ArticlePDF Available

Adverse reactions to vitamin B12 injections due to benzyl alcohol sensitivity: Successful treatment with intranasal cyanocobalamin

Allergy

October 2004
59(9):1023-4

DOI:10.1111/j.1398-9995.2004.00507.x

Source
PubMed

Authors:

Stuart E Turvey

University of British Columbia

Beth Cronin

Brown University

Alana D Arnold

Boston Children's Hospital

Show all 5 authorsHide

Content uploaded by Stuart E Turvey

Content may be subject to copyright.

*De

´partement d’Anesthe

´sie-re

´animation

CHU de Nancy

Hoˆ pital Central

29 Avenue de Lattre de Tassigny

54035 Nancy Cedex

France

Tel: 33-383-85-15-31

Fax: 33-383-85-10-39

E-mail: pm.mertes@chu-nancy.fr

Accepted for publication 3 December 2003

Allergy 2004: 59:1022–1023

References

1. Laxenaire MC, Mertes PM. Anaphylaxis

during anaesthesia. Results of a two-year

survey in France. Br J Anaesth

2001;87:549–558.

2. Banchereau J, Steinman RM. Dendritic

cells and the control of immunity. Nature

1998;392:245–252.

3. Bernard J, Ittelet D, Christoph A,

Potron G, Adjizian JC, Kochman S

et al. Adherent-free generation of func-

tional dendritic cells from purified blood

monocytes in view of potential clinical use.

Hematol Cell Ther 1998;40:17–26.

4. Pichler WJ, Yawalkar N. Allergic

reactions to drugs: involvement of

T cells. Thorax 2000;55(Suppl. 2):

S61–S65.

Adverse reactions to vitamin

B12 injections due to benzyl

alcohol sensitivity:

successful treatment with

intranasal cyanocobalamin

S. E. Turvey*, B. Cronin, A. D. Arnold, F. J. Twarog,

A. F. Dioun

Key words: benzyl alcohol; cyanocobalamin; drug

reaction; hydroxycobalamin; vitamin B12.

A 16-year-old female was referred for

assessment of possible anaphylactic

reactions follow-

ing vitamin B12

injections. In

March 2001, the

patient received

an intramuscular

injection of vita-

min B12 (cyano-

cobalamin

1000 lg) and

experienced pain

at the injection site. In May 2001, 1 h

after her second injection, she reported a

sensation of substernal burning and

pleuritic pain that resolved over days.

Within minutes of her third injection in

June 2001, she felt similar chest discom-

fort and developed pruritus of the arms

and legs, but no rash.

As the reactions to cyanocobalamin

injections were becoming progressively

more serious, she was referred for

assessment. A number of allergic reac-

tions following parenteral administration

of vitamin B12 have been described (1–4).

Cobalamin is synthesized for therapeutic

use as either cyanocobalamin or hydrox-

ycobalamin. There are reports of patients

with reactions to one form of cobalamin

who have been able to tolerate the

alternate formulation (4–7). Unfortu-

nately, this management strategy was not

available to us as the hydroxycobalamin

preparation is not available in the United

States.

She was skin tested to three commer-

cial preparations of injectable cyanoco-

balamin and to the benzyl alcohol (0.9%)

preservative found in each. Prick testing

was negative (Table 1a), but intradermal

testing to all cyanocobalamin prepara-

tions and benzyl alcohol was positive

(Table 1b).

These results indicated that the patient

was likely reacting to the benzyl alcohol

preservative present in the cyanocobal-

amin injections. However, the data did

not eliminate the possibility of sensitiza-

tion to both the benzyl alcohol and

cyanocobalamin. Hypersensitivity reac-

tions to benzyl alcohol have been docu-

mented in patients treated with a variety

of medications containing benzyl alcohol

as a preservative (8, 9).

Although there was no commercially

available parenteral formulation of vita-

min B12 lacking the benzyl alcohol pre-

servative, we were fortunate to identify

Nascobal



(Questcor Pharmaceuticals

Intranasal

administration of

cyanocobalamin is an

option for vitamin

B12-deficient patients

sensitive to benzyl

alcohol.

Table 1. Skin test results

Patient Healthy control

(a) Skin prick testing results

Cyanocobalamin brand no. 1 (1 mg/ml) Negative Negative

Cyanocobalamin brand no. 2 (1 mg/ml) Negative Negative

Cyanocobalamin brand no. 3 (1 mg/ml) Negative Negative

Benzyl alcohol (0.9%) Negative Negative

Histamine (6 mg/ml) 10 mm wheal + ﬂare 10 mm wheal + ﬂare

Normal saline Negative Negative

(b) Intradermal testing results

Cyanocobalamin brand no. 1 (0.01 mg/ml) 7 mm wheal + ﬂare Negative

Cyanocobalamin brand no. 2 (0.01 mg/ml) 6 mm wheal + ﬂare Negative

Cyanocobalamin brand no. 3 (0.01 mg/ml) 10 mm wheal + ﬂare Negative

Benzyl alcohol (0.009%) 9 mm wheal + ﬂare Negative

Normal saline Negative Negative

ALLERGY Net

1023

Inc., Union City, CA, USA), a cyanoco-

balamin gel for intranasal administration

that does not contain benzyl alcohol. The

patient was skin tested to this nasal

preparation at its full concentration and

demonstrated no reaction. She was given

a test dose of 500 lg, with no adverse

reaction. Subsequently her vitamin B12

deﬁciency was successfully treated with

the nasal preparation of cyanocobalamin

as demonstrated by her relatively stable

levels of vitamin B12 since beginning

treatment (Fig. 1).

This patient’s reactions to benzyl

alcohol, along with previously reported

cases, conﬁrm the importance of con-

sidering benzyl alcohol as a cause of

hypersensitivity reactions to parenteral

medications. Intranasal administration

of cyanocobalamin gel is an option for

vitamin B12-deﬁcient patients who are

sensitive to benzyl alcohol.

*Division of Immunology

Children’s Hospital

300 Longwood Avenue

Boston MA 02115

USA

Tel: 617 355 5635

Fax: 617 232 3877

E-mail: stuart.turvey@tch.harvard.edu

Accepted for publication 5 January 2004

Allergy 2004: 59:1023–1024

References

1. Hovding G. Anaphylactic reaction after

injection of vitamin B12. Br Med J

1968;3:102.

2. James J, Warin RP. Sensitivity to cyano-

cobalamin and hydroxocobalamin. Br

Med J 1971;2:262.

3. Woodliff HJ. Allergic reaction to cyano-

cobalamin injection. Med J Aust

1986;144:223.

4. Heyworth-Smith D, Hogan PG. Allergy

to hydroxycobalamin, with tolerance of

cyanocobalamin. Med J Aust

2002;177:162–163.

5. Vidal C, Lorenzo A. Anaphylactoid

reaction to hydroxycobalamin with toler-

ance of cyanocobalamin. Postgrad Med J

1998;74:702.

6. Tordjman R, Genereau T, Guinnepain

MT, Weyer A, Lortholary O, Royer I,

Casassus P, Guillevin L. Reintroduction

of vitamin B12 in 2 patients with prior B12-

induced anaphylaxis. Eur J Haematol

1998;60:269–270.

7. Branco-Ferreira M, Clode MH, Pere-

ira-Barbosa MA, Palma-Carlos AG.

Anaphylactic reaction to hydroxycobalam-

in. Allergy 1997;52:118–119.

8. Wilson JP, Solimando DA Jr, Edwards

MS. Parenteral benzyl alcohol-induced

hypersensitivity reaction. Drug Intell Clin

Pharm 1986;20:689–691.

9. Grant JA, Bilodeau PA, Guernsey BG,

Gardner FH. Unsuspected benzyl alcohol

hypersensitivity. N Engl J Med

1982;306:108.

Figure 1. Serum vitamin B12 levels and replacement schedule.

ALLERGY Net

1024

Anaphylaxie auf Hilfsstoffe in Arzneimitteln

Article

Jul 2022

Wolfgang Pfützner

Neben dem therapeutischen Agens enthalten Arzneimittel Hilfsstoffe als beispielsweise Stabilisatoren, Konservierungsstoffe, Löslichkeitsvermittler oder Farbstoffe, die teilweise identisch mit Zusatzstoffen in Nahrungsmitteln sind. Anaphylaxien auf diese Hilfsstoffe sind ein vermutlich unterschätztes Problem. Nachdem erste Beschreibungen anaphylaktischer Reaktionen auf Arzneimittelhilfsstoffe bereits vor über 30 Jahren auftauchten, hat die Zahl entsprechender Berichte in den letzten Jahren deutlich zugenommen. Eine diagnostische Lücke besteht allerdings in der Abklärung arzneimittelallergischer Reaktionen, wenn das Indexpräparat nicht bekannt ist und/oder nicht als Originalpräparat für Testungen zur Verfügung steht. In der vorliegenden Arbeit werden einzelne Hilfsstoffe exemplarisch vorgestellt, für die Publikationen zu Anaphylaxien vorliegen. Des Weiteren werden die Optionen allergologischer Testungen sowohl in vivo als auch in vitro besprochen. Die Pathogenese derartiger Reaktionen ist vielfach noch unklar, hier werden abschließend aktuelle Konzepte kurz vorgestellt. Mit zunehmendem Wissen über Anaphylaxien auf Arzneimittelhilfsstoffe ist davon auszugehen, dass diese auch vermehrt wahrgenommen und diagnostisch aufgeklärt werden können. Zitierweise: Pfützner W. Anaphylaxis to drug excipients. Allergo J Int 2022;31:137-40 https://doi.org/10.1007/s40629-022-00214-9

Anaphylaxis to drug excipients

Article

Full-text available

May 2022

Wolfgang Pfützner

In addition to the therapeutic agent, drugs contain excipients such as stabilizers, preservatives, solubilizers, or dyes, some of which are identical to additives in foods. Anaphylaxis to these excipients is probably an underestimated problem. After the first descriptions of anaphylactic reactions to drug excipients appeared more than 30 years ago, the number of corresponding reports has increased significantly over the years. However, a diagnostic gap exists in the clarification of drug allergic reactions when the index product is not known and/or is not available for testing. In the present work, individual excipients are presented as examples for which publications on anaphylaxis are available. Furthermore, the options of allergological testing both in vivo and in vitro are discussed. The pathogenesis of such reactions is still unresolved in many cases, and current concepts are briefly presented in the conclusion. With increasing knowledge about anaphylaxis to drug excipients, it is assumed that these can then be recognized more often and diagnostically clarified.

Antimicrobial Preservatives for Protein and Peptide Formulations: An Overview

Article

Full-text available

Feb 2023

Biological drugs intended for multi-dose application require the presence of antimicrobial preservatives to avoid microbial growth. As the presence of certain preservatives has been reported to increase protein and peptide particle formation, it is essential to choose a preservative compatible with the active pharmaceutical ingredient in addition to its preservation function. Thus, this review describes the current status of the use of antimicrobial preservatives in biologic formulations considering (i) appropriate preservatives for protein and peptide formulations, (ii) their physico-chemical properties, (iii) their in-/compatibilities with other excipients or packaging material, and (iv) their interactions with the biological compound. Further, (v) we present an overview of licensed protein and peptide formulations.

Anaphylaxis to food additives

Article

Full-text available

Mar 2022

A variety of additives found in foodstuffs have been associated with triggering of a number of clinical pictures. Hypersensitivity reactions of allergic and non-allergic etiology have been widely described, but are reported to be rare overall. This review presents a selection of food additives for which anaphylactic reactions have been described. These include colorants (e.g., tartrazine, carmine, patent blue), preservatives (e.g., sulfites, sodium benzoate), and thickeners/gelling agents (e.g., carboxymethylcellulose, guar, gum arabic). Possible diagnostic procedures (skin test, specific IgE, cellular antigen stimulation test, oral provocation) are presented. For those affected, avoidance of consumption is facilitated by the mandatory declaration (class name, E‑number/designation) required in the European Union. Only sulfur dioxide and sulfites have to be highlighted as food allergens, depending on the concentration. Due to the limited diagnostic procedures available, it cannot be excluded that the frequency of hypersensitivity to food additives is underestimated.

Vitamin B12 Hypersensitivity: A Retrospective Multicenter Study

Article

Oct 2023

Anaphylaxie auf Zusatzstoffe in Nahrungsmitteln

Article

Jul 2022

In Nahrungsmitteln kann sich eine Vielzahl von Zusatzstoffen befinden, die mit der Auslösung unterschiedlicher klinischer Bilder in Zusammenhang gebracht werden. Überempfindlichkeitsreaktionen allergischer und nicht allergischer Genese sind vielfach beschrieben, sollen aber insgesamt selten sein. In dieser Übersichtsarbeit wird eine Auswahl von Nahrungsmittelzusatzstoffen präsentiert, für die anaphylaktische Reaktionen beschrieben wurden. Hierzu zählen unter anderem Farbstoffe (z. B. Tartrazin, Karmin, Patentblau), Konservierungsstoffe (z. B. Sulfite, Natriumbenzoat) und Dickungs-/Geliermittel (z. B. Carboxymethylcellulose, Guar, Gummi arabicum). Mögliche diagnostische Verfahren (Hauttest, spezifisches IgE, zellulärer Antigen-Stimulationstest, orale Provokation) werden vorgestellt. Für Betroffene ist die Meidung des Verzehrs durch die in der Europäischen Union nötige Deklarationspflicht (Klassenname, E-Nummer/Bezeichnung) erleichtert. Als Nahrungsmittelallergen hervorgehoben werden müssen konzentrationsabhängig nur Schwefeldioxid und Sulfite. Aufgrund der nur begrenzt zur Verfügung stehenden diagnostischen Verfahren kann nicht ausgeschlossen werden, dass die Häufigkeit der Überempfindlichkeit auf Nahrungsmittelzusatzstoffe unterschätzt wird. Zitierweise: Treudler R, Simon JC. Anaphylaxis to food additives. Allergo J Int 2022;31:141-4 https://doi.org/10.1007/s40629-022-00203-y

New Challenges in Drug Allergy: the Resurgence of Excipients

Article

Full-text available

Sep 2022

Purpose of Review Allergy to excipients is a cause of multidrug allergy and if it is not taken into account, it can lead to unexpected severe reactions. If an excipient allergy is suspected, an accurate examination followed by algorithms is very important for a correct diagnosis and to give patients detailed information in order to avoid future reactions. Recent Findings In recent times, due to allergy COVID vaccine reactions, interest in excipients as polyethylene glycol derivatives (PEGs) has increased as a possible cause of drug and vaccine hypersensivity. In addition to PEGs many other excipients as gelatin, alpha-gal, protamine, benzalkonium chloride, and benzyl alcohol have been described as a cause of allergy to drugs and vaccines. For most excipients, the dilutions used for skin testing (ST) are not standardized and proper algorithms to reach a diagnosis are not available. Summary The purpose of this article is to review the excipients that may produce inmediate hypersensitivity drugs and vaccine reactions and update diagnostic procedures to reach an accurate diagnosis. We highlight the in vivo and in vitro diagnostic tests used in published reports and detail the dilution used for each excipient to perform ST in order to confirm this vital pathology and to prevent new reactions.

Pathomechanisms of Drug Hypersensitivity Targeting the Liver and Skin

Chapter

Jan 2022

Drug hypersensitivities are either immune- or nonimmune-mediated reactions which usually manifest in a limited number of individuals, mostly after the drug has been licensed for clinical use. This implies that certain unique patient susceptibility factors in combination with the drug-derived antigen(s) are responsible for the initiation and progression of these reactions. Drug hypersensitivity cannot be predicted from the primary and secondary pharmacology of the drug like type A (on target) adverse drug reactions. These reactions present with a complex dose-response relationship and may significantly affect therapeutic options available for patients and clinicians while costing the pharmaceutical industry millions of pounds in the unfortunate event of drug withdrawal. About half a century ago, Coombs and Gell classified drug hypersensitivity reactions into four main classes, types I–IV. Their classification was based on three main factors, namely, (1) time to onset of clinical symptoms, (2) molecular mechanisms, and (3) biochemical mediators involved. Over the past two decades, intensive cellular, molecular, biochemical, and clinical research have resulted in new information that has enhanced our understanding of the pathomechanisms of drug hypersensitivity. Some of the important novel information include risk HLA alleles, antigen-specific T-cell receptors, novel T-cell subsets, and miRNA expressions. Hence, there is a need to incorporate these new findings into the current classification of drug hypersensitivity reactions. The specifics of Coombs and Gell classification and the extended classification by Werner Pichler together with limitations and gaps as a result of more recent findings will be discussed in further details in this chapter.

Additives: Preservatives, Antioxidants, Dyes, and Others

Chapter

Jul 2022

Annick Barbaud

An excipient—also called additive—is an inert substance added to a drug to change dissolution or the kinetics of absorption, improve stability, influence palatability, or create a distinctive appearance. Preservatives, emulsifiers, stabilizers, or thickeners, reactions to them may lead to a false-positive diagnosis of drug hypersensitivity to the specific active principle.KeywordsExcipientsSulfitesCarboxymethylcelluloseSodium benzoateVaccinesAluminum

The problem of hypersensitivity to vitamin preparations

Article

Full-text available

Sep 2021

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.

Allergie reaction to cyanocobalamin injection

Article

Feb 1986

H.J. Woodliff

Anaphylaxis during Anesthesia. Results of a Two-Year Survey in France

Article

Sep 2002

Parenteral Benzyl Alcohol-Induced Hypersensitivity Reaction

Article

Oct 1986
Drug Intell Clin Pharm

An uncommon hypersensitivity reaction due to parenteral benzyl alcohol administration is reported. One patient treated with benzyl alcohol-preserved cytarabine, vincristine, and heparin solutions developed a systemic hypersensitivity reaction on three separate occasions. Hypersensitivity to benzyl alcohol was confirmed by skin testing. Clinically, the patient presented with a fever and a maculopapular rash on the chest and arms. None of the reactions were life-threatening or required hospitalization of the patient.

Allergic reaction to cyanocobalamin injection

Article