Statistical analysis
Reporting frequencies were estimated for the following variables:
gender, age group, seriousness, mortality, HCQ dose, HCQ treatment
length, HCQ indication, concomitantly used medications, as well as type
of ADR grouped by MedDRA system and organ classification (SOC). SPSS v24
and Excel programme were used for this purpose.
When possible, daily doses of HCQ were estimated based on posology.
Incomplete posologies that did not allow daily dose to be estimated were
considered unknown. Daily doses were categorised into three levels: low
(400 mg /day), medium (400-600 mg/day), and high (800 mg/day). Also,
total administered dose was estimated and categorised as follows: low (≤
50.000 mg), medium (51,000-200,000 mg), and high (> 200,000
mg)
For each period, the disproportionality analysis was carried out based
on the FEDRA database “Signal generation module”. The Reporting Odds
Ratio (ROR) was obtained to estimate disproportionality of the different
ADRs reported with HCQ [11]. We used a case/non case approach to
determine the strength of the association between HCQ and whichever ADR.
The lower limit of the 95% confidence interval was -ROR. We considered
a potential HCQ-ADR association when - ROR was higher than 1 and there
were at least 3 cases reported. Standardised MedDRA Queries (SMQ) from
MedDRA were used to identify ADRs. SMQs are validated pre-determined
sets of MedDRA terms grouped together that are associated with a
specific medical condition [12] . We identified the HCQ-ADR
associations with at least 3 reported cases and with the lower
confidence interval (IC 95%) larger than 1 in at least one of the
periods of interest.
To explore potential interactions, Omega (Ω) statistic was obtained.
This analysis compares the observed relative reporting rate of a given
ADR, granted that the reports include the co-existence of two drugs,
with its expected value estimated based on the relative reporting rates
of the ADR for each drug separately. The observed number of cases is the
number of reports in FEDRA for the two drugs together that include the
ADR of interest. When Ω is positive, then the drug-drug-ADR association
is reported more often than expected [13]. The lower limit of the
95% credibility interval is referred to as Ω -025. We
considered a potential drug-drug interaction to exist when Ω-025>0.
For the disproportionality analysis, exposure to a given drug was
defined as the recording of the drug in a report, whether or not it was
suspected of causing the reaction.