3

23

3

28

3

33

3

38

3

58

3

Case reports have identified systemic hypersensitivity reactions following the use of anthracyclines such as urticaria, bronchospasm, and angioedema immediately after administration.[A216397] The most common manifestations of anthracyclines include urticaria and pruritus.[A216397,L15252,L15257]. Prescribing information for anthracyclines mentions the possibility of anaphylaxis, skin reactions, fever, and chills following anthracycline administration. [L15252, L15262] Mild infusion-related reactions can occur, although rare.[A221555]

Anthracyclines

categorical

8

Acetylcysteine administration may cause non-immunologic anaphylaxis (anaphylactoid reaction), including symptoms of urticaria, angioedema, bronchospasm, pruritus, and hypotension.[A3995, A216572, A216547] The management for acetylcysteine hypersensitivity is outlined in a review article.[A3995] If urticaria occurs, acetylcysteine infusion may continue and the patient should be treated with diphenhydramine.[A3995] If angioedema, bronchospasm, or other respiratory symptoms occur, acetylcysteine should be stopped temporarily, and the patient should be treated with diphenhydramine and other supportive measures.[A3995] A systematic review found that extra caution should be exercised in patients with asthma as they may be at a higher risk for experiencing acetylcysteine adverse effects, including non-immunologic anaphylaxis.[A216547, A216557]

Acetylcysteine

drug-specific

13

In clinical trials, the use of aminoglutethimide has been associated with cutaneous allergies. [A216412] One case report mentions the occurrence of anaphylaxis following the use of aminoglutethimide.[A216417] Prescribing information mentions the occurrence of skin rash and urticaria following the use of aminoglutethimide in clinical trials. In addition, hypersensitivity pneumonitis has rarely occurred following administration.[L15267]

Aminoglutethimide

drug-specific

18

Hypersensitivity reactions to aminoglycosides are rare, with an incidence of less than 2%, and tend to be non-immediate reactions.[A216592] Hypersensitivity reactions are common with the use of topical aminoglycosides, with contact dermatitis being the most frequently reported reaction.[A216672] Other cutaneous reactions include exfoliative erythroderma, urticaria, pruritus, rash, ulcerative dermatitis, exfoliative dermatitis, conjunctivitis, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), fixed exanthema, and toxic epidermal necrolysis (TEN). Anaphylaxis was reported with the use of gentamicin and amikacin. Rare cases of anaphylaxis have also been reported with streptomycin.[A233744,A233749] Other systemic hypersensitivity reactions documented in case reports are serum sickness with gentamicin, and arthralgia, bronchospasm, eosinophilia, fever, and bronchospasm with tobramycin.[A216592] Cross-sensitivity may occur even between less structurally-related aminoglycosides. Successful desensitization to both tobramycin and streptomycin has been reported.[L14210]

Aminoglycosides

categorical

23

Clinical trials have identified that an allergy to amprenavir can lead to cutaneous hypersensitivity reactions. One case report mentions the occurrence of a maculopapular exanthem following amprenavir administration.[A216422,A216552] Prescribing information for amprenavir indicates the possibility of serious and life-threatening skin rash, including Stevens-Johnson Syndrome.[L15282]

Amprenavir

drug-specific

3

hypersensitivity_type

Unclassified

8

hypersensitivity_type

Unclassified

18

hypersensitivity_type

Unclassified

23

hypersensitivity_type

Type I

28

hypersensitivity_type

Type I

3

13608

Non-immunologic anaphylaxis - formerly known as “anaphylactoid reaction” - is a life-threatening reaction mimicking anaphylaxis, a condition that causes difficulty breathing and low blood pressure. Non-immunologic anaphylaxis can occur after exposure to a medication, chemical, or other substance.

Non-immunologic anaphylaxis - commonly known as “anaphylactoid reaction” - is similar to anaphylaxis and often causes urticaria, bronchospasm, peripheral vascular collapse, and life-threatening hypotension. Non-immunologic anaphylaxis currently replaces the term “anaphylactoid reaction”, according to the World Allergy Organization, with the aim of preventing clinicians from dismissing this life-threatening reaction as a benign condition.[L14378] Although non-immunologic anaphylaxis and true anaphylaxis have similar clinical presentations, the pathophysiology for each condition is distinct.[A214499,L14378] Non-immunologic anaphylaxis reactions are, as the name suggests, non-immune in nature; anaphylactic reactions are associated with the release of IgE, IgG, or immune complex/complement activity. During non-immunologic anaphylaxis, mast cell and basophil-mediated activation occurs (by non-immune mediated mechanisms), leading to histamine release and the subsequent development of clinical signs and symptoms.[A203774,L14378]

Non-immunologic anaphylaxis is a life-threatening condition and should be treated with the same rigor as true anaphylaxis.[A214499] Management should begin with immediate discontinuation of the causative drug followed by administration of subcutaneous or intramuscular epinephrine, and administration of intravenous fluids.[A214499] The patient should be carefully monitored and provided with additional supportive treatment as necessary.[A214499] Antihistamines, steroids, beta agonists, and ventilatory support may be beneficial in some cases.[A203774,A203825]

8

12293

Serum sickness-like reaction is a reaction to a medication that causes fever, rash, swelling, and joint pain. It may be mistaken for a different reaction - serum sickness - due to similar symptoms. Blood tests are required to distinguish true serum sickness from serum sickness-like reactions.

Serum sickness-like reactions (SSLRs) are drug reactions that present similarly to serum sickness, but do not involve the formation of the immune complexes that are characteristic of true serum sickness. The physiologic mechanism behind these reactions is unclear, although some evidence suggests they may be the result of aberrant reactions to metabolites produced by the biotransformation of certain medications.[L14417] SSLRs may also result from infection by a number of pathogens, including streptococcus bacteria and hepatitis B virus.[A214565] Drug-induced SSLRs typically occur within 1 to 3 weeks following exposure to the culprit medication and frequently present with a generalized, pruritic, urticarial rash. Other common symptoms include fever, malaise, facial swelling, and symmetrical joint pain/swelling, especially in the knees and hands.[L14417] Serum sickness-like syndrome may rarely present with headache, myalgia, lymphadenopathy, or gastrointestinal symptoms.[L14417] SSLRs can be distinguished from true serum sickness by measuring circulating levels of two complement proteins: C3 and C4. True serum sickness results in activation and depletion of complement proteins, resulting in reduced C3 and C4 levels; patients experiencing an SSLR will have normal serum complement levels.[A214565] Additionally, SSLRs do not typically affect kidney function or include the multiorgan involvement that is sometimes seen in more severe cases of serum sickness (for example, blurred vision, splenomegaly, anterior uveitis, and peripheral neuropathy).[A214565]

The management of drug-induced SSLRs involves identifying and discontinuing the culprit medication.[A214565] Generally self-limiting, SSLRs tend to resolve within a few days of withdrawing the offending agent without the need for additional treatment.[A214565,L14417] Symptomatic treatment with antihistamines and corticosteroids may be initiated, however, evidence for their benefit is lacking.[L14417] Patients should be instructed to avoid the offending agent indefinitely if possible, since the risk of recurrence is unclear following subsequent exposures.[L14417]

18

57398

ACE inhibitor-associated angioedema is a non-allergic reaction that can occur in patients taking a type of blood pressure medication called an “ACE inhibitor”. It typically involves significant swelling of the face, lips, and tongue, and may cause difficulties breathing or stomach upset. This condition most commonly occurs within weeks of starting treatment with an ACE inhibitor, but can manifest months to years later.

Angiotensin converting enzyme inhibitor (ACEi) associated angioedema is a well-documented, non-allergic drug hypersensitivity resulting from the use of angiotensin converting enzyme inhibitors. It has an estimated prevalence of 0.5-0.7%[A216113] amongst all patients taking ACEi, although the risk may be greater based on ethnicity, age, sex, comorbidies, smoking status, and concomitant administration of certain medications (e.g. mTOR inhibitors, NSAIDs, DPP-4 inhibitors, etc).[A216138,A216133,A38152] The pathogenesis of ACEi-induced angioedema likely involves bradykinin, a peptide responsible for increasing local vasopermeability (via generation of nitric oxide and prostaglandins)[A216138,A216133] resulting in the extravasation of fluid and subsequent edema.[A216113] Bradykinin is principally broken down by angiotensin converting enzyme, with lesser contributions by other enzymes such as DPP-4[A216138,A216133] - the use of ACEi drugs, therefore, can largely inhibit the catabolism of bradykinin. The resulting supraphysiologic bradykinin concentrations are thought to be responsible for the symptoms of ACEi-induced angioedema, although there is some evidence that other mediators such as substance P contribute.[A216138,A216133] ACEi-induced angioedema most commonly occurs within weeks of starting therapy, but primary episodes have been documented months to years into treatment.[A216138,A216133] The classic clinical presentation involves significant swelling of facial subcutaneous tissue and the mucosa of the lips and oral cavity (e.g. tongue).[A216138,A216133] Notably, facial swelling caused by ACEi-induced angioedema is not accompanied by pruritus or pain.[A216138,A216133] Additionally, patients may experience shortness of breath and, in some cases, abdominal symptoms.[A216138]

If ACEi-induced angioedema is suspected, immediate withdrawal of the culprit medication is the first priority. Patients should not be re-treated with the offending drug, since the recurrence rate - especially within the first month following medication withdrawal.[A216113] Most cases of ACEi-induced angioedema are mild and resolve within 48-72 hours of withdrawing the offending drug, however, severe and fatal cases have been reported.[A216113] Severe cases may require hospitalization and intubation to maintain respiratory status.[A216113] Evidence for effective pharmacologic treatment of ACEi-induced angioedema is lacking.[A179773] Although traditional treatments for allergic reactions (e.g. antihistamines, corticosteroids, epinephrine) may be useful in severe cases,[A216133] they do not target the underlying bradykinin-mediated pathogenesis of ACEi-induced angioedema.[A216113] Agents targeting bradykinin - such as C1 esterase inhibitors or icatibant[A216113] - are indicated for the treatment of hereditary angioedema, but are not currently approved for ACEi-induced angioedema, and are therefore not commonly used in practice.[A216133,A179773] For example, C1 esterase inhibitors and icatibant (a bradykinin B2 receptor antagonist[L15202]) are indicated for the treatment of hereditary angioedema, however, evidence is limited or conflicting for the use of these agents to treat ACEi-induced angioedema.[A179773,A216352,A35494,L15197]

23

1820

Anaphylaxis is a life-threatening allergic reaction that can cause low blood pressure, difficulty breathing, and a skin rash.

Anaphylaxis is an allergic reaction that causes urticaria, dyspnea, wheezing, nausea, vomiting, syncope, and hypotension. It typically manifests seconds to minutes following exposure to a drug or other allergen. Rarely, it may be delayed by several hours after exposure. Protracted anaphylaxis may last for hours to days.[A214499] Anaphylaxis is caused by activation of the immune system, causing the release of IgG, IgE, and the formation of immune complexes that lead to various symptoms.[L14378] Cardiovascular, cutaneous, and respiratory symptoms are the most frequently reported clinical manifestations of anaphylaxis, and may result in fatal outcomes.[A199128,A214499]

Anaphylaxis is a life-threatening condition and is generally treated with prompt withdrawal of the offending medication, early intramuscular or subcutaneous epinephrine, and intravenous fluids.[A199128,A214499] The patient should be monitored closely. Adjunctive treatment options include antihistamines, beta agonists, and corticosteroids. In some cases, ventilatory support may be required. Patients with anaphylaxis should be monitored for protracted anaphylaxis, which may persist for hours or days without resolution of symptoms.[A214499,A215392]

28

13538

Urticaria is an allergic skin condition, more commonly known as “hives”. It is associated with itching, swelling, and raised skin welts.

Urticaria is a common skin manifestation associated with drug allergies.[A214511] The condition is classified according to symptom duration: acute urticaria symptoms last for up to 6 weeks while chronic urticaria symptoms may persist for more than 6 weeks.[A199137] Medications may cause acute, chronic, and contact urticaria.[L14393] The most common drug classes implicated in drug-induced urticaria are penicillins, sulfonamides, and nonsteroidal anti-inflammatory agents. Drug-induced urticaria may occur after an initial exposure or after several previously well-tolerated exposures to the causative drug.[A214511] Urticaria commonly presents with generalized itching, wheals, isolated lesions, and sometimes, deep tissue swelling.[A199137] Itchy wheals and lesions frequently subside within 24 hours.[A214511] Urticaria can occur anywhere on the body and tends to have a wide area of distribution. Drug-induced urticaria may be accompanied by other conditions, such as serum sickness, erythema, morbilliform eruption, dyspnea, shock, and rarely, death.[A199137,A214511] In some cases, urticaria may present similarly to angioedema, and both conditions may overlap. About 40% of urticaria cases are associated with angioedema.[A216118] To distinguish between these conditions, angioedema is associated with pain rather than an itch[A216118] and is more commonly associated with the swelling of face and neck structures - the perioral area, the tongue, soft palate, uvula, larynx, and the eyelids.[L14390]

If a drug-induced allergy is suspected or confirmed, the causative agent should be discontinued immediately. Supportive care measures and symptomatic treatment are the cornerstones of management and should be tailored to each individual’s clinical presentation. When choosing an alternative agent, consider cross-sensitivity and avoid agents that are structurally related, if possible.[A201914, A204257] Manifestations of acute urticaria, such as wheals, tend to disappear within several days of drug discontinuation, however, a prolonged relapsing-remitting course can be observed with chronic urticaria.[L14393] In some cases, urticaria can be managed with second-generation antihistamines and corticosteroids.[A199137]

1

1046

6

As a Hirudin, Lepirudin is known to be cross-sensitive with Hirudins

1

1046

11169

As a Hirudin, Lepirudin is known to be cross-sensitive with Hirudins

2

931

54

As a Monoclonal Antibodies From The Murine (Sp2/0) Cell Line, Cetuximab is known to be cross-sensitive with Monoclonal Antibodies From The Murine (Sp2/0) Cell Line

2

931

65

As a Monoclonal Antibodies From The Murine (Sp2/0) Cell Line, Cetuximab is known to be cross-sensitive with Monoclonal Antibodies From The Murine (Sp2/0) Cell Line

2

931

74

As a Monoclonal Antibodies From The Murine (Sp2/0) Cell Line, Cetuximab is known to be cross-sensitive with Monoclonal Antibodies From The Murine (Sp2/0) Cell Line

3

Theoretical

Cases of anticonvulsant hypersensitivity syndrome following lamotrigine use have been reported, but no evidence has been recorded of cross-reactivity between lamotrigine and aromatic anticonvulsant drugs.[A203786] Lamotrigine does not share the common aromatic benzene structure believed to be the main causative factor contributing to the development of anticonvulsant hypersensitivity syndrome and cross-reactivity. Despite this, the risk of cross-sensitivity cannot be entirely excluded, and caution is advised in patients receiving lamotrigine who previously had allergic reactions to aromatic anticonvulsants.[A215793]

8

Single case reports

Rare case reports of hypersensitivity reactions to both lamivudine and emtricitabine were reported. Patients developed skin rashes, oral and genital ulceration, fever, hepatitis, diarrhea, unconsciousness, with a later diagnosis of Stevens-Johnson syndrome. It is speculated that this possible cross-sensitivity may occur from chemical structure similarities shared by lamivudine and emtricitabine.[A218011, A215668]

13

Rare

A case report illustrates a patient who previously experienced photocontact dermatitis from ketoprofen gel, later developing a pruritic, erythematous papulovesicular eruption following fenofibrate treatment. In one review comprising subjects who are allergic to ketoprofen and previously developed photocontact dermatitis, some patients showed a positive patch test to fenofibrate and experienced photosensitivity reactions related to drug hypersensitivity. Photosensitivity reactions manifested as skin eruptions that were vesiculobullous, erythematovesicular, erythematopapular, eczematous, or erythematobullous in nature. It is believed that chemical similarities between two drugs led to a cross-sensitivity reaction, as ketoprofen and fenofibrate share double benzene rings linked by a ketone group. While the true incidence of cross-sensitivity reactions between ketoprofen and fibrates is largely unknown, the authors of this review suggest that patients with a history of hypersensitivity to ketoprofen avoid using fenofibrate, if possible.[A218556]

18

Single case reports

The diphenylketone group of ketoprofen is similar to that of fenofibrate.[A218556] This structural similarity may be the reason for observed cases of cross-sensitivity.[A218556,A218576]

28

Theoretical

Theoretical evidence suggests that beta-lactams sharing the same R1 side chains are likely to result in hypersensitivity reactions caused by cross-reactivity. The R1 side chain is the primary driver of beta-lactam allergy.[A214343] In one study, 12-38% of patients proven to be selectively allergic to amoxicillin, and were tolerant to penicillin, also reacted to cefadroxil.[A214337]

3

evidence_type

varying_reports

8

evidence_type

case_reports

13

evidence_type

review

18

evidence_type

case_reports

18

evidence_type

review

1

123

Hypersensitivity to Lepirudin (as a Hirudin) can present as: Cutaneous Manifestations of Drug Allergy, Anaphylaxis, Exanthema, Arthus Reaction, and Nonimmunologic Anaphylaxis

1

1983

Hypersensitivity to Lepirudin can present as: Arthus Reaction, Cutaneous Manifestations of Drug Allergy, Infusion related reaction, Allergy-Induced Respiratory Symptoms, Angioedema, Anaphylaxis, and Nonimmunologic Anaphylaxis

2

1010

Hypersensitivity to Cetuximab can present as: Cutaneous Manifestations of Drug Allergy, Stevens-Johnson Syndrome Toxic Epidermal Necrolysis Spectrum, Anaphylaxis, Infusion related reaction, Angioedema, Exanthema, and Bronchospasm

4

583

Hypersensitivity to Denileukin diftitox can present as: Stevens-Johnson Syndrome Toxic Epidermal Necrolysis Spectrum, Nonimmunologic Anaphylaxis, Anaphylaxis, Urticaria, Exanthema, Cutaneous Manifestations of Drug Allergy, and Erythema multiforme

5

1374

Hypersensitivity to Etanercept can present as: Angioedema, Cutaneous Manifestations of Drug Allergy, Anaphylaxis, Erythema multiforme, Nonimmunologic Anaphylaxis, and Urticaria