Instability of Misoprostol Tablets Stored Outside the Blister: A Potential Serious Concern for Clinical Outcome in Medical Abortion

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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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Most cited references 11

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Absorption kinetics of misoprostol with oral or vaginal administration.

N Benowitz, M Zieman, Stephen Fong … (1997)

To compare the pharmacokinetics of vaginal and oral administration of the prostaglandin E1 analogue, misoprostol. Twenty women received 400-micrograms doses of misoprostol either orally or as tablets placed in the vagina. Serum levels of principal metabolite, misoprostol acid, were measured at 7.5, 15, 30, 45, 60, 90, 120, and 240 minutes. The first ten women were pregnant and undergoing first-trimester abortions, and the last ten were not pregnant and had additional blood sampling at 360 minutes. We compared the pharmacokinetics of misoprostol acid after oral and vaginal administration. All 20 subjects completed the study. The maximum mean (+/- standard deviation [SD]) of misoprostol acid differed significantly between the oral and vaginal groups (277 +/- 124 compared with 165 +/d- 86 pg/mL, respectively; P = .03, analysis of variance), as did the mean +/- SD time to peak levels (34 +/- 17 compared with 80 +/- 27 minutes, respectively; P < .001) and areas under the misoprostol concentration versus time curve (mean +/- SD) up to 4 hours (n = 20,273.3 +/- 110.0 compared with 503.3 +/- 296.7 pg.hour/mL, respectively; P = .033) and up to 6 hours (n = 10, 300.0 +/- 103.3 compared with 956.7 +/- 541.7 pg.hour/mL, respectively; P = .029). The extent of absorption was highly variable among subjects in each group. There are significant differences in the pharmacokinetics of misoprostol administered by vaginal and oral routes that may explain the difference observed in clinical efficacy. Assuming that the pharmacologic effect of misoprostol is related to its concentration in the plasma, our observation of the prolonged serum concentrations in the vaginal group suggests that vaginal administration could be dosed at longer intervals than oral.

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Comparison between oral and vaginal administration of misoprostol on uterine contractility.

Iris Wong, L Marions, S Bygdeman … (1999)

To compare the degree of absorption and the effect on uterine contractility of the prostaglandin E1 analogue misoprostol after vaginal and oral administration. Thirty women with a normal intrauterine pregnancy between 8 and 11 weeks' gestation who requested termination of pregnancy were given either 0.2 mg (orally n = 5; vaginally n = 6) or 0.4 mg (orally n = 10; vaginally n = 9) of misoprostol. Intrauterine pressure was recorded using a Grass polygraph connected to a pressure transducer 30 minutes before misoprostol was given and for 4 hours thereafter. At the end of the recording, suction curettage was performed. Blood samples were obtained at 0, 0.5, 1, 2, 4, and 6 hours for measurement of misoprostol, which was assayed by high-pressure liquid chromatography-mass spectrometry. In all patients, the first effect was an increase in uterine tonus. After 0.4 mg of misoprostol administered orally, uterine tonus started to increase after a mean (+/- standard deviation) time of 7.8+/-3.0 minutes and reached its maximum after 25.5+/-5.0 minutes. The corresponding times after vaginal administration were 20.9+/-5.3 minutes and 46.3+/-20.7 minutes, respectively. The initial increase in tonus was also more pronounced after oral than after vaginal administration. After vaginal administration, all patients developed uterine contractions; the activity, measured in Montevideo units, increased continuously during the observation period. This was not the case after oral administration. Plasma levels of misoprostol were measured in 18 patients. The highest levels were found 30 minutes after oral treatment and 1-2 hours after vaginal administration. The long-lasting and continuously increasing uterine contractility after vaginal administration can be explained only in part by a direct effect of misoprostol. The longer period of elevated plasma levels of misoprostol may also have initiated the prolonged events leading to increased uterine contractility.

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Medical abortion regimens: historical context and overview.

Mitchell Creinin (2000)

Medical abortion offers an important alternative to surgical abortion for women with early pregnancies who wish to avoid a surgical procedure. More than 3 million women worldwide have had medical abortions in the past decade alone. The best-studied regimens include mifepristone orally followed 36 to 48 hours later by a prostaglandin analog administered either orally or intravaginally. Because of political and social restrictions related to mifepristone, however, researchers have investigated alternative regimens, most notably methotrexate and misoprostol. Mifepristone regimens are approximately 95% effective for abortion at

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Author and article information

Contributors

Shannon M. Hawkins: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 15 December 2014

Volume: 9

Issue: 12

Electronic Location Identifier: e112401

Affiliations

[1 ]ICB - CNRS, Division MaNaPI, Département Nanosciences, Université de Bourgogne, Dijon, France

[2 ]Gynmed Clinic, Vienna, Austria

[3 ]Chalmers Centre, NHS Lothian, Edinburgh, Scotland

[4 ]Obstetric Service, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal

[5 ]San Filippo Neri Hospital, Rome, Italy

[6 ]Department of Women’s and Children’s Health, Division of Obstetrics and Gynecology, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden

Baylor College of Medicine, United States of America

Author notes

* E-mail: vberard@ 123456u-bourgogne.fr

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.

Conceived and designed the experiments: VB. Performed the experiments: VB. Analyzed the data: VB CF KG. Contributed reagents/materials/analysis tools: VB. Wrote the paper: VB CF SC KG. Contributed to appraising the manuscript: MP TB.

Article

Publisher ID: PONE-D-14-03678

DOI: 10.1371/journal.pone.0112401

PMC ID: 4266501

PubMed ID: 25502819

SO-VID: bf09ecf6-d3b8-45e3-834f-e3d101c0029d

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 24 January 2014

Date accepted : 15 October 2014

Page count

Pages: 13

Funding

VB, CF, SC, TB, KG, MP received honoraria from Exelgyn for participating in an independent expert board. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Instability of Misoprostol Tablets Stored Outside the Blister: A Potential Serious Concern for Clinical Outcome in Medical Abortion

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Abstract

Introduction

Objective

Methods

Results

Conclusion

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PLOS: COVID-19 pandemic

Most cited references 11

Absorption kinetics of misoprostol with oral or vaginal administration.

Comparison between oral and vaginal administration of misoprostol on uterine contractility.

Medical abortion regimens: historical context and overview.

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