Senegal is a West African country, with a population of approximately 12,141,673 inhabitants (2010). Malaria is endemic with a high transmission season between July and November. The entire country’s population is at risk of malaria.
Malaria case management is integrated into primary health services. Health services are provided nationwide through 75 health districts, which cover 78 district hospitals and 1,018 health posts. Implementation of the pharmacovigilance system involves all public health facilities. Between April 2006 and June 2009, artesunate + amodiaquine (AS + AQ) in a co-blister was used to treat uncomplicated malaria. In July 2009, co-blisters were replaced by fixed dose artesunate-amodiaquine (AS-AQ fixed dose). Drugs cost 0.6 US$ per course for adults and 0.3 US$ per course for children during the period covered by the study.
The treatment was administered once a day for three days using the following drugs:
Between April 2006 and June 2009: AS + AQ in co-blistered or Falcimon® (Cipla, India). It contains 50 mg of AS per tablet and 153 mg AQ base per tablet. The recommended doses were 4 mg/kg/day for AS and 10 mg/kg/day for AQ. The product was available in three formulations: three AS tablets and three AQ tablets for children 0–6 years, six AS tablets and six AQ tablets for children 6–13 years and 12 AS tablets and 12 AQ tablets for adults ≥ 14 years.
From July to December 2009: AS-AQ fixed-dose co-formulation or ASAQ Winthrop® (Sanofi-Aventis). There were four different formulations: AS 25 mg and AQ base 67,5 mg tablets for children 2–11 months; AS 50 mg and AQ base 135 mg tablets for children 1–5 years; and AS 100 mg and AQ base 270 mg tablets for children 6–13 years (three tablets) and for adults ≥ 14 years (six tablets).
This study was conducted countrywide and patients have been reported by public health facilities located in different regions in Senegal. All patients who received partial or full treatment of ACT and who presented ADEs which had been reported by health providers, were enrolled in the study.
This study is a retrospective analysis of ADEs cases related to ACT as self-reported by patients at health facilities during a period of three years.
Data collection and analysis
Data were collected by health workers using the standard ADEs reporting form developed by the Ministry of Health. Collected data were:(i) the patient (age, sex, identification number, antecedents, risk factor), (ii) all the drugs used by the patients (names, dose, dosage form, route, start/stop dates), (iii) the adverse reactions presented by the patient (date of onset, symptoms and signs, evolution), (iv) and the reporter (name, address, telephone, email).
When an ADE was diagnosed, the health worker filled the standard form and sent it out to the NMCP focal point for case management and pharmacovigilance through the District Health Officer. All forms were checked and validated, including telephoning the reporter if necessary. In all cases a letter was sent to the reporter to acknowledge receipt of the form.
After validation the forms were sent to the National Centre of Pharmacovigilance (Centre Antipoison) for causality analysis. Afterwards all reported cases and causality results were recorded in the NMCP pharmacovigilance database using Microsoft® Excel programme.
The seriousness of the ADEs
Intensity of events was defined using the Moroccan pharmacovigilance centre grades, which identifies three grades of intensity: serious, severe and mild . Serious: a serious adverse event was defined as one that was fatal, life-threatening, caused or prolonged hospital admission, caused persistent incapacity or disability, or caused congenital anomaly. Severe: ADE not serious, but drugs must be discontinued and an additional treatment initiated. Mild: minor symptoms, neither serious nor severe
This is the relationship between the ADEs and the ACT. Causality was determined using the WHO method. The WHO causality categories benefit from long and extensive use and have the advantage of being internationally agreed and easy to use. The WHO method has six causality categories . Causality assessment was performed on a daily basis by a team which includes a medical doctor, a pharmacist and a pharmacologist. Each quarter the results are reviewed and endorsed by the pharmacovigilance technical committee. An annual report is prepared and presented by the technical committee to the National Pharmacovigilance Advisory Committee, which involves all stakeholders.
The WHO causality categories are: (1) Certain: clinical event occurring in a plausible time relationship to drug administration, which cannot be explained by concurrent disease or other drugs of chemicals. The response to withdrawal of the drugs (dechallenge) should be clinically plausible. Finally, the event must be definitive pharmacologically or phenomenologically, using a satisfactory rechallenge procedure if necessary. (2) Probably/Likely: clinical event with a reasonable time sequence to administration of the drug; unlikely to be attributed to concurrent disease or other drugs or chemicals, which follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge information is not required to fulfil this definition. (3) Possible: clinical event, with a reasonable time sequence to administrations of the drug, but which could also be explained by concurrent disease or other drugs or chemicals. Information on drug withdrawal may be lacking or unclear. (4) Unlikely: Clinical event with a temporal relationship to drug administration which makes a causal relationship improbable, and in which other drugs, chemicals or underlying disease provide plausible explanations. (5) Conditional/Unclassified: Clinical event, reported as an adverse reaction, about which more data is essential for a proper assessment, or the additional data is under examination. (6) Unassessable/Unclassifiable: a report suggesting an adverse reaction which cannot be judged because information is insufficient or contradictory, and which cannot be supplemented or verified.
Data analysis was done using Stata 11. Age was treated as a categorical variable using strata. In addition age and appearance of ADEs were summarized as means. Other socio-demographic variables and safety indicators were presented as frequencies and percentages. Incidence of ADEs was calculated using the number of treatment distributed per year. Lastly signs and symptoms have been classified on the basis of the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) .
This intervention was administered by the Ministry of Health and included in the routine work of health workers according to its malaria policy. Institutional Review Board clearance was not required.