Smallpox Vaccine, Dried, Calf Lymph Type - Dryvax; live vaccinia virus vaccine against variola -virus
Status: approved but no longer manufactured; existing stocks withdrawn in the U.S. in 2008
Organizations involved:
Wyeth Pharmaceuticals – Manuf.; R&D; Tech.
Centers for Disease Control and Prevention (CDC) Drug Service – USA mark.
Cross ref: See the entry above for Smallpox Vaccine Products (#535), and the entries below for other smallpox vaccines.
Description: Smallpox Vaccine, Dried, Calf Lymph Type or Dryvax is a lyophilized (freeze-dried) formulation of live attenuated vaccinia (cowpox) virus for topical vaccination against a closely related virus, variola (smallpox) virus. The vaccine contains about 1 X 108 (100 million) pock-forming units (live infectious virions) per mL. The vaccine was manufactured from the lymph fluid (pus) of calves (bovine) skin infected with the New York City Board of Health (NYCBH) strain of vaccinia virus. The calf lymph was purified, concentrated, and dried by lyophilization. During processing, polymyxin B sulfate, dihydrostreptomycin sulfate, chlortetracycline hydrochloride, and neomycin sulfate are added; and trace amounts of these antibiotics may be present in the final product. Besides live vaccinia virus, the vaccine is not sterile. Reconstituted vaccine contains not more than 200 viable bacterial organisms/mL. The diluent for lyophilized Dryvax contains 50% glycerin, 0.25% phenol, and 0.005% brilliant green (dye) in Sterile Water for Injection, USP. After reconstitution, the vaccine is administered by multiple-puncture (poking) into the superficial layers of the skin, usually on the upper arm, using a bifurcated needle.
This vaccine was originally manufactured and used for about 80 years, with its manufacture ending in the early 1980s. However, with recent concerns about biological warfare and bioterrorism use of variola virus (smallpox), long frozen stocks of virus have been retested and reapproved for vaccination of selected high-risk individuals, e.g., health care professionals likely to have to treat any cases of smallpox and military personnel, and for emergency use by the general population.
Dryvax is packaged in 100-dose kits, each containing a 100-dose vial of lyophilized vaccine, one pre-filled diluent syringe (0.25 mL), one transfer needle, and one box of 100 individually wrapped bifurcated needles (20 strips, 5 needles per strip). The current dating period for the lyophilized vaccine is 24 months at 2-8°C (refrigerated). The dating period starts the date of transfer of Dryvax from storage at -20°C to 2-8°C (thawing). Reconstituted Dryvax may be held at 2-8˚C (refrigerated) for 90 days. Prior to administration, the lyophilized vaccine is reconstituted with the supplied diluent containing a brilliant green dye to assist in visualizing its administration into the skin using the bifurcated needle. This sterile single-use needle is dipped into the vaccine, with the needle holding liquid between its tines/prongs, and is jabbed into the skin on the upper arm 15-times to induce localized skin infection with vaccinia virus. The new needle and packaging has been redesigned to help prevent “needlestick injury.”
As originally approved, bulk vaccine could be stored, e.g., by the manufacturer, immediately after manufacture at a temperature below 5˚C for 3 years. The period of validity (shelf life) began at the time that the vaccine was released by the manufacturer. The marketed product shelf life was 18 months when stored at 2-8˚C (refrigerated). When stored at this temperature, the period of validity was 12 months. By these criteria, all remaining stocks are decades past their dating period.
About 10 million doses of Dryvax were reported in early 1999 to be in storage in the U.S. (under control of the Centers for Disease Control and Prevention and the Department of Defense), potentially available in case of smallpox outbreaks (whether natural or biological warfare/bioterrorism). Wyeth-Ayerst Labs. stored a reported 6-7 million doses of vaccine (Dryvax) under contract for the CDC. Subsequently, an estimated total 15.4 million doses are reported to be held in storage by the U.S. government.
The new bifurcated (forked) needle from Becton Dick-inson & Co. (approved in 2002), like other needle-type devices for delivery of smallpox vaccines, is designed to penetrate (by poking) the outer stratum corneum layer of the skin and deliver a small amount of vaccine to the deep epidermis, leading to localized topical vaccinia virus infection. The needle is dipped into liquid reconstitutued Dryvax, and holds ~0.0025 mL of fluid by capillary action between its two prongs (tines).
Nomenclature: Smallpox Vaccine/Wyeth [BIO]; Smallpox Vaccine, Dried, Calf Lymph Type [FDA]; Dryvax [TR]; Smallpox Vaccine USP [USP]; Vaccinum Variolae Cryo-desiccatum Dermicum [SY Latin]; variola virus vaccine, live [SY]; NDC 0008-0348-08 [NDC]
Companies.: Dryvax was manufactured by Wyeth-Ayerst Laboratories, Inc. (now Wyeth); CBER/FDA est. no. 0003. It was formerly marketed in the U.S. by Wyeth and internationally by Wyeth affiliates. Dryvax was manufactured at Marietta, PA, facilities, which Wyeth closed in 2003. Becton Dickinson & Co. manufactures the new bifurcated (two-pronged) needle being in new Dryvax vaccination kits.
Manufacture: Dryvax was manufactured by a traditional/classic method from the lymph (pus) of vaccinia virus lesions on topically-infected healthy young cattle (calves). Wyeth owned a farm where the calves were raised. The calves’ bellies were scratched with vaccinia virus, inducing localized infection, and developed pustules. The infected calves were killed, hung up on hooks, blood was drained, and the pustules were scraped off with a knife. After unspecified processing (not including substantive purification steps), the product obtained was lyophilized (freeze dried) and stored in sealed ampoules. The vaccine is not sterile ( although it has a rather low level of contaminating non-pathogenic microorganisms), and contains particles of hair, skin, and other bovine material. The final product is an almost white powder containing no added antibiotics or preservatives.
By current standards, this vaccine may be considered crude in terms of its manufacture and quality control (although the vaccine has a safety record, acceptable at the time, spanning decades). Dryvax can be presumed to be contaminated with various bovine viruses, which may or many not have survived lyophilization. Any bovine virus contamination did not pose a detectable problem among the many millions having received Dryvax vaccine over decades (although there were certainly significant adverse and fatal reactions to the vaccinia virus infection it causes).
Quality control testing included various contaminating microorganism assays. The reconstituted vaccine was examined by microscopic and culture methods for Escherichia coli and for other pathogens, in particular, hemolytic streptococci, staphylococci, Bacillus anthracis, and anaerobic spore-bearing organisms, especially Clostridium tetani. The vaccine is free from these contaminants. The total number of non-pathogenic bacteria does not exceed 50/mL. Available materials make no mention of testing for bovine or other viruses, BSE/TSE, mycoplasma, or other potential pathogen contamination. A heat-resistance test involves keeping the freeze-dried vaccine at a temperature of 37˚C for not less than 4 weeks. The vaccine is reconstituted and must retain at least one-tenth of its original viral titer, and not less than 1 X 108 pock-forming units per milliliter. The Abnormal Toxicity (V.2.1.5) assay involves injection of 0.2 mL of reconstituted vaccine into mice and 0.5 mL into guinea pigs. Virus titer was determined by titrating the reconstituted vaccine by inoculation onto the chorioallantoic membrane of fertilized hen eggs in comparison with the International Reference Preparation of Smallpox Vaccine. Other tests included inoculating the vaccine into the scarified skin of a rabbit or into cell cultures, with the vaccine inducing the formation of characteristic pox lesions; and after neutralization of the virus by a specific antiserum of high potency, the preparation no longer induces the formation of lesions.
FDA class: Biologic PLA
Approvals: Date = 19030821; PLA; first approval granted to a company (Gilliland Labs. or Reichel Labs.) now part of Wyeth; reported in 1979 Office of Technology Assessment (OTA) vaccines approvals list (from data supplied by FDA); historical references also refer to approval in early 1900s
Date = 19440519; first approval, according to the CBER/FDA database [official, but wrong]; This is the date of license transfer to Wyeth after the 1944 formation of its vaccine division through acquisition of Gilliland Labs. and Reichel Labs.
Date = 20020402; medical device 510(k) approval granted to Becton Dickinson & Co. for a new bifurcated needle for administration of Dryvax
Date = 20021025; BLA supplement; Indication = (re)approval of Dryvax (remaining ~15.4 million stockpiled frozen doses) in new 100-dose kit (packaged with new bifurcated needles and diluent solution), including allowing storage at 2-8˚C (refrigeration) for 30 days after reconstitution
Date = 20030212; BLA supplement; Indication = allow storage at 2-8˚C (refrigeration) for 90 days after reconstitution
Date = 20030626; BLA supplement; Indication = include in product labeling/insert new safety information regarding reports of cardiac events, and addition of product storage changes (from the Feb. 12, 2003 approval)
Date = 20040511; BLA supplement; Indication = inclusion in the package insert of a Black Box Warning that acute myopericarditis has been observed after administration of Dryvax to healthy adults
Date = 20051011; BLA supplement; Indication = new Black Box Warning for cardiac events and other safety information
Date = 20071213; BLA supplement; Indication = extended the expiration date for remaining Dryvax lots from Dec. 31, 2007 to Feb. 29, 2008
Indications: [full text of the "Indications and USAGE” section of product insert/labeling; 7/2003]:
Smallpox vaccine is indicated for active immunization against smallpox disease. The Advisory Committee on Immunization Practices (ACIP) recommends vaccination of laboratory workers who directly handle a) cultures or b) animals contaminated or infected with non-highly attenuated vaccinia virus, recombinant vaccinia viruses derived from non-highly attenuated vaccinia strains, or other Orthopoxviruses that infect humans (e.g., monkeypox, cowpox, vaccinia and variola). The ACIP also recommends that vaccination can be considered for healthcare workers who have contact with clinical speci-mens, contaminated materials (e.g., dressings), or patients receiving vaccinia or recombinant vaccinia viruses. Laboratory and other healthcare personnel who work with highly-attenuated poxvirus strains such as modified vaccinia Ankara (MVA), NYVAC (derived from the Copen-hagen vaccinia strain), ALVAC (derived from canarypox virus), and TRO-VAC (derived from fowlpox virus) do not require routine vaccination. For those in the above special-risk categories, revaccination is recommended at appropriate intervals (every ten years). The Armed Forces continue to recommend use of smallpox vaccine for certain categories of personnel. See the most recent issue of Immunizations and Chemoprophylaxis, Departments of the Army, the Navy, the Air Force, and Transportation (Army Regulation 40-562, BUMEDINST 6230.15, Air Force Joint Instruction 48-110, CG COMDTINST M6230.4E) and Department of Defense (DoD) Directive 6205.35 for current recommendations concerning use.
The judicious use of smallpox vaccine has been reported to have eradicated smallpox. At the World Health Assembly in May 1980, the World Health Organization (WHO) declared the world free of smallpox infection.
As with any vaccine, smallpox vaccine may not protect all individuals receiving the vaccine.
Use of Smallpox Vaccine in Response to Bioterrorism: Recommendations for use of smallpox vaccine in response to bioterrorism are periodically updated by the Centers for Disease Control and Prevention (CDC), and the most recent recommendations can be found at http://www.cdc.gov.
Status: Dryvax has been reapproved for indications: including bioterrorism/biological warfare defense. It is also approved for use among those occupationally exposed, e.g., researchers, to vaccinia and certain other poxviruses, including some commonly used as recombinant poxvirus vectors.
Dryvax is no longer manufactured or marketed. manufacture of Dryvax by Wyeth for commercial sale ceased in 1982, but Wyeth, then the only active licensed producer of smallpox vaccine in the U.S., continued for a short time to produce vaccine for the Department of Defense (DOD), which halted routine vaccination of military personnel in the early 1990s. In May 1983, Wyeth halted civilian distribution of vaccine. With smallpox then considered eradicated for over a decade, the vaccine was presumed to no longer be needed for its indicated use, prevention of circulating wild smallpox. Smallpox vaccination has not been required for international travelers since Jan. 1982, and international Certificates of Vaccination no longer require smallpox vaccination.
Dryvax is available in the U.S. for non-military use only from the Drug Service, National Center for Infectious Diseases (NFID), Centers for Disease Control and Prevention (CDC) and the Division of Quarantine, NFID, CDC. The CDC provides the vaccine only “for laboratory workers directly involved with smallpox or closely related orthopox viruses (e.g., monkeypox and vaccinia).” The vaccine is supplied free to those meeting CDC criteria.
In Nov. 2002, with the reapproval of Dryvax administration kits with new bifurcated needles and diluent vials, U.S. (CDC and Army/DOD) stocks of Dryvax totalled an estimated 15.4 million doses in frozen storage. The first 1.7 million doses of new vaccination kits have been transferred to the Army/Department of Defense, and the remaining 13.7 million doses have been transferred to the CDC for use in civilian vaccination programs, e.g., the failed attempt to vaccinate health care workers/first responders, and for use in an outbreak/attack.
DOD continued to use Dryvax to vaccinate U.S. military personnel. In Feb. 2004, DOD reported that 578,286 of its personnel had been vaccinated, and that there had been 30 reported cases of uncomplicated vaccinia virus infection among contacts of immunized persons. A more formal study of military vaccinees was published in the June 25, 2003 issue of the Journal of the American Medical Association, with only a few, fewer than expected, adverse events among 450,293 vaccine recipients. One case of encephalitis (brain inflammation) and 37 cases of myopericarditis (heart inflammation) occurred. No deaths were attributed to the vaccine in this healthy cohort.
Tech. transfer: The strain of vaccinia virus used, the New York City Board of Health (NYCBH) strain, originally developed over a century ago, is not covered by any in-force U.S. patents. No relevant U.S. patents were located (using computerized databases limited to recent decades).
Wyeth/American Home Products Corp. developed the bifurcated needle for delivery of Dryvax in the 1960s. Wyeth/AHP waived all rights to its patented bifurcated needle in 1968, alowing other manufacturers worldwide to adopt the needle.
In the May 2004 issue of the Journal of the American College of Cardiology, it was reported that heart complications from Dryvax administered to American troops were occurring at a higher rate than expected. About 16 of every 100,000 given vaccine for the first time between Dec. 2002 and Sept. 2003 developed myopericarditis, an inflammation of the heart muscle or the sac surrounding it. If these results were generalizable to the general public, this could potentially result in thousands of cases of Dryvax-associated myopericarditis.
Trials: An article in the April 25, 2003 issue of the New England Journal of Medicine reported results from a 680 subject trial demonstrating that the existing U.S. stockpile of 15.4 million doses of Dryvax could be diluted and still retain its potency. Subjects randomly received undiluted vaccine (n = 106), vaccine diluted 5-fold (n = 234) or vaccine diluted 10-fold (n = 340). Subjects were then monitored for 56 days. Overall, over 97% responded with a ‘take’ (induction of localized skin lesion), a surrogate marker for vaccine efficacy, after the first vaccination. There were no statistically significant differences in the take rates between the different vaccine dosages. Undiluted vaccine provided a 97% take, 1:5 dilution provided a 100% take, and 1:10 dilution provided a 98% take. This and other studies support current U.S. government plans, if needed, to dilute existing stocks of Dryvax (use more diluent for reconstitution) up to 10-fold to vaccinate >150 million persons.
In the Dec. 7, 2005 issue of in the Journal of the American Medical Association (JAMA), investigators from Centers for Disease Control and Prevention (CDC) reported that only 100 out of the nearly 37,901 U.S. emergency (first responder) workers inoculated with Dryvax under the failed federally-sponsored first responders and healthcare workers vaccination program had become seriously ill from vaccination, considered a relatively low rate of adverse reactions. There were 722 “nonserious adverse events,” while 100 others became seriously ill. Most reactions showed up within two weeks of vaccination, with 21 involving inflammation of muscular tissue or a membrane around the heart (myopericarditis). There were no cases of life-threatening rashes that were more common when the vaccine was used widely four decades ago, no contact transmissions, and no adverse reactions that required vaccinia immune globulin (VIG). Ten patients had ischemic events such as strokes that had not been seen before, two had skin eruptions, and one developed inflammation of the brain. Eighty-five patients recovered after a hospital stay, two suffered permanent disabilities, 10 had life-threatening illnesses, and three died. The investigators concluded that improved screening for potential heart, skin or other problems could further cut down on adverse reactions in large-scale vaccination programs. Other critics site the adverse effects and deaths associated with Dryvax (and other smallpox vaccines) as too high and not worth the risks for large-scale prophylactic vaccination programs.
Another study published in the same Dec. 6, 2005 issue of JAMA reported that the inoculation of 665,000 members of the U.S. military between Dec. 2002 and March 2004 showed that vaccination of healthy soldiers was relatively safe (or safer than many had feared), had triggered relatively few adverse neurological reactions, with most of these mild. Of more than 600,000 people inoculated in the two programs, 214 had adverse reactions ranging from transitory headaches to cases of encephalitis. Other infrequent reactions included Guillain-Barre Syndrome and Bell’s palsy. These and other studies suggest that large-scale use of Dryvax in healthy Americans is safer (relatively) than had been presumed (feared), which may support the position that government-backed liability insurance for smallpox vaccines is feasible.
In March 2007, Dr. R. Couch and colleagues, Baylor College of Medicine reported results of additional dilution trials with Dryvax and Wetvax (see related entries below) showing that diluted vaccines not only remain effective, but are associated with reduced vaccine-associated morbidity. In this study, 330 vaccinia naïve persons were randomly assigned to 1 of 11 vaccine-dose groups in a double-blinded fashion. Virus titers in the undiluted vaccine ranged from 107.46 to 108.27 pfu/mL (mean 108.2 pfu/mL). The combined take rates for recipients of 1:100 diluted Dryvax was 83.3%, mainly due to 4 of 6 subjects without a take at one testing site (perhaps, an aberration). Differences in take rates for each group were not statistically significant, other than a linear trend toward reduced take with reduced dose of Dryvax.
On Dec. 17, 2007, FDA extended the expiration date for remaining Dryvax lots from Dec. 31, 2007 to Feb. 29, 2008.
In Feb. 2008, CDC reported it had begun distribution ACAM2000 (see related entry) to civilian laboratory personnel, the military, and state public health preparedness programs. Also in early 2008, DOD transitioned from Wyeth’s Dryvax brand of smallpox vaccine to Acambis’ ACAM2000 brand of smallpox vaccine. With this the U.S. transitioned to ACAM2000. Wyeth asked that all remaining quantities of Dryvax held by civilian and military users be quarantined by Feb. 29, 2008, for the purpose of destruction. This withdrawal is not necessitated by any safety, purity, but all lots of Dryvax vaccine expired on Feb. 29, 2008 and should not to be used after that date. The CDC disposed the last of its 12 million doses of Dryvax, and notified other health departments and the military to do the same by Feb. 29.
With its withdrawal and expiration of all Dryvax stocks in Feb. 2008, Wyeth intended to withdraw the BLA for Dryvax.
Medical: One dose is administered by the scarification (bifurcated needle jabbing) method, both for pre- and post-exposure prevention of disease from variola virus infection. The vaccination site is then bandaged, and should be kept bandaged to prevent others from becoming infected with vaccinia virus. Primary vaccination elicits a ~97% response (take) rate. The original vaccination schedule called for repeat (booster) doses every ten years. Vaccinia immune globulin (VIG) may also be administered after known/suspected variola virus exposures.
The vaccine is administered into the skin by scarification (pricking/poking) –15 quick pokes into the skin on the upper arm with a bifurcated needle holding reconstituted vaccine. The resulting localized infection generally induces immunity, both humoral antibodies and cellular hypersensitivity, providing protection against disease and death from infection with variola (smallpox) virus when administered prior to or shortly after variola virus infection. Many recipients experience short-lived mild fever. With the primary vaccination, a papule appears at the site of vaccination on about the 2nd to 5th day. This becomes a vesicle on the 5th or 6th day, which becomes pustular, umbilicated, and surrounded by erythema and induration. The maximal area of erythema is attained between the 8th and 12th day following vaccination (usually the 10th). The erythema and swelling then subside, and a crust forms which comes off about the 14th to 21st day. At the height of the primary reaction, known as the Jennerian response, there is usually regional lymphadenopathy and there may be systemic manifestations of fever and malaise.
Serious side effects of Dryvax (vaccinia virus infection), beyond the lesion at the site of vaccination, e.g., encephalitis and death, are generally infrequent. Vaccinated persons can transmit live vaccinia virus to non-vaccinated persons. Both those vaccinated and those exposed to virus from vaccinated individuals can develop vaccinia necrosum, a progressive spreading necrosis at the site of vaccination; eczema vacci-na-tum, pox lesions on the skin at the vaccination site or elsewhere on the body, particularly in patients with a history of eczema; and accidental infection, or lesions when the vaccine is unintentionally transferred to the eye or mouth or other parts of the body.. These occur at low frequency, but there would be significant morbidity and mortality during a large vaccination campaign, which could involve millions.
Various studies have reported the incidence of complications associated with Dryvax, including generalized vaccinia infection, to be about 23.4/100,000 in those receiving primary vaccination and 1.2/100,000 in those receiving a booster; with progressive vaccinia infection in 10.4/100,000 receiving primary vaccination and 0.7/100,000 receiving a booster. Generally, an estimated 1/1,000,000 healthy vaccinees die. In the U.S. in the 1960s, two studies of the adverse effects of Dryvax reported similar results. Among 6.2 million primary vaccinations in 1963 and 5.6 million vaccinations in 1968, the vaccine caused 54 vaccinee deaths due to eczema vaccinatum in 1963 and 58 deaths in 1968, as well as 54 contact deaths in 1963 and 60 in 1968. There were 85 deaths from accidental infection in 1963 and 142 in 1968, and 22 infection deaths through contact with vaccinees in 1963 and 44 deaths in 1968.
Vaccinia virus infection can be life-threatening in those with immune suppression, eczema, and other predisposing conditions. Because of the danger of an unchecked vaccinia virus infection, this live vaccine is contraindicated in patients with immune deficiencies (e.g., AIDS, transplant recipients), patients with eczematous or exfoliative skin disorders, and pregnant women. All but a few recent studies of the adverse effects of Dryvax and other smallpox vaccines were performed decades ago on a U.S. population much different than today. Persons with immune suppression, e.g., HIV/AIDS, cancer, and transplant recipients, and others for whom the vaccine is contraindicated (likely to cause serious infection) are now a much larger portion of the population, and obesity and some other diseases now much more common.
In comparison with marketed vaccines, smallpox vaccine has a very high incidence of adverse effects, such that no company would likely get involved in its manufacture and marketing without federal exemption/insurance from liability.
No clinical or other human data are available regarding the efficacy of Dryvax for prevention of disease from bioterrorism/biological warfare use of variola virus, including the strain(s) manufactured by the former Union of Soviet Socialist Republics (USSR) and other states known/presumed to have variola virus weapons. For U.S. biological warfare defense, this uncertainty regarding the efficacy of smallpox vaccine against likely threats is compounded by the aged state of preexisting frozen vaccines (Dryvax and the Aventis Pasteur/Sanofi Pasteur vaccine) and the untested efficacy of new cell cultured vaccines.
In addition to its prior use in the U.S., Dryvax was used in the successful program to eliminate smallpox in West and Central Africa and in other parts of the global eradication program (Federal Register 45:25683-25688, 1980). As demonstrated during this and other major vaccination campaigns, a vaccine “take,” as evidenced by development of a pustule after vaccination or the presence of a scar from previous smallpox vaccination, was associated with protection against disease. Other vaccines from foreign manufacturers were used in other international vaccination programs.
Recent studies have shown Dryvax to partially protect monkeys against aerosol exposure to monkeypox (a model for variola virus biological warfare/bioterrorism).
As discussed in the Smallpox Vaccine Products (#535) entry and the entries for smallpox vaccines in development and available for emergency use, e.g, ACAM2000, the federal government has contracted for research, development, manufacture, and stockpiling of new cell cultured vaccines. Once these are approved and, presumably, shown comparably effective to Dryvax, these will replace Dryvax as the first-line postexposure prophylactic agent against variola virus (i.e., for the U.S. biodefense stockpile).
Companies involvement:
Full monograph
536 Smallpox Vaccine/Wyeth
Nomenclature:
vaccinia virus, live, NYCBH []
Smallpox Vaccine/Wyeth [BIO]
Dryvax [TR]
Smallpox Vaccine, Dried, Calf Lymph Type [FDA]
Smallpox Vaccine USP [USP]
Vaccinum Variolae Cryodesiccatum Dermicum [SY Latin]
variola virus vaccine [SY]
NDC 0008-0348-08 [NDC]
FDA Class: Biologic PLA
Year of approval (FDA) = 1903
Date of 1st FDA approval = 19030821
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
bovine materials used<!-- bovinesource -->
live microorganisms (as active agent)
vaccines, live
vaccines, viral
bovine lymph
neutropenia
vaccinia virus vaccine
virus culture
breast cancer
glycerin
lyophilized (freeze-dried)
phenol
Sterile Water for Injection
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
BHK-21 (C-13)
conjugates
conjugates
EU200 Currently Approved in EU
US200 Currently Approved in US
UM999 Not Available/Not Marketed in US
US200 Currently Approved in US
US666 Biodefense stockpile
EM160 Controlled/Gov't Distribution in EU
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