Tolmetin: An Option for Multiple NSAID Hypersensitivity in a Preschooler

Introduction

Nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity in children is less prevalent than in adults and is rare, particularly in preschool age.^1,2 When a child is found to be reactive to NSAIDs, weak inhibitors of cyclooxygenase-1 (COX-1) might be an alternative for him/her. ¹ Among the weak COX-1 inhibitors, acetaminophen is the only allowed drug in preschool age. However, NSAID-hypersensitive preschoolers are also found to be 9.3-times more reactive to this medication than older children. ³ Concomitant reactions to acetaminophen severely limit the options for antipyretics and anti-inflammatory treatment in children. In this report, we describe the case of a 3-year-old child reactive to all the usual antipyretics, including acetaminophen, but can safely tolerate tolmetin sodium, which is an approved NSAID for pediatric use with an antipyretic effect in this preschooler.

Case Report

A 3-year-old boy was admitted to our clinic with complaints of swelling about the lips, hands and feet, thirty minutes after receiving 100 mg of ibuprofen syrup. He first displayed the condition at age 1, when he suffered lip edema 30 min after administration of 5 mg of ketoprofen. He had also 3 more episodes of lip edema, once again 30 min after taking 5 mg of ketoprofen syrup, 2 h after ingestion of 250 mg acetaminophen (12.5 mg/kg), and 2 h after metamizole sodium injection for fever. He had no urticaria, naso-ocular, or respiratory complaints in none of the events. He has intermittent allergic rhinitis since his first birthday, atopy to grass pollens, but no family history of NSAID hypersensitivity. The patient has no reported episodes of unprovoked angioedema or chronic urticaria. A diagnosis of multiple NSAID-induced angioedema was confirmed by modified oral provocation tests (Table 1). The challenges with ketoprofen, ibuprofen, metamizole sodium, and acetaminophen produced facial angioedema without urticaria. He had no alternative approved preparation for pediatric use according to the European network on drug allergy recommendations. ¹ We made an oral challenge test to find a safe substitute with tolmetin sodium, for which he gave no reaction. He has also used it twice during febrile respiratory tract infections without any reaction.

Discussion

We report a 3-year-old boy developing facial angioedema with ibuprofen, ketoprofen, metamizole sodium, and acetaminophen, who tolerated tolmetin sodium. This is a case of multiple NSAID-induced angioedema that is seen in otherwise healthy subjects without chronic respiratory and/or skin disorders. The mechanism of multiple drug-induced reactions is thought to be related with the COX-1 inhibitory potential of the culprit drug. ¹ The diagnostic process of multiple NSAID hypersensitivity should result in providing the patient an alternative drug. ¹ However, the management of those children with concomitant reactivity to acetaminophen is not clear. In published reports, a low dose (5–10 mg/kg) of acetaminophen in conjunction with physical measures of lowering body temperature ² and unapproved use of selective COX-2 inhibitors^4,5 and nimesulide ⁶ were reported as possible alternatives. However, these recommended alternative drugs are approved only for children after the age of 12 years. There is no reported safe alternative recommended for preschool-age children with multiple NSAID hypersensitivity. The recommendation of tolmetin sodium as an approved drug is not reported yet.

To the best of our knowledge, this is the first presentation of the safe use of tolmetin sodium in multiple NSAID hypersensitivity in childhood. It is approved in children after the age of 2. In published reports, patients reactive to tolmetin sodium are specified as tolerable to aspirin and other potent inhibitors of COX. Although it is emphasized as causing immediate hypersensitivity reactions after interrupted dosage, neither an Ig E-mediated nor a nonallergic pathogenesis could be established. ⁷

Tolmetin sodium is a pyrolle-derivative anti-inflammatory drug possessing an antipyretic effect, ⁷ but the mode of action is not known exactly. It is shown that it inhibits prostaglandin synthetase in vitro and lowers prostaglandin E levels in man. ⁸ Although it might have a potential to cause similar reactions, the absence of direct effect on COX enzyme may not be able to change the leukotriene/prostaglandin ratio dramatically, which may explain the low incidence of a clinically detectable event.

We performed oral challenge at 6 steps. This might be a limitation, because it is possible that performing challenges with 6 steps can cause desensitization. However, the history of no reaction after full drug on further use twice suggests that this is a true negativity on the drug provocation test.

This is the first report of the safe use of approved drug tolmetin sodium in a preschool child with multiple NSAIDs and concomitant acetaminophen hypersensitivity. Although it is difficult to make a general recommendation depending on one case, tolmetin sodium may be tried as an alternative antipyretic, analgesic, and anti-inflammatory drug in young children below the age of 12 with multiple NSAIDs and acetaminophen hypersensitivity.