1. Drug Allergies vs. Pseudoallergies vs. Expected Side Effects
Idaho Society of Health-Systems Pharmacists
Drug Allergies vs. Pseudoallergies vs. Expected Side Effects
Kaitlyn McDonald, PharmD
Pharmacy Practice Resident
Kootenai Health
March 6, 2016

2. Disclosures
The author of this presentation has no conflicts of interest to disclose.

3. Abbreviations ACE – Angiotensin-converting enzyme inhibitor
ADR – Adverse drug reaction
COX – cyclooxygenase
IgE – immunoglobulin E
NSAID – non-steroidal anti-inflammatory
PCN – Penicillin
Abbreviations used throughout presentation

4. Learning Objectives
Recognize the difference between an allergy and an adverse reaction
Demonstrate the ability to obtain an accurate patient allergy history
Identify common adverse drug reactions to specific high incidence medications

5. Drug Allergy vs. Pseudoallergy

6. Background
~250,000,000 people are treated in emergency departments annually due to drug allergies
Most common offenders:
Aspirin
Opioids
Penicillins
Sulfa drugs
Technician Tutorial: Drug Allergies. Pharmacist’s Letter 2009.

7. Ramifications
Incorrect reporting of an “allergy” can mislead providers, resulting in modification of treatment
Alternatives will be given, which may not have the same efficacy or therapeutic benefit, and may be more expensive

8. Signs & Symptoms of an Allergy
Swollen, red, itchy, rash
Hives (red, itchy patches)
Swelling of the face, tongue, lips and/or throat
Difficulty breathing or swallowing

9. What’s the difference? Drug Allergy Pseudoallergy
An over-reaction of the immune system to a foreign substance
Not caused by a direct activation of the immune system, instead histamine is released directly from subcutaneous mast cells
Mimics an allergic reaction
What is the difference between a drug allergy and a pseudoallergy? An allergy is immune-mediated while a pseudoallergy is not, but I presents very similarly.

10. What’s the difference? Drug Allergy Pseudoallergy
Anaphylaxis from penicillin
Stevens-Johnson’s syndrome from sulfonamides
Red Man Syndrome from vancomycin
Rash or hives after radiocontrast media
Bronchospasm after aspirin
Angioedema and anaphylaxis from ACE inhibitors
examples

11. Pathophysiology - Allergy
When white blood cells encounter an antigen they produce IgE antibodies. These antibodies attach to mast cells in the immune system. Once an allergen activates these antibodies, the mast cells release histamine and cytokines into the body. These produce allergic symptoms, such as sneezing, rhinitis, itching, hives, and inflammation.

12. Medical Charting Record most pseudoallergies as an allergy
Exception: reactions that occurred which can be eliminated by a dose reduction or infusion rate change
Red Man Syndrome
Even though they are not technically caused by an immune-mediated process they are severe and can be life-threatening

13. Drugs commonly causing allergic reactions

14. “My mom told me I’m allergic”
Penicillin
How many times have you heard this one?
“My mom told me I’m allergic”

15. Penicillin
~10% of the population reports an allergy to PCN
Skin Testing
Skin-testing revealed that only ~10% of these patients had a true PCN allergy
Number of positive PCN test decreased by 10% each year after allergic reaction
After 10 years, 78% patients will have negative skin tests
% have life-threatening anaphylactic reaction
Also of note – reactions that occurred in the 40s or 50s were more common due to “dirty” formulations (higher rate of contamination)
Salkind AR, et al. JAMA 2001;285: Puchner TC, et al. Ann Allergy Asthma Immunol 2002;88:24-29
Pullen H. Lancet 1967;1: Solensky R. Ann Allergy Clin Immunol 2010;105:273

16. Penicillin Most common reactions:
Uritcaria
Pruritus
Angioedema
Incidence of a rash due to ampicillin is almost 100% if the patient has a mononucleosis infection
PCN are the drug of choice for certain infections, so avoiding their use because of easy-to-treat adverse effects would be inappropriate
The rash that occurs while a patient is taking amoxicillin or ampicillin for a vial infection is actually due to the disease, but is often associated with the antibiotic.
Salkind AR, et al. JAMA 2001;285:

17. Cross-Reactivity Beta-lactam family includes PCN Cephalosporins
Carbapenems
Azobactam*
*Azobactam has very weak cross-reactivity with the other beta-lactams.
So can a patient who is allergic to PCN have a cephalosporin (or carbapenem or monobactam)? Depends
Each class of beta-lactams is defined by its side chain structure. It is thought that Azobactam’s lack of a similar side chain group explains why is appears to share very little cross-reactivity with the other beta-lactam groups. Incidence is reported as 0.9%
Frumin J, et al. Ann Pharmacother 2009;43:

18. Cross reactivity Cephalosporins 1st & 2nd generation: ~5%
3rd & 4th generation: <1%
Carbapenems
~1-10%
Originally the incidence of cross-reactivity between PCN and cephalosporins was ~10-15%, but this was due to the contamination of cephalosporin products with trace amounts of PCN back in the 60s and 70s.
Frumin J, et al. Ann Pharmacother 2009;43: Pichichero ME. Pediatrics 2005;115:
Solensky R, et al. Ann Allergy clin Immunol 2010;105:

19. Desensitization Induces temporary tolerance to a drug
Slow re-introduction of drug until induction of reaction (if any)
Protocols for most antibiotics, aspirin, NSAIDS, chemotherapy, sulfa, etc.
Used for critical situations where there is no alternative drug or the alternative is suboptimal.

20. Sulfonamides Incidence is ~3% Most common reaction: maculopaular rash
Usually develops after 7-14 days
Severe reactions: Stevens-Johnson syndrome, toxic epidermal necrosis, anaphylaxis
The difference in chemical structure between the sulfonylarylamines and other types of sulfonamides implies that cross-reactivity is unlikely. However, T-cell mediated immune response has been reported to occur occasionally. It is unknown whether T-cell recognition is related to the sulfonamide moiety or some other functional group. Until the mechanism behind T-cell recognition is more clearly understood, cross-reactivity between sulfonylarylamines and the other types of sulfonamides remains theoretically possible.

21. Cross-Reactivity Drugs that contain a sulfa moiety Simeprevir
Amprenavir
Fosamprenavir
Sulfates, sulfites, sulfur
Morphine sulfate
Spironolactone
Ranitidine
Omeprazole
No cross-reactivity between sulfa and any of these agents, but cannot completely rule out the possibility for drugs with a sulfa moiety
What about drugs/agents with sulfur, sulfites, and sulfates? No cross-reactivity
Also procainamide, dapsone, and some local anaesthetics contain a similar functional group (though it’s technically not a sulfa moiety) and have been known to cause cross-sensitivity reactions
Saccharin is a sulfonamide derivative. Skin reactions have been reported in pts who also had reaction to a sulfonamide.

22. Aspirin Most common reactions:
Asthma
Rhinorrhea
Urticaria
Angioedema
COX-1 inhibition from aspirin and NSAIDs
Blocks the production of prostaglandins which degranulate mast cells
Increase production of leukotrienes which cause bronchoconstriction and increased mucus production
Leukotriene-modifying drugs (monteleukast) can reduce severity of aspirin-induced asthma
This theory is not 100% confirmed. It’s still possible that the drugs themselves stimulate release of inflammatory mediators directly from mast cells..
No apparent cross-reactivity with COX-2 inhibitors
Stevenson DD, et al. Immunol Allergy Clin North Am 2004;24:

23. Opioids True allergy is rare Most common reactions:
Codeine, morphine, meperidine
Most common reactions:
Pruritis
Hallucinations
Commonly reported as an allergy on patient charts, but most reactions should be labeled as an adverse reaction.
Most common true allergies are reported with the more natural opioids (morphine & codeine)
Histamine release from mast cells in the skin, not systemic immune system, causes the pruritis

24. Opioids Allergic reaction or adverse drug event with a combo product
Clarify with patient if they have tolerated any of the single agents in the past

25. Non-Drug Allergies Food
Soy & peanut (same family) – propofol, clevidipine
Gluten – some tablet and capsule formulations
Egg – flu vaccine (except recombinant flu vac)
Pertinent food & latex allergies
The recombinant flu vaccine (Flublok) doesn’t contain eggs

26. Non-Drug Allergies Latex Incidence is ~2%
More likely if allergy to avocado, kiwi, or banana
Injectable vial stoppers, IV tubing, gloves
Pollart SM, et al. Am Fam Physician 2009;80:

27. Non-Drug Allergies Dyes
Yellow No. 5
Yellow No. 6
Yellow No. 10
Red No. 40
Blue No. 2
Most common reactions: contact dermatitis, rhinitis, urticarial, bronchospasm, anaphylaxis
Check with manufacturer if your patient has an allergy or ADR to a dye that is not as common. Only the major culprits are reported in package inserts.
Even drugs that are white are not always free of dye
American Academy of Pediatrics Committee on Drugs. Pediatrics 1985;76:

28. Adverse Drug Reaction vs. Side Effect

29. What’s the difference? Adverse Drug Reaction Side Effect
harmful or unpleasant reaction as a result of the administration of a medication
unintended effects that can be either intolerable or beneficial
What’s the difference between an adverse drug reaction and a side effect? Splitting hairs here, but a side effect can encompass ADRs as well as beneficial effects caused by a drug.

30. Common or serious ADRs General Medication Classes
Chemotherapy agents – nausea or vomiting
Antibiotics – diarrhea, nausea
Opioids – pruritis, constipation, hallucinations, sedation
NSAIDs – peptic ulcer
Antipsychotics – weight gain, extrapyramidal symptoms
Statins – myopathy, rhabdomyolysis
Anti-insomnia agents – daytime somnolence
Anticoagulants – GI bleed
ACE inhibitors – cough, angioedema
Antacids (PPIs>H2Bs) – bone fractures

31. Common or serious ADRs Specific Medications Isosorbide – headache
Digoxin – yellow vision
Fluoroquinolones – QTc prolongation
Acetaminophen – liver damage
Dabigatran – GI upset
Varenicline – nightmares
Most commonly reported meds to the FDA in 2011 were:
Dabigatran, warfarin, levofloxacin, ciprofloxacin, lisinopril, simvastatin, cisplatin, carboplatin, sulfamethoxazole/trimethoprim, and duloxetine

32. Taking a Patient History

33. Recording an Allergy Detail Reason Drug name
Include all active ingredients
Dose, frequency, route, infusion rate
May be dose- or rate-related
Onset and offset of reaction
Helps determine causality and type of reaction that occurred
Description of reaction and how it was managed
Helps classify reaction as allergy or ADR
Allows the provider to use their clinical judgment for further treatment plans
Reaction severity
Determines level of contraindication to the medication and related agents
Original indication of drug
Rule out whether or not the reaction was caused by the disease
Date of original (and most recent) reaction
Mostly applicable to products that used to contain contaminants or were animal-based. We have much cleaner (less immunogenic) products now

34. Patient Interview Please describe the reaction.
How long ago did the reaction occur?
Have you ever had the same reaction with a different drug?
Have you ever tolerated similar drugs? (provide examples)
How soon after the reaction did the reaction occur?
How was the reaction managed?

35. Assessment Questions

36. Assessment Question #1
Which of the following symptoms is classified as a hypersensitivity reaction (allergy)?
Cough
Bronchospasm
Hiccups
Nausea
Sedation

37. Assessment Question #1
Which of the following symptoms is classified as a hypersensitivity reaction (allergy)?
Cough
Bronchospasm
Hiccups
Nausea
Sedation
Correct answer: B, Bronchospasm. The other options are considered adverse drug reactions and are not immune-mediated.

38. Assessment Question #2
You are reviewing a new patient’s allergies. The patient reports that they are allergic to Penicillin. Which of the following questions will provide you with further relevant information?
What type of reaction did you experience?
How long ago did the reaction occur?
What is the name of the doctor who prescribed you the medication you had a reaction to?
A & B only
All of the above

39. Assessment Question #2
You are reviewing a new patient’s allergies. The patient reports that they are allergic to Penicillin. Which of the following questions will provide you with further relevant information?
What type of reaction did you experience?
How long ago did the reaction occur?
What is the name of the doctor who prescribed you the medication you had a reaction to?
A & B only
All of the above
Correct answer: D, A& B only. The name of the original prescribing doctor is not necessary information for other providers. However, the specific symptoms and length of time since the reaction will help future providers make accurate assessments and treatment plans regarding the patients allergy history.

40. Assessment Question #3
Which of the following common medication - adverse drug reaction matches does not belong?
Inhalers – peptic ulcer
Opioids – constipation
ACE inhibitors – cough
Antipsychotics – weight gain
Chemotherapy agents – nausea

41. Assessment Question #3
Which of the following common medication - adverse drug reaction matches does not belong?
Inhalers – peptic ulcer
Opioids – constipation
ACE inhibitors – cough
Antipsychotics – weight gain
Chemotherapy agents – nausea
Correct answer: A, Inhalers – peptic ulcer. Common reactions to inhalers may include hoarseness (corticosteroid formulations), tremor, palpitations, or headache.