Research Article: Post-licensure safety evaluation of dihydroartemisinin piperaquine in the three major ecological zones across Ghana

Date Published: March 30, 2017

Publisher: Public Library of Science

Author(s): Abraham R. Oduro, Seth Owusu-Agyei, Margaret Gyapong, Isaac Osei, Alex Adjei, Abena Yawson, Edward Sobe, Rita Baiden, Martin Adjuik, Fred Binka, Thomas L Richie.

http://doi.org/10.1371/journal.pone.0174503

Abstract

Uncommon and rare adverse events (AEs), with delayed onset may not be detected before new drugs are licensed and deployed. The present study examined the post licensure safety of dihydroartemisinin-piperaquine (DHP) as an additional treatment for malaria in Ghana. The relationship between the incidence of AEs, treatment completion rate, participant characteristics and concomitant medications are reported.

A study conducted from September 2013 to June 2014 in Navrongo, Kintampo and Dodowa health research centres in Ghana is presented. Participants had confirmed malaria and no known allergy to study drug. Patients provided informed consent and had their symptoms and results of their clinical examinations documented. Treatment with Eurartesim® (20/160mg dihydroartemisinin and 40/320mg piperaquine by Sigma-Tau Incorporated) was given, according to the body weight of patients. First treatment doses were under observation but the second and third doses were taken at home except in a sub-study involving a nested cohort. Patients were contacted at Day 5 (± 2 days) either on telephone or by a home visit to document any AEs experienced. Patients were asked to report to the study team any other AEs that occurred within 28 days post-treatment. All patients in the nested cohort had electrocardiogram (ECG).

A total of 4563 patients, 52.1% females and 48.2% <6 years completed the study. A total of 444 patients were enrolled into the nested cohort. About 33% had temperature ≥ 37.5°C at enrolment. Approximately 3.4% reported taking prior antimalarials, 19.4% other medications and 86% took at least one concomitant medication. Incidence of AEs was 7.6% including infections (4.6%), gastrointestinal disorders (1.0%) and local reactions at the site of venesection (0.5%). Others were respiratory disorders (0.4%) and nervous system disorders (0.3%). There were nine adverse events of special interest (AESI); itching/pruritus (7), dizziness (1), and skin lesions (1). Patients who took medications prior to enrolment had higher incidence of AEs compared with those without (9.3% vs. 6.1%; P<0.001). Statistically significant associations were found between the reported AEs and age of patients (P<0.001), their body mass index (BMI) (P< 0.001) and parasite densities (P< 0.001). Dihydroartemisinin-Piperaquine was well tolerated with no serious safety concerns identified. Obesity and prior enrolment medication were among significant factors associated with increased AEs reporting.

Partial Text

Systematic clinical studies in human volunteers are often carried out in order to discover the effects of new medicinal products [1, 2]. Sometimes, these new medicinal products are developed and introduced in populations on the premise that the individual and community benefits justify it. However, uncommon and rare adverse events (AEs) with delayed onset are usually not detected before such new products are deployed into the general population for widespread use [3]. Significant subpopulations with underlying medical conditions are often excluded in clinical trials but get exposed to these new products once they are introduced into the public health system [3, 4]. When new medicinal products are introduced for use in the general population, recipients are no longer critically monitored for AEs as in clinical trials. Factors such as sample size, participants’ selection, follow-ups and surrogate endpoints often limit the generalizability of findings from clinical trials. Moreover, due to health system challenges, when large numbers of the population are exposed to new medicinal products, there can be an exaggerated emergence of AEs that may undermine the usefulness of such new products [5–7]. Besides, conditions and reasons for safety monitoring may change following routine use of new medicinal products in the public health system [8, 9]. Thus, post-licensure surveillances are carried out to expand the evidence base of the characteristics of new products for which licensure has been granted [8–10].

The study determined additional safety data on DHP as a first line treatment for uncomplicated falciparum malaria in Ghana and the capacity of the three sites to undertake post-licensure surveillance of new medicinal products [12].

This study has added additional safety data to show that DHP is safe even in challenged and post licensure settings. No significant serious AEs or ASEI were documented. The findings indicate that in rural settings, obese patients and pre-enrolment medication were the significant factors associated with AEs. This study demonstrated the capacity of the three research sites to undertake phase four studies to detect rare AEs of new drugs over a much larger patient population. Further technical support and collaboration will enable the sites to conduct similar studies for other drugs and vaccines across Ghana and beyond.

 

Source:

http://doi.org/10.1371/journal.pone.0174503

 

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