Kavita Gulati Department of Pharmacology Vallabhbhai Patel Chest Institute

1. 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,

2. 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

3. 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

4. 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

5. Pharmacovigilance methods • Spontaneous reports (most commonly) • PEM (prescription event monitoring) • Observational Studies(Case Control and Cohort Studies)

6. 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

7. 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”

8. Causality Assessment scales • Naranjo’s scale • WHO causality assessment scale

9. 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

10. Naranjo ADR Probability Scale Naranjo CA. Clin Pharmacol Ther 1981;30:239-45

12. 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

13. 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

14. 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

15. SEX-WISE DISTRIBUTION OF MALES AND FEMALES ENROLLED IN THE STUDY

16. GENERAL PROFILE OF DRUG TREATMENT AND ADVERSE EFFECTS IN COPD

17. PERCENTAGE OF OUTPATIENTS RECEIVING DIFFERENT DRUGS FOR TREATMENT OF COPD +LA b2 agonist

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

19. ADR profile with respiratory drugs

20. 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

21. 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

22. Prescription monitoring in obstructive airway disease (theophylline)

23. Prescription audit in obstructive airway disease (theophylline)

24. ADR incidence with theophylline

25. ADVERSE EFFECT PROFILE IN COPD PATIENTS WITH ORAL THEOPHYLLINE

26. PERCENTAGE OF DIFFERENT ADRs WITH ORAL THEOPHYLLINE IN COPD PATIENTS

27. 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 ------------------------------------------------------------------------------------

28. Incidence of ADRs after theophylline in patients of Bronchial Asthma

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

30. 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

31. Comparison of ADRs after theophylline and doxofylline in bronchial asthma anxiety Muscle spasm Dizziness Sore throat No ADRs insomnia No ADR

32. Comparison of ADRs after theophylline and doxofylline in COPD anxiety anxiety Muscle spasm Dry mouth insomnia Tremors Gastritis Nausea No ADR No ADRs

33. 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

34. Acknowledgements • Dr. V K Vijayan • Prof. A Ray • Dr. Neeraj Tyagi • Dr. Gaurav Vishnoi • Dr. Dushyant Lal