod Info ATGAM(R) IV injection, 2005).
    b) Rash and pruritus were occasionally reported in patients treated with antithymocyte globulin rabbit (Soulillou et al, 1990; Copeland et al, 1990).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) DISORDER OF THYROID GLAND
    1) WITH THERAPEUTIC USE
    a) ANTITHYMOCYTE GLOBULIN EQUINE
    1) CASE REPORT: A 25-year-old patient developed Graves' disease approximately 26 months after successful treatment of severe aplastic anemia with antithymocyte globulin equine (Todd & Todd, 1999).
    b) ANTITHYMOCYTE GLOBULIN RABBIT
    1) CASE REPORT: A 55-year-old female with a history of type I diabetes and Hashimoto's thyroiditis, was found unresponsive at home. In the previous 2 years, she received a kidney transplant and was treated with antithymocyte globulin rabbit. Her immunosuppression regimen following transplant was steroid free. Upon admit, all metabolic, infectious, and structural causes were ruled out, but the patient did have elevated antithyroid peroxidase antibodies (448 International Units/mL; reference range = 0-60 International Units/mL). This finding along with the patient's encephalopathy met criteria for diagnosis of Hashimoto's encephalopathy. Following aggressive steroid therapy, the patient resumed full cognitive and neurologic function on day 24. The authors speculate that the use of antithymocyte globulin followed by maintenance without steroids or calcineurin inhibitors may facilitate expansion of self-reactive T-lymphocytes, thus increasing the possibility of autoimmune diseases (Stevens et al, 2008).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLAXIS
    1) WITH THERAPEUTIC USE
    a) Anaphylaxis was rarely reported in clinical trials of both antithymocyte globulin equine and antithymocyte globulin rabbit (Prod Info ATGAM(R) IV injection, 2005; Prod Info THYMOGLOBULIN(R) IV injection, 2006).
    B) SERUM SICKNESS DUE TO DRUG
    1) WITH THERAPEUTIC USE
    a) ANTITHYMOCYTE GLOBULIN EQUINE
    1) In postmarketing experience, serum sickness was reported in 5% to 10% of patients receiving antithymocyte globulin equine (Prod Info ATGAM(R) IV injection, 2005).
    2) CASE REPORT: A 13-year-old male with aplastic anemia was admitted and began therapy with antithymocyte globulin equine. After 4 doses, the patient became febrile and hypotensive with joint swelling in his hands and extremity petechia. He also developed a large bruise on his lower abdomen after 3 days. The symptoms were consistent with serum sickness, and therapy was discontinued. All symptoms gradually resolved following treatment with steroids, antihistamines, and antipyretics (Nabavizadeh et al, 2006).
    b) ANTITHYMOCYTE GLOBULIN RABBIT
    1) CASE REPORT: A renal transplant patient received a 7 day treatment of antithymocyte globulin rabbit (1.5 mg/kg/day) for acute transplant rejection. The patient presented one week following treatment with myalgias, back pain, muscle weakness, arthralgias, and descending paralysis. Her symptoms were diagnosed as serum sickness. Plasmapheresis was initiated, and the patient had immediate joint pain relief as well as extremity weakness improvement. The patient received a total of 2 plasmapheresis sessions, and at 1 week follow-up, the patient had full resolution of all symptoms (Pham et al, 2007).

Reproductive

    3.20.1) SUMMARY
    A) Antithymocyte globulin equine and antithymocyte globulin rabbit are classified as FDA pregnancy category C. Animal reproduction data are lacking, and no studies have been conducted in pregnant or lactating women.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) No data are currently available to assess the teratogenic potential of antithymocyte globulin equine or antithymocyte globulin rabbit (Prod Info ATGAM(R) IV injection, 2005; Prod Info THYMOGLOBULIN(R) IV injection, 2006).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) No data are currently available to assess the potential effects of exposure to antithymocyte globulin equine or antithymocyte globulin rabbit during pregnancy in humans (Prod Info ATGAM(R) IV injection, 2005; Prod Info THYMOGLOBULIN(R) IV injection, 2006).
    B) PREGNANCY CATEGORY
    1) The manufacturers have classified antithymocyte globulin equine and antithymocyte globulin rabbit as FDA pregnancy category C (Prod Info ATGAM(R) IV injection, 2005; Prod Info THYMOGLOBULIN(R) IV injection, 2006).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is not known if antithymocyte globulin equine or antithymocyte globulin rabbit are excreted into human milk, and there is insufficient clinical experience to confirm the safety in nursing women (Prod Info ATGAM(R) IV injection, 2005; Prod Info THYMOGLOBULIN(R) IV injection, 2006).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Multiple myeloma and lymphomas have been reported in adult patients following therapy with equine and rabbit antithymocyte globulin, respectively.
    3.21.3) HUMAN STUDIES
    A) NEOPLASM
    1) ANTITHYMOCYTE GLOBULIN EQUINE
    a) CASE REPORT: A 63-year-old male diagnosed with aplastic anemia received an 8 day course of antithymocyte globulin equine (1580 mg/day). The patient required repeat treatment 5 months later, which was successful. Approximately 5 months following the second round of therapy, the patient presented with renal insufficiency, epistaxis, hypercalcemia; a bone marrow biopsy showed neoplastic plasma cells. A diagnosis of IgA multiple myeloma was made, and the patient expired 2 months later from sepsis despite aggressive treatment (Beyer et al, 1986).
    2) ANTITHYMOCYTE GLOBULIN RABBIT
    a) CASE SERIES: A group of 323 renal transplant patients received antithymocyte globulin rabbit as part of their immunosuppressive regimen and were followed for 10 years for malignancy incidence. The overall incidence of tumors was 16 of 323 (5%) patients, and this was not significantly different compared to the control group (18 of 298 (6%) patients) who did not receive antithymocyte globulin rabbit as part of their immunosuppressive regimen. There was a significantly higher incidence of lymphomas in the treatment group (37.5% versus 5.5% [p < 0.05]), and an earlier occurrence of tumors in the treatment group (Luciani et al, 1993).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs, mental status, and renal function in symptomatic patients.
    B) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) Monitor CBC with differential and platelet count.
    D) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with severe symptoms despite treatment should be admitted.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) Monitor vital signs, mental status, and renal function in symptomatic patients.
    B) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) Monitor CBC with differential and platelet count.
    D) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not recommended; administered via the parenteral route.

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. A dose of 7000 mg antithymocyte globulin equine (7 times the recommended total dose) was administered to a renal transplant patient with no signs of acute intoxication.
    B) THERAPEUTIC DOSE: ANTITHYMOCYTE GLOBULIN EQUINE: Renal transplant rejection prophylaxis: 15 mg/kg/day IV for 14 days, then every other day for 14 more days for a total of 21 doses; 10 to 30 mg/kg/day has been used in adults. Renal transplant rejection: 10 to 15 mg/kg/day IV for 14 days, then every other day for 14 more days if needed up to 21 total doses; 10 to 30 mg/kg/day has been used in adults. Aplastic anemia: 10 to 20 mg/kg/day IV for 8 to 14 days, then every other day up to 21 total doses if needed. ANTITHYMOCYTE GLOBULIN RABBIT: Renal transplant rejection: 1.5 mg/kg/day IV for 7 to 14 days.

Therapeutic Dose

    7.2.1) ADULT
    A) ANTITHYMOCYTE GLOBULIN EQUINE
    1) RENAL TRANSPLANT REJECTION PROPHYLAXIS: 15 mg/kg/day IV for 14 days, then every other day for 14 more days for a total of 21 doses. The first dose should be administered within 24 hours before or after transplant; 10 to 30 mg/kg/day has been used in adults (Prod Info Atgam(R) intravenous injection solution, 2014).
    2) RENAL TRANSPLANT REJECTION: 10 to 15 mg/kg/day IV for 14 days, then every other day for 14 more days if needed up to 21 total doses; 10 to 30 mg/kg/day has been used in adults (Prod Info Atgam(R) intravenous injection solution, 2014).
    3) APLASTIC ANEMIA: 10 to 20 mg/kg/day IV for 8 to 14 days, then every other day for up to 21 total doses if needed (Prod Info Atgam(R) intravenous injection solution, 2014).
    B) ANTITHYMOCYTE GLOBULIN RABBIT
    1) RENAL TRANSPLANT REJECTION: 1.5 mg/kg/day IV for 7 to 14 days (Prod Info Thymoglobulin(R) intravenous powder for injection, 2008).
    2) All infusions should be administered through an in-line 0.22 micron filter. The first dose should be infused over at least 6 hours, and all subsequent doses should be infused over a minimum of 4 hours (Prod Info Thymoglobulin(R) intravenous powder for injection, 2008).
    7.2.2) PEDIATRIC
    A) ANTITHYMOCYTE GLOBULIN EQUINE
    1) RENAL TRANSPLANT REJECTION PROPHYLAXIS: Data are limited; 15 mg/kg/day IV for 14 days, then every other day for 14 more days for a total of 21 doses. The first dose should be administered within 24 hours before or after transplant; 5 to 25 mg/kg/day has been used in some pediatric patients (Prod Info Atgam(R) intravenous injection solution, 2014).
    2) RENAL TRANSPLANT REJECTIONS: Data are limited; 10 to 15 mg/kg/day IV for 14 days, then every other day for 14 more days if needed up to 21 total doses; 5 to 25 mg/kg/day has been used in some pediatric patients (Prod Info Atgam(R) intravenous injection solution, 2014).
    3) APLASTIC ANEMIA: Data are limited; 10 to 20 mg/kg/day IV for 8 to 14 days, then every other day up to 21 total doses if needed (Prod Info Atgam(R) intravenous injection solution, 2014)
    B) ANTITHYMOCYTE GLOBULIN RABBIT
    1) Safety and efficacy in the pediatric population have not been established (Prod Info Thymoglobulin(R) intravenous powder for injection, 2008).

Maximum Tolerated Exposure

    A) A dose of 7000 mg antithymocyte globulin equine (7 times the recommended total dose) was administered to a renal transplant patient with no signs of acute intoxication (Prod Info ATGAM(R) IV injection, 2005).
    B) Some renal transplant patients have received up to 50 doses (10 to 20 mg/kg/dose) of antithymocyte globulin equine in 4 months, and there are other reports of patients receiving 3 or more 28-day courses. None of these regimens resulted in increased toxicity (Prod Info ATGAM(R) IV injection, 2005).
    C) CASE REPORT: A 51-year-old woman was treated with antithymocyte globulin rabbit at the time of kidney transplant (ordered dose of 2 mg/kg/day). The patient complained of abdominal pain consistent with appendicitis 28 hours after transplant. A laparotomy showed a normal appendix, but there was a retroperitoneal hematoma and a preperitoneal dissecting hematoma. By post-operative day 5, the patient was persistently febrile with a decreasing hematocrit and platelet count in addition to her abdominal pain. It was then discovered that the patient had received a 10 fold overdose of antithymocyte globulin rabbit on therapy days 1 and 2 (1000 mg versus 100 mg). Treatment was discontinued, and symptoms resolved by post-operative day 15 (Titiz et al, 1994).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The exact mechanism of immunosuppression is not fully understood. Antithymocyte globulins reduce the quantity of circulating T-lymphocytes, which are involved in cell-mediated and humoral immunity. Possible mechanisms include clearance of T-lymphocytes from circulation and alteration of T-lymphocyte activation, homing, and cytotoxic activities (Prod Info ATGAM(R) IV injection, 2005; Prod Info THYMOGLOBULIN(R) IV injection, 2006).

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