Important Drug Information

By Jay S. Epstein, M.D., Ann Gaines, Ph.D., Richard Kapit, M.D., Ross Pierce, M.D., Richard Potter, R.Ph., Frederick Varricchio, M.D., Ph.D., Center for Biologics Evaluation and Research, FDA

Immune Globulin Intravenous (Human) (IGIV) was first licensed in the U.S. in 1981. From 1981 to July 1998, the FDA received over 114 worldwide (approximately 83 U.S.) adverse event reports¹ for IGIV products that consisted of acute renal dysfunction (ARD). Although ARD was successfully managed in the majority of cases, 17 deaths occurred in which renal failure was possibly contributory. Of the U.S. reports, approximately 69%² were associated with the use of the IGIV 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). Approximately 22% were associated with Gammar-P I.V./Gammar I.V., manufactured by Centeon L.L.C. The Swiss Red Cross and Centeon LLC IGIVs are the only two IGIV products licensed in the U.S. that contain sucrose as a stabilizer (1.67 and 1.0 g sucrose/g immunoglobulin, respectively). Preliminary evidence suggests that IGIV products containing sucrose may present a greater risk for acute renal failure.

In approximately four-fifths of the reported cases of IGIV-associated renal dysfunction, the patients either had some degree of pre-existing renal insufficiency and/or had a disease such as diabetes mellitus or hypertension, which frequently leads to renal impairment.

The onset of ARD was typically 2-3 days after IGIV therapy was begun, but ranged from one day to one week. Peak serum creatinines were most commonly reached 4-5 days after initiation of IGIV therapy (range 3-8 days). Recovery of kidney function commonly started after four days but required two or more weeks in some patients.

Renal histopathology was consistent with an osmotic injury to the proximal renal tubules in 7 out of the 8 cases where these data were available. The same type of proximal renal tubule injury (acute tubular necrosis with vacuolization/osmotic nephrosis) has been reported following exposure to IV sucrose alone (when formerly used as an osmotic diuretic), IV mannitol, and I.V. iodinated radiographic contrast media. However, the lesion may not be due to sucrose per se but rather to hyperosmolarity and the fact that sucrose, when administered I.V., is essentially not metabolized.

Prescribing information for all IGIV products is being updated with a boxed warning to advise physicians of these reports and of the following precautions intended to minimize the occurrence of acute renal failure.

FDA recommends the following precautions be taken when administering IGIV products:

1. Assure that patients are not volume depleted prior to the initiation of the infusion of IGIV.
2. Exercise particular caution in the administration of IGIV in patients at increased risk for developing acute renal failure. Such patients include those with: any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, and those receiving known nephrotoxic drugs.
   For patients at increased risk, physicians should carefully weigh the potential benefits of administering sucrose-containing IGIV products (Sandoglobulin®, Panglobulin®, and Gammar®-P I.V.) against the risks of causing renal damage.
   
3. Do not exceed the recommended dose. Reduction in dose, concentration, and/or infusion rate in patients at risk of ARD has been proposed in order to reduce the risk. Because no prospective data are presently available to identify a maximal safe dose, concentration, or infusion rate for IGIV products for patients at risk of ARD, FDA recommends that, for such patients, prescribers reconstitute/dilute and administer the product in such a manner as to produce both the minimum concentration and infusion rate practicable. For sucrose-containing IGIVs, a maximum infusion rate of 3 mg sucrose/kg/minute (2 mg Ig/kg/min for Sandoglobulin® and Panglobulin® 3 mg Ig/kg/min for Gammar®-P I.V) should not be exceeded. These corrrespond to a maximum infusion rate of 3 mg sucrose/kg/minute.
4. Baseline urine output and blood urea nitrogen (BUN)/serum creatinine measurements should be assessed prior to infusion of IGIV, particularly in patients at potentially increased risk for developing acute renal failure, and again at appropriate intervals. If renal function deteriorates, discontinuation of IGIV should be considered.

Physicians and other healthcare professionals are strongly encouraged to report any serious adverse events that are associated with the use of IGIV to respective pharmaceutical manufacturers or distributors. Alternatively, adverse events for an IGIVs or other FDA-licensed products may be report to FDA's MedWatch program by telephone at 800-FDA-1088, by FAX at 800-FDA-0178, by mail to MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787, or online at http://www.fda.gov/medwatch/index.html. A list of IGIV manufacturers and distributors together with their addresses and telephone numbers and the FDA-approved indications for each IGIV product, together with additional literature references, is available at http://www.fda.gov/medwatch/safetey/1998/safety98.htm#igiv.

1. Additional literature reports were under review at time of printing.
2. Seven Renal Adverse Event Reports (4 international and 3 U.S. cases) were associated with unspecified IGIV products.
3. Kessler DA, Introducing MedWatch: A new approach to reporting medication and device adverse effects and product problems. 1993; JAMA 269:2765-2768.
4. Cayco AV, Perazella MA, Hayslett JP: Renal insufficiency after intravenous immune globulin therapy: A Report of Two Cases and an Analysis of the Literature. 1997; J Amer Soc Nephrology 8:1788-1793.
5. Winward DB, Brophy MT: Acute renal failure after administration of intravenous immunoglobulin: review of the literature and case report. 1995; Pharmacotherapy 15:765-772.
6. Anderson W, Bethea W: Renal lesions following administration of hypertonic solutions of sucrose. 1940; JAMA 114:1983-1987.

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