insulin allergy

A pregnant woman with insulin allergy

Wat Mitthamsiri, M.D.Allergy and Clinical Immunology Unit

Department of MedicineKing Chulalongkorn Memorial Hospital

A 28-years old Thai female

U/D diabetes mellitus > 2 years, most likely T1DM

Now she is pregnant, G2P0A1 (criminal abortion), GA about 6 months

ConsultationOShe used to use oral hypoglycemic

agent before becoming pregnant but eventually changed to insulin by endocrinologist

OAfter pregnancy, her endocrinologist adjust her DM Rx using multiple insulin injection as timeline in the next slide

Her DM Rx after pregnancy

Insulin used Feb Mar Apr May Junrapid-acting

Humulin-R® 28/2/13 11/3/13Actrapid® 11/3/13 17/6/13

NovoRapid® 17/6/13Apidra® 19/6/13

Long-actingHumulin-N® 28/2/13Insulatard® ??/4/13 17/6/13

Levemir® 17/6/133/6/13Early rash

17/6/13Large area of

rash

Related HxODosage of insulin was gradually

increased due to her GAOShe took a brand of combined

vitamins pill received from ANC clinic

OShe denied any other concurrent medicine

OShe denied previous Hx of drug and food allergy

Related HxO Injection sites

O Humulin-R® and Actrapid® to Rt.side of her belly

O Humulin-N® and Insulatard® to Lt.side of her belly

OThe reaction started about 3-4 hr after injection

17/6/2013ODue to her rash, she consulted her

endocrinologist.OActrapid® was changed to

NovoRapid®O Insulatard® was changed to

Levemir®

19/6/2013O2 days of new insulin usageOShe got some rash on her thighs at

injection sites

19/6/2013ODue to rash on her thighs, her

endocrinologist planned to try using 2 other insulin: Apidra® and Levemir®

OBut before trying new insulin brands, she was sent to consult allergist about “insulin allergy”

Insulin allergyReview of Literatures

HistoryO1922: 1st use of insulin extracted

from animal islet cells -> Bovine insulin caused a 7.5-cm callus at the injection site.Bliss M. The discovery of insulin. Chicago: University of Chicago,Press; 1982. p. 155.

O1936: 1st use of protamine + zinc to develop slow-release insulin

O1950: Introduction of NPHJersild M. Insulin zinc suspension; four years’ experience. Lancet 1956; 271:1009-13.

HistoryO1970s: Highly purified animal

insulin was introduced and dramatically decrease allergic reactions

Schernthaner G. Immunogenicity and allergenic potential of animal and human insulins. Diabetes Care 1993;16(suppl 3):155-65.

O1975: Fully synthetic insulin was produced

O1978: Human insulin was produced from genetically-engineered E.coli plasmids.

Katsoyannis PG, Tometsko A, Zalut C, Insulin peptides XII. Human insulin generation by combination of synthetic A and B chains. J Am Chem Soc 1966;88:186.

PrevalenceOThe current prevalence of reactions

during insulin treatment: about 2%OLess than 1% have been

considered to be related to the insulin therapy.

Schernthaner G. Immunogenicity and allergenic potential of animal and human insulins. Diabetes Care 1993;16(suppl 3):155-65.

Matheu V. Et al. Insulin allergy and resistance successfully treated by desensitisation with Aspart insulin. Clin Molec Allergy 2005;3:16.

Possible causal componentsO InsulinOLocal

disinfectantsONickelOZincOProtamine

Plantin P, Sassolas B, Guillet MH. Accident cutanes allergiques aux insulines. Ann Dermatol Venereol 1988; 115:813-7.

OPreservatives and solventsO MetacresolO GlycerolO PhenolO Sodium

phosphate

Insulin

David RO, New horizons — alternative routes for insulin therapy, Nature Reviews Drug Discovery.2002;1:529-540

ProtamineOA low-molecular-weight

polycationic proteinOPurified from the sperm of salmon

or related fishOUsed for prolong insulin’s

pharmacologic effect by decreased absorption

ProtamineONo certainly known secondary and

tertiary structure but there were several proposals

Martins RP, Ostermeier GC, Krawetz SA. Nuclear matrix interactions at the human protamine domain: a working model of potentiation. J. Biol. Chem. 2004; 279 (50): 51862–8.

Vilfan ID, Conwell CC, Hud NV. Formation of native-like mammalian sperm cell chromatin with folded bull protamine. J. Biol. Chem. 2004; 279 (19): 20088–95.

Biegeleisen K. The probable structure of the protamine-DNA complex. J. Theor. Biol. 2006;241 (3): 533–40.

OBinding mode of the insulin–protamine complex is not known

Mathias N, Frantisek H, Gerd S, Structural characterization of insulin NPH formulations, European Journal of Pharmaceutical Sciences, 2007; 30(5); 414-423

ProtamineOAn anaphylactic reaction to

protamine sulfate during cardiac surgery was reported

Mishra DK, Sathyamurthy I, Subramanyan K, Girinath MR. Life threatening protamine reaction during bypass surgery—a case report. Indian Heart J 2009;61:216-7.

OPatient with antiprotamine Ab, were high risk for Ig-mediated protamine reactions

Chang LC, Liang JF, Lee HF, Lee LM, Yang VC. Low molecular weight protamine (LMWP) as nontoxic heparin/low molecular weight heparin antidote (II): in vitro

evaluation of efficacy and toxicity. AAPS PharmSci 2001;3 article 18

ProtamineONon-immunologic mechanism might also

cause the reactionO Heparin-protamine complexes could

activate the classical complement pathway

O -> Sequestration of neutrophils in the lungs

O -> Formation of thromboxane A2 and release of histamine

Chang LC, Liang JF, Lee HF, Lee LM, Yang VC. Low molecular weight protamine (LMWP) as nontoxic heparin/low molecular weight heparin antidote (II): in vitro evaluation of efficacy

and toxicity. AAPS PharmSci 2001;3 article 18

ZincOAlter immunogenicity of insulin by

changing the structure of the β chainO Immediate type of localized nodular

reaction at the injection sites was reported to be caused by zinc

Simpson K, Clements M, Ogilvie A, et al. A case of insulin allergy: something to zinc about. Endocrine Abstracts 2008;18:36

Insulin-Zinc complex

Chang X, Jorgensen AM, Bardrum P, Led JJ. Solution structures of the R6 human insulin hexamer,. Biochemistry, 1997;36 (31): 9409–22.

CresolOC7H8OOA group of aromatic organic

compounds called “Phenolics”OUse as preservative in some

insulin preparations

CresolO3 forms

Todd H. http://chemistry.about.com/od/factsstructures/ig/Chemical-Structures---C/Cresol-Isomers.htm, online article, accessed June 2013.

CresolODTH reactions to meta-cresol in

insulin was reported:O Erythematous burning lesions at

the injection sites on the day after SC use

O Mild headache + gastric pain + erythematous burning lesions at the injection sites on the day after SC use

Clerx V, Keybus VD, Kochuyt A, Goossens A. Drug intolerance reaction to insulin therapy caused by metacresol. Contact Dermatitis 2003;48:162-3

Kim D, Baraniuk J. Delayed-type hypersensitivity reaction to the metacresol component of insulin. Ann Allergy Asthma Immunol 2007;99:194-5.

GlycerolOA simple polyol compound

GlycerolO Increased insulin stability by

decreasing precipitationA.M. Gualandi-Signorini, G. Giorgi, Insulin formulations – a review, Eur Rev Med

Pharmacol Sci. 2001; 5: 73-83.Blackshear PJ, Rohde TD, Palmer JL. Glycerol prevents insulin precipitation and

interruption of flow in an implantable insulin infusion pump. Diabetes Care 1983; 6: 387-392.

ONumerous of contact allergic reactions from glycerol were reported

ONo report of reaction to glycerol in insulin preparations from PubMed

PhenolOC6H6O

ONo reported reaction to phenol in insulin preparations found on PubMed

Reported reactionsOType I: IgE-mediated reactions

(most common) with rare anaphylaxis case

OType III: immune complex-type (Arthus reaction-localized or serum sickness-generalized)

OType IV: delayed-type hypersensitivity (no report of occurrence due to insulin, but occur due to added components)

Heinzerling L, Raile K, Rochlitz H, Zuberbier T, Worm M. Insulin allergy. Allergy 2008;63:148-55.

Diagnostic testsOType I: IgE-mediated reactions

O Skin tests:OPrick testOIntradermal test

O Specific IgE titerO Drug provocation test

Diagnostic testsOType III: immune complex-type

O Clinical DxO Immune complex titerO Skin Biopsy

OType IV: delayed-type hypersensitivityO Skin patch test

Mohammad KG, Graham AJ. Insulin allergy. Clinics in Dermatology 2011; 29:300–305

Let’s go back to our patientSearching for causative

agent

Diagnostic tests doneOType I: IgE-mediated reactions

O Skin prick testO Intradermal skin test

OType IV: delayed-type hypersensitivityO Skin patch test

Skin prick testOrapid-acting insulin tested (All 1:10)

O Actrapid® -> ActraO Apidra® -> ApidO NovoRapid® -> Nov

OLong-acting insulin tested (All 1:10)O Insulatard® -> InsO Levemir® -> LevO Lantus® -> Lan

All Negative

Intradermal skin testOrapid-acting insulin tested (All 1:10)

O Actrapid® -> AcO Apidra® -> Ap

OLong-acting insulin tested (All 1:10)O Insulatard® -> InO Lantus® -> La

Intradermal skin test results

Orapid-acting insulin tested (All 1:10)O Actrapid® 7x7 mm -> 28x10 mmO Apidra® 7x7 mm ->

9x7mm

OLong-acting insulin tested(All 1:10)O Insulatard® 9x9 mm -> 11x8

mmO Lantus® 10x10 mm ->

16x11 mm

Skin patch testOrapid-acting insulin tested (All 1:10)

O Actrapid® -> AcO Apidra® -> ApO NovoRapid® -> No

OLong-acting insulin tested (All 1:10)O Insulatard® -> InO Levemir® -> LeO Lantus® -> La

Properties of involved agents

OActrapid® Novo NordiskOApidra® Sanofi-AventisONovoRapid® Novo NordiskO Insulatard® Novo NordiskOLevemir® Novo NordiskOLantus® Sanofi-Aventis

Actrapid®O Insulin humanOProduced by recombinant DNA

technology in Saccharomyces cerevisiae

ONo restriction in pregnancy

Novo Nordisk A/S, Actrapid® Prescribing information leaflet, 2011.

Actrapid®OList of excipients

O Zinc chlorideO GlycerolO MetacresolO Sodium hydroxide (for pH

adjustment)O Hydrochloric acid (for pH

adjustment)O Water for injections

Novo Nordisk A/S, Actrapid® prescribing information leaflet, 2011.

Actrapid®O Immune-related undesirable effects

O Uncommon - Urticaria, rashO Very rare - Anaphylactic reactionsO Generalized hypersensitivity

OGeneralized skin rashOItchingOSweatingOgastrointestinal upset


Actrapid®O Immune-related undesirable effects

O Generalized hypersensitivity OAngioneurotic edemaODifficulties in breathingOPalpitationOReduction in blood pressureOFainting/loss of consciousness


Apidra®O Insulin glulisine (rapid-acting)ORecombinant insulin analogueOProduced from non-pathological

laboratory strain E.coli (K12)OPregnancy category C

Sanofi-Aventis, Apidra® prescribing information leaflet, 2009.

Apidra®


Apidra®OList of excipients

O TromethamineO MetacresolO Sodium chlorideO PolysorbateO Water for injections


Apidra®OAllergic reactions

O LocalORedness, swelling and itching at

injection siteO Systemic (4.3% in 12-mo controlled

trial)OAnaphylaxisOWhole body rashODyspnea


Apidra®OAllergic reactions

O Systemic (4.3% in 12-mo controlled trial)OWheezingOHypotensionOTachycardiaODiaphoresis


NovoRapid®O Insulin aspartOBiosynthetically modified human

insulin analog (rapid-acting)OProduced using a modified strain of

the yeast Saccharomyces cerevisiae

OWell-tolerated and may benefit the fetus in pregnant women

Novo Nordisk A/S, NovoRapid® product monograph, 2001.

NovoRapid®


NovoRapid®OList of excipients

O GlycerolO PhenolO MetacresolO Zinc chlorideO Disodium phosphate dihydrateO Sodium chlorideO Hydrochloric acid/Sodium hydroxideO Water for injections


NovoRapid®OAllergic reactions

O Few potentially allergic eventsO No anaphylactic reactions O Incidence of potentially allergic

events was no greater than soluble human insulin

O No increase the risk of injection site reactions compared with soluble human insulin


Insulatard®O Isophane NPH insulinO Insulin human, produced by

recombinant DNA technology in Saccharomyces cerevisiae

ONo restriction of use in pregnancyNovo Nordisk A/S, Insulatard® prescribing information leaflet, 2007.

Insulatard®OList of excipients

O Zinc chlorideO GlycerolO MetacresolO PhenolO Disodium

phosphate dihydrate

.

O Sodium hydroxide or/and hydrochloric acid

O Protamine sulphate

O Water for injections

Novo Nordisk A/S, Insulatard® prescribing information leaflet, 2007.

Insulatard®OUndesirable effects (immune

system)O Uncommon – Urticaria, rashO Very rare- Anaphylatic reactionsO Generalized skin rashO ItchingO SweatingO Gastrointestinal upset


Insulatard®OUndesirable effects (immune

system)O Angioneurotic edemaO Difficulties in breathingO PalpitationO reduction in blood pressure O Fainting/loss of consciousnessO Generalized hypersensitivity

reactions are potentially life threatening.


Levemir®O Insulin determirOLong-acting insulin analogOProduced from recombinant DNA in

Saccharomyces cerevisiae followed by chemical modification

OPregnancy Category BNovo Nordisk A/S, Levemir® prescribing information leaflet, 2013.

Levemir®

Novo Nordisk A/S, Levemir® prescribing information leaflet, 2013.

Levemir®OList of

excipients:O ZincO MetacresolO GlycerolO PhenolO Disodium

phosphate dihydrate

O Sodium chloride

O water for injection

O Hydrochloric acid and/or sodium hydroxide


Levemir®OHypersensitivity and allergic

reactionsO Local reactions:

OLocalized erythemaOPainOPruritusOUrticariaOEdemaOInflammation.


Levemir®OHypersensitivity and allergic

reactionsO Systemic reactions:

OGeneralized skin reactionsOAngioedemaOBronchospasmOHypotensionOShockOAnaphylaxis


Lantus®O Insulin glargineOLong-acting recombinant human

insulin analogOProduced by utilizing a

nonpathogenic laboratory strain of Escherichia coli (K12)

OPregnancy Category CSanofi-Aventis, Lantus® Product information leaflet, 2007

Lantus®OMolecular structure

Sanofi-Aventis, Lantus® Product information leaflet, 2007

Lantus®OList of excipients:

O Meta-cresolO GlycerolO Zinc chlorideO Hydrochloric acidO Sodium hydroxideO Water for injections


Lantus®OAllergic reactions

O RednessO PainO ItchingO Hives (urticarial rash)O SwellingO Inflammation


Lantus®OAllergic reactions

O Immediate-type allergic reactions are rare

O Generalized skin reactionsO AngioedemaO BronchospasmO HypotensionO Shock

O Sanofi-Aventis, Lantus® Product information leaflet, 2007

Insulin brands Type Source Zinc

Prot-amin

eCres

olGly-cerol

Others

Rapid-acting

Actrapid® Human S.cerevisiae

Apidra®Analog (Glulisin

e)E.coli Tromet

h-amine

NovoRapid®

Analog (Aspart) S.cerevisiae Phenol

Long-actingInsulatard

® Human S.cerevisiae Phenol

Levemir®Analog

(Determir)

S.cerevisiae Phenol

Lantus®Analog (Glargin

e)E.coli

Comparison of involved agents

Next Rx by endocrinologist

ORapid-acting insulinO Apidra®

OLong-acting insulin testedO Levemir® (intradermal test was not

done)

ORx was started on 19/6/2013

Next Rx by allergistOAntihistamine

O Cetirizine 10 mg b.i.d. (Pregnancy cat.B)

OTopical steroidO 0.1% TA creamO Elomet lotion

OVitamins-> Continue as usualORx was started on 19/6/2013

24/6/2013OPatient reported that more rash

occurred since 20/6/2013 and spread more on all limbs

ORash on her abdominal wall was darker with some greenish-bluish area.

OShe injected both types of insulin to her lateral aspect of both thighs, without local rash at injection sites.

Right thigh

Left thigh

Skin patch test results

Current Rx since 24/6/2013

OLevemir® = suspected cause -> Stopped

OTry using only rapid-acting insulin:O Apidra® 14-12-12 U + 4 U sc at 23.00,

3.00OMaintain cetirizine at 10 mg b.i.d.

+advice to add more dose prn (max 40 mg/d)

OContinue TA cream and Elomet lotion

OStop all other medications (vitamin, etc)

What to do next?Management of insulin

reactions

Possible useful managementO If specific causal agent can be

identifiedOChanging the preparation is

obviously usefulO If not,

O DesensitizationO Changes in the route or the rate of

administrationO Immunotherapy

Mohammad KG, Graham AJ. Insulin allergy. Clinics in Dermatology 2011; 29:300–305

In this patientOShe is pregnantOFrom current data, Apidra® and

Insulatard® is the most likely usable agent

OBut when she has stress (e.g. in-labor), short/rapid-acting, dose-adjustable insulin infusion is needed

OSo we try only Apidra® first

In this patientO If Apidra® can be tolerated, it will

be used until she give birth to her child

OAfter that, we can retest any insulin preparation again without limitation from her pregnancy

OWe will know that on next Monday…

But if Apidra® cause the reaction again…

What should we do next?

Please help me….(^_^!)

insulin allergy

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