A study to monitor adverse drug reaction profile of theophylline in patients of obstructive airway

disease

Kavita Gulati, N Tyagi, G Vishnoi, VK Vijayan, A Ray

Department of Pharmacology & Clinical Research Centre, Vallabhbhai Patel Chest Institute, University of

Delhi, Delhi-110 007

Pharmacovigilance and Drug Safety Conference (SOPI-2006), Bangalore,

11-12 November 2006

Introduction• 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

• Bronchodilators and corticosteroids are the mainstay in the treatment of these conditions

• Theophylline : Emerging as an important adjuvant in the treatment of bronchial asthma and COPD

• Combination with other drugs has synergistic effects in many situations

• Theophylline : A drug of herbal origin (Camellia sinensis – tea plant)

• Widely used earlier as bronchodilator

• Pharmacoeconomically viable

• Narrow therapeutic index and has high propensity to induce toxicity, resulting in the restricted use

• Recently : A resurgence in the interest in theophylline

• Low doses (lower than those needed to induce bronchodilation) exert beneficial effects

• Anti-inflammatory and immunomodulatory effects reported

• Judicious use could be of benefit in obstructive airway disease in developing countries

• Adverse Drug Reactions : Noxious/untoward effects to drugs or chemicals given for therapeutic, preventive or diagnostic purposes

• Common with drugs with narrow safety margin

• Mostly preventable

• Knowledge of PK-PD of the drug crucial

• ADR monitoring and TDM important exercises

Objectives

• To monitor adverse drug reactions (ADRs) with theophylline in patients of bronchial asthma and COPD attending the OPD of Vallabhbhai Patel Chest Institute, Delhi

• Predict strategies to rationalize drug therapy with theophylline in such patients with obsturctive airway disease

Methods

• Subjects : OPD patients of bronchial asthma and COPD

• Prospective study

• Ethical clearance obtained

• ADR profile recorded as per proforma for the National Pharmacovigilance Programme

• Causality assessment : Naranjo`s scale (1981)

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

Methods…

• Age : 18 – 60 years

• Standard inclusion/exclusion criteria Clinical + Lab. (PFT) diagnosis confirmed Stable, Ambulatory patients

• Exclusion : Pulm. TB, Pregnancy/Lact. IHD/overt LVF, Liver/Kidney disease

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

ADVERSE EFFECT PROFILE IN PATIENTS WITH ORAL THEOPHYLLINE

------------------------------------------------------------------------------ADR No. of Patients %

------------------------------------------------------------------------------

Dyspepsia 21 33

Anxiety 22 34

Spasm of Muscles 13 21

Insomnia 11 17

Paresthesia 04 06

Others 10 16

-------------------------------------------------------------------------------

Incidence of ADRs after theophylline

0

10

20

30

40

50

60

70

80

90

100

Dys Anx Ms sp Ins Par Oth Tot

Conclusions

• A study was conducted to assess the ADR profile of theophylline in bronchial asthma and COPD patients (total 120)

• An appreciable proportion (54%) of patients complained of ADRs

• Most patients reported anxiety and GI related problems

• Others : muscle cramps, paresthesia, etc.

Conclusions…contd.

• Causality assessment by Naranjo`s scale showed that most ADRs fell in Probable category

• Dechallenge confirmed the incidence in some cases

• These results indicate that theophylline admn. should be carefully monitored and such ADRs could be prevented by rational therapy

Aminophylline (Amino) - induced anxiety and its mechanisms

-------------------------------------------------------------------------------

Treatment Elevated Plus Maze (%)(mg/kg) OA entry OA time-------------------------------------------------------------------------Vehicle 30.0 ± 5.6 23.2 ± 3.6Amino (10) 16.6 ± 4.2* 13.3 ± 2.8*Amino (50) 9.0 ± 1.3* 5.3 ± 1.1*AA(100)+Amino(50) 22.2 ± 7.0 15.2 ± 5.0Mel(50)+ Amino(50) 18.7 ± 6.5a 12.1 ± 4.6a-------------------------------------------------------------------------* p< 0.05 (compared to vehicle)a. p<0.05(compared to Amino-50)AA: ascorbic acid ; Mel: melatonin

Aminophylline (Amino)-induced gastric ulcers and its mechsnisms

-------------------------------------------------------------------------------Treatment Gastric Ulcer parameters(mg/kg) Incidence (%) Severity (mm)-------------------------------------------------------------------------------Vehicle 80 25.3 ± 5.6Amino (10) 70 31.0 ± 9.6 Amino (50) 100 55.6 ± 8.0 *AA(100)+Amino(50) 50a 22.8 ± 6.1aMel(50)+ Amino(50) 40a 18.2 ± 6.9a -------------------------------------------------------------------------------------* p< 0.05 (compared to vehicle)a. p<0.05(compared to Amino-50)AA: ascorbic acid ; Mel: melatonin

Conclusions• The role of oxidant/anti-oxidant balance in obstructive airway disease has been proposed

• A connection between theophylline and oxidative stress pathways are reported

• These experimental studies show that theophylline-induced anxiety may be due to oxidative stress, and antioxidants may have protective role