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 Yellow) 52 Chest heaviness 53

0 New coccine Urticaria, unspecified subjective symptoms 48 Purpura 54

Neutral Red Contact dermatitis 55,56

Sunset Yellow (FD & C Yellow No.6) Urticaria, rhinitis, nasal congestion 48 Bronchoconstriction (combined with amaranth, ponceau) 49 Anaphylactoid reaction (combined with ponceau) 52 Eosinophilotactic response 53 Purpura 54 Abdominal pain, vomiting, indigestion, distaste for food 57

D & C Yellow No.11 Contact dermatitis 58,59

Quinoline Yellow Contact dermatitis 59

Brillant Blue (FD & C Blue No. 1) Bronchoconstriction (combined with erythrosine, Indigo Car- 49 mine) Eosinophilotactic response 53

Indigo Carmine (FD & C Blue No.2) Bronchoconstriction (combined with Brillant Blue, erythro- 49 sine)

Evans Blue (C.!. Direct Blue 53) Dermatitis 60-62

Patent Blue Unspecified subjective symptoms 48 Purpura 54 Dermatitis 63

Methyl Blue (C.!. Acid Blue 93) Wheezing, dyspnea 64 0 Gentian Violet (C.I. Basic Violet 3) Contact dermatitis 65,66

Downloaded from www.aappublications.org/newsAMERICAN by guest on ACADEMY October 2, 2021OF PEDIATRICS 637 TABLE 4. Examples of Dye-Free Orally Administered Liquid Medications C1asification and Product (Manufacturer) Active Ingredients (per 5 mL unless indicated otherwise) Analgesics Demerol* (Winthrop-Breon) Meperidine 50 mg Analeptics Coramine* (Ciba) Nikethamide 1.25 g Antibiotic/antiinfective Antepar (Burroughs-Wellcome) Piperazine citrate 500 mg Antiminth (Pfizer) Pyrantel pamoate 250 mg Chloromycetin (Parke-Davis) Chloramphemcol 150 mg Coco-Quinine (Lilly) Quinine 110 mg Coly-Mycin S (Parke-Davis) Colistin 25 mg Furoxone (Norwich-Eaton) Furazolidone 50 mg Gantrisin syrup (Roche) Sulfisoxazole 500 mg Gantrisin pediatric suspension (Roche) Sulfisoxazole 500 mg Mandelamine-250 (Parke-Davis) Methenamine mandelate 250 mg Minocin (Lederle) Mincoycline 50 mg Mintezol (Merck Sharp & Dohme) Thiabendazole 500 mg Pediazolet (Ross) Erythromycin 200 mg, sulfisoxazole 600 mg Vancocint (Lilly) Vancomycin 417 mg Antihistamine/decongestant/antitussive Chlorafed (Hauck) Chlorpheniramine 2 mg, pseudoephedrine 30 mg Codiclear (Central) Hydrocodone 5 mg, potassium gualacolsulfonate 300 mg Deconamine syrup (Berlex) Pseudoephedrine 30 mg, chlorpheniramine 2 mg Elixir terpin hydrate/codeine (Lilly) Terpin hydrate 85 mg, codeine 10 mg Pseudoephedrine and triprolidine syrup (Roxane) Pseudoephedrine 30 mg, triprolidine 1.25 mg Pseudoephedrine syrup (Roxane) Pseudoephedrine 30 mg SK-terpin hydrate/codeine (Smith Kline) Terpin hydrate 85 mg, codeine 10 mg Tussionex (Pennwalt) Hydrocodone 5 mg, phenyltoloxamine 10 mg Thss-Ornade (Smith Kline) Phenyipropanolamine 12.5 mg, caramiphen 6.7 mg Cardiovascular agents 0 Aldomet (Merck Sharp & Dohme) Methyldopa 250 mg Colestidt (Upjohn) Colestipol 5 g/packet Gastrointestinal Alternagel (Stuart) Aluminum hydroxide 600 mg Aromatic cascara sagrada fluidextract (Roxane) Hydroxymethylanthraquinones equivalent to cascara sagrada extract 1 g/mL Camalox (Rorer) Aluminum hydroxide 225 mg, magnesium hy- droxide 200 mg, calcium carbonate 250 mg Citrocarbonatet (Upjohn) Sodium citrate 1.82 g, sodium bicarbonate 0.78 g Doxinate (Hoechst) Docusate 50 mg Effersylliu.mt (Stuart) Psyllium hydrocolloid 3 g Ipecac syrup USPt (Roxane) Ipecac alkaloids 20 mg/15 mL Kaopectate (Upjohn) Kaolin 975 mg, pectin 22 mg Maalox Plus (Rorer) Aluminum hydroxide 225 mg, magnesium hy- droxide 200 mg, simethicone 25 mg Maalox TC (Rorer) Aluminum hydroxide 600 mg, magnesium by- drOxide 665 mg Milk of magnesia USP (Roxane) Magnesium hydroxide 400 mg Mylanta II (Stuart) Aluminum hydroxide 400 mg, magnesium by- drOxide 400 mg, simetbicone 30 mg Neutralox (Lemmon) Aluminum hydroxide 300 mg, magnesium by- droxide 150 mg Parapectolin (Rorer) Opium 2.5 mg, kaolin 916 mg, pectin 27 mg Paregoric (Lilly) Morphine (equivalent) 2 mg Paregoric (Roxane) Morphine (equivalent) 2 mg Perdiemt (Rorer) Psyllium (82% w/v), senna (18% w/v) Hormonal agents Dexamethasone solution (Roxane) Dexamethasone 0.5 mg Intensol* (Roxane) Dexametbasone 5 mg Maxibolin (Organon) Etbylestrenol 2 mg Proglycem (Schering) Diazoxide 250 mg 0

638 PHARMACEUTICALDownloaded PRODUCTS from www.aappublications.org/news by guest on October 2, 2021 TABLE 4. Continued

Classification and Product (Manufacturer) Active Ingredients (per 5 mL unless indicated otherwise) O Psychotropics Cibalith-S (Ciba) Lithium 8 mEq (= lithium carbonate 300 mg) Haldol* (McNeill) Haloperidol 10 mg Navane (Roerig) Thiotbixene 25 mg Permitil (Schering) Flupbenazine 25 mg Sinequan (Roerig) Doxepin 50 mg Thorazine syrup (Smith Kline) Chlorpromazine 10 mg Trilafon (Schering) Perphenazine 16 mg Sedatives/hypnotics Chloral hydrate syrup (Roxane) Chloral hydrate 250 mg Spasmolytics/bronchodilators Alupent inhalent solution* (boehringer Ingelheim) Metaproterenol 50 mg/mL Aquaphyllin (Ferdale) Theophylline 5.33 mg Elixicon (Berlex) Theophylline 100 mg Marax DF (Roerig) Ephedrine 6.25 mg, theophylline 32.5 mg, hy- droxyzine 2.5 mg Neothylline (Lemmon) Dypbylline 53.3 mg Slo-Phyllin GG (Rorer) Theophyffine 50 mg, Guaifenesin 30 mg Somophyllin-DF (Fisons) Tbeophylline 90 mg Theoclear (Central) Theophylline 5.33 mg Miscellaneous Glyoxide (Marion) Carbamide peroxide 100 mg/mL, anhydrous gly- cerol qs Glycerin oral solution USP (Roxane) Glycerin 50% v/v (0.6 g/mL)

* Flavoring-free. t Preservative-free.

uid medications that do not contain dyes are listed asthma), urticaria, angioedema, flushing, weakness, in Table 4. Examples of nutritional supplements/ or nausea.7478 Anaphylaxis has occurred.76’77’79’#{176} 0 vitamins that do not contain dyes are presented in Metabisulfite hypersensitivity has been demon- Table 5. These listings were compiled from volun- strated in 19 of 29 (66%) children with a history of tary responses to personal communications re- chronic asthma.8’ ceived from 56 US drug manufacturers (out of 96 Of particular concern is the presence of sulfites contacted) between June 1983 and March 1984. in many medications used by asthmatics. Although Until complete ingredient labeling is mandated, many nebulizer solutions contain sulfites, metered- these lists will provide a tool to prevent reactions dose aerosol bronchodilators do not contain sulfites through avoidance in sensitive children using liquid and, thus, may be recommended for sulfite-sensi- dosage forms. Because inactive ingredients may tive asthmatics. Parenteral drugs such as cortico- change without changes in labeling, information in steroids and antibiotics as well as intravenous so- Tables 4 and 5 should be verified. lutions may contain sulfites (Table 6). A total of 47 nonoral prescription bronchodilator products are Sulfites known to contain sulfites.82 Nonsulfite-containing products used for treatment of asthma are pre- Sulfiting agents are widely used as antioxidants. sented in Table 7. Six sulfite compounds (sulfur dioxide, sodium sul- Diagnosis of sulfite sensitivity is made by history fite, sodium and potassium bisulfite, and sodium and through challenge testing.76 Avoidance of foods and potassium metabisulfite) have been categorized containing sulfites through careful reading of the as “Generally Recognized as Safe” (GRAS) for use label and inquiry at restaurants as to use of sulfiting in foods and drugs. Their GRAS status is currently agents may prevent reactions. Drug manufacturers under reconsideration, however, as the FDA has are not currently required to include sulfites in the received reports of approximately 250 cases of ad- labeling of oral products. verse reactions, including six deaths associated with ingestion of sulfites in foods.73 Serious reactions Saccharin have also occurred following oral or inhalational administration of certain drugs. Symptoms most Many oral drugs, including both solid and liquid 0 frequently include wheezing, dyspnea, chest tight- dosage forms, contain saccharin as a sweetening ness (particularly in patients with a history of agent. Saccharin is not included in drug labeling.

Downloaded from www.aappublications.org/newsAMERICAN by guest on ACADEMY October 2, 2021OF PEDIATRICS 639 TABLE 5. Examples of Dye-Free Nutritional Supplements/Vitamins* Product (Manufacturer) Active Ingredients (5 mL unless indicated otherwise)

Vitamin Vitamin Vitamin Vitamin Vitamin Other B, (mg) B2 (mg) B3 (mg) B5 (mg) B (mg) Aquasol A (USV) Vitamin A 5,000 U/0.1 mL 0 Aquasol E (USV) Vitamin E 50 U/mL Betalin complex (Lilly) 2.7 1.4 6.8 2.7 0.6 Vitamin B12 3 ig Drisdolt (Winthrop-Breon) Ergocalcifero 8,000 U/mL Feostat suspension (O’Neal) Iron 100 mg Ferrous sulfate liquid (Roxane) Iron 300 mg Homicebrin (Lilly) 1 1.2 10 3 0.5 Vitamin B,2 3 ig Hytakerol (Winthrop-Breon Dihydrotacbysterol 0.25 mg/mL Incremin with iron (Lederle) 6 3 Vitamin B,2 g Lederplex (Lederle) 1.1 1.3 15 7.5 1.5 Lipomul (Upjohn) Corn oil 3.3 g Livitimin (Beecham) 1 1 2 0.7 1 Vitamin B,2 1 ig Theragran (Squibb) 10 10 100 21 4.1 Vitamin B,2 5 gig, Vitamin C 200 mg, Vitamin A 10,000 U, Vitamin D400U Zentron (Lilly) 1 1 3 1 1 Vitamin B,2 3 gig, Vitamin C 100 mg, iron 12 mg Zymalixir (Upjohn) 1 1 8 2 Liver concentrate 65 mg, iron 15 mg

* List excludes infant vitamin drops; none contain dyes. t Flavoring-free and preservative-free.

TABLE 6. Some Bisulfite-Containing Medications Used by Asthmatics

Brand Name Manufacturer Adrenalin Chloride 1:100 Parke-Davis Adrenalin injection 1:1000 Parke-Davis Alupent solution 5% Boehringer Ingetheim Alupent syrup Boehringer Ingetheim Amikin injection Bristol Apogen injection Beecbam 0 Bristagen injection Bristol Bronkosol inhalant 1.0% Breon Bronkosol solution 0.25% Breon Bronkosol unit dose 0.25% Breon Celestone injection Scbering 4-Way nasal spray Bristol-Meyers Garamycin injection (all but intravenous piggy- Scbering back and intratbecal) Hexadrol phosphate injection Organon Isoetharine HCL 0.25%, 1% Philips Roxane Isoetbarine HC1 Dispos-a-Med 0.5% Parke-Davis Isoetharine HC1, 1% Philips Roxane Isoproterenol Dispose-a-Med Parke-Davis Isuprel injection Breon Isuprel solution 0.5%, 1% Breon Metaprel solution 5% Dorsey Micronefrin solution 2.25% Bird Minocin syrup Lederle Nebcin injection Dista Netromycin injection Sebering Reglan injection Robins Vaponefrmn solution 2.25% Fisons Vapo-Iso solution 0.5% Fisons

Artificially sweetened foods (such as low-calorie Saccharin may be present in drugs in substantial soft drinks) that contain saccharin are labeled with amounts. Ingestion of the recommended daily dos- the caution, “use of this product may be hazardous age of chewable aspirin or acetaminophen tablets to your health. . .contains saccharin which has been in a school-aged child would provide approximately determined to cause cancer in laboratory animals.” the same amount of saccharin contained in one can 0

640 PHARMACEUTICAL PRODUCTSDownloaded from www.aappublications.org/news by guest on October 2, 2021 TABLE 7. Some Medications Used by Asthmatics That Do Not Contain Bisulfites Brand Name Manufacturer Accurbron elixir Merrell Dow Aerolone solution 0.25% Lilly 0 Alupent aerosol Boehringer Ingetheim Alupent tablets Boehringer Ingetheim Aminopbylline injection Elkins-Sinn Bretbine injection 0.1% Geigy Brethine tablets Geigy Bronitin Mist aerosol Whitehall Bronkaid Mist aerosol Winthrop Bronkometer aerosol Breon Duo-Medihaler aerosol Riker Elixopbyllin elixir Berlex Intal capsules Fisons Intal solution 1% Fisons Medibaler-Epi aerosol Riker Medihaler-Iso aerosol Riker Metaprel aerosol Dorsey Norisodrine aerosol Abbott Norisodrine sulfate powder Abbott Primatene mist suspension aerosol Whitehall Primatene mist solution aerosol Whitehall Proventil aerosol Schering Quibron capsule Mead Johnson Quibron liquid Mead Johnson Sus-Phrine injection Berlex Theo-Dur sprinkle Key Theo-Dur tablets Key Vanceril inhaler Schering Ventolin aerosol Glaxo Ventolin inhaler Glaxo Ventolin tablets Glaxo

0 of a diet soft drink. Relative to the body weight of Howard C. Mofenson, MD a child less than 9 or 10 years of age, this amount Robert J. Roberts, MD used chronically would fall into the category of Barry H. Rumack, MD “heavy use” as defined in a major large-scale FDA! Harvey S. Singer, MD NCI (National Cancer Institute) epidemiologic Stephen P. Spielberg, MD, PhD study. In this study, heavy use of artificial sweet- Liaison Representatives eners was associated with a significantly increased Donald R. Bennett, MD, PhD risk for development of bladder cancer. Several Sumner J. Yaffe, MD other case-control studies have failed to document Louis Farchione, MD an association of saccharin use and cancer in hu- Martha M. Freeman, MD mans, although the magnitude or risk of carci- Melvin V. Gerbie, MD nogenesis is still not fully resolved. Saccharin inges- Sam A. Licata, MD tion has occasionally been associated with devel- Mary Lund Mortensen, MD opment of episodic urticarial reactions.87.ss AAP Section Liaison RECOMMENDATIONS Sanford N. Cohen, MD

Labeling ofpharmaceutical agents should include Consultants qualitative listings of inactive ingredients so that Larry K. Golightly, PharmD adverse reactions or complications can be avoided Susan C. Smolinske, BS, RPh in susceptible persons. Provision of such informa- Rocky Mountain Drug Consultation Center tion should be a mandatory part of the manufac- Advisor turer’s labeling for all prescription and over-the- Jeffrey Lee Brown, MD counter products. REFERENCES COMMITFEE ON DRUGS, 1984-1985 1. Brown JL: Incomplete labeling of pharmaceuticals: A list of PrUitt, Chairman 0 Albert W. MD, “inactive” ingredients. N Engi J Med 1983;309:439-441 Ralph E. Kauffman, MD 2. Smith JM, Dodd DRP: Adverse reactions to pharmaceutical

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