INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
ATGAM™ (Sterile solution)


SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

ATGAM™ (Sterile solution)

COMPOSITION:
Each 1 mL contains equine gamma globulin 50 mg

PHARMACOLOGICAL CLASSIFICATION:
A 30.4 Other

PHARMACOLOGICAL ACTION:
ATGAM is a lymphocyte-selective immunosuppressant as is demonstrated by its ability to reduce the number of circulating, thymus-dependent lymphocytes that form rosettes with sheep erythrocytes. This anti-lymphocytic effect is believed to reflect an alteration of the function of the T-lymphocytes, which are responsible in part for cell-mediated immunity and are involved in humoral immunity. In addition to its anti-lymphocytic activity, ATGAM contains low concentrations of antibodies against other formed elements of the blood. In rhesus and cynomolgus monkeys, ATGAM reduces lymphocytes in the thymus-dependent areas of the spleen and lymph nodes. It also decreases the circulating sheep-erythrocyte-rosetting lymphocytes that can be detected.

INDICATIONS:
Renal Transplantation:
ATGAM is indicated in combination with concomitant immunosuppressive therapy for the management of allograft rejection in renal patients.
Aplastic Anaemia:
ATGAM is indicated for the treatment of moderate to severe aplastic anaemia in patients who are unsuitable for bone marrow transplantation.

CONTRA-INDICATIONS:
Do not administer ATGAM to a patient who has had a severe systemic reaction during prior administration of ATGAM or any other equine gamma globulin preparation.
The usefulness of ATGAM has not been demonstrated in patients with aplastic anaemia who are suitable candidates for bone marrow transplantation or in patients with aplastic anaemia secondary to neoplastic disease, storage disease, myelofibrosis, Fanconi's syndrome or in patients known to have been exposed to myelotoxic agents or radiation.
Safety in pregnancy and lactation has not been established.
Experience in children has been limited.

WARNINGS:

Only physicians experienced in immunosuppressive therapy in the management of renal transplant or aplastic anaemia patients should use ATGAM. Patients receiving ATGAM should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources.

Precise methods of determining the potency of ATGAM have not been established, thus activity may potentially vary from lot to lot.
Discontinue treatment with ATGAM if any of the following occurs:

1.	Symptoms of anaphylaxis (See side-effects)
2.	Severe and unremitting thrombocytopenia in renal transplant patients.
3.	Severe and unremitting leucopenia in renal transplant patients.

As this product is derived from human blood components, the possibility of transmission of infectious agents exists.
Allergic reactions such as anaphylaxis have occurred in patients whose skin test is negative.

DOSAGE AND DIRECTIONS FOR USE:
Skin Testing
Before the first infusion of ATGAM, skin testing of potential recipients is strongly recommended before commencing treatment. A conservative, conventional approach would first employ epicutaneous (prick) testing with undiluted ATGAM. If the patient does not show a wheal 10 minutes after pricking, proceed to intradermal injection of 0,02 mL of a 1:1000 v/v dilution of ATGAM in saline and a separate saline control injection of similar volume.
Use only freshly diluted ATGAM for skin testing.
Read the result at 10 minutes: A wheal of 3 mm or greater than that of the saline control site, with erythema or both with or without pseudopod formation and itching or a marked local swelling, should be considered a positive test, and an increased possibility of a systemic allergic reaction should the drug be dosed intravenously.
Note: The predictive value of this test has not been proven clinically.
A systemic reaction such as a generalized rash, tachycardia, dyspnea, hypotension, or anaphylaxis precludes any additional administration of ATGAM. (See Warnings, Side-Effects and Special Precautions).
Renal Allograft Recipients
Delaying the onset of allograft rejection: 15 mg/kg daily for 14 days, then every other day for 14 days for a total of 21 doses in 28 days. Administer the first dose within 24 hours before or after the transplant.
Treatment of rejection: The first dose of ATGAM can be delayed until the diagnosis of the first rejection episode. The recommended dose is 10 to 15 mg/kg daily for 14 days.
Additional alternate-day therapy up to a total of 21 doses can be given.
Aplastic Anaemia
The recommended dosage regimen is 10 to 20 mg/kg daily for 8 to 14 days. Additional alternate-day therapy up to a total of 21 doses can be administered.
Preparation of Solution
Inspect visually for particulate matter and discolouration prior to administration. ATGAM can be transparent to slightly opalescent, colourless to faintly pink or brown, and may develop a slight granular or flaky deposit during storage. ATGAM (diluted or undiluted) should not be shaken 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). The concentration should not exceed 4 mg of ATGAM per mL. The diluted solution should be gently rotated or swirled to effect thorough mixing.
Administration
The diluted ATGAM should be allowed to reach room temperature before infusion. ATGAM is appropriately administered into a vascular shunt, arterial venous fistula, or a high-flow central vein through an in-line filter with a pore size of 0,2 to 1,0 micron. The in-line filter should be used with all infusions of ATGAM to prevent the administration of any insoluble material that may develop in the product during storage. The use of high-flow veins will 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 Side-Effects).
Compatibility and Stability
ATGAM, once diluted, 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.
It is recommended that diluted ATGAM be stored in a refrigerator if it is prepared prior to the time of infusion. Even if it is stored in a refrigerator, the total time in dilution should not exceed 24 hours (including infusion time).

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Renal Transplantation:
Frequently reported side-effects: fever; chills; leucopenia; thrombocytopenia and dermatological reactions, such as rash, pruritus, urticaria, wheal, and flare.
Less frequently reported side-effects are arthralgia, chest or back pain or both, clotted A/V fistula, diarrhoea, dyspnea, headache, hypotension, nausea or vomiting or both, night sweats, pain at the infusion site, peripheral thrombophlebitis, and stomatitis. Anaphylaxis, dizziness, weakness or faintness, oedema, herpes simplex reactivation, hiccoughs or epigastric pain, hyperglycaemia, hypertension, iliac vein obstruction, laryngospasm, localized infection, lymphadenopathy, malaise, myalgia, paraesthesia, possible serum sickness, pulmonary oedema, renal artery thrombosis, seizures, systemic infection, tachycardia, toxic epidermal necrosis, and wound dehiscence, have also been reported.
Aplastic Anaemia
Fever and skin reactions have been reported. Other frequently reported adverse reactions were chills, arthralgia, headache, myalgia, nausea, chest pain and phlebitis.
Less frequently reported side-effects: diaphoresis, joint stiffness, periorbital oedema, aches, oedema, muscle ache, vomiting, agitation/lethargy, listlessness, lightheadedness, seizures, diarrhoea, 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 patients with aplastic anaemia and other haematologic abnormalities who have received ATGAM, abnormal tests of liver function (SGOT, SGPT, alkaline phosphatase) and renal function (serum creatinine) have been observed. Clinical and laboratory findings of serum sickness were seen in a majority of patients.
Chemical phlebitis can be caused by infusion of ATGAM through peripheral veins.
Precautions:
Anaphylaxis may occur at any time during therapy with ATGAM. Stop infusion immediately and do not resume therapy with ATGAM. Respiratory distress and hypotension may indicate an anaphylactoid reaction. Discontinue infusion of ATGAM if this occurs. Pain in chest, flank, or back may indicate anaphylaxis or haemolysis.
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 carefully 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 with a physician familiar with the treatment of potentially life threatening allergic reactions in attendance.
Positive skin testing will not predict later development of serum sickness.
Monitor patients carefully for signs of leucopenia, thrombocytopenia or concurrent infection. An increase in the incidence of cytomegalovirus infection in patients receiving ATGAM has been observed. Severe and unremitting haemolysis may require discontinuation of therapy with ATGAM.
Because thrombocytopenia can be associated with the administration of ATGAM, patients receiving it for the treatment of aplastic anaemia may need prophylactic platelet transfusions to maintain platelets at clinically acceptable levels.
When the dose of corticosteroids and other immunosuppressants is being reduced, some previously masked reactions to ATGAM may appear. Under these circumstances, observe patients especially carefully during therapy with ATGAM.
Interactions:
We do not recommend the dilution of ATGAM Sterile Solution in Dextrose Injection, USP, as low salt concentrations may cause precipitation. The use of highly acidic infusion solutions is also not recommended because of possible physical instability over time.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF TREATMENT:
See Side-effects and Special Precautions. Treatment is symptomatic and supportive.

IDENTIFICATION:
ATGAM is a transparent to slightly opalescent aqueous protein solution. It may appear colourless to faintly pink or brown and is nearly odourless. It may develop a slight granular or flaky deposit during storage.

PRESENTATION:
ATGAM Sterile Solution is available in 5 mL ampoules in cartons of 5 ampoules.

STORAGE DIRECTIONS:
Store in a refrigerator at 2°C to 8°C. Do not freeze.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER:
T/30.4/717

NAME AND ADDRESS OF APPLICANT:
Pharmacia South Africa (Pty) Limited
Alphen West G
George Street
Midrand
1685

DATE OF PUBLICATION OF THIS INSERT:
27 July 1996

^TM Trademark

New addition to this site: February 2005
Source: Pharmaceutical Industry
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