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. 2014 Dec 15;9(12):e112401.
doi: 10.1371/journal.pone.0112401. eCollection 2014.

Instability of misoprostol tablets stored outside the blister: a potential serious concern for clinical outcome in medical abortion

Veronique Berard  1 , Christian Fiala  2 , Sharon Cameron  3 , Teresa Bombas  4 , Mirella Parachini  5 , Kristina Gemzell-Danielsson  6
Affiliations

Instability of misoprostol tablets stored outside the blister: a potential serious concern for clinical outcome in medical abortion

Veronique Berard et al. PLoS One. .

Abstract

Introduction: Misoprostol (Cytotec) is recognised to be effective for many gynaecological indications including termination of pregnancy, management of miscarriage and postpartum haemorrhage. Although not licensed for such indications, it has been used for these purposes by millions of women throughout the world. Misoprostol tablets are most often packaged as multiple tablets within an aluminium strip, each within an individual alveolus. When an alveolus is opened, tablets will be exposed to atmospheric conditions.

Objective: To compare the pharmaco technical characteristics (weight, friability), water content, misoprostol content and decomposition product content (type A misoprostol, type B misoprostol and 8-epi misoprostol) of misoprostol tablets Cytotec (Pfizer) exposed to air for periods of 1 hour to 720 hours (30 days), to those of identical non exposed tablets.

Methods: Four hundred and twenty (420) tablets of Cytotec (Pfizer) were removed from their alveoli blister and stored at 25°C/60% relative humidity. Water content, and misoprostol degradation products were assayed in tablets exposed from 1 to 720 hours (30 days). Comparison was made with control tablets (N=60) from the same batch stored in non-damaged blisters. Statistical analyses were carried out using Fisher's exact test for small sample sizes.

Results: By 48 hours, exposed tablets demonstrated increased weight (+4.5%), friability (+1 300%), and water content (+80%) compared to controls. Exposed tablets also exhibited a decrease in Cytotec active ingredient dosage (-5.1% after 48 hours) and an increase in the inactive degradation products (+25% for type B, +50% for type A and +11% for 8-epi misoprostol after 48 hours) compared to controls.

Conclusion: Exposure of Cytotec tablets to 'typical' European levels of air and humidity results in significant time-dependent changes in physical and biological composition that could impact adversely upon clinical efficacy. Health professionals should be made aware of the degradation of misoprostol with inappropriate storage of misoprostol tablets.

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Conflict of interest statement

Competing Interests: The authors confirm that Sharon Cameron as well as Kristina Gemzell Danielsson are PLOS ONE Editorial Board members. This does not alter the authors’ adherence to PLOS ONE Editorial policies and criteria. Veronique Berard received funding from a commercial source “Exelgyn” but this does not alter Veronique Berard’s adherence to PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Change over time in medical abortion as percentage of first trimester abortions.
Note below the figure: references regarding figures may be found at the following addresses. Scotland: http://www.isdscotlandarchive.scot.nhs.uk/isd/6207.html; Sweden: http://www.socialstyrelsen.se/statistik/statistikefteramne/aborter; France: http://www.drees.sante.gouv.fr/les-interruptions-volontaires-de-grossesse-en-2011,11149.html; Switzerland: http://www.bfs.admin.ch/bfs/portal/de/index/themen/14/02/03/key/03.html; Finland: www.stakes.fi/; UK: https://www.gov.uk/government/collections/abortion-statistics-for-england-and-wales; Germany: https://www.destatis.de/DE/ZahlenFakten/GesellschaftStaat/Gesundheit/Schwangerschaftsabbrueche/Schwangerschaftsabbrueche.html; Norway: http://www.ssb.no/en/abort; Denmark: http://www.dst.dk/da/; Portugal: http://www.spdc.pt/files/Relatorio_Interrupo_de_gravidez_2012.pdf.
Figure 2
Figure 2. Changes over time in percentage of water content of tablets stored at 25°C/60% RH in comparison with to T0.
The vertical bars represent the 95% confidence interval limits for the measured water levels.
Figure 3
Figure 3. Changes over time in the weight of tablets stored at 25°C/60% RH in comparison with T0.
The vertical bars represent the 95% confidence interval limits for the measured weight variation.
Figure 4
Figure 4. Changes over time in the diameter and thickness of tablets stored at 25°C/60% RH in comparison with T0 over time.
The vertical bars represent the 95% confidence interval limits for respectively the measured diameter variation and the measured thickness variation.
Figure 5
Figure 5. Changes over time in the hardness (A) and friability (B) of tablets stored at 25°C/60% RH in comparison with T0.
The vertical bars represent the 95% confidence interval limits for the measured hardness (A) and friability (B) variation.
Figure 6
Figure 6. Changes over time in the misoprostol concentration of tablets stored at 25°C/60% RH in comparison with T0.
The vertical bars represent the 95% confidence interval limits for the measured content variation.
See this image and copyright information in PMC

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