3-year-old girl requiring oral nadolol 100mg twice daily. The only UK licensed formulation available was 80mg tablets. Family had been instructed by another hospital to disperse 2 x 80mg nadolol tablets in 10ml water and administer 6.25ml. However, tablets did not disperse well with concerns about dose accuracy and consistency. Possible alternative formulations were an ‘in-house’ extemporaneous suspension (10mg in 5ml) or an unlicensed ’special’ suspension (40mg in 5ml). Latter sourced and supplied. However, the family subsequently reported an increase in ectopy and child reverted to use of dispersed tablets. Could the change in formulation have a clinically significant effect? How accurate is the dose delivered via these formulations?
Method We asked regional QC to investigate (using Corgard(R) 80mg tablets):
Accuracy and uniformity of nadolol tablet breaking
Uniformity of nadolol distribution within the tablets
Nadolol assay by HPLC of
nadolol 80mg and 160mg in 10ml distilled water
nadolol 40mg and 20mg segments (of 80mg tablets)
nadolol 10mg in 5ml suspension (‘in-house’ extemporaneous suspension)
nadolol 40mg in 5ml suspension (unlicensed special)
Results Whilst the distribution of nadolol in Corgard(R) 80mg tablets was demonstrated to be uniform, the process of breaking Corgard(R) 80mg tablets into halves and quarters demonstrated variability with segment weights.
Nadolol formulations of dispersed tablets in water 80mg in 10ml and 160mg in 10ml suggest nadolol is not fully soluble as supernatant assay concentration was lower than the initial concentration (after initial dilution and shaking) for both strengths. The solubility limit of nadolol in water estimated to be ~8mg/ml.
Nadolol 10mg in 5ml suspension assay concentration was 112% of the expected concentration demonstrating a suitable manufacturing process for the ‘in-house’ 10mg in 5ml extemporaneous formulation.
Nadolol 40mg in 5ml (unlicensed special) assay concentration was only 79.9% of the expected concentration. However, the low assay result could have been due to the analytical method used for analysis which may require further validation for testing of this suspension type. Of note, only a single sample was tested.
Conclusion In this case, the patient was complex and unstable, and her clinical condition may well have contributed to the increase in ectopy experienced. However, the work done by regional QC identified the risk of inaccuracy and/or variation in the dose of nadolol delivered using different formulations and/or methods of administration.
The solubility limit of nadolol in water is estimated to be ~8mg/ml. Dispersed oral solutions must be thoroughly mixed prior to patient use especially if a proportional dose is required. Inconsistency of the dose of nadolol delivered should be considered when using this method.
Further, the change in formulation to the oral suspension could, unintentionally, have resulted in a difference in the dose delivered to the patient.
A consistent method for administration should be followed and, if a change in formulation is considered necessary, the patient monitored for any sign of reduction in efficacy and/or increase in adverse effects.
Regional QC. Investigation into the preparation of various nadolol oral formulations. LD2019017. Version C. 29th July 2021
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