Background
Methods
Category | Safety status | Description | No of excipients identified |
---|---|---|---|
1
| Potentially safe | No adverse reactions reported | 42 |
2
| Potentially harmful and known to be harmful | Adverse reactions reported | 47 |
3
| No safety data found | No data found in the literature on human exposure and toxicity | 19 |
4
| Description of the excipient in SPC or PIL unspecific | Description does not allow a specific literature search | 15 |
Total
| 123 |
Results
Classification of excipients and neonatal exposure
Excipient§
| No of medications containing / Total Number of prescriptions | Medications containing excipients (number of prescriptions†) |
---|---|---|
Known to be harmful to neonates
| ||
Parabens (methyl- and propyl parahydroxybenzoate) | 6 / 343 | Gentamicin inj (200), heparin inj (86), iron oral solution (32), heparin sodium ointment (12), prednisolone inj (7), cetirizine oral solution (6) |
Saccharin sodium | 6 / 173 | Simeticone oral suspension (108), iron oral solution (32), zidovudine oral solution (17), cetirizine oral solution (6), miconazole ointment (6), sultamicilline powder for suspension (4) |
Sodium benzoate | 4 / 156 | Simeticone oral suspension (108), caffeine solution (29), zidovudine oral solution (17), fludrocortisone inj (2) |
Benzyl alcohol | 6 / 125 | Heparin inj (86), hydrocortisone inj (23), phenobarbital inj (13), clotrimazole ointment (1), diazepam rectal suspension (1), diclofenac inj (1) |
Benzalkonium chloride | 6 / 104 | Salbutamol nebulisation solution (54), chloramphenicol ophthalmic solution (29), fusidic acid opthalmic solution (16), troxerutin gel (3), ipratropium bromide nebulisation solution (1), dexamethasone + neomycin + polymyxin B opthalmic solution (1) |
Propylene glycol | 7 / 79 | Salbutamol nebulisation solution (54), phenobarbital inj (13), cetirizine oral solution (6), diazepam oral solution (3), ibuprofen tablet (1), diclofenac inj (1), diazepam rectal solution (1) |
Polysorbate 80 | 4 / 70 | Budesonide nebulisation solution (31), chloramphenicol ophalmic solution (29), miconazole ointment (6), tobramycin opthalmic ointment (4) |
Ethanol | 7 / 31 | Heparin sodium ointment (12), miconazole ointment (6), dinoprostone inj (5), Lipase + amylase + protease tablet (3), diazepam oral solution (3), diosmectide powder for oral suspension (1), alprostadil inj (1) |
Potentially harmful excipients
| ||
Sodium metabisulphite | 6 / 297 | Gentamicin inj (200), dobutamine inj (45), epinephrine inj (36), morphine inj (14), diclofenac inj (1), norepinephrine inj (1) |
Silica, colloidal anhydrous | 10 / 195 | Simeticone oral suspension (108), phenobarbital tablet (29), hyoscine butylbromide tablet (20), spironolactone tablet (18), furosemide tablet (6), ursodeoxycholic acid tablet (5), sotalol tablet (4), propranolol tablet (3), diosmectide powder for oral suspension (1), ibuprofen tablet (1) |
Sorbic acid | 2 / 168 | Simeticone oral suspension (108), laurilsulphate + sorbitol + sodium citrate rectal solution (60) |
Anhydrous sodium hydrogen phosphate (monobasic, dibasic) | 10 / 122 | Paracetamol suppository (29), paracetamol infusion solution (24), hydrocortisone powder for infusion solution (23), epoetin beta inj (22), dexamethazone inj (8), oxacillin powder for infusion solution (7), sultamicillin powder for infusion solution (4), ranitidine inj (2), pentoxifylline inj (2), ipratropium bromide nebulisation solution (1) |
Sodium cyclamate | 1 / 108 | Simeticone oral suspension (108) |
Disodium edetate | 10 / 106 | Budesonide nebulisation solution (31), piperacillin + tazobactam inj (25), fusidic acid ophthalmic solution (16), metoclopramide inj (10), dexamethazone inj (8), sulphametizole opthalmic solution (6), aminophylline inj (4), troxerutin ointment (3), esomeprazole inj (2), acetylcysteine inj (1) |
Gelatin | 5 / 51 | Phenobarbital tablet (29), hydrochlorothiazide tablet (10), ursodeoxycholic acid tablet (5), digoxin tablet (4), lipase + amylase + protease tablet (3) |
Sodium bicarbonate | 4 / 44 | Meropenem inj (32), povidone-iodine ointment (8), ceftazidime powder for infusion solution (3), enalapril tablet (1) |
Boric acid | 2 / 33 | Chloramphenicol opthalmic solution (29), tobramycin opthalmic solution (4) |
Borax | 1 / 29 | Chloramphenicol opthalmic solution (29) |
Macrogols - polyethylene glycol | 5 / 25 | Povidone-iodine ointment (8), pentoxifylline tablet (7), Hydrocortisone + chlorhexidine ointment (4), lipase + amylase + protease tablet (3), propranolol tablet (3) |
Trometamol | 2 / 25 | Ibuprofen inj (21), tobramycin ophthalmic ointment (4) |
Glycine | 1 / 22 | Epoetin beta inj (22) |
Calcium chloride dihydrate | 1 / 22 | Epoetin beta inj (22) |
Leucine | 1 / 22 | Epoetin beta inj (22) |
Titanium dioxide | 5 / 21 | Pentoxifylline tablet (7), ursodeoxycholic acid tablet (5), lipase + amylase + protease tablet (3), propranolol tablet (3), sildenafil tablet (3) |
Povidone | 4 / 19 | Pentoxifylline tablet (7), furosemide tablet (6), drotaverine tablet (5), teophylline tablet (1) |
Trolamine | 2 / 15 | Heparin sodium ointment (12), troxerutin ointment (3) |
Cresol | 1 / 11 | Diosmectide powder for oral suspension (1) |
Maltose | 2 / 7 | Tobramycin ophthalmic ointment (4), immunoglobuline inj (3) |
Erythrosine | 1 / 7 | Pentoxifylline tablet (7) |
Benzethonium chloride | 1 / 7 | Ketamine inj (7) |
Sodium acetate trihydrates | 2 / 7 | Cetirizine oral solution (6), flecainide inj (1) |
Cetostearyl alcohol | 2 / 5 | Hydrocortisone + chlorhexidine ointment (4), clotrimazole ointment (1) |
Ethylendiamine | 1 / 4 | Aminophylline inj (4) |
Macrogol cetostearyl ether | 1 / 4 | Hydrocortisone + chlorhexidine ointment (4) |
Sodium laurilsulfate | 1 / 3 | Lipase + amylase + protease tablet (3) |
Lactic acid | 1 / 3 | Milrinone inj (3) |
Copovidone | 1 / 3 | Propranolol tablet (3) |
Sodium formaldehyde sulfoxylate | 2 / 2 | Diazepam rectal solution (1), diclofenac inj (1) |
Castor oil | 1 / 1 | Teophylline tablet (1) |
Sorbitan stearate | 1 / 1 | Clotrimazole ointment (1) |
Acacia | 1 / 1 | Diosmectide powder for oral suspension (1) |
Potentially and known to be harmful excipients in medicines used in neonates
Excipient | Functional category†
| Applications and typical concentration ranges†
| Safety concern |
---|---|---|---|
Known to be harmful to neonates
| |||
Parabens (methyl- and propyl parahydroxybenzoate) | Antimicrobial | Antimicrobial activity against yeasts and molds. Combination of Methyparaben (0.18%) and propylparaben (0.02%) for parenteral formulations. In combinations with propylene glycol (2-5%)/ imidurea | |
Saccharin sodium | Sweetening | 0.02-0.5% w/w* | Urticaria with pruritus and photosensitivity reactions. [14] |
Sodium benzoate | Antimicrobial, tablet / capsule lubricant | 0.02-0.5% in oral medicines; 0.5% in parenteral medicines; 2-5% w/w tablet lubricant | Contact urticaria. [21] Topical irritant. Increased risk of hyperbilirubinaemia in neonates. |
Benzyl alcohol | Antimicrobial, solvent | Up to 2% v/v* in parenteral/oral preparations, typically 1% v/v. 5% v/v and up used as solubilisers. 10% v/v local anaesthetic properties (parenterals, ophthalmic solutions, oitments) | |
Benzalkonium chloride | Antimicrobial, antiseptic, solubilising, wetting | Ophthalmic preparations – preservative, 0.01-0.02% w/v*; In combination with other preservatives | |
Propylene glycol | Antimicrobial, humectant, plasticizer, solvent, stabilizing, water-miscible cosolvent | Humectant – topical – approx.15%. Preservative –solutions / semisolids – 15-30%. Solvent or cosolvent: aerosol solutions 10-30%, oral solutions 10-25%, parenterals 10-60%, topical 5-80% | |
Polysorbate 80 | Dispersing, emulsifying, non-ionic surfactant, solubilising, suspending, wetting | Emulsifying: alone in oil-in-water emulsions 1-15%; in combination 1-10%. To increase water-holding prop of ointments 1-10%. Solubilising: poorly soluble API*s in lipophilic bases 1-5%; insoluble APIs in lipophilic bases 0.1-3% | E-Ferol syndrome - thrombocytopenia, renal dysfunction, hepatomegaly, cholestasis, ascites, hypotension, metabolic acidosis. [18] |
Ethanol | Solvent | In the USA, the max quantity of alcohol included in over the counter (OTC) medicines 0.5% v/v for products for use by children under 6 years of age. Parenteral products containing up to 50% of alcohol (e 95 or 96% v/v) | |
Potentially harmful excipients
| |||
Sodium metabisulphite | Antimicrobial, antioxidant | Antioxidant in oral, parenteral, and topical formulations: 0.01–1.0% w/v, intramuscular 27% w/v. Antimicrobial: syrups. | |
Colloidal anhydrous silica | Adsorbent; anticaking; emulsion stabilizer; glidant; suspending; tablet disintegrant; thermal stabilizer; viscosity-increasing | Improves flow properties of dry powders (0.1-0.5%) (tabletting); stabilizes emulsions (1.0-5.0%); thixotropic thickening/ suspending (2.0-10.0%); in aerosols to promote particulate suspension, eliminate hard settling, minimize clogging of spray nozzles (0.5-2.0%) | A possible sarcoidosis-inducing antigen [22] |
Anhydrous sodium hydrogen phosphate (monobasic, dibasic) | Buffering; emulsifying; sequestering. | Buffering agent; sequestering agent. Concentrations are dependent on the formulation. | Gastrointestinal (GI) disturbances including diarrhea, nausea, and vomiting [18] |
Sodium bicarbonate | Alkalizing; therapeutic. | To produce or maintain an alkaline pH in a preparation | Exacerbation of chronic heart failure in elderly [18] |
Macrogols - polyethylene glycol | Ointment base; plasticizer; solvent; suppository base; tablet and capsule lubricant. | High molecular weight macrogols can be used as lubricants in tablet formulations; water solubility and bad penetration through skin makes them useful as ointment bases | Hypersensitivity reactions, hyperosmolarity, metabolic acidosis, and renal failure in burn patients. [18] |
Trometamol | Buffering | Buffering agent, buffer range from 7.1–9 | Hypersensitivity reactions. [23] |
Cetostearyl alcohol | Emollient; emulsifying; viscosity-increasing. | Increasing viscosity; stabilizes emulsions; co-emulsifier; decreasing the amount of surfactant required | |
Sodium lauryl sulphate | Anionic surfactant; detergent; emulsifying; skin penetrant; tablet and capsule lubricant, wetting | Tablet lubricant (1.0-2.0%) | Irritation to the skin, eyes, mucous membranes, upper respiratory tract, and stomach. [18] |
Sorbitan stearate | Dispersing; emulsifying; nonionic surfactant; solubilizing; suspending; wetting | When used alone produces water-in-oil emulsions / microemulsions. In combination with polysorbate produces water-in-oil or oil-in-water emulsions / creams. | Hypersensitive reactions.[18] |
Lactic acid | Acidulant | In injections in the form of lactate as a source of bicarbonate (0.012-1.16%) | Neonates have difficulty in metabolizing R-lactic acid, and this isomer and the racemate should therefore not be used in infants aged less than 3 months old. [18] |
Sodium cyclamate | Sweetening | 0.17% w/v as sweeter, in combination with saccharin | Photosensitivity. [18] |
Disodium edetate | Chelating | Forms stable water-soluble complexes with alkaline earth and heavy-metal ions; concentrations 0.005-0.1% | Local inflammatory reactions. [18] |
Gelatin | Coating; film-forming; gelling; suspending; tablet binder; viscosity-increasing | Tablet binder; microencapsulation | Local irritation. Hypersensitivity reactions, including serious anaphylactoid reactions [21] |
Povidone | Disintegrant; dissolution enhancer; suspending; tablet binder | Binder in wet-granulation process; coating; solubilizer for poorly soluble drugs (0.5-5%) | Subcutaneous granulomas at the injection site. [21] |
Trolamine | Alkalizing; emulsifying | When mixed in equimolar proportions with a fatty acid an emulsifying agent to produce fine-grained, stable oil-in-water emulsions will be formed (2-4%) | Hypersensitivity, skin irritant. [18] |
Cresol | Antimicrobial preservative; disinfectant. | Antimicrobial preservative in parenteral formulations (0.15-0.3%) | Skin hypersensitivity reactions. [18] |
Maltose | Sweetening; tablet diluent | Osmotic - ophthalmic drops and parenteral inf. | Single report of hyponatremia in a liver transplantation patient. [18] |
Sorbic acid | Antimicrobial | As antimicrobial preservative (0.05-0.2%) | |
Boric acid | Antimicrobial, buffering | As antimicrobial preservative in eye drops. Good buffering capacity to control pH. | Poisoning - abdominal pain, vomiting, diarrhea, erythematous rash, CNS depression. Convulsions, hyperpyrexia, and renal tubular damage. [18] |
Borax | Alkalizing; antimicrobial; buffering; disinfectant; emulsifying; stabilizing | Antimicrobial preservative in eye preparations | Vomiting, diarrhea, erythema, CNS depression, and kidney damage. [18] |
Glycine | Buffering; bulking; freeze-drying; tablet disintegrant; wetting | Cofreeze-dried excipient in injectable formulations | Disturbances of fluid and electrolyte balance; cardiovascular and pulmonary disorders. [18] |
Calcium chloride dihydrate | Antimicrobial, water-absorbing. | Dehydrating properties | Stomach and heart disturbances. Eye irritant, dermatitis. [18] |
Leucine | Antiadherent; flavoring; lubricant | As antiadherent to improve the deagglomeration | Moderately toxic by the s/c route.[18] |
Titanium dioxide | Coating as opacifier, pigment | As a white pigment and opacifier | Possibly carcinogenic [24] |
Benzethonium chloride | Surfactant, antiseptic, wetting and/or solubilizing | As an antimicrobial preservative (0.01-0.02% w/v) | Probably neurotoxic [25] |
Erythrosine | Cherry-pink/red synthetic coal tar dye | Dye | Toxic to human lymphocytes in vitro, binds directly to DNA. [26] |
Sodium cetate trihydrate | Antimicrobial; buffering; flavoring, stabilizing | As a buffering agent and as an antimicrobial preservative | Poisonous if injected i/v, an irritant to the skin and eyes. [18] |
Ethylendiamine | Counter ion | Counter ion of theophylline | Hypersensitivity reactions [27] |
Macrogol cetostearyl ether | Emulsifying; penetration enhancer; solubilizing; wetting | Solubilizing agent, enhancing effect on the skin permeation | Moderately toxic. [18] |
Copovidone | Film-forming; granulation aid; tablet binder | As a film-forming agent (0.5-5%); tablet binder (direct compression and wet granulation) (2.0-5.0%) | Moderately toxic by ingestion, gastric disturbances. [18] |
Sodium formaldehyde sulfoxylate | Antioxidant | Antioxidant in parental, rectal solutions | Moderately toxic by ingestion, when heated to decomposition it emits toxic fumes. [18] |
Castor oil | Emollient; oleaginous vehicle; solvent. | extended release agent | Contact dermatitis. [18] |
Acacia | Emulsifying; stabilizing; suspending; tablet binder; viscosity-increasing. | Viscosity increasing agent (as it is in powder for oral suspensions) | Hypersensitivity reactions. [18] |
Rank | Active substance, drug formulation | No of prescriptions | Potentially harmful or known to be harmful excipients |
---|---|---|---|
1 | Gentamicin, inj solution | 200 | Parabens, sodium metabisulphite |
2 | Simeticone, oral suspension | 108 | Sodium benzoate, saccharin sodium, silicium dioxide, sodium cyclamate, sorbic acid |
3 | Heparin, inj solution | 86 | Benzyl alcohol, parabens |
4 | Laurilsulphate + Sorbitol + Sodium citrate, rectal solution | 60 | Sorbic acid |
5 | Salbutamol, nebulisation solution | 54 | Benzalkonium chloride, propylene glycol |
6 | Dobutamine, inj solution | 45 | Sodium metabisulphite |
7 | Epinephrine, inj solution | 36 | Sodium metabisulphite |
8 | Iron, oral solution | 32 | Parabens, saccharin sodium |
9 | Budesonide, nebulisation solution | 31 | Polysorbate 80, disodiumedetate |
10 | Chloramphenicol, opthalmic solution | 29 | Benzalkonium chloride, polysorbate 80, borax, boric acid |
11 | Caffeine, solution | 29 | Sodium benzoate |
12 | Phenobarbital, tablet | 29 | Silicium dioxide, gelatin |
13 | Paracetamol, suppository | 29 | Disodium hydrogen phosphate |
14 | Piperacillin + tazobactam, inj solution | 25 | Disodium edetate |
15 | Paracetamol, inj solution | 24 | Disodium hydrogen phosphate |
16 | Hydrocortisone, inj solution | 23 | Benzyl alcohol, disodium hydrogen phosphate |
17 | Epoetin beta, inj solution | 22 | Disodium hydrogen phosphate, glycine, calcium chloride dihydrate, leucine, |
18 | Ibuprofen, inj solution | 21 | Trometamol |
19 | Hyoscine butylbromide, tablet | 20 | Silicium dioxide |
20 | Spironolactone, tablet | 18 | Silicium dioxide |
21 | Zidovudine, oral solution | 17 | Sodium benzoate, saccharin sodium |
22 | Fusidic acid, ophthalmic solution | 16 | Benzalkonium chloride, disodium edetate |
23 | Morphine, inj solution | 14 | Sodium metabisulphite |
24 | Phenobarbital, inj solution | 13 | Benzyl alcohol, propylene glycol |
25 | Heparin sodium, topical gel | 12 | Parabens, ethanol, trietanolamine, |
26 | Insulin, inj solution | 11 | Cresol |