Insulin allergy

A pregnant woman
with insulin allergy
Wat Mitthamsiri, M.D.
Allergy and Clinical Immunology Unit
Department of Medicine
King 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

Consultation
O She used to use oral hypoglycemic
agent before becoming pregnant but
eventually changed to insulin by
endocrinologist
O After 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 Jun
rapid-acting
Humulin-R® 28/2/13 11/3/13
Actrapid® 11/3/13 17/6/13
NovoRapid® 17/6/13
Apidra® 19/6/13
Long-acting
Humulin-N® 28/2/13
Insulatard® ??/4/13 17/6/13
Levemir® 17/6/13
3/6/13
Early rash
17/6/13
Large area of rash

Related Hx
O Dosage of insulin was gradually
increased due to her GA
O She took a brand of combined vitamins
pill received from ANC clinic
O She denied any other concurrent
medicine
O She denied previous Hx of drug and
food allergy

Related Hx
O Injection sites
O Humulin-R® and Actrapid® to Rt.side of
her belly
O Humulin-N® and Insulatard® to Lt.side
of her belly
O The reaction started about 3-4 hr after
injection

17/6/2013
O Due to her rash, she consulted her
endocrinologist.
O Actrapid® was changed to NovoRapid®
O Insulatard® was changed to Levemir®

19/6/2013
O 2 days of new insulin usage
O She got some rash on her thighs at
injection sites

19/6/2013
O Due to rash on her thighs, her
endocrinologist planned to try using 2
other insulin: Apidra® and Levemir®
O But before trying new insulin brands,
she was sent to consult allergist about
―insulin allergy”

Insulin allergy
Review of Literatures

History
O 1922: 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.
O 1936: 1st use of protamine + zinc to
develop slow-release insulin
O 1950: Introduction of NPH
Jersild M. Insulin zinc suspension; four years’ experience. Lancet 1956; 271:1009-13

History
O 1970s: 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.
O 1975: Fully synthetic insulin was
produced
O 1978: 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.

Prevalence
O The current prevalence of reactions
during insulin treatment: about 2%
O Less 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 components
O Insulin
O Local
disinfectants
O Nickel
O Zinc
O Protamine
Plantin P, Sassolas B, Guillet MH. Accident cutanes allergiques aux insulines. Ann Dermatol
Venereol 1988; 115:813-7.
O Preservatives and
solvents
O Metacresol
O Glycerol
O Phenol
O Sodium
phosphate

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

Protamine
O A low-molecular-weight polycationic
protein
O Purified from the sperm of salmon or
related fish
O Used for prolong insulin’s
pharmacologic effect by decreased
absorption

Protamine
O No 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.
O Binding 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

Protamine
O An 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.
O Patient 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

Protamine
O Non-immunologic mechanism might
also cause the reaction
O 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

Zinc
O Alter immunogenicity of insulin by
changing the structure of the β chain
O 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.

Cresol
O C7H8O
O A group of aromatic organic
compounds called ―Phenolics‖
O Use as preservative in some insulin
preparations

Cresol
O 3 forms
Todd H. http://chemistry.about.com/od/factsstructures/ig/Chemical-Structures---C/Cresol-
Isomers.htm, online article, accessed June 2013.

Cresol
O DTH 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.

Glycerol
O A simple polyol compound

Glycerol
O Increased insulin stability by
decreasing precipitation
A.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.
O Numerous of contact allergic
reactions from glycerol were
reported
O No report of reaction to glycerol in
insulin preparations from PubMed

Phenol
O C6H6O
O No reported reaction to phenol in
insulin preparations found on
PubMed

Reported reactions
O Type I: IgE-mediated reactions (most
common) with rare anaphylaxis case
O Type III: immune complex-type (Arthus
reaction-localized or serum sickness-
generalized)
O Type 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 tests
O Type I: IgE-mediated reactions
O Skin tests:
O Prick test
O Intradermal test
O Specific IgE titer
O Drug provocation test

Diagnostic tests
O Type III: immune complex-type
O Clinical Dx
O Immune complex titer
O Skin Biopsy
O Skin patch test

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

Let’s go back to
our patient
Searching for causative agent

Diagnostic tests done
O Type I: IgE-mediated reactions
O Skin prick test
O Intradermal skin test
O Skin patch test

Skin prick test
O rapid-acting insulin tested (All 1:10)
O Actrapid® -> Actra
O Apidra® -> Apid
O NovoRapid® -> Nov
O Long-acting insulin tested (All 1:10)
O Insulatard® -> Ins
O Levemir® -> Lev
O Lantus® -> Lan

Intradermal skin test
O Actrapid® -> Ac
O Apidra® -> Ap
O Insulatard® -> In
O Lantus® -> La

Intradermal skin test results
O Actrapid® 7x7 mm -> 28x10 mm
O Apidra® 7x7 mm ->
9x7mm
O Long-acting insulin tested(All 1:10)
O Insulatard® 9x9 mm -> 11x8 mm
O Lantus® 10x10 mm -> 16x11 mm

Skin patch test
O Actrapid® -> Ac
O Apidra® -> Ap
O NovoRapid® -> No
O Insulatard® -> In
O Levemir® -> Le
O Lantus® -> La

Properties of involved agents
O Actrapid® Novo Nordisk
O Apidra® Sanofi-Aventis
O NovoRapid® Novo Nordisk
O Insulatard® Novo Nordisk
O Levemir® Novo Nordisk
O Lantus® Sanofi-Aventis

Actrapid®
O Insulin human
O Produced by recombinant DNA
technology in Saccharomyces
cerevisiae
O No restriction in pregnancy
Novo Nordisk A/S, Actrapid® Prescribing information leaflet, 2011.

Actrapid®
O List of excipients
O Zinc chloride
O Glycerol
O Metacresol
O 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, rash
O Very rare - Anaphylactic reactions
O Generalized hypersensitivity
O Generalized skin rash
O Itching
O Sweating
O gastrointestinal upset

Actrapid®
O Immune-related undesirable effects
O Generalized hypersensitivity
O Angioneurotic edema
O Difficulties in breathing
O Palpitation
O Reduction in blood pressure
O Fainting/loss of consciousness

Apidra®
O Insulin glulisine (rapid-acting)
O Recombinant insulin analogue
O Produced from non-pathological
laboratory strain E.coli (K12)
O Pregnancy category C
Sanofi-Aventis, Apidra® prescribing information leaflet, 2009.

Apidra®

Apidra®
O Tromethamine
O Metacresol
O Sodium chloride
O Polysorbate

Apidra®
O Allergic reactions
O Local
O Redness, swelling and itching at injection
site
O Systemic (4.3% in 12-mo controlled trial)
O Anaphylaxis
O Whole body rash
O Dyspnea

Apidra®
O Systemic (4.3% in 12-mo controlled trial)
O Wheezing
O Hypotension
O Tachycardia
O Diaphoresis

NovoRapid®
O Insulin aspart
O Biosynthetically modified human insulin
analog (rapid-acting)
O Produced using a modified strain of the
yeast Saccharomyces cerevisiae
O Well-tolerated and may benefit the fetus
in pregnant women
Novo Nordisk A/S, NovoRapid® product monograph, 2001.

NovoRapid®

NovoRapid®
O Glycerol
O Phenol
O Metacresol
O Zinc chloride
O Disodium phosphate dihydrate
O Sodium chloride
O Hydrochloric acid/Sodium hydroxide

NovoRapid®
O Few potentially allergic events
O 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 insulin
O Insulin human, produced by
recombinant DNA technology in
Saccharomyces cerevisiae
O No restriction of use in pregnancy
Novo Nordisk A/S, Insulatard® prescribing information leaflet, 2007.

Insulatard®
O Zinc chloride
O Glycerol
O Metacresol
O Phenol
O 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®
O Undesirable effects (immune system)
O Uncommon – Urticaria, rash
O Very rare- Anaphylatic reactions
O Generalized skin rash
O Itching
O Sweating
O Gastrointestinal upset

Insulatard®
O Undesirable effects (immune system)
O Angioneurotic edema
O Difficulties in breathing
O Palpitation
O reduction in blood pressure
O Fainting/loss of consciousness
O Generalized hypersensitivity reactions
are potentially life threatening.

Levemir®
O Insulin determir
O Long-acting insulin analog
O Produced from recombinant DNA in
Saccharomyces cerevisiae followed by
chemical modification
O Pregnancy Category B
Novo Nordisk A/S, Levemir® prescribing information leaflet, 2013.

Levemir®

Levemir®
O List of excipients:
O Zinc
O Metacresol
O Glycerol
O Phenol
O 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.

Levemir®
O Hypersensitivity and allergic reactions
O Local reactions:
O Localized erythema
O Pain
O Pruritus
O Urticaria
O Edema
O Inflammation.

Levemir®
O Hypersensitivity and allergic reactions
O Systemic reactions:
O Generalized skin reactions
O Angioedema
O Bronchospasm
O Hypotension
O Shock
O Anaphylaxis

Lantus®
O Insulin glargine
O Long-acting recombinant human insulin
analog
O Produced by utilizing a nonpathogenic
laboratory strain of Escherichia coli
(K12)
O Pregnancy Category C
Sanofi-Aventis, Lantus® Product information leaflet, 2007

Lantus®
O Molecular structure

Lantus®
O List of excipients:
O Meta-cresol
O Glycerol
O Zinc chloride
O Hydrochloric acid
O Sodium hydroxide

Lantus®
O Redness
O Pain
O Itching
O Hives (urticarial rash)
O Swelling
O Inflammation

Lantus®
O Immediate-type allergic reactions are
rare
O Generalized skin reactions
O Angioedema
O Bronchospasm
O Hypotension
O Shock
O Sanofi-Aventis, Lantus® Product information leaflet, 2007

Insulin
brands
Type Source Zinc
Prot-
amine
Creso
l
Gly-
cerol
Other
s
Rapid-acting
Actrapid® Human S.cerevisiae   
Apidra®
Analog
(Glulisine
)
E.coli

Tromet
h-
amine
NovoRapid
®
Analog
(Aspart)
S.cerevisiae    Phenol
Long-acting
Insulatard® Human S.cerevisiae     Phenol
Levemir®
Analog
(Determir
)
S.cerevisiae    Phenol
Analog
Comparison of involved agents

Next Rx by endocrinologist
O Rapid-acting insulin
O Apidra®
O Long-acting insulin tested
O Levemir® (intradermal test was not
done)
O Rx was started on 19/6/2013

Next Rx by allergist
O Antihistamine
O Cetirizine 10 mg b.i.d. (Pregnancy cat.B)
O Topical steroid
O 0.1% TA cream
O Elomet lotion
O Vitamins-> Continue as usual
O Rx was started on 19/6/2013

24/6/2013
O Patient reported that more rash
occurred since 20/6/2013 and spread
more on all limbs
O Rash on her abdominal wall was darker
with some greenish-bluish area.
O She injected both types of insulin to her
lateral aspect of both thighs, without
local rash at injection sites.

Current Rx since 24/6/2013
O Levemir® = suspected cause ->
Stopped
O Try using only rapid-acting insulin:
O Apidra® 14-12-12 U + 4 U sc at 23.00, 3.00
O Maintain cetirizine at 10 mg b.i.d.
+advice to add more dose prn (max 40
mg/d)
O Continue TA cream and Elomet lotion
O Stop all other medications (vitamin, etc)

What to do next?
Management of insulin
reactions

Possible useful management
O If specific causal agent can be identified
O Changing the preparation is obviously
useful
O If not,
O Desensitization
O Changes in the route or the rate of
administration
O Immunotherapy
Mohammad KG, Graham AJ. Insulin allergy. Clinics in Dermatology 2011; 29:300–305

In this patient
O She is pregnant
O From current data, Apidra® and
Insulatard® is the most likely usable
agent
O But when she has stress (e.g. in-labor),
short/rapid-acting, dose-adjustable
insulin infusion is needed
O So we try only Apidra® first

In this patient
O If Apidra® can be tolerated, it will be
used until she give birth to her child
O After that, we can retest any insulin
preparation again without limitation from
her pregnancy
O We 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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