A PROJECT REPORT ON PHARMACOVIGILANCE

(BP815PW)
For partial fulfillment Of B.Pharm 4th year (8th SEM)

Session 2021 – 2022

Rameshwaram Institute of Technology and

Management

Under the supervision of

Mr. Mohd.Faizan
(Assistant professor)
Department of pharmacy

Affiliated to the Dr. Abdul Kalam Technical

University
Submitted by

PRATIKSHA SINGH

ROLL NO. - 1820350071

 CERTIFICATE

This is to certify that Ms. Pratiksha singh , Roll No. 1820350071 in the partial

fulfillment of the requirement for the award of the Degree of Bachelor of

Pharmacy by the RAMESHWARAM GROUP OF INSTITUTIONS has

satisfactorily completed Project work on Pharmacovigilance in Pharmacy

Department in academic session 2021-2022.

Mr.Mohd.Faizan
(Assistant Professor)

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 CONTENTS

S.No. TITLE Page.No

01 Preclinical Study 05
02 Clinical study 06
03 Pharmacovigilance 10
04 Reporting Method 11
05 Individual Case Safety Report 12
06 Argus Software 12
07 MedRA 15
08 Drug 16
09 Retrospective Data 21
10 ADR Form 24
11 Conclusion 25
12 References 25

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 ACKNOWLEDGEMENT
I would like to express my special thanks of gratitude to our Honorable
Director Maam Dr.Shalini Tripathi who gave me the golden opportunity
to do this wonderful project of subject “Report on Pharmacovigilance”
which also help me to get more knowledge about the ADRs and Reporting
system so many new things I am really thankful to them .
I am also grateful to our subject teacher and HOD. Mr. Mohd. Faizan for
his patience , guidance ,helpful information , practical advice and ideas
that have helped me tremendously in my whole project work .
I would like to thank my friends and seniors who helped me a lot in
finalizing this project with in timeline.

Pratiksha Singh
B.Pharm 4th year
Roll no. 1820350035

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 PRECLINICAL
In the drug development , preclinical development , also termed as preclinical
studies or non clinical studies , is a stage of research that begins before clinical
trials (testing in humans) and during which important feasibility, iterative testing
and drug safety data are collected , typically in laboratory animals.
The main goals of preclinical studies are to determine a starting , safe dose for
first in human study and assess potential toxicity of the product which , which
typically include new medical device , prescription drugs , and diagnostics.
Companies use stylized statistics to illustrate the risks in preclinical research
,such as that on average , only one in every 5000 compounds that enters drug
discovery to the stage of preclinical development becomes an approved drug

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 CLINICAL TRIALS
● The International Conference Harmonization define a clinical trials as “
Any investigation in human subjects intended to discover or verify the
clinical pharmacological and other pharmacodynamic effect of an
investigational drug and / or to identify any ADR to an any
investigational drug and to study ADME of drug with the objectives of
ascertaining the safety and efficacy .”
● This is also known as randomized control trials.
● Clinical trials are a set of procedure in medical research conducted to
allow safety and efficacy data to be collected for health intervention.
● There are 4 phases of biomedical clinical trials:
● Phase 0
● Phase 1
● Phase 2
● Phase 3
● Phase 4

PHASE 0
✔ A clinical trial's Phase 0 involves a small group of patient Before utilising
it in bigger doses for later phases, researchers utilise a very modest dose
of drug to make sure it isn't dangerous to humans.

✔ If the medication behaves differently than planned, the researchers will

probably conduct more preclinical study before determining whether or
not to continue the experiment.

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 PHASE 1
✔ The purpose of phase 1 is to ensure that the treatment is safe in humans
and to determine how and where it distributes with in the body .This
testing normally takes place with a small group of healthy volunteers .
The trial sponsor monitor
✔ for potential adverse effect .

✔ At the end of PHASE 1 the result are submitted to the FDA for
permission to proceed for the PHASE 2 clinical trials

✔ If FDA found any SAE associated with drug then they refused the further
study of that investigational drug.

PHASE 2
✔ The purpose of a phase 2 Clinical trial is to determine the right dosage
and effectiveness in treating that particular disease .

✔ This testing normally takes place with a large number of volunteers who
have the disease .

✔ There are many different ways that a trial sponsor can conduct their trial ,
but the plan normally involves assigning participants to different doses or
delivery
✔ Of the treatment .

✔ Normally there is a control group that receives either the current standard
of care , If another type of treatment is already available on the market
for that disease or a placebo treatment such as a sugar pill or harmless
injection that does not contain the treatment

✔ Then compare both the group if there is LOE or any SAE then FDA may
not give permission to proceed the PHASE 3 .

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 PHASE 3
✔ A PHASE 3 Clinical Trial involves a much large group of volunteers and
primarily focuses on determining whether the treatment would be safe and
effective for a wide variety of people .

✔ The plan normally involves assigning participants to treatment or control

groups.

✔ After completion of PHASE 3 Clinical Trials the health of the patient

who received the different type of treatment are compared with the
control group.
✔ If the results show the treatment did not work better then than the current
standard of care or even caused acceleration of the disease or other
unexpected serious adverse event the FDA may not give permission to
proceed to apply for a NEW DRUG APPLICATION.

✔ This special NDA contains all of the discoveries made at every stage of
the process ( Starting from the basic research /Drug discovery through to
results of the Phase 3 Clinical Trials ) and is submitted to the FDA for
their consideration to approve the sales of the treatment on the market.

PHASE 4
✔ The PHASE 4 trial is also referred to as post marketing surveillance and
as the name suggests, it is conducted after the drug is already marketed
and available to the general public.

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✔ The main objective of the phase 4 trial is to check the drug’s
performance in real life scenarios ,to study the long term risks and
benefits of using the drug and to discover any rare side effects

PHASES OF CLINICAL TRIAL

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 PHARMACOVIGILANCE

❑ Pharmacovigilance is the science and activities relating to the detection ,

assessment, understanding and prevention of the adverse effects or any other
medicine /vaccine related problem.

AIM
❑ To improve patient care and safety in relation to the use of medicines , and all
medicinal and paramedical interventions.
❑ The assessment and communication of the risk and benefits of the drugs on the
market.
❑ To ensure optimum safety of drug product in the market.

ADVERSE DRUG REACTION

An ADR is defined according to definition of WHO “ Any response to a drug which
is noxious , unintended and that occurs at normal dose.”

SERIOUSNESS DETERMINATION
● Fatal
● Hospitalization
● Disability
● Life Threatening
● Important Medical Event
● Congenital anomalies

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 REPORTING METHODS

PASSIVE SURVEILLANCE: VOLUNTARY

REPORTING

Spontaneous Reporting = A country wide system for the reporting of

suspected adverse reactions to drugs.
A case report is a notification from a health care professional, describing the history of a
patient with a disorder that is suspected to be drug induces.

ACTIVE SURVEILLANCE: Active surveillance works completely in

contrast with that of passive surveillance. It monitors adverse event continuously through
pre organized management program in which the survey of the follow up of patients who
were being treated with specific drug to conducted .besides the patients who are still under
treatment are requested to complete a brief survey form .It is considered as more reliable
and feasible reporting system to that of passive surveillance .

REPORTING PROCESS

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 INDIVIDUAL CASE SAFETY REPORT
A document that contains details about a specific case of a medicine's alleged
negative effects. The establishment of a valid individual case safety report is one of
the core principles of adverse event reporting. Individual case safety reports have
"four" elements:-
● An identifiable patient
● An identifiable reporter
● A suspect drug
● An adverse event
If one or more of these elements are missing, the case is not a valid individual case
safety report.

ARGUS SOFTWARE
Argus Safety is a complete pharmacoviglance database software system designed to solve
the pharmaceutical industry’s toughest regulatory challenges. It provides the most
comprehensive global Adverse Events case data management and regulatory reporting in
the pharmaceutical industry. Argus Safety software is developed by ORACLE which is
Japanese company.
Argus Safety brings the single global database for the Japanese market to include
localization and regulation support.

Types of Tabs In The Argus Software

1. General Tab
2. Patient Tab
3. Product Tab
4. Event Tab

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 5. Analysis Tab
6. Activity tab
7. Additional Informational Tab
8. Regulatory Tab
1. General Tab

🞂 The general tab is designed to capture case information in categorized sections that
capture specific information.
▪ General Tab Classification
1. Spontaneous
2. Solicited
3. Intial Receipt Date
4. Reporter : HCP/NON HCP

2. Patient Tab
⮚ This section of the case form helps you to enter patient information such as the
patient’s demographic data, past medical history and current conditions , and
laboratory tests and test result. The medical information entered here could be very
useful to the person analyzing the event.
3. Product Tab
🞂 The Product tab enables you to enter and view details about products and dosage
regimens. The product tab conatains the name of the drug that has been entered
within the tab

🞂 The product tab includes the following sections

▪ Product information

▪ Dosage regimens

▪ QC Info

▪ Product details

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4. Event Tab
● It enables you to enter or view details for adverse events associated with a dose
5. Analysis Tab
● The analysis tab enables you to generate or view a narrative description of the
case together with other notes. The typical users of this tab are responsible for:
● Making a medical assessment of the case
● Approving the case for completeness and accuracy
6. Activity Tab
● The Activities tab presents detailed information about the contact log ,routing
comments, action items, and case lock/closure

7. Additional Information Tab

● The additional information tab enables you to attach notes and other items to the
case. For example, you could attach a fax message that came in as part of the case
and needs to be scanned and attached or an electronic file received by e-mail.
8. Regulatory Tab
● The regulatory tab enables you to:
● View all scheduled reports
● Schedule new reports

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 MeDRA
🞂 MeDRA- Medical Dictionary for Regulatory Activites

🞂 MeDRA is highly specific standardised medical terminology developed by ICH to

facilitate sharing of regulatory information internationally for medical product

🞂 Hiearchies- Five level structure

1. LLT-Low Level Term

2. PT- Preferred Term

3. HLT-High Level Term

4. HLGT-High Level Group Term

5. SOC- System Organ Class

Example

🞂 System Organ Class-GIT DISORDER

🞂 High Level Group Term-GIT Sign Symptoms

🞂 High Level Term-Nausea Vomiting

🞂 Preferred Term-Nausea

🞂 Low Level Term-Feeling queasy

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 DRUG: LASIX
Manufacturer:- Snaofi India Ltd.
Generic name :- Furosemide
DrugBank Accession Number :- DB00695
Structure:-

PHARMACOLOGY:-
Furosemide is a potent loop diuretic that acts on the
kidneys to ultimately increase water loss from the body. It is an anthranilic acid
derivative. Furosemide is used for edema secondary to various clinical conditions,
such as congestive heart failure exacerbation, liver failure, renal failure, and high
blood pressure. It mainly works by inhibiting electrolyte reabsorption from the
kidneys and enhancing the excretion of water from the body. Furosemide has a
fast onset and short duration of action and has been used safely and effectively in
both pediatric and adult patients. The use of furosemide is particularly beneficial
in clinical settings that require a drug with a higher diuretic potential. In addition to
oral formulations, the solution for intravenous and intramuscular administration is
also available, which is typically limited to patients who are unable to take oral
medication or for patients in emergency clinical situations

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INDICATION:-

• Furosemide is indicated for the treatment of edema associated with

congestive heart failure, cirrhosis of the liver, and renal disease,
including the nephrotic syndrome, in adults and pediatric patients.
• Oral furosemide is indicated alone for the management of mild to
moderate hypertension or severe hypertension in combination with
other antihypertensive medications.
• Intravenous furosemide is indicated as adjunctive therapy in acute
pulmonary edema when a rapid onset of diuresis is desired.

PHARMACODYNAMIC:-
Furosemide manages hypertension and edema associated with congestive
heart failure, cirrhosis, and renal disease, including the nephrotic syndrome.
Furosemide is a potent loop diuretic that works to increase the excretion of
Na+ and water by the kidneys by inhibiting their reabsorption from the
proximal and distal tubules, as well as the loop of Henle. It works directly
acts on the cells of the nephron and indirectly modifies the content of the
renal filtrate. Ultimately, furosemide increases the urine output by the
kidney. Protein-bound furosemide is delivered to its site of action in the
kidneys and secreted via active secretion by nonspecific organic
transporters expressed at the luminal site of action.

MECHANISM OF ACTION :-
Furosemide promotes diuresis by blocking tubular reabsorption of sodium
and chloride in the proximal and distal tubules, as well as in the thick
ascending loop of Henle. This diuretic effect is achieved through the
competitive inhibition of sodium-potassium-chloride cotransporters (NKCC2)
expressed along these tubules in the nephron, preventing the transport of
sodium ions from the lumenal side into the basolateral side for reabsorption.
This inhibition results in increased excretion of water along with sodium,

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 chloride, magnesium, calcium, hydrogen, and potassium ions. As with other
loop diuretics, furosemide decreases the excretion of uric acid.

Furosemide exerts direct vasodilatory effects, which results in its therapeutic

effectiveness in the treatment of acute pulmonary edema. Vasodilation
leads to reduced responsiveness to vasoconstrictors, such as angiotensin II
and noradrenaline, and decreased production of endogenous natriuretic
hormones with vasoconstricting properties. It also leads to increased
production of prostaglandins with vasodilating properties. Furosemide may
also open potassium channels in resistance arteries. The main mechanism
of action of furosemide is independent of its inhibitory effect on carbonic
anhydrase and aldosterone

ABSORPTION:-
Following oral administration, furosemide is absorbed from the
gastrointestinal tract. It displays variable bioavailability from oral dosage
forms, ranging from 10 to 90%. The oral bioavailability of furosemide from
oral tablets or oral solution is about 64% and 60%, respectively, of that from
an intravenous injection of the drug.
VOLUME OF DISTRIBUTION:-
The volume of distribution following intravenous administration of 40 mg
furosemide were 0.181 L/kg in healthy subjects and 0.140 L/kg in patients
with heart failure.
PROTEIN BINDING:-
Plasma concentrations ranging from 1 to 400 mcg/mL are about 91-99%
bound in healthy individuals. The unbound fraction is about 2.3-4.1% at
therapeutic concentrations. Furosemide mainly binds to serum albumin

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ROUTE OF ELIMINATION:-
The kidneys are responsible for 85% of total furosemide total clearance,
where about 43% of the drug undergoes renal excretion. Significantly more
furosemide is excreted in urine following the I.V. injection than after the
tablet or oral solution. Approximately 50% of the furosemide load is excreted
unchanged in urine, and the rest is metabolized into glucuronide in the kidney.
HALF-LIFE:-
The half-life from the dose of 40 mg furosemide was 4 hours following oral
administration and 4.5 hours following intravenous administration. The
terminal half-life of furosemide is approximately 2 hours following parenteral
administration. The terminal half-life may be increased up to 24 hours in
patients with severe renal failure.
Clearance:-
Following intravenous administration of 400 mg furosemide, the plasma
clearance was 1.23 mL/kg/min in patients with heart failure and 2.34
mL/kg/min in healthy subjects, respectively.

INTERACTION:-
Drug interaction of furosemide include aminoglycoside
antibiotics, ethacrynic acid, aspirin, lithium,sucralfate, other antihypertensive
drugs, NSAIDs etc.
CONTRAINDICATION:-
Lactating mother should avoid taking furosemide drug ,it
may affect child.

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 CASE STUDY

Case 1:-
• PATIENT:- 40 years male
• SYMPTOMS :- swelling of lower limbs for 3 days, facial puffiness for 2 days,
breathlessness for 3 days, decreased urination since 2 days.
• FACTORS TO BE CONSIDERED:- patient was an alcoholic for 8 yrs but
left for 3 months. No history of allergy.
• DIAGNOSIS:- acute renal failure and acute liver failure
• TREATED WITH:-Pantoprazole 40mg, furosemide 40mg b.d.,
spirinolactone 50mg, dexamethasone 8mg.
• ADVERSE EVENT:- after 2 days, hyperpigmentation on trunk, multiple
well-defined hyperpigmentation seen over right hand, foot and umbilical
region with erosion buccal mucosa (Fixed drug eruption).

ACTION TAKEN:- Furosemide as suspected drug was discontinued by

doctor.

CAUSALITY ASSESSMENT:-Naranjo’s, WHO-UMC scales showed the

reaction as ‘probable’ adverse reaction.

MODIFIED TREATMENT:- Furosemide stopped, Dexmethasone 8mg b.d.

given along with other supportive measures

Patient was improved and recovered

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Case 2:-
• Patient:- 76 years old male
• Diagnosis:- stage 4 chronic kidney disease
• Treated with:-Telmisartan,metformin, Furosemide, iron, calcium & vitamin
D
• ADVERSE EVENT:- Lesions on arms and foot, peripheral erythema, crust
in legs
• ACTION TAKEN:- biopsy of the lesions was performed with
histopathological examination----furosemide induced psuedoporphyria
(cutaneous reaction) was then established
• MODIFIED TREARMENT:-Furosemide was stopped and patient was
improved and recovered .(Dechallange +ve)

Case 3:-
• PATIENT:- 75 years old male
• SYMPTOMS:- multiple tense bullae (skin disorder) over both upper limbs,
forearms & chest.
• FACTORS TO BE CONSIDERD:- History of myocardial infarction,
undergone coronary artery bypass grafting, treated with multiple medication
,furosemide was one of the drug.
• ADVERSE EVENT:- After 2 days of administration, filled bullae & itching
developed over arms and chest.
• DIAGNOSIS:- bollus pemphigoid
• ACTION TAKEN:- Furosemide (suspected drug) was removed from
therapy, treated with prednisoslon, halobetasol and antibiotics.
• CAUSALITY ASSESSMENT:- Naranjo’s scale showed this ADR as
‘probable’ and WHO scale showed it as ‘probable/likely’.

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ADR REPORTING FORM:-

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CONCLUSION:-
• Treating of ADR involves discontinuation of the suspecting agent and
symptomatic treatment .
• ADRs was confirmed by causality assessment scales , following ADRs of
furosemide was established using assessment:
Fixed drug eruption(hyperpigmentation of skin)
Furosemide induced pseudo porphyria
Bullous pemphigoid
In all the three cases we observed that furosemide is causing somewhat cutaneous
reaction as an adverse effect, this can be considered as signal for furosemide’s ADR

REFERENCE:-

Kidney Disease Outcomes Quality Initiative (K/DOQI) K/DOQI clinical practice

guidelines on hypertension and antihypertensive agents in chronic kidney disease.
Am J Kidney Dis. 2004 May;43(5 Suppl 1):S1-290.

Runyon BA, AASLD Introduction to the revised American Association for the Study
of Liver Diseases Practice Guideline management of adult patients with ascites
due to cirrhosis 2012. Hepatology. 2013 Apr;57(4):1651-3.

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