DELHI INSTITUTE OF PHARMACEUTICAL SCIENCES AND

RESEARCH
CONSTITUENT COLLEGE OF DPSR UNIVERSITY

Sector-3, M.B. Road, PushpaVihar,

NEW DELHI-110017
2021-2022

CASE STUDY (REMDESIVIR ASSOCIATED

HEPATIC LIVER FAILURE AND SINUS
BRADYCARDIA IN COVID 19 PATIENTS)

PROJECT REPORT SUBMITTED IN FULFILLMENT OF THE

REQUIREMENT FOR B.PHARM VII SEM- PRACTICE SCHOOL

SUBMITTED TO: SUBMITTED BY:

Prof. (Dr.) SAURABH DAHIYA BHAVYA

ASSOCIATE PROFESSOR B. PHARM VII SEM

ROLL NO- 14364
DPSRU
Contents
i) ADR Monitoring ............................................................................ ….1
ii) Details required for ADR reporting……………………………………………....2
iii) ADR reporting form……………………………………………………………………...3
iv) Pharmacovigilance
a) Scope of Pharmacovigilance……………………………………………………..4
b) Need of pharmacovigilance ..................................................... ….5
v) Causality Assessment…………………………………………………………………….5
vi) Naranjo scale…………………………………………………………………………………7
vii) WHO UMC casualty assessment scale……………………………………………8
viii) Project Work
a) Abstract ................................................................................... ….9
b) Drug profile of Remdesivir………………………………………………………10
c) Case study 1……………………………………………………..11
d) Case study 2……………………………………………………………………………13
e) Case study 3……………………………………………………15
f) Case study 4 ................................................................................ 17
g) Case study 5. ............................................................................... 18
h) Naranjo inference……………………………………………………………………20
i) Discussion………………………………………………………………………………..21
j) Conclusion………………………………………………………………………………..22
ix) References ........................................................................................ 23
 ADR Monitoring [1]

A lot of academic intelligence goes into the drug development process right from
lead discovery to phase 3 of clinical trials in humans. But the drug molecule is
subjected to ultimate test when it reaches the phase 4 when it’s finally out in the
market for the direct consumption by the patients. Strict vigilance and astute
observation are an integral part of this phase called post marketing surveillance.
Adverse drug reactions (ADRs) are the most common causes of morbidity,
mortality and poor economical outcomes.
Therefore, post marketing surveillance is extremely important for monitoring the
risks and benefits of pharmaceutical products after they have been marketed.

Adverse Drug Reactions monitoring is a process of continual monitoring of

undesirable effects suspected to be associated with use of medicinal products.
ADR reporting would help healthcare practitioners and patients not only by
improving the quality of care offered to patients and reducing drug related
problems leading to optimum treatment outcomes but it also goes a long way in
enhancing the patients’ confidence in the healthcare service providers- the
physicians, pharmacists and the nurses. The patient goes back home from the
hospital with the assurance that he’s in safe hands and if any untoward reaction
were to happen, it’ll be dealt responsibly.

For efficient ADR monitoring, it is imperative that pharmacists are a core part of
this process. There is a need for pharmacists to move on from just the roles of
preparing and dispensing medications to other critical aspects of patient care
including patient therapy, ADR reporting, ADR monitoring, improving patients’
health and economic outcomes.

In India there is very miniscule amount of data present on ADR reporting in

community set up as pharmacists are largely confined to their trade only. There is
thus a need to educate and train the pharmacists in pharmacovigilance services
with simultaneous incentivization as well.
 DETAILS REQUIRED FOR REPORTING ADR EVENTS

ELEMENTS IN
ADR NECESSARY INFORMATION OTHERS REFERENCES
REPORTING
What should be Adverse reactions of the drug, suspected drug’s Medications overdose, Goldman1998
reported details, patient’s information pharmaceutical defect,
drug interactions

Who can report medical practitioners or health care professionals, Manufacturers, all Palaian et
doctors, nurses, pharmacists, assistants, government and private al.2006
pharmaceutical technicians, pharmaceutical hospital’s health center
assistants, clinical officers and other health care
providers

When it can be Any adverse reactions if noticed should be – Ravi Shankar et

reported reported as soon as possible. al.2010

How to report Through completely filled yellow card form – Ravi Shankar et
al.2010

Where it can be Fully filled completely ADR form should be – Palaian et

reported submitted to pharmacovigilance center al.2006
[3]
 Pharmacovigilance
Pharmacovigilance is defined by WHO as “the science and activities related to the
detection, assessment, understanding and prevention of adverse drug effects or any
other possible drug-related problems”

Scope of Pharmacovigilance:

Adverse
Drug
Reactions
Interaction of Medication
Medications Errors

Pharmacovigilance

Abuse and
Counterfeit
Misuse of
Medications
Medications
Lack of
Efficacy
 Need of Pharmacovigilance

❖ To ameliorate patient care and safety

❖ To contribute to the assessment of risk-benefit ratio
❖ To promote education and clinical training
❖ To promote rational and safe use of drugs
❖ To produce mindfulness among health care professionals about ADR

Causality Assessment
• Causality assessment is the method by which the extent of the
connection between a drug and a suspected reaction is estimated
• Used to gauge and to see if the actual treatment being
administered is the explanation for an observed adverse event or
not
• Whether the drug is capable of causing a specific AE within
the population is typically of greater interest than whether the
drug caused the event in each patient who reported the event.

FDA ON CASUALITY

"For any given case report, knowing with a high degree of certainty whether the
occurrence was caused by the product, is rare. There are currently no
internationally agreed-upon rules or criteria for determining causality in specific
circumstances, particularly for events that occur frequently and unexpectedly
(e.g., stroke, pulmonary embolism). To determine causality in such cases,
rigorous pharmacoepidemiologic studies, such as case-control studies and cohort
studies with long-term follow-up, are frequently required."
 FACTORS TO BE CONSIDERED
• Temporal relationship between drug administration and onset of
adverse reaction
• Clinical and pathological characteristics of the event
• Response to de challenge and re challenge
• Patients’ previous medical history
• Drug interaction

Methods of Causality Assessment

Global introspection (clinical judgment)
Having smart, experienced medical people (usually MDs) make a
judgment

Algorithms
Use of a formal, defined mechanism or decision tree to come to a
conclusion
• Immutability (France)
• Roussel-Uclaf (France)
• Venulet (Switzerland)
• Karsh-Lasagna (US)
• WHO (Sweden)
• Naranjo (Canada)

Probabilistic, Bayesian analysis & other statistical methods

Generally require more data than is available or data that is
introspective
Not yet practical.

Causality Assessment Scales

Naranjo's algorithm Kramer's scale
Kartch Lasagna`s algorithm Jones scale
WHO probability scale European ABO system
Spanish quantitative imputation scale Bayesian system
 Naranjo’s Scale [4]

Questions Yes No Don’t

Know

1 Are there previous conclusive reports on this +1 0 0

reaction?

2 Did the adverse event appear after the +2 -1 0

suspected drug was given?

3 Did the adverse reaction improve when the +1 0 0

drug was discontinued or a specific antagonist
was given?

4 Did the adverse reaction appear when the +2 0 0

drug was readministered?

5 Are there alternative causes that could have -1 +2 0

caused the reaction?

6 Did the reaction reappear when a placebo -1 +1 0

was given?

7 Was the drug detected in any body fluid in +1 0 0

toxic concentrations?

8 Was the reaction more severe when the dose +1 0 0

was increased, or less severe when the dose
was decreased?

9 Did the patient have a similar reaction to the +1 0 0

same or similar drugs in any previous
exposure?

10 Was the drug event confirmed by any +1 0 0

objective evidence?
 WHO-UMC Causality Assessment Scale [5]

Causality Term Assessment Criteria

Certain • Event or laboratory test abnormality, with plausible time
relationship to drug intake
• Cannot be explained by disease or other drugs
• Response to withdrawal plausible (pharmacologically,
pathologically)
• Event definitive pharmacologically or phenomenologically
(i.e. an objective and specific medical disorder or a
recognized pharmacological phenomenon)
• Rechallenge satisfactory, if necessary
Probable/ • Event or laboratory test abnormality, with reasonable time
Likely relationship to drug intake
• Unlikely to be attributed to disease or other drugs
• Response to withdrawal clinically reasonable
• Rechallenge not required
Possible • Event or laboratory test abnormality, with reasonable time
relationship to drug intake
• Could also be explained by disease or other drugs
• Information on drug withdrawal may be lacking or unclear
Unlikely • Event or laboratory test abnormality, with a time to drug
intake that makes a relationship improbable (but not
impossible)
• Disease or other drugs provide plausible explanations
Conditional/ • Event or laboratory test abnormality
Unclassified • More data for proper assessment needed, or
• Additional data under examination
Unassessable / • Report suggesting an adverse reaction
Unclassifiable • Cannot be judged because information is insufficient or
contradictory
• Data cannot be supplemented or verified
 PROJECT WORK

Abstract
SARS-CoV-2, a coronavirus that causes severe acute respiratory syndrome, spread
across the globe triggering a pandemic in 2019. Healthcare infrastructure was in
serious jeopardy when there was exponential rise in covid cases and no substantial
treatment measures. It compelled physicians to resort to experimental,
unapproved therapies for the same. One such investigational drug was Remdesivir
developed by Gilead Sciences, based in California,USA. Remdesivir was found to be
a potent antiviral, acting against SARS CoV-2 inhibiting RNA polymerase and
eventually viral replication.
In Adaptive covid 19 treatment trial (ACTT 1) it was found to shorten recovery time
in in patients hospitalized with COVID-19 but no significant reduction in mortality
rate was seen.
WHO Solidarity randomization trial showed little to no effect on hospitalized
patients with COVID-19, as indicated by overall mortality, initiation of ventilation,
and duration of hospital stay.
In view of above and due to lack of sufficient clinical safety data, Remdesivir
received an Emergency Use Authorization from FDA. It is therefore a reserve drug,
not indicated in mild covid cases and need to be prescribed by physicians with
utmost care. In light of rampant prescription of this drug and its acute shortage
that took place during peak covid, hereby are reported 5 case studies and its
analysis (by Naranjo scale) of remdesivir associated acute liver failure and sinus
bradycardia in patients with covid 19 in which the conditions improved on
dechallenge of the drug showing positive co relation between remdesivir and the
adverse effects.
 DRUG PROFILE OF REMDESIVIR TRIPHOSPHATE [6]
• Molar mass: 531.20 g/mol
• Formula: C12H16N5013P3
• Drug Class: - Antiviral
• Route of administration: - Intravenous
• Mechanism:- Nucleotide analogue; interferes with the action of viral RNA
polymerase ultimately inhibiting replication of viral genome
• Adverse effects include: - Respiratory failure, elevated bilirubin, elevated
hepatic enzyme levels, cardiac abnormalities

• Contraindications: - Sinus bradycardia, Abnormal liver function, Kidney

disease stage 4 (severe), Chronic kidney disease stage 5 (failure)

• Dosing :-
(a)In covid 19 hopistalised patients
IV: On the first day, take 200 mg as a single dose, then 100 mg once daily.
The duration is usually 5 days or until the patient is discharged from the
hospital, whichever comes first, but it can be up to 10 days in some cases
(when no substantial clinical improvement by day 5, on mechanical
ventilation or extracorporeal membrane oxygenation). Begin as soon as
feasible following a positive SARS-CoV-2 test, ideally within 72 hours after a
diagnosis of symptomatic COVID-19.

• Breastfeeding considerations
In a patient diagnosed with COVID-19 infection 2 days after delivery at 38
weeks' gestation, remdesivir quantities in breast milk were measured. On the
first day, Remdesivir 200 mg IV was given, followed by 100 mg daily for the
next four days. Prior to the diagnosis, the mother had started nursing and
was pumping to keep the milk supply going during the Remdesivir treatment.
Breast milk was sampled on treatment day 5 before and after remdesivir
administration, as well as 1, 3, 6, and 24 hours later.
 Case Study- 1 : Increased ALT associated with
remdesivir therapy for COVID-19 in a 59-year-old
man [7]
A 59-year-old man presented to hospital with cough and shortness of breath after
a positive polymerase chain reaction test for SARS-CoV-2, 1 week earlier. He had
no past medical history, a normal body mass index, and was not taking any
prescription or over-the-counter medications.On physical examination, his vital
signs were normal (BP 129/74 mm Hg, heart rate 89 BPM, body temp 36.9°C), HB,
creatinine and liver enzyme [ALT] levels were normal. His ECG showed normal
sinus rhythm with a heart rate of 79 BPM.

The patient was admitted to hospital and started on dexamethasone 6 mg daily

and enoxaparin for DVT. On day 2, remdesivir was administered as a loading dose
of 200 mg IV followed by 100 mg IV on day 3 and daily thereafter. On day 4, he
developed sinus bradycardia with a heart rate of 50 beats/min. Bloodwork was
notable for an elevated ALT (127 unit/L).

The fourth dose of remdesivir was held, given his bradycardia and elevated ALT.
After we stopped the remdesivir, the patient’s heart rate began to increase and on
day 7, his heart rate had increased to 62 BPM, his ALT was 133 unit/L and he was
discharged home. We did not restart the remdesivir.
CASE 1: NARANJO ANALYSIS

TOTAL SCORE: 3
 CASE STUDY 2- Remdesivir-Associated Acute Liver
Failure in COVID-19 patient [8]
A 68-year-old woman with a history of hypertension, hyperlipidemia and
CAD presented to an outside hospital with a complaint of shortness of
breath and tightness across her chest.
By day 8, she developed cough and worsening infiltrates on chest
radiograph. A loading dose of remdesivir 200 mg intravenous (i.v.) was
administered the same day and a maintenance of remdesivir 100 mg i.v.
every 24 hours was started on day 9 for a planned total of 5 days of
therapy. Before remdesivir administration, the patient’s liver function
enzymes were within normal limits.

On day 10, the patient had increasing oxygen demands and an

amiodarone infusion was initiated for new-onset, postoperative atrial
fibrillation. Over the course of the next 24 hours, both the AST and ALT
were greater than 5000 units/L along with a total bilirubin of 3.1 mg/dL.
Both remdesivir and amiodarone were discontinued and on the evening
of day 10, a continuous infusion of acetylcysteine was initiated for the
suspected remdesivir-induced ALF

By the end of the 21-hour acetylcysteine protocol, the patient’s AST and
ALT had decreased to 1348 and 1861 units/L, respectively. Over the
course of the rest of her hospital stay, the patient’s oxygen requirements
improved until she was weaned to room air on day 20 and her liver
function tests returned to normal limits by day 24 of hospitalization.
 CASE STUDY 2: NARANJO ANALYSIS

Question Yes No Do Not

Know
1.Are there previous conclusive reports on this reaction? 0

2. Did the adverse event appear after the suspected drug 2

was administered?
3. Did the adverse event improve when the drug was 1
discontinued or a specific antagonist was administered?
4. Did the adverse event reappear when the drug was 0
readministered?
5. Are there alternative causes that could on their own 0
have caused the reaction?
6. Did the reaction reappear when a placebo was given? 0
7. Was the drug detected in blood or other fluids in 0
concentrations known to be toxic?
8. Was the reaction more severe when the dose was 0
increased or less severe when the dose was decreased?
9. Did the patient have a similar reaction to the same or 0
similar drugs in any previous exposure?
10. Was the adverse event confirmed by any objective 1
evidence?

TOTAL SCORE: 4
CASE STUDY 3- Drug-induced Liver Injury in a Patient
With Coronavirus Disease 2019 [9]
A 64-year-old man presented at our hospital with a 7-day history of
fever, headache, cough, and progressive dyspnea. He had a history of
hypertension and hypercholesterolemia for which he used
enalapril, amlodipine, and simvastatin. He did not smoke or use
illicit drugs. His blood pressure was 143/80 mm Hg, with a pulse rate
of 80 beats per minute, his body temperature was 38.8°C, his
respiratory rate was 40 BPM and O2 satn was 88%.

The diagnosis of COVID-19 was confirmed by a positive SARS-CoV-2

PCR test. He was admitted to the hospital for oxygen therapy; a 5-day
chloroquine course (loading dose 600 mg followed by 300 mg twice
daily) was started. Due to respiratory insufficiency on day 3, he was
transferred to ICU for mechanical ventilation.

On day 16, remdesivir was started. Because of new-onset atrial

fibrillation, amiodarone (700 mg on day 18) was temporally given 2
days after initiation of remdesivir. Five days after start of remdesivir,
an acute increase in ALT (1305 IU/L) and AST (1461 IU/L) alkaline
phosphatase 269 U/L, total bilirubin 8 µmol/L, γ-glutamyltransferase
227 U/L, and creatine kinase 103 U/L was seen. Remdesivir was
immediately stopped, resulting in a rapid decrease of ALT and AST
values to eventually normal levels. On day 48 the patient was
discharged to a rehabilitation centre. Two weeks thereafter, he
returned home, and he was able to restart his normal daily activities.
CASE STUDY 3: NARANJO ANALYSIS

TOTAL SCORE: 4
 CASE STUDY 4- Sinus Bradycardia Associated with
Remdesivir Treatment in COVID-19 [10]
36-year-old male hospitalized due to severe COVID-19 symptoms. He was presented with a 10-
day history of fever (up to 39.7 °C), productive cough, fatigue and hypoxemia.
The patient received supplemental oxygen, dexamethasone, remdesivir and empirical
antibiotic treatment according to protocol. Asymptomatic sinus bradycardia developed on
hospital day 3 (namely, heart rate 39/min compared to 92/min on admission).
Secondary causes of bradycardia were excluded based on the absence of relevant evidence
from laboratory work-up and echocardiographic examination. The patient’s rhythm restored
to normal 9 days after the discontinuation of remdesivir

NARANJO ANALYSIS

TOTAL SCORE: 6
 CASE STUDY 5- Cardiac Adverse Events with
Remdesivir in COVID-19 Infection [11]

A 26 year old African American female presented with cough, chills, nausea,
decreased appetite, loose stools, and dry cough for one week. Upon initial
evaluation, she had a temperature of 100.3 °F, heart rate of 83, and blood
pressure of 120/68 mmHg. A non-rebreather facemask was used to maintain her
saturations over 94%. Her medical comorbidities included obesity with a body
mass index greater than 35.

The nasal polymerase chain reaction was positive for SARS-CoV-2. On admission,
her blood work revealed an elevated lactate dehydrogenase (LDH) of 441 IU/L
(normal reference: 98-230 IU/L), an elevated c-reactive protein (CRP) of 237 mg/L
(normal reference: 0-9mg/L), an elevated procalcitonin of 0.61 ng/mL (normal
reference: 0-0.08ng/mL) and an increased d-dimer of 0.54 ug/ml (normal
reference: 0.27-0.5). Her liver and renal function tests were within normal limits.
Computed tomography of the chest showed extensive bilateral consolidative
changes. Due to her worsening respiratory status, she was initiated on a
multimodal therapy of the antibiotics ceftriaxone and azithromycin, the steroid
methylprednisolone, convalescent plasma and remdesivir.

At baseline she was in normal sinus rhythm with a heart rate of 80 to 100 bpm
and a QTc interval of 439 ms. Her baseline EKG showed no rhythm abnormalities
(Figure 1). After her third dose of a five-day treatment course of remdesivir, she
was in sinus bradycardia with her heart rate dropping to 40-50 beats per minute,
prolonged QTc interval of 555 ms, and T wave abnormality. The remdesivir
treatment was discontinued and the patient’s heart rate returned to baseline
with her QT interval stabilizing to 448ms in three days.
 CASE STUDY 5: NARANJO ANALYSIS

Question Yes No Do Not Know

1.Are there previous conclusive reports on this reaction? 0

2. Did the adverse event appear after the suspected drug 2

was administered?
3. Did the adverse event improve when the drug was 1
discontinued or a specific antagonist was administered?
4. Did the adverse event reappear when the drug was 0
readministered?
5. Are there alternative causes that could on their own have 0
caused the reaction?
6. Did the reaction reappear when a placebo was given? 0

7. Was the drug detected in blood or other fluids in 0

concentrations known to be toxic?
8. Was the reaction more severe when the dose was 0
increased or less severe when the dose was decreased?

9. Did the patient have a similar reaction to the same or 0

similar drugs in any previous exposure?
10. Was the adverse event confirmed by any objective 1
evidence?

TOTAL SCORE: 4
 NARANJO’S ADR PROBABILITY SCALE
Score Interpretation of Scores
Total Score Definite. The reaction (1) followed a reasonable temporal
≥9 sequence after a drug or in which a toxic drug level had been
established in bodyfluids or tissues
(2) followed a recognized response to the suspected drug, and
(3) was confirmed by improvement on withdrawing the drug
and reappeared on re exposure.
Total Score Probable. The reaction
5 to 8 (1) followed a reasonable temporal sequence after a drug
(2) followed a recognized response to the suspected drug
(3) was confirmed by withdrawal but not by exposure to the drug
(4) could not be reasonably explained by the known
characteristics of the patient’s clinical state.

Total Score Possible. The reaction

1 to 4 (1) followed a temporal sequence after a drug
(2)possibly followed a recognized pattern to the suspected drug
(3)could be explained by characteristics of the patient’s disease.

Total Score Doubtful. The reaction was likely related to factors other than a
≤0 drug.

CASE STUDY 1: 3 POSSIBLE

CASE STUDY 2: 4 POSSIBLE
CASE STUDY 3: 4 POSSIBLE
CASE STUDY 4: 6 PROBABLE
CASE STUDY 5: 4 POSSIBLE
 DISCUSSION
Common adverse events for remdesivir include rash, headache, nausea, diarrhea,
and elevated transaminases. Chance occurrences of hypersensitivity, hypotension
and renal impairment are also possible .

Bradycardia: In ACTT-1, arrhythmias (other than ventricular fibrillation and

tachycardia, supraventricular tachycardias and atrial fibrillation) affected 0.2% of
patients receiving remdesivir, compared with no reported events in the placebo
group. Supraventricular tachycardia was reported in 0.6% of patients in the ACTT-1
experimental group. 0.9% patients reported serious atrial fibrillation. A case of
cardiac arrest was also reported. Data specifically on bradycardia weren’t
reported.
Adaptive COVID-19 Treatment Trial (ACTT-1) and the World Health Organization
Solidarity Trials did not recognize bradycardia as a potential ADR of remdesivir in
Covid 19 patients. But it’s an equally relevant fact that clinical trials are often
insufficient to detect unusual adverse effects. Some case studies conducted
afterward, although, did report incidences of bradycardia in remdesivir
administered covid patients,

ALT: There have been several studies conducted describing aminotransferase

elevation following remdesivir therapy.
A PALM study was conducted where hepatotoxicity was not seen as a serious ADR
in a study conducted in around 175 Ebola patients. In the ACTT 1 trial-
hepatotoxicity (aminotransferase elevations of grade 1 or higher) was seen less in
remdesivir administered covid patients compared to placebo patients. Wang et al
conducted trials where 1 of 155 patients experienced grade 3 AST elevations.
 CONCLUSION

In all of the cases above, bradycardia occurred soon after initiation of the
medication and subsequently improved within 48 hours of de-challenge. No other
significant cause of bradycardia was seen in the regimen. Although case reports
cannot definitively establish causality, this time course is evident enough that
remdesivir was a causative factor.

Through analysis of above case studies, it has indeed been ascertained than
occurrence of bradycardia has an association with the administration of remdesivir
in covid patients. This association will be particularly relevant for patients who
have other risk factors for bradycardia
for eg: elderly people, concomitant β-blocker regimen.

Regarding liver injury, remdesivir toxicity can be concluded on the basis of time
relation, positive de challenge and the absence of any other probable cause of the
elevated liver enzymes. Covid infection itself could be the cause of high ALT levels
but the increase was seen sufficiently after the first onset of symptoms, by which
time viral replication was highly unlikely.
These case studies should add to the literature available on association between
remdesivir and its cardiotoxic and hepatotoxic effects.

Remdesivir got an emergency approval for covid treatment. Substantial clinical

safety data not available. The current safety profile of remdesivir is still largely
unknown. Remdesivir is the most widely used medication for covid 19 patients, the
mean age for which is 70 yrs. Patients prone to co-morbidities are further at risk.
Therefore, further clinical trials on a large scale can need to be conducted to
better understand the co-relation and devise safe risk management methods.
 REFERENCES
[1]Sahu, R. K., Yadav, R., Prasad, P., Roy, A., & Chandrakar, S. (2014). Adverse drug reactions monitoring:
prospects and impending challenges for pharmacovigilance. SpringerPlus, 3, 695.
https://doi.org/10.1186/2193-1801-3-695

[2]Deepalakshmi, M., & Preethi Kumar, P. K. (2019, May 26). Impact of Continuing Pharmacy Education on the
Knowledge, Attitude and Practice of Community Pharmacists about ADR Monitoring and Reporting. Indian
Journal of Pharamceutical Sciences. https://www.ijpsonline.com/articles/impact-of-continuing-pharmacy-
education-on-the-knowledge-attitude-and-practice-of-community-pharmacists-about-adr-monitoring-and-r-
3664.html?view=mobile#:~:text=Adverse%20drug%20reactions%20(ADRs)%20are,after%20they%20have%20
been%20marketed.

[3]https://cdsco.gov.in/opencms/export/sites/CDSCO_WEB/Pdf-
documents/Consumer_Section_PDFs/ADRRF_2.pdf

[4] LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD):
National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Adverse Drug Reaction Probability
Scale (Naranjo) in Drug Induced Liver Injury. [Updated 2019 May 4]. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK548069/

[5]https://who-umc.org/media/164200/who-umc-causality-assessment_new-logo.pdf

[6]https://go.drugbank.com/drugs/DB14761

[7]Day, L. B., Abdel-Qadir, H., & Fralick, M. (2021). Bradycardia associated with remdesivir therapy for COVID-
19 In a 59-year-old man. Canadian Medical Association Journal, 193(17), E612–E615.
https://doi.org/10.1503/cmaj.210300

[8]Carothers, C., Birrer, K., & Vo, M. (2020). Acetylcysteine for the Treatment of Suspected Remdesivir‐
Associated Acute Liver Failure in COVID‐19: A Case Series. Pharmacotherapy: The Journal of Human
Pharmacology and Drug Therapy, 40(11), 1166–1171. https://doi.org/10.1002/phar.2464

[9] Leegwater, E., Strik, A., Wilms, E. B., Bosma, L. B. E., Burger, D. M., Ottens, T. H., & van Nieuwkoop, C.
(2020). Drug-induced Liver Injury in a Patient With Coronavirus Disease 2019: Potential Interaction of
Remdesivir With P-Glycoprotein Inhibitors. Clinical Infectious Diseases, 72(7), 1256–1258.
https://doi.org/10.1093/cid/ciaa883

[10] Barkas, F., Styla, C. P., Bechlioulis, A., Milionis, H., & Liberopoulos, E. (2021). Sinus Bradycardia Associated
with Remdesivir Treatment in COVID-19: A Case Report and Literature Review. Journal of Cardiovascular
Development and Disease, 8(2), 18. https://doi.org/10.3390/jcdd8020018

[11] Gupta, A. K., Parker, B. M., Priyadarshi, V., & Parker, J. (2020). Cardiac Adverse Events With Remdesivir in
COVID-19 Infection. Cureus. https://doi.org/10.7759/cureus.11132