ATGAM- equine thymocyte immune globulin injection, solution
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Patient Information

Advise patients receiving ATGAM that they will be monitored in a facility equipped and staffed with adequate laboratory and supportive medical resources.

Inform patients that ATGAM may cause serious allergic reactions, infection or abnormal liver or renal function.

Serious Allergic Reactions

• Advise the patient to discontinue ATGAM and seek immediate medical attention if any signs/symptoms of an allergic or immune reaction occur[seeWarnings and Precautions (5.1)].

Skin Testing

• Despite screening and testing, products manufactured using components of human blood such as ATGAM may carry a risk of transmitting infectious agents (e.g., viruses). Discuss the risks and benefits of therapy with patients before initiating treatment[seeWarnings and Precautions (5.2)].

Infections

• Advise the patient to discontinue ATGAM and report any sign/symptoms of leukopenia, thrombocytopenia, or infection (e.g., fever, sweating, chills, muscle aches, cough, shortness of breath, diarrhea or stomach pain)[seeWarnings and Precautions (5.1),(5.2),(6)].

Healthcare providers should refer to labels.fda.gov or DailyMed for the most updated version of the labeling.

This product's label may have been updated. For full prescribing information, please visit www.pfizer.com.

U.S. Govt. License No. 1216

LAB-0019-8.0

1. Highlights Of Prescribing Information
2. Warning: Anaphylaxis
3. See Full Prescribing Information For Complete Boxed Warning.
4. Indications And Usage
5. Dosage And Administration
6. Dosage Forms And Strengths
7. Contraindications
8. Warnings And Precautions
9. Adverse Reactions
10. Drug Interactions
11. Use In Specific Populations
12. 1 Indications And Usage
13. 2 Dosage And Administration
14. 3 Dosage Forms And Strengths
15. 4 Contraindications
16. 5 Warnings And Precautions
17. 6 Adverse Reactions
18. 7 Drug Interactions
19. 8 Use In Specific Populations
20. 10 Overdosage
21. 11 Description
22. 12 Clinical Pharmacology
23. 13 Nonclinical Toxicology
24. 14 Clinical Studies
25. 15 References
26. 16 How Supplied/storage And Handling
27. Principal Display Panel - 5 Ml Ampule Label
28. Principal Display Panel - 5 Ml Ampule Carton

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use ATGAM safely and effectively. See full prescribing information for ATGAM.

ATGAM (lymphocyte immune globulin, anti-thymocyte globulin [equine]), sterile solution for intravenous use only
Initial U.S. Approval: 1981

Warning: Anaphylaxis ⮝

Antithymocyte globulins can cause anaphylaxis when injected intravenously. Although ATGAM is processed to reduce the level of antibodies that will react to non-T cells, physicians should be prepared for the potential risk of anaphylaxis and monitor patients for signs and symptoms during infusion.

See Full Prescribing Information For Complete Boxed Warning.  ⮝

Antithymocyte globulins can cause anaphylaxis when injected intravenously. Although ATGAM is processed to reduce the level of antibodies that will react to non-T cells, physicians should be prepared for the potential risk of anaphylaxis and monitor patients for signs and symptoms during infusion.

Indications And Usage ⮝

ATGAM is an immunoglobulin G indicated for:

• Renal transplant rejection. (1.1)
• Aplastic anemia (moderate to severe) in patients unsuitable for bone marrow transplantation. (1.2)
• Limitations of Use: The usefulness of ATGAM has not been demonstrated in patients with aplastic anemia who are suitable candidates for bone marrow transplantation or in patients with aplastic anemia secondary to neoplastic disease, storage disease, myelofibrosis, Fanconi's syndrome, or in patients known to have been exposed to myelotoxic agents or radiation. (1.2)

Dosage And Administration ⮝

Intravenous use only.

Indication	Dosage
Renal transplant rejection	10 to 15 mg/kg daily intravenously for 14 days; additional alternate-day therapy up to a total of 21 doses may be given. (2.1)
Aplastic anemia	10 to 20 mg/kg daily intravenously for 8 to 14 days; additional alternate-day therapy up to a total of 21 doses may be given. (2.1)

Dosage Forms And Strengths ⮝

• ATGAM 50 mg/mL concentrate for solution for infusion. (3)

Contraindications ⮝

• Systemic reaction (e.g., anaphylactic reaction) during prior administration of ATGAM or any other equine gamma globulin preparation. (4)

Warnings And Precautions ⮝

• Discontinue ATGAM if anaphylaxis occurs. (5.1)
• Serious immune-mediated reactions, including anaphylaxis, have been reported. To identify those at greatest risk, skin testing before treatment is strongly recommended. (5.1)
• Monitor patients for concurrent infection, including cytomegalovirus. (5.2)
• Do not administer live vaccines to patients about to receive, receiving, or after treatment with ATGAM due to a potential of uncontrolled viral replication in the immunosuppressed patient. (5.3)

Adverse Reactions ⮝

The most common (>10%) adverse reactions are pyrexia, chills, rash, thrombocytopenia, leukopenia and arthralgia. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions ⮝

• Previously masked reactions to ATGAM may appear following reduced doses of immunosuppressants. (7)

Use In Specific Populations ⮝

• Pregnancy: Use only if the potential benefit justifies the risk. (8.1)
• Nursing Mothers: Discontinue nursing when administering ATGAM. (8.3)
• Geriatric: Start dosing at the low end of the dosage range. (8.5)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 5/2018

1 Indications And Usage ⮝

1.1 Renal Allograft Rejection

Renal transplant rejection: ATGAM is indicated for the management of allograft rejection in renal transplant patients; when administered with conventional therapy at the time of rejection ATGAM increases the frequency of resolution of the acute rejection episode [see Clinical Studies (14.1)].

1.2 Aplastic Anemia

ATGAM is indicated for the treatment of moderate to severe aplastic anemia in patients unsuitable for bone marrow transplantation [see Clinical Studies (14.2)].

The usefulness of ATGAM has not been demonstrated in patients with aplastic anemia who are suitable candidates for bone marrow transplantation or in patients with aplastic anemia secondary to neoplastic disease, storage disease, myelofibrosis, Fanconi's syndrome, or in patients known to have been exposed to myelotoxic agents or radiation.

2 Dosage And Administration ⮝

ATGAM is intended for intravenous use only.

ATGAM is used with concomitant immunosuppressants. During repeat courses of ATGAM, observe patients for signs of allergic reactions [see Warnings and Precautions (5.1)].

2.1 Dose

Renal Allograft Recipients

• Renal transplant rejection: The recommended dose is 10 to 15 mg/kg daily intravenously for 14 days. Additional alternate-day therapy up to a total of 21 doses may be given.

Aplastic Anemia (Moderate to Severe)

The recommended dose is 10 to 20 mg/kg daily intravenously for 8 to 14 days. Additional alternate-day therapy up to a total of 21 doses may be given. Because thrombocytopenia can be associated with the administration of ATGAM, patients receiving it for the treatment of aplastic anemia may need prophylactic platelet transfusions to maintain platelets at clinically acceptable levels.

Geriatric population ( 65 years of age)

Select the dose for an elderly patient with caution, starting at the low end of the dosage range [see Use in Specific Populations (8.5)].

2.2 Preparation and Administration

Preparation of Solution

• Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. However, because ATGAM is a gamma globulin product, it can be transparent to slightly opalescent, colorless to faintly pink or brown, and may develop a slight granular or flaky deposit during storage. Do not shake ATGAM (diluted or undiluted) because excessive foaming and/or denaturation of the protein may occur.
• Dilute ATGAM for intravenous infusion in an inverted bottle of sterile vehicle so the undiluted ATGAM does not contact the air inside. Add the total daily dose of ATGAM to the sterile vehicle (see Compatibility and Stability). Do not exceed a concentration of 4 mg of ATGAM per mL. Gently rotate or swirl the diluted solution to effect thorough mixing.

Administration

• Allow the diluted ATGAM to reach room temperature before infusion. ATGAM is appropriately administered into a vascular shunt, arterial venous fistula, or a high-flow central vein using an in-line filter with a pore size of 0.2 to 1.0 micron. Use the in-line filter with all infusions of ATGAM to prevent the administration of any insoluble material that may develop in the product during storage. Use high-flow veins to minimize the occurrence of phlebitis and thrombosis. Do not infuse a dose of ATGAM in less than 4 hours. Always keep appropriate resuscitation equipment at the patient's bedside while ATGAM is being administered. Observe the patient continuously for possible allergic reactions throughout the infusions [see Warnings and Precautions (5.1) and Adverse Reactions (6)].

Compatibility and Stability

• Once diluted, ATGAM has been shown to be physically and chemically stable for up to 24 hours at concentrations of up to 4 mg per mL in the following diluents: 0.9% Sodium Chloride Injection, 5% Dextrose and 0.225% Sodium Chloride Injection, and 5% Dextrose and 0.45% Sodium Chloride Injection.
• Do not dilute ATGAM in Dextrose Injection, USP, as low salt concentrations may cause precipitation. Do not use highly acidic infusion solutions since these solutions may contribute to physical instability over time.
• Store diluted ATGAM in a refrigerator if it is prepared prior to the time of infusion. Even if it is stored in a refrigerator, do not exceed a total time in dilution of 24 hours (including infusion time).

3 Dosage Forms And Strengths ⮝

ATGAM 50 mg/mL concentrate for solution for infusion

4 Contraindications ⮝

Do not administer ATGAM to a patient who has had a systemic reaction (e.g., anaphylactic reaction) during prior administration of ATGAM or any other equine gamma globulin preparation [see Warnings and Precautions (5.1)].

5 Warnings And Precautions ⮝

5.1 Hypersensitivity

Serious immune-mediated reactions have been reported with the use of ATGAM. Clinical signs associated with anaphylaxis, other infusion associated reactions, and serum sickness have been reported.

Discontinue ATGAM if anaphylaxis occurs. A systemic reaction such as a generalized rash, tachycardia, dyspnea, hypotension, or anaphylaxis precludes any additional administration of ATGAM.

Skin Testing

To identify those at greatest risk of systemic anaphylaxis, skin testing potential recipients is strongly recommended before commencing treatment. A conservative, conventional approach would first employ epicutaneous (prick) testing with undiluted ATGAM. If the subject does not show a wheal ten minutes after pricking, proceed to intradermal testing with 0.02 mL of a 1:1000 v/v (volume/volume) saline dilution of ATGAM with a separate saline control injection of similar volume. Read the result at 10 minutes: a wheal at the ATGAM site 3 or more mm larger in diameter than that at the saline control site (or a positive prick test) suggests clinical sensitivity and an increased possibility of a systemic allergic reaction should the drug be dosed intravenously.

The predictive value of this test has not been proven clinically. Allergic reactions such as anaphylaxis have occurred in patients whose skin test is negative. Also, skin testing done as described above will not predict for later development of serum sickness. In the presence of a locally positive skin test to ATGAM, serious consideration to alternative forms of therapy should be given. The risk to benefit ratio must be weighed. If therapy with ATGAM is deemed appropriate following a locally positive skin test, treatment should be administered in a setting where intensive life support facilities are immediately available and a physician familiar with the treatment of potentially life threatening allergic reactions is in attendance.

5.2 Transmissible Infectious Agents

Because ATGAM is made from equine and human blood components, it may carry a risk of transmitting infectious agents, e.g., viruses, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

No cases of transmission of viral diseases or CJD have been associated with the use of ATGAM.

All infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Pfizer, Inc. at 1-800-438-1985.

Monitor patients for concurrent infection. Some studies have suggested an increase in the incidence of cytomegalovirus infection in patients receiving ATGAM.

5.3 Immunizations

Do not administer live vaccines to patients about to receive, receiving, or after treatment with ATGAM. Concomitant administration of ATGAM with live virus vaccines carries a potential of uncontrolled viral replication in the immunosuppressed patient. There is insufficient information to fully define the extent of the risk, or the period of time during which the risk exists. If administered, live viruses may interfere with ATGAM treatment.

5.4 Hepatic and Renal Function Tests

In patients with aplastic anemia and other hematologic abnormalities who have received ATGAM, abnormal tests of liver function (SGOT, SGPT, alkaline phosphatase) and renal function (serum creatinine) have been observed.

6 Adverse Reactions ⮝

The most clinically significant adverse reactions are anaphylaxis, infection, thrombocytopenia, leukopenia, arthralgia, edema, bradycardia, and abnormal renal and liver function tests.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of ATGAM has been evaluated in 367 patients with renal transplant and 109 patients with aplastic anemia.

The renal transplantation and aplastic anemia patients received a similar dosing regimen, and these data were pooled to obtain the frequencies listed in Tables 1 and 2 below.

The most commonly reported adverse reactions (occurring in greater than 10% of patients) are pyrexia, chills, rash, thrombocytopenia, leukopenia and arthralgia.

Table 1. Adverse Reactions Occurring in 1% of Patients who Received ATGAM

Adverse Reaction*,	ATGAM
	Frequency (%)
	(N = 476)
* Percentages are treatment-emergent all-causality events Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms
Pyrexia	39.5
Chills	26.5
Rash	25.6
Thrombocytopenia	21.6
Leukopenia	17.9
Arthralgia	17.2
Urticaria	9.2
Headache	5.3
Pruritus	4.6
Nausea	4.2
Infection	3.4
Vomiting	3.4
Thrombophlebitis	3.2
Hypertension	2.9
Hypotension	2.9
Diarrhea	2.9
Abdominal pain upper	2.7
Chest pain	2.7
Infusion site pain	2.1
Edema	2.1
Bradycardia	1.5
Back pain	1.5
Lymphadenopathy	1.3
Arteriovenous fistula thrombosis	1.3
Dizziness	1.1
Dyspnea	1.1
Tachycardia	1.1
Liver function test abnormal	1.0

Table 2. Adverse Reactions Occurring in <1% of Patients who Received ATGAM

Adverse Reaction*,	ATGAM
	Frequency (%)
	(N = 476)
* Percentages are treatment-emergent all-causality events Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms
Convulsion	0.8
Pleural effusion	0.8
Night sweats	0.8
Serum sickness	0.6
Hyperglycemia	0.6
Stomatitis	0.6
Renal function test abnormal	0.6
Herpes simplex	0.4
Agitation	0.4
Hiccups	0.4
Proteinuria	0.4
Asthenia	0.4
Malaise	0.4
Wound dehiscence	0.4
Anaphylactic reaction	0.2
Encephalitis	0.2
Paresthesia	0.2
Renal artery thrombosis	0.2
Iliac vein occlusion	0.2
Laryngospasm	0.2
Pulmonary edema	0.2
Dermatitis allergic	0.2
Periorbital edema	0.2
Toxic epidermal necrolysis	0.2

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post approval use of ATGAM. Because reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Infections and infestations: Hepatitis viral, Localized infection, Systemic infection

Blood and lymphatic system disorders: Anemia, Eosinophilia, Granulocytopenia, Hemolysis, Hemolytic anemia, Neutropenia, Pancytopenia

Psychiatric disorders: Confusional state, Disorientation

Nervous system disorders: Dyskinesia, Syncope, Tremor

Cardiac disorders: Cardiac failure congestive

Vascular disorders: Deep vein thrombosis, Vasculitis

Respiratory, thoracic and mediastinal disorders: Apnea, Cough, Epistaxis, Oropharyngeal pain

Gastrointestinal disorders: Abdominal pain, Gastrointestinal hemorrhage, Gastrointestinal perforation, Oral pain

Skin and subcutaneous tissue disorders: Hyperhidrosis

Musculoskeletal and connective tissue disorders: Flank pain, Muscle rigidity, Myalgia, Pain in extremity

Renal and urinary disorders: Kidney enlargement, Kidney rupture, Renal failure acute

Congenital, familial and genetic disorders: Aplasia

General disorders and administration site conditions: Infusion site erythema, Infusion site swelling, Pain

7 Drug Interactions ⮝

Previously masked reactions to ATGAM may appear when the dose of corticosteroids and other immunosuppressants is being reduced.

8 Use In Specific Populations ⮝

8.1 Pregnancy

ATGAM was not teratogenic in rats or monkeys at a dose up to 20 mg/kg. However, 20 mg/kg/day ATGAM for 16 days during organogenesis in cynomolgus monkeys was fetotoxic. No fetal or maternal toxicity was seen with 10 mg/kg/day ATGAM administered for 16 days during organogenesis [see Nonclinical Toxicology (13.1)].

There are no adequate and well-controlled studies in pregnant women. It is also not known whether ATGAM can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.

ATGAM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

In animal studies, a single dose of ATGAM up to 40 mg/kg was not detected at the limit of quantification in the milk of lactating cynomolgus monkeys. It is not known whether ATGAM is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing neonates and infants from ATGAM, a decision should be made whether to discontinue nursing or to discontinue the drug taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Experience with children has been limited. ATGAM has been administered safely to a small number of pediatric renal allograft recipients and pediatric aplastic anemia patients at dosage levels comparable to those in adults.

8.5 Geriatric Use

Clinical experience in a limited number of elderly patients ( 65 years of age) has not identified differences in responses between the elderly and younger patients. The dose for an elderly patient should be selected with caution, starting at the low end of the dosage range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in this age group.

10 Overdosage ⮝

The maximum tolerated dose of ATGAM Sterile Solution would be expected to vary from patient to patient due to the biological nature of the product. The largest single daily dose known to be administered to a patient (renal transplant recipient) was 7,000 mg administered at a concentration of approximately 10 mg/mL Sodium Chloride Injection, USP, seven times the recommended total dose and infusion concentration. In this patient, the administration of ATGAM was not associated with any signs of acute intoxication or late sequelae.

A maximum therapeutic dose has not been established therefore the definition of overdose for ATGAM has not been clearly defined. Some renal transplant patients have received up to 50 doses in 4 months, and others have received 28-day courses of 21 doses followed by as many as 3 more courses for the treatment of acute rejection. The incidence of toxicologic manifestations did not increase with any of these regimens; however, close monitoring of the patient is recommended.

11 Description ⮝

ATGAM Sterile Solution contains lymphocyte immune globulin, anti-thymocyte globulin [equine]. It is the purified, concentrated, and sterile gamma globulin, primarily monomeric IgG, from hyperimmune serum of horses immunized with human thymus lymphocytes. ATGAM is a transparent to slightly opalescent aqueous protein solution. It may appear colorless to faintly pink or brown and is nearly odorless. It may develop a slight granular or flaky deposit during storage [see Dosage and Administration (2.2)].

Precise methods of determining the potency of ATGAM have not been established, thus activity may potentially vary from lot to lot. Before release for clinical use, each lot of ATGAM is tested to assure its ability to inhibit rosette formation between human peripheral lymphocytes and sheep red blood cells in vitro. In each lot, antibody activity against human red blood cells and platelets is also measured and determined to be within acceptable limits. Only lots that meet the acceptance criteria for pyrogens and test negative for antihuman serum protein antibody and antiglomerular basement membrane antibody are released.

Each milliliter of ATGAM contains 50 mg of horse gamma globulin stabilized in 0.3 molar glycine to a pH of approximately 6.8.

12 Clinical Pharmacology ⮝

12.1 Mechanism of Action

ATGAM is composed of antibodies that bind a wide variety of proteins on the surface of lymphocytes. In addition, ATGAM binds to granulocytes, platelets, bone marrow cells, and other cell types. The mechanism of ATGAM-induced immunosuppression has not been determined. Published data indicate that the primary mechanism is the depletion of circulating lymphocytes, with greatest effect on T lymphocytes. Lymphocyte depletion may be caused by complement dependent lysis and/or activation-induced apoptosis. In addition, immunosuppression may be mediated by the binding of antibodies to lymphocytes which results in partial activation and induction of T lymphocyte anergy.

The mechanism of ATGAM therapy for aplastic anemia is attributed to its immunosuppressive actions. In addition, ATGAM directly stimulates the growth of hematopoietic stem cells and release of hematopoietic growth factors such as interleukin-3 and granulocyte/macrophage colony stimulating factor.

12.3 Pharmacokinetics

Distribution

During infusion of 10 to 15 mg/kg/day, the mean peak value (n = 27 renal transplant patients) was found to be 727 310 g/mL.

Metabolism and Elimination

The half-life of equine immunoglobulin after ATGAM infusion was found to be 5.7 3.0 days in one group of recipients. The range for half-life was 1.5 to 13 days.

13 Nonclinical Toxicology ⮝

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Mutagenicity and carcinogenicity studies have not been conducted on ATGAM.

In fertility studies, ATGAM at doses 10, 20 and 40 mg/kg/day was administered to cynomolgus monkeys (Macaca fascicularis) for 14 days either before (male monkeys) or before and after (female monkeys) cohabitation with untreated mates. ATGAM treatment was not associated with male or female hormonal or copulation behavior changes. A decrease in fertility index in female monkeys receiving ATGAM was seen. Female toxicity, including death, was observed with ATGAM doses of 20 mg/kg/day. While the etiology of this toxicity is uncertain, it may be attributed to hemolytic anemia due to cross-reactivity of ATGAM to a monkey red blood antigen.

In embryo-fetal toxicity studies, ATGAM was administered to rats and cynomolgus monkeys for 11 and 16 days, respectively during organogenesis. In rats, hypoplastic cervical vertebrae, a finding consistent with delayed skeletal development, were observed in fetuses whose dams received ATGAM at doses of 100 mg/kg/day during organogenesis. In monkey reproduction studies, maternal toxicity (vaginal bleeding, decreased body weight and loss of appetite) was observed with ATGAM doses 20 mg/kg/day after 16 days of dosing. Fetal deaths occurred in dams treated with 20 mg/kg/day ATGAM earlier in organogenesis (days 20 35), but not when treatment was given at a later part of organogenesis (days 35 50). The maternal and fetal deaths were attributed to maternal anemia due to red blood cell antigen that humans do not share. Therefore, this toxicity is not considered relevant to human fetal development.

14 Clinical Studies ⮝

14.1 Renal Allograft Rejection

Renal Transplant Rejection

US Studies

The effectiveness of ATGAM for treatment of acute allograft rejection was evaluated in three different treatment applications: as a substitute for standard therapy, in conjunction with standard therapy at the time of diagnosis of the first rejection episode, and in conjunction with standard therapy in steroid resistant rejection episodes.

A randomized controlled trial of the use of ATGAM as a substitute for standard therapy for treatment of the first acute rejection episode was conducted at one transplant center in recipients of living related renal allografts. A total of 22 patients were studied; 11 in each of the two treatment groups [ATGAM versus standard therapy (bolus doses of Solu-Medrol )]. Patients randomized to the ATGAM group received 14 21 doses of ATGAM therapy, starting on the day the rejection was diagnosed. ATGAM was administered daily according to a dose-by-rosette regimen which resulted in a mean daily dose of approximately 15 mg/kg. Patients randomized to the control group received Solu-Medrol at a dosage of 15 mg/kg starting on the day the rejection was diagnosed, administered either daily or on alternate days for 3 to 7 doses to complete a maximum total dose of 5,000 mg for the course of the rejection episode. In this study, ATGAM was at least effective as standard therapy for treatment of acute allograft rejection. All 11 ATGAM treated patients achieved resolution of first rejection compared with 10/11 control patients. At one year, the functional graft survival rate was 91% in the ATGAM group (10/11) and 64% in the control group (7/11). Patient survival was similar in the two treatment groups (11/11 ATGAM patients versus 10/11 control patients).

The effect of ATGAM when administered in conjunction with standard therapy at the time of diagnosis of the first rejection episode was studied under two different protocols with cadaveric and living related renal transplant patients. The results from these studies demonstrate the efficacy associated with the addition of ATGAM to standard therapy for treatment of the first rejection episode in renal allograft recipients. In Study 1, a randomized controlled, two center trial of ATGAM use for treatment of acute rejection in cadaveric renal transplant patients, the addition of ATGAM to standard rejection therapy (methylprednisolone sodium succinate) resulted in an increased frequency of resolution of the first acute rejection episode which was statistically significant (p <0.01). ATGAM-treated patients achieved a rejection resolution rate of 80% (36/45) compared with 54% (25/46) in the control group. There was a statistically significant improvement in functional graft survival favoring the ATGAM group (p <0.01), and a statistically significant steroid sparing effect during the first rejection episode among patients in the ATGAM group. There was no difference in the patient survival rate between the two treatment groups. Study 2 was a randomized controlled trial conducted at five different transplant centers. In this study, the addition of ATGAM to standard rejection therapy (bolus doses of Solu-Medrol ) for treatment of acute rejection in recipients of living related renal transplants resulted in an increased frequency of rejection resolution and improvement in functional graft survival. Due to the small sample size, the difference between the ATGAM group and the control group in functional graft survival rate did not achieve statistical significance. Marginal statistical significance was demonstrated in rejection reversal rate and intravenous steroid sparing among ATGAM patients (p=0.10 and p=0.07). Patient survival rates were similar in the two treatment groups.

Results from randomized controlled trials in patients with first acute renal allograft rejection episodes refractory to conventional steroid therapy have demonstrated that ATGAM, when administered in conjunction with standard therapy, yields efficacy results superior to those of standard therapy alone. One study investigated two different regimens of ATGAM; immediate and delayed therapy. Patients were enrolled at the time of first rejection episode and randomized among three treatment groups: control (no ATGAM), immediate ATGAM, and delayed ATGAM. Patients in all three treatment groups received standard rejection therapy in the form of bolus doses of Solu-Medrol 15 mg/kg/day IV, while patients in the two ATGAM groups received ATGAM therapy in addition to Solu-Medrol . In the immediate ATGAM group, ATGAM administration started at the time of diagnosis of rejection (concurrent with standard therapy). In the delayed ATGAM group, ATGAM administration started on rejection day 4 (following the first three doses of Solu-Medrol ). Patients in both of the treated groups received from 10 to 21 doses of ATGAM. Results favored the two ATGAM groups (and particularly the immediate ATGAM group) in both outcome of first rejection and functional graft survival. The improvement in functional graft survival was statistically significant (p=0.05). There was also a statistically significant difference in patient survival rate favoring the ATGAM-treated groups (p=0.02).

The effectiveness of ATGAM for reversal of acute renal allograft rejection was also demonstrated in other controlled studies performed in various medical centers. In these studies, ATGAM was administered at time of diagnosis of the first rejection episode at a range of 10 to 15 mg/kg per day for 14 to 15 days, followed by alternate day therapy for a total of 21 doses in 28 days.

14.2 Aplastic Anemia

The use of ATGAM for the treatment of moderate to severe aplastic anemia in patients who are unsuitable for bone marrow transplantation is based on data from three controlled studies.

The effectiveness of the ATGAM therapy in the studies described below was evaluated by the hematological response and survival rates (Table 3).

10 to 20 mg/kg daily for 8 to 14 days

Study 1

A total of 41 patients with moderate or severe aplastic anemia ages 6 to 69 years, who were not candidates for bone marrow transplantation were enrolled in a randomized controlled study. The objective of this study was to determine the efficacy of ATGAM as a single agent, in restoring hematopoiesis in patients with moderate to severe aplastic anemia. Twenty-one (n=21) patients in the ATGAM treatment group received 20 mg/kg/day for 8 days, while control patients (n=20) were observed for 3 months. All patients were given oral prednisone (40 mg/m2/day) starting on day 8 then tapered over 1 to 2 weeks.

At 3 months post-study enrollment, 11 patients in the supportive care group who showed no improvement became eligible and were crossed over to receive ATGAM therapy. Efficacy was evaluated as sustained improvement in peripheral blood counts within 3 months of entry into the study. A statistically significant (p<0.01) difference was observed between the two treatment groups in hematological improvement based on the investigator's evaluation; 11 of 21 (52%) patients in the ATGAM group responded, compared with no patients (0 of 20) in the control group. Six of the 11 crossover patients from the control group showed improvement after 3 months of therapy. Overall, of 32 patients in both the ATGAM group and the control group who crossed over to receive ATGAM, 17 patients (53%) had a hematological improvement. Estimated 1-year survival rate was 62% for all 32 patients treated with ATGAM. The 2-year survival rate was 100% among the ATGAM responders [17 of the 32 patients (53%) compared to 14% for the nonresponders].

Fever, chills, and erythematous or urticarial rash were seen in all ATGAM treated patients. Platelet counts decreased during ATGAM infusion and daily platelet transfusions were necessary. Serum sickness occurred in all patients within 6 to 18 days of ATGAM initiation and was well-controlled with standard therapy. Three patients experienced transient hypotension.

Study 2

A randomized double-blind, placebo prospective, controlled study was conducted to compare the safety and efficacy of ATGAM and androgen (oxymetholone; OXY) immunosuppressive therapy with the combination of ATGAM, androgen (OXY) and an infusion of HLA mismatched bone marrow in patients with severe aplastic anemia who were not candidates for bone marrow transplantation. Allocation to treatment group was based on the availability of mismatched bone marrow donors. A total of 42 patients, ages 1 to 69 years were treated. Eighteen patients received ATGAM at a dose of 16 mg/kg/day for 10 doses with concomitant androgens (OXY) at a dose of 3 mg/kg/day for a minimum of 3 months, and 24 patients received an infusion of bone marrow from an HLA-mismatched donor 48 hours after the completion of ATGAM treatment.

At 3 months after entry into the study, 51% of patients with disease of idiopathic etiology (21 of the 41 evaluable patients from both groups) showed improvement based on investigator's evaluation of transfusion requirements and peripheral blood counts. Hematological response rate (complete/moderate based on sponsor's evaluation) at 3 months for the ATGAM and androgen group was 44% compared with 43% for the group receiving ATGAM, androgen and bone marrow infusion. The group of patients who received mismatched bone marrow infusion had better estimated 1-year survival rate, although the difference between these estimates was not statistically significant (p=0.14); 83% at 12 months for the group receiving bone marrow infusion versus 59% for the ATGAM and androgen alone group. Estimated 1-year survival rate for both groups combined was 73%.

The most commonly reported adverse events were rash, fever, arthralgias, chills, headache, myalgia and pruritus.

A pooled analysis of data from Studies 1 and 2 revealed an overall estimated 1-year survival rate of 69% in ATGAM-treated patients.

Study 3

A total of 53 patients (3 to 76 years of age) participated in this randomized, placebo-controlled, double-blind study to determine if androgens add to the efficacy of ATGAM in providing favorable hematologic response rates in patients with moderate to severe aplastic anemia. All patients were treated with ATGAM 20 mg/kg/day IV for 8 days, and were randomized to receive the oral androgen (oxymetholone 4 mg/kg/day or fluoxymesterone 25 mg/m2/day) (n=26), or a matched placebo (n=27). Both groups received oral prednisone (40 mg/m2/day) beginning on Day 8 which was tapered and discontinued in 1 to 2 weeks. A group of historical controls from previous studies (n=68; 1 to 72 years of age) who received ATGAM (20 mg/kg/day IV for 8 days) without androgens were included for treatment results comparison. The proportions of subjects who presented complete or partial response at 6 months were 42% in the ATGAM plus androgen group, 44% in the ATGAM plus placebo group, and 51% in the historical controls. The difference in response rates was not significant (p>0.9). Survival at 2 years was also comparable in the two groups for patients with severe aplastic anemia; 55% in the ATGAM plus androgen group compared with 50% in the ATGAM plus placebo group (p=0.65), and 56% for the historical controls. In patients with moderate aplastic anemia, two-year survival for the ATGAM plus androgen group was 63% compared with 100% in those receiving ATGAM plus placebo and 72% in the historical controls who received ATGAM alone.

Adverse reactions in both groups were comparable and included rash, chills, gastrointestinal disturbances, and joint pain during ATGAM infusion, as well as symptoms of serum sickness in all patients. Five patients had asymptomatic sinus bradycardia; six patients required antihypertensive therapy. Alanine transaminase or alkaline phosphatase levels increased to >2 times the upper limits of normal in 7 patients receiving ATGAM plus androgen, and in nine patients receiving ATGAM plus placebo.

Table 3. Key Studies with ATGAM for the Treatment of Aplastic Anemia

Study	ATGAM + comparator or other therapy	No. of Subjects	Response rate % (endpoint)*	P Value	Survival rate % (time point)	P Value (or 95% CI)
* Hematologic response was defined differently in different studies. Sponsor's evaluation of response Investigator's evaluation of response This survival estimate includes the 21 subjects who were randomized to receive ATGAM, plus another 11 subjects who were crossed over from the control group. Patients with severe aplastic anemia only.
10 to 20 mg/kg/day for 8 to 14 days
Study 1	ATGAM	21	47 / 52 (3 mo)	<0.01 /<0.01	62 (12 mo)	NA
	Control	20	6 / 0 (3 mo)
Study 2	ATGAM + Bone marrow infusion	24	43 (3 mo)	Not reported	83 (12 mo)	=0.14
	ATGAM	18	44 (3 mo)		59 (12 mo)
Study 3	ATGAM + Androgen	26	42 (6 mo)	>0.9	55 (24 mo)	=0.65
	ATGAM + Placebo	27	44 (6 mo)		50 (24 mo)
	ATGAM historical controls	68	51 (6 mo)	NA	56 (24 mo)

15 References ⮝

1. Hardy MA, Nowygrod R, Elberg A, Appel G. Use of ATG in treatment of steroid-resistant rejection. Transplantation 1980; 29(2):162 4.
2. Nowygrod R, Appel G, Hardy MA. Use of ATG for reversal of acute allograft rejection. Transplant Proc 1981; 13(1):469 72.
3. Filo RS, Smith EJ, Leapman SB. Reversal of acute renal allograft rejection with adjunctive ATG therapy. Transplant Proc 1981; 13(1):482 90.
4. Shield CF III, Cosimi AB, Tolkoff Rubin N, et al. Use of antithymocyte globulin for reversal of acute allograft rejection. Transplantation 1979; 28(6):461 4.
5. Rubin RH, Cosimi AB, Hirsch MS, Herrin JT. Effects of antithymocyte globulin on cytomegalovirus infection in renal transplant recipients. Transplantation 1981; 31(2):143 5.
6. Cosimi AB, Wortis HH, Delmonico FL, Russell PS. Randomized clinical trial of antithymocyte globulin in cadaver renal allograft recipients: importance of T cell monitoring. Surgery 1976; 80(2):155 63.
7. Wechter WJ, Brodie JA, Morrell RM, et al. Antithymocyte globulin (ATGAM) in renal allograft recipients: multicenter trials using a 14-dose regimen. Transplantation 1979; 28(4):294 302.
8. Butt KMH, Zielinski CM, Parsa I, et al. Trends in immunosuppression for kidney transplantation. Kidney Int 1978; 13(Suppl 8): S95 S8.
9. Ettenger RB, Rosenthal JT, Marik JL, et al. Improved cadaveric renal transplant outcome in children. Pediatric Nephrol 1991; 5:137 42.

16 How Supplied/storage And Handling ⮝

ATGAM Sterile Solution, containing 50 mg/mL lymphocyte immune globulin, anti-thymocyte globulin [equine], is supplied as follows:

5 5 mL ampoules

NDC 0009-7224-02

Store in a refrigerator at 2 to 8 C (36 to 46 F). DO NOT FREEZE.

For storage conditions of diluted solution, see Dosage and Administration (2.2).

Principal Display Panel - 5 Ml Ampule Label ⮝

NDC 0009-7224-01

5 mL

Atgam

lymphocyte immune globulin,
anti-thymocyte globulin (equine)

250 mg protein

50 mg/mL For Intravenous use only

DOSAGE AND USE: See accompanying
prescribing information.

ATTENTION May contain particles; this is
normal. Use 0.2 micron to 1.0 micron in-line
filter. See insert.

Manufactured by Pharmacia & Upjohn Co
Division of Pfizer Inc, NY, NY 10017

U.S. Govt. License No. 1216
Rx only

PAA111210

LOT / EXP

Principal Display Panel - 5 Ml Ampule Carton ⮝

NDC 0009-7224-02
Contains 5 of NDC 0009-7224-01

5 5 mL Ampoules
(single use containers)

Atgam

lymphocyte immune globulin,
anti-thymocyte globulin (equine)

250 mg protein

50 mg/mL

ATTENTION This product may contain a granular
or flaky deposit; this is normal. See infusion
instructions described in the enclosed product insert.

Sterile Solution For Intravenous Use Only

Pfizer Injectables
Rx only

ATGAM equine thymocyte immune globulin injection, solution

Product Information Product Type PLASMA DERIVATIVE Item Code (Source) NDC:0009-7224 Route of Administration INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength EQUINE THYMOCYTE IMMUNE GLOBULIN (UNII: 475247QF1Z) (EQUINE THYMOCYTE IMMUNE GLOBULIN - UNII:475247QF1Z) EQUINE THYMOCYTE IMMUNE GLOBULIN 50 mg in 1 mL

Inactive Ingredients Ingredient Name Strength GLYCINE (UNII: TE7660XO1C)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0009-7224-02 5 in 1 CARTON 1 NDC:0009-7224-01 5 mL in 1 AMPULE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103676 11/17/1981

Labeler - Pharmacia and Upjohn Company LLC (618054084)

Establishment
Name	Address	ID/FEI	Business Operations
Pharmacia and Upjohn Company LLC		618054084	ANALYSIS(0009-7224) , API MANUFACTURE(0009-7224) , LABEL(0009-7224) , MANUFACTURE(0009-7224) , PACK(0009-7224)

Revised: 12/2018 Document Id: 58b245de-7ae9-4949-8098-1b0075988096 60683-0 Set id: bd545ba1-2366-4df1-bd67-10dfd7632b54 Version: 15 Effective Time: 20181211 Pharmacia and Upjohn Company LLC