1. Somayyeh Nasiripour Pharm.D assistant professor at IUMS

2. Adverse Drug Reaction WHO definition:
Any response to a drug which is Noxious and Unintended, and which occurs at doses used in men of prophylaxis, diagnosis or treatment.

3. Adverse Drug Reaction vs. Adverse Event
Diseases
Adverse Drug Reaction
(event attributed to drug)
Diet
Genetics
Other
factors
All Spontaneous
reports
Other Drugs
Events not attributed to drug
Compliance
Environment

4. Relationship Between ADEs and ADRs
Preventable
Medication Errors
Not Preventable
Inherent Risk of Drug
Adverse Drug Reactions
Adverse Drug Events
Potential Adverse Drug Events
Trivial Medication Errors
Adapted From:

5. Pharmacovigilance
The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other
drug-related problem.

6. Vigilance Vigilare = to watch alert watchfulness
forbearance of sleep; wakefulness
watchfulness in respect of danger; care; caution; circumspection
the process of paying close and continuous attention

7. Why Pharmacovigilance?
Adverse Drug Reactions are the 4th to 6th largest cause of mortality in the USA
(Lazarou J. et al., 1998) 7

8. Why Pharmacovigilance?
The percentage of hospital admissions due to drug related events in some countries is about or more than 10%.
UK Study : 10.1 % (Bhalla et al, 2003)
French study : 10.3 % prevalence of ADRs (Imbs et al, 1999) 8

9. How common are ADRs?
Up to 40% patients in the community experience ADRs
In the UK Non Steroidal Anti-Inflammatory Drug (NSAID) use alone accounts for1
65,000 emergency admissions/year
12,000 ulcer bleeding episodes/year
2,000 deaths/year
1Blower et al. Emergency admissions for upper gastrointestinal disease and their relation to NSAID use. Aliment Pharmacol Ther 1997; 11:
Things to say
1) Up to 40% patients receiving drugs in the community are though to experience ADRs. It is difficult to study ADRs in the community and there are very few well designed studies
2) NSAID use is associated with significant morbidity and mortality in the UK each year. There is a strong association between NSAID use and likelihood for upper GI emergency admission.
Useful information
Ref for 1) In a 1979 study in general practice 41% of 817 patients surveyed were thought to have certainly or probably experienced an ADR. Martyrs C. Adverse reactions to drugs in general practice. BMJ 1979; 2: )
Ref for 2) The data recorded in the trial was extrapolated to give the estimated UK figures. The study was a retrospective survey of case notes of all emergency upper GI admissions per annum attributable to NSAID use. The study was undertaken at 2 District General Hospitals in the North West of England (catchment population 550,000). Matched controls were emergency admissions not caused by upper GI diagnoses. (Blower et al. Emergency admissions for upper gastrointestinal disease and their relation to NSAID use. Aliment Pharmacol Ther 1997; 11: )

10. In 1922, there was an enquiry into the JAUNDICE associated with the use of SALVARSAN, an organic arsenical used in the treatment of Syphillis.
In 1961, it was reported in West Germany that there was an outbreak of PHOCOMELIA (hypoplastic and aplastic limb deformities) in the new born babies.
It was shown subsequently that thalidomide, a non barbiturate hypnotic, was to blame.
The crucial period of pregnancy during which thalidomide is TERATOGENIC is the first three months.

11. History of drug safety after thalidomide disaster
1961 :
Dr William McBride (Australia)( thalidomide 4000 cases)
1964 :
UK started “yellow cards” system
1968 :
start of WHO Programme for International Drug Monitoring

12. DRUGS THAT HAVE BEEN WITHDRAWN OR HAVE HAD THEIR USES RESTRICTED BECAUSE OF ADVERSE DRUG REACTIONS:
Year
Adverse Reaction
Outcome
Sulfanilamide
1937
Liver damage due to diethylene glycol
Solvent changed; FDA established
Thalidomide
1961
Congenital Malformations
Withdrawn
Chloramphenicol
1966
Blood Dyscrasias
Uses restricted
Benoxaprofan
1982
Liver damage
Aspirin
1986
Reye’s syndrome
Flecainide
1989
Cardiac Arrhythmias
Noscapine
1991
Gene toxicity
Triazolam
Psychiatric disorders
Tuesday, May 08, 2018

13. DRUGS THAT HAVE BEEN WITHDRAWN OR HAVE HAD THEIR USES RESTRICTED BECAUSE OF ADVERSE DRUG REACTIONS:
year
Adverse reaction
Outcome
Temafloxacin
1992
Various serious adverse effects
Withdrawn
Co-trimoxazole
1995
Serious allergic reactions
Uses restricted
Terfenadine
1997
Interactions
(e.g. with grapefruit juice)
Withdrawn from OTC sale
Sotalol
Cardiac arrhythmias
Astemizole
1998
Cisapride
2000
Cerivastatin
2001
Rhabdomylosis
Tuesday, May 08, 2018
ASHUTOSH MISHRA

14. DOSE-RELATED ADVERSE DRUG REACTIONS
Dose related adverse reactions have led to the concept of the THERAPEUTIC INDEX, or the TOXIC:THERAPEUTIC RATIO.
This indicate the margin between the therapeutic dose and the toxic dose.
The bigger the ratio, the better.
Examples of drugs with a low TOXIC:THERPEUTIC RATIO:
Anticoagulants (warfarin, heparin)
Hypoglycemic drugs (insulin, sulfonylurea)
Antiarrythmic drugs (lidocaine, amiodarone)
Tuesday, May 08, 2018
ASHUTOSH MISHRA

15. Adverse Drug Reactions: How do we learn about them?
Most common adverse reactions are detected in premarketing clinical trials (reported in prescribing information)
However, most clinical trials are of short duration, and patient numbers in trials are low compared to population
Latent ADRs often missed
3000 patients at risk needed to detect with an incidence rate of 1/1000 with 95% certainty
Most trials also exclude the very young and old, pregnant women, patients with multiple diseases, and any potentially interacting medications
Additional ADRs are discovered once a drug enters the marketplace
References: Ahmad S.R., J Gen Intern Med, 2003; 18:57-60

16. Types of Drug Reactions: Nonimmunologic
Predictable
Pharmacologic side effect
Dry mouth from antihistamines
Secondary pharmacologic side effect
Thrush while taking antibiotics
Drug toxicity
Hepatotoxicity from methotrexate
Drug-drug interactions
Seizure from theophylline while taking erythromycin
Drug overdose
Seizure from excessive lidocaine (Xylocaine)
Unpredictable
Pseudoallergic
Anaphylactoid reaction after radiocontrast media
Idiosyncratic
Hemolytic anemia in a patient with G6PD deficiency after primaquine therapy
Intolerance
Tinnitus after a single, small dose of aspirin
G6PD = glucose-6-phosphate dehydrogenase.
Adapted From:

17. Types of Drug Reactions: Immunologic
Type I reaction (IgE-mediated)
Anaphylaxis from b-lactam antibiotic
Type II reaction (cytotoxic)
Hemolytic anemia from penicillin
Type III reaction (immune complex)
Serum sickness from anti-thymocyte globulin
Type IV reaction (delayed, cell-mediated)
Contact dermatitis from topical antihistamine
Specific T-cell activation
Morbilliform rash from sulfonamides
Fas/Fas ligand-induced apoptosis
Stevens-Johnson syndrome Toxic epidermal necrolysis
Other
Drug-induced, lupus-like syndrome Anticonvulsant hypersensitivity syndrome
Adapted From:

18. ADRs by Drug Class
Adapted From:

19. Body Systems Commonly Involved
Central Nervous System
Hematologic
Cardiovascular
Renal/Genitourinary
Sensory
Neuropathy
Auditory
Dermatologic
especially visible lesions or eruptions
Gastrointestinal
Metabolic

20. ADR Effects (Gingival Enlargement due to Ca2+-Channel Blockers)
Used with permission from Carl Allen, DDS and eMedicine.com, Inc., 2005

21. ADR Effects (Coumadin Necrosis of the Leg)
Used with permission from Michelle Ehrlich, MD and eMedicine.com, Inc., 2005

22. هدف از گزارش عوارض:

23. The Yellow Card .

24. Ref: Ernst Frank R, Grizzle Amy J. J Am Pharm Assoc. 2001; 41: 192-9
Since 1995 the costs associated with drug-related problems (DRPs) have more than doubled.
The total cost of drug-related morbidity and mortality exceeds the cost of the medications themselves.
Ref: Ernst Frank R, Grizzle Amy J. J Am Pharm Assoc. 2001; 41: 192-9

25. هدف از گزارش عوارض ثبت عوارض جدید: Unepected ADR تداخلات وابستگی
Long term efficacy
Risk factor
کیفیت فراورده
تشخیص سریع تر واکنش های ناخواسته
Increase frequency
رده بارداری و شیردهی

26. “yellow cards”

27. مزیت جمعیت بزرگی را در بر می گیرد مشاهده ای و هزینه ای ندارد
عوارض ناخواسته ثبت میشود

28. Are all ADRs reported? NO
Only 2-4% of all ADRs are reported
Only 10% of serious ADRs are reported
Things to say
The are many reasons proposed for under reporting including,
Complacency - only safe drugs get to the market!
Fear - of litigation, or breach of confidentiality
Guilt - because the patient was harmed due to treatment prescribed
Ambition - to collect a series of cases for publication
Ignorance - of how and what to report
Diffidence - lack of confidence about reporting suspicions
Lethargy - lack of interest, time, no card available
Useful information
Reference: Pirmohamed et al. Adverse drug reactions. BMJ 1998; 316:
Never assume that someone else will report!

29. دلايلي كه باعث كاهش گزارشاتADR ميگردد:
1- عدم اطلاع از مكانيزم موجود براي ارسال گزارش
2- عدم دسترسي به فرم مربوطه
3- عدم اهميت عارضه از نظر گزارشگر
4- نداشتن وقت در رابطه با فرم مربوطه
5- اجتناب از درگيري در كارهاي اداري
6- ترس از شكايات حقوقي, كيفري توسط داروADR
7- عدم اطمينان از بوجود آمدن

30. Do I have to be completely certain what I have seen is an ADR?NO
The Yellow Card Scheme
collects SUSPICIONS
Do I have to be completely certain what I have seen is an ADR?

31. What is a serious reaction?
A reaction that:
is fatal
is life threatening
is disabling
results in hospitalisation
prolongs hospitalisation
Is teratogen
Useful information
If anyone asks..
To find this list from the CSM website homepage,
1 Click on the ‘Yellow Card Scheme’ button in the toolbar on the left hand side of the page
2 Click on the ‘what to report’ hyperlink in the yellow box
3 Click on the ‘what are the differences between serious and severe reactions?’ hyperlink in the yellow box
4 Click on the ‘examples of some reactions which are medically significant are attached here’ hyperlink (PDF file)

32. What information must I have to complete a Yellow Card?
Four critical pieces of information are needed:
. Patient details
2 . Suspect drug
. Suspect reaction
. Reporter details
Things to say
The following slides give further information on the 4 pieces of critical information.

33. Remember!
“All health-care professionals have a responsibility to inform colleagues about clinically important adverse drug reactions that they detect, even if a well-recognised or causal link is uncertain.”
Edwards IR and Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet 2000; 356:
Things to say
Reporting suspected a ADR on a Yellow Card to the CSM is one way of fulfilling this responsibility.

34. Do not assume someone else will report it!
If you suspect an ADR..
Do not assume someone else will report it!
Things to say
Never assume someone else will report
It does not matter if someone else has reported, duplicates are picked up and usually complement each other.
It doesn’t matter if it turns out not to be an ADR. Don’t not report just because you are not sure.

35. How do I recognise ADRs? Things to say
We now know what an ADR is and why ADRs are a problem So
How can you identify ADRs?

36. Who is most at risk from ADRs?
Patients who:
are young, or old or female
are taking multiple therapies
50% of patients on 5 drugs or more
have more than one medical problem
have a history of allergy or a previous reaction to drugs
Things to say
Age – The very old and the very young are more susceptible to ADRs. In children, systems for handling drugs are not developed and in the elderly these systems may be slowing with age. The elderly are also likely to have multiple and often chronic diseases. E.g. Elderly patients much more susceptible to the effects of benzodiazepines leading to drowsiness the next day.
Gender – Women appear to be at a higher risk of suffering ADRs. The reason is not clear.
Multiple therapies – The incidence of ADRs increases sharply with the number of drugs taken, 50% patients on 5 drugs are likely to experience an ADR.
Intercurrent diseases – Drug handling may be altered in patients with renal, hepatic, and cardiac disease.
Allergy – patients with a history of allergic disorders are at the greatest risk of experiencing an allergic reaction.
Useful information
Specific diseases predispose to ADRs eg in HIV positive patients there is an increased frequency of idiosyncratic toxicity with anti-infective drugs such as co-trimoxazole (50% vs 3% in HIV negative patients).

37. What should raise my suspicion of an ADR?
A symptom that
appears soon after a new drug is started
appears after a dosage increase
disappears when the drug is stopped
reappears when a drug is restarted

39. Listen to the patient! Things to say
Patients can be a really important source of information about ADRs , listen to them and ask questions about how their medication is suiting them

40. What questions should I be asking if I suspect an ADR?
Does the patient have a history of other drug-induced problems?
ask the patient
Does the patient take more than one drug ?
could an interaction be causing the ADR?
long term medication is unlikely to cause new problems

41. Are ADRs avoidable? 30-50% are preventable Obvious interactions
many drugs interact with warfarin
Use of contra-indicated drugs
use of a non-selective beta-blocker in an asthmatic  bronchospasm
Drug use in an inappropriate clinical indication or medically unnecessary
antibiotics for a viral infection
antibiotics for viral infections
Things to say
You can use these examples or examples of your own
Obvious interactions
-many drugs interact with warfarin causing alteration of the INR which may lead to bleeding episodes
Use of contra-indicated drugs
- use of a non-selective beta-blocker in an asthmatic can lead to bronchospasm
Drug use in an inappropriate clinical indication or medically unnecessary
-antibiotics for a viral infection will not cure the infection but will expose patients to the adverse effects of the drug. 41

42. Iranian ADR Monitoring Center
Pharmacovigilance
Iranian ADR Monitoring Center

43. مركز ثبت و بررسي عوارض ناخواسته داروها معاونت غذا و دارو
دستورالعمل گزارش دهي عوارض دارويي به مركز ثبت و بررسي عوارض ناخواسته داروها توسط شركت هاي سازنده و وارد كننده دارويي
مركز ثبت و بررسي عوارض ناخواسته داروها
معاونت غذا و دارو
وزارت بهداشت، درمان و آموزش پزشكي
تاريخ تدوين: فروردين 1384

44. Diclofenac Na ( VOLTAREN )
176 cases of Foot drop and walking difficulty ( )
2 New cases (1385)

45. 4 Cases of Para-plegia following IT injection
Bupivacaine
4 Cases of Para-plegia following IT injection
2 of them led to Death
درود-1380

46. Tramadol
5 cases of death
آبان ماه 1382

47. Stevens Johnson Syndrome 5 years old child تهران- آذر ماه 1382
Lamotrigin
Stevens Johnson Syndrome
5 years old child
تهران- آذر ماه 1382

48. 2 cases of Cardiac Arrest تهران- بهمن ماه 1382
Cisapride
2 cases of Cardiac Arrest
تهران- بهمن ماه 1382

49. One case of Cardiac Arrest تهران- 1383
Sildenafil
One case of Cardiac Arrest
تهران- 1383

50. Anaphylactoid reactions دی ماه 1383
Cephalosporins
Anaphylactoid reactions
دی ماه 1383

51. محلولهای دیالیز صفاقی شرکت ثامن
250 مورد پریتونیت شیمیایی
اردیبهشت 1385

52. Vancomycin
Many cases of Flushing and Red Neck Syndrome following rapid infusion of Vancomycin

53. شناسایی و ارسال گزارش موارد افزایش فراوانی در عوارض و/یا عدم اثربخشی جهت بررسی فرآورده در موارد زیر: - فنوباربیتال - وانکومایسین - فنی توئین - واکسن MMR - هپارین - هیدروکورتیزون کاسپین تامین و داروپخش - محلول پوویدون آیداین - اکسی توسین - شیرخشک یارا نه ای - سیناوکس - کنتراسپتیوهای خوراکی - سیکلوسپورین - سفتریاکسون

54. تعداد گزارشهای دانشگاهها در سال 1386
تهران
1522
زنجان 15
لرستان 10

55. The basis of Drug Interactions.

56. Classification of Interactions:
Pharmacokinetic
Pharmacodynamic
Both
Chemical

57. Pharmacokinetic Interactions:
Absorption(ciprofloxacin/antacids)
Distribution(sulfa drugs/warfarin)
Metabolism(erythromycin/terfenadine)
Excretion(smx-tmp,NSAIDs/MTX)

58. Bioavailability Alteration:
Anticholinergic,opioids,food (Cmax/AUC)
Prokinetic agents
OCPs
Divalent-trivalent cations PH C t

59. CYP450
1A2
2C9,2C19
2D6
3A4

60. SUBSTRATE OF 1A2 TCA(tert.amines) Clozapine Theophylline Propranolol
Tacrin
Caffeine
Halopridol
Phenothiazines …

61. SUBSTRATE OF 2C 2C19: TCA(tert.amines) Citalopram Barbiturates
Propranolol
Omeprazol
2C9:
bupropion
Phenytoin
Tolbutamide
(S)-Warfarin
NSAIDs

62. SUBSTRATE 2D6 Risperidone Codeine TCA(second. amines) Hydrocodone
Dextrometorphan
Chlorpheniramine
Propranolol
metoprolol
TCA(second. amines)
Fluoxetine
Paroxetine
Venlafaxine
Nefazodone(mcpp met.)
amphetamines

63. SUBSTRATE 3A4 TCA(tert.amines) Fluoxetine Sertraline
Venlafaxine
Nefazodone
Carbamazepine
Quetiapine,pimozide
Triazolobenzodiazepine
Zolpidem
Protease inhibitors
Astemizole,Terfenadine
Cisapride
Macrolides
Calcium channel blockers
Sex hormones(estrogen)
Corticosteroids
Lovastatin
Cyclosporine,Tacrolimus
Sildenafil,tadalafil,vardenafil

64. Altered Renal Excretion
MTX/Sulfonamides,Trimethoprim,NSAIDs
Probenecid
Potassium/trimethoprim
Li/Diuretics

65. OCPs

66. Dalfopristin/Quinupristin(Synercid)
Inhibitor of 3A4
Digoxin ?

67. Grapefruit juice

68. SUBSTRATE 3A4 TCA(tert.amines) Fluoxetine Sertraline
Venlafaxine
Nefazodone
Carbamazepine
Quetiapine,pimozide
Buspirone
Triazolobenzodiazepine
Zolpidem
Protease inhibitors
Astemizole,Terfenadine
Cisapride
Macrolides
Calcium channel blockers
Sex hormones(estrogen)
Corticosteroids
Lovastatin
Cyclosporine,Tacrolimus
Sildenafil,tadalafil,vardenafil

69. Linezolid(Zyvox)
MAOI effect (reversible)
MAO

70. Fluoroquinoloes Cations(…90%) NSAIDS(fenbufen,naproxen…)
Azlocillin/cipro
Cyclosporine,cimetidine
Seizure threshold(/foscarnet)
Cipro,enoxacin,norfloxacin…inhibitor of 1A2

71. SUBSTRATE OF 1A2 TCA(tert.amines) Clozapine Theophylline Propranolol
Tacrin
Caffeine
Halopridol
Phenothiazines …

72. SMX/TMP Warfarin(2C9 inhibition?) MTX Cyclosporine
Azathiprione (leukopenia)

73. Macrolides Cimetidine transient reversible deafness. Ergot amputation
Inhibition of 1A2, 3A4

74. SUBSTRATE OF 1A2 TCA(tert.amines) Clozapine Theophylline Propranolol
Tacrin
Caffeine
Halopridol
Phenothiazines …

75. SUBSTRATE 3A4 TCA(tert.amines) Fluoxetine Sertraline
Venlafaxine
Nefazodone
Carbamazepine
Quetiapine,pimozide
Buspirone
Triazolobenzodiazepine
Zolpidem
Protease inhibitors
Astemizole,Terfenadine
Cisapride
Macrolides
Calcium channel blockers
Sex hormones(estrogen)
Corticosteroids
Lovastatin
Cyclosporine,Tacrolimus

76. Rifampin
Clarithromycin,fluconazol,itraconazol, protease inhibitor/rifampin
Inducer of 1A2,2C ,3A4

77. Metronidazole
Alcohol(disulfiram-like effect)
5FU
warfarin

78. Furazolidone
Alcohol(disulfiram…)
MAOI(weak)
Amitriptyline(psychosis)

79. Azole Antifungals PH Ket.,Food / Itra.,Food
Rifampin(ket.,itra.),phenytoin,
Carbamazepine
Fluconazol inhibition of 2C9
Ket.,Itra. Inhibition of 3A4

80. Herbal Interactions

81. Ephedra
Antihypertensives

82. Ginseng Warfarin…. effectiveness Digoxin …. level up to 75%
Phenelzine,Haloperidol…. side effects
Morphine….block analgesic effects

83. Licorice
Digoxin….Toxicity
Warfarin…..effects

84. ST.John`s Wort(Hypiran)
Digoxin…. level up to 25%
SSRIs…. Side effects
Theophylline…. level up to 50%
Inhibitor of 3A4

85. Hand book of Drug Informations (Apha), 2009
Thanks for your attention
Hand book of Drug Informations (Apha), 2009