Cutaneous drug eruption from cetirizine and hydroxyzine

Topical application of the antihistamines commonly leads to sensitization for patients, but skin reactions provoked by their systemic use are very rare. The antihistamines cetirizine and hydroxyzine are piperazine derivatives, on the structural basis of an ethylenediamine, but the cross-reactions between the 2 have rarely been reported. A 44-year-old man visited because of the generalized morbilliform eruptions with pruritus over his whole body, after intake of hydroxyzine (Ucerax) and azelastine (Azeptine), administered during a 2-day period for chronic urticaria. Previously, he had presented the same cutaneous reactions after oral administration of cetirizine (Lotec). Oral challenge tests performed with cetirizine and hydroxyzine led to the same cutaneous reactions. He was given the diagnosis of drug eruption from cetirizine and hydroxyzine, which suggests that there were cross-reactions among cetirizine, hydroxyzine, and ethylenediamine.     

Fixed drug eruption to cetirizine with positive lesional patch tests to the three piperazine derivatives

BACKGROUND: The H1-antihistamine cetirizine, a piperazine derivative widely used in daily practice, is rarely the cause of cutaneous drug reaction. Nevertheless, four cases of fixed drug eruption (FDE) as a result of this drug have been described recently. We present the case of a 45-year-old woman with a multilocalized FDE following oral intake of cetirizine for allergic rhinitis. METHODS: Patch testing with hydroxyzine 1% and 10% in petrolatum (Chemotechnique), and with powdered Zyrtec (cetirizine) and Xyzal (levocetirizine) pills, prepared at 20% in water and at 20% in petrolatum, was performed in both residual lesions and healthy skin. RESULTS: Positive results (++) to these drugs (24 h occlusion and readings at days 2 and 3) were obtained in residual lesions only. These results allowed us to confirm the drug responsible for this FDE and to study cross-reactions between antihistamines of the same chemical family. CONCLUSIONS: To the best of our knowledge, this is the first report of FDE to cetirizine with positive patch testing to hydroxyzine, cetirizine, and levocetirizine. This case highlights the importance of patch testing in the study of cutaneous drug reactions, namely FDE.     

Skin reactions to hydroxyzine

Sensitivity to histamine H1-antagonists has mainly been observed with phenothiazine and ethylenediamine, and is very rare with hydroxyzine. We report 3 cases of sensitization to hydroxyzine, which was prescribed to treat urticaria and atopic dermatitis. A generalized maculopapular eruption appeared shortly after taking the drug. Patch tests with Atarax® tablet were positive +++, and ++ or +++ with different dilutions of hydroxyzine. Patch tests with ethylenediamine, piperazrne and other antihistamines were negative: therefore, there is no cross-allergy. We believe these rapid systemic reactions to hydroxyzine after the initial dose may have been due to prior systemic sensitivity to this drug, which cannot be used topically. Allergy to antihistamines must be considered when cutaneous lesions worsen on such therapy.     

Cutaneous drug eruption induced by antihistamines

Topical application of antihistamines commonly leads to sensitization for patients, but systemic administration of antihistamines rarely induces allergic hypersensitivity, which is mainly linked to phenothiazine‐derived and piperazine‐derived compounds. We report a 70‐year‐old woman whose medical history included lichen planus, and who was referred by the dermatology department of our hospital for suspected allergy to corticosteroids. The reason for referral was that on the fourth day of treatment with prednisone and hydroxyzine, the patient presented a bilateral highly pruritic palmar erythema that evolved to a generalized morbilliform rash with subsequent complete desquamation. At a later time, she took cetirizine for a cold, and developed palmar erythema and desquamation. Skin tests (prick and intradermal tests) were performed with steroids, and patch tests (read after 48 and 96 h) with corticosteroids and antihistamines. Controlled oral challenge tests were performed with prednisone and with an alternative antihistamine. Skin tests were negative for all corticosteroids. Patch tests were negative for all corticosteroids, but the antihistamine test was positive for hydroxyzine. Oral challenge with prednisone and dexchlorpheniramine was negative. The patient was diagnosed with cutaneous drug eruption from hydroxyzine and cetirizine. We consider it is important to assess every patient whose skin condition worsens after treatment with antihistamines, especially hydroxyzine, because it is known that antihistamines are often not recognised as the culprit in cases of cutaneous eruption.     

Suppression of wheal and flare in histamine test by the main H1 antihistamines commercialized in Brazil

Background:Several dermatoses are mediated by histamine, such as urticaria, angioedema, and papular urticaria. There are no Brazilian studies comparing the potency of antihistamines.Objectives:To evaluate the tolerability and efficacy of the main commercial brand and generic H1 antihistamines, regarding the suppression of the wheal and flare to the histamine test.Methods:A quasi-experimental, open study with 10 healthy adults submitted to the histamine test on the ventral aspect of the forearms. After 20 minutes, wheal and flares were measured. The tests were performed after two hours of intake of dexchlorpheniramine, hydroxyzine, levocetirizine, fexofenadine, cetirizine, loratadine, ebastine, desloratadine, epinastine and rupatadine, as well as generics of loratadine, cetirizine and fexofenadine.Results:All antihistamines presented a reduction in the wheal compared to the control (p <0.02), as well as in the flare, except for rupatadine (p = 0.70). In the internal comparison, cetirizine, fexofenadine, epinastine, levocetirizine, dexchlorpheniramine and hydroxyzine were the most potent, with no difference between them (p > 0.1). As for halo, cetirizine, epinastine, hydroxyzine and fexofenadine were the most potent, with no difference between them (p > 0.1). The most common adverse effect was drowsiness, which was more prevalent among first-generation drugs (p < 0.01). Generic loratadine, fexofenadine and cetirizine halos were higher than their controls (p >0.03)..Study limitations:A single-center study evaluating only aspects related to histamine.Conclusions:Brazilian commercial antihistamines presented different profiles of inhibition of wheal and flares in the histamine test, as well as adverse effects. Generic loratadine, fexofenadine and cetirizine presented larger flares than brand drugs.     

Therapy of acute and chronic urticaria

Background The drug management of chronic urticaria can be divided into three approaches: (i) blockade of released histamine at the receptor sites; (ii) blockade of histamine release from mast cells; and (iii) blockade of other mediators and possible inflammatory and cellular components. The first approach is the most successful and widely used. It primarily involves the use of H₁-antihistamines, although tricyclic antidepressants and H₂-antihistamines also have a place. Treatments The usefulness of classic H₁-antihistamines, such as hydroxyzine, may be limited by side-effects (most notably, sedation). The four most widely used of the newer antihistamines are loratadine, terfenadine, astemizole and cetirizine. These antihistamines are significantly superior to placebo and have similar efficacies comparable with hydroxyzine. Novel agents and methods, including nifedipine, sulphasalazine and plasmapheresis have been tried with some success in refractory patients. Guidelines If acute cases are inadequately controlled, short-term oral corticosteroids may be added. Systemic corticosteroids are occasionally indicated for the management of severe acute urticaria, severe serum sickness, pressure urticaria or urticarial vasculitis, or to break the cycle of a resistant case, but have no place in regular therapy for chronic urticaria. For those with severe acute urticaria with signs of respiratory distress, possible treatments include subcutaneous epinephrine, systemic corticosteroids and intramuscular H₁-antihistamines. Patients with chronic urticaria inadequately controlled on H₁-antihistamines alone may benefit from the addition of a classic antihistamine, a tricyclic antidepressant or an H₂-antihistamine. A short course of systemic corticosteroids may help those with severe chronic refractory disease.     

Multiple H1-antihistamine-induced urticaria

H₁‐antihistamines are widely used in the treatment of various allergic diseases. Particularly, a cornerstone of the management of chronic idiopathic urticaria is treatment with H₁‐antihistamines. However, a few cases of H₁‐antihistamine‐induced urticaria have been reported. A 34‐year‐old woman presented with a 4‐month history of recurrent urticaria, which was prominently exacerbated by the administration of H₁‐antihistamines. The patient consented to a provocation test of fexofenadine among drugs including cetirizine and hydroxyzine, which were suspected of inducing severe symptoms in episodes. One hour after challenge with 12 mg fexofenadine (one‐fifth of the therapeutic dose), a urticarial reaction rapidly developed on nearly the entire body with remarkably increased levels of plasma histamine (190 nmol/L) and plasma leukotriene B4 (150 pg/mL). In challenge tests with other antihistamines, generalized urticaria occurred 5 and 1 h after intake of 10 mg loratadine and 10 mg bepotastine, respectively, whereas challenges with chlorpheniramine, mequitazine and azelastine were all negative. Skin prick tests with H₁‐antihistamines used in the challenges were all negative, indicating that the urticarial reactions after challenges with the causative drugs might not be immunoglobulin E‐mediated. Among the causative drugs in our case, cetirizine and hydroxyzine are the piperazine derivatives, whereas fexofenadine, bepotastine, ebastine and loratadine are the piperidine derivatives. The chemical structures of both derivatives are very similar. Therefore, in this case, H₁‐antihistamine‐induced urticaria may have been due to cross‐reactivity between metabolites of these drugs, but not to drugs before metabolization. Hypersensitivity to H₁‐antihistamines should be considered when urticarial lesions worsen after H₁‐antihistamine treatment.     

Fixed drug eruption due to clarithromycin

Clarithromycin is one of the macrolide antibiotics used for cutaneous and respiratory system infections. Only a few cases of adverse cutaneous reactions to this drug have been reported. Here we report a rare case of clarithromycin-induced fixed drug eruption which could be reproduced by a peroral provocation test, whereas patch tests on both unaffected and residual pigmented skin yielded negative results. All cutaneous lesions that recurred due to the challenge test developed the same pigmentation after a short course of intravenous corticosteroid.     

Quantitative time course study of the skin response to histamine and the effect of H1 blockers. A 3-week crossover double-blind comparative trial of cetirizine and terfenadine

A controlled, randomized, double-blind, crossover study was performed in 10 healthy volunteers to compare changes of cutaneous blood flow values (CBFV) determined by laser Doppler flowmetry before and after intake of a capsule containing either 10 mg cetirizine or 60 mg terfenadine. After the determination of the initial response to the anti-H1 agents, drugs were taken daily (cetirizine 10 mg, terfenadine 120 mg) over a 3-week period and the cutaneous response to histamine and saline was evaluated weekly, exactly 4 h after the last drug intake. The following significant variations were observed (analysis of variance for repeated measurements, p less than 0.05): (1) there is a decrease of histamine-induced wheal and flare under antihistamines (anti-H1), cetirizine being more potent than terfenadine; (2) CBFV, measured on the usual flare area, i.e. at 1 cm of the site of agonist injection, decreased after drug intake. There was a gradual increase of the CBFV inhibition over the 3-week follow-up, cetirizine being more effective than terfenadine, and (3) at the site of agonist injection, reduction of the edematous wheal was associated with significant increases of CBFV after drug intake. This quantitative pharmacologic in vivo assay on the agonist action indicates that at lower doses, cetirizine has a significantly higher anti-H1 activity than terfenadine and that this effect is maintained over a 3-week period. There was no tachyphylaxis.     

Patch testing in fixed drug eruptions--a 20-year review

Background. The fixed drug eruption is a common adverse drug reaction. Clear identification of the culprit drug is not always possible in the clinical setting, and oral rechallenge may induce new lesions or severe reactions. Objectives. The main purpose of this study was to evaluate the diagnostic value of patch testing in establishing an aetiological diagnosis in fixed drug eruptions. Method. A retrospective analysis was conducted evaluating 52 patients (17M/35F, mean age 53±17 years) with clinical diagnoses of fixed drug eruptions submitted to patch tests in a 20‐year period in a Dermatology Department. Nonsteroidal anti‐inflammatory drugs (NSAID) were clinically suspected in 90.4% of the cases, followed by antibiotics (28.9%) and paracetamol (15.4%). Results. Patch tests on pigmented lesions were reactive in 21 patients (40.4%), 20 of those to NSAID (nimesulide, piroxicam and etoricoxib) and 1 to an antihistamine (cetirizine). All patch tests using other drugs were negative, even under conditions of high clinical suspicion. Oral rechallenge allowed confirmation of drug imputability in 5 of 31 test‐negative cases. Cross reactivity was frequently observed between piroxicam and other oxicams, and between different antihistamines. Conclusions. Patch testing was shown to be a simple and safe method to confirm drug imputabililty in fixed drug eruption, mainly when NSAID or multiple drugs are suspected. Persistent lack of reactivity to drug classes such as antibiotics and allopurinol represent an important limitation.     

Fixed drug eruption caused by mefenamic acid: a case series and diagnostic algorithms

Background: Fixed drug eruption is a fairly common drug‐induced hypersensitivity reaction of the skin and the mucous membranes, which is characterized by the re‐occurrence of the lesion(s) exactly on the previously involved sites after repeated administration. The pathogenetic mechanisms of this site‐specificity are not fully elucidated. Patients and Methods: We report on three cases of fixed drug eruption, including a non‐pigmenting generalized bullous fixed drug eruption, caused by mefenamic acid in its pure form. Results and Conclusion: Provocation tests with the assumed causative drug represent the gold standard for establishing the diagnosis and for identifying the culprit. Advantages and pitfalls of topical and systemic provocation tests as diagnostic approaches are discussed.     

Eczematous drug eruption from carbamazepine: coexistence of contact and photocontact sensitivity

We report a 46-year-old patient with an eczematous eruption on sun-exposed areas which we believe was caused by carbamazepine intake. Oral provocation with the drug produced papulo-vesicular eruptions that were greatly potentiated by long-wave ultraviolet irradiation. Positive reactions to carbamazepine were elicited by patch and photopatch tests and by lymphocyte stimulation tests 6 months after cessation of the intake of carbamazepine.     

Treatment of Urticaria

Urticaria is a cutaneous syndrome characterized by dermal edema (wheal) and erythema (flare) that blanches with pressure. The lesions typically last less than 24 hours and are usually pruritic. In 1983, Christensen and Maibach summarized the theory behind the use of histamine H₁ receptor antagonists (antihistamines) in clinical dermatology. These agents remain the mainstay of treatment for urticaria. This article reviews the medical literature on the effectiveness of antihistamines in urticarial syndromes, including acute, chronic idiopathic and the physical urticarias. Older antihistamines, such as chlorpheniramine and hydroxyzine, are effective in the treatment of urticarias, but they also have marked sedative and anticholinergic effects. Newer nonsedating antihistamines (second-generation antihistamines) have been developed that have reduced adverse effects because they do not cross the blood-brain barrier; these agents (acrivastine, cetirizine, loratadine, mizolastine, fexofenadine, ebastine, azelastine and epinastine) cause significantly less sedation and psychomotor impairment than their older counterparts. A review of the literature reveals that there are few studies which document the efficacy of second-generation antihistamines in the treatment of acute urticaria, a biologic entity that usually resolves within 3 weeks. We did not identify controlled studies that suggested superiority of any antihistamine in the treatment of acute urticaria. Loratadine or cetirizine, and possibly mizolastine, appear to be treatments of choice for chronic idiopathic urticaria. For symptomatic dermatographism, the combination of an antihistamine and an H₂ antagonist, e.g. chlorpheniramine and cimetidine, appears to be effective. Very few studies have been conducted on the use of antihistamines in the treatment of cold, cholinergic, and pressure urticaria. Antihistamines are the mainstay of urticarial therapy. This evidence-based review suggests that there are efficacy differences between newer, nonsedating antihistamines and older agents in some forms of the disorder. Clearly, further well-controlled clinical trials in larger numbers of patients are needed to clarify the role of these agents in the treatment of urticaria.     

Multiple fixed drug eruption due to drug combination

We report the case of a multiple fixed drug eruption (FDE) after taking 1 g of PL and 100 mg of levofloxacin (Cravit) at the same time. Patch tests with PL alone, levofloxacin alone and the combination of PL and levofloxacin were all negative on the involved and uninvolved sites. Lymphocytic stimulation tests were also negative for PL alone, levofloxacin alone and the combination of PL and levofloxacin. Oral provocation tests with PL alone or levofloxacin alone produced no reactivation. However, we could provoke multiple erythematous plaques on the involved areas by taking a 1/10th dose of the combination of PL and levofloxacin at the same time. Drug eruption due to a drug combination appears to be very rare. This is the first case of multiple FDE caused by taking PL-levofloxacin combination.     

Oral drug provocation test to generate a list of safe drugs: Experience with 100 patients

Background: Following a drug eruption, patients and their doctors need to know which drugs can be safely administered for subsequent illnesses. Currently available laboratory tests are unable to answer this question in a clinically meaningful manner. Aims: To describe our use of oral provocation tests to provide a list of safe drugs to patients. Methods: We studied the records of 100 patients who underwent oral provocation testing in our department between 2003 and 2009. All patients were admitted to hospital and drugs were administered under supervision, one drug per day. A dermatologist evaluated all symptoms and signs that developed following drug intake. Results: Sixty nine women and 31 men underwent provocation testing. There were 96 reactions in 61 patients, of which 44 reactions in 34 patients were judged to be true reactions. All reactions could be controlled, with treatment or spontaneously. A list of safe drugs was provided to the patient along with written instructions to avoid any drug(s) that had produced a reaction. Conclusions: Oral provocation tests are safe and effective in providing patients with a list of drugs they can take safely. These tests should preferably be undertaken after admitting the patient to hospital.     

High dose cetirizine: a case report

We report the case of a 46-year-old man who tolerated 50 mg per day of cetirizine for the treatment of chronic idiopathic urticaria. The patient denied any sedation or somnolence and had no difficulty performing routine daily functions including driving. He had tried other antihistamines, including fexofenadine, loratadine, and hydroxyzine without improvement.     

Peculiar unilateral fixed drug eruption of the breast

BACKGROUND: Fixed drug eruption (FDE) is a common cutaneous disorder which develops within hours of taking the offending drug and recurs at the same site with subsequent exposure to the same drug. Non-steroidal anti-inflammatory drugs (NSAIDs) are common offending drugs. METHODS: A 14-year-old girl initially presented with a 1-year history of a recurrent reddish-brown plaque around her right areola. The lesion became pruritic and raised during menses, and subsided during the remainder of her menstrual cycle with the exception of persistent residual hyperpigmentation. The patient had a pattern of naproxen use during menses for dysmenorrhea. RESULTS: The skin biopsy specimen revealed focal bullae formation and scattered necrotic keratinocytes in epidermis, hydropic degeneration of the basal cell layer, pigmentary incontinence and a perivascular infiltrate composed of lymphocytes and eosinophils. These changes confirmed the diagnosis of fixed drug eruption. CONCLUSION: Fixed drug eruption to nonsteroidal anti-inflammatory drugs is common. However, FDE due to naproxen, one of the NSAIDs, is rarely reported. We describe an unusual case of FDE, which recurred at each menses.     

The usefulness of skin tests to prove drug hypersensitivity

BACKGROUND: Suspected drug hypersensitivity is common. Only a minority of cutaneous adverse drug reactions (CADRs) are allergic in origin and will reappear after the next exposure. Methods to confirm suspected CADRs are needed and skin testing could serve as one possibility. OBJECTIVES: To analyse the usefulness of skin tests in revealing drug allergy. The relevance of skin test results was evaluated with drug provocation studies. METHODS: During 1989-2001, 947 patients with a history of suspected CADR were examined with skin tests including patch tests (PTs) (826 patients), skin prick tests (SPTs) (935 patients) and photopatch tests (12 patients). The occurrence of positive and negative test reactions to different drugs was correlated with clinical history. Drug provocation was carried out in 246 patients. RESULTS: Antimicrobial drugs were suspected and tested most often. A positive PT reaction to one or more drug was seen in 89 of 826 (10.8%), most often to beta-lactams, clindamycin and trimethoprim. A positive SPT reaction was seen in 10 of 935 (1.1%) patients. Challenge was carried out in 17 patients with positive skin test results. Thirteen of 16 (81.2%) PT positives developed exanthema, three remained negative and one SPT-positive patient developed urticaria. Among skin test negatives, 207 of 229 (90.4%) challenges were negative and 22 of 229 (9.6%) were positive, 12 with exanthema, three with fixed drug eruptions and seven with urticaria. CONCLUSIONS: Skin testing, especially the PT, was a useful screening method to find a cause of CADR if the reaction was exanthema and if antimicrobial, cardiovascular or antiepileptic drugs were suspected. The SPT detected occasional positives with antimicrobials. In cases of fixed drug eruption, PTs performed at the earlier reaction site were useful. When skin tests are negative or dubious, oral challenge should be carried out to confirm the association.     

Negative predictive value of drug skin tests in investigating cutaneous adverse drug reactions

Summary Background Drug skin tests are useful in aetiological analyses of cutaneous adverse drug reactions to determine if the drug can be rechallenged, or to avoid a cross‐reaction with a substitute drug. Objectives To evaluate the negative predictive value of drug skin tests. Methods We retrospectively analysed the files of patients referred for drug reactions. We have enrolled those having strictly determined drug reactions with clinical features, delayed onset after drug intake, drug causality assessment, and negative drug skin tests followed by drug administration. Oral provocation tests or substitution tests with a drug of the same class as that suspected of causing the drug reactions were performed. Results From 1957 files analysed, 200 patients were included. After 403 patch tests, 403 prick tests and 304 intradermal tests, which were all negative, 260 oral provocation tests and 143 substitution tests were done; 307 different drugs were rechallenged. There were 42 positive drug re‐administrations in 27 oral provocation tests and 15 substitution tests. The negative predictive value of our drug skin tests was 89·6%. The negative predictive value for beta‐lactams was 87% for oral provocation tests and 96% for substitution tests, and for corticosteroids it was 100% and 74%, respectively. Conclusions  Negative drug skin tests do not eliminate the responsibility of a drug in drug reactions, and must be followed by drug re‐administration under hospital surveillance.