Adverse drug reaction monitoring in
patients of bronchial asthma and
COPD with focus on methylxanthines
Kavita Gulati
Department of Pharmacology
Vallabhbhai Patel Chest Institute
University of Delhi, Delhi-110007
SOPI-2010, LHMC, New Delhi, 27/11/2010,
Adverse Drug Reactions
• A response to a drug that is noxious and
unintended and that occurs at doses used in
humans for prophylaxis, diagnosis, or therapy
of disease, or for the modification of
physiologic function
• Excludes therapeutic failures, overdose, drug
abuse, non-compliance, and medication
errors
Adverse Drug Reactions
• ADR contribute significantly to the morbidity and
mortality and increased health costs
• Over 2 million serious ADRs per year,
responsible for 5% of hospital admissions,
1,00,000 deaths yearly
• ADRs :leading cause of morbidity, ahead of lung
disease, diabetes, AIDS, Trauma
Need of ADR monitoring
• India : 4th largest producer of the pharmaceuticals in the
world
• Drugs prescribed (sometimes indiscriminately and
irrationally) in various combinations (polypharmacy)
• Large sections of population exposed
• ADR contribute significantly to the morbidity and
mortality and increased health costs
• Clinical trial data not sufficient
• A dire need for a scientific/systematic and uniform
method to monitor ADRs
Pharmacovigilance methods
• Spontaneous reports (most commonly)
• PEM (prescription event monitoring)
• Observational Studies(Case Control and Cohort
Studies)
Spontaneous reporting
• Unsolicited communication by health care
professionals or consumers to a company,
regulatory authority or any other organization
(WHO, Regional Centers) that describes one or
more Adverse Drug Reactions in patient who
was given one or more medicinal products
• It does not derive from a study or any organized
data collection scheme
Causality assessment
Hutchison defined causality assessment as a
“method for eliciting a state of information about
a particular drug-event connection as input and
delivering as output a degree of belief about the
truth of the proposition that the drug caused the
event to occur”
Causality Assessment scales
• Naranjo’s scale
• WHO causality assessment scale
Causality Assessment
•
•
•
•
•
•
•
Prior reports of reaction
Temporal relationship
De-challenge
Re-challenge
Dose-response relationship
Alternative etiologies
Past history of reaction to same or similar
medication
T o a sses s th e ad verse drug re ac ti o n, plea se an sw er th e f o llow in g q ue stion na ir e an d gi v e th e p er tin e nt sc ore.
1.
2.
3.
Naranjo ADR
Probability
Scale
4.
5.
6.
7.
8.
Naranjo CA. Clin Pharmacol
Ther 1981;30:239-45
9.
10 .
A re th e re p rev ious conc lu si ve repo rt s on
th is re ac ti on?
D id th e adve rs e ev e n t appe a r a ft er t he
su spec ted d rug wa s ad mi n ist er e d?
D id th e adve rs e reac ti on im prove when t he
d rug wa s d is con ti nued o r a sp e cifi c
an tagon ist wa s ad mi n is te re d?
D id th e adve rs e reac ti on s app e ar when the
d rug wa s read mi n is te re d?
A re th e re a lt erna ti ve c ause s (o the r than t he
d rug) t ha t cou ld on the ir o w n have cau sed
the re a cti on?
D id th e reac ti on re a ppea r when a p lacebo
wa s g iven ?
Wa s the d rug de tec te d in th e b lood (or
o the r fl u ids ) in concen tr ati ons known to be
tox ic?
Wa s the r eac ti on m o re sev e re when the
dos e wa s inc rea sed , o r less sev e re when t he
dos e wa s d e cr e ased ?
D id th e pa ti en t have a si m il ar re a cti on to
the sa m e or simil ar d rugs i n any prev iou s
expo sure ?
Wa s the adve rse even t con fi rm ed by a ny
ob jec ti ve ev idence ?
Ye s
+1
No
0
Do No t Know
0
S co re
____
+2
-1
0
____
+1
0
0
____
+2
-1
0
____
-1
+2
0
____
-1
+1
0
____
+1
0
0
____
+1
0
0
____
+1
0
0
____
+1
0
0
____
T ot al S co re
____
T o tal Sco re
A DR P robab ilit y C la ssifi ca tion
9
5 -8
1 -4
0
H igh ly Pr obab le
P rob a b le
P os si b le
Doub tf u l
•
Respiratory diseases
• Respiratory diseases : a major cause of hospital
admissions
• Obstructive airway disease (Bronchial Asthma
and COPD) affect 5-7% population in
industrialized countries
• Several factors (allergy and smoking) contribute
to their genesis
• Optimization and rationalization of drug therapy :
key to effective management
Respiratory disease….
• Drug therapy involves polypharmacy
• Multiple routes of drug administration –
sometimes in the same individual
• Complex drug – drug interactions always a
possibility
• Long term drug usage compounds the problem
• Drugs with narrow therapeutic indices
ADR monitoring in Asthma and COPD
• 120 patients of bronchial asthma and COPD
were selected from the VPCI OPD
• Ethical clearance and GCP guidelines
• Standard inclusion/exclusion criteria
• Diagnosed by clinical features and PFT findings
• ADR profile was recorded as per National
Pharmacovigilance Programme proforma
• Dechallenge and rechallenge were done
wherever appropriate
• Causality Assessment was done by using the
Naranjo`s scale
SEX-WISE DISTRIBUTION OF MALES AND FEMALES
ENROLLED IN THE STUDY
FEMALES
7%
MALES
93%
MALE
FEMALES
GENERAL PROFILE OF DRUG TREATMENT
AND ADVERSE EFFECTS IN COPD
Drug Given
No. of Patient Receiving
the Drug
No. of Patient
Complaining of ADR
Percentage
Inhaled Steroids
53
30
56%
Inhaled
Anticholinergics
44
10
22.7%
Oral
Theophylline
43
20
46.5%
Oral Steroids
14
3
21.4%
Antibiotics (Oral)
14
3
21.7%
Short Acting 2
agonist
55
3
5%
N-acetyl
cysteine
2
2
100%
PERCENTAGE OF OUTPATIENTS RECEIVING
DIFFERENT DRUGS FOR TREATMENT OF COPD
100%
90%
80%
% of Patients
70%
60%
50%
40%
30%
20%
10%
0%
Inhaled Stero ids
+LA b2 agonist
Inhaled
A nticholinergics
Oral
Theo phylline
Oral Stero ids
A ntibio tics
(Oral)
Sho rt A cting b2
A gonist
NA cetylcysteine
PERCENTAGE OF OUTPATIENTS COMPLAINING OF ADR
WITH DIFFERENT DRUGS USED FOR TREATMENT OF COPD
•
100%
90%
Percentage of Patients
80%
70%
60%
50%
40%
30%
20%
10%
0%
Inhaled Stero ids
Inhaled
A nticholinergics
Patents Receiving the Drug
Oral
Theo phylline
Oral Stero ids
A ntibio tics (Oral) Sho rt A cting b2 N-Acetylcysteine
A gonist
Percentage of Patients Complaining of ADR due to the Drug
ADR profile with respiratory drugs
Drugs
Br. Asthma COPD
Profile
Inhaled steroids 54/60 (90%)
30/60 (50%)
Sore
throat,dysguesia,
hoarseness,gloss
itis, others
Inhaled
anticholinergics
25/40 (62%)
10/44 (23%)
Dry mouth,thirst,
urinary difficulty
Inhaled beta-2
agonists(SA)
15/35 (43%)
3/55 (5%)
Hand tremors
Oral steroids
28/32 (87%)
3/14 (21%)
Wt. gain, acne,
cramps, mood
changes
Oral
theophylline
14/20 (70%)
20/43 (46%)
Anxiety,
dyspepsia, mus.
spasm,
paresthesia, etc
Results
• Most ADRs : mild to moderate, few were intolerable
and required dose reduction ( oral steroid and
theophylline)
• 75% of patients complained of one or other ADR
• 23 % of COPD patients and 53 % of bronchial asthma
patients required oral steroids
• Oral steroids were associated with incidence of ADRs 21% (in COPD) and 87% (in br. asthma)
• 84 of total patients received inhaled anticholinergics out
of which ADRs were noted in 41% patients
Theophylline
• Bronchodilators and corticosteroids are the
mainstay in the treatment of OADs
• Recently a resurgence in the interest in
theophylline due to anti-inflammatory and
immunomodulatory effects reported
• Low doses (lower than those needed to induce
bronchodilation) exert beneficial effects
• Judicious use could be of benefit in OAD in
developing countries (reduces dose of steroids
and a pharmacoeconomically viable drug
Prescription monitoring in obstructive
airway disease (theophylline)
Prescriptions Total
No.
With
theophylline
%
All patients
120
63
52.6
Br. Asthma
60
20
33.3
COPD
60
43
71.6
Prescription audit in obstructive
airway disease (theophylline)
100
90
80
70
60
Total
Theoph
50
40
30
20
10
0
All Rx
Asthma
COPD
ADR incidence with theophylline
Patients
Received
Showed
Theophylline ADRs
%
Br. Asthma
20
14
70
COPD
43
20
46.5
Total
63
34
53.9
ADVERSE EFFECT PROFILE IN COPD
PATIENTS WITH ORAL THEOPHYLLINE
ADR
No. of Patients
Percentage
Dyspepsia
13
65%
Anxiety
12
60%
Spasm of Muscles
6
30%
Insomnia
2
10%
Dizziness
2
10%
Theophylline Withdrawal Induced
Constipation
1
5%
Paraesthesia
2
10%
Others
1
5%
PERCENTAGE OF DIFFERENT ADRs WITH ORAL
THEOPHYLLINE IN COPD PATIENTS
70%
60%
50%
40%
30%
20%
10%
0%
Dyspepsia
Anxiety,
Palpitation
Spasm of
M uscles
Insomnia
Vertigo,
Dizziness
Theophylline Paraesthesia
Withdrawal
Constipation
Percentage of Patients Complaining of ADR
Others
Adverse effect profile in patients with oral
theophylline in bronchial asthma
-----------------------------------------------------------------------------ADR
No. of Patients
%
-----------------------------------------------------------------------------Dyspepsia
09
45
Anxiety
10
50
Spasm of Muscles
07
35
Insomnia
08
40
Paresthesia
04
20
Dizziness
03
15
Others
02
10
------------------------------------------------------------------------------------
Incidence of ADRs after theophylline
in patients of Bronchial Asthma
50
45
40
35
30
25
20
15
10
5
0
Dys
Anx Ms sp
Ins
Par
Dizz
Oth
Causality assessment of ADRs due to oral
theophylline using the Naranjo’s scale
Oral
Theophyllin
Highly
Probable (9)
Probable
(5-8)
Spasm
of
muscle of
calves (most
commonly)
sternocleido
mastoid,
intercoastal
muscles
(1)Dyspepsia
(2)Insomnia
(3) Anxiety
(4)Dizziness
(5)Withdrawal
induced
Constipation
(6)Paraesthesia
(7)Colicky Pain
(8)Diuresis
Possible
(1-4)
Doubtful
(0)
A comparative study…
• A prospective, open label, randomized, parallel design
study was carried out to compare the efficacy and safety
of two methylxanthines, namely theophylline and
doxofylline in patients of bronchial asthma and COPD
• A total of 60 patients, 30 each of bronchial asthma and
COPD were enrolled for the study as per the laid down
inclusion and exclusion criteria
• Each group of 30 patients received standard treatment
for asthma and COPD
Comparison of ADRs after theophylline
and doxofylline in bronchial asthma
anxiety
Muscle spasm
Dizziness
Sore throat
No ADRs
insomnia
No ADR
Comparison of ADRs after theophylline
and doxofylline in COPD
anxiety
Muscle spasm
insomnia
anxiety
Dry mouth
Tremors
Gastritis
Nausea
No ADR
No ADRs
Summary
• Doxofylline was more therapeutically effective than
theophylline in COPD
• ADR profiles of theophylline and doxofylline included
dyspepsia, anxiety, muscle spasm, tremors,
dizziness, and headache
• Doxofylline treated group was associated with lesser
frequency of ADRs as compared to the theophylline
group
• Such focussed studies will be helpful in rationalizing
drug therapy in OAD
Acknowledgements
•
•
•
•
•
Dr. V K Vijayan
Prof. A Ray
Dr. Neeraj Tyagi
Dr. Gaurav Vishnoi
Dr. Dushyant Lal