Volume 10
`Number 6
`June, 1984
`
`Carcinoma associated with radioactive gold
`
`4. Boggs RF, Schmidt GD, Williams KD: Radiological
`health aspects of spent radon seeds. DREW, Radiological
`Health Data and Reports 10:185-190, 1969.
`5. Lever WF, Schaumburg-Lever G: Histopathology of the
`skin, ed. 6. Philadelphia, 1983, J. B. Lippincott Co., pp.
`214-215.
`6. Jones D, Bjamgard B, Simon N, Harley J: The application
`
`of phosphor-Teflon thermoluminescent dosimeters to the
`measurement of the dose-rate from radioactive jewelry. Br
`J Radio! 41:944-946, 1968.
`7. Baptiste MS, Rothenberg R, Nasca PC, et al: Health effects
`associated with exposure to radioactively contaminated
`gold rings. JAM ACAD DERMATOL 10:1019-1023, 1984.
`
`Adverse reactions to sulfites in drugs
`and foods
`
`Sulfites are antioxidants that are used as preser(cid:173)
`vatives in drugs and foods. Six sulfites have been
`listed as Generally Recognized and Safe (GRAS)
`by the Food and Drug Administration (FDA) for
`use in foods, and they are as follows: sulfur diox(cid:173)
`ide, sodium sulfite, sodium and potassium bisulfite
`and sodium and potassium metabisulfite. These
`antioxidants keep fruits and vegetables fresh look(cid:173)
`ing, and because of this feature and the current
`increased popularity of salad bars in restaurants,
`increased ingestion of sulfites has occurred.
`Metabisulfite reactions are important to der(cid:173)
`matologists because of symptoms that involve the
`skin. The predominant skin lesion is severe flush(cid:173)
`ing, but urticaria/angioedema, tingling, and pruri(cid:173)
`tus have been reported. Besides flushing, the other
`major symptoms are acute bronchospasm and hy(cid:173)
`potension-one death has been reported to the
`FDA. The onset of these symptoms after an en(cid:173)
`counter with a particular substance is critical for
`the diagnosis to be suspected. The onset is ex(cid:173)
`tremely rapid, occurring between 2 to 15 minutes,
`depending on whether the sulfite is in the form of
`an inhaler, solution, capsule, or solid food parti(cid:173)
`cle. The first two forms result in a reaction within
`2 minutes. Adverse reactions to aspirin, tartrazine,
`monosodium glutamate, and most food allergy
`occur at a significantly longer period of time,
`about 1 hour or more after ingestion.
`The recognition and acceptance of metabisulfite
`reaction appears to be taking the slow course as in
`
`the early days of discovering and accepting the
`entity of tartrazine sensitivity, which was first dis(cid:173)
`covered in 19591 and began to be accepted in
`1967. 2
`4 Similar to tartrazine, early manuscripts
`-
`dealing with metabisulfite were not accepted for
`publication in many medical journals. Finally,
`they were accepted for publication in Annals of
`Allergy, presenting a strong case for preserving
`specialty publications.
`When dissolved in an aqueous solution, sulfites
`generate so2, which may be the cause of, at least,
`some of the adverse reactions attributed to sulfi tes.
`Asthmatic patients are extremely sensitive to small
`concentrations of S02 gas and will respond with
`acute bronchospasm. 5 ' 6 The first reported case7 of
`an asthmatic patient dying of acute bronchospasm
`from S02 sensitivity probably occurred in 79 A.D.,
`at the time of the eruption of Vesuvius. It seems
`that Pliny the Elder, a known asthmatic, was in(cid:173)
`vestigating this eruption when the smell of sulfur
`in the air caused him to stand in distress, and while
`leaning on two slaves, he suddenly collapsed and
`died. The two slaves with him survived. Report(cid:173)
`edly, sulfur dioxide exceeds 20% of total active
`gases in most volcanic samples.
`The frequency of sulfite sensitivity in an asth(cid:173)
`matic population is estimated to be about 10%.
`These figures were approximated by obtaining data
`from Freedman7 and using known information
`from epidemiology studies of aspirin and tartra(cid:173)
`zine. Freedman investigated 272 asthmatic patients
`1077
`
`Page 1 of 4
`
`SENJU EXHIBIT 2322
`LUPIN v. SENJU
`IPR2015-01105
`
`

`
`1078 Settipane
`
`Journal of the
`American Academy of
`Dermatology
`
`Table I. Reports of bisulfite reactions (adults)*
`
`Investigators
`
`Prenner and Stevens9
`Freedman7
`Stevenson and
`Simonw
`Werth11
`Twarog and Leung12
`Schwartz13
`Habenicht et aF4
`
`Year
`
`1976
`1977
`1981
`
`1982
`1982
`1983
`1983
`
`Patients
`
`Type
`
`No. I
`1
`Normal
`Asthmatics
`8
`Asthmatics
`4
`
`1
`1
`2
`2
`
`Asthmatic
`Asthmatic
`Asthmatics
`Normals
`
`Positive
`bisulfite
`oral challenge
`
`Symptom
`onset
`(min)
`
`Positive
`bisulfite
`skin test
`
`Yes
`Yes
`Yes
`
`Yes
`Yes
`Yes
`Yes (1)
`
`Few
`1-2
`10-15
`
`2
`2
`10
`15
`
`Yes
`ND
`Neg
`
`ND
`Yes
`Neg
`ND
`
`Remarks
`
`Pas P-K
`Pas smog
`Pas smog
`
`Pos smog
`Neg P-K
`
`ND: Not done; P-K: Prausnitz-Kiistner reaction.
`*From Settipane GA: N Eng! Reg Allergy Proc 4:304, 1983.
`
`and reported that thirty had adverse reactions to a
`soft drink that contained both tartrazine and sul(cid:173)
`fi tes. Since approximately 10% of asthmatics have
`aspirin intolerance and about 10% of this subgroup
`also have tartrazine sensitivity, the extrapolation of
`these figures results in the approximation that
`twenty-seven ( 10%) of Freedman's 272 asthmatics
`had adverse reactions to sulfites. A recent report8
`stated that 8.2% of asthmatic patients without a
`suggestive history had positive metabisulfite chal(cid:173)
`lenges.
`In the modern literature in which a positive
`challenge was used to establish the diagnosis,
`Prenner and Stevensu were the first to report, in
`1976, that bisulfite caused a severe adverse reac(cid:173)
`tion in an asthmatic patient. In 1977, Freedman7
`reported that eight asthmatic patients had severe
`reactions to bisulfites. In 1981, Stevenson and
`Simon10 reported four bisulfite cases, followed by
`other reports in rapid succession: Werth, 11 Twarog
`and Leung, 12 Schwartz, 1a and Habenicht et al 14
`(Table I).
`Although the FDA has received reports of over
`ninety cases of adverse reactions, only about one
`third of these cases have been published in the
`medical literature. Most of the patients reported in
`the medical literature had a prior history of
`asthma. All had a positive oral challenge to bisul(cid:173)
`fite, and all had reactions within 15 minutes from
`challenge. In only two of these reports, positive
`skin tests to bisulfite were found.
`One of these reports also demonstrated a posi-
`
`tive Prausnitz-Kustner (P-K) reaction, while the
`other report stated that the P-K reaction was nega(cid:173)
`tive. In four reports, asthmatic patients not only
`reacted to bisulfites in foods, but also reacted to
`inhaled bisulfites or to smog (S02 ), demonstrating
`the strong relationship between bisulfites and so2.
`It is apparent that a significant number of these
`asthmatics with bisulfite sensitivity have negative
`allergy skin tests and, therefore, are nonatopic in
`nature. 10•12 The lack of IgE mechanism is con(cid:173)
`firmed by the finding that normal IgE, total eosin(cid:173)
`ophil count, and histamine levels were observed
`during acute reactions. 12
`The pathogenic mechanism of bisulfite reaction
`appears to be through neural reflex actions, involv(cid:173)
`ing the irritant receptors in the nose and upper
`airways, with the vagus nerve being the main ef(cid:173)
`ferent pathway. Atropine inhibits the broncho(cid:173)
`spasm induced by S02 •5•6 Stimulation of the
`parasympathetic system may also account for
`pruritus, urticaria/angioedema, as well as gastro(cid:173)
`intestinal and cardiovascular complaints. The
`rapid onset of symptoms and absent allergic
`markers add credence to this neurogenic theory.
`Freedman/ Stevenson and Simon, 10 and Werth"
`also have mentioned this reflex action as a possible
`mechanism among other theories. An overall view
`of all reports appears to make the neurogenic
`theory the most likely mechanism.
`A major aim of this editorial is to list medica(cid:173)
`tions that contain the preservative bisulfite (Table
`II). Most of these medications were obtained by
`
`Page 2 of 4
`
`

`
`Volume 10
`Number 6
`June, 1984
`
`Table II. Drugs that contain sulfites
`
`I. Bronchodilator inhalant solutions
`Alupent (metaproterenol sulfate)
`Bronkephrine (ethylnorepinephrine HCl)
`Bronkosol (isoetharine HCl)
`Isuprel hydrochloride solution (isoproterenol HCl)
`Metaprel (metaproterenol sulfate)
`Micronefrin (racemic epinephrine)
`Il. Tablets
`Isuprel HCl Glossets (isoproterenol HCI)
`ill. Injectables
`A. Adrenalin II 1 , 000 (epinephrine)
`Aldomet Esther HCl injection (methyldopate
`HCl, MSD)
`Aramine (metaraminol bitartrate)
`Celestone phosphate (brand of metamethasone
`sodium)
`Compazine (prochlorperazine)
`Decadron-LA suspension (dexamethasone
`acetate)
`Decadron phosphate injection (dexamethasone
`sodium phosphate)
`Decadron phosphate with Xylocaine (dexa(cid:173)
`methasone sodium phosphate and lidocaine
`HCl)
`Dopastat (dopamine HCl)
`Intropin (dopamine HCl)
`Isuprel HCI sterile injection 1 :5,000 (isopro-
`terenol HCl)
`Largon (propiomazine HCl)
`Levophed bitartrate (norepinephrine bitartrate)
`Levoprome (methotrimeprazine)
`Lidocaine HCl with epinephrine
`Marcaine HCl with epinephrine (bupivacaine
`·
`HCl and epinephrine)
`Mepergan (meperidine and promethazine HCl)
`Nesacaine (chloroprocaine HCl)
`Nesacaine-CE (chloroprocaine HCl)
`Novocaine (procaine HCl injection '[U.S.P.])
`
`Adverse reactions to suljites 1079
`
`Nubain (nalbuphine HCl)
`Phenergan (promethazine HCl)
`Pronestyl (procainamide HCl)
`Reglan (metoclopramide HCl)
`Serpasil (reserpine USP)
`Thorazine (chlorpromazine HCl)
`Tofranil (imipramine HCl [U.S.P.])
`Torecan (brand of thiethylperazine [U.S.P.])
`10% Travasol (amino acid) injection without
`electrolytes
`Trilafon (brand of perphenazine [U.S.P.])
`Tubocurarine chloride injection (U.S.P.)
`Yutopar (ritodrine HCl)
`B. Antibiotics
`Amikin ( amikacin sulfate)
`Bactrim IV infusion (trimethoprim and sulfa-
`methoxazole)
`Bristagen (gentamicin sulfate)
`Gantrisin (sulfisoxazole)
`Garamycin injectable (gentamicin sulfate)
`Kantrex injection (kanamycin sulfate injec-
`tion)
`Nebcin (tobramycin sulfate)
`Septra IV infusion
`IV. Miscellaneous
`Cortisporin otic solution (polymyxin B-neomycin(cid:173)
`hydrocortisone)
`Decadron in ocumeter (dexamethasone sodium
`phosphate)
`Decadron phosphate-0.1% sterile ophthalmic
`solution (dexamethasone sodium phosphate)
`Neodecadron sterile ophthalmic solution (neomy-
`cin sulfate-dexamethasone sodium phosphate)
`Otocort ear drops
`Pred-forte ophthalmic suspension
`Pred-mild ophthalmic suspension
`Propine ophthalmic solution (dipivefrin HCl)
`
`our review of Physicians' Desk Reference, and
`some were obtained from published reports. *· 12
`•15
`These medications should be used with caution in
`asthmatic patients and should not be used in those
`with a known history of sulfite or S02 sensitivity.
`Foods that contain bisulfite have been ade(cid:173)
`quately described by Twarog16 and others .10-
`14
`•17
`These foods are listed in Table III. It has been
`estimated that the average U.S. diet contains about
`2 to 3 mg of sulfite daily. However, a restaurant
`
`*Washington Drug Letter, April 4, 1983.
`
`meal may contain 20 to 200 mg of sulfites as pre(cid:173)
`servatives.
`Besides avoidance, preventive treatment for
`these sulfite-sensitive patients is based on a recent
`report by Jacobsen, Simon, and Singh. 18 They
`demonstrated that these patients have a deficiency
`of the enzyme sulfite oxidase. Also, they reported
`that cyanocobalamin (vitamin B 12) can serve as an
`extracellular, nonenzymatic catalyst for the oxi(cid:173)
`dation of sulfites in these deficient individuals.
`When given as an oral dose of 1 to 5 mg preceding
`sulfite challenge, vitamin B12 offers excellent pro-
`
`Page 3 of 4
`
`

`
`1080 Settipane
`
`Table Ill. Sulfites in foods
`
`Restaurant salads and fresh fruits
`Vegetables wrapped in cellophane
`Dried fruits (e.g. , apricots)
`Potato (e.g., French fries and potato chips)
`Avocados
`Wine and vinegar
`Beer
`Cider
`Some fruit drinks (especially outside U.S.A.)
`Baked products
`Gelatin
`Beet sugar
`Com sweeteners
`Food starches
`Shrimp
`Sausage meats (outside U.S.A.)
`
`tection to these patients. Other drugs that are able
`to prevent clinical sulfite reactions as shown in
`challenge studies are atropine, cromolyn, and
`d<Yx.epin .w
`The FDA and state health departments have ini(cid:173)
`tiated steps in alerting consumers to the possible
`dangers of bisulfites and in getting producers to
`identify these chemicals in their packages. How(cid:173)
`ever, bureaucratic processes are slow, and it is up
`to the physician to demonstrate leadership in pre(cid:173)
`scribing medications and educating patients. 20
`
`Guy A. Settipane, M.D.
`Clinical Associate Professor, Brown University
`and the Department of Medicine,
`Rhode Island Hospital, Providence, Rl
`
`REFERENCES
`I. Lockey SD: Allergic reactions due to FD and C yellow
`No. 5, tartrazine, and aniline dye used as a coloring and
`identify1ng agent in various steroids. Ann Allergy 17:
`719-721, 1959.
`2. Chafee FH, Settipane GA: Asthma caused by FD & C
`approved dyes. J Allergy 40:65-72, 1967.
`
`Journal of the
`American Academy of
`Dermatology
`
`3. Samter M, Beers RE Jr: Concerning the nature of intoler(cid:173)
`ance to aspirin. J Allergy 40:281-293, 1967.
`4. Settipane GA, editor: National Symposium on Aspirin
`and Endogenous Mediators of Disease. Proceedings of
`the New England Society of Allergy, vol. 2, pp. 54-107,
`1981.
`5. Boushey HA: Bronchial hyperreactivity to sulfur diox(cid:173)
`ide: Physiologic and political implications. J Allergy
`Clin Immunol 69:335-338, 1982.
`6. Sheppard D, Wong WS, Vehara CF, et al: Lower
`threshold and greater bronchomotor responsiveness of
`asthmatic subjects to sulfur dioxide. Am Rev Respir Dis
`122:873-878, 1980.
`7. Freedman BJ: Asthma induced by sulfur dioxide, ben(cid:173)
`zoate and tartrazine contained in orange drinks. CJin Al(cid:173)
`lergy 7:407-415, 1977.
`8. Simon RA, Green L, Stevenson DD: The incidence of
`ingested metabisulfite sensitivity in an asthmatic popula(cid:173)
`tion. J Allergy Clin Immunol 69:118, 1982. (Abst.)
`9. Prenner BM, Stevens JJ: Anaphylaxis after ingestion of
`sodium bisulfite. Ann Allergy 37:180-182, 1976.
`10. Stevenson DD, Simon RA: Sensitivity
`to
`ingested
`metabisulfites in asthma subjects. J Allergy Clin lmmu(cid:173)
`nol 68:26-32, 1981.
`11. Werth GR: Inhaled metabisulfite sensitivity. J Allergy
`Clin Immunol 70:143, 1982. (Letter to Editor.)
`12. Twarog FJ, Leung DYM: Anaphylaxis to a component of
`isoetharine (sodium bisulfite). JAMA 248:2030-2031,
`1982.
`to
`13. Schwartz HF: Sensitivity
`ingested metabisultlte:
`Variations in clinical presentation. J Allergy Clin lmmu(cid:173)
`nol 71:487-489, 1983.
`14. Habenicht HA, Preuss L, Lovell RG: Sensitivity to in(cid:173)
`gested metabisulfites: Cause of bronchospasm and ur(cid:173)
`ticaria. Immunol Allergy Pract 5:243-245, 1983.
`15. Keopke JW, Selner JC, Dunhill AL: Presence of sulfur
`dioxide in commonly used bronchodilator solutions. J
`Allergy Clin Immunol 72:504-508, 1983.
`16. Twarog FJ: Metabisulfite sensitivity in asthma: A re(cid:173)
`view. N Eng! Reg Allergy Proc 4: 100-103, 1983.
`17. Editorial. Sulfites in foods and drugs. FDA Drug Bull
`13(2):11-12, 1983.
`18. Jacobsen DW, Simon RA, Singh M: Sulfite oxidase
`deficiency and cobalamin protection in sulfite-sensitive
`asthmatics (SSA). J Allergy Clin Immunol 73:135,
`1984. (Abst.)
`19. Simon R. Goldfarb G, Jacobsen D: Blocking studies in
`sulfite sensitive asthmatics (SSA). J Allergy Clin Immu(cid:173)
`nol 73:136, 1984. (Abst.)
`20. Settipane GA: Metabisulfite in drugs. N Eng! Reg Al(cid:173)
`lergy Proc 4:304-306, 1983.
`
`Page 4 of 4