ADR Reporting, Medication Error Reporting System (MERS) & Cold Chain ManagementUpdates from Bengkel Laporan Kesan Advers Ubat-Ubatan dan Vaksin 18-20 March 2009 Organized By: Bahagian Perkhidmatan Farmasi, KKM

Pharmacovigilance: Ensuring the Safe use of Medicine and Role of Pharmacists

Registration Criteria

Efficacy

Evaluated from data obtained from clinical trials Compliance to established standards, manufacture by GMP licensed premise Toxicology, clinical trials

Quality

Safety**

** (Very limited information)(Further established through post registration studies) (Discovering new dangers of drugs after marketing is common)

What is Pharmacovigilance (PV)?

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

Why is PV needed?

HISTORY

Registration of New Chemical Entities was very much dependent 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 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 Phamacovigilance

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

Adverse Event

Side Effect

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 Adulterants Contamination

Extrinsic factors

Underlying medical conditions Interactions Wrong usage

WHAT SHOULD BE REPORTED

New drugs

Report all suspected reactions including minor ones All serious, unexpected, unusual ADRs

For established or well known drugs

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

WHAT SHOULD 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, labeling changes, safety issues

GENERIC PRODUCTS

Monitor efficacy Monitor adverse effect profile to study differences in ADR pattern compared with 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 on outcome data for drugs used in pregnancy

Current issue of association between lamotrigine use and cleft palate syndrome

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

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 COOPERATIONMALAYSI A

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 The National Drug Safety Monitoring Centre, was accepted as the 30th member of the WHO Safety Monitoring Program in 1990.

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

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

Recognizing, Reporting and Reducing Adverse Drug Reactions

Limitations of Clinical Trials

too few - normally < than 1500 patients too simple - use patients without complications, other medical conditions too narrow - limited indications too brief - limited time too median - very old/very young patients, pregnant women not included

Classification of ADRs

Type A (Augmented ) reactions Reactions which can be predicted from the known pharmacology of the drug Dose dependent, can be alleviated by a dose reduction E.g. Bleeding with anticoagulants, bradycardia with beta blockers, headache with nitrates, postural hypotension with prazosin

Classification of ADRs

Type B (Bizarre) reactionsCannot

be predicted from the pharmacology of the drug Not dose dependent, host dependent factors important in pre-disposition E.g. anaphylaxis with penicillin, anticonvulsant hypersensitivity

Classification of ADRs

Type C (Chemical) reactions Biological characteristics can be predicted from the chemical structure of the drug/metabolite E.g. paracetamol hepatotoxicity Type D (Delayed) reactions Occur after many years of treatment. Can be due to accumulation E.g. Secondary tumours after treatment with chemotherapy, teratogenic effects of phenytoin taken during pregnancy, analgesic nephropathy, tardive dyskinesia with antipsychotic agents

Classification of ADRs

Type E ( End of treatment) reactions Occur on withdrawal especially when drug is stopped abruptly E.g. withdrawal seizures on stopping phenytoin, adrenocortical insufficiency on withdrawal of steroids

How to recognize ADRs?

Since ADRs may act through the same physiological and pathological pathways as different disease, they are difficult and sometimes impossible to distinguish

Drug administered Pt develops a new condition/symptoms Drug suspected? Check literature

Documented ? (for the product or similar class of products)

Highly suggestive of ADR

Not documented in literature Drug continued Drug discontinuedSymptoms improve (+ve dechallenge)

Worsening of symptoms

Drug restarted Any other possible causes? Concomitant therapy Underlying conditions

Symptoms recur (+ve rechallenge)

Definitions

Dechallenge withdrawing the drug(s) and recording the outcome improved or not improved Rechallenge giving one drug again under the same conditions as before and recording the outcome recurrence or no recurrence.

Preventing, Reducing and Reporting ADRs

Completely avoiding ADRs may be impossible Some simple approaches to prevent the occurrence can be applied

HOW?

Charting all medications when ordered and refilled drug allergies, types of allergy Close attention to the written prescription correct dosing, proper dosage form, avoid abbreviations, cautious of drugs with similar names Being familiar with all potential side effects, interactions Choosing the oral route when possible Taking careful history of patients esp. elderly pts

CONT.

Initiate a committee of Post-Marketing Drug Risk Management at hospital level Initiate active surveillance (rather than relying on spontaneous reporting) Assess whether physicians are following recommended DCA warnings Having a high index of suspicion for ADRs

ADR ReportingIntensive safety surveillance New Zealand Prescription event monitoring US, UK Spontaneous adverse drug reaction monitoring Australia, Malaysia

SPONTANEOUS REPORTING SYSTEM

Passive surveillance system Spontaneous ADR reporting system has 3 phases: Data

collection most problematic Data processing Data analysis and interpretation

HOW TO REPORT?

ONLINE REPORTING www.bpfk.gov.my ADR

forms

REPORTING MECHANISM Directly by the prescribers Through the pharmacists Through the drug companies

CAUSALITY ASSESSMENT OF SUSPECTED ADVERSE DRUG REACTION

INTRODUCTION

Spontaneous reporting system data acquisition, assessment, presentation and interpretation. Causality assessment part of the 1st step in case assessment and is based on a general system that is intended for all reactions and all drug.

Standardized case causality assessment has become a routine at pharmacovigilance centre around the world. Decrease the ambiguity of the data and prevention of erroneous conclusion It neither eliminates nor quantifies uncertainty but, at best, categorizes it in a semi quantitative way

METHODS OF CAUSALITY ASSESSMENTThere were several method that can be use to make a causality assessment of ADRs reports. The literature (9 points of consideration Morges, Switzerland , 1981) Probability calculation (Bayes Theorem) Aetiological Diagnostic Systems (Bnchious group method) French imputation systems The European ABO Systems The US Reasonable Possibility Systems The Naranjo ADR Probability Scale WHO Causality Categories

The Naranjo ADR Probability ScaleQuestions 1) Are there previous conclusive reports on this reaction? 2) Did the ADR appear after the suspected drug was administered? 3) Did the ADR improve when the drug was discontinued? 4) Did the ADR appear with re-challenge? 5) Are there alternative causes for the ADR? 6) Did the reaction appear when placebo was given? 7) Was the drug detected in blood at toxic levels? 8) Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? 9) Did the patient have a similar reaction to the same or similar drug in any previous exposure? 10) Was the ADR confirmed by any objective evidence? Yes +1 +2 +1 +2 -1 -1 +1 +1 No 0 -1 0 -1 +2 +1 0 0 Dont Know 0 0 0 0 0 0 0 0

+1 +1

0 0

0 0

The Naranjo Probability ScaleThe score :> 8 = Highly probable 5-8 = probable 1-4 = possible 0 = doubtful

WHO Causality Categories C1

Certain C2 Probable C3 Possible C4 Unlikely C5 Unclassifiable

WHO Causality Categories

C1: Plausible time, not related to underlying condition, concurrent disease, other drugs or chemicals, related pharmacologically, +ve dechallenge, +ve rechallenge C2: Reasonable time, unlikely to be related to concurrent disease, other drugs,+ve dechallenge, no rechallenge

CAUSALITY ASSESSMENT

C3: Reasonable time, may be due to concurrent disease, other drugs, no information on dechallenge C4: Improbable temporal relationship, other confounding factors such as drugs, chemicals, underlying disease C5: Insufficient information to analyse the report

Case causality assessmentHow close is the relationship between drug and event? Did the drug cause the event?

CONSUMERS MEDICINES SURVEILLANCE

The protocol for the medicines surveillance integrating consumer reporting

The surveillance of medicines integrating consumer reporting will be an extension and expansion of the existing surveillance activities carried out by NPCB NPCB will be the focal point which will receive, analyze and investigate the reports submitted by the consumers.

The importance of involving consumer in medicines surveillance

The ultimate goal is to improve the quality, efficacy and safety of the marketed product Empower consumers to be aware ofQuality Safety Correct usage of medication

Alleviate the problem of consumers wasting their valuable resources on medicines which may expose their health to risks.

Reporting by consumers can be done through

Reporting forms On-line reporting Other channels eg: letters, phone calls, emails and complaints done personally to Drug Regulatory Agencies (DRA) Information channeled through health professionals, the product owner, consumer associations or other trade and industry organizations which will then be directed to NPCB

What to report?

Quality defects Lack of efficacy Adverse drug reactions Suspected counterfeit product Unregistered product Suspected adulterated products Medication error / near misses Fraudulent / misleading claims

WORK PROCESSReceive product complaint Verify registration status

Inform reg. holder without identifying complainant - Must respond with findings within 2 wks

BPFK conduct own investigations based on nature of complaint

Decide on action to be taken based on outcome of the findings -Product recall - Intensified surveillance -GMP inspection of premises, of manufacturer/other products -No generalised action because problem is not due to product per se Inform complainant on action taken QAP indicator: 85% of all complaints received must be resolved within 6 weeks

Quality DefectsCan arise due to Manufacturing problems Improper storage and handling by Manufacturer End

/ distributor

user

Inappropriate handling during repacking

Decision Making Process

Problem identified confined to a particular batchBatch recall Warning letter

Problem involves product in generalTotal product recall Suspension / cancellation of registration GMP inspection of premise

Cancellation of manufacturing license

Legal action if necessary

Regulatory actions taken

Active ingredients withdrawn Revocation of product, manufacturing license Product withdrawn from the market Restriction of usage Carries a warning Precautionary statement included Review of labeling requirements Make changes to product information based on new findings

Report acknowledgement

All complainants will receive an acknowledgement from NPCB Information on actions which are taken based on the report will be made known to the complainant after the necessary actions have been taken

Confidentiality

The confidentiality of complaints will be maintained as far as possible Only the outcome of actions may need to be publicized in the interest of public safety

R P R IN EO T G

T e in rm n th y u p h fo atio at o b u fo th so p rp s e sed r e le u o T e r ep rter is req ire h o u in rm n is req ired fo atio u an p n o tsid th d g y erso u e e ru

Links

Form BPFK 418.3 Product Comp

ADVERSE EVENTS FOLLOWING IMMUNIZATION

Definition of Adverse Events Following Immunization Any adverse event that follows immunization that is believed to be caused by the immunization

Classification of AEFIsVaccine reaction Event caused or precipitated by the vaccine when given correctly, caused by the inherent properties of the vaccine Programme error Event caused by an error in vaccine preparation, handling or administration Coincidental Event that happens after immunization but not caused by the vaccine a chance association Injection reaction Event from anxiety about, or pain from, the injection itself rather than the vaccine Unknown Events cause cannot be determined

A. Vaccine Reactions

Classified as common, minor reactions and rare, serious reactions Most reactions are minor and settle on their own Serious reactions very rare and generally do not result in long-term problems

Common, Minor Reactions

Immune responses such as local reactions (pain, swelling, redness of inj. site), systemic reactions (fever, irritability, malaise, loss of appetite) Some vaccines components such as adjuvant, stabilizers or preservatives can lead to reactions Only last for one/two days except measles/MMR (6-12 days)

Rare, Serious Reactions

Eg : seizures, thrombocytopenia, hypotonic hyporesponsive episodes, persistent inconsolable screaming, anaphylaxis, paralytic poliomyelitis, disseminated BCG infection

Prevention and Treatment

Rarely contraindicated check allergy status (vaccines and its components) Advice parents on managing common reactions/serious reactions

B. Programme Errors

Result from errors and incidents in vaccine preparation, handling or administration Eg

: reuse of syringes/needles, incorrect diluents, wrong injection sites, improper storage/transport, contraindications ignored

May lead to a cluster of events

How to avoid programme errors?

Reconstituted with correct diluents (supplied by manufacturers) Discard any leftover at the end of immunization session Provide refrigerator specially for vaccines Trained workers, closely supervised and procedures followed Investigation team for AEFI

C. Coincidental Events

Falsely considered to be caused by immunization (event happens after immunization) Eg : sudden death after the mass campaign

D. Injection Reactions

Unrelated to the content of the vaccine Eg

: fainting (older children due to stress), hyperventilation, vomiting, convulsion (due to anxiety), hysteria (needle-phobic)

AEFIs vs ADRs

Vaccines administered to large numbers of healthy people Vaccines not only benefited to individuals but community as well Vaccines given to an entire cohort of population Events normally serious, clusters and cause public concern

AEFI is part of the monitoring system of adverse drug reactions (not similar to individual drugs) The priority for immunization safety surveillance is to identify and correct programme errors

Estimated AEFI Rates Following Vaccination (WHO figures)Vaccine Estimated rate (severe reactions only) 1 in 1 000 1 in 50 000 doses 1 in 2-3 million doses (or 1 in 750 000 doses for the first dose) 1 in 1 million doses 1 in 750 000 doses

BCG Oral Polio Vaccine

Measles DTP

Errors Which Can Lead to AEFIs

Too much vaccine given/dose Improper immunization site or route Syringes/needless improperly sterilized Incorrect diluents, wrong amount used Drug given instead of vaccine Vaccine prepared incorrectly (not to be shaken) Vaccine/diluent contaminated Vaccine stored incorrectly Contraindications ignored Expired vaccines have been used

List of reportable AEFIsOccurring within 24 hours of immunizationAnaphylactoid reaction (acute hypersensitivity reaction) Anaphylaxis Persistent (more than 3 hours) inconsolable screaming Hypotonic hyporesponsive episode (HHE) Toxic shock syndrome (TSS) # Severe local reaction # Sepsis # Injection site abscess (bacterial/sterile) # Seizures, including febrile seizures (6-12 days for measles/MMR; 0-2 days for DTP) Encephalopathy (6-12 days for measles/MMR; 0-2 days for DTP) Acute flaccid paralysis (4-30 days for OPV recipient; 4-75 days for contact) Brachial neuritis (2-28 days after tetanus containing vaccine) Thrombocytopenia (15-35 days after measles/MMR) Lymphadenitis # Disseminated BCG infection Osteitis/Osteomyelitis Any death, hospitalization, or other severe and unusual events that are thought by health workers or the public to be related to immunization #

Occurring within 5 days of immunization Occurring within 15 days of immunization Occurring within 3 months of immunization Occurring between 1 and 12 months after BCG immunization No time limit

# limit reporting to these events, if only limited reporting capacity

Reporting AEFIs Who should report?Peripheral health workersDetect and report event

Doctors/Pharmacists/IndustriesStimulates report, investigates, filters, provides feedback, proposes classification National Drug Safety Monitoring Centre

Product holders

Receives, transmits, share database, evaluates, take action, notifies

WHO

Reporting AEFIs

When to report? Immediately

Reporting AEFIs

How to report?ON-LINE REPORTING www.bpfk.gov.my MANUAL ADR Forms (Fax & Mail)

Reporting AEFIs

Barriers to reporting? Not considering the event as related to immunization Not knowing about the reporting system and process Lethargy lack of interest/time, inability to find report form Fear that the report will lead to personal consequences Guilt about having caused harm and being responsible for the event Diffidence about reporting an event when not confident

Reporting AEFIs

How to overcome? Increase

awareness

Importance of reporting, system of reporting, user friendly, posters, training, talks

Emphasizing

that investigations are finding problems, not blaming individuals Giving positive feedback for reporting

Investigating AEFIs

Which reports should be investigated?

May have been caused by programme error Not listed events defined for AEFI surveillance Serious event of unexplained cause Causing significant parental or community concern

[accurate denominator of vaccine use (to get the rate) is important compared to the number of reports]

Who should investigate?

National Drug Safety Monitoring Centre together with the state/districts committee

When to investigate?

As soon as practicable

Why local reports are important?

Differ among countries in the occurrence of AEFIs and other related problems Due to differencesdiseases and prescribing practices genetics, diet, traditions drug manufacturing process drug distribution and use use of traditional and complementary drugs

Actions taken upon completion of the investigation/assessment by DCA Recall Suspension Withdrawal Advice logistics, procedure, storage, training Labeling changes boxed warning, CI DHCP Letter Circulars Media

RATIONAL DRUG USE

Knowledge of AEFIs should be used to

Minimise adverse events in susceptible patients, at risk groups Advice prescribers/consumers on the proper use of vaccines Monitor patients in order to further enhance knowledge on safety issues Provide information to regulators, decision makers on vaccines being used so that appropriate action may be taken if warranted

CASE REPORT - PEDIACEL A 3-month old female child was vaccinated with a second dose of Pediacel which contains DPT/Polio/HIB on 29th December 2006 at 9.50am. The child developed lethargy, poor feeding and intermittent cry with no fever in the afternoon of the vaccination day. The child was only brought back to the clinic on 30th December 2006 at about 4.20pm in near collapse condition. The child was pallor with perfusion > 3 second, heart rate 100/min, poor pulse volume and poor lung function. She was resuscitated at the clinic but collapsed at 5.45pm. CPR was given for about one hour but unfortunately the child passed away at 6.45pm. Her body was sent to Hospital Kajang. The post mortem was done in Hospital Kajang and the result shown she died due to Acute Lymphocytic Infiltration to Heart and Mild Endocarditis (viral). This report was sent to MADRAC on 3rd January 2007. The reporter also reported that the child was well prior to the 1st dose of Pediacel.

CASE REPORT ON TRITANRIX HB HiB VACCINEA 3 month old infant received the 2nd dose Tritanrix HB HiB and OPV Vaccine given at Klinik Desa Mata Air. The vaccine was administered intramuscularly into left thigh at around 9am on the 18/06/2008. Within 2 hours after administration, the baby started crying excessively and soon collapsed. She was immediately brought to Hospital Tuanku Fauziah, where she was confirmed dead upon arrival at the hospital. Previous exposure, 1st dose vaccination with the same vaccine did not result in any adverse event. The baby was otherwise well with no significant background medical history or known allergies. From the post mortem and toxicology findings, the cause of death was interstitial pneumonia. There is no objective evidence showed the possibility of fatal anaphylaxis reaction towards the vaccine. Information from the WHO Immunization Safety Programme, showed the expected rate for crying abnormal and collapsed after vaccinated with the DTP was 1/100 dose and 1/1750 doses respectively. After the discussion, MADRAC agreed that the adverse event crying abnormal and collapsed cause by the vaccine. Causality C1 (certain) had been given for the reaction because, there was no other concomitant drug given together with the vaccine, with a plausible temporal relation time and there was no other underlying disease which can be link to the ADR.

CASE REPORT - Pentaxim and Euvax 2 month old male infant received the 1st dose of DTAP-IPV given at Klinik Kesihatan WP Labuan. The vaccine was administered on 12/1/2009 (time was unknown). The baby then developed low grade fever at 12.00 noon on the same day and 1.5mls Syrup Paracetamol given. The baby fed as usual after that. The mother then noticed that the baby had an injection site swelling and the mother put a warm compress at the injection site. The baby was again given Paracetamol Syrup at 8 pm and a last dose at 4 am. The mother noticed that the infant choked a little after the administration of the last dose of paracetamol and had fed the child immediately after giving the medicine. Mother and child went to sleep. At around 6 am the mother found that the baby was not moving, looked pale and had bleeding from the ears and nose. The parents brought the baby to the Hospital WP Labuan at 7.50 am. At the A&E Department the baby was found to have already stopped breathing. The parents refused to do a postmortem. Cause of death - UNKNOWN. Suspected drug - Pentaxim and Euvax ADR- low grade fever Concomitant drug Paracetamol MADRACs Causality C2

February 13, 2007 The Food and Drug Administration (FDA) is notifying health care providers and consumers about 28 post-marketing reports of intussusception following administration of Rotavirus, Live, Oral, Pentavalent vaccine (trade name RotaTeq), manufactured by Merck and Co., Inc. Intussusception is a serious and potentially life-threatening condition that occurs when the intestine gets blocked or twisted. One portion of the intestine telescopes into a nearby portion, causing the intestinal obstruction. The most common site is where the small intestine joins the large intestine. In Malaysia, Rota Teq, marketed by MSD and the company has been informed to disseminate this information to relevant healthcare professionals.

T R E N D L A P O R A N V A K S IN140 120 100 BIL. LAPORAN VAKSIN 80 60 40 20 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 TAHUN 14 26 10 13 52 68 39 75 132

T R E N D L A P O R A N A D R D A N V A K S IN6000 5000 BIL. LAPORAN 4000 3000 2000 1000 3068 2 3 6 32 5 4 3 1665 1 0 0 01 0 6 3 4826 B IL . L A P O R A N A D R B IL . L A P O R A N V A K S IN

792 787 0 14 10 26 13 52 68 39 75 132 2 0 0 02 0 0 12 0 0 22 0 0 32 0 0 42 0 0 52 0 0 62 0 0 72 0 0 8 T AH U N

THANK YOU