Is it safe for a patient allergic to ibuprofen to take meloxicam? What is the incidence of cross-allergenicity between meloxicam and other NSAIDs?

Comment by InpharmD Researcher

Limited data suggest meloxicam may be safe in patients with a documented history of NSAID allergy. While the true incidence of cross-reactivity is unknown, it is unlikely for an enolic acid derivative NSAID (i.e., meloxicam) to precipitate a true allergic reaction in someone with allergy to an arylpropionic acid NSAID (e.g., ibuprofen, naproxen). The incidence of cross-allergenicity may be lower at low meloxicam doses, as it is known to be more COX-2 preferential at lower doses. If in doubt, skin tests or oral challenges performed in an appropriate setting may be warranted. Studies show the incidence of meloxicam allergy in patients intolerant to other NSAIDs may range from 4-8%.

Background

A 2008 review summarized the information available on the clinical manifestation, diagnosis, and management of reactions associated with NSAID drugs. NSAIDs that inhibit major COX isoenzymes, COX-1 and COX-2, can be classified according to their chemical structure (see Table 4). For IgE-mediated reactions to a single NSAID, another NSAID from a different chemical group can be administered. It is recommended not to use an NSAID from the same group since cross-reactions can occur between NSAIDs of similar chemical structures. In delayed-type reactions, discontinuing offender medication and applying pharmacological treatment with corticosteroids and antihistamines are recommended. The choice of a diagnostic test for adverse reactions induced by NSAIDs should be based on the clinical picture and possible pathogenesis. Patch tests offer a simple, fast, and relatively safe method for the diagnosis of delayed reactions to NSAIDs. The concentration of NSAIDs commonly used for patch testing for meloxicam, a COX-2 preferential inhibitor, is usually around 1%. [1]

A 2018 review discussing non-steroidal anti-inflammatory drug hypersensitivity (NSAID-HS) provides recommendations for diagnostic workup and patient management. Type B reactions, accounting for 20% of NSAIDs-associated side effects, are further subcategorized into the more frequently reported non-immunological NSAID-HS (acronyms NERD [NSAID exacerbated respiratory disease], NECD [NSAID exacerbated cutaneous disease], NIUA [NSAID-induced urticaria/angioedema]), and the much rarer true drug allergies of type I and IV (acronyms SNIUAA [single NSAID-induced urticaria/angioedema or anaphylaxis] and SNIDR [single NSAID-induced delayed reaction]). Across different classes of NSAIDs, ibuprofen belongs to arylpropionic acid derivatives, whereas meloxicam is considered an enolic acid derivative. In general, true drug allergies are not cross-reactive and all other NSAIDs are well-tolerated. In contrast, marked cross-reactivities between structurally different NSAIDs may be more commonly seen in NERD, NECD, and NIUA, mediated via the common blockage of the COX enzyme. [2]

Depending on the clinical presentations and history of clinical reaction patterns and underlying diseases, acute reactions to NSAIDs <24 h along with symptoms such as bronchospasm, dyspnea, nasal discharge/blockage, flushing, urticaria, angioedema, and anaphylaxis, are indicative of NERD, NECD, and NIUA, posing higher chance of cross-reactions. On the other hand, skin reactions to NSAIDs after 24 h (lasting days to weeks) with drug eruption and severe cutaneous adverse reactions in the absence of underlying diseases are more likely caused by true drug allergies with low possibility of cross-reactions. Skin testing with triggering NSAIDs is normally indicated in the settings of true drug allergies. [2]

Management of NSAID-HS should be individualized based on patient factors. Again, in rare cases of true drug allergies, other NSAIDs can continue to be used as long as the offending agent is avoided. Although marked cross-reactions are to be expected in non-immunological NSAID-HS, some patients may still be able to tolerate NSAIDs that tend towards stronger COX-2 inhibition, such as meloxicam. [2]

Relevant Prescribing Information

Meloxicam is contraindicated in the following patients:
Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to meloxicam or any components of the drug product
History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients
In the setting of coronary artery bypass graft (CABG) surgery. [3]

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

Is it safe for a patient allergic to ibuprofen to take meloxicam? What is the incidence of cross-allergenicity between NSAIDs?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-4 for your response.

Safety of meloxicam in patients with aspirin⁄non-steroidal anti-inflammatory drug-induced urticaria and angioedema
Design	Prospective, single-center, single-blind, placebo-controlled, cohort trial N= 116
Objective	To assess the tolerability of meloxicam specifically in patients with non-steroidal anti-inflammatory drug (NSAID)-induced urticaria (UR)⁄angioedema (AE)
Study Groups	NSAID allergy (N= 116)
Inclusion Criteria	Patients admitted to a tertiary allergy clinic; had a reliable or documented history of urticaria or angioedema triggered by one or multiple NSAIDs
Exclusion Criteria	History of hypersensitivity reactions such as cutaneous fixed eruptions, exfoliative dermatitis, toxic epidermal necrolysis, Steven–Johnson syndrome, erythema multiforme, and allergic contact dermatitis; aspirin-intolerant asthma; patients with active UR or AE
Methods	This was a prospective study of patients referred to a single allergy center in Turkey. Any medications that could interfere with a meloxicam challenge (e.g., H1 antagonists) were stopped 3 days before the intervention. Then, patients underwent an oral challenge with placebo and meloxicam over two days. Patients were given one-quarter and three-quarter divided doses of meloxicam (total, 7.5 mg) and placebo at 1-hour intervals over two consecutive days. During the challenge, patients' blood pressure, forced expiratory volume in 1 s (FEV1), and physical reactions were monitored every hour after each placebo or meloxicam dose was given. Patients were followed up for 24 h to detect a delayed reaction. In case of no reaction at the end of 24 h, patients were accepted as meloxicam tolerant.
Duration	Follow-up: 24 hours after medication administration
Outcome Measures	Allergic symptoms
Baseline Characteristics		NSAID allergy (N= 116)
	Age, years (range)	39.6 ± 12.7 (18-81)
	Female	86 (74.1%)
	Reaction to a single NSAID Reaction to multiple NSAIDs	59 (50.9%) 57 (49.1%)
	Allergy to other medications	31 (26.7%)
	Only 3 (1.6%) of 189 documented allergic reactions were due to ibuprofen. Aspirin was the most common culprit of allergy, followed by naproxen.
Results		NSAID allergy (N= 116)
	Allergic reaction to meloxicam Pruritis/erythema Localized angioedema and erythema	10 (8.6%) 5 (4.3%) 5 (4.3%)
	No reactions were observed with placebo. The dose of meloxicam-inducing reaction was mainly the total cumulative dose but the one-quarter dose of the drug-induced erythema in three patients. All intolerance reactions were easily controlled with oral antihistamines.
Adverse Events	No patient showed asthmatic or naso-ocular reaction during challenges.
Study Author Conclusions	This study indicates that 7.5 mg meloxicam is a safe alternative for NSAID-intolerant urticaria or angioedema patients. Intolerance reactions to meloxicam are much milder forms of the patients' historical ASA⁄NSAID-induced cutaneous reactions.
InpharmD Researcher Critique	This study included a number of patients with allergy to acetaminophen, which is not an NSAID. Diagnosis was mainly based on patient history and referral, which may not have been confirmed by medical documentation. Another limitation was the tested dose of 7.5 mg of meloxicam, as higher doses reduce the COX-2 preference for meloxicam.

References:

Göksel O, Aydin O, Misirligil Z, Demirel YS, Bavbek S. Safety of meloxicam in patients with aspirin/non-steroidal anti-inflammatory drug-induced urticaria and angioedema. J Dermatol. 2010;37(11):973-979. doi:10.1111/j.1346-8138.2010.00948.x

Meloxicam Tolerance in Hypersensitivity to Nonsteroidal Anti-Inflammatory Drugs
Design	Prospective, single-blind, single-center, placebo-controlled study N= 108
Objective	To test the tolerability of meloxicam in nonsteroidal anti-inflammatory drug (NSAID)-sensitive patients
Study Groups	NSAID allergy (N= 108)
Inclusion Criteria	Adults with documented reactions with at least two different NSAIDs or positive oral challenge to acetylsalicylic acid (aspirin)
Exclusion Criteria	Contraindication to discontinuing the use of histamine 1 receptor antagonists 5 days before the oral challenge; contraindication to discontinuing the use of drugs like beta-blockers 2 days before the oral challenge; patients with gastrointestinal symptoms; pregnancy or breastfeeding; contraindication to epinephrine use; subjects with psychosomatic disorders
Methods	On the challenge day, all subjects received first a placebo capsule and then, after 30 minutes, the first dose of meloxicam (7.5 mg) was administered. After 30 minutes, if no response appeared, the last dose of meloxicam (15 mg) was given for a total accumulated dose of 22.5 mg. During the challenge forced expiratory volume in 1 second (FEV₁) was monitored. The test was considered positive if urticaria, erythema, and/or angioedema appeared.
Duration	January 2005 and February 2006 Observation: 3 hours
Outcome Measures	Development of urticaria, erythema, angioedema, and/or respiratory symptoms
Baseline Characteristics		All subjects (N= 108)
	Age, years	45.81
	Female	64%
	Reaction to at least 2 different NSAIDs (clinical diagnosis)	90.35%
	Reaction to a positive oral challenge test to aspirin (tested diagnosis)	9.65%
	Previous adverse reactions after taking various NSAIDs Urticaria Angioedema Urticaria + angioedema	35.18% 41.66% 23.14%
	Latency period between drug intake and the reaction < 1 hour 2-6 hours > 6 hours	39.47% 50% 10.53%
Results		All subjects (N= 108)
	Allergic reaction to meloxicam Slight urticaria	5 (4.62%) 5 (4.62%)
	FEV₁of > 80%	108 (100%)
Study Author Conclusions	This study shows that meloxicam can be a good option for NSAID-intolerant patients: it was safe for over 95% of the patients and is easier to obtain than celecoxib or etoricoxib. However, we think that a patient should be tested in an allergy unit before it is prescribed.
InpharmD Researcher Critique	The findings of this study are limited by its small sample size, short-term duration, and single-blind design.

References:

Domingo MV, Marchuet MJ, Culla MT, Joanpere RS, Guadaño EM. Meloxicam tolerance in hypersensitivity to nonsteroidal anti-inflammatory drugs. J Investig Allergol Clin Immunol. 2006;16(6):364-366.

Safety of Selective COX-2 Inhibitors in Aspirin/Nonsteroidal Anti-inflammatory Drug-Intolerant Patients: Comparison of Nimesulide, Meloxicam, and Rofecoxib
Design	Prospective, non-randomized, single-blind, placebo-controlled trial N= 140
Objective	To assess the safety of nimesulide, meloxicam, and rofecoxib in a group of aspirin (ASA)/nonsteroidal antiinflammatory drug (NSAID)-intolerant patients
Study Groups	Nimesulide (n= 127) Meloxicam (n= 61) Rofecoxib (n= 51) All 3 medications (n= 37)
Inclusion Criteria	Patients with a reliable history of urticaria/ angioedema, naso-ocular symptoms, bronchospasm, and/or anaphylactoid reaction to a prescribed ASA and/or NSAIDs
Exclusion Criteria	Patients taking antihistamines, systemic corticosteroids, cromolyn, sympathomimetics, or beta-blockers during the week prior to enrollment; patients with active urticaria
Methods	Patients with a history of NSAID allergy were enrolled to receive an oral challenge test with nimesulide 100 mg, meloxicam 7.5 mg, and/or rofecoxib 25 mg. The oral challenge tests were performed by an experienced allergist in the hospital setting where emergency equipment was available. Patients were given oral administration of each drug and placebo with increasing doses in 1-hour intervals on separate days. The medications were given in two divided doses (one-fourth and three-fourths) separated by 60-minute intervals. On the first day, divided doses of placebo were given. After a washout of 3 days, oral provocation tests were conducted with the other medications. Blood pressure and FEV1 values as well as the skin, ocular, nasal, and bronchial reactions were monitored every hour after each placebo or active drug dose was given. The oral challenge test was considered positive if one of the following symptoms existed: conjunctival reaction; upper and lower respiratory tract reactions such as sneezing, rhinorrhea, nasal blockage, dyspnea, wheezing, and cough with a 20% decrease in FEV1, cutaneous reactions such as erythema, pruritus with erythema, urticaria/angioedema; and/or anaphylactoid reaction with urticaria and/or angioedema and hypotension (a 30-mm Hg drop in systolic blood pressure) and/or laryngeal edema.
Duration	Follow-up: 24 hours after oral challenge test
Outcome Measures	Positive allergic reaction
Baseline Characteristics		All patients (N= 140)
	Age, years (range)	39.80 ± 10.82 (16–70)
	Female	99 (70.7%)
	Allergy to one NSAID Allergy to multiple NSAIDs	65 (46.4%) 75 (53.6%)
	Reaction type Respiratory reaction Cutaneous reaction Respiratory and cutaneous reaction Anaphylactoid reaction Laryngeal edema	38 (27.1%) 63 (45%) 17 (12.1%) 20 (14.2%) 2 (1.4%)
Results		Nimesulide (n= 127)	Meloxicam (n= 61)	Rofecoxib (n= 51)
	Positive allergic reaction	18 (14.3%)	5 (8.1%)	1 (1.9%)
	Of the 5 patients with a meloxicam allergy, 5 had asthmatic reactions (who had histories of asthmatic reactions to NSAIDs) and urticaria-angioedema was detected in 3 subjects. All of the subjects who reacted to meloxicam had multiple analgesics intolerance.
	Of the 37 patients who received all three oral challenges, 11 (29.7%), 5 (10.8%), and 1 (2.7%) of the subjects reacted to nimesulide, meloxicam, and rofecoxib, respectively. Three patients reacted to more than one of the drugs tested, and one of them reacted to all drugs.
Adverse Events	N/A
Study Author Conclusions	This is the first placebo-controlled report comparing these three drugs. The results indicate that among these alternative drugs for ASA/NSAID-intolerant patients, rofecoxib seems to have the most favorable tolerability.
InpharmD Researcher Critique	This study also included patients with an acetaminophen allergy, which is not an NSAID allergy. Allergy diagnosis was mainly based on patient history and referral, which may not have been confirmed by medical documentation. Another limitation was the tested dose of 7.5 mg of meloxicam, as higher doses reduce the COX-2 preference of meloxicam.

References:

Bavbek S, Celik G, Ozer F, Mungan D, Misirligil Z. Safety of selective COX-2 inhibitors in aspirin/nonsteroidal anti-inflammatory drug-intolerant patients: comparison of nimesulide, meloxicam, and rofecoxib. J Asthma. 2004;41(1):67-75. doi:10.1081/jas-120026063

Chemical Classification of NSAIDs
Chemical Group	Drugs
Alkanones	Nabumetone
Anthranilic acids (fenamates)	Meclofenamic acid, mefenamic acid
Arylpropionic acids	Fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, oxaprozin
Enolic acids	Oxicams (piroxicam, tenoxicam, meloxicam), pyrazolidinediones (oxyphenthatrazone, phenylbutazone)
Heteroaryl acetic acids	Diclofenac, ketorolac, tolmetin
Indole and indene acetic acids	Etodolac, indomethacin, sulindac
Para-aminophenol derivatives	Acetaminophen (paracetamol)
Pyrazol derivatives	Aminopyrine, antipyrine, dipyrone
Salicylic acid derivatives	Aspirin, choline magnesium trisalicylate, diflunisal, olsalazine, salicylsalicylic acid, salsalate, sodium salicylate, sulfasalazine

References:

Adapted from:
Sánchez-Borges M. Clinical Management of Nonsteroidal Anti-inflammatory Drug Hypersensitivity. World Allergy Organ J. 2008;1(2):29-33. doi:10.1097/WOX.0b013e3181625db2