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September 24, 1999
Dear Doctor:
This letter is intended to alert physicians to safety precautions that should be taken to reduce the potential risk of ACUTE RENAL FAILURE (ARF) reported to be associated with the administration of Immune Globulin Intravenous (Human) (IGIV) products.
Since IGIVs were first introduced in 1981, the U.S. Food and Drug Administration (FDA) has received over 114 worldwide (approximately 83 U.S.) adverse event reportsa of renal dysfunction and / or acute renal failure associated with the administration of these products1-16. Although acute renal failure was successfully managed in the majority of cases, deaths were reported in 17 patients worldwide. Many of the patients who died had serious underlying conditions.
Preliminary evidence suggests that IGIV products containing sucrose may present a greater risk for this complication. Hyperosmolality of certain reconstituted products, as well as differences in stabilizer sugar choice and content between IGIVs, may be among the factors that have contributed to different reported rates of renal dysfunction for the various IGIV products. A disproportionate share of the cases (approximately 88% of U.S. reports) have been associated with the sucrose-containing products. The sucrose containing products are: (A) the product manufactured by the Central Laboratory Blood Transfusion Service, Swiss Red Cross (SRC), (Sandoglobulin, distributed by Novartis, and Panglobulin, distributed by the American Red Cross), and (B) the IGIV products manufactured by Centeon L.L.C. (Gammar-P I.V./Gammar-I.V.b).
Renal histopathologic examination was performed in 15 of the IGIV-associated ARF cases. The findings were consistent in 7 of 15, suggesting an osmotic injury to the proximal renal tubules (acute tubular necrosis, vacuolar degeneration, and osmotic nephrosis). Approximately 55 percent of the reported cases of renal dysfunction involved patients being treated for idiopathic thrombocytopenic purpura (ITP) and fewer than five percent involved patients with primary immune deficiency (PID). This may relate to the fact that higher and consecutive doses are used for ITP, in contrast to the dosing regimens used for PID. It is not known whether age and baseline glomerular filtration rate (GFR) differences could also be factors explaining the greater proportion of case reports of renal dysfunction following the administration of IGIV for ITP.
Table 1
| Manufacturer |
Distributor |
Product |
g sucrose/ g Ig |
No. (%) of U.S. cases of Renal Adverse Eventse |
| Alpha Therapeutic Corporation |
Alpha Therapeutic Corporation |
Venoglobulin-S
Venoglobulin-I |
0 |
None Reported |
| Baxter Healthcare Corporation |
Baxter |
Iveegam |
0 |
None Reported |
| Gammagard S/Dc |
0 |
3 (4%) |
| American Red Cross |
Polygam S/Dc |
| Bayer Corporation |
Bayer Corporation |
Gamimune-N, 5%
Gamimune-N, 10% |
0 |
4 (5%) |
| Centeon L.L.C. |
Centeon L.L.C. |
Gammar-P I.V.
Gammar I.V.b |
1.0 |
18 (22%) |
| Central Laboratory Blood Transfusion Service, Swiss Red Cross |
Novartis Pharmaceuticals |
Sandoglobulind |
1.67 |
56 (69%) |
| American Red Cross |
Panglobulind |
a - Additional literature reports were under review at time of printing.
b - Gammar I.V. was withdrawn from the market after the introduction of Gammar-P I.V.
c - Same formulation
d - Same formulation
e - Three renal adverse event reports were associated with unspecified IGIV products.
In an effort to reduce the risk of acute renal failure, the following precautions should be taken when considering administration of IGIV products:
- Assure that patients are not volume depleted prior to the initiation of the infusion of IGIV.
- Exercise particular caution in the administration of IGIV products in patients at increased risk for developing acute renal failure, which includes patients with:
- any degree of pre-existing renal insufficiency
- diabetes mellitus
- age greater than 65
- volume depletion
- sepsis
- paraproteinemia
- concomitant nephrotoxic drugs.
For patients at increased risk, physicians should carefully weigh the potential benefits of administering sucrose-containing IGIV products against the risks of causing renal damage.
- Do not exceed the recommended dose. Reduction in dose, concentration, and/or rate of administration in patients at risk for acute renal failure has been proposed in order to reduce the risk16. Because no prospective data are presently available to identify a maximal safe dose, concentration, or rate of infusion for IGIV products for patients at risk for acute renal failure, FDA recommends that, for such patients, recommended doses should not be exceeded and the concentration and infusion rate selected should be the minimum levels practicable. For sucrose-containing IGIVs, a maximum infusion rate of 3 mg sucrose/kg/minute (2 mg Ig/kg/min for Sandoglobulin and Panglobulin; 1 mg Ig/kg/min for Gammar-P I.V) should not be exceeded.
- Periodic monitoring of renal function tests and urine output is particularly important in patients judged to have a potential increased risk for developing acute renal failure. Renal function, including measurement of blood urea nitrogen (BUN)/serum creatinine, should be assessed prior to the initial infusion and again at appropriate intervals thereafter. If renal function deteriorates, discontinuation of the product should be considered.
- Patients should be instructed to immediately report symptoms of decreased urine output, sudden weight gain fluid retention/edema, and/or shortness of breath (which may suggest kidney damage) to their physicians.
A list of the FDA-approved indications for each of the IGIV products marketed in the U.S. is shown in Table 2. Please refer to the revised package inserts for these products for additional prescribing information. Revised package inserts are available on the websites listed in Table 2 and may also be obtained by directly contacting the manufacturer.
Table 2
| Manufacturer / Distributor |
Product |
Approved Indications |
Alpha Therapeutic Corporation
5555 Valley Boulevard
Los Angeles, CA 90032
(800) 292-6118
www.alphather.com/products/ins_veno.htm
www.alphather.com/products/ins_veno2.htm |
Venoglobulin-S
Venoglobulin-I |
Primary Immune Deficiencies (PID)
Immune Thrombocytopenic Purpura (ITP)
Kawasaki Syndrome |
The American Red Cross
(Medical Affairs)
1616 North Fort Myer Drive
Roslyn, VA 22209
(800) 293-5023
www.redcross.org/plasma/polygamsd/index.htm
www.redcross.org/plasma/panglobulin/aba4.htm |
Polygam S/D |
Primary Immune Deficiencies (PID)
Idiopathic Thrombocytopenic Purpura (ITP)
Chronic B-Cell Lymphocytic Leukemia
Kawasaki Syndrome |
| Panglobulin |
Primary Immune Deficiencies (PID)
Immune Thrombocytopenic Purpura (ITP) |
Baxter Healthcare Corporation
550 North Brand Boulevard
Glendale, CA 91203
(800) 423-2090
www.baxter.com/doctors/blood_therapies/ hyland_immuno/index.html |
Gammagard S/D |
Primary Immune Deficiencies (PID)
Idiopathic Thrombocytopenic Purpura (ITP)
Chronic B-Cell Lymphocytic Leukemia
Kawasaki Syndrome |
| Iveegam |
Primary Immune Deficiencies (PID)
Kawasaki Syndrome |
Bayer Corporation
1884 Miles Avenue
Elkhart, IN 46514
(800) 288-8371
http://www.univgraph.com/bayer/BioInserts.html |
Gamimune-N, 5%
Gamimune-N, 10% |
Primary HumoraI Immunodeficiency
Idiopathic Thrombocytopenic
Purpura (ITP)
Bone Marrow Transplant
Pediatric HIV Infection |
Centeon L.L.C.
1020 First Avenue
King of Prussia, PA 19406
(800) 504-5434
www.centeon.com/na/hq/hq_9a.htm |
Gammar P.I.V. |
Primary Immune Deficiencies (PID) |
Novartis Pharmaceuticals Corp
59 Route 10
East Hanover, NJ 07936
(888) 669-6682
www.pharma.us.novartis.com/product/ pi/sandoglobulin.html |
Sandoglobulin |
Primary Immune Deficiencies (PID)
Immune Thrombocytopenic Purpura (ITP) |
As with all medical products, healthcare professionals are strongly encouraged to report any serious adverse events that are associated with the use of IGIVs, including cases of acute renal failure, to the manufacturer or distributor. (See Table 2). Alternatively, adverse events may be reported to FDA's MEDWATCH program by phone (800) FDA-1088, FAX (800) FDA-0178, or mail to MEDWATCH, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787.
Sincerely,
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-- signature -- |
Jay S. Epstein, M.D.
Director
Office of Blood Research and Review
Center for Biologics Evaluation and Research |
Kathryn C. Zoon, Ph.D.
Director
Center for Biologics Evaluation and Research |
References
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