102

K.J. presents with classic symptoms of angioedema and does not have symptoms

of a true anaphylactic reaction, further strengthening the diagnosis of drug-induced

angioedema. Symptoms of angioedema usually occur within the first week of starting

therapy, although they can occur at any time, even years later. Thus, although

angioedema developed 3 weeks after K.J. began enalapril, the temporal relationship

is reasonable.

CASE 32-7, QUESTION 2: How should K.J. be treated? Would an angiotensin receptor blocker (ARB) be

an appropriate substitute for her ACE inhibitor?

Although angioedema can be life-threatening, symptoms are usually mild and

resolve within hours to days of stopping the offending drug. The most common lifethreatening complication of angioedema is airway obstructions. More severe

reactions affecting the upper airway must be treated emergently with appropriate

measures to maintain airway patency. A small clinical trial of ACE-induced

angioedema comparing treatment with corticosteroid and antihistamine (prednisolone

500 mg IV and clemastine 2 mg IV) to treatment with icatibant (30 mg subcutaneous

injection) found that the time to initial relief and complete symptom resolution were

significantly shorter with icatibant.

102 Additional trials are currently evaluating

icatibant and hopefully will help define which patients will be most likely to benefit

from this drug.

K.J. does not need to be hospitalized because her respirations are not

compromised and she is not experiencing swallowing difficulty; however, she should

be kept under observation at the urgent care center to ensure that her angioedema

does not worsen. She can be treated with icatibant 30 mg subcutaneously or she can

be observed and later sent home with instructions to seek emergent help if her

breathing or swallowing becomes difficult. She should be instructed to discontinue

her enalapril, follow up with her primary physician as soon as possible, and to

request her community pharmacist to record this adverse reaction to enalapril into

her drug profile at the pharmacy. Because angioedema occurs with all ACE

inhibitors, K.J. must avoid all drugs in this class.

Angioedema with ARBs has also been reported,

103,104 although with less frequency

than with ACE inhibitors. Many of the cases of ARB-induced angioedema involved

patients with a history of ACE inhibitor–induced angioedema, but this is not

consistently the case. Similar to the ACE inhibitors, angioedema to ARBs can occur

at any time during treatment. In K.J.’s case, it would be best to avoid ARBs and ACE

inhibitors. Instead, other antihypertensive agents that have little effect on cholesterol

(e.g., calcium channel blockers) should be used.

Several other drugs have been associated with angioedema including aspirin,

NSAIDs, antibiotics, radiocontrast media, and DPP-IV inhibitors (e.g., sitagliptin

and saxagliptin).

101 The causes of angioedema with these drugs are less well

understood but often occur after having ACE inhibitor–induced angioedema. These

drug should be used with caution if KJ needs them in the future.

CASE 32-7, QUESTION 3: Are there other pseudoallergic reactions that occur with ACE inhibitors and

ARBs?

Besides angioedema, cough is a pseudoallergic reaction caused by ACE

inhibitors. It may occur in up to 39% of patients after 1 week to 6 months of therapy.

Interestingly, it is more common in nonsmokers than in smokers; the incidence does

not increase in patients with chronic airway disease or asthma. Cough is more

common in women than men, is not dose-related, and, as with angioedema, occurs

with all ACE inhibitors.

93,101,105 Several mechanisms appear to be responsible,

including inhibition of the breakdown of bradykinin in the lung and increases in local

mediators of inflammation such as prostaglandins and substance P. Although many

approaches to the management of ACE-induced cough have been proposed,

105

angiotensin II–receptor blocking agents are the most promising alternative. Cough can

occur with an ARB, but the frequency appears to be no more than that of placebo.

Furthermore, most direct comparative trials between ARBs and ACE inhibitors

demonstrate that the frequency of cough with ARBs is much lower than with ACE

inhibitors.

105

Radiocontrast Media

Radiocontrast media are widely used diagnostic agents, exceeding 75 million

administrations annually.

106 Adverse reactions to radiocontrast media can be divided

into immediate reactions (occurring within 1 hour of administration and include

nausea, flushing, BP changes, bronchospasm, urticaria, angioedema, cardiac

arrhythmias, convulsions, angina, and symptoms indistinguishable from true

anaphylaxis) and non-immediate reactions (occurring 1 hour to 10 days after

administration and include pruritus, maculopapular drug eruption, Stevens–Johnson

syndrome, toxic epidermal necrolysis, and vasculitis). The cause of radiocontrast

media reactions remains unknown, although histamine release, complement

activation, and direct toxic effects on end organs might all play a role. Many of the

adverse effects to radiocontrast media have historically been classified as

pseudoallergic reactions because evidence did not support IgE mediation of these

reactions. Recently, however, skin tests and laboratory evidence suggest an

immunologic mechanism for radiocontrast media reactions.

106 The overall incidence

of reaction to radiocontrast media is 0.7% to 13%, depending on the type of agent

selected and whether the patient was pretreated before administration.

107

Conventional, ionic, high-osmolality contrast media produce reactions in 4% to 13%

of recipients, whereas nonionic, low-osmolality agents produce fewer reactions

(0.7%–3.1%). The mortality rate from

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p. 696

radiocontrast media is 1 to 2 cases per 100,000 procedures and is the same for ionic

and non-ionic agents.

108

Female sex, a history of asthma, and a history of reaction to contrast media are risk

factors for reactions to radiocontrast media. Of these, a history of reaction is the most

important; 21% to 60% of patients with a history of reaction to radiocontrast media

will have a reaction on reexposure.

106 Several pretreatment regimens have been

developed to minimize such occurrences. For example, 32 mg of oral

methylprednisolone given 12 hours and 2 hours before a procedure involving a highosmolality contrast medium can reduce the reaction rate by up to 45%.

107 Another

pretreatment regimen uses oral prednisone 50 mg taken 13 hours, 7 hours, and 1 hour

before the procedure, plus diphenhydramine 50 mg orally or intramuscularly 1 hour

before the examination.

109 This latter regimen lowers the occurrence of

pseudoallergic reactions to high-osmolality contrast media, even in high-risk patients

(i.e., those with a history of severe anaphylactoid reactions). Note that a “seafood

allergy” is not a risk factor for a reaction to radiocontrast media. Patients with food

allergies do not require special pretreatment prior to procedures involving these

agents.

108,110

Narcotic Analgesics

Some opiates stimulate histamine release and, thereby, cause hypotension,

tachycardia, facial flushing, increased sweating, or pruritus. Severe reactions are

uncommon, however. In many cases, the opiate can be continued with administration

of an antihistamine to treat the symptoms. If the reaction is significant, a non-narcotic

alternate analgesic may be considered, or an opiate that does not cause histamine

release can be substituted. Morphine and meperidine cause the greatest histamine

release in both in vitro and in vivo studies. Codeine, hydromorphone, oxycodone,

and butorphanol stimulate histamine release less commonly; and levorphanol,

fentanyl, sufentanil, methadone, and oxymorphone have little to no effect on histamine

levels. One of the more frequent reactions to epidurally or intrathecally administered

opiates is pruritus, which does not appear to be mediated by histamine because

narcotics that do not release histamine (e.g., fentanyl and sufentanil) still cause

pruritus after spinal administration. Furthermore, the pruritus tends to develop

several hours after the opiate has been administered, when serum levels of histamine

are insignificant. The cause of pruritus from spinal opiates remains unclear. The

reaction can be managed with antihistamines and low-dose naloxone or nalbuphine,

while continuing with the spinal narcotic.

91

Iron-dextran Injection

Parenteral iron is used in the treatment of iron deficiency when oral iron preparations

cannot be used or are ineffective. This is most commonly seen in patients with

anemia of chronic renal failure, particularly those treated with epoetin alfa or

darbepoetin and undergoing hemodialysis (Chapter 28, Chronic Kidney Diseases).

Iron preparations are associated with a wide spectrum of adverse events (e.g., chest

pain, hypotension, hypertension, abdominal pain, nausea, vomiting, weakness,

syncope, backache, arthralgias, myalgias, and hypersensitivity reactions).

Hypersensitivity reactions can be manifested as urticaria, sweating, dyspnea, rash,

fever, and as anaphylactoid reactions, which can be fatal. Consistent with a

nonimmunologic mechanism, hypersensitivity reactions to iron are not dose-related

and can occur with the first drug exposure.

111

Iron preparations differ in regard to the salt or carbohydrate carrier used,

molecular weight, and rate of hypersensitivity reactions. The first commonly used

iron preparations were iron dextran, available as a high-molecular weight ferric

oxyhydroxide and dextran solution (Dexferrum) and later as a low-molecular weight

ferric hydroxide and dextran solution (INFeD). Adverse events occur more often

with iron dextran preparations compared to non-dextran preparations and are highest

with high-molecular weight iron dextran. Data reported to the FDA MedWatch

program between 2001 and 2003 was used to determine the odds of adverse events

between iron dextran products and two non-dextran products: sodium ferric

gluconate and iron sucrose (also known as iron saccharate). Relative to the InFeD

brand of iron dextran, patients receiving sodium ferric gluconate or iron sucrose

were half as likely to experience an allergic reaction or any adverse reaction. An

equal risk existed of experiencing an allergic reaction, or any adverse reaction,

between sodium ferric gluconate and iron sucrose. Although sodium ferric gluconate

and iron sucrose were safer than iron dextran, at least one death and five lifethreatening reactions were reported with each of the four agents studied.

112

Ferumoxytol, an agent approved in 2009, was designed with a modified dextrose

shell to reduce hypersensitivity reactions. In a comparison trial, there was a

comparable safety profile but did include one anaphylactoid reaction but no deaths

compared to iron sucrose.

113 Since approval, post-marketing FDA surveillance has

demonstrated several reports of life-threatening and serious anaphylactoid reactions,

including six deaths in a 10-month reporting period.

114 The prescribing information

has been updated to include a black box warning for fatal and serious

hypersensitivity reactions.

115 The newest iron product is ferric carboxymatltose

complex, which releases iron from a carbohydrate polymer. Hypersensitivity

reactions are expected to be lower as it does not contain an dextran or modified

dextran component. In comparison to iron sucrose, no significant difference was

found in the rate of hypersensitivity reactions or anaphylactoid reactions.

116,117

Although approval FDA was initially delayed because of a potential safety

imbalance in the risk of death, subsequent pooled analysis has not validated the early

findings, and the product was approved with only a warning for hypersensitivity

reactions.

118,119

All patients receiving iron dextran should receive a test dose to assess tolerance,

the other iron preparations do not require a test dose per their prescribing

information. It appears iron dextran–tolerant patients have little risk of experiencing

a serious hypersensitivity or anaphylactoid reaction to sodium ferric gluconate or

iron sucrose injection and can safely be given one of these products without a prior

test dose. Similarly, patients who have never received any parenteral iron product

can be administered sodium ferric gluconate or iron sucrose for injection without a

prior test dose. Although studies support the safety of both sodium ferric gluconate

and iron sucrose for injection in iron dextran–sensitive patients, such patients may be

at increased risk for an anaphylactoid reaction or other serious hypersensitivity

response, and test dosing in this population may be reasonable. Because of the risks

associated with any of the parenteral iron products, close monitoring of the patient

for at least 30 minutes after drug administration is necessary and the availability of

resuscitative medication and personnel trained to evaluate and address anaphylaxis is

prudent.

PREVENTION AND MANAGEMENT OF

ALLERGIC REACTIONS

CASE 32-8

QUESTION 1: A.M., a 40-year-old woman, is hospitalized with a diagnosis of community-acquired

pneumonia. Her medical history is noncontributory except for an uneventful course of ampicillin 6 months

before admission for an ear infection. A.M. is empirically

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p. 697

treated with cefuroxime 0.75 g IV every 8 hours. On day 2 of therapy, she develops a raised pruritic

maculopapular rash on her back, abdomen, and upper extremities. Antacid, docusate sodium, albuterol by

metered-dose inhaler, and multivitamins were initiated on the same day as the cefuroxime. How should A.M.’s

allergic reaction be managed? How might her allergic reaction have been prevented?

When examining methods to prevent allergic reactions, three possibilities exist:

(a) the patient has unknowingly been sensitized to a drug and experiences an allergic

reaction on receiving the same or a similar drug again; (b) the patient has a history of

an allergic reaction to a medication and mistakenly receives the same or a similar

medication a second time and again develops an allergic reaction; and (c) the patient

has a history of an allergic reaction to a medication and intentionally receives the

same or similar medication again. As in the first situation, A.M.’s allergic reaction

was unpredictable and, therefore, could not be prevented. To prevent future allergic

reactions (i.e., the second situation), however, A.M.’s reaction should be well

documented in the medical chart and pharmacy records. In addition, all patients

should undergo a thorough drug history on hospitalization. Careful attention should be

paid to differentiating drug intolerance (e.g., stomach upset) from true allergic

reactions, and any allergic reactions elicited during an interview should be

documented appropriately. Adequate communication of allergic reactions is the

single most important method of preventing their occurrence.

As described earlier, the first step in managing an allergic reaction is to determine

its cause. Given A.M.’s history of exposure to ampicillin, the timing of the reaction,

and the low frequency of allergic reactions to her other medications, cefuroxime is

the most likely candidate. Second, a decision regarding whether to stop the suspect

drug should be made. This decision must be based on the severity of the reaction, the

condition being treated, and the availability of suitable alternatives. When possible,

an equally effective alternative drug should be substituted for the suspect agent,

preferably one that is immunologically distinct to avoid cross-sensitivity (see Case

32-1, Question 4, for a discussion of cross-reactivity).

120

If a suitable alternative

exists, the offending agent should be stopped and the reaction treated symptomatically

if necessary. In the case of A.M., another antimicrobial (e.g., azithromycin,

clarithromycin, trimethoprim–sulfamethoxazole) could be substituted for cefuroxime

(Chapter 67, Respiratory Tract Infections) and her symptoms treated with an oral or

parenteral antihistamine, as well as a low-potency topical corticosteroid if

necessary.

Some cases are described by the third situation: a patient develops an allergic

reaction (or has a well-documented history of drug allergy), and it is inappropriate or

not possible to change to an alternative drug. If the sensitivity reaction is severe or

life-threatening, desensitization should be considered (Case 32-9, Questions 1 and

2); premedication to prevent or minimize anaphylaxis is not effective.

29

If the reaction

is minor (e.g., pruritus, rash, or gastrointestinal symptoms), premedication or

management of the reaction with antiallergy medications (e.g., antihistamines) might

be sufficient to allow completion of therapy. It is rare in such cases for the reaction

to progress to more serious allergic symptoms such as anaphylaxis

120

; however,

suppression of allergic symptoms should be undertaken cautiously because many

immunologic reactions are not IgE mediated and may progress to serious reactions,

despite treatment. In general, allergy suppression should be reserved for prevention

of mild reactions that are known or strongly suspected to be IgE mediated.

7,120

Desensitization

β-LACTAMS

CASE 32-9

QUESTION 1: K.A. is a 24-year-old primigravida in her eighth week of pregnancy with a history of

angioedema secondary to penicillin. Her initial pregnancy screening revealed a positive Venereal Disease

Research Laboratory reaction and a fluorescent treponemal antibody absorption titer of 1:64. K.A. denies a

history of genital lesions, currently does not exhibit clinical signs or symptoms of syphilis, and denies previous

treatment for syphilis. Based on the serologic evidence and her history, a diagnosis of early latent syphilis is

made. Current treatment guidelines indicate that penicillin is the drug of choice for K.A. How can a possible

reaction to penicillin be prevented in K.A.? Is premedication an alternative to preventing a reaction?

There are situations where a drug is medically necessary in a patient with a known

or suspected allergy to the drug, alternative therapy is not available, and diagnostic

testing does not exist. In such cases there are two options: induction of tolerance

(also called desensitization) or a graded challenge. Desensitization is the process of

administering gradually increasing doses of a drug in an effort to modify a patient’s

response to the drug so that it can then be safely administered.

108 This process has

been used successfully to manage both immune-mediated and non–immune-mediated

reactions. A graded challenge (also called incremental test dosing) is the process of

careful administration of subtherapeutic doses of drug to determine if a patient is

truly allergic. Although similar sounding, there are distinct differences between the

two processes.

108 For example, unlike induction of tolerance, a graded challenge

does not alter a patient’s response to the drug. The initial drug doses used for

inducing tolerance are sub-allergenic—as low as 1/10,000th of the final dose and the

process can take several hours involving multiple doses, each slightly larger than the

preceding dose. Starting doses for a graded challenge may be 1/100th of the final

dose. The process generally involves fewer steps (as few as two) and can be

typically accomplished more rapidly. If the graded challenge is completed and a

therapeutic course of drug tolerated, a graded challenge is not required before future

courses of the drug. Tolerance induction, on the other hand, is only maintained as

long as the patient receives the suspect drug; any interruption of therapy will require

the desensitization procedure to be repeated (see Case 32-9, Question 4).

The choice of drug desensitization or using a graded challenge depends on the

likelihood of the patient having a true allergic reaction. A graded challenge may be

appropriate in patients with a distant or unclear history of drug allergy; when the

reaction seems minor or for which diagnostic testing is unavailable; or in cases

where cross-reactivity is expected to be low. For example, a patient with a

maculopapular rash to ceftriaxone may undergo a graded challenge to imipenem–

cilastatin to assess tolerance. On the other hand, a patient with a well-described,

severe IgE-mediated reaction to a drug may be better suited for tolerance induction.

Importantly, graded challenge or tolerance induction should not be used in patients

with a history of a severe non-IgE–mediated reaction such as hepatitis, hemolytic

anemia, Stevens–Johnson syndrome, toxic epidermal necrolysis, or DRESS

syndrome because of the risk of provoking a potentially life-threatening reaction.

108

Because K.A.’s reaction to penicillin may be potentially severe, premedication is not

an option and desensitization to penicillin should be started. (See Chapter 72

Sexually Transmitted Diseases, for alternative therapy.)

p. 697

p. 698

CASE 32-9, QUESTION 2: How should K.A. be desensitized? Why should she be skin-tested before

desensitization?

If possible before tolerance induction is begun, K.A. should be skin-tested (see

Case 32-1, Questions 3 and 4) to confirm her penicillin allergy.

7,34,120 Patients who

have a positive history of penicillin allergy, but whose skin tests are negative, can

receive full therapeutic doses without desensitization with little risk of developing an

allergic reaction. One author, for example, reported only one case of acute

anaphylaxis in a skin test–negative patient given full therapeutic doses of penicillin in

more than 1,500 skin tests; similar results have been reported by other

investigators.

34,120

If skin testing cannot be performed or if K.A.’s skin test is

positive, desensitization should be initiated. Acute oral desensitization to penicillin

and other β-lactam antibiotics is well established.

121

The oral route for β-lactam desensitization is preferred to the parenteral route

because (a) exposure by the oral route is less likely to cause a systemic allergic

reaction than parenteral exposure; (b) fatal anaphylaxis from oral β-lactam drug

therapy is rare; (c) preformed polymers and conjugates of penicillin major and minor

determinants to Penicillium proteins are not well absorbed after oral administration;

(d) blood levels rise gradually, favoring univalent haptenation; and (e) fatal or lifeendangering reactions have not occurred using current methods. In addition, oral

desensitization can be accomplished over several hours.

7

If oral desensitization is not

possible (e.g., if oral absorption is questionable), parenteral desensitization can be

instituted. Although the subcutaneous and IM routes have been used, the IV route is

quicker and allows better control over the rate and concentration of drug

administered, and any untoward reaction can be detected promptly and treated

rapidly.

7,122 Oral and parenteral desensitization methods have not been compared

formally, however. Patients should not be premedicated before desensitization,

because this may prevent detection of minor allergic responses that may precede

more serious reactions. In addition, only experienced personnel should undertake

desensitization in an appropriate setting where emergency resuscitative equipment is

readily available because severe reactions can develop.

120 Thus, K.A. should

undergo oral desensitization if her skin test is positive or if skin testing cannot be

performed.

CASE 32-9, QUESTION 3: Is K.A. at risk for an allergic reaction during tolerance induction? If tolerance

induction is successful, is she at risk for a reaction during full-dose penicillin therapy?

Acute β-lactam desensitization, regardless of the route or protocol chosen, is not

without risk. Approximately 5% of patients experience mild cutaneous reactions

during desensitization, although one study reported reactions in 20% of patients

during oral desensitization.

7,123

If a reaction occurs during the desensitization

procedure itself, the reaction may be treated and desensitization continued using

lower doses, increased intervals between doses, or both, after the reaction has

abated. Severe, fatal reactions during desensitization are rare.

122

Uneventful β-lactam desensitization, however, does not guarantee patients will be

without reaction during full-dose therapy. Approximately 25% to 30% of patients

experience a mild reaction during therapy, and 5% experience more severe reactions,

including drug-induced serum sickness, hemolytic anemia, or urticaria.

7 Reaction

rates are no different in severely ill or pregnant patients compared with stable or

nonpregnant patients, although those with cystic fibrosis may be more difficult to

desensitize because of their high frequency of allergic reactions.

123,124 Despite the

occurrence of reactions, full-dose therapy is possible for most tolerance-induction

procedures, but suppression of the reaction (e.g., by diphenhydramine) may be

required.

122 Tolerance induction is also dose-dependent as allergic symptoms can

appear after a substantial increase in the dose after tolerance has been achieved.

7

CASE 32-9, QUESTION 4: If K.A. requires penicillin at a later date, will she need to undergo desensitization

again? What is chronic desensitization?

The desensitized state, once achieved, will persist for approximately 48 hours

after the last full dose of antibiotic; after this time, drug sensitivity will return.

7,122

Thus, if K.A. requires future courses of penicillin, she will need to undergo

desensitization once again. In some cases, those requiring long-term antibiotic

therapy (e.g., for endocarditis), those who may require β-lactams at a future date

(e.g., those with cystic fibrosis), or those who have occupational exposure to β-

lactams, maintenance of the desensitized state can be considered. Chronic twice daily

dosing of oral penicillin has safely resulted in “chronic desensitization.” Similar to

acute desensitization, once therapy is interrupted, the allergic state returns.

7,27

OTHER DRUGS

CASE 32-9, QUESTION 5: Have patients allergic to drugs besides β-lactams been desensitized

successfully?

Although most experience with desensitization is with penicillin and other βlactams, desensitization also has been accomplished with numerous other drugs,

including allopurinol, vancomycin, antineoplastic agents, aspirin, and monoclonal

antibodies.

66,123,124

Interestingly, not all of these cases represent IgE-mediated

hypersensitivity reactions. For example, reactions to trimethoprim–sulfamethoxazole

commonly occur in patients infected with HIV and may not be IgE mediated. Yet,

given its role in treating and preventing Pneumocystis jiroveci pneumonia, successful

desensitization to trimethoprim–sulfamethoxazole is commonly used.

124

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A full list of references for this chapter can be found at

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