- Medicines and Healthcare products Regulatory Agency
- Therapeutic area:
- Dentistry, Paediatrics and neonatology, and Pain management and palliation
Topical oral salicylate gels are no longer indicated for people younger than 16 years for pain associated with infant teething, orthodontic devices, cold sores, or mouth ulcers.
Article date: June 2009
The Commission on Human Medicines (CHM) has recommended that topical oral pain-relief products that contain salicylate salts should be contraindicated in those younger than age 16 years. This decision followed an in-depth review of these products, which was triggered by the publication of a report of a suspected case of Reye’s syndrome associated with the use of an oral gel that contained choline salicylate in a 20-month-old child.1
The child presented with a 1-day history of severe vomiting, lethargy, and photophobia after receiving one tube a day of a teething gel that contained choline salicylate. Investigations revealed a raised white-cell count, low blood glucose, and raised transaminases, but serum ammonia, coagulation, and urine toxicology were normal. The authors diagnosed Reye’s syndrome after exclusion of metabolic disorders and because the systemic salicylate concentration was only just above the therapeutic range.
Serum salicylate levels, however, reflect a complicated, and to some extent unpredictable, combination of factors and are therefore considered a poor indicator of salicylate toxicity. Critical among these factors are: the saturation of hepatic enzymatic metabolism after chronic (ie, >2 days’) ingestion;2 changes in binding to plasma proteins; and movement of salicylate into tissues, which occurs mainly during metabolic acidosis. These factors result in an increase in the plasma salicylate half-life from 2–4.5 hours to 18–36 hours. 3 Given that the salicylate level was not measured until 24 hours after admission in the current case, 1 salicylate levels could have been considerably higher at the onset of symptoms.
Chronic toxicity has been reported after doses of 100 mg/kg per day for 2 days or longer.4 Under conditions of chronic toxicity, children (particularly those younger than age 4 years) are more likely to develop serious complications such as hypoglycaemia and metabolic acidosis, 5 and seem particularly susceptible to the hepatotoxicity of salicylate. 6 7 8 9 In this case, 1 the child received one tube of teething gel a day for an unspecified time. A tube of Bonjela (15 g) contains 1·31 g choline salicylate (equivalent to approximately 930 mg aspirin). Thus, in a child who weighs 10 kg, this equates to 93 mg/kg aspirin per day.
Reye’s syndrome is usually diagnosed in a child younger than age 16 years with unexplained non-inflammatory encephalopathy and one or more of:
- serum hepatic transaminases increased ≥3-times upper limit of normal
- plasma ammonia concentration increased ≥3-times upper limit of normal
- hepatic panlobular microvesicular fatty infiltration
In addition, there should be no other reasonable explanation for the cerebral or hepatic disorders.
Thus, it would be atypical in a case of Reye’s syndrome for plasma ammonia to be normal in the presence of raised transaminases. The child was young for classic Reye’s syndrome, the median age of which is thought to be 6–7 years.
MHRA conclusions and CHM advice
We conclude that the clinical features in this patient1 are more consistent with salicylate toxicity than with Reye’s syndrome. Our assessment is based on the fact that all of the diagnostic criteria for Reye’s syndrome were not met, and the child had received a significant dose of salicylate (equivalent to 93 mg/kg aspirin per day) through the excessive use of the topical preparation. Irrespective of the diagnosis, it is clear that a choline salicylate gel, if applied chronically and excessively, can result in systemic levels of salicylate of at least therapeutic levels. Given that no information is available as to the threshold concentration of salicylate required to precipitate Reye’s syndrome, there is a theoretical risk that oral gels that contain choline salicylate, if used in excess, could increase the risk of Reye’s syndrome.
On the basis of this evidence, while acknowledging that there is only a theoretical risk of Reye’s syndrome with these oral gel products, CHM advised that any topical oral product that contains salicylate should be contraindicated in children younger than age 16 years in line with current advice on aspirin from the former Committee on the Safety of Medicines. An important factor in this decision is the availability of alternative treatment options to alleviate pain associated with infant teething, orthodontic braces, and mouth ulcers.
The MHRA has approved amendments to the product information for the relevant products and communicated the new advice to healthcare professionals and the general public.
Advice for healthcare professionals:
- advise parents and patients that those younger than age 16 years should use alternative treatments or products. There are several dental gels available which contain a local anaesthetic/mild antiseptic
- gentle pressure with something cool such as a chilled teething ring may help relieve teething pain for infant teething
- for pain associated with orthodontic devices, salt water mouthwashes are recommended for sore areas. For discomfort arising from tooth movement, a paracetamol-based painkiller is recommended
Article citation: Drug Safety Update June 2009, vol 2 issue 11: 4.
Gibson T, et al. Br J Clin Pharm 1975; 8: 233–38 ↩
Done AK. Pediatrics 1960; 26: 800–07 ↩
Temple AR. Arch Intern Med 1981; 141 (3 spec no): 364–69 ↩
Winters RW, et al. Pediatrics 1959: 23: 260–85 ↩
Prescott LF. Br J Clin Pharmacol 1980; 10 (suppl): 373S–79S ↩
Rich RR, Johnson JS. Arthritis Rheum 1973; 16: 1–9 ↩
Athreya BH, et al. Arthritis Rheum 1975; 19: 347–53 ↩
Bernstein BH, et al. Am J Dis Child 1977; 131: 659–63 ↩