insulin allergy
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A pregnant woman with insulin allergy
Wat Mitthamsiri, M.D.Allergy and Clinical Immunology Unit
Department of MedicineKing Chulalongkorn Memorial Hospital
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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
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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
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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
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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
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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
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17/6/2013ODue to her rash, she consulted her
endocrinologist.OActrapid® was changed to
NovoRapid®O Insulatard® was changed to
Levemir®
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19/6/2013O2 days of new insulin usageOShe got some rash on her thighs at
injection sites
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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”
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Insulin allergyReview of Literatures
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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.
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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.
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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.
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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
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Insulin
David RO, New horizons — alternative routes for insulin therapy, Nature Reviews Drug Discovery.2002;1:529-540
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ProtamineOA low-molecular-weight
polycationic proteinOPurified from the sperm of salmon
or related fishOUsed for prolong insulin’s
pharmacologic effect by decreased absorption
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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
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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
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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
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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
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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.
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CresolOC7H8OOA group of aromatic organic
compounds called “Phenolics”OUse as preservative in some
insulin preparations
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CresolO3 forms
Todd H. http://chemistry.about.com/od/factsstructures/ig/Chemical-Structures---C/Cresol-Isomers.htm, online article, accessed June 2013.
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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.
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GlycerolOA simple polyol compound
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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
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PhenolOC6H6O
ONo reported reaction to phenol in insulin preparations found on PubMed
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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.
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Diagnostic testsOType I: IgE-mediated reactions
O Skin tests:OPrick testOIntradermal test
O Specific IgE titerO Drug provocation test
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Diagnostic testsOType III: immune complex-type
O Clinical DxO Immune complex titerO Skin Biopsy
OType IV: delayed-type hypersensitivityO Skin patch test
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Mohammad KG, Graham AJ. Insulin allergy. Clinics in Dermatology 2011; 29:300–305
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Let’s go back to our patientSearching for causative
agent
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Diagnostic tests doneOType I: IgE-mediated reactions
O Skin prick testO Intradermal skin test
OType IV: delayed-type hypersensitivityO Skin patch test
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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
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All Negative
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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
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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
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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
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Properties of involved agents
OActrapid® Novo NordiskOApidra® Sanofi-AventisONovoRapid® Novo NordiskO Insulatard® Novo NordiskOLevemir® Novo NordiskOLantus® Sanofi-Aventis
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Actrapid®O Insulin humanOProduced by recombinant DNA
technology in Saccharomyces cerevisiae
ONo restriction in pregnancy
Novo Nordisk A/S, Actrapid® Prescribing information leaflet, 2011.
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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.
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Actrapid®O Immune-related undesirable effects
O Uncommon - Urticaria, rashO Very rare - Anaphylactic reactionsO Generalized hypersensitivity
OGeneralized skin rashOItchingOSweatingOgastrointestinal upset
Novo Nordisk A/S, Actrapid® prescribing information leaflet, 2011.
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Actrapid®O Immune-related undesirable effects
O Generalized hypersensitivity OAngioneurotic edemaODifficulties in breathingOPalpitationOReduction in blood pressureOFainting/loss of consciousness
Novo Nordisk A/S, Actrapid® prescribing information leaflet, 2011.
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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.
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Apidra®
Sanofi-Aventis, Apidra® prescribing information leaflet, 2009.
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Apidra®OList of excipients
O TromethamineO MetacresolO Sodium chlorideO PolysorbateO Water for injections
Sanofi-Aventis, Apidra® prescribing information leaflet, 2009.
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Apidra®OAllergic reactions
O LocalORedness, swelling and itching at
injection siteO Systemic (4.3% in 12-mo controlled
trial)OAnaphylaxisOWhole body rashODyspnea
Sanofi-Aventis, Apidra® prescribing information leaflet, 2009.
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Apidra®OAllergic reactions
O Systemic (4.3% in 12-mo controlled trial)OWheezingOHypotensionOTachycardiaODiaphoresis
Sanofi-Aventis, Apidra® prescribing information leaflet, 2009.
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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.
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NovoRapid®
Novo Nordisk A/S, NovoRapid® product monograph, 2001.
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NovoRapid®OList of excipients
O GlycerolO PhenolO MetacresolO Zinc chlorideO Disodium phosphate dihydrateO Sodium chlorideO Hydrochloric acid/Sodium hydroxideO Water for injections
Novo Nordisk A/S, NovoRapid® product monograph, 2001.
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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
Novo Nordisk A/S, NovoRapid® product monograph, 2001.
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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.
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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.
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Insulatard®OUndesirable effects (immune
system)O Uncommon – Urticaria, rashO Very rare- Anaphylatic reactionsO Generalized skin rashO ItchingO SweatingO Gastrointestinal upset
Novo Nordisk A/S, Insulatard® prescribing information leaflet, 2007.
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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.
Novo Nordisk A/S, Insulatard® prescribing information leaflet, 2007.
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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.
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Levemir®
Novo Nordisk A/S, Levemir® prescribing information leaflet, 2013.
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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
Novo Nordisk A/S, Levemir® prescribing information leaflet, 2013.
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Levemir®OHypersensitivity and allergic
reactionsO Local reactions:
OLocalized erythemaOPainOPruritusOUrticariaOEdemaOInflammation.
Novo Nordisk A/S, Levemir® prescribing information leaflet, 2013.
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Levemir®OHypersensitivity and allergic
reactionsO Systemic reactions:
OGeneralized skin reactionsOAngioedemaOBronchospasmOHypotensionOShockOAnaphylaxis
Novo Nordisk A/S, Levemir® prescribing information leaflet, 2013.
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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
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Lantus®OMolecular structure
Sanofi-Aventis, Lantus® Product information leaflet, 2007
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Lantus®OList of excipients:
O Meta-cresolO GlycerolO Zinc chlorideO Hydrochloric acidO Sodium hydroxideO Water for injections
Sanofi-Aventis, Lantus® Product information leaflet, 2007
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Lantus®OAllergic reactions
O RednessO PainO ItchingO Hives (urticarial rash)O SwellingO Inflammation
Sanofi-Aventis, Lantus® Product information leaflet, 2007
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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
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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
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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
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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
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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.
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Right thigh
Left thigh
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Skin patch test results
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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)
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What to do next?Management of insulin
reactions
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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
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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
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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…
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But if Apidra® cause the reaction again…
What should we do next?
Please help me….(^_^!)