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Adverse effects of excipients: implications for their use in children Sheridan Roth, Teresa Brooks and Penny North Lewis Leeds Teaching Hospitals NHS Trust The authors Getting the right start: National Service Framework for Children … Standard for Hospital Services “policies and procedures … ensuring that formulations of medicines are appropriate to the age and ability of the child” Huge task! Extemps project Rationalise preparations Formulary/Catalogue Standard worksheets Excipients Excipients Project Aim To investigate the safety profile of commonly used excipients in particular adverse effects in children To identify any specific concerns with excipients To identify the acceptable level or threshold dose for each excipient Method The following excipients were investigated Hydroxybenzoates (parabens) Benzoates (benzyl alcolhol, sodium benzoate, benzoic acid) Benzalkonium chloride Chloroform Ethanol Propylene glycol Aspartame Saccharin Sorbitol Lactose Method Searches Medline (Ovid) and Embase – using adverse effects, drug toxicity, poisoning and contraindication as search terms Meyler’s Side Effects of Drugs Micromedex Pharmline Google Method Data was collected and summarised to include: Special concerns with that excipient for a particular patient or age group The acceptable intake or threshold level where available Adverse effects reported Results Several thousand hits for some excipients which made finding answers long winded Lots of work done in the 70’s and 80’s, more recent research tends to relate to carcinogenicity Changing opinion as to safe limits e.g. saccharin 5mg/kg to 2.5mg/kg to 5mg/kg Results Lots of chat sites referring to excipients on the internet Often not referenced Gossipy! Rarely a definitive answer Acceptable daily limits include other sources Sweeteners - dietary Chloroform - showers Excipient Age/other concerns Concentrations/threshold Adverse effects reported Benzoates: -benzyl alcohol (Benzyl alcohol is oxidised in vivo to benzoic acid.) Neonates can receive high mg dose per kg of benzoates and have an immature benzoic acid detoxification pathway leading to the accumulation. If possible, benzoates should be avoided completely in premature, VLBW infants. In neonates, benzoates can displace bilirubin from albumin binding sites. Non-fatal toxicity has been reported following a daily intake of 32-105mg/kg/day. 100mg/kg/day is the lowest dose reported to have caused death in infants. Gasping syndrome in very low birth weight infants that received benzyl alcohol from IV preparations. This includes: -metabolic acidosis -seizures -neurological deterioration -renal dysfunction -hepatic dysfunction -cardiovascular collapse -death Also seen in neonates: intraventricular haemorrhage, cerebral palsy and developmental delay. If given intrathecally can cause paraparesis. Hypersensitivity, skin rashes, contact dermatitis, nausea, fever and angiodema. Acceptable daily intakes were established by the World Health Organization at 5 mg/kg for total Benzyl Alcohol, Benzoic Acid, and Sodium Benzoate. Topically could be used safely at concentrations up to 5% and 10% for hair dyes. Excipient Age/other concerns Concentrations/threshold Adverse effects reported Ethanol Little is known about the pharmacokinetics of ethanol in the very young who may be extremely sensitive to its toxic effects. Adverse reactions after alcohol ingestion were mainly reported by those subjects who showed the lack of aldehyde dehydrogenase isozyme I. This deficiency is mostly seen in Asian/oriental people. In general, a small amount (eg. 15%v/v) is unlikely to be harmful unless relatively large volumes are administered. The effects of chronic dosing and accumulation also require consideration. Many reported mostly associated with larger doses and include: Sedation/CNS depression Induction of hepatic enzymes (chronic use) Narcosis, coma Respiratory failure, death (at large doses) Hypothermia, hypertension Acidosis, electrolyte disturbance Hepatotoxicity Hypoglycaemia (especially in children) Radiating pain (IV) Haematological abnormalities Headache, cerebral ischaemia Seizures, neuropathy Ataxia, slurred speech Allergy, vasomotor rhinitis The American Academy of Paeditrics has arbitrarily established a blood ethanol concentration (BEC) of 25mg per 100mL as a value that should not be exceeded following a single dose of ethanol containing medication. Ethanol volume %ethanol(v / v) 0.79 BEC (mg / 100mL) 0.6 L / kg weight (kg) Where: volume % ethanol 0.79 0.6L/kg weight = = = = = of dose of medicine of the formulation specific gravity of ethanol volume of distribution of ethanol weight of the child in kg Ethanol Standard phenobarbital elixir BP (15mg/5ml) contains 38% alcohol A dose of 5mg/kg in a 3kg baby gives a BEC of 83mg/100ml Legal limit for drink driving is 80mg/100ml! Problem excipients Hydroxybenzoates in neonates – esp if hyperbilirubinaemic Benzoates in neonates Propylene glycol in children under 4 yrs Ethanol – esp in infants Sorbitol, aspartame, lactose – children with metabolic disorders Conclusion Children more at risk of ADRs to excipients – especially neonates Can of worms! Future steps Extend list of excipients, including dyes Develop guidelines with maximum concentrations of excipient which can be used when making purchase decisions, if necessary buying off contract for paeds Review formulations currently stocked to assess potential for harm Future steps Extemp project Divide formulations into 2 groups with a reduced excipient load formulation available for at risk groups e.g. neonates Shorter shelf life Thanks to Sheridan and Teresa and the QC department at LTHT