AMERICAN ACADEMY OF PEDIATRICS Committee on Drugs “Inactive” Ingredients in Pharmaceutical Products: Update (Subject Review) ABSTRACT. Because of an increasing number of re- bronchospasm from antiasthmatic drugs, aspartame- ports of adverse reactions associated with pharmaceutical induced headache and seizures, saccharin-induced excipients, in 1985 the Committee on Drugs issued a cross-sensitivity reactions in children with sulfon- position statement1 recommending that the Food and amide allergy, benzyl alcohol toxicity in neonates Drug Administration mandate labeling of over-the- receiving high-dose continuous infusion with pre- counter and prescription formulations to include a qual- served medications, dye-related cross-reactions in itative list of inactive ingredients. However, labeling of inactive ingredients remains voluntary. Adverse reac- children with aspirin intolerance, lactose-induced di- tions continue to be reported, although some are no arrhea, and propylene glycol-induced hyperosmola- longer considered clinically significant, and other new lity and lactic acidosis. Although many other excipi- reactions have emerged. The original statement, there- ents have been implicated in causing adverse fore, has been updated and its information expanded. reactions, these are the most significant in the pedi- atric population. ABBREVIATIONS. FDA, Food and Drug Administration; MDIs, metered-dose inhalers ANTIASTHMATIC MEDICATIONS It is readily appreciated that some percentage of asthmatic children will develop a “paradoxical” Pharmaceutical products often contain agents that bronchospasm after they inhale their medication. Be- have a variety of purposes, including improvement cause many of these reactions were attributed to of the appearance, bioavailability, stability, and pal- sulfite, which had been highly publicized as a caus- atability of the product. Excipients (substances ative agent, it was often first suspected. During the added to confer a suitable consistency or form to a past 10 years, however, the active ingredient in sul- drug, such as the vehicle, preservatives, or stabiliz- b fite-containing preparations, the nonselective 2-ago- ers) frequently make up the majority of the mass or nists isoproterenol, isoetharine, and metaproterenol, volume of oral and parenteral drug products. These have been replaced as drugs of choice by more se- pharmaceutical adjuvants are usually considered to lective agents, primarily albuterol, that do not con- be inert and do not add to or affect the intended tain sulfites. Paradoxical reactions continue to be action of the therapeutically active ingredients. reported, in some cases resulting in product refor- Some 773 chemical agents have been approved by mulation because of excessive adverse reactions. In- the Food and Drug Administration (FDA) for use as 2 active ingredients that have been implicated in caus- inactive ingredients in drug products. Inasmuch as ing these reactions include benzalkonium chloride, these compounds are classified as “inactive,” no reg- oleic acid, chlorofluorocarbons, soya lecithin, and ulatory statutes require listing on product labeling. sorbitan trioleate. Pharmacopeial guidelines, enforceable under the Food, Drug, and Cosmetic Act, do require labeling of Sulfites inactive ingredients for topical, ophthalmic, and par- Sulfiting agents are widely used as antioxidants. enteral preparations; orally administered products Six sulfite compounds (sulfur dioxide, sodium sul- are currently exempt. Because of pressure from pro- fite, sodium bisulfite, potassium bisulfite, sodium fessional and consumer organizations asking the metabisulfite, and potassium metabisulfite) have FDA to require complete disclosure of all ingredi- been categorized as “Generally Recognized as Safe” ents, voluntary labeling was adopted by the two for use in foods and drugs. This status was revoked major pharmaceutical industry trade associations. for raw fruits and vegetables (excluding potatoes) in These voluntary guidelines contain an exemption for 1986 after the FDA received reports of more than 250 “trade secret” components and do not require com- cases of adverse reactions, including six deaths asso- plete disclosure of all fragrance and flavoring ingre- ciated with the ingestion of sulfites in foods.3,4 Al- dients. though primary exposure in children is through Current problems encountered with “inactive” in- foods, serious reactions have also occurred after oral, gredients include benzalkonium chloride-induced inhalational, parenteral, and ophthalmic administra- tion of sulfite-containing drugs. The recommendations in this statement do not indicate an exclusive course Signs and symptoms most frequently reported in- of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate. clude wheezing, dyspnea, and chest tightness in pa- 5–9 PEDIATRICS (ISSN 0031 4005). Copyright © 1997 by the American Acad- tients with known reactive airway disease. Nonim- emy of Pediatrics. munologic anaphylactoid reactions have also 268 PEDIATRICS Vol. 99Downloaded No. 2 February from www.aappublications.org/news 1997 by guest on September 29, 2021 occurred.7,8,10,11 Reactions to sulfites rarely occur in TABLE 2. Some Sulfite-containing Medications Used by patients without reactive airway disease.12 Met- Asthmatics abisulfite hypersensitivity was demonstrated in 19 Brand Name Manufacturer (66%) of 29 children with a history of chronic mod- 13 Adrenalin Chloride 1:100 Parke-Davis erately severe asthma. The incidence of sulfite sen- Adrenalin injection 1:1000 Parke-Davis sitivity increases with age in severely asthmatic chil- Amikin injection Apothecon dren (31% of children up to 10 years of age and 71% Arm-a-Med isoetharine solution Armour of older children).14 AsthmaNefrin Menley & James Beta 2 isoetharine solution Nephron The presence of sulfites in antiasthmatic medica- Bronkosol solution Sanofi-Winthrop tions has been a concern, but many of these medica- Dey-dose epinephrine Dey tions have been reformulated or replaced in clinical Dey-dose isoetharine solution Dey practice by more b-selective agents, which do not Dispos-a-Med isoetharine Parke-Davis Epipen/Epipen Jr Center contain sulfites. Metered-dose aerosol bronchodila- Garamycin injection (all but intravenous Schering tors do not contain sulfites. Nonsulfite-containing piggyback and intrathecal) products used to treat asthma are presented in Table Isoetharine hydrochloride Roxane 1. Parenteral drugs, such as corticosteroids, amin- Isuprel injection Sanofi-Winthrop oglycosides, and epinephrine, may contain sulfites Isuprel solution Sanofi-Winthrop MicroNefrin Bird (Table 2) but rarely produce reactions because of the Minocin syrup Lederle small amounts present. Patients who react to oral Nebcin injection Lilly challenges with small amounts (5 to 10 mg) are at Netromycin injection Schering risk for similar reactions from these parenteral agents.15 Local dermal reactions accompanied by eo- sinophilia have been reported after continuous infu- sion with dobutamine.16 Sulfite-preserved amino ac- TABLE 1. Some Medications Used by Asthmatics That Do ids contained in most mixtures of total parenteral Not Contain Sulfites nutrition are a less commonly appreciated source. Brand Name* Manufacturer Nevertheless, life-threatening situations requiring Aerobid inhaler Forest the administration of epinephrine should be treated Airet solution Adams with sulfite-preserved epinephrine if no preserva- Alupent aerosol Boehringer Ingelheim tive-free product is available, even in very sensitive Alupent solution 5%* Boehringer Ingelheim patients. The diagnosis of sulfite sensitivity is made Alupent solution Unit-dose 0.4, 0.6% Boehringer Ingelheim 7 Alupent syrup Boehringer Ingelheim by history and through challenge testing. Avoidance Alupent tablets Boehringer Ingelheim of foods containing sulfites through careful reading Atrovent aerosol Boehringer Ingelheim of packaged food labels and inquiry at restaurants as Azmacort Rhone-Poulenc Rorer to the use of agents that contain sulfites may prevent Beclovent inhaler Glaxo reactions. A commercial sulfite-detection strip was Brethine injection Ciba-Geigy Brethine tablets Ciba-Geigy found to be unreliable, especially when used on Bricanyl injection Marion Merrell Dow acidic foods or foods removed from their original Bronkaid Mist aerosol Sterling-Winthrop containers.17 Drug manufacturers must disclose the Bronkometer aerosol Sterling-Winthrop presence of sulfites in product labeling. Celestone injection* Schering Decadron respihaler Merck Benzalkonium Chloride Duo-Medihaler aerosol 3M Elixophyllin elixir Forest Benzalkonium chloride is a commonly used bacte- Intal capsules, solution, inhaler Fisons ricidal preservative in albuterol and metaproterenol Isoetharine solution Astra nebulizer solutions in the United States and in be- Isoetharine solution Dey Isuprel Mistometer Winthrop-Breon clomethasone and ipratropium bromide nebulizer Maxair autohaler 3M solutions in other countries. Inhalation of pure ben- Medihaler-Epi aerosol 3M zalkonium chloride causes reproducible, dose- Medihaler-Iso aerosol 3M related, cumulative bronchoconstriction, with a Metaprel aerosol Sandoz Metaprel solution 5%* Sandoz rapid onset and prolonged duration compared with Primatene Mist suspension aerosol Whitehall sulfites. It is frequently accompanied by a cough and Primatene Mist solution aerosol Whitehall burning sensation and, occasionally, by facial flush- Proventil aerosol