Atg

Renal Transplantation

ATGSterile Solution is indicated for the management of allograft rejection in renal

transplant patients. When administered with conventional therapy at the time of rejection,

it increases the frequency of resolution of the acute rejection episode. The drug has also

been administered as an adjunct to other immunosuppressive therapy to delay the onset of

the first rejection episode. Data accumulated to date have not consistently demonstrated

improvement in functional graft survival associated with therapy to delay the onset of the

first rejection episode.

Aplastic Anemia

ATGis indicated for the treatment of moderate to severe aplastic anemia in patients

who are unsuitable for bone marrow transplantation.

When administered with a regimen of supportive care, ATGmay induce partial or

complete hematologic remission. In a controlled trial, patients receiving ATGshowed

a statistically significantly higher improvement rate compared with standard supportive

care at 3 months. Improvement was defined in terms of sustained increase in peripheral

blood counts and reduced transfusion needs.

Clinical trials conducted at two centers evaluated the 1-year survival rate for patients with

severe and moderate to severe aplastic anemia. Seventy-four of the 83 patients enrolled

were evaluable based on response to treatment. The treatment groups studied consisted of

1) ATGand supportive care, 2) ATGadministered following 3 months of

supportive care alone, 3) ATG, mismatched marrow infusion, androgens, and

supportive care, or 4) ATG, androgens, and supportive care. There were no

statistically significant differences between the treatment groups. The 1-year survival rate

for the pooled treatment groups was 69%. These survival results can be compared with a

historical survival rate of about 25% for patients receiving standard supportive care

alone.

The usefulness of ATGhas 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

Do not administer ATG Sterile Solution to a patient who has had a severe systemic

reaction during prior administration of ATGor any other equine gamma globulin

preparation.

When the dose of corticosteroids and other immunosuppressants is being reduced, some

previously masked reactions to ATGmay appear. Under these circumstances,

observe patients especially carefully during therapy with ATG.

Renal Transplantation

The primary clinical experience with ATGSterile Solution has been in renal allograft

patients who were also receiving concurrent standard immunosuppressive therapy

(azathioprine, corticosteroids). In controlled trials, investigators frequently reported the

following adverse reactions: fever in 1 patient in 3; chills in 1 patient in 7; leukopenia in

1 patient in 7; thrombocytopenia in 1 patient in 9; and dermatologic reactions, such as

rash, pruritus, urticaria, wheal, and flare, in 1 patient in 8. The following reactions were

reported in more than 1% but less than 5% of the patients: arthralgia; chest or back pain,

or both; clotted A/V fistula; diarrhea; dyspnea; headache; hypotension; nausea or

vomiting, or both; night sweats; pain at the infusion site; peripheral thrombophlebitis; and

stomatitis.

Reactions reported in less than 1% of the patients in the controlled trials were

anaphylaxis, dizziness, weakness or faintness, edema, herpes simplex reactivation,

hiccoughs or epigastric pain, hyperglycemia, hypertension, iliac vein obstruction,

laryngospasm, localized infection, lymphadenopathy, malaise, myalgia, paresthesia,

possible serum sickness, pulmonary edema, renal artery thrombosis, seizures, systemic

infection, tachycardia, toxic epidermal necrosis, and wound dehiscence.

Aplastic Anemia

In premarketing clinical trials with ATGin the treatment of aplastic anemia, patients

were also being concurrently managed with support therapy (transfusions, steroids,

antibiotics, antihistamines).

In these trials most patients experienced fever and skin reactions. Other frequently

reported adverse reactions were chills, 1 patient in 2; arthralgia, 1 patient in 2; headache,

1 patient in 6; myalgia, 1 patient in 10; nausea, 1 patient in 15; chest pain, 1 patient in 15

and phlebitis, 1 patient in 20.

The following reactions were reported by at least one patient and less than 5% of the total

patients: diaphoresis, joint stiffness, periorbital edema, aches, edema, muscle ache,

vomiting, agitation/lethargy, listlessness, light-headedness, seizures, diarrhea,

bradycardia, myocarditis, cardiac irregularity, hepatosplenomegaly, possible encephalitis

or post viral encephalopathy, hypotension, congestive heart failure, hypertension, burning

soles/palms, foot sole pain, lymphadenopathy, post-cervical lymphadenopathy, tender

lymph nodes, bilateral pleural effusion, respiratory distress, anaphylactic reaction, and

proteinuria.

In other support studies 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.

In some trials, clinical and laboratory findings of serum sickness were seen in a majority

of patients.

Postmarketing Experience

During approximately 5 years of post approval marketing experience, the frequency of

adverse reactions in voluntarily reported cases is as follows: fever 51%; chills 16%;

thrombocytopenia 30%; leukopenia 14%; rashes 27%; systemic infection 13%. Events

reported in 5% to 10% of reported cases include abnormal renal function tests; serum

sickness-like symptoms; dyspnea/apnea; arthralgia; chest, back, or flank pain; diarrhea

and nausea and/or vomiting. Events reported with a frequency of less than 5% include:

hypertension, Herpes Simplex infection, pain, swelling or redness at infusion site,

eosinophilia, headache, myalgias, or leg pains, hypotension, anaphylaxis, tachycardia,

edema, localized infection, malaise, seizures, GI bleeding or perforation, deep vein

thrombosis, sore mouth/throat, hyperglycemia, acute renal failure, abnormal liver

function tests, confusion or disorientation, cough, neutropenia or granulocytopenia,

anemia, thrombophlebitis, dizziness, epigastric or stomach pain, lymphadenopathy,

pulmonary edema or congestive heart failure, abdominal pain, nosebleed, vasculitis,

aplasia or pancytopenia, abnormal involuntary movement or tremor, rigidity, sweating,

laryngospasm/edema, hemolysis or hemolytic anemia, viral hepatitis, faintness, enlarged

or ruptured kidney, paresthesias, and renal artery thrombosis.

The recommended management for some of the adverse reactions that could occur with

treatment with ATGfollows:

1. Anaphylaxis is uncommon but serious and may occur at any time during therapy

with ATGAM. Stop infusion of ATGimmediately; administer 0.3 mL

aqueous epinephrine (1:1,000 solution) intramuscularly. Administer steroids;

assist respiration; and provide other resuscitative measures. DO NOT resume

therapy with ATGAM.

2. Hemolysis can usually be detected only in the laboratory. Clinically significant

hemolysis has been reported rarely. Appropriate treatment of hemolysis may

include transfusion of erythrocytes; if necessary, administer intravenous mannitol,

furosemide, sodium bicarbonate, and fluids. Severe and unremitting hemolysis

may require discontinuation of therapy with ATGAM.

3. Thrombocytopenia is usually transient in renal transplant patients; platelet

counts generally return to adequate levels without discontinuing therapy with

ATGAM. Platelet transfusions may be necessary in patients with aplastic anemia.

4. Respiratory distress may indicate an anaphylactoid reaction. Discontinue

infusion of ATGAM. If distress persists, administer an antihistamine, epinephrine,

corticosteroids, or some combination of the three.

5. Pain in chest, flank, or back may indicate anaphylaxis or hemolysis. Treatment

is that indicated above for those conditions.

6. Hypotension may indicate anaphylaxis. Stop infusion of ATGand stabilize

blood pressure with pressors if necessary.

7. Chills and fever occur frequently in patients receiving ATGAM. ATGmay

release endogenous leukocyte pyrogens. Prophylactic and/or therapeutic

administration of antihistamines, antipyretics, or corticosteroids generally controls

this reaction.

8. Chemical phlebitis can be caused by infusion of ATGthrough peripheral

veins. This can often be avoided by administering the infusion solution into a

high-flow vein. A subcutaneous arterialized vein produced by a Brescia fistula is

also a useful administration site.

9. Itching and erythema probably result from the effect of ATGon blood

elements. Antihistamines generally control the symptoms.

10. Serum sickness-like symptoms in aplastic anemia patients have been treated

with oral or IV corticosteroids. Resolution of symptoms has generally been

prompt and long-term sequelae have not been observed. Prophylactic

administration of corticosteroids may decrease the frequency of this reaction.