Thursday, September 23, 2010

Stability of Injectable Oxytocics in Tropical Climates: Results of Field Surveys and Simulation Studies on Ergometrine, Methylergometrine and Oxytocin - EDM Research Series N° 08

Post-partum haemorrhage is a major cause of direct maternal death, especially in developing countries. Parenteral ergometrine and methylergometrine are invaluable drugs in the treatment and prevention of excessive uterine bleeding following obstetric delivery; oxytocin is sometimes used as an alternative. Storage guidelines for injectable oxytocics are often contradictory and stability data from manufacturers are far from consistent. However, most reference books note that parenteral ergometrine should be stored at a temperature not exceeding 8°C and be protected from light, but these requirements are very often not followed. Several studies have reported that ergometrine injection is unstable under tropical conditions and in earlier studies a very low level of active ingredient has been found in many field samples.
The research questions for this study are as follows:
1 What is the pattern of stability of common injectable oxytocics (ergometrine/methylergometrine and oxytocin)?
2 What is the effect of long-term dark storage at 25 and 30°C, and of short-term exposure to higher temperatures and to light?
3 Can guidelines be developed for the selection and storage of injectable oxytocics in tropical climates?
4 Is there a correlation between the colour of the solution and its level of active ingredient?
5 Is there a correlation between the pH of the product and its stability under tropical conditions?
The study consists of two components. The first is a series of field surveys in Gambia, Malawi, Sudan and Zimbabwe, covering 29 samples of ergometrine injection taken from medical stores and rural health facilities, produced by 10 manufacturers from 6 countries. In the discussion the results are combined with those of earlier field surveys.
The second and largest component is a laboratory study on the stability of injectable oxytocic drugs under simulated tropical conditions, measuring the level of active ingredient at various temperature and light conditions at regular intervals over a period of up to two years. This part of the study is limited to 11 brands of ergometrine, methylergometrine and oxytocin injection that are most commonly supplied to developing countries by IDA and UNICEF. The main outcome measure is the amount of active ingredient in the sample, expressed as percentage of the stated amount; the colour of the solution, expressed on a dilution scale of brown; and oxygen content and pH of the solution.
There is a widespread problem with the stability of injectable ergometrine. In only 31% of field samples taken from six tropical countries the level of active ingredient complied with USP/BP limits of 90-110% of the stated content, while 31% of samples contained less than 60%, No field data on methylergometrine are available. The few field data on oxytocin suggest that the average quality at the level of the end user is acceptable, mainly because many products contain more active ingredient than the stated amount.
Simulation studies on eleven brands of injectable ergometrine, methylergometrine and oxytocin under different conditions of temperature and light show that there is no difference in stability between ergometrine and methylergometrine other than differences between brands, which however can be considerable. When kept under refrigeration for twelve months, the eight brands of ergometrine and methylergometrine lost, on average, about 4-5% of their active ingredient (range 0-14%). When kept at 30°C in the dark the products lost on average about 25% after twelve months (range 2-57%). When kept at 21-25°C under exposure of light, as so often happens in tropical countries, 21-27% of the active ingredient was lost after one month, and over 90% after one year. Two months exposure to 40°C in the dark led to a loss of potency of about 5%.
For oxytocin the pattern is different. There was, on average, no loss of potency after twelve months refrigerated storage, and about 14% loss after one year at 30°C in the dark (range 9-19%), No destabilizing effect of light was found.
We conclude that the stability of oxytocin is better than that of ergometrine and methylergometrine, mainly because it lacks the adverse effects of exposure to light but also because it is probably more stable when kept in the dark with or without refrigeration.
There is a strong correlation between the colour of the solution of (methyl)ergometrine and its level of active ingredient (r=0.8487 for ergometrine, r=0.8730 for methylergometrine). We conclude that any discolouration of (methyl)ergometrine of good initial quality which makes the solution different from water implies, with a sensitivity of 97-100%, that the level of active ingredient is below USP/BP standards of 90% of the stated content, and should not be used. When this rule is applied, about 15% of colour failures are false-positives. The comparison should be made in identical dear glass tubes against a well-lit white background.
Instability of some of the samples could not be related to an abnormal pH or oxygen content of the initial solution.
Selection of injectable oxytocic for tropical climates
There is no difference between the stability of ergometrine and methylergometrine per se, other than differences between brands. Oxytocin is more stable than (methyl)ergometrine, certainly under exposure of light arid probably also when kept in the dark with or without refrigeration.
In view of the observed differences between brands, ergometrine and methylergometrine should only be procured from a reputable supplier who submits all necessary documents in accordance with the WHO Certification Scheme, and whose product is of proven quality and stability. Upon arrival in the country, or upon delivery to Central Medical Stores, every batch should at least be tested for colour of the solution, and, if possible, for level of active ingredient. Ergometrine and methylergometrine delivered in clear glass ampoules should be rejected.
Injectable ergometrine, methylergometrine and oxytocin should be stored under refrigeration as much as possible. All products should clearly be marked with "keep under refrigeration" and ergometrine and methylergometrine should additionally be marked with "protect from light". For most products short periods of unrefrigerated transport are acceptable (not exceeding one month at 30°C or 2 weeks at 40°C).
In dispensaries and labour wards ampoules of ergometrine, methylergometrine and oxytocin should be kept under refrigeration, and should only be taken from their box when actually used. Especially ampoules of ergometrine and methylergometrine should not be kept ready in open trays, as this would reduce the level of active ingredient by about 21-27% per month. In case refrigerated storage is not available temporary storage outside the refrigerator at a maximum of 30°C is acceptable for most products for a period not exceeding 3 months. The actual recommended storage conditions for a particular brand may differ from the above recommendations, due to the differences in stability between brands.
Identification of ampoules with low level of (methyl)ergometrine
Before being administered to the patient, every injection of (methyl)ergometrine should be visually checked by the health worker, and any product for which the colour is different from clear water should not be used. In addition, staff responsible for the quality of drugs (e.g. hospital pharmacists) should regularly check on the colour of the injectable (methyl)ergometrines in stock, by means of a careful comparison in glass tubes between the product and clear water.

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