The problem of hypersensitivity to vitamin preparations


ABSTRACT. The problem of the development of adverse reactions as a result of the use of diagnostic and medicinal products (drugs) is becoming increasingly important. Patients more often report reactions to local anesthetics (43.2 % of cases), antibiotics (18.8 %), nonsteroidal anti-inflammatory drugs (9.7 %), other drugs (28.4 %), B vitamins (4-5 %). It is important to understand that hypersensitivity (HS) to vitamin preparations (VP) is very common, according to patients, but not so often confirmed by their in-depth allergy examination. Basic data on HS before the VP were obtained in the 80-90s of the 20th century, but since then the situation has changed radically. The frequency of HS on these drugs is based on medical history when patients use multicomponent VP for oral administration, allergens in which may be other components (shell tablets and capsules, metal salts, flavors, sweeteners, dyes, preservatives). The causative allergens in the injectable forms of VP can also be auxiliary ingredients of the drug, in particular lidocaine and benzyl alcohol. There are only a few scientific publications with the appropriate evidence base for HS to individual VP, more often B vitamins. The clinical picture of HS reactions to VP is diverse (systemic, cutaneous, respiratory, rarely other visceral manifestations). They can develop both immediately and in a delayed type. Part of the VP (B vitamins, vitamin K) can cause the development of anaphylaxis with fatal consequences. VP, as a rule, do not belong to vital drugs therefore it is possible for this reason till now in real clinical practice insufficiently developed methods of allergodiagnostics both in vivo (skin, provocative tests), and in vitro (laboratory tests) among patients with suspicion for the development of HS to VP. It is not possible to perform allergy diagnostics in persons who have taken complex VP, so there is a problem of hyperdiagnosis of drug allergy to them. Therefore, the problem of determining the true allergic reaction in patients who report the development of a history of HS to VP remains relevant. As a rule, after the development of any adverse reaction during the reception of VP on the patient hangs the label “allergy to vitamins” for life without further allergy examination. That is why the problem of HS to VP needs further study.

Keywords: hypersensitivity, vitamin preparations, clinic, diagnosis.


Drannik H.M. Klinichna imunolohiya ta alerholohiya. Kyiv, 2010. 482 p.

Zaikov S.V., Kaidashev I.P., Gumeniuk G.L. Problema hiperchutlivosti do mistsevikh anestetykiv. Infusion & Chemotherapy. 2020; 3: 43-52.

Kaidashev I.P. Hiperchutlyvist do likarskykh preparativ. Kerivnytstvo dlya likariv. Kyiv, 2016. 288 p.

Klinichna alerholohiya: ker-vo dlya praktychnykh likariv. Pid red. R.M. Khaitova. Moscow: MEDpress-inform, 2002. 624 p.

Kolkhir P.V. Dokazova alerholohiya-imunolohiya. Moscow: Praktychna medytsyna, 2010. 528 p.

Likarska alerhiya: metodychni rekomendatsiyi dlya likariv. Za red. akad. RAN i RAMN R.M. Khaitova. Moscow, 2012. 73 p.

Pukhlyk B.M., Viktorov O.P., Zaikov S.V. Likarska allerhich i pobichni efekty likarskykh zasobiv v alerholohiyi. Lviv: Medytsyna svitu, 2008. 108 p.

Stepanova E.V. Suchasni aspekty diahnostyky ta likuvannya likarskoyi alerhiyi. Likuyuchyy likar. 2004; 9.

Unifikovaniy klinichnyy protokol ekstrenoyi, pervynnoyi, vtorynnoyi (spetsializovanoyi) ta tretinnoyi (visokospetsializovanoyi) medychnoyi dopomohy. Adaptovana klinichna nastanova, zasnovana na dokazah «Medykamentozna alerhiya, vklyuchayuchi anafilaksiyu». Nakaz MOZ 1. Ukrayiny № 916 vid 30.12.2015.

Khaitov R.M., Ilyina N.I., Latysheva T.V., ta in. Ratsionalna farmakoterapiya alerhichnykh zakhvoryuvan: ker. dlya praktykuyuchyh likariv. Moscow: Litterra, 2007. 504 p.

Aberer W., Bircher A., Romano A., et al. The ENDA and the EAACI interest group on drug hypersensitivity. Drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations. Allergy. 2003; 58: 854-863.

Adams A.K., Connolly S.M. Allergic contact dermatitis from vitamin E: the experience at Mayo Clinic Arizona, 1987 to 2007. Dermatitis. 2010 Jul-Aug; 21 (4): 199-202.

Agache I., Ryan D., Rodriguez M., et al. Allergy management in primary care across European countries – actual status. Allergy. 2013; 68 (7): 836-843.

Alani J.I., Davis M.D., Yiannias J.A. Allergy to cosmetics: a literature review. Dermatitis. 2013 Nov-Dec; 24 (6): 283-90.

Anderson I.A. Allergic reaction to drug and biologic agents. JAMA. 1992; 268: 2848-2857.

Atanaskovic-Markovic M., Caubet J. Management of drug hypersensitivity in the pediatric population. Expert Rev. Clin. Pharmacol. 2016: 1-9.

Bamess L.A. Safety considerations with high dose ascorbic acid dosage. Ann. NY Acad. Sci. 1975; 258: 523.

Bajaj A.K., Rastogi S., Misra A., et al. Occupational and systemic contact dermatitis with photosensitivity due to vitamin B6. Contact Dermatitis. 2001; 44: 184.

Beeler A., Pichler W. In vitro tests of T-cell-mediated drug hypersensitivity. Drug Hypersensensivity. Basel: Karger. 2007: 380-390.

Belhadjali H., Giordano-Labadie F., Bazex J. Contact dermatitis from vitamin C in a cosmetic anti-aging cream. Contact Dermatitis. 2001; 45 (5): 317.

Benchalal M., Yahchouchy-Chouillard E., Fouere S., et al. Anaphylactic shock secondary to intravenous administration of folinic acid. Ann. Oncol. 2002; 13: 480-481.

Berger-Czop B., Bilewicz-Stebel M., Stankowska A., Bilewicz-Wyrozumska T. Side effects of retinoid therapy on the quality of vision. Acta Pharm. 2016: 471-478.

Blondeel A. Contact allergy to vitamin A. Contact Dermatitis. 1984; Sep; 11 (3): 191-192.

Bousquet P.-J., Demoly P., et al. Position paper. Pharmacovigilance of drug allergy and hypersensitivity using the ENDA-DAHD database and the GA2 LEN platform. The Galenda project. Allergy. 2009; 64: 194-203.

Branco-Ferreira M., Clode M.H., Pereira-Barbosa M.A., et al. Anaphylactic reaction to hydroxycobalamin. Allergy. 1997; 52: 118-119.

Brockow K., Garvey L., Aberer W., et al. ENDA/EAACI Drug Allergy Interest Group. Skin test concentrations for systemically administered drugs – an ENDA/EAACI Drug Allergy Interest Group position paper. Allergy. 2013; 68 (6): 702-12.

Bruynzeel I., Hebeda C., Folkers E., et al. Cutaneous hypersensitivity reactions to vitamin K: 2 case reports and a review of the literature. Contact Dermatitis. 1995; 32: 78-82.

Bryant R., Fortner B.R. Jr., Richard E., Danriger R.E., Rabinowitz P.S., Nelson H.S. The effect of ascorbic acid on cutaneous and nasal response to histamine and allergen. J. Allergy Clin. Immunol. 1982; 69 (6): 484-488.

BSACI guidelines for the management of drug allergy. Clinical and Experimental Allergy. 2008; 39: 43-61.

Byung-Keun K., Woo-Jung S., Bomi S., Ju-Young K., Sae-Hoon K., Hak C.J., Ki-Woong K., Yoon-Seok C. Retinol-binding protein-4 was associated with sensitization to inhalant allergens in the elderly population. Korean J. Intern. Med. 2020; kjim.2019.348.

Caballero M.R., Lukawska J., Lee T.H., et al. Allergy to vitamin B12: two cases of successful desensitization with cyanocobalamin. Allergy. 2007; 62: 1341-1342.

Camarasa J.G., Serra-Baldrich E., Lluch M. Contact allergy to vitamin B6. Contact Dermatitis. 1990; 23: 115.

Chanarin I., Fenton J.C., Mollin D.L. Sensitivity to folic acid. British Medical Journal. 1957; 1 (5028): 1162-1163.

Choudhary B., Kumari S., Dhingra B., Jhaj R. A clinically suspected case of anaphylactoid reaction to vitamin K injection in a child – a case report and review of literature. Indian J. Pharmacol. 2016 Jul-Aug; 48 (4): 455-457.

Clemmensen A., Thormann J., Andersen К. Allergic contact dermatitis from retinyl palmitate in polycaprolactone. Contact Dermatitis. 2007; 56 (5): 288-289.

Corazza M., Minghetti S., Borghi A., Bianchi A., Virgili A. Vitamin E contact allergy: a controversial subject. Dermatitis. 2012; 23 (4): 167-169.

De Moly P., Adkinson F., Brockow K., et al. International consensus on drug allergy. Allergy. 2014; 69: 420-437.

Drug allergy: diagnosis and management of drug allergy in adults, children and young people. NICE (National Institute of Health and Care Excellence). Clinical guideline 183. September 2014: 1-167.

Dykewicz M.S., Orfan N.A., Sun W. In vitro demonstration of IgE antibody to folate-albumin in anaphylaxis from folic acid. J. Allergy Clin. Immunol. 2000; 106 (2): 386-389.

Ebo D., Leysen J., Mayorga C., et al. The in vitro diagnosis of drug allergy: status and perspectives. Allergy. 2011; 66 (10): 1275-1286.

European Academy of Allergology Asthma and Immunology (EAACI). Drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations. Available at:

Fernandez M., Barcelo M., Munoz C., et al. Anaphylaxis to thiamine (vitamin B1). Allergy. 1997; 52: 958-960.

Fiore L.D., Scola M.A., Cantillon C.E., et al. Anaphylactoid reactions to vitamin K. J. Thromb. Thrombolysis. 2001; 11: 175-83.

Fonacier L., Bernstein D., Pacheco R., et al. Contact dermatitis: a practice parametere update. J. Allergy Clin. Immunol. Pract. 2015; 3: 1-39.

Foti C., Carnimeo L., Bonamonte D., et al. Tolerance to calcitriol and tacalcitol in three patients with allergic contact dermatitis to calcipotriol. J. Drugs Dermatol. 2005; 4: 756-759.

Garcia-Bravo B., Mozo P. Generalized contact dermatitis from vitamin E. Contact Dermatitis. 1992; 26 (4): 280.

Giordano-Labadie F., Laplanche G., Bazex J. Contact eczema caused by calcipotriol (Article in French). Ann. Dermatol. Venereol. 1996; 123: 196-197.

Greco M., Dupre-Goetghebeur D., Leroy J., et al. DRESS syndrome related to hexaquine (quinine and thiamine) (Article in French). Ann. Dermatol. Venereol. 2006; 133: 354-366.

de Groot A. Contact allergy to calcipotriol. Contact Dermatitis. 1994; 30: 242-243.

de Groot A.C., Berretty P.J., van Ginkel C.J., den Hengst C.W., van Ulsen J., Weyland J.W. Allergic contact dermatitis from tocopheryl acetate in cosmetic creams. Contact Dermatitis. 1991; 25 (5): 302-304.

Hamanaka M., Kanto H., Mikai H., Tanaka H., Ito T., Washizaki K., Ishiko A. A rare case of allergic contact dermatitis caused by 3‐O‐ethyl‐L‐ascorbic acid in skin‐whitening cosmetics identified under immunosuppressive therapy. First published: 3 July 2020.

Heidenheim M., Jemec G.B.E. Occupational allergic contact dermatitis from vitamin A acetate. Contact Dermatitis. 1995; 33 (6): 49.

Heyworth-Smith D., Hogan P. Allergy to hydroxycobalamin with tolerance of cyanocobalamin. Med. J. Aust. 2002; 177: 162.

Johri S., Shetty S., Soni A., et al. Anaphylaxis from intravenous thiamine long-forgotten? Am. J. Emer. Med. 2000; 18: 642-643.

Jordan W.P. Jr., Higgins M., Dvorak J. Allergic contact dermatitis to all-transretinoic acid; epicutaneous and leukocyte migration inhibition testing. Contact Dermatitis. 1975 Oct; 1 (5): 306-310.

Kano Y., Hirahara K., Mitsuyama Y., et al. Utility of the lymphocyte transformation test in the diagnosis of drug sensitivity: dependence on its timing and the type of drug eruption. Allergy. 2007; 62 (12): 1439-1444.

Kosari Р., Alikhan А., Sockolov М., Feldman S. Vitamin E and allergic contact dermatitis. Dermatitis. May-Jun 2010; 21(3): 148-153.

Krayenbuhl B., Elsner P. Allergic and irritant contact dermatitis to calcipotriol. Am. J. Contact Dermat. 1999; 10: 78-80.

Lammintausta K., Kortekangas-Savolainen O. The usefulness of skin test to prove drug hypersensitivity. Br. J. Dermatol. 2005; 152 (5): 968-974.

Levander-Lindgren M. Hypersensitivity to folic acid in a case of erythroblastomatosis. Acta Medica Scandinavica. 1957; 157 (3): 233-234.

Lieberman Р., Nicklas R., Oppenheimer J., et al. The diagnosis and management of anaphylaxis practice parameter: 2010 update. J. Allergy Clin. Immunol. 2010; 126 (3): 477-480.

Lindgren S., Groth O., Molin L. Allergic contact response to vitamin A acid. Contact Dermatitis. 1976; 2 (4): 212-217.

Manzano D., Aguirre A., Gardeazabal J., Eizaguirre X., Diaz Perez J. Allergic contact dermatitis from tocopheryl acetate (vitamin E) and retinol palmitate (vitamin A) in a moisturizing cream. Contact Dermatitis. 1 Nov 1994; 31 (5): 324.

Marmsjo K., Rosenlund H., Kull I., Hakansson N., Wickman M., Pershagen G., Bergstrom A. Use of multivitamin supplements in relation to allergic disease in 8-y-old children. The American Journal of Clinical Nutrition. 2009; 90 (6): 1693-1698.

Metz J., Hundertmark U., Pevny I. Vitamin C allergy of the delayed type. Contact Dermatitis. 1980 Apr; 6 (3): 172-174.

Michalska-Krzanowska G. Tryptase in diagnosing adverse suspected anaphylactic reaction. Adv. Clin. Exp. Med. 2012 May-Jun; 21 (3): 403-408.

Mitchell J. Contact urticaria from a vitamin E preparation (vitamin E – vegetable oil) in two siblings. Int. J. Dermatol. 1975; 14: 246.

Mirakian R., Ewan P.W., Durham S.R., et al. BSACI guidelines for the management of drug allergy. Clin. Exp. Allergy. 2009 Jan; 39 (1): 43-61.

Morinville V., Jeannet-Peter N., Hauser C. Anaphylaxis to parenteral thiamine (vitamin B1). Schweitz Med. Wochenschr. 1998; 128: 1743-1744.

Muraro A., Lemanske R.F. Jr., Castells M., et al. Precision medicine in allergic disease – food allergy, drug allergy, and anaphylaxis – PRACTALL document jn the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma and Immunology. Allergy. 2017; 72: 1006-1021.

Muraro A., Roberts G., Clark A., et al. The management of anaphylaxis in childhood: position paper of the European academy of allergology and clinical immunology. Allergy. 2007; 62: 857-871.

Murata Y., Kumano K., Ueda T., et al. Photosensitive dermatitis caused by pyridoxine hydrochloride. J. Am. Acad. Dermatol. 1998; 39: 314-317.

Nishitani N., Adachi A., Fukumoto T., et al. Folic acid-induced anaphylaxis showing cross-reactivity with methotrexate: a case report and review of the literature. International Journal of Dermatology. 2009; 48 (5): 522-524.

Nordqvist B., Mehr K. Allergic contact dermatitis to retinoic acid. Contact Dermatitis. 1977 Feb; 3 (1): 55-56.

Nucera E., Aruanno A., Mezzacappa S., et al. Hypersensitivity reactions to folic acid: three case reports and a review of the literature. Int. J. Immunopathol. Pharmacol. 2018 Mar-Dec; 32: 2058738418817704.

Nyfeler B., Pichler W. The lymphocyte transformation test in for the diagnosis of drug allergy: sensitivity and specificity. Clin. Exp. Allergy. 1997; 27: 175-181.

Ou L.S., Kuo M.L., Huang J.L. Anaphylaxis to riboflavin (vitamin B2). Ann. Allergy Asthma Immunol. 2001; 87: 430-433.

Ohko K., Ito A., Ito M. Allergic contact dermatitis syndrome due to tocopherol acetate, in addition to glycyrrhetinic acid. Journal of Cosmetics, Dermatological Sciences and Applications. 2012; 2 (1): 38-40.

Park Y.K., Lee J.H., Chung W.G. Allergic contact dermatitis from calcipotriol. Acta Derm. Venereol. 2002; 82: 71-72.

Park M.E., Zippin J.H. Allergic contact dermatitis to cosmetics. Dermatol. Clin. 2014 Jan; 32 (1): 1-11.

Pevny I., Hartmann A., Metz J. Vitamin B12-(cyanocobalamin)-allergy. Hautarzt. 1977 Nov; 28 (11): 600-603.

Pfab F., Willi R., Albert A., et al. Anaphylactic reaction to folic acid verified by provocational test. Allergy. 2007; 62: 823-824.

Pichler W., Tilch J. The lymphocyte transformation test in for the diagnosis of drug hypersensitivity. Allergy. 2004; 59 (8): 809-820.

Porebski G., Gschwend-Zawodniak A., Pichler W. In vitro diagnosis of T-cellmediated drug allergy. Clin. Exp. Allergy. 2011; 41 (4): 461-470.

Posadas S.J., Pichler W.J. Delayed drug hypersensitivity reactions – new concepts. Clin. Exp. Allergy. 2007; 37: 989-999.

Proebstle T.M., Gall H., Jugert F.K., et al. Specific IgE and IgG serum antibodies to thiamine associated with anaphylactic reaction. J. Allergy Clin. Immunol. 1995; 95: 1059-1060.

Riegert-Johnson D.L., Volcheck G.W. The incidence of anaphylaxis following intravenous phytonadione (vitamin K1): a 5 year retrospective review. Ann. Allergy Asthma Immunol. 2002; 89: 400-406.

Rudzki E., Grzywa Z. Dermatitis from retinoic acid. Contact Dermatitis. 1978 Oct; 4 (5): 305-306.

Sanders G.M., Fritz S.B. Allergy to natural and supplemental folic acid as a cause of chronic, intermittent urticaria and angioedema. Annals of Allergy Asthma & Immunology. 2004; 93: 51-52.

Renaudin J.-M., Beaudouin E., Ponvert C., Demoly P., Moneret-Vautrin D.-A. Severe drug-induced anaphylaxis: analysis of 333 cases recorded by the Allergy Vigilance Network from 2002 to 2010. Allergy. 2013 Jul; 68 (7): 929-937.

Roy S., Roy M. A case of folic acid allergy in pregnancy. Journal of Obstetrics and Gynaecology of India. 2012; 62 (Suppl. 1): 33-34.

Saperstein H., Rapaport M., Rietschel R. Topical vitamin E as a cause of erythema multiforme-like eruption. Arch. Dermatol. 1984 Jul; 120 (7): 906-908.

Scherer K., Brockow K., Aberer W., et al. Desensitization in delayed drug hypersensitivity reactions – an EAACI position paper of the Allergy Interest Group. Allergy. 2013; 68 (7): 844-852.

Sesin G., Kirschenbaum H. Folic acid hypersensitivity and fever: a case report. Am. J. Hosp. Pharm. 1979; 36: 1565-1567.

Schrijvers R., Chiriac A., Demoly P. Allergy workup for suspected folic acid hypersensitivity. Journal of Investigational Allergology & Clinical Immunology. 2015; 25 (3): 233-236.

Shelley W.B., Shelley E.D., Talanin N.Y. Hypersensitivity to retinol palmitate injection. BMJ. 1995; 311: 232.

Simons E., Ardusso L.R.F., Dimov V., et al. World Allergy Organization Anaphylaxis Guidelines: 2013 update of the evidence base. Int. Arch. Allergy Immunol. 2013; 162: 193-204.

Smith J., Empson M., Wall C. Recurrent anaphylaxis to synthetic folic acid. Lancet. 2007; 370 (9588): 652.

Soto-Aguilar M.C., de Shazo R.D., Danson E.S. Approach to the patient with suspected local anestethic sensitivity. Immunol. and Allergy Clinic of North America. 1998; 18: 851-865.

Speca S.J., Boynes S.G., Cuddy M.A. Allergic reactions to local anesthetic formulations. Dent. Clin. North Am. 2020; 54: 655-664.

Sparling R., Abela M. Hypersensitivity to folic acid therapy. Clinical and Laboratory Haematology. 1985; 7 (2): 184-185.

Sulli M.M., Ezzo D.S. Drug interactions with vitamins and minerals. US Pharm. 2007; 1: 42-55.

Tanaka M., Niizeki H., Shimizu S., et al. Photoallergic drug eruption due to pyridoxine hydrochloride. J. Dermatol. 1996; 23: 708-709.

Thong B., Mirakian R., Castells M., et al. A World Allergy Organization International Survey on Diagnostic Procedures and Therapies in Drug Allergy / Hypersensitivity. WAO Journal. 2011; 4: 257-270.

Thyssen J.P., Menne T., Elberling J., Plaschke P., Johansen J.D. Hypersensitivity to local anaesthetics – update and proposal of evaluation algorithm. Contact Dermatitis. 2008; 589: 69-78.

Tordjman R., Genereau T., Guinnepain M., et al. Reintroduction of vitamin B12 in 2 patients with prior B12-induced anaphylaxis. Eur. J. Haematol. 1998; 60: 269-270.

Turvey S.E., Cronin B., Arnold A.D., et al. Adverse reactions to vitamin B12 injections due to benzyl alcohol sensitivity: successful treatment with intranasal cyanocobalamin. Allergy. 2004; 59: 1023-1024.

Valdivieso R., Cevallos F., Caballero M., et al. Chronic urticaria caused by folic acid. Annals of Allergy Asthma & Immunology. 2009; 103 (1): 81-82.

Venemalm L., Degerbeck F., Smith W. IgE-mediated reaction to mepivacaine. J. Allergy Clin. Immunol. 2008 Apr; 121 (4): 1058-9. doi: 10.1016/j.jaci.2007.12.1154.

Wilbur Johnson, Jr. Retinol and retinyl palmitate. Int. J. Toxicol. October 12, 2017; 36 (5 suppl. 2): 53-58.

Yagami A., Suzuki K., Morita Y., Iwata Y., Sano A., Matsunaga K. Allergic contact dermatitis caused by 3-O-ethyl-L-ascorbic acid (vitamin C ethyl). Contact Dermat. 2014 Jun; 70 (6): 376377.

Wilkins K., de Koven J., Assaad D. Cutaneous reactions associated with vitamin K1. J. Cutan. Med. Surg. 2000; 4: 164-168.

Wjasow C., McNamara R. Anaphylaxis after low dose intravenous vitamin K. J. Emerg. Med. 2003; 24: 169-172.

How to Cite
Zaikov, S., Gumeniuk, G., & Veselovsky, L. (2021). The problem of hypersensitivity to vitamin preparations. Infusion & Chemotherapy, (3), 30-39.

Author Biographies

S.V. Zaikov, National University of Healthcare of Ukraine named after P.L. Shupyk, Kyiv, Ukraine

Zaikov Sergii Viktorovych
Professor of the Department of phthisiology and pulmonology
MD, professor.
9, Dorohozhytska st., Kyiv, 04112, Ukraine.

G.L. Gumeniuk, National University of Healthcare of Ukraine named after P.L. Shupyk, Kyiv, Ukraine

Gumeniuk Galyna Lvivna
Professor of the Department of phthisiology and pulmonology; Senior Researcher of Treatment, Diagnosis and Clinical Pharmacology of Lung Disease NIFP NAMNU.
MD, professor.
9, Dorohozhytska st., Kyiv, 04112, Ukraine.

L.V. Veselovsky, National University of Healthcare of Ukraine named after P.L. Shupyk, Kyiv, Ukraine

Veselovsky Leonid Viktorovych
Assistant of the Department of phthisiology and pulmonology
9, Dorohozhytska st., Kyiv, 04112, Ukraine.

Most read articles by the same author(s)