AMERICAN ACADEMY OF PEDIATRICS
`Committee on Drugs
`
`“Inactive” Ingredients in Pharmaceutical Products: Update
`(Subject Review)
`
`ABSTRACT. Because of an increasing number of re-
`ports of adverse reactions associated with pharmaceutical
`excipients, in 1985 the Committee on Drugs issued a
`position statement1 recommending that the Food and
`Drug Administration mandate labeling of over-the-
`counter and prescription formulations to include a qual-
`itative list of inactive ingredients. However, labeling of
`inactive ingredients remains voluntary. Adverse reac-
`tions continue to be reported, although some are no
`longer considered clinically significant, and other new
`reactions have emerged. The original statement, there-
`fore, has been updated and its information expanded.
`
`ABBREVIATIONS. FDA, Food and Drug Administration; MDIs,
`metered-dose inhalers
`
`Pharmaceutical products often contain agents that
`have a variety of purposes, including improvement
`of the appearance, bioavailability, stability, and pal-
`atability of
`the product. Excipients (substances
`added to confer a suitable consistency or form to a
`drug, such as the vehicle, preservatives, or stabiliz-
`ers) frequently make up the majority of the mass or
`volume of oral and parenteral drug products. These
`pharmaceutical adjuvants are usually considered to
`be inert and do not add to or affect the intended
`action of the therapeutically active ingredients.
`Some 773 chemical agents have been approved by
`the Food and Drug Administration (FDA) for use as
`inactive ingredients in drug products.2 Inasmuch as
`these compounds are classified as “inactive,” no reg-
`ulatory statutes require listing on product labeling.
`Pharmacopeial guidelines, enforceable under the
`Food, Drug, and Cosmetic Act, do require labeling of
`inactive ingredients for topical, ophthalmic, and par-
`enteral preparations; orally administered products
`are currently exempt. Because of pressure from pro-
`fessional and consumer organizations asking the
`FDA to require complete disclosure of all ingredi-
`ents, voluntary labeling was adopted by the two
`major pharmaceutical
`industry trade associations.
`These voluntary guidelines contain an exemption for
`“trade secret” components and do not require com-
`plete disclosure of all fragrance and flavoring ingre-
`dients.
`Current problems encountered with “inactive” in-
`gredients include benzalkonium chloride-induced
`
`The recommendations in this statement do not indicate an exclusive course
`of treatment or serve as a standard of medical care. Variations, taking into
`account individual circumstances, may be appropriate.
`PEDIATRICS (ISSN 0031 4005). Copyright © 1997 by the American Acad-
`emy of Pediatrics.
`
`bronchospasm from antiasthmatic drugs, aspartame-
`induced headache and seizures, saccharin-induced
`cross-sensitivity reactions in children with sulfon-
`amide allergy, benzyl alcohol toxicity in neonates
`receiving high-dose continuous infusion with pre-
`served medications, dye-related cross-reactions in
`children with aspirin intolerance, lactose-induced di-
`arrhea, and propylene glycol-induced hyperosmola-
`lity and lactic acidosis. Although many other excipi-
`ents have been implicated in causing adverse
`reactions, these are the most significant in the pedi-
`atric population.
`
`ANTIASTHMATIC MEDICATIONS
`It is readily appreciated that some percentage of
`asthmatic children will develop a “paradoxical”
`bronchospasm after they inhale their medication. Be-
`cause many of these reactions were attributed to
`sulfite, which had been highly publicized as a caus-
`ative agent, it was often first suspected. During the
`past 10 years, however, the active ingredient in sul-
`fite-containing preparations, the nonselective b
`2-ago-
`nists isoproterenol, isoetharine, and metaproterenol,
`have been replaced as drugs of choice by more se-
`lective agents, primarily albuterol, that do not con-
`tain sulfites. Paradoxical reactions continue to be
`reported, in some cases resulting in product refor-
`mulation because of excessive adverse reactions. In-
`active ingredients that have been implicated in caus-
`ing these reactions include benzalkonium chloride,
`oleic acid, chlorofluorocarbons, soya lecithin, and
`sorbitan trioleate.
`
`Sulfites
`Sulfiting agents are widely used as antioxidants.
`Six sulfite compounds (sulfur dioxide, sodium sul-
`fite, sodium bisulfite, potassium bisulfite, sodium
`metabisulfite, and potassium metabisulfite) have
`been categorized as “Generally Recognized as Safe”
`for use in foods and drugs. This status was revoked
`for raw fruits and vegetables (excluding potatoes) in
`1986 after the FDA received reports of more than 250
`cases of adverse reactions, including six deaths asso-
`ciated with the ingestion of sulfites in foods.3,4 Al-
`though primary exposure in children is through
`foods, serious reactions have also occurred after oral,
`inhalational, parenteral, and ophthalmic administra-
`tion of sulfite-containing drugs.
`Signs and symptoms most frequently reported in-
`clude wheezing, dyspnea, and chest tightness in pa-
`tients with known reactive airway disease.5–9 Nonim-
`munologic
`anaphylactoid reactions have
`also
`
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`occurred.7,8,10,11 Reactions to sulfites rarely occur in
`patients without reactive airway disease.12 Met-
`abisulfite hypersensitivity was demonstrated in 19
`(66%) of 29 children with a history of chronic mod-
`erately severe asthma.13 The incidence of sulfite sen-
`sitivity increases with age in severely asthmatic chil-
`dren (31% of children up to 10 years of age and 71%
`of older children).14
`The presence of sulfites in antiasthmatic medica-
`tions has been a concern, but many of these medica-
`tions have been reformulated or replaced in clinical
`practice by more b-selective agents, which do not
`contain sulfites. Metered-dose aerosol bronchodila-
`tors do not contain sulfites. Nonsulfite-containing
`products used to treat asthma are presented in Table
`1. Parenteral drugs, such as corticosteroids, amin-
`oglycosides, and epinephrine, may contain sulfites
`(Table 2) but rarely produce reactions because of the
`small amounts present. Patients who react to oral
`challenges with small amounts (5 to 10 mg) are at
`risk for similar reactions from these parenteral
`agents.15 Local dermal reactions accompanied by eo-
`
`Some Medications Used by Asthmatics That Do
`TABLE 1.
`Not Contain Sulfites
`Brand Name*
`
`Manufacturer
`
`Forest
`Aerobid inhaler
`Adams
`Airet solution
`Boehringer Ingelheim
`Alupent aerosol
`Boehringer Ingelheim
`Alupent solution 5%*
`Alupent solution Unit-dose 0.4, 0.6% Boehringer Ingelheim
`Alupent syrup
`Boehringer Ingelheim
`Alupent tablets
`Boehringer Ingelheim
`Atrovent aerosol
`Boehringer Ingelheim
`Azmacort
`Rhone-Poulenc Rorer
`Beclovent inhaler
`Glaxo
`Brethine injection
`Ciba-Geigy
`Brethine tablets
`Ciba-Geigy
`Bricanyl injection
`Marion Merrell Dow
`Bronkaid Mist aerosol
`Sterling-Winthrop
`Bronkometer aerosol
`Sterling-Winthrop
`Celestone injection*
`Schering
`Decadron respihaler
`Merck
`Duo-Medihaler aerosol
`3M
`Elixophyllin elixir
`Forest
`Intal capsules, solution, inhaler
`Fisons
`Isoetharine solution
`Astra
`Isoetharine solution
`Dey
`Isuprel Mistometer
`Winthrop-Breon
`Maxair autohaler
`3M
`Medihaler-Epi aerosol
`3M
`Medihaler-Iso aerosol
`3M
`Metaprel aerosol
`Sandoz
`Metaprel solution 5%*
`Sandoz
`Primatene Mist suspension aerosol
`Whitehall
`Primatene Mist solution aerosol
`Whitehall
`Proventil aerosol
`Schering
`Proventil solution 0.5%*
`Schering
`Quibron tablet, capsule
`Bristol-Myers Squibb
`Sus-Phrine injection
`Forest
`Theo-Dur sprinkle, tablets
`Key
`Tilade inhaler
`Fisons
`Tornalate inhaler
`Sterling Winthrop
`Tornalate solution
`Sterling Winthrop
`Vanceril inhaler
`Schering
`Ventolin aerosol
`Glaxo
`Ventolin nebules solution 0.083%
`Glaxo
`Ventolin solution 0.5%*
`Glaxo
`Ventolin rotacaps, syrup, tablets
`Glaxo
`* Contains benzalkonium chloride.
`
`TABLE 2.
`Asthmatics
`
`Some Sulfite-containing Medications Used by
`
`Brand Name
`
`Adrenalin Chloride 1:100
`Adrenalin injection 1:1000
`Amikin injection
`Arm-a-Med isoetharine solution
`AsthmaNefrin
`Beta 2 isoetharine solution
`Bronkosol solution
`Dey-dose epinephrine
`Dey-dose isoetharine solution
`Dispos-a-Med isoetharine
`Epipen/Epipen Jr
`Garamycin injection (all but intravenous
`piggyback and intrathecal)
`Isoetharine hydrochloride
`Isuprel injection
`Isuprel solution
`MicroNefrin
`Minocin syrup
`Nebcin injection
`Netromycin injection
`
`Manufacturer
`
`Parke-Davis
`Parke-Davis
`Apothecon
`Armour
`Menley & James
`Nephron
`Sanofi-Winthrop
`Dey
`Dey
`Parke-Davis
`Center
`Schering
`
`Roxane
`Sanofi-Winthrop
`Sanofi-Winthrop
`Bird
`Lederle
`Lilly
`Schering
`
`sinophilia have been reported after continuous infu-
`sion with dobutamine.16 Sulfite-preserved amino ac-
`ids contained in most mixtures of total parenteral
`nutrition are a less commonly appreciated source.
`Nevertheless,
`life-threatening situations requiring
`the administration of epinephrine should be treated
`with sulfite-preserved epinephrine if no preserva-
`tive-free product is available, even in very sensitive
`patients. The diagnosis of sulfite sensitivity is made
`by history and through challenge testing.7 Avoidance
`of foods containing sulfites through careful reading
`of packaged food labels and inquiry at restaurants as
`to the use of agents that contain sulfites may prevent
`reactions. A commercial sulfite-detection strip was
`found to be unreliable, especially when used on
`acidic foods or foods removed from their original
`containers.17 Drug manufacturers must disclose the
`presence of sulfites in product labeling.
`
`Benzalkonium Chloride
`Benzalkonium chloride is a commonly used bacte-
`ricidal preservative in albuterol and metaproterenol
`nebulizer solutions in the United States and in be-
`clomethasone and ipratropium bromide nebulizer
`solutions in other countries. Inhalation of pure ben-
`zalkonium chloride causes
`reproducible, dose-
`related, cumulative bronchoconstriction, with a
`rapid onset and prolonged duration compared with
`sulfites. It is frequently accompanied by a cough and
`burning sensation and, occasionally, by facial flush-
`ing and pruritus. Bronchoconstriction is inhibited by
`concurrent treatment or pretreatment with b
`2-ago-
`nists and cromolyn sodium and partially by hista-
`mine1 antagonists.18–20 The mechanism appears to be
`non-IgE-mediated release of mast cell mediators,
`with atopic patients being more susceptible.21
`Because the reaction is dose-related and cumula-
`tive and may be masked by the active agent in many
`patients, few clear-cut cases of paradoxical broncho-
`constriction have been attributed to benzalkonium,
`primarily in patients using more than one agent con-
`taining this excipient or in those receiving frequent
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`dosing.22–26 Unit-dose vials deliver five times as much
`benzalkonium as the same dose given from a multi-
`ple-dose vial, which resulted in one case of broncho-
`constriction.26 Other potential sources of benzalko-
`nium in children with asthma and concurrent
`sinusitis include nasal saline, nasal corticosteroid,
`and nasal decongestant solutions.
`In several studies of adult asthmatics, the lowest
`dose of pure benzalkonium chloride that produced a
`20% decrease in forced expiratory volume in 1 sec-
`ond ranged from 124 to 159 mg. Albuterol (from a
`multidose vial) contains 50 mg per 0.5 mL of solu-
`tion18,19; thus, a single dose is unlikely to cause a
`reaction. Even in patients without overt deterioration
`after the use of benzalkonium-preserved antiasth-
`matic agents, some evidence exists that benzalkoni-
`um-free solutions may have improved efficacy.21,27
`Thus, although the presence of benzalkonium prob-
`ably has a minimal effect in most patients using
`single, infrequent doses of a preserved bronchodila-
`tor, development of a unit-dose, nonpreserved prep-
`aration may significantly benefit the severely ill,
`hospitalized patient in whom disease-related deteri-
`oration in pulmonary function may be difficult to
`distinguish from preservative toxicity.
`
`Metered-dose Inhalers (MDIs)
`Paradoxical bronchoconstriction has been reported
`in up to 6.9% of asthmatic patients after inhalation of
`pure MDI vehicle.28 When combined with an active
`ingredient, this incidence decreases to approximately
`1.5% to 4%.29 Most studies of MDI-related broncho-
`constriction have been confounded by the lack of
`testing of individual vehicle components, inherent
`irritability of some active ingredients (corticoste-
`roids), or concurrent use of potent active ingredients
`(bronchodilators).
`Inactive ingredients that have
`been implicated in the deterioration of pulmonary
`function attributable to hypersensitivity or irritant
`effects include chlorofluorocarbons,30–33 sorbitan tri-
`oleate,30,34 oleic acid,28,35 and soya lecithin (H. G.
`Wilms, written communication, October 27, 1989).28,36
`One metaproterenol product, reformulated to con-
`tain soya lecithin, was withdrawn from the market
`after 1 month because of escalating reports of cough-
`ing, gagging, and asthma exacerbation (H. G. Wilms,
`written communication, October 27, 1989).
`
`ARTIFICIAL SWEETENERS
`
`Aspartame
`Aspartame, a dipeptide of aspartic acid and a
`methyl ester of phenylalanine, is approved for use in
`pharmaceutical products and is being used increas-
`ingly in chewable tablet and sugar-free formulations.
`Labels for both prescription and nonprescription
`products must include the phenylalanine content.
`The major consideration in the use of aspartame in
`children is in patients with autosomal recessive phe-
`nylketonuria. Although heterozygotes do not appear
`to have clinically significant increases in phenylala-
`nine after ingestion of even large amounts (equiva-
`lent to 24 12-oz cans of diet beverages), homozygotes
`with strict dietary restrictions should avoid aspar-
`
`tame. Children without dietary restrictions could
`safely ingest 10 mg/kg/d.37–40 Dietary consumption
`of aspartame is typically less than 5 mg/kg/d41;
`young children, however, could ingest considerably
`more. For example, a 2-year-old child weighing 12 kg
`consumes 17 mg/kg from drinking one 12-oz can of
`diet soda and one serving of a sweetened product
`(eg, cereal, pudding, gelatin, or frozen dessert).42
`Headache is the most common adverse effect at-
`tributed to aspartame but is seldom confirmed by
`single-dose double-blind challenge. Up to 11% of
`patients with chronic migraine headaches reported
`headaches triggered by aspartame43; however, a dou-
`ble-blind challenge with three doses of 10 mg/kg
`given every 2 hours triggered no more headaches
`than did placebos in patients with vascular head-
`aches believed to be exacerbated by aspartame.44 A
`small, double-blind 4-week trial showed an increase
`in frequency of headaches after ingestion of 1200
`mg/d, indicating that a longer challenge period may
`be necessary.45
`In anecdotal reports, aspartame has been linked to
`various neuropsychiatric disorders, including panic
`attacks, mood changes, visual hallucinations, manic
`episodes, and isolated dizziness.46–49 A small, dou-
`ble-blind crossover study of patients with major de-
`pression revealed a higher incidence of reactions in
`these patients compared with nondepressed volun-
`teers after administration of 30 mg/kg for 7 days;
`symptoms included headache, nervousness, dizzi-
`ness, memory impairment, nausea,
`temper out-
`bursts, and depression.50 None of these conditions
`has been rigorously proven to be caused by aspar-
`tame, but carefully conducted double-blind chal-
`lenges may be indicated in patients with histories
`that suggest aspartame as a cause. Patients with un-
`derlying mitral valve prolapse or affective disorders
`may be at increased risk for neuropsychiatric ef-
`fects51; several studies have shown that individuals
`without psychiatric or seizure disorders do not dem-
`onstrate these effects.50,52
`Seizures have been reported via passive surveil-
`lance data collected by the FDA and in a few case
`reports.47,48,53 A recent analysis of FDA reports
`showed 41 cases of rechallenge with a temporal re-
`lationship to aspartame consumption. Most seizures
`occurred in patients who had an acceptable dietary
`intake, except for a 16-year-old who ingested up to
`57 mg/kg of aspartame.54 Aspartame is generally
`considered safe for children with epilepsy. One
`study found increased spike-wave discharges in chil-
`dren with untreated absence seizures after a high
`dose of aspartame and suggested that children with
`poorly controlled absence seizures avoid aspar-
`tame.55
`Several studies have shown no relationship be-
`tween aspartame and aggressive or hyperactive be-
`haviors or cognitive function in children; thus, chil-
`dren with attention deficit disorder, with or without
`hyperactivity,56,57 do not need to avoid this sweet-
`ener.
`Isolated confirmed hypersensitivity reactions re-
`sulting from ingestion of aspartame have been re-
`ported, including two patients who developed sub-
`
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`TABLE 3.
`
`Parenteral Medications That Contain Benzyl Alcohol
`Drug
`Benzyl Alcohol
`Content, %
`
`Estimated Average Daily Intake
`of Benzyl Alcohol in Infants
`
`Aminophylline
`Aquamephyton neonatal injection
`Ativan injection
`Bacteriostatic saline
`Bacteriostatic water
`Dexamethasone injection
`Dopram
`Folate sodium
`Heparin injection (1000 U/mL)
`Multivitamin infusion
`Netromycin injection*
`Norcuron with supplied diluent
`Pavulon injection
`Tracrium multidose vial
`Vasotec injection
`* Netromycin neonatal injection does not contain benzyl alcohol.
`
`2.0
`0.9
`2.0
`1.5
`1.5
`1.0
`0.9
`1.5
`1.0
`0.9
`1.0
`0.9
`1.0
`0.9
`0.9
`
`2–4 mg/kg
`4.5 mg
`0.4–1 mg/kg
`99–234 mg/kg
`99–234 mg/kg
`2.5 mg
`21.6–32.4 mg/kg
`0.6–0.9 mg
`1.2 mg
`45 mg
`0.4–0.65 mg/kg
`0.4 mg/kg
`2–3 mg/kg
`3.6 mg/kg
`0.1–0.5 mg/kg
`
`resembling
`cutaneous nodules or granulomas
`erythema nodosum.58,59 Other reported reactions in-
`clude orofacial granulomatosis, erythema, pruritus,
`urticaria, and angioedema.60–62 A meticulous workup
`with double-blind challenge usually fails to confirm
`the purported reaction; hypersensitivity reactions
`appear to be rare.63,64 These reactions may be related
`to breakdown products formed during the storage of
`liquid products, such as diketopiperazine deriva-
`tives, especially after exposures to higher tempera-
`tures.62 If so, rechallenge with fresh encapsulated
`powder could produce a false-negative reaction.
`
`Saccharin
`Many oral drugs, including both solid and liquid
`dosage forms, contain saccharin as a sweetening
`agent. Saccharin is not included in drug labeling. The
`most frequent use of saccharin is in foods and bev-
`erages, accounting for 70% of the total consumption.
`A British survey found that conventional soft drinks
`were the predominant source of saccharin in children
`aged 2 to 9 years, replaced by diet soft drinks in
`adolescents. The median intake of saccharin was 0.2
`to 0.9 mg/kg/d in the general population and 0.6 to
`2.3 mg/kg/d in diabetics.65 Foods containing saccha-
`rin must carry a label stating that the “use of this
`product may be hazardous to your health . . . con-
`tains saccharin which has been determined to cause
`cancer in laboratory animals.”
`Saccharin may be present in drugs in substantial
`amounts. Ingestion of the recommended daily dos-
`age of chewable aspirin or acetaminophen tablets in
`a school-age child would provide approximately the
`same amount of saccharin contained in one can of a
`diet soft drink. This amount, relative to the body
`weight of a child younger than 9 or 10 years, ingested
`for prolonged periods would be considered as
`“heavy use,” as defined in a major large-scale FDA/
`National Cancer Institute epidemiologic study.66 In
`this study, heavy use of artificial sweeteners was
`associated with a significantly increased risk for the
`development of bladder cancer. An independent re-
`view of this study concluded that there was no as-
`sociation.67 An investigation of saccharin performed
`by the American Medical Association in 1985 con-
`
`cluded that bladder changes were species-specific,
`were confined to the second generation of male rats,
`and occurred in association with large doses (equiv-
`alent to several hundred cans of diet soft drink per
`day). The no-effect level was equivalent to 500 mg/
`kg/d.68,69 Saccharin is not genotoxic; the presumed
`mechanism of toxicity is the binding of saccharin to
`urinary proteins (not normally found in humans),
`creating a nidus for the formation of silicate crystals,
`which are cytotoxic to bladder epithelium.70
`Saccharin is an o-toluene sulfonamide derivative
`and causes similar dermatologic reactions. Cross-
`sensitivity with sulfonamides has been demonstrat-
`ed; therefore, children with “sulfa” allergy should
`also avoid saccharin. Hypersensitivity can usually be
`confirmed by a radioallergosorbent test for saccha-
`rin.71 In a series of 42 patients with adverse effects
`resulting from consumption of saccharin in pharma-
`ceutical agents, pruritus and urticaria were the most
`common reactions, followed by eczema, photosensi-
`tivity, and prurigo.72 Other reactions include wheez-
`ing, nausea, diarrhea, tongue blisters, tachycardia,
`fixed eruptions, headache, diuresis, and sensory
`neuropathy.73–77
`Ingestion of saccharin-adulterated milk formula by
`infants was associated with irritability, hypertonia,
`insomnia, opisthotonos, and strabismus, which re-
`solved within 36 hours after ingestion. Two anec-
`dotal reports of an accidental overdose in an adult
`and a child discussed reactions of generalized
`edema, oliguria, and persistent albuminuria.75 Be-
`cause of the paucity of data on the toxicity of saccha-
`rin in children, the American Medical Association
`has recommended limiting the intake of saccharin in
`young children and pregnant women.68
`
`BENZYL ALCOHOL
`Benzyl alcohol is commonly used as a preservative
`in many injectable drugs and solutions. A number of
`neonatal deaths and severe respiratory and meta-
`bolic complications in low-birth-weight premature
`infants have been associated with use of this agent in
`bacteriostatic saline intravascular flush and endotra-
`cheal tube lavage solutions.78–80 In a controlled study,
`intraventricular hemorrhage, metabolic acidosis, and
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`TABLE 4.
`
`Examples of Dye-free Orally Administered Liquid Medications
`Classification and Product
`(Manufacturer)
`
`Active Ingredients (per 5 mL Unless
`Otherwise Indicated)
`
`Analgesics
`Demerol (Sanofi Winthrop)
`Indomethacin (Roxane)
`Meperidine* (Roxane)
`Methadone Intensol* (Roxane)
`Opium tincture (Lilly)
`Rescudose* (Roxane)
`Roxanol* (Roxane)
`Roxanol* (Roxane)
`Roxicodone Intensol* (Roxane)
`Antibiotics/anti-infective
`Furoxone (Roberts)
`Gantrisin syrup (Roche)
`Gantrisin pediatric suspension (Roche)
`Mandelamine 250 (Parke-Davis)
`Minocin (Lederle)
`Mintezol (Merck Sharp & Dohme)
`Nystatin (Roxane)
`Pediazole (Ross)
`Suprax (Lederle)
`Vancocin*1 (Lilly)
`Vantin (Upjohn)
`Antihistamine/decongestant/antitussive
`Atarax syrup (Roerig)
`Chlorafed (Hauck)
`Codiclear DH (Central)
`Deconamine syrup (Berlex)
`Entuss-D (Hauck)
`
`Iodinated glycerol (Roxane)
`Iodinated glycerol/Dextromethorphan (Roxane)
`Isoclor (Fisons)
`Tuss-Ornade (SmithKline Beecham)
`Cardiovascular agents
`Aldomet (Merck Sharp & Dohme)
`Colestid*1 (Upjohn)
`Digoxin elixir (Roxane)
`Hydrochlorothiazide (Roxane)
`Propranolol oral solution (Roxane)
`Propranolol Intensol (Roxane)
`Gastrointestinal
`AlternaGEL (Johnson & Johnson-Merck)
`Aluminum hydroxide gel (Roxane)
`Aluminum hydroxide concentrated (Roxane)
`Aromatic cascara fluid extract (Roxane)
`Castor oil*1 (Roxane)
`Citrocarbonate1 (Upjohn)
`Doxinate (Hoechst-Roussel)
`Effersyllium1 (Johnson & Johnson-Merck)
`Gaviscon ESRF (Marion Merrell Dow)
`
`Ipecac syrup (Roxane)
`Kaolin pectin (Roxane)
`Kaopectate regular flavor (Upjohn)
`Loperamide (Roxane)
`Maalox plus, extra strength (Rhone-Poulenc Rorer)
`
`Milk of Magnesia* (Roxane)
`Milk of Magnesia concentrated (Roxane)
`Mylanta double strength (Johnson & Johnson-
`Merck)
`Parapectolin (Rhone-Poulenc Rorer)
`Perdiem1 (Rhone-Poulenc Rorer)
`Hormonal agents
`Dexamethasone solution (Roxane)
`Dexamethasone Intensol* (Roxane)
`Prednisone solution (Roxane)
`Prednisone Intensol* (Roxane)
`Proglycem (Baker Cummins)
`
`Meperidine 50 mg
`Indomethacin 25 mg
`Meperidine 50 mg
`Methadone 50 mg
`Morphine 50 mg
`Morphine sulfate 20 mg
`Morphine sulfate 100 mg
`Morphine sulfate 20 mg
`Oxycodone 100 mg
`
`Furazolidone 50 mg
`Sulfisoxazole 500 mg
`Sulfisoxazole 500 mg
`Methenamine mandelate 250 mg
`Minocycline 50 mg
`Thiazbendazole 500 mg
`Nystatin 500,000 units
`Erythromycin 200 mg, sulfisoxazole 600 mg
`Cefixime 100 mg
`Vancomycin 250 or 417 mg
`Cefpodoxime axetil 50 mg
`
`Hydroxyzine 10 mg
`Chlorpheniramine 2 mg, pseudoephedrine 30 mg
`Hydrocodone 5 mg, guaifenesin 100 mg
`Chlorpheniramine 2 mg, pseudoephedrine 30 mg
`Hydrocodone 5 mg, pseudoephedrine 30 mg,
`guaifenesin 300 mg
`Iodinated glycerol 60 mg
`Iodinated glycerol 30 mg, dextromethorphan 10 mg
`Chlorpheniramine 2 mg, pseudoephedrine 30 mg
`Phenylpropanolamine 12.5 mg, caramiphen 6.7 mg
`
`Methyldopa 250 mg
`Colestipol 5 g per packet
`Digoxin 0.25 mg
`Hydrochlorothiazide 50 mg
`Propranolol 20 or 40 mg
`Propranolol 400 mg
`
`Aluminum hydroxide 600 mg
`Aluminum hydroxide 450 mg
`Aluminum hydroxide 675 mg
`Cascara sagrada extract equivalent to 1 g/mL
`Castor oil
`Sodium citrate 1.82 g, sodium bicarbonate 0.78 g
`Docusate 50 mg
`Psyllium hydrocolloid 3 g
`Aluminum hydroxide 254 mg, magnesium
`carbonate 237.5 mg
`Ipecac alkaloids 20 mg/15 mL
`Kaolin, pectin
`Attapulgite 200 mg
`Loperamide 1 mg
`Aluminum hydroxide 500 mg, magnesium
`hydroxide 450 mg, simethicone 40 mg
`Magnesium hydroxide 400 mg
`Magnesium hydroxide 1200 mg
`Aluminum hydroxide 400 mg, magnesium
`hydroxide 400 mg, simethicone 40 mg
`Attapulgite 200 mg
`Psyllium (82% w/v), senna (18% w/v)
`
`Dexamethasone 0.5 mg
`Dexamethasone 5 mg
`Prednisone 5 mg
`Prednisone 25 mg
`Diazoxide 250 mg
`
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`TABLE 4.
`
`Continued
`
`Classification and Product
`(Manufacturer)
`
`Psychotropics
`Chlorpromazine Intensol (Roxane)
`Cibalith-S (Ciba-Geigy)
`Haldol* (McNeil)
`Haloperidol Intensol* (Roxane)
`Lithium citrate (Roxane)
`Navane (Roerig)
`Prozac (Lilly)
`Sinequan (Roerig)
`Thioridazine solution (Roxane)
`Thioridazine Intensol (Roxane)
`Thiothixene Intensol* (Roxane)
`Thorazine (SmithKline Beecham)
`Trilafon (Schering)
`Sedatives/hypnotics
`Chloral hydrate syrup (Roxane)
`Lorazepam Intensol*1 (Roxane)
`Spasmolytics/bronchodilators
`Aquaphylline (Ferndale)
`Elixophyllin GG (Forest)
`Marax DF (Roerig)
`Slo-Phyllin GG (Rhone-Poulenc Rorer)
`Somophyllin DF (Fisons)
`Theoclear-80 (Central)
`Theolair liquid (3M Riker)
`Theophylline solution (Roxane)
`Theostat 80 syrup (Laser)
`Vitamins
`DHT intensol (Roxane)
`Drisdol (Sanofi Winthrop)
`Theragran liquid (Apothecon)
`Miscellaneous
`Antiminth (Roerig)
`Glyoxide (Marion Merrell Dow)
`Klorvess (Sandoz)
`* Flavoring free.
`1 Preservative free.
`
`Active Ingredients (per 5 mL Unless
`Otherwise Indicated)
`
`Chlorpromazine 150, 500 mg
`Lithium 8 mEq
`Haloperidol 10 mg
`Haloperidol 10 mg
`Lithium 8 mEq
`Thiothixene 25 mg
`Fluoxetine 20 mg
`Doxepin 50 mg
`Thioridazine 80 mg/15 mL
`Thioridazine 150, 500 mg
`Thiothixene 25 mg
`Chlorpromazine 10 mg
`Perphenazine 16 mg
`
`Chloral hydrate 250, 500 mg
`Lorazepam 10 mg
`
`Theophylline 5.33 mg
`Theophylline 100 mg, guafenesin 100 mg,
`Ephedrine 6.25 mg, theophylline 32.5 mg, hydroxyzine 2.5 mg
`Theophylline 50 mg, guafenesin 30 mg
`Theophylline 90 mg
`Theophylline 26.66 mg
`Theophylline 26.66 mg
`Theophylline 26.66 mg
`Theophylline 26.66 mg
`
`Dihydrotachysterol 1 mg
`Ergocalciferol 8000 U/mL
`Multivitamins
`
`Pyrantel pamoate 250 mg
`Carbamide peroxide 100 mg/mL, anhydrous glycerol
`Potassium chloride 10%
`
`increased mortality were positively correlated with
`substantial benzoic acid and benzyl alcohol levels in
`neonates.81 The incidence of premature infant mor-
`tality, kernicterus, and intraventricular hemorrhage
`decreased markedly after discontinuation of pre-
`served flush solutions.82–84 In surviving infants, ex-
`posure to benzyl alcohol was also found to be asso-
`ciated with morbidity, including cerebral palsy and
`developmental delay.83
`Most therapeutic agents, other than large-volume
`fluids, contain amounts of benzyl alcohol smaller
`than those associated with neonatal death. The ef-
`fects of lower amounts, however, have not been ad-
`equately studied (Table 3). Toxicity has been de-
`scribed in one infant weighing 3350 g who received
`32 to 105 mg/kg/d.80 Continuous infusions of high
`doses of some medications containing benzyl alco-
`hol, such as doxapram, may reach the range of ben-
`zyl alcohol dosage associated with toxicity in this
`case report. Premature infants receiving low doses in
`medications were found to have peak benzoic acid
`levels 10 times higher than those in term infants but
`without evidence of toxicity.85 Two studies noting
`the striking decrease in kernicterus after removal of
`benzyl alcohol did not reveal a dose–response rela-
`tionship and could not exclude the possibility that
`other advances in therapy were responsible.84,86
`
`The US Pharmacopeia requires labeling of bacteri-
`ostatic water and saline for injection with the phrase,
`“Not for use in newborns.” The FDA declined similar
`labeling for multidose parenteral medications, be-
`cause serious toxic effects from benzyl alcohol had
`virtually disappeared.87 The toxic effects in newborns
`relate primarily to the use of preservative-containing
`flush solutions, which clearly are to be avoided in
`newborns. At low doses, such as those present when
`medications preserved with benzyl alcohol are ad-
`ministered, benzyl alcohol is safe for newborns.
`Bacteriostatic saline solution containing benzyl al-
`cohol was associated with severe bronchitis and he-
`moptysis when used to dilute albuterol for nebuliza-
`tion in an adult man.88 Nonpreserved saline solution
`should be used in children to dilute nebulized bron-
`chodilators.
`Benzyl alcohol may also rarely cause hypersensi-
`tivity reactions. Contact dermatitis,89 as well as more
`generalized allergic symptoms including nausea, fa-
`tigue, fever, maculopapular rash, or angioedema,
`may occur after parenteral administration of prod-
`ucts containing benzyl alcohol as a preservative.90–92
`
`COLORING AGENTS
`Numerous dyes are used in pharmaceutical man-
`ufacturing. These dyes give products a distinctive,
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`identifiable appearance, and they impart a uniform
`and attractive color to products that might otherwise
`be drab and unappealing or exhibit color variation
`among batches.
`Several groups of dyes have been associated with
`serious adverse effects. The azo dye tartrazine
`(FD&C Yellow No. 5) is known to be potentially
`dangerous in aspirin-intolerant individuals. Approx-
`imately 2% to 20% of asthmatics are sensitive to
`aspirin. The incidence of cross-reaction to tartrazine
`was previously believed to be as high as 10%,93,94 but
`more recent carefully blinded studies have shown
`the incidence to be less than 2.4%.95–98 Unlike aspirin,
`tartrazine does not alter prostaglandin synthesis and
`does not, therefore, exert anti-inflammatory actions.
`Nonetheless, reactions to tartrazine are similar to
`those produced by aspirin, occur in patients both
`with and without a history of aspirin intolerance,
`and include acute bronchospasm, nonimmunologic
`urticaria,
`eosinophilia,
`and angioedema.94,99–107
`Rarely, nonimmunologic anaphylactoid reactions oc-
`cur.108,109 The most likely mechanism for these reac-
`tions is dose-related histamine release from mast
`cells.110,111 Patients with recurrent allergic vascular
`purpura may experience exacerbations after expo-
`sure to azo dyes, such as tartrazine, sunset yellow,
`and new coccine.112–114 Because of both the serious-
`ness of these reactions and the widespread use of
`tartrazine in foods and over-the-counter and pre-
`scription drugs, since 1980 the FDA has required that
`all products containing tartrazine be labeled so that
`these substances can be avoided.115
`Patients with the classic aspirin triad reaction
`(asthma, urticaria, and rhinitis) or anaphylactoid re-
`actions may also develop similar reactions from dyes
`other
`than tartrazine,
`including amaranth,116–118
`erythrosine,118,119 indigo carmine (FD&C Blue No.
`2),103 ponceau,106,116,118 new coccine,113,117 sunset yel-
`low,103,106,108,113,117,118 Brilliant Blue (FD&C Blue No.
`1),106,118 methyl blue,120 quinolone yellow,121 and
`FD&C Red No. 40.122
`Gastrointestinal intolerance, with abdominal pain,
`vomiting, an