PV-PG Dr. Anjan Adhikari

PharmacovigilanceDr. Anjan AdhikariAssistant ProfessorDepartment of PharmacologyR G Kar Medical CollegeKolkata

Right Drug for Right Person at Right Time in Right Dose..........

Why we are so concern about safety of Drugs ?

Drugs can do good

Drugs can do harm

Whenever a drug is taken a risk is taken

Thalidomide

• 1st introduced in 1957 –

as sedative

for morning sickness and nausea

●Considered as one of the most safe drug

Thalidomide

• Thalidomide – German Pharmaceutical Company

• Marketed at least 40 Brand name- Talimol, Nibrol, Sedimide, Softenon, Neurosedyn, Quietoplex, Contergan

• From 1956 to 1962, approx. 10,000 children in Africa and Europe were born with severe malformation

Thalidomide

• Early in 1962 Speirs tried to identify whether the mothers of babies born with limb deformities in Stirlingsire, Scotland, had taken thalidomide

• Smithells, searching for the same cause in Liverpool

Thalidomide

• It was established that thalidomide –main cause of thousands of babies with birth defects-Seal babies, Phocomelia

Thalidomide

• 1965 – removed from market

Thalidomide

• In 1964 Israeli physician Jacob Sheskin was trying to help a critically ill French patient with erythema nodosum leprosum (ENL), a severe painful condition, complication of leprosy. He searched in his small nursing home for anything to help his patient to relieve his pain and for a good sleep. He found a bottle of thalidomide tablets in one corner of his table. Dr.Jacob remembered that thalidomide had been effective in inducing sleep and it was also known to him that the drug was banned. Desperately, Sheskin administered two tablets of thalidomide, and the patient slept for hours and was able to get out of bed without aid upon awakening.

Thalidomide

• This starts the new era of evolution of thalidomide. This result was followed by more favorable experiences and a number of clinical trials started to investigate the antiinflammatory and immunomodulatory effects of thalidomide.

Classical examples of serious and unexpected adverse reactions

Medicine Adverse reaction

Chloramphenicol

Clioquine

Erythromycin estolate

Methyldopa

Oral Contraceptives

Practolol

Statins

Aplastic anaemia

Myeloptic neuropathy

Cholestatic hepatitis

Haemolytic anaemia

Thromboembolism

Sclerosing peritonitis

Rhabdomyolis

What is ADR ?

What is adverse drug reaction?

• It is defined as any noxious change which is suspected to be due to a drug, occurs at doses normally used in men, requires treatment or decrease in dose or indicates caution in the future use of the drug. This definition excludes trivial or expected side effects and poisoning or overdose.

Why are ADRs Important?

USA: 39 prospective studies from US hospitals

Overall incidence of serious ADRs = 6.7%Overall incidence of fatal ADRs = 0.32% 4th - 6th leading cause of death

Lazarou et al JAMA 1998;279: 1200 - 1205

In England and Wales the number of deaths related to ADRs has raised during last 10 years

– Study of 3,277 Coroner’s Inquests in one UK district showed during 1986-1991 10 deaths due to prescribing errors and 36 due to ADRs

– These 46 deaths made approximately 1 in 2000 Ferner et al. J R Soc Med, 1994;87:145-148

Why are ADRs Important?

Hospital admissions due to ADRs: 4.2-6.0% with a median of 5.8%

Pharmacoepidem & Drug Safety 6; suppl 3: s71-s77 (1997)

• Adverse Drug Reaction (ADR) recently emerged as leading killers, management of drug induced illness requires more than 100billion US dollars annually

• -Bremnan et al. New Eng J Med, 1991.

Why are ADRs Important?

Increased healthcare costs Admission to hospital, or prolonged stay. Costs of treating symptoms.

Cost of drug-related morbidity and mortality >177.4 billion US$. Ernst & Grizzle J Am Pharm Assoc. 41: 192(2001)

The annual cost of ADR related hospital costs 1.6-4 billion US $

Median length of stay in hospital was 8.7 daysTotal estimated cost of ADRs in Germany = 588 million $/year

Pharmacoepidemiol & Drug Safety 6; suppl 3: S79-S90 (1997)

England: ADR related costs to NHS £466 million/yearPirmohamed M. et al. Br Med J 329:15-19 (2004)

Why are ADRs Important?

Impairs the safe and rational use of medicinesOverall increase in ADR throughout the worldIncrease in the fatal ADRIncrease Hospital admissions due to ADR or prolonged

stayIncrease in cost of drug-related morbidity and mortality

Experience in India

• 3.7% of patients in hospital

• 0.7 % of admissions

• 1.8% fatal

• Cost Rs 187-2820, mean Rs 690 per ADR- Ramesh et al. Pharmacoepidemiol & Drug Saf 2003

• 1.5% of admissions at Dept Gastroenterol- Devi et al, Pharmacoepidemiol & Drug Saf 13:859 (2004)

Withdrawn from market

– THALIDOMIDE (1961) Congenital limb defects– BENOXAPROFEN (1982) Hepatotoxicity– PHENFORMIN (1982) Lactic acidosis– FENFLURAMINE (1997) Heart-valve abnormalities– ASTEMIZOLE (1999) Many drug interactions– PHENYLPROPANOLAMINE(2000) Haemorragic stroke– KAVA KAVA Liver abnormalities– CERIVASTATIN (2001) Rhabdomyolysis– CISAPRIDE (2000) Cardiac arrythmias– ROFECOXIB (2004) Cardiovascular events– VALDECOXIB (2005) Cardiovascular events,

serious skin reactions– COMFREY, SENECIO Nephrotoxicity – TEGASEROD (2007) Cardiovascular events– CLOBUTINOL (2007) Cardiac arrhythmia

How do we get information on drug safety?

• animal experiments (Toxicity studies, organ damage, metabolism, kinetics, carcinogenicity, mutagenicity, teratogenicity)

• clinical trials

• epidemiological methods

• meta-analysis

Methods for monitoring ADRs

• 1. Case Reports• 2. Anecdotal Reporting• 3. Spontaneous Reporting System• 4. Intensive Event Recording• 5. Cohort studies (prospective studies)• 6. Case-control Studies (retrospective studies)• 7. Case-cohort studies• 8. Record Linkage- Prescription Event Monitoring

Scheme (PEMS)• 9. Meta analysis• 10. Use of population statistics

Drugs are marketed after phase III clinical trial has the following limitations:-

• Conducted in a small number of patients

• Duration of trial is usually short

• Conducted in well controlled patients avoiding the vulnerable groups (children, pregnant women, elderly patients, patients with hepatic or renal insufficiency)

Naturally the phase III clinical trial fails to detect:-

• Rare but serious adverse drug reactions• Chronic toxicity of the drug• ADR in vulnerable groups • Information about drug interactions

• In fact, there is nothing that could tell you whole story of a drug

• It is the benefit-risk profile which is more important

• It is never possible to know the whole story of a drug through clinical trials

• A clinical trial can inform the minimum information determined by the legislation and by contemporary judgments about the acceptable balance between benefit and harm

• How to Enhance Drug Safety ?

• To overcome the shortcomings of pre-marketing trial, WHO has formulated a global Pharmacovigilance Program as an important post marketing tools in

ensuring the safety of pharmaceutical and related health

products.

Pharmacovigilance

• It is an umbrella term used to describe the process of monitoring and evaluating ADRs – is a key component of effective drug regulation systems, clinical practice and public health programmes

What is Pharmaco-vigilance ?

Pharmaco = Drug

Vigilance = To keep alert, To keep watch

Pharmacovigilance is defined as thePharmacovigilance is defined as the sciencescience and and activitiesactivities concerned with theconcerned with the detection, detection, assessment, understandingassessment, understanding andand preventionprevention ofof adverse effects of drugsadverse effects of drugs (adverse drug (adverse drug reactions or ADR) orreactions or ADR) or any other drug related any other drug related problemproblem. .

(WHO, 2002, ISBN 9241590157)

• To identify new information about hazards associated with medicines

• Preventing harms to the patients

• Pharmacovigilance is related with adverse effects or any other possible drug-related problems

• Treatment evaluation science

Why Pharmacovigilance?

• First, do no harm

• Economical concerns

• Drug monitoring & surveillance

• Pharmacovigilance: check the drugs on the market to fulfill their intended role in society

The ultimate goal of this activity is to The ultimate goal of this activity is to improve the improve the safe and rational use of safe and rational use of medicinesmedicines, therapy by , therapy by improving improving patient care and public healthpatient care and public health

• It is basically deals with-• Collecting• Monitoring• Researching• Assessing• and evaluating

------information from health care providers and patients on the adverse effects of medication

• Pharmacovigilance in practice

Cerivastatin

• 1st approved in 1997 – lipid-regulating agent• By 2000 – 549 cases of rhabdomyolysis

reported esp. in combination with gemfibrozil• ►a signal was issued regarding the association

between Cerivastatin, myopathy and rhabdomyolysis

• Warning statement in the PI – contraindication for this combination (USA Nov 1999, Canada Mar2000, Aust. Feb 2001, Europe June 2001)

• 8 Aug 2001 – manufacturer voluntarily withdrew from market

Cisapride

• 1st approved in 1993 – gastroesophageal reflux disease (GERD)

• 1999 - 341 reports of heart rhythm abnormalities including 80 reports of deaths

• Labeling has been revised several times

• July 14, 2000 – manufacturer voluntarily withdrew from market

Pharmacovigilance in public health

• Malaria

• Artemisinin Combination Therapy

• African countries

• Presently, its concerns have been widened to include-

• • herbals• traditional and complementary medicines• blood products• biological• medical devices• vaccines.

Other issues relevant to PV

– Substandard medicines– Medication errors– Lack of efficacy – Use of medicines for indications that are

not approved and for which there is inadequate scientific basis

Other issues relevant to PV

– Acute and chronic poisoning– Assessment of drug- related mortality– Abuse and misuse of medicines– Adverse interactions of medicines with

chemicals, other medicines and food

Widening horizons

• Within the last decade, there has been a growing awareness that the scope of pharmacovigilance should be extended beyond the strict confines of detecting new signals of safety concerns.

• These changes have given rise to new kinds of safety concerns such as:• • illegal sale of medicines and drugs of abuse over the Internet• • increasing self-medication practices• • irrational and potentially unsafe drug donation practices• • widespread manufacture and sale of counterfeit and substandard

medicines• • increasing use of traditional medicines outside the confines of the

traditional culture of use• • increasing use of traditional medicines and herbal medicines with other

medicine with potential for adverse interactions•

Aims of Pharmacovigilance

• Improve patient care and safety in use of drugs • Improve public health and safety in use of drugs• Contribute to the assessment of benefit, harm,

effectiveness, and risk of drugs• Encouraging safe, rational and more effective

(including cost-effective) use of drugs • Promote understanding, education and clinical

training in pharmacovigilance • Effectively communicate to the public

-- World Health Organization

Formal research studies Vigilance

• Defined aim (identified problem)

• Hypothesis testing (problem solving)

• Established methods (clinical trial, case control, cohort)

• Comparison• Limited in time, drugs,

population, place

• Open question: looking for the unexpected

• Hypothesis generation (‘problem raising’)

• Exploratory, controversial (SR, PEM, CCS)

• No comparison• Continuous, all drugs,

total population

How pharmacovigilance?

• Spontaneous Reporting • Intensive monitoring (hospital)• Prescription Event Monitoring• Case Control Surveillance• Comprehensive population databases, data-

mining• Patient series• Observational studies

• Spontaneous reporting is the core data generating system of international

pharmacovigilance

►►Proactive pharmacovigilance throughout the product life cycle is the only way for drug safety

Partners

• The management of the risk associated with the use of medicines demands close and effective collaboration between the key players in the field of pharmacovigilance

Partners

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

Pharmacovigilance responsibilities

• Timely collection of data: recording and notification

• Appropriate assessments (data completeness, seriousness, relatedness, expectedness)

• Periodic reporting

WHO Programme for international drug monitoring

• Started 1968• Purpose-to create an international database of ADR• It is a network of National Centres, WHO Headquarters,

Geneva, and the WHO Collaborating Centre for International Drug Monitoring, the Uppsala Monitoring Centre, in Uppsala, Sweden.

• Collaborating centre for maintaining global ADR database – Vigibase/ Vigiflow

• In UMC the data are processed, evaluated and entered into WHO international database

Roles of WHO Collaborating Centre

• When there are several reports of adverse reactions to a particular drug → this process may lead to the detection of a signal→ an alert about possible hazards communicated to member countries.

• Identify early warning signals of serious adverse reactions to medicines

• Evaluate the hazard• Advice and alert to countries• Undertake research into the mechanisms of action to aid

the development of safer and more effective medicines

Pharmacovigilance in National Drug Policy

• Establishment of national pharmacovigilance systems for the reporting of adverse events & regional pharmacovigilance centers

• Development of legislation / regulation for medicine monitoring

• National policy development (to include costing, budgeting and financing)

Pharmacovigilance in National Drug Policy

• Continuing education of health-care providers on safe and effective pharmacotherapy

• Provision of up-to-date information on adverse reactions to professionals and consumers

• Monitoring the impact of pharmacovigilance through process indicators and outcome

Now….What to do?• Participate in the Pharmacovigilance

Programme

• Set your mind

• Start sending report

• Send not only quantity reports But….

QUALITY REPORTS

Why local reports are important?

• Local report differ among countries in the occurrence of ADRs and other related problems

• Because different– diseases and prescribing practices– genetics, diet, traditions– drug manufacturing process– drug distribution and use– use of traditional and complementary drugs

How?

• Monitor clinical status of patients

• Identify the correct ADRs not side effects

• Get more information

• Investigate at hospital level

• Help others to fill-up the ADR forms

• Keep patient’s record if more information needed

What should be reported

• For 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 • ADRs to traditional medicines

What should be reported

• All suspected drug-drug, drug-food, drug-food supplement interactions

• Reactions associated with drug withdrawals

• ADRs due to medication errors

• ADRs due to lack of efficacy or suspected pharmaceutical defects

• Report about any drug which are suspected of significantly affecting a patients management, including reactions suspected of causing :-

• • * Death • * Life threatening with real risk of dying• * Hospitalization • * Disability• * Congenital anomaly • * Required intervention to prevent • permanent impairment or damage

Who can report?

• Any health care professional- doctors including dentist, nurses and pharmacists

• Report from any other person is not acceptable

How to report?

• The report should be sent by filling up a proforma known as “Adverse Drug Event Reporting Form” for the purpose of National Pharmacovigilance Programme.

Where to report?

• To the same Pharmacovigilance Centre from it is collected

• OR• To any one of the Pharmacovigilance Centre

nearest to the reporter • OR • To the NPC at CDSCO, Directorate General of

Health Services ( DGHS), Ministry of Health and Family Welfare, Nirman Bhawan, New Delhi-11011

Where to report?

Patient Health

Professional

Regional Centre

Manufacturer

Hospital

National Centre

Causality assessment

• It is the method by which the extent of relationship between a drug and a suspected reaction is established

• Currently wide variety of causality assessment scales exist, to attribute clinical events to drugs in individual patients or in case reports, each with their own advantages and limitations

Causality assessment scales

• Karch & Lasagna scale Naranjo's scale WHO probability scale Spanish quantitative imputation scale Kramer's scale Jones scale European ABO system Bayesian system.

• The Naranjo's scale and the WHO scale are the most commonly used scales.

Naranjo's Scale

Question Yes No

Are there previous conclusion reports on this reaction?

+1 0

Did the adverse event appear after the suspect drug was administered?

+2 -1

Did the AR improve when the drug was discontinued or a specific antagonist was administered?

+1 0

Naranjo's Scale

Question Yes No

Did the AR reappear when drug was readministered? +2 -1

Are there alternate causes [other than the drug] that could solely have caused the reaction?

-1 +2

Did the reaction reappear when a placebo was given? -1 +1

Naranjo's Scale

Was the drug detected in the blood [or other fluids] in a concentration known to be toxic?

+1 0

Was the reaction more severe when the dose was increased, or less severe when the dose was decreased?

+1 0

Did the patient have a similar reaction to the same or similar drugs in any previous exposure?

+1 0

Was the adverse event confirmed by objective evidence?

+1 0

Naranjo's Scale-Scoring

• A METHOD FOR ESTIMATING THE PROBABILITY OF ADVERSE DRUG REACTIONS

• • > 9 = definite ADR • 5-8 = probable ADR • 1-4 = possible ADR • 0 = doubtful ADR

Severity Assessment

• Hartwig Scale

Preventability assessment

• Scumock & Thornton Scale

Signal

• Reported information on a possible causal relationship between an adverse event and a drug the relationship being unknown or incompletely documented previously

• Usually more than a single report is required to generate

a signal, depending upon the seriousness of the event and the quality of the information

• The publication of a signal usually implies the need for some kind of review or action

Signal

This describes the first alert of a problem with a drug

By its nature a signal cannot be regarded as definitive but indicates the need for further enquiry or action.

The SIGNAL document

• Sent to all National Centres (national distribution)

• Individualized section available to industry

• All recipients encouraged to comment on topics presented

• ADR Database

Examples of computerized databases

Data base Location

G Practice Res Data Base

UK

Medicaid USA

PHARMO data base

Netherlands

Examples of computerized databases

Data base Location

Odense Denmark

Ontario Drug Benefit

Canada

Vigibase

• Vigibase is the name of the WHO ADR database. VigiBase™ is a unique collection of international drug safety data

• UMC receives summary clinical reports about individual suspected adverse reactions to pharmaceutical products from National Centres in countries participating in the WHO Programme for International Drug Monitoring

• Only limited details about each suspected adverse reaction are received at the centre. The member countries have access to the collected data and analyze it in order to investigate potential ADR signals and statistics

Vigibase

• The data collected from countries participating in WHO Programme for International Drug Monitoring

• VigiBase™ comprises more than 4.7 million case reports, to which around 50,000 new reports are added quarterly. All of these cases are available to anyone with a health professional degree-level education (physician, dentist, nurse, pharmacist).

• The Vigibase™ data resource is the largest and most comprehensive in the world and is developed and maintained by the UMC on behalf of the World Health Organization.

Vigibase verified the case reports &

clinically assessed • UMC does not take part in any clinical review of case

reports before they are entered in Vigibase. This process is done by the reporting National Centre

• A number of National Centres make an assessment of the likelihood that a pharmaceutical product caused the suspected reaction

Vigibase include reports from manufacturers

• All reports in Vigibase are sent from the responsible authority in each country

• However, these may originally be sent in by manufacturers.

ADR reports on herbal preparations

• Vigibase contains adverse reactions reports related to herbal preparations

Growth of the WHO database since its inception. 

Vigiflow

• It is web based and designed to allow for simultaneous multiple use

• All customer-specific data is stored in the database connected to the specific customer and not accessible to others

• It is web designed and hosted by the UMC, Sweden

• Maintained centrally by UMC

Vigiflow

• Advantages of Vigiflow server setup• -Data security• -Work balancing• -Performance

• Vigiflow is a cost effective system built with a modern design which ensures quality, performance and reliability with a future increasing usages

Vigiflow

• UPSALA MONITORING CENTRE

WHO Collaborating Centre for International Drug Monitoring

The Uppsala Monitoring CentreStora Torget 3, 75320 Uppsala, Sweden

www.who-umc.org

Uppsala Monitoring Centre

• Uppsala Monitoring Centre manage the international database of ADR reports received from National Centres

• The majority of national centers have easy electronic access to these

• UMC has established standardized reporting by all National Centres and has facilitated communication between countries to promote rapid identification of signals.

Uppsala Monitoring Centre

• The purpose of the programme is to collate data, analyze it and use the inferences to recommend informed regulatory interventions, besides communicating risks to healthcare professionals and the public

• An international advisory panel of clinical experts determines the validity and clinical importance of the signals generated

WHO Programme for International Drug Monitoring

• The WHO Programme for International Drug Monitoring provides a forum for WHO member states to collaborate in the monitoring of drug safety

• Within the Programme, individual case reports of suspected adverse drug reactions are collected and stored in a common database

• In each of the countries participating in the Programme, the government has designated a National Centre for pharmacovigilance

•

WHO Programme for International Drug Monitoring

• The WHO Programme for International Drug Monitoring started as a small project with a few countries wishing to pool their resources and information from spontaneous reporting of ADRs

• The ten countries first participating in the project had organized national pharmacovigilance systems at that time.The Programme was established 1968 following the thalidomide disaster and the intention was to develop international collaboration to make it easier to detect rare adverse drug reactions not revealed during clinical trials.

WHO Programme for International Drug Monitoring

• The WHO Programme, consists of a network of the National Centres, WHO Headquarters, Geneva and the WHO Collaborating Centre for International Drug Monitoring, the Uppsala Monitoring Centre, in Uppsala, Sweden

• As of September 2009, 96 countries had joined the WHO Drug Monitoring Programme and in addition, 30 'associate members' were awaiting compatibility between the national and international reporting formats.

WHO Programme for International Drug Monitoring

• Functions of the WHO Programme for International Drug Monitoring include:

• Identification and analysis of new adverse reaction signals from the case report information submitted to the National Centres

• Provision of the WHO database as a reference source for signal strengthening and ad hoc investigations

• Information exchange between WHO and National Centres• Publication of periodical newsletters, (WHO Pharmaceuticals

Newsletter and Uppsala Reports), guidelines and books • Supply of tools for management of clinical information • Provision of training and consultancy support

Countries participating in the WHO Programme for International Drug Monitoring

IMPORTANCE OF ADR REPORTING IN INDIA

• There is a rapid increase in the number of new drugs entering the market from last few decades

• India being the second most populated country has over one billion potential drug consumers, and no amount of pre-clinical and clinical data is sufficient to conclude the complete safety of a drug

IMPORTANCE OF ADR REPORTING IN INDIA

• In India, general practitioners, with an large outpatient base tend to be among the first ones to use the drugs entering the market, hence they are in the best position to assess the adverse drug reactions associated with drugs

• ADR in India is increasing

National Pharmacovigilance Programme

• India's Drugs Control Department within the Ministry of Health & Family Welfare initiated the establishment of a nationwide network to build a comprehensive pharmacovigilance data system in 2004

• The National Pharmacovigilance Advisory Committee (NPAC) was created under the chairmanship of the Director General of Health Services and the Drug Controller General of India (DCGI), who functions as the member secretary of the Committee

National Pharmacovigilance Programme

• Central Drugs Standard Control Organization

• The NPP is based on the recommendations made in the WHO document titled "Safety Monitoring of Medicinal Products - Guidelines for Setting and Running a Pharmacovigilance Centre"

• It was on November 23 2004, The CDSCO launched a formal National Pharmacovigilance Programme (NPP) and NPP became functional from January 1, 2005.

•

Objectives

• To identify previously unrecognized adverse effects or changes in the patterns their adverse effects.

• To assess the risk benefit of medicines

• To provide information to users to optimize safe and effective use of medicine

THE NATIONAL PHARMACOVIGILANCE CENTRE AT CDSCO

• The National Pharmacovigilance Centre is based at CDSCO

• Monitor in order to identify previously unexpected adverse drug reactions or indicate that certain reactions occur more commonly than previously believed

• Collation, review and evaluation of all spontaneous ADR reports received by the unit on a nation-wide basis

• Maintain contacts with international regulatory bodies• Assess the regulatory information relating to safety in

order to determine action on product label amendments, product withdrawals and suspension

• Provide information to end-users through adverse drug reaction news, bulletins, drug alerts and seminars.

The National Pharmacovigilance Centre

• Office of Drugs Controller General of India,• Central Drugs Standard Control Organization,

• Room No. 347-A,• D.G.H.S., Ministry of Health & Family Welfare

• Nirman Bhawan, New Delhi 110 011.• Tel: (11) 23018806 Fax: (11) 23012648

• Email: dci@nb.nic.in www.cdsco.nic.in

India

• AIIMS-National Pharmacovigilance coordinating centre

• Actively participated by –• Central Drug Standard Control Organization –

CDSCO• Drug Controller General of India• Director General of Health Service• Supported by WHO• Financed by World bank

WHO - UMC & INDIA

• INDIA is a country with a large pool of patients and healthcare professionals, yet the Adverse Drug Reaction reporting is in its infancy

• Very few reports have been sent to UMC's Vigibase, which is relatively a less figure considering the number of healthcare professionals in our country.

PharmacovigilanceSummary

• Now global activity• All kinds of drug related problems• Acknowledged as major concern• Laws and regulations• Public health programmes• Data mining, internet reporting and new data

sources• Traditional medicines• Influencing safe prescribing and use• Tool for Rational Drug Use

• Patient safety

rather

than

• drug safety

Right Drug for Right Person at Right Time in Right Dose..........

Thank you