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CHAPTER 5

INVESTIGATION ON ADVERSE DRUG REACTION OF

AMIODARONE AND DRONEDARONE

An important challenge for the medical industry in developing a new

drug is the Adverse Drug Reaction (ADR) which is the fourth leading cause of
death. The study of the adverse drug reactions of the newly released drugs is
called Pharmacovigilance which educates the people on the benefit and risk of
drugs and warns them. The main objective of the research work is to extract
information from FAERS data which contains structured and unstructured
information of the patients who had already suffered adverse drug reactions.
The research work analyses the adverse event associated with the drug
Amiodarone and its safety profile compared to Dronedarone.
Disproportionality analyses of the adverse reactions for the drugs are also
presented.

Pharmacovigilance aims at the best use of medicine to cure the disease

with no adverse effects. Amiodarone is a medicine that helps in keeping
heartbeat of a person normal. Even though Amiodarone showed many adverse
effects, it was effective in handling risky arrhythmias that cannot be treated by
other drugs. Amiodarone is a broad spectrum antiarrhythmic medication with
many side effects like fatigue, eye deposits, tremor, unsteady gait, nausea,
vomiting, constipation, weight loss, dizziness, and visual changes.
Amiodarone is related to pulmonary fibrosis, heart block, heart failure,
liver failure etc. Multaq (dronedarone), Betapace, Tikosyn are the other
alternatives of Amiodarone

Pharmacovigilance deals with science and activities relating to the

identification, analysis and stoppage of ADRs. So each country has Safety
monitoring of medicinal products guidelines for setting up and running a
pharmacovigilance centre with the aim to observe ADRs.
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Few decades ago in India, the safety evaluation of drug was based on
the chronic use of that drug. But this practice was inaccurate and failed to
claim complete safety (Report E, 1997). There is a severe reluctance to adopt
the new technology. Because of the insufficient data and lack of reporting of
the adverse event, Indian pharmacovigilance programme is renamed as
Pharmacovigilance Programme of India (PvPI) (Sharma,G. et al., 2017). The
aim of PvPI is to gather, assemble and investigate the data and recommend
their results to corresponding authorities.

Figure 5.1 Pharmacovigilance in different stages of drug development

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A signal in pharmacovigilance is more than just a statistical association.

It consists of a hypothesis together with data and arguments, arguments in
favor and against the hypothesis. These relate to numbers of cases, statistics,
clinical medicine, pharmacology (kinetics, actions, previous knowledge) and
epidemiology, and may also refer to findings with an experimental character
(Meyboom et al. 1997).

Because of the boundaries of clinical trials done before entering into

the market, adverse events due to a specific drug cannot be assessed before its
release (Harpaz et al., 2012). Table 5.1 shows the report on year-wise FDA
dataset. Literature revealed that adverse reactions in drugs released to the
public has deaths and hospitalisations numbering in millions (up to 5%
hospital admissions, 28% emergency visits, and 5% hospital deaths), and
associated costs of about seventy-five billion dollars annually (Xu et al.,2014).
Pharmacovigilance becomes necessary to identify these ADRs (Bate et
al.,2009). Hence, present research focus is on ADR detection (Wang et al.
2009).

Table 5.1 Year wise FDA Dataset

Total Non-
Year Expedited Directed
Reports Expedited

2017 1,212,999 615,558 557,058 40,383

2016 1,684,722 864,309 769,534 50,879

2015 1,718,515 831,924 845,052 41,539

2016 1,684,722 864,309 769,534 50,879

2015 1,718,515 831,924 845,052 41,539

2014 1,196,845 739,581 423,150 34,114

2013 1,058,363 626,692 403,368 28,303

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As information from a single source has many limitations, present

research focused on gathering information from multiple sources (Tuarob et
al. 2013). Figure 5.1 shows pharmacovigilance in different stages of drug
development which can be divided into a premarket and post-market analysis
into many phases.

The first step in proposed methodology is to extract or mine

information about the drug Amiodarone from FAERS dataset which is
unstructured and collects information from throughout the world. Extracted
data from FAERS is then cleaned, and missing values are handled
appropriately. Figure 5.2 shows the information flow in Pharmacovigilance.
The whole process is carried out using OpenVigil 2.

Figure 5.2 Information flow in Pharmacovigilance

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5.1 Experimental Results of Amiodarone and Dronedarone

Figure 5.3 shows the occurrence of adverse events. For Amiodarone,

3623 unique adverse event classes are observed with a total number of adverse
event being 61,598. Table 5.2 shows the disproportionality analysis table, and
shows the interpretation of disproportionality information.

1200

1000
Occurrence Value

800

600

400

200

0
78
1
8
15
22
29
36
43
50
57
64
71

85
92
99
106
113
120
127
134
141
148
Adverse Event Occurence

Figure 5.3 Adverse events occurrence rate for Amiodarone

Table 5.2 Disproportionality Analysis for drug interaction

This drug
Other
Groups (AMIODARO Sums
drugs
NE)

This event
719 67284 68003
(DRUG+INTERACT
DE dE E
ION)

Another event 10602 7668698 7679300

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De de e

11321 7735982 7747303

Sums
D d N (total)

Figure 5.4 Comparison of AE of drugs Amiodarone and Dronedarone

Fig 5.4 shows the comparison between the adverse events of the drugs
amiodarone and dronedarone with Amiodarone leading with 20278 ADRs
compared to Dronedarone 9327 ADRs. Figure 5.5 shows the AE profile when
both the drugs are used.
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25

20

Count_both_drugs
15

10

Adverse Events of both drugs

Figure 5.5 AE profile of drugs Amiodarone and Dronedarone

Table 5.3 shows adverse events count reported in FAERS (Dec 2017)
due to Amiodarone & Dronedarone. Table 5.4 shows the DPA for
Amiodarone and AE drug interaction and the interpretation given.

Interpretation: According to the criteria by Evans, which requires a

report count > 3 (this combination: 719) and a PRR > 2 (here: 7.3) and a Chi-
squared > 4 (here: 3897.3) this drug and event are statistically significantly
related (=putative ADVERSE DRUG REACTION).

Table 5.4 DPA for Amiodarone and AE drug interaction

Disproportionality Value Interpretation

indicators

Rate 6.35103 Percentage of this drug-

this adverse event vs this
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drug-all adverse events

(%DE/D)

Chi-squared Yates 3897.29354 Does the 2x2 table have

(chisq) a normal distribution
(chi-squared dist.)?
Values greater than 4
correspond to p<0.05.

Relative Reporting 7.23547 These ratios compare the

Ratio (RRR) observed counts to
expected counts and
Proportional 7.3021 allow quantifying the
Reporting Ratio additional risk/odds of
(PRR) the drug and event
selected above compared
Reporting Odds 7.72949
to the general
Ratio (ROR) (7.16443;8.33911)
background noise.
(95%-CI)
Roughly, RRR/ PRR/
ROR values greater than
Haldane's Odds 7.73444
2 indicate that this drug-
Ratio (HOR)
adverse event-

Information 2.85509 combination is 2-fold

Component (IC) more likely than all

other combinations.

Figure 5.6 shows the plot of chi-square and Proportional Reporting

Ratio (PRR) and Figure 5.7 shows the chi-square and RRR plot for
Amiodarone.
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35000

30000

25000
PRR Value

20000

15000

10000

5000

0
0 500 1000 1500 2000 2500 3000 3500 4000
chi-square Value

Figure 5.6 Chi-square Vs PRR plot for Amiodarone

400

350

300

250
RRR Value

200

150

100

50

0
0 5000 10000 15000 20000 25000 30000 35000
chi-square Value

Figure 5.7 Chi-square vs RRR plot for Amiodarone

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5.2 Summary

The ADRs due to the drug Amiodarone has been extracted using
OpenVigil 2 and disproportionality analysis has been done. A comparison of
AE profile between Amiodarone and Multaq (Dronedarone) shows that
ADRs decreases by more than 50% for dronedarone compared to
Amiodarone validating that Dronedarone can be used with less risk. DPA
analysis for drug interaction shows that drug interaction is a statistically
significant adverse event (AE).