Review: Off-label use of IVIG is supported only for Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy
ACP J Club. 1996 Jan-Feb;124:7. doi:10.7326/ACPJC-1996-124-1-007
Ratko TA, Burnett DA, Foulke GE, Matuszewski KA, Sacher RA. Recommendations for off-label use ofintravenously administeredimmunoglobulin preparations. JAMA. 1995 Jun 21;273:1865-70. [PubMed ID: 7776504]
To make evidence-based recommendations for the use of intravenous immunoglobulin (IVIG) preparations for indications that are not included in the product labeling approved by the U.S. Food and Drug Administration (off-label).
MEDLINE and EMBASE (1982 to 1994) were searched to identify all English-language review articles and original studies of IVIG for clinical use; bibliographies were reviewed.
Of the relevant articles (201 reviews and 1904 original studies), 87 review articles and 250 original studies reported off-label use of IVIG and were judged appropriate to the project aims by 1 of the investigators.
Clinical effectiveness was assessed by laboratory and clinical findings, objective measures, and clinical impressions. Each study or review was categorized by level of evidence of study design (type I: randomized controlled trials; type II: controlled trials without randomization, cohort or case-control studies, or case series; type III: expert opinions, descriptive studies, or expert committee reports; and type IV: insufficient evidence to determine role). Recommendations were made after complete consensus was achieved by members of an expert panel. The members considered therapeutic and pharmaceutic interchangeability and adverse effects in making their recommendations.
The expert panel members made recommendations to support or discourage the use of IVIG in 53 conditions. Evidence that was graded level I was available for 17 conditions. IVIG was recommended as an equivalent alternative to plasma exchange in children and adults with the Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy. The panel judged that IVIG may have a role in patients with multiple myeloma at high risk for recurrent infections, in low-birth-weight infants with a high baseline infection rate or morbidity, in cytomegalovirus-seronegative recipients of seropositive transplanted organs, and in patients with severe dermatomyositis in whom other treatments have failed. In 11 conditions (the chronic fatigue syndrome, cystic fibrosis, diabetes mellitus, the nephrotic syndrome, euthyroid ophthalmopathy, acute renal failure, acute lymphoblastic leukemia, surgery or trauma, treatment of infection in hypogammaglobulinemic neonates, and the motor neuron syndrome), level I evidence did not support IVIG use.
For the 53 conditions considered, evidence that was graded level I supports the off-label use of intravenous immunoglobulin preparations for 2 conditions, Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy, with weaker evidence for use in an additional 4 conditions.
Source of funding: Not stated.
For article reprint: Dr. T. Ratko, University Hospital Consortium, 2001 Spring Road, Suite 700, Oak Brook, IL 60521-1890, USA. FAX 630-954-4730.
Ratko and colleagues should be congratulated for their comprehensive and timely analysis of off-label use of IVIG. The use of IVIG has dramatically increased in the past few months and in certain cases has been abused. The product's potential for serious adverse effects (viral transmission, aseptic meningitis, and nephrotoxicity) and its high cost (U.S. $42 to $104/g) argue for the development of efficacy-based guidelines.
3 points are worth emphasizing. First, even in those few selected autoimmune diseases or infections in which level I evidence suggests that IVIG might be indicated, it is generally only to be used if conventional therapy is contraindicated or ineffective and if the disease is life-threatening. Second, outcome markers, such as autoantibody level, target organ function, and infection load, should be monitored during IVIG therapy (1, 2) so that an informed conclusion regarding the benefit and risk of each patient can be made. Third, clinicians should be aware that IVIG only provides passive antibodies to prevent infections and to correct immunoglobulin or antibody deficiencies, to provide monomeric IgG to block sequestration of antibody-coated cells, or to correct immune regulation abnormalities.
Randomized, double-blind, placebo-controlled, multicenter studies are needed to resolve the issue of IVIG off-label use. Clinicians should be encouraged to report negative results with off-label use of IVIG to avoid its future use in similar clinical situations. Insurance companies may wish to use the information provided by this review for decisions on reimbursement or may need to form their own expert panels to approve or disapprove the use of IVIG for off-label recommendations.
Until conclusive studies are published in refereed journals showing whether IVIG provides a benefit (3), off-label use should be individualized and, according to the guidelines of Ratko and colleagues, supervised by experts with specific goals outlined to monitor possible benefits from IVIG.
Nabih I. Abdou, MD, PhD
Saint Luke's HospitalKansas City, Missouri, USA
3. Fanaroff AA, Korones SB, Wright LL, et al. A controlled trial of intravenous immune globulin to reduce nosocomial infections in very-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network. N Engl J Med. 1994;330:1107-13.