Pharmacovigilance

WHAT IS PHARMACOVIGILANCE (PV)?

The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other medicine-related problem - WHO

WHY PV IS NEEDED

HISTORY..
Registration of New Chemical Entities was very much dependant on the status of products in the reference countries Changes to product information was mainly industry driven Few pre-clinical studies conducted in the region and hardly any Phase IV studies Adverse drug reaction reporting was very minimal and mainly involved reports submitted by health care professionals

CONT.
Most reports were for known reactions involving older drugs which were used in government-run hospitals Signal detection not possible as there were too few reports Only able to detect some quality defects of generics which manifested as ADRs Pharmacovigilance was mainly about getting ADR reports and submitting them to WHO No significant regulatory changes made based on these reports

CURRENT SCENARIO
Increased awareness and interest amongst doctors and pharmacists to report ADRS as they have seen some benefit in reporting Increasing number of clinical trials being conducted especially in Singapore, Thailand and Malaysia GCP training for investigators served to increase awareness of SAE and ADR reporting amongst health care professionals and the industry

CONT..
More hospitals and companies using on-line reporting system less hassle than submitting hard copy reports Increasing involvement by hospital pharmacists in pharmacovigilance during clinical ward rounds and when counseling patients

The Aims of Pharmacovigilance

To improve patient care and safety To improve public health and safety To contribute to the assessment of benefit, harm, effectiveness and risk of medicines To promote understanding, education and clinical training

Who are the partners?

Government Industry Hospitals and academia Medical and pharmaceutical associations Poisons information centres Health professionals Patients Consumers Media WHO

DEFINITION
Adverse Drug Reaction
"A response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function."

Adverse Event
Any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment

Side Effect
Any unintended effect of a pharmaceutical product occurring at doses normally used in man which is related to the pharmacological properties of the drug

WHAT TO REPORT?
SERIOUS ADRS A serious adverse event (experience) or reaction is any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization of prolongation of existing hospitalization, is a congenital anomaly/birth defect. NOTE: The term life-threatening in the definition of serious refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it was more severe.

Adverse Reactions:Possible Causes

Intrinsic factors of the drug
Pharmacological Idiosyncratic Carcinogenicity, Mutagenicity Teratogenicity

Extrinsic factors
Adulterants Contamination

Underlying medical conditions Interactions Wrong usage

WHAT SHOULD BE REPORTED

New drugs
Report all suspected reactions including minor ones

For established or well known drugs

All serious, unexpected, unusual ADRs

Change in frequency of a given reaction ADRs to generics not seen with innovator products ADRs to traditional medicines

WHAT SHOUD BE REPORTED

All suspected drug-drug, drug-food, drug-food supplement interactions
Statement highlighting marine source of supplements such as glucosamine so that can be avoided by those with allergy to sea food

ADRs associated with drug withdrawals ADRs due to medication errors

eg vincristine given IT

ADRs due to lack of efficacy or suspected pharmaceutical defects

INNOVATOR PRODUCTS
Limited information available at time when drug is first marketed Minimal information on use in Asian population, interactions with indigenous medicines Conduct intensive monitoring to identify new, unlabeled adverse reactions, monitor for rare reactions Provide updates to prescribers on new findings, labelling changes, safety issues

GENERIC PRODUCTS
Monitor efficacy Monitor adverse effect profile to study differences in ADR pattern c.f innovator products Help in improving quality of generics used
Does the problem arise due to ADR or quality defects ? Problems appearing in sequence Abrupt increase in frequency Problem only arises with certain brands

NON-PRESCRIPTION MEDICATIONS
Quality defects can also lead to ADRs e.g. Pan Pharmaceuticals (Australia) case Patients can develop ADRs to food supplements, health products Overuse of supplements Current issue of dioxin contamination in Cod Liver Oil preparations resulting in product withdrawals in UK

TRADITIONAL & COMPLEMENTARY MEDICINES

Minimal information available on traditional medicines
ADRs Drug interactions At risk groups e.g. alfalfa and exacerbation of SLE

Misnomer of because it is natural, it is safe

Association of Black Cohosh with liver problems

Health professionals should try to get as much information as possible

Name of product Indication Place of purchase (esp for unregistered products)

PREGNANCY
Very little information available on outcome data for drugs used in pregnancy
Current issue of association between lamotrigine use and cleft palate syndrome ACE Inhibitors and congenital anomalies

Should follow-up cases where drugs are prescribed intentionally or have been used inadvertently to monitor outcome of pregnancy, effect to the foetus/baby

ACTIVE INGREDIENTS WITHDRAWN

THALIDOMIDE (1961) Congenital limb defects BENOXAPROFEN (1982) Hepatotoxicity PHENFORMIN (1982) Lactic acidosis FENFLURAMINE (1997) Heart-valve abnormalities ASTEMIZOLE Many drug interactions PHENYLPROPANOLAMINE(2000) Haemorragic stroke KAVA KAVA Liver abnormalities CERIVASTATIN Rhabdomyolysis CISAPRIDE Cardiac arrythmias ROFECOXIB (2004) Cardiovascular events VALDECOXIB (2005) Cardiovascular events, serious skin reactions COMFREY, SENECIO Nephrotoxicity TEGASEROD (2007) Cardiovascular events CLOBUTINOL (2007) Cardiac arrhythmia

COMMUNICATING THE OUTCOME OF PV

DHCP Letter product holders Product Alerts National Health Authorities Media statements - National Health Authorities/Pharmacovigilance Centres Newsletters National Pharmacovigilance Centres and WHO Feedback to reporters National Pharmacovigilance Centres

INTERNATIONAL COOPERTATION
MALAYSIA

WHO

OTHER REGULATORY AGENCIES eg USFDA, EMEA, TGA, HSA

WHO PROGRAMME FOR INTERNATIONAL DRUG MONITORING

Started 1968 Located in Uppsala, Sweden Collaborating centre for maintaining global ADR database - Vigibase

Roles of WHO Collaborating Centre

Identify early warning signals of serious adverse reactions to medicines Evaluate the hazard Undertake research into the mechanisms of action to aid the development of safer and more effective medicines

ANALYSIS OF REPORTING RATE (n=3068)

3500

No. of Reports

3068
3000

2500

2543 2363

2000

1665
1500

1063
1000

1000 875 792 603 787

500

530 400 150 216 263 233

0 1987

10
1988

38
1989

40
1991 1992 1993 1994 1995 1996 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Year

TOTAL ADRs REPORT BY STATE (n=3068)

800 700 600

N o . o f R e p o r ts

500 400 300 200 100 0

WPKL 2000 2001 2002 2003 2004 2005 2006 2007 112 157 245 188 304 532 401 466 SELANGOR 112 126 209 257 397 491 456 745 PERAK 106 114 97 66 100 134 146 158 JOHOR 88 61 92 74 109 101 163 264 PAHANG 47 20 26 102 124 105 102 107 SARAWAK 43 39 42 34 76 116 162 157 SABAH 48 46 58 50 88 316 394 242 N TERENGGA P PINANG SEMBILAN NU 58 53 53 54 102 121 138 217 34 32 30 33 49 110 128 142 29 38 29 17 42 36 100 106 KEDAH 24 24 17 65 96 123 101 140 KELANTAN 19 18 36 30 56 73 57 84 MELAKA WP LABUAN 17 24 41 50 69 72 110 168 8 16 16 36 42 14 7 11 PERLIS 3 9 5 5 8 13 18 23 PUTRAJAY UNKNOWN A 0 1 0 1 3 5 16 20 0 0 0 1 1 11 44 18

2000 2001 2002 2003 2004 2005 2006 2007

TEN DRUGS WITH THE MOST REPORTED ADRs

NO 1 2002 CO TRIMOXAZOLE (47) CARBAMAZEPINE (32) CLOXACILLIN (31) AMOXYCILLIN (28) ALLOPURINOL (22) 2003 ALLOPURINOL (33) 2004 ALLOPURINOL (37) 2005 CAPTOPRIL (52) 2006 TRADITIONAL MEDICINE (68) DICLOFENAC (65) CARBAMAZEPINE (62) NIFEDIPINE (58) ALLOPURINOL (57) 2007 PERINDOPRIL (97)

CLOXACILLIN (30)

PARACETAMOL (29)

ALLOPURINOL (51)

ALLOPURINOL (75)

MEFENAMIC ACID (25)

CARBAMAZEPINE (29)

CLOXACILLIN (50) DICLOFENAC (44) NIFEDIPINE (44) METFORMIN (39)

CLOXACILLIN (71)

DICLOFENAC (24) CHLOROTHIAZIDE (22)

NIFEDIPINE (28) CO TRIMOXAZOLE (28) ERYTHROMYCIN (23)

DICLOFENAC (71)

METFORMIN (69)

TRADITIONAL MEDICINE (22) ALENDRONATE (19)

CARBAMAZEPINE (19)

PERINDOPRIL (57)

ASPIRIN (67)

TRADITIONAL MEDICINE (18) AMOXYCILLIN (18) PENICILLIN G SODIUM (15)

AMOXYCILLIN (23)

PARACETAMOL (38)

CO TRIMOXAZOLE (55)

TICLOPIDINE (50)

DICLOFENAC (19) ISOSORBIDE DINITRATE (18) LOVASTATIN (13)

MEFENAMIC ACID (21)

CO TRIMOXAZOLE (37) ATENOLOL (37)

ASPIRIN (41) ERYTHROMYCIN (40)

RIFAMPICIN (46)

ASPIRIN (19)

PHENYTOIN (44)

10

VANCOMYCIN (15)

CLOXACILLIN (18)

CEFUROXIME (36)

PHENYTOIN (39)

AMOXYCILLIN (43)

NO. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

10 BEST HOSPITALS HOSP. SELAYANG HOSP. KUALA LUMPUR UNIVERSITY MALAYA MEDICAL CENTRE HOSP. DUCHESS OF KENT HOSP. TUANKU JAAFAR HOSP. PULAU PINANG HOSP. SULTANAH AMINAH HOSP. MELAKA HOSP. UMUM SARAWAK HOSP. PAKAR SULTANAH FATIMAH

NO. OF REPORTS (2007) 197 170 156 140 137 126 122 121 97 95

SO.WHAT IS OUR ROLE?

SEND NOT ONLY QUANTITY BUT.

QUALITY REPORTS

HOW?
Monitor clinical status of patients Identify the correct ADRs not side effects Get more information Investigate at hospital level Help doctors to fill-up the forms Keep patients record if more information needed

TERIMA KASIH