Signal Management of Disproportionate Reporting in Moroccan Pharmacovigilance: The Lower Limb Edema Induced by Anti-Tuberculosis Drugs

Objective: To detect and validate new signals in Pharmacovigilance of a combined anti-TB drug ERIP-K4. Methods: It was a prospective study (October 2012-December 2013), conducted in majority Moroccan TB Diagnosis Centers (MTDC). All TB patients admitted to these MTDC and presented ADRs were eligible for inclusion in the study during this period. Each ADR notified was handled by the WHO accountability method and sent to the international database (Vigibase). The detection of signals was based on 3 statistical methods measuring disproportionality of reporting of combined anti-TB form (ERIP-K4) induced ADRs: the information component (IC), the proportional reporting ratio (PRR), and the reporting odds ratio (ROR). Results: 927 ADRs were reported during the study. The average age of patients was 40.7 ± 17.5 years with a sex ratio of 0.8. Adverse drug reactions of skin and appendages disorders predominated (24.2%), followed by ADRs of gastrointestinal system disorders (21%) and ADRs of liver and biliary system disorders (14.5%). From 11 signals, a new signal never described in our database: edema of the lower limbs which disproportionate scores (IC, PRR, ROR) were (2.03, 7.5, 7.9). Conclusion: Edemas of the lower limbs are a potential signal in Pharmacovigilance requiring more investigations to argue well the relation of cause and effect and to find risk factors to manage and avoid these effects. Journal of Pharmacovigilance Jo ur na l of Pharmacoilance


Introduction
Tuberculosis (TB) is a major public health worldwide scourge. Clinicians that treat TB patients are familiar with these medications and their adverse reactions (ADRs) [1]. These ADRs are frequent because the treatment is long and patients taking multiple medications simultaneously. This increases the likelihood of adverse reactions, some of which are serious. A recent study showed that two-thirds of patients with resistant form of TB at least once stopped treatment temporarily or permanently following the occurrence of adverse effects [2]. These events may diminish public confidence in a structured health program and affect the adhesion of relevant patient for the success of a program [3,4]. Patients who do not properly adhere to their TB treatment pose a risk to themselves and to others, and the generation of TB resistance is a serious risk because the treatment is complex and exposes many serious ADRs.
In spite of public health programs (PHPs) are supported by the Ministry of health, the risk of occurrence of ADRs are important because all vulnerable population is concerned such as the young, the elderly, pregnant women and malnourished. In addition, health professionals and the public need more information on the potential benefits, the rationality of the use and risks of medications prescribed.
Tuberculosis in Morocco also remains a public health problem, with an average incidence of 83.5 cases per 10 5 inhabitants in 2014. Fortunately, the resistant forms of TB treatment do not exceed 1.3% of all cases [5]. Currently the WHO recommends for all countries to create or develop Pharmacovigilance (PV) in their health programs. Morocco is among the first countries that received Global Fund grants to strengthen the PV in AIDS and TB [5].
Since 2010, in Morocco, there is a combined form called ERIP-K4 on the market containing 4 anti-TB drugs (Ethambutol, Rifampicin, Isoniazid, Pyrazinamide) and whose Pharmacovigilance knowledge is still incomplete in a large Moroccan TB population. That is why our objective of this work was to detect and validate new signals of this combined anti-TB drug ERIP-K4.

Study design and setting
It was a prospective study (October 2012-December 2013), conducted in majority Moroccan TB Diagnosis Centers (MTDC) who are in charge of treating TB patients. These MTDC exist in all cities and receive about 27000 TB patients per year.

Study population
All TB patients admitted to these MTDC and presented ADRs were eligible for inclusion in the study during this period. TB patients who not presented ADRs were excluded of this study.

Data collection
A broad national sensitization about TB PV was performed for all practitioners who treat TB patients, and by successive workshops a spontaneous reporting system for adverse effects was validated between the MTDC and the Moroccan Pharmacovigilance Centre (MPVC). Each notified ADR was treated by the WHO accountability method [6], which determines the relationship of cause and effect, all adverse events were sent to the international database (Vigibase) [7]. An electronic registry of adverse events has been established that serves as a tool to send responses to different notifiers and exchange information between the MPVC and them.

Analysis
The detection of signals was based on 3 statistical methods measuring disproportionality of reporting of combined anti-TB form (ERIP-K4) induced ADRs: 1. The information component (IC) [8]  There is a potential signal when the value of IC is greater than 0. In other words, the probability of the observed ADRs is greater than the likelihood of expected ADRs. (IC 025 : Information Component within a range of 95% confidence).
2. The proportional reporting ratio (PRR) [9]: statistical method used to detect ADRs in Moroccan PV database. This relative increase in the adverse event reporting for the medicinal product (P) is reflected in Table 1 based on the total number of individual cases contained in a PV database.
The PRR is computed as follows: PRR=(A/A+B)/(C/C+D). Signal if The PRR ≥ 2 and the number of individual cases greater or equal to 3.
3. The reporting odds ratio (ROR) [10]: statistical method used to detect ADRs in Moroccan PV database. ROR=AD/CB. Signal if the PRR>1 and the number of individual cases greater or equal to 3.

Descriptive study: general information
The MPVC registered 927 ADRs from 600 TB patients during the study. The average age of patients was 40.7 ± 17.5 years with a sex ratio of 0.8. The ERIP-K4 was prescribed in the intensive phase of treatment (83.7%), followed by Riniazide (Rifampicin, Isoniazid) in maintenance treatment (10.1%). Accountability of cases according to the WHO method showed that 5% had a certain relationship of cause to effect, 25% had a probable relationship, and 70% had a possible relationship. About gravity, 140 of the cases were serious (23%) with 7 deaths (1.3%), 21 cases had a commitment prognosis (3.4%), 4 cases developed sequelae (0.6%), and 107 cases required hospitalization or prolongation of hospitalization (17.5%). The outcome was favorable in 47.2% of cases, 16.2% were healing, 35.2 were unknown, and 1.3% died.
Descriptive study: nature of ADRs (Table 2) Adverse drug reactions of skin and appendages disorders predominated (24.2%) with pruritus as the most predominant symptom, followed by ADRs of gastrointestinal system disorders (21%) with epigastric pain and vomiting as the most predominant symptom and ADRs of liver and biliary system disorders (14.5%) with cytolytic hepatitis as the most predominant symptom.
The signal detection was focused on the cases related to combined anti-TB drug form (ERIP-K4) recorded in the international database VigiMine. We found 875 ADRs related to this combination; 268 of them were issued from Morocco (30.6%). 18 international signals have been generated; 11 of them were from Morocco (Table 3).
We were interested to a new signal never described in our database: edema of the lower limbs which Moroccan IC was 2.03.

2.
The proportional reporting ratio (PRR) in moroccan PV database was 7.5.

3.
We also calculated the reporting odds ratio (ROR) of these edemas in our database, which were 7.9.

Discussion
Among 927 ADRs collected during this period, a new signal has emerged never described in our database: 27 edemas of the lower limbs with the combined form ERIP-K4.
According to the European Medical Agency [11], the term signal in PV causes enormous ambiguity among health professionals. The use of statistical algorithms for the detection of PV signals, devoid of any clinical setting, amplifies this confusion. So it is better to use the term disproportionate reporting ratio instead of the signal. This requires more clinical investigation of the occurrence of the ADR in the patient. In other words the relationship of cause and effect between a drug and an adverse event cannot be established only in the context of the analysis of databases.
This agency stressed that there is currently no officially validated statistical method for the detection of PV signals. Only some considerations on the evaluation of the performance of different methods have been discussed [12,13].
Any potential signal must be validated by a didactic approach to become a true signal. We followed different steps to confirm this signal:

Data collection
We collected 27 edemas of the lower limbs in 12 months from different regions of Morocco following use of the ERIP-K4. The average age of these patients was 39.3 ± 17.3 years with no particular history, the sex ratio was 1.2. The median time to onset of these edemas was 20 days [1-90 days]. Hepatic and renal laboratory tests of patients were normal.

Event (R) All other events Total
Medicinal Product (P) All other medicinal products Total    Table 3: Moroccan signals with anti-TB combined form. Summary of product characteristics and literature [14,15] specify that only Rifampicin used daily or intermittently rarely gives edema probably by immunoallergic mechanism.

Relationship of cause to effect
Apart the active ingredients contained in the ERIP-K4, we studied drug's excipients which are: Cornstarch, Pregelatinized corn starch, Crospovidone, Povidone, Sodium lauryl sulfate, Magnesium stearate, Opadry.
We found that sodium lauryl sulfate (C12H25SO4Na) is an excipient with known effect because it may cause fluid retention and can explain this edema of lower limbs. Study of accountability: accountability according to the French method: [16] -Intrinsic accountability was doubtful because no pharmacological mechanism in the genesis of these edemas is known and nondrug etiologies have not been eliminated by other diagnostic tests well defined.
-Extrinsic accountability (B1): Effect not described according to the definitions of B2 or B3

Qualitative assessment: analysis of individual case safety reports (ICSRs)
The majority of these edemas occurred after taking the ERIP-K4 in the intensive phase, and declined after the transition to the maintenance phase with RINIAZIDE. It strengthens the relationship of cause and effect between the ERIP-K4 and this ADR.
-The Moroccan PV database doesn't recorded similar cases except these 27 edemas.
-The international PV database contained in addition to the Moroccan cases, 3 other cases: 2 cases in Thailand and one case in Togo.
Quantitative assessment: scores of disproportionate reporting ratios -The PRR of edema in Moroccan PV database was 7.5 (there are 7.5 times more edema of the lower limbs with ERIP-K4 than with other drugs in our database).
-The ROR of edema in Moroccan database was 7.9 (there are 7.9 times more edema of the lower limbs with ERIP-K4 than with other drugs in our database).

Information
We informed all Moroccan TB health practitioners from this potential signal and to sensitize their patients to declare any effect particularly fluid retention. Each case of edema must be investigated correctly to eliminate other causes of edema and sent to the National PV Center.

Validation by Technical Comity of Pharmacovigilance
The Technical Comity of PV has been assembled on July 2013 and decided some recommendations: -Importance to examine patients with edemas because do not appear if there are not important.
-Diagnose these edemas and eliminate differential diagnosis.
-Measures to be occurred if significant edema: -Achieve a pharmaco-epidemiological study to determine the risk factors for these edemas -The comity concluded that this side effect may be due to: • Medication: ERIP-K4 particularly Rifampicin by immunoallergic mechanism • Excipient: sodium lauryl sulfate?

Conclusion
Edemas of the lower limbs are a potential signal in Pharmacovigilance requiring more clinical, biological and pharmacoepidemiological investigations to argue well the relation of cause and effect, and to find risk factors to manage and avoid these effects.