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

•Prior reports of reaction•Temporal relationship•De-challenge•Re-challenge•Dose-response relationship•Alternative etiologies•Past history of reaction to same or similar

medication

Causality Assessment

Naranjo ADR Probability Scale

Naranjo CA. Clin Pharmacol

Ther 1981;30:239-45

To assess the adverse drug reaction, please answer the following questionnaire and give the pertinent score.

Yes No Do Not Know Score1. Are there previous conclusive reports on

this reaction?+1 0 0 ____

2. Did the adverse event appear after thesuspected drug was administered?

+2 -1 0 ____

3. Did the adverse reaction improve when thedrug was discontinued or a specificantagonist was administered?

+1 0 0 ____

4. Did the adverse reactions appear when thedrug was readministered?

+2 -1 0 ____

5. Are there alternative causes (other than thedrug) that could on their own have causedthe reaction?

-1 +2 0 ____

6. Did the reaction reappear when a placebowas given?

-1 +1 0 ____

7. Was the drug detected in the blood (orother fluids) in concentrations known to betoxic?

+1 0 0 ____

8. Was the reaction more severe when thedose was increased, or less severe when thedose was decreased?

+1 0 0 ____

9. Did the patient have a similar reaction tothe same or similar drugs in any previousexposure?

+1 0 0 ____

10. Was the adverse event confirmed by anyobjective evidence?

+1 0 0 ____

Total Score ____

Total Score ADR Probability Classification

9 Highly Probable5-8 Probable1-4 Possible0 Doubtful

•

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

FEMALES7%

MALES93%

MALE FEMALES

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%

GENERAL PROFILE OF DRUG TREATMENT AND ADVERSE EFFECTS IN COPD

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

% o

f P

atie

nts

Inhaled Steroids InhaledAnticholinergics

OralTheophylline

Oral Steroids Antibiotics(Oral)

Short Acting b2Agonist

N-Acetylcysteine

PERCENTAGE OF OUTPATIENTS RECEIVING DIFFERENT DRUGS FOR TREATMENT OF COPD

+LA b2 agonist

PERCENTAGE OF OUTPATIENTS COMPLAINING OF ADR WITH DIFFERENT DRUGS USED FOR TREATMENT OF COPD

•

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Per

cen

tag

e o

f P

atie

nts

Inhaled Steroids InhaledAnticholinergics

OralTheophylline

Oral Steroids Antibiotics (Oral) Short Acting b2Agonist

N-Acetylcysteine

Patents Receiving the Drug Percentage of Patients Complaining of ADR due to the Drug

ADR profile with respiratory drugs

Drugs Br. Asthma COPD ProfileInhaled steroids 54/60 (90%) 30/60 (50%) Sore

throat,dysguesia,hoarseness,glossitis, 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)

0

10

20

30

40

50

60

70

80

90

100

All Rx Asthma COPD

Total

Theoph

ADR incidence with theophylline

Patients Received Theophylline

Showed ADRs

%

Br. Asthma 20 14 70

COPD 43 20 46.5

Total 63 34 53.9

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%

ADVERSE EFFECT PROFILE IN COPD PATIENTS WITH ORAL THEOPHYLLINE

PERCENTAGE OF DIFFERENT ADRs WITH ORAL THEOPHYLLINE IN COPD PATIENTS

0%

10%

20%

30%

40%

50%

60%

70%

Dyspepsia Anxiety,P alpitation

Spasm ofMuscles

Insomnia Vertigo,Dizziness

TheophyllineWithdrawal

Constipation

P araesthesia Others

Percentage of Patients Complaining of ADR

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

0

5

10

15

20

25

30

35

40

45

50

Dys Anx Ms sp Ins Par Dizz Oth

Highly Probable (9)

Probable (5-8)

Possible(1-4)

Doubtful (0)

Oral Theophyllin

Spasm of muscle of calves (most commonly) sternocleidomastoid, intercoastal muscles

(1)Dyspepsia(2)Insomnia(3) Anxiety(4)Dizziness(5)Withdrawal induced Constipation (6)Paraesthesia(7)Colicky Pain(8)Diuresis

Causality assessment of ADRs due to oral theophylline using the Naranjo’s scale

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

Sore throat

insomnia

No ADR

Dizziness

No ADRs

Comparison of ADRs after theophylline and doxofylline in COPD

anxiety

Muscle spasm

insomnia

Gastritis

No ADR

Dry mouth

Tremors

Nausea

No ADRs

anxiety

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