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In favor: Beck, Campbell, Finger, Gilsdorf, Hill, Lieu, Marcuse, Morita, Abramson
Opposed: Allos, Womeodu
Abstained: None (Dr. Treanor had a conflict but was not present to vote)
The vote passed.
Varicella Zoster Immune Globulin (V.Z.I.G.)
Dr. Judith Campbell, Working Group Chair
The A.C.I.P. issued recommendations for the use of varicella zoster immune globulin (V.Z.I.G.) in 1984, and revised them in 1996 and 1999. V.Z.I.G. is used for post-exposure prophylaxis (P.E.P.) among those with no evidence of immunity, those for whom exposure is likely to result in infection, and those at high risk of severe varicella disease. The latter group includes immunocompromised individuals (children, adolescents and adults), perinatally exposed neonates and exposed premature infants, pregnant women, healthcare workers and individually exposed adolescents and adults. Vaccination offers the best protection to high-risk groups, directly or indirectly (for example, household contacts of neonates and immune-compromised individuals) and is recommended for primary protection.
Over the last ten years, the need for V.Z.I.G. has decreased and its sole producer, the Massachusetts Biological Laboratory (MBL), decided in 2004 to stop manufacturing the product. In response, the Working Group held conference calls to discuss the key issues relevant to varicella post-exposure prophylaxis, with the participation of a representative of the F.D.A.’s blood products advisory committee. The manufacturer estimated the supply to be available through April 2006, but may be exhausted at an earlier date.
F.D.A. Update on V.Z.I.G. Status/New Product
Presenter: Dr. Dorothy Scott, F.D.A.
Overview: F.D.A. update on V.Z.I.G. status and possible licensure of new product.
V.Z.I.G. is an intramuscular plasma preparation containing high anti-V.Z.V. antibody titers. It should be administered within 96 hours of exposure to persons at high risk for severe varicella and complications. The supply is now expected to last only until January 2006. Annually, an equivalent of about 10,000 125-unit vials (625-unit vials are also available) are administered to approximately 2000 to 10,000 patients (the dose is weight dependent).
F.D.A.’s Blood Products Advisory Committee has publicly encouraged the development of an investigational new drug (I.N.D.) application for V.Z.I.G., and has communicated with C.D.C. about various options. The Committee, which last met in July 2005, is working to define a feasible path to the licensure of a new V.Z.I.G. preparation. This includes defining the necessary lab and clinical efficacy data. Target populations and surrogate markers with which to assess efficacy and support licensure have been discussed.
Also discussed were the considerations for clinical trials and the current knowledge relative to the use of I.G.I.V. or acyclovir rather than V.Z.I.G. These cannot be studied quickly, as vaccination has left few remaining susceptible persons. Other challenges included the variety of clinical situations that will further reduce the number of subjects in each category.
For surrogate markers, the committee indicated pharmacokinetic equivalence in normal subjects compared to the licensed V.Z.I.G. product, coupled with laboratory-demonstrated equivalence or superiority to the (old) licensed product. Then, a Phase IV trial will be needed to further study the product among those with an indication for use.
Committee conclusions. The committee had some uncertainty that I.G.I.V. could substitute for V.Z.I.G., for several reasons: an unknown variability of varicella antibody titer between I.G.I.V. lots, the potential of lessened titers among the donor vaccinees replacing naturally-infected donors, and whether the latter affects antibody quality or affinity. The committee also decided that there was insufficient evidence to recommend the use of acyclovir as a V.Z.I.G. substitute.
C.D.C. assessed the anti-varicella-zoster virus (V.Z.V.) antibody titers in the I.G.I.V. products licensed for general use. These are normally used to replace immune globulin in patients with primary immune deficiency or with thrombocytopenia. Other off-label uses are also known.
F.D.A. sent blinded samples of seven licensed I.G.I.V. products, and the MBL sent V.Z.I.G., to C.D.C. The g.p.E.L.I.S.A. analysis showed the titers in V.Z.I.G. to be highest of all, but a number of I.G.I.V. lots also had fairly comparable levels. This suggests that current immune globulins have anti-varicella titers following natural infection or vaccination, but the titers are unpredictable even within one product type.
The F.D.A.’s ongoing monitoring of the V.Z.I.G. supply indicates that there are no remaining 125-unit vials, and a current use of approximately 200, 625-unit vials per month. With F.D.A. encouragement, the one distributor (FFF Enterprises) is shipping only on an as-needed basis. FFF also tracks the supply to allow stock transfers as needed.
F.D.A. awaits I.N.D. applications and will review them under the financially-attractive orphan drug classification, which allows cost recovery requests. Treatment protocols with the new product also will be considered for patients in need.
F.D.A. is communicating the licensed uses of V.Z.I.G., how to obtain V.Z.I.G. from FFF, and the anticipated shortage (http://www.fda.gov/cber/infosheets/mphvzig092005.htm). They are also urging clinicians and pharmacists to order V.Z.I.G. only for identified patients in need. Shipment within 24 hours in the continental U.S. can be arranged and hospital-to-hospital product transfer is possible.
At least one company has expressed interest in manufacturing a V.Z.I.G. product. F.D.A. will make an I.N.D. available as soon as possible, but that is not likely by January 2006.
Varicella Zoster Virus and P.E.P. Options
Presenter: Philip LaRussa, MD, Columbia University
Overview: High risk groups, correlates of protection, options for post-exposure prophylaxis, alternatives to V.Z.I.G.
Varicella’s pathogenesis involves two viremic phases that can be targeted for prophylactic interventions: a small primary viremia within a day or two following exposure and the larger, secondary viremia, at 10 to 12 days following exposure (1 to 2 days before the rash). The disease is highly contagious to naïve populations. Some groups are at higher risk for serious disease:
Correlates of protection - Literature review.
As far as markers for correlates of protection, vaccine studies or skin test measurements of C.M.I. response have clearly demonstrated varicella susceptibility among persons with FAMA titers less than 2. For vaccinated children, a g.p.E.L.I.S.A. titer ≥5 units at six weeks after immunization correlated highly with protection (95.5 percent, versus 83 percent at less than 5 units). The challenge was in distinguishing the antibody effects from those of the vaccine-induced C.M.I. Gershon’s small study of vaccinated leukemic children who were later exposed to varicella at home, and who had an antibody plus C.M.I. response, showed that none developed the disease. All the children with neither antibody nor C.M.I. response developed varicella, and those with one or the other had variable rates of disease.
Options for post-exposure prophylaxis (P.E.P.) for persons at high risk for severe varicella disease, other than V.Z.I.G. (if produced again), were outlined with their advantages and disadvantages.
Intravenous gamma globulin (Immune globulin intravenous, I.G.I.V.): Advantages: There are some data to support the use of I.G.I.V. It produces good anti-varicella titers, although more is needed to be comparable to V.Z.I.G. in effectiveness; supply is normally good. Because it produces a peak serum level faster than V.Z.I.G. does, the window for prophylactic use may be extended beyond that of V.Z.I.G. The disadvantages include I.G.I.V.’s greater cost (approximately 240 dollars per 10 kg child) than V.Z.I.G. (approximately 125 dollars); unclear volume to be used in neonates; possible variation in efficacy, since these preparations are not titered for anti-V.Z.V. antibodies; and the possibility, with rising numbers of vaccinated individuals, that higher doses will be needed.
Studies of I.G.I.V. use as prophylaxis against varicella are few.
Vaccine used as prophylaxis has the advantages of being highly efficacious if given to healthy children within 36 hours of exposure, and of being a one-time, easy administration. The disadvantages include its inappropriateness for use among immunocompromised patients, pregnant women, or newborns, lack of certainty that one dose is efficacious as post exposure prophylaxis in adults, and difficulty of administering two doses in a prophylactic setting.
Antivirals for use as prophylaxis include acyclovir, famciclovir, and valacyclovir. Some data support their use. Advantages: They can be effective after the V.Z.I.G. window and therefore can be given later in the incubation period. Disadvantages include limited data on their use among immunocompromised patients and their status as Class B drugs for use in pregnancy. Animal trials showed the drugs to be safe. Data are very limited on antiviral use as prophylaxis in newborns. Most of the data are with Acyclovir, where there is concern about absorption when administered orally. The absence of a liquid formulation for the other two drugs limits their use among very young children and infants. In addition, antivirals require compliance with multi-day regimens and that may influence the efficacy. Suga et al (Arch Disease Child, 1993) studied infection in children given acyclovir for seven days in a dose of 40 milligrams/kilograms. The infection rates, compared between prophylaxis begun at 3-, 6-, and 10-days post-exposure, versus none, were comparable. However, when administered at the end of the incubation period, at onset of the large, secondary viremia, acyclovir was very effective and disease was much milder. Acyclovir inhibits viral replication, and the antibody titers in children receiving acyclovir were somewhat lower than in children not receiving it. There have been no follow-up studies to see if that affects later exposures.
Options. Most of the immunocompromised patients seen now will probably have been vaccinated as healthy hosts. If they are not immune, I.G.I.V. or an antiviral can be used. In those for whom a vaccine is not appropriate (neonates, pregnant women, children aged less than 1 year), I.G.I.V. or an antiviral can be used. Vaccine may be used for P.E.P. among non-pregnant healthy adolescents and adults.
In summary, a substitute product is still needed. I.G.I.V. is probably equivalent or superior to V.Z.I.G. at an appropriate dose, but will have to be re-evaluated periodically. Whether the window for I.G.I.V. use matches that for V.Z.I.G. also needs to be determined. Antivirals could be useful, especially when the window for administration of I.G.I.V. is missed. More studies are needed to test antivirals in populations other than healthy children. Vaccine is currently of limited utility as a substitute for V.Z.I.G.
Issues Related to P.E.P. with V.Z.I.G. or I.G.I.V. Use
Presenter: Dr. Mona Marin, N.I.P.
Overview: Content of the proposed statement on P.E.P. against severe varicella during a V.Z.I.G. shortage.
The Working Group reviewed the literature on alternative methods for post-exposure prophylaxis of persons at high risk for severe varicella. The current scientific data is not strong enough to fully support one or another alternative method – there are limitations due to the studies’ small numbers and design (lack of a control group), difficulty in ascertainment of exposure, and limited data among immunocompromised persons or clinical data showing efficacy. Although limited, there is stronger scientific evidence supporting I.G.I.V. use as P.E.P. against severe varicella when V.Z.I.G. is not available. However, some experts indicated that based on limited clinical experience, acyclovir could be considered, especially for cases occurring ≥96 hours after exposure, when it is too late to administer I.G.I.V. A footnote states this as a consideration with or without use of other methods. There are no data to support its use among immunocompromised persons.
Based on the literature and expert opinion, the Working Group identified V.Z.I.G. as the preferred method for P.E.P. for patients at high risk for severe varicella and complications. If V.Z.I.G. is not available, I.G.I.V. can be used for:
Exposed patients already receiving I.G.I.V. therapy at greater than or equal to 400 milligrams/kilograms at regular intervals with the last dose within three weeks after exposure, may not need a new I.G.I.V. dose.
Any patient receiving I.G.I.V. for varicella prevention should subsequently receive varicella vaccine, if not contraindicated, but not before eight months after the I.G.I.V. administration. Vaccination is not necessary if varicella develops after I.G.I.V.
Acyclovir used as P.E.P. should be administered late in the incubation period (from day 7 to day 10 after exposure) and given for seven consecutive days. Children’s dose should be 40 to 80 milligrams/kilograms per day; adults should receive 80 mg five times a day. Varicella vaccine should be administered at a later date unless contraindicated and the patient does not develop varicella.
Patient management after P.E.P. Any patient receiving I.G.I.V. or acyclovir should be monitored closely for varicella for 28 days after exposure. Antiviral therapy should begin at the earliest signs or symptoms. Physicians should judge the route and duration of administration, based on specific host factors, extent of infection, and initial response to therapy.
Dr. Myers questioned the wisdom of waiting to administer acyclovir until the mother is symptomatic, since the fetus may be affected by the mother’s viremia. The Working Group discussed this extensively. The Working Group physicians were uncomfortable recommending acyclovir in the first or second trimester of pregnancy. Since there are no efficacy or safety data to support that, the decision favored monitoring the mother. They agreed that physicians could have I.G.I.V. as an option, but acknowledged concerns about the necessary high doses. Dr. Campbell reassured all that Dr. Stan Gall, of ACOG, had participated in the discussion and in preparation of the documentation. Dr. Jim Cherry, of UCLA, urged that the importance be stressed of diagnosing the index case. There is anecdotal evidence of V.Z.I.G. being administered after exposure to rashes that were not varicella. Dr. Abramson agreed.
Dr. Campbell moved to accept the recommendation that I.G.I.V. be the primary P.E.P. method against varicella in a situation of V.Z.I.G. shortage. Dr. Marcuse seconded the motion.
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