Analysis of patient information leaflets on Artemisinin-based combination therapy

The objective of this research was to analyze the various patient information leaflets on Artemisininbased combination therapy (ACTs) sold in Côte-D’Ivoire. A descriptive cross-sectional study was conducted from January 1st to February 20th, 2016, that included all patient information leaflets relating to ACTs registered and marketed in Côte-d’Ivoire. The leaflets were compared to European standards of writing summaries of product characteristics, by focusing particularly on side effects. Regarding artemether-lumefantrine, all leaflets mentioned digestive disorders. As far as endocrine and metabolic systems are concerned, appetite loss and anorexia were outlined in 28.5% and 42.8% of leaflets examined. With regard to skin and annexes, we noticed: rash (100%), pruritus (90%), slate-gray pigmentation (28%) and redness of the face (14%). Finally, only Plasmocid® and Coartem® leaflet reported biological side effects. Regarding artesunate-amodiaquine, side effects involving blood were outlined: agranulocytosis (60%), blood dyscrasia and leucopenia (40%), along with hemolytic anaemia (20%). Side effects affecting gastrointestinal system were nauseas, vomiting and diarrhoea (80%), hepatitis (60%) and fatal hepatitis (20%). Side effects affecting the nervous system include peripheral neuropathy (80%) and extrapyramidal syndrome (20%). Regarding information from pharmaceutical companies differing from one specialty to another for the same molecule, it would be desirable that they harmonize the patient information leaflets contents.


INTRODUCTION
The Ministry of Health and Population of Ivory Coast, since January 2007 has adopted a new treatment protocol for malaria by a Ministerial Order No. 024/CAB cases of hepatonephritis and blackwater fever have been reported following the use of antimalarials.That led to a psychosis among population.A working committee has been put in place in the Health Ministry to investigate these cases.Epidemiological and pharmacovigilance surveys were conducted.Hepatonephritis was a new and serious life-threatening event.The role of antimalarials, in particular ACTs, in the occurrence of these serious adverse effects has been highlighted (Bodi et al., 2014;Guevart, 2009;Kamagate, 2004).Factors identified were misuse, short and repeated therapeutic sequences.This situation was related to the lack of knowledge of the tolerance profile of the products by the population and health professionals (Bakayoko, 2009).Although the benefit/risk ratio is always favorable, these serious side effects are mostly preventable and therefore unacceptable.So information or population's training and health professional awareness are useful and crucial.The working committee then deemed it necessary to assess the benefit provided by these substances as against the risk involved.The summary of product characteristics or the patient information leaflet for drug seemed to be a reliable source of data that could provide useful safety and security information.This leaflet is exhaustive and provide clinical, pharmacological and pharmaceutical data according to European standard, adopted by Côted'Ivoire.The European standard provides data on efficiency, tolerance profile, security and quality of use.It should also guarantee the authenticity of the products through its administrative information.The objective of this study, was to analyze the information of the package leaflets of the various ACTs marketed in Cote-d'Ivoire to appreciate this information's quality.

MATERIALS AND METHODS
This descriptive cross-sectional study was conducted from January 1 st to February 20 th , 2016 in ten pharmacies or drugstores selected in the ten municipalities of Abidjan.In this study, any patient information leaflets of ACTs, sulfadoxine/pyrimethamine and quinine were included.The leaflets examined concerned drugs registered and sold in Côte d'Ivoire until 2015.These products also had to be available in drugstores.The selected drugstores were randomised.The study was conducted in the private drugstores mentioned above only with the prior agreement of the pharmacist in charge.The work consisted of collecting and analyzing the various information of the package leaflets written by the pharmaceutical companies on antimalarial drugs, particularly ACTs.The data were collected with record form that consisted of three parts: 1-General data on the active ingredient; 2-Data on the form of the leaflet ; and 3-General information on drugs.This information included indication, dosage, warnings and cautions, interactions, pharmacodynamics and pharmacokinetics, side effects, contraindications and other administrative information.The collected leaflets were analysed by comparing to the European model for drafting the Summaries of Product Characteristics (SmPC) (Table 1).
We emphasized on information regarding the pharmacovigilance of ACTs (under side effect section), therapy (indication, contraindication, dosage, warnings and cautions for use), pharmacokinetics and pharmacodynamics (pharmacokinetic, pharmacodynamics, interaction sections).

Form of the patient information leaflets
About 20 leaflets were collected which showed that the European standard plan concerning the drafting of information in package leaflets was not followed in 85% of cases (Table 2).
With regard to the missing headings, in 80% of the cases, the preclinical safety and incompatibility headings were not mentioned.Also, in 70% of cases, the heading pharmacokinetics were missing (Table 3).

Substance or heart of the patient information leaflets
The antimalarial indication in the leaflets was curative in 95% of cases and prophylactic in 5% of cases.This indication of the antimalarial was not mentioned for adults in 20% of cases, for children in 25% of cases and for infants in 60% of cases.In 65% of cases, the daily dosage according to weight of child was not mentioned.However, 4 of the 5 leaflets of artesunate-amodiaquine mentioned it.In most of the cases, the following criteria were missing in the leaflet: ATC classification (anatomical, therapeutic and clinical), metabolites causing enzymes and severity and frequency of adverse effects.The side effect profile for different antimalarial drugs was different.Concerning artemether-lumefantrine (Table 4), digestive disorders have been mentioned in all specialties.The metabolic and endocrine adverse effects described were either a loss of appetite (28.57%) or anorexia (42.86%).Two package leaflets (Plasmocid® and Laritem®) did not mention metabolic and endocrine effects.The Laritem® and Artefan® leaflets described most of the neurological side effects (88%) followed by the Plasmocid® leaflets (66%).In most of the cases, headache.The package leaflets of Artrine®, Lufanter®, Bimalaril®, and Coartem® have almost no neurological side effects mentioned (Table 4).Regarding the side effects affecting the skin by artemether-lumefantrine, the most commonly mentioned side effects were skin rash (100%) and pruritus (85%).The redness of the face and the slate pigmentation were rarely mentioned (14 and 28%, respectively).
Regarding adverse effects affecting the immune system, hypersensitivities were the most mentioned (60%), followed by angioedema (40%).Biological side effects were only mentioned in leaflet of Plasmocid® and Coartem® (Table 4).
Regarding seven antimalarials containing artesunateamodiaquine (Table 5), Artepal's leaflet described 75% of side effects relating to blood.It was agranulocytosis, blood dyscrasia, and leukopenia.Artediam®'s leaflet mentioned a deadly agranulocytosis.Adverse effects relating to blood had not been mentioned in Camoquin's package leaflet.Damage affecting the gastrointestinal system has often been mentioned in Camosunate® and Coarsucam® leaflets.The majority of neurological side effect was mentioned in the Camoquin plus® and Coarsucam® leaflets.The most mentioned adverse effects were peripheral neuropathies (57%) followed by dizziness (28%) and neuromyopathy (28%).Skin damages have been mentioned: pruritus (40%), skin rash (60%) and slate pigmentation (40%).Camosunate® and Coarsucam® package leaflets did not mention any adverse effects relating to the skin.General adverse effects like asthenia and weakness were mentioned only in the package leaflet of Camoquin plus®.Ophthalmological disorders were most often described in the package leaflet of Artediam® and Camoquin plus®.Biological disorders have been mentioned maximally in the package leaflet of Coarsucam®.The most common disorders were the drop in reticulocyte count (100%) and the transient increase in transaminases (100%).
Well described quinine adverse effects were relating to blood, metabolic and endocrine, nervous and skin systems.Side effects relating to cardiovascular and general systems have been poorly described (Table 6).

DISCUSSION
The lack of references in this area made it impossible to confront the findings.It is a princeps work for better understanding of drug security data for the public.This study revealed that records were easily readable, clearly written and easily usable.This measure is intended to avoid any negligence on the part of pharmaceutical companies and aims to protect a sensitive and fragile population: the elderly, the sick, pregnant women who may have impaired understandings and who may find themselves in difficulty due to a mistake in dosage (article 49 de la directive 2004/24/CE).This work showed a lack of information both in the form and in the substance (L'Expert Econome, 2018;Bandello and D'Addario, 2015).The writing plan of the leaflet was not followed for most of them (85% of the cases).In fact, the package leaflets of artesunate-amodiaquine, dihydroartemisinpiperaquine, artesunate-sulphamethopyrazinepyrimethamine, dihydroartemisine-piperaquinetrimethoprim and sulphadoxine-pyrimethamine were not in conformity with the European Plan for writing package leaflets.Those of artemether-lumefantrine and quinine were also non-compliant in 71.4% of cases.This constitutes a breach from the legal point of view in Cote d'Ivoire.Two to eight sections were missing.It was most often: preclinical safety, incompatibility, pharmacokinetics, pharmacodynamics, overdose, interactions and effects on ability to drive and use machines.This would be an information bias on safety and tolerance.The most often listed sections were general information (denomination, galenic form, presentation and composition) and clinical data (indication, posology and method of administration, contraindications, side effects).These sections remain important for informing about the security of use of medicines to the general public.On the other hand, pharmacological data were missing in most of the cases.The pharmaceutical information given is limited to the conditions of conservation.The administrative information (+) information mentioned and (-) information not mentioned.given is limited to the identification of the pharmaceutical companies.Notable missing information could therefore be observed in the leaflet.Indeed, the sections outlined were not sufficient enough to allow patients, assess the benefit-risk ratio of the prescribed drug.Sections for assessing risk, such as preclinical safety, interactions, overdose, incompatibility and cautions for use were missing (Table 2).The cautions for use section, would make it possible to take steps to avoid or lessen the adverse drug reactions of drugs.Apart from quinine and sulfadoxine-pyrimethamine, most medications were contraindicated during pregnancy and in infants.However, it can be noted that these important pregnancy and breastfeeding sections were missing.
In the leaflets examined, most of the adverse drug reactions mentioned were benign: gastrointestinal, neurological, and cutaneous.However, in the literature, serious adverse drug reactions have been observed with antimalarials.Serious haematologic effects like blackwater fever and epidermolysis have been noted with sulfadoxine-pyrimethamine and artemether-lumefantrine.These progressed to kidney failure in 80-90% of cases.The mortality rate was 15-30% (Daubrey-Potey et al., 2004b;Hasegawa et al., 2018;Huggan et al., 2018;Olupot-Olupot, et al, 2017;Sweetman, 2007).There were also rare neurological adverse effects like orofacial dyskinesias observed with amodiaquine in children and adults.The onset occurred within 2 days after stopping the drug (Daubrey-Potey et al., 2004a;Kamagate et al., 2004).Hepatitis and fulminant hepatitis have been related to artesunate or to artesunate-amodiaquine.Generally, they were of the cytolytic type (Guevart et al., 2009;Roussel et al., 2017).In addition, recent and new fatal cases of hepatonephritis coinciding with the antimalarial use (in particular ACTs) have been described in several Ivorian pharmacovigilance surveys.The onset occurred within 3 days; with an observed recrudescence of cases in the rainy season when malaria is raging (Bakayoko, 2009;Die-Kakou et al., 2009, 2010;Kamagate et al., 2017).In the leaflets examined, none of these effects have been mentioned.This could be related to the fact that the adverse drug reactions described in the leaflets were the effects observed during precommercialization clinical trials of these drugs and without post-commercialization safety data.Since clinical trials are only performed with a limited number of patients, it could be understood why these serious effects with low prevalence were not observed (Organisation mondiale de la sante -OMS, 2004).After commercialization, the consumption of these drugs on a larger scale, allowed the observation of these hepatonephritis and other serious adverse effects.Unlike the SmPC that are regularly updated with pharmacovigilance data, that of the package leaflets seems to be rarely updated.In addition, the severity and frequency of adverse drug reactions were most often not mentioned in the leaflets, leaving the patient in a state of complete ignorance.This could be judged as an ethical problem.
Finally, a disparity in the information provided by different pharmaceutical companies could be observed, for the same active substance.This was the case of serious adverse drug reactions of amodiaquine.Indeed, according to the specialties, they were found or not in the leaflets.These included agranulocytosis, haemolytic anaemia, and sometimes fatal hepatitis (Sweetman, 2007).

Conclusion
In this work, the package leaflets of ACTs sold in Cote d'Ivoire have been analysed.The analysis concerned both the substance content and the form of the leaflets.Majority of leaflets did not comply with the European Plan for writing leaflets.In addition, the information provided by the pharmaceutical companies differed from one specialty to another, for the same active molecule.This is detrimental to the patient.It would therefore be desirable for the regulatory authorities to ask the pharmaceutical companies to harmonize the content of the different leaflets.

Table 1 .
European model of summary of product characteristics.

Table 2 .
Accordance of pharmaceutical leaflet with European Plan.

Table 6 .
Adverse effects of quinine.