“Inactive” Ingredients in Pharmaceutical Products
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AMERICAN ACADEMY OF PEDIATRICS Committee on Drugs “Inactive” Ingredients in Pharmaceutical Products Pharmaceuticals often contain agents that have dosis, and increased mortality were positively cor- a variety of purposes including improvement of the related with substantial benzoic acid and benzyl appearance, bioavailabiity, stability, and palatabil- alcohol levels in neonates.6 Therapeutic doses of ity of the product. Excipients frequently make up agents other than large-volume fluids do not con- the majority of the mass or volume of oral and thin the amounts of benzyl alcohol associated with parenteral drug products. These pharmaceutical ad- this syndrome. However, the effects of lower juvants are usually considered to be inert and do amounts have not been adequately studied (Table not add to or affect the intended action of the 2). The American Academy of Pediatrics7 and the therapeutically active ingredient. Centers for Disease Control8 as well as the FDA9 Some 773 chemical agents have been approved now recommend that use of products containing by the Food and Drug Administration for use as this agent should be avoided in infants and that inactive ingredients in drug products.1 Inasmuch as intravascular flush solutions containing preserva- these compounds are classified as “inactive,” man- tives should be avoided in newborns. 0 ufacturers are not presently required to list them Benzyl alcohol may also cause hypersensitivity on the product label. These ingredients are used for reactions. Contact dermatitis’#{176} as well as more gen- a variety of different purposes (Table 1). Because eralized allergic symptoms including nausea, fa- of the large number of these agents and their fre- tigue, or angioedema may occur following paren- quency of use, practicing physicians have recently teral administration of benzyl alcohol-preserved become concerned about their possible physiologic products.11”2 effects. The increasing number ofreports of adverse effects associated with pharmaceutical excipients2 Propylene GIycoI has led to professional and consumer organizations This agent is commonly used as a drug solubilizer formally requesting the FDA (Food and Drug Ad- in topical, oral, and injectable medications. A num- ministration) to require complete disclosure on the ber of cases of localized contact dermatitis from product label of all substances contained in phar- application of propylene glycol to skin or mucus maceuticals. Problems encountered with “inactive” membranes have been reported.’3’5 In a series of ingredients, include the following. 400 patients with eczematous contact dermatitis, ADVERSE EFFECTS OF PHARMACEUTICAL six (1.5%) were found to be sensitive to propylene EXCIPIENTS glycol.’6 Absorption from creams applied to burns’7 and injection of multivitamin products in infants’8 Benzyl Alcohol have resulted in serum hyperosmolality. Hyperos- molality related to propylene glycol occurred in nine This antimicrobial agent is commonly used as a of 262 hospitalized burn patients.’9 Cardiac ar- preservative in many injectable drugs and solutions. rhythmias, CNS depression, and seizures have oc- A number of neonatal deaths and severe respiratory curred in children who have ingested oral liquid and metabolic complications in infants have been medications containing propylene glycol.#{176}’2’The associated with use of this agent. In a controlled high concentrations of propylene glycol contained study, intraventricular hemorrhage, metabolic aci- in certain parenteral drug products such as pheny- 0 PEDIATRICS (ISSN 0031 4005). copyright C 1985 by the tom, diazepam, and digoxin may induce thrombo- American Academy of PediathcS. phlebitis when administered intravenously.22 Be- Downloaded from www.aappublications.org/news PEDIATRICSby guest on OctoberVol. 2, 2021 76 No. 4 October 1985 635 cause propylene glycol is metabolized to lactic acid, bloating, and flatulence following ingestion of milk lactic acidosis may be produced. Hemolysis, CNS products or lactose. These effects are produced depression, hyperosmolality, and lactic acidosis either by lactic acid formed in the intestine by have also been reported after intravenoos admfn- bacteria from undigested lactose or by a high intes- istration of propylene glycol.’ Rapid intravenous tinal osmotic load caused by unabsorbed carbohy- 0 injection of products containing propylene glycol diate with production of carbon dioxide and hydro- has also been associated with respiratory depres- gen gas by bacterial fermentation. Lactose intol- sion, dysrhythmias, hypotension, and seizures. erance in infants and young children may be asso- ciated with severe, prolonged diarrhea complicated Lactose by bacterial proliferation in the small bowel, dehy- Lactose (milk sugar) is widely used as a filler or dration, and metabolic acidosis.27 Lactose may be diluent in tablets and capsules and to give bulk to detrimental to the galactose-intolerant infant. powders. Lactase deficiency, occurring either as a Late-onset lactase deficiency (adult hypolacta- rare congenital disorder or more commonly as an sia) is a common disorder. Approximately 90% of acquired lack of intestinal brush border disaccha- adult American blacks and 60% to 80% of Mexican- ridase, may lead to diarrhea, abdominal cramping, Americans, native American Indians, Asians, and most Middle-Eastern and Mediterranean popula- TABLE 1. Categories of Pharmaceutical Excipients tions have abnormal findings on lactose tolerance Aerating agents and gases tests. About 10% of the white population with Air displacement agents Scandinavian or European ancestry is affected. Color additives Lactase deficiency may develop sporadically in Denaturing agents otherwise tolerant individuals during intestinal dis- Dispersing agents eases such as tropical sprue or acute gastroenteri- Emollients Emulsifiers and emulsifying salts tis.34 Sensitivity to lactose varies widely in severity, Flavors and flavoring adjuncts although some individuals (adults and children) Fragrances may experience diarrhea, gaseousness, or cramping Humectants after ingestion of as little as 3 g of lactose and Levigating agents possibly less.’ Such symptoms can occur in sen- Ointment bases pH control agents sitive individuals following ingestion of drugs con- Preservatives taming lactose.37 Propellants 0 Solvents and vehicles Stiffening agents Coloring Agents Suppository basis Surface-active agents Numerous dyes are used in pharmaceutical man- Suspending agents ufacturing. These agents give products a distinctive, Tablet and capsule diluents identifiable appearance, and they impart a uniform Tablet bases and attractive color to products that might other- Tablet binders wise be drab, unappealing, or exhibit color variation Tablet-coating agents from batch to batch. TABLE 2. Parenteral Medications That Contain Benzyl Alcohol Drug Benzyl Alcohol Estimated Average Content (%) Daily Intake of Benzyl Alcohol in Infants Aminophylline 2.0 2-4 mg/kg Aquamephyton neonatal injection 0.9 4.5 mg Bacteriostatic saline 1.5 99-234 mg/kg Bacteriostatic water 1.5 99-234 mg/kg Dexamethasone injection 1.0 2.5 mg Folate sodium 1.5 0.6-0.9 mg Heparin injection 1000 ag/mL 1.0 1.2 mg Multivitamin infusion 0.9 45 mg Pavulon injection 1.0 2-3 mg/kg Phenobarbital injection 1.5 1.15-2.3 mg/kg Solu-Cortef injection 0.905 0.18 mg/kg Trace elements 0.9 9 mg Valium injection 1.5 4.5-10.5 mg/kg Vitamin E injection 2.0 2-20 mg/kg 0 636 PHARMACEUTICAL PRODUCTSDownloaded from www.aappublications.org/news by guest on October 2, 2021 Several groups of dyes have been associated with use of tartrazine in foods and over-the-counter and serious adverse effects. The azo dye tartrazine (FD prescription drugs, the FDA in 1980 required all & C Yellow No. 5) is well known as a potential products containing tartrazine to be labeled so as danger in aspirin-intolerant individuals. Approxi- to provide a means to avoid this substance. No 0 mately 2% to 20% of patients with asthma are other dye or pharmaceutical excipient is currently sensitive to aspirin; of these, approximately 10% subject to similar labeling requirements. are also sensitive to tartrazine.’39 Unlike aspirin, In addition to tartrazine, many other dyes have tartrazine does not alter prostaglandin synthesis caused unwanted effects. Examples of these effects and does not, therefore, exert anti-inflammatory are listed in Table 3. actions. Nonetheless, reactions to tartrazine are Dyes and other food additives have also been similar to those produced by aspirin and include suggested as a cause or aggravating factor in some acute bronchospasm or increased bronchial reactiv- cases of hyperactivity in children47; carefully con- ity as well as urticaria and angioedema.3 Rarely, trolled trials’69 and current opinion7#{176}72 generally anaphylaxis occurs.”t Because of the seriousness refute a possible association. of these reactions and because of the widespread Hypersensitive individuals should avoid dyes; liq- TABLE 3. Reactions Associated with Pharmaceutical Coloring Agents Dye Effect Reference No. Amaranth (FD & C Red No.2) Angioedema, urticaria, pruritus 47 Urticaria, unspecified subjective symptoms 48 Bronchoconstriction (combined with ponceau, Sunset Yellow) 49 Erythrosine (FD & C Red No.3) Bronchoconstriction (combined with Brillant Blue, Indigo Car- 49 mine) Sequential vascular response, unspecified symptoms 50 Elevation of protein-bound iodide 51 Ponceau (FD & C Red No. 4) Bronchoconstriction (combined with amaranth, Sunset Yellow) 49 Anaphylactoid reaction (combined with Sunset