Stability of misoprostol tablets collected in Malawi and Rwanda: Importance of intact primary packaging

Hagen, Nhomsai; Bizimana, Thomas; Kayumba, Pierre Claver; Khuluza, Felix; Heide, Lutz

doi:10.1371/journal.pone.0238628

Cited by 6 publications

(8 citation statements)

References 23 publications

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“…Blister packaging offers additional protection to tablet and capsule dosage units through prevention of direct contact with atmospheric air, humidity and sunlight; which are the major factors that facilitate the deterioration of medicines on storage [ 37 – 39 ]. Our results provide further evidence on this, as it was found that medicine samples that used blisters for primary packaging were of significantly better quality as compared to those that used bottles for primary packaging.…”

Section: Discussionmentioning

confidence: 99%

Burden of and factors associated with poor quality antibiotic, antimalarial, antihypertensive and antidiabetic medicines in Malawi

et al. 2022

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Objective To assess the prevalence and factors associated with substandard and falsified (SF) medicines among antibiotic, antimalarial, antihypertensive and antidiabetic medicines in Malawi. Methods We conducted a cross-sectional study in 23 public, faith-based and private health facilities in Zomba, Machinga and Nsanje districts. We analyzed oral medicine samples of commonly used medicines among antibiotics, antimalarial, antihypertensive and antidiabetics in accordance with Malawi Essential Medicines List and local treatment guidelines. These medicines were subjected to visual inspection for any defects and screening for the content of active pharmaceutical ingredient and disintegration of dosage units. Samples that failed during screening and at least 10% of those that passed were subjected to pharmacopeia assay and dissolution test for confirmation. We used thin layer chromatography and disintegration test methods provided in the Global Pharma Health Fund minilab® for the screening purposes. We conducted confirmatory test using High-Performance Liquid Chromatography (HPLC) or ultra-violet/visible spectrophotometer and dissolution. Results Of the 293 medicine samples collected, 14.3% were SF medicines. Among the SF medicines were 12.5% of Amlodipine (1/8), 19.2% of Amoxicillin (5/26), 72.2% of Atenolol (8/11), 21.2% of Ciprofloxacin (7/33), 14.3% of Enalapril (1/7), 44.4% of Flucloxacillin (4/9), and 35.7% of sulfadoxine/ pyrimethamine (10/28). Medicine quality was associated with therapeutic medicine class, stated origin of manufacturer, primary packaging material and geographical location. Antimalarial and antidiabetic medicines were of better quality as compared to antibiotics, odds ratio OR 4.2 (95% CI 1.7–9.49), p < 0.002 and OR 5.6 (95% CI 1.21–26.09), p < 0.028 respectively. In terms of stated country of origin, the prevalence of SF medicines was 30% (15/50), 33% (9/27), 26.7% (4/15) and 6.6% (8/122) for medicines stated to be manufactured in Malawi, China, Kenya and India respectively. Conclusion This study presents the first findings on the assessment of quality of medicines since the establishment of the national pharmacovigilance center in 2019 in Malawi. It is revealed that the problem of SF medicines is not improving and hence the need for further strengthening of quality assurance systems in Malawi.

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Section: Discussionmentioning

confidence: 99%

Burden of and factors associated with poor quality antibiotic, antimalarial, antihypertensive and antidiabetic medicines in Malawi

et al. 2022

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“…10 Oxytocin is relatively inexpensive but requires refrigerated storage, electronic infusion pumps, and continuous electronic fetal monitoring by trained staff. [11][12][13] Dinoprostone also needs refrigeration and is more expensive than oxytocin or misoprostol. 8,14 Misoprostol is widely available in many LMICs as quality-assured generic tablets (25, 50, 100, and 200 μg).…”

Section: Introductionmentioning

confidence: 99%

“…Dinoprostone also needs refrigeration and is more expensive than oxytocin or misoprostol 8,14 . Misoprostol is widely available in many LMICs as quality‐assured generic tablets (25, 50, 100, and 200 μg) 11 . Misoprostol is cheaper than dinoprostone and does not require refrigerated storage, making it better‐suited for labor induction in resource‐constrained, high‐volume obstetric settings 8,12,14 …”

Section: Introductionmentioning

confidence: 99%

“…8,14 Misoprostol is widely available in many LMICs as quality-assured generic tablets (25, 50, 100, and 200 μg). 11 Misoprostol is cheaper than dinoprostone and does not require refrigerated storage, making it better-suited for labor induction in resource-constrained, high-volume obstetric settings. 8,12,14 Among the various routes of administration of misoprostol (buccal, oral, sublingual, vaginal), the oral and vaginal routes are commonly used.…”

Section: Introductionmentioning

confidence: 99%

“…The commonest induction method used in many low‐ and middle‐income countries (LMICs) in Africa and Asia when the cervix is favorable is oxytocin infusions following amniotomy 10 . Oxytocin is relatively inexpensive but requires refrigerated storage, electronic infusion pumps, and continuous electronic fetal monitoring by trained staff 11–13 . Dinoprostone also needs refrigeration and is more expensive than oxytocin or misoprostol 8,14 .…”

Section: Introductionmentioning

confidence: 99%

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The efficacy and safety of 25 μg or 50 μg oral misoprostol versus 25 μg vaginal misoprostol given at 4‐ or 6‐hourly intervals for induction of labour in women at or beyond term with live singleton pregnancies: A systematic review and meta‐analysis

Yenuberi

Mathews

Cherian

et al. 2023

Intl J Gynecology & Obste

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BackgroundMisoprostol is widely used for cervical ripening and labour induction as it is heat‐stable and inexpensive. Oral misoprostol 25 μg given 2‐hourly is recommended over vaginal misoprostol 25 μg given 6‐hourly, but the need for 2‐hourly fetal monitoring makes oral misoprostol impractical for routine use in high‐volume obstetric units in resource‐constrained settings.ObjectivesTo compare the efficacy and safety of oral misoprostol initiated at 25 or 50 μg versus 25 μg vaginal misoprostol given at 4‐ to 6‐hourly intervals for labor induction in women at or beyond term (≥ 37 weeks) with a single viable fetus and an unscarred uterus.Search StrategyWe identified eligible randomized, parallel‐group, labor‐induction trials from recent systematic reviews. We additionally searched PubMed, Cochrane CENTRAL, Epistemonikos, and clinical trials registries from February 1, 2020 to December 31, 2022 without language restrictions. Database‐specific keywords for cervical priming, labor induction, and misoprostol were used.Selection CriteriaWe excluded labor‐induction trials exclusively in women with ruptured membranes, in the third trimester, and those that initiated misoprostol at doses not specified in the review's objectives. The primary outcomes were vaginal birth within 24 h, cesarean section, perinatal mortality, neonatal morbidity, and maternal morbidity. The secondary outcomes were uterine hyperstimulation with fetal heart rate changes, and oxytocin augmentation.Data Collection and AnalysisTwo or more authors selected studies independently, assessed risk of bias, and extracted data. We derived pooled weighted risk ratios with 95% confidence intervals (CIs) for each outcome, subgrouping trials by the dose and frequency of misoprostol regimens. We used the I2 statistic to quantify heterogeneity and the random‐effects model for meta‐analysis when appropriate. We used the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach to assess certainty (confidence) in the effect estimates.Main ResultsThirteen trials, from Canada, India, Iran, and the US, randomizing 2941 women at ≥37 weeks of gestation with an unfavorable cervix (Bishop score <6), met the eligibility criteria. Five misoprostol regimens were compared: 25 μg oral versus 25 μg vaginal, 4‐hourly (three trials); 50 μg oral versus 25 μg vaginal, 4‐hourly (five trials); 50 μg followed by 100 μg oral versus 25 μg vaginal, 4‐hourly (two trials); 50 μg oral, 4‐hourly versus 25 μg vaginal, 6‐hourly (one trial); and 50 μg oral versus 25 μg vaginal, 6‐hourly (two trials).The overall certainty in the evidence ranged from moderate to very low, due to high risk of bias in 11/13 trials (affecting all outcomes), unexplained heterogeneity (1/7 outcomes), indirectness (1/7 outcomes), and imprecision (4/7 outcomes).Vaginal misoprostol probably increased vaginal deliveries within 24 h compared with oral misoprostol (risk ratio [RR] 0.82, 95% CI 0.70–0.96; 11 trials, 2721 mothers; moderate‐certainty evidence); this was more likely with 4‐hourly than with 6‐hourly vaginal regimens. The risk of cesarean sections did not appreciably differ (RR 1.00, 95% CI 0.80–1.26; 13 trials, 2941 mothers; very low‐certainty evidence), although oral misoprostol 25 μg 4‐hourly probably increased this risk compared with 25 μg vaginal misoprostol 4‐hourly (RR 1.69, 95% CI 1.21–2.36; three trials, 515 mothers). The risk of perinatal mortality (RR 0.67, 95% CI 0.11–3.90; one trial, 196 participants; very low‐certainty evidence), neonatal morbidity (RR 0.84, 95% CI 0.67–1.06; 13 trials, 2941 mothers; low‐certainty evidence), and maternal morbidity (RR 0.83, 95% CI 0.48–1.44; 6 trials; 1945 mothers; moderate‐certainty evidence) did not differ appreciably. The risk of uterine hyperstimulation with fetal heart rate changes may be lower with oral misoprostol (RR 0.70, 95% CI 0.52–0.95; 10 trials, 2565 mothers; low‐certainty evidence). Oxytocin augmentation was probably more frequent with oral compared with vaginal misoprostol (RR 1.29, 95% CI 1.10–1.51; 13 trials, 2941 mothers; moderate‐certainty evidence).ConclusionsLow‐dose, 4‐ to 6‐hourly vaginal misoprostol regimens probably result in more vaginal births within 24 h and less frequent oxytocin use compared with low‐dose, 4‐ to 6‐hourly, oral misoprostol regimens. Vaginal misoprostol may increase the risk of uterine hyperstimulation with fetal heart changes compared with oral misoprostol, without increasing the risk of perinatal mortality, neonatal morbidity, or maternal morbidity. Indirect evidence indicates that 25 μg vaginal misoprostol 4‐hourly may be more effective and as safe as the recommended 6‐hourly vaginal regimen. This evidence could inform clinical decisions in high‐volume obstetric units in resource‐constrained settings.

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Development and validation of a stability‐indicating method, structural elucidation of new degradation products from misoprostol by LC–MS time‐of‐flight, and an ex vivo study of vaginal permeation

da Silva,

Duarte,

Ribeiro

et al. 2024

Biomedical Chromatography

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Misoprostol (MSP) is commonly prescribed in obstetrics and gynecology clinical practice for labor induction, cervical ripening, first‐trimester pregnancy termination, and the treatment of postpartum hemorrhage. Furthermore, there is a lack of comprehensive discussion evaluating how different commercially available formulations influence the overall efficacy of MSP, even though reports indicate issues with the quality of these formulations, particularly regarding stability and vaginal absorption processes. This study investigates the stability of MSP under acidic conditions and its in vitro permeation using swine vaginal mucosa. A forced degradation study was conducted using 0.2 M HCl, and a high‐efficiency LC method was developed. Three degradation products were identified and characterized using electrospray ionization–high‐resolution quadrupole‐time‐of‐flight–MS, with respective m/z values of 391.2508, 405.2705, and 387.2259, respectively. These results suggest that the degradation mechanism involves dehydration of the β‐hydroxy ketone moiety, followed by isomerization to its most resonance‐stable form and de‐esterification. Finally, the in vitro permeation study revealed that the esterified form of MSP was unable to permeate the mucosa and required prior degradation for any component to be detected in the receptor fluid.

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Stability of misoprostol tablets collected in Malawi and Rwanda: Importance of intact primary packaging

Cited by 6 publications

References 23 publications

Burden of and factors associated with poor quality antibiotic, antimalarial, antihypertensive and antidiabetic medicines in Malawi

Burden of and factors associated with poor quality antibiotic, antimalarial, antihypertensive and antidiabetic medicines in Malawi

The efficacy and safety of 25 μg or 50 μg oral misoprostol versus 25 μg vaginal misoprostol given at 4‐ or 6‐hourly intervals for induction of labour in women at or beyond term with live singleton pregnancies: A systematic review and meta‐analysis

Development and validation of a stability‐indicating method, structural elucidation of new degradation products from misoprostol by LC–MS time‐of‐flight, and an ex vivo study of vaginal permeation

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