Day 1 Updates

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Joint American College of Cardiology/Journal of the American College of Cardiology: Late-Breaking
Clinical Trials
CSL112 (Apolipoprotein A-I) infusions and cardiovascular outcomes in patients
1 with acute myocardial infarction (ApoA-I event reducing in ischemic syndromes II 1
(AEGIS-II) trial): Primary trial results
A double-blind, randomized placebo procedure-controlled trial of an interatrial
2 8
shunt in patients with HfrEF and HfpEF: Principal results from the RELIEVE-HF trial

3 Empagliflozin after acute myocardial infarction: Results of the EMPACT-MI trial 13

Featured Clinical Research

Using Inclisiran as a First-Line Approach Safe and Effective for Controlling LDL-C in
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Patients with ASCVD: Results From The VICTORION-INITIATE Randomized Trial
Remote Acute Assessment Of Patients With High Cardiovascular Risk Post-acute
5 23
Coronary Syndrome (TELE-ACS)

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Joint American College of Cardiology/Journal of the

American College of Cardiology: Late-Breaking Clinical
Trials
1. CSL112 (Apolipoprotein A-I) infusions and cardiovascular
outcomes in patients with acute myocardial infarction (ApoA-I
event reducing in ischemic syndromes II (AEGIS-II) trial): Primary
trial results
(Presenter: C. Michael Gibson (Natick, MA), ACC Conference 2024)

The primary function of HDL-C is to transport cholesterol from cells to the liver, where hepatocytes break down
cholesterol for excretion through bile. Although higher HDL-C levels are associated with lower cardiovascular
events, therapies aimed at raising HDL-C numbers have not resulted in reduced events. Therefore, the study
hypothesized that enhancing HDL function by infusing human ApoA-1, the primary functional component of
HDL, would improve outcomes.
Measuring HDL Function Instead of HDL-C Number: Measuring Cholesterol Efflux Capacity
From Macrophages

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Improved cholesterol efflux capacity (CEC) is associated with improved 6 year survival
following MI

CSL112 is human ApoA-1 purified from human plasma, reconstituted with phosphatidylcholine, and stabilized
with sucrose. It is suitable for intravenous infusion and results in a substantial, dose-dependent enhancement
in cholesterol efflux in post-myocardial infarction patients.

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Hypothesis of the AEGIS 2 Trial

» Prior Observations:
• CSL 112 ApoA-1 infusions improved cholesterol efflux in the setting of MI and reduced fat and macrophage
content in atherosclerotic plaque
• Improved cholesterol efflux is associated with improved CV outcomes in the setting of MI
» Hypothesis:
• CSL 112 infusion will improve CV outcomes in the setting of MI
ApoA-1 Event ReducinG in Ischemic Syndromes II
» A phase 3, multicenter, double-blind, randomized, placebo-controlled, event-driven, parallel-group study

Trial compliance and follow-up

» 90%subjects successfully completed all four infusions, with 99.5% completing 90 days of follow-up and
99% completing 365 days of follow-up. Notably, one patient was lost to follow-up in each group.
» At 90 days, the primary outcome, which encompasses cardiovascular (CV) death, myocardial infarction
(MI), or stroke, was observed in 4.8% of patients in the CSL112 apoA-1 infusion group compared to 5.2% in
the placebo group (p = 0.24). These findings remained consistent across all examined subgroups.

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» Secondary outcomes revealed that at 365 days, the incidence of cardiovascular (CV) death, myocardial
infarction (MI), or stroke was 9.8% in the CSL112 apoA-1 infusion group and 10.5% in the placebo group
(p = 0.14). Among patients with LDL-C levels ≥100 mg/dL, the rate of CV death, MI, or stroke at 365 days
was 7.8% in the CSL112 apoA-1 infusion group compared to 9.9% in the placebo group (p = 0.006, p for
interaction = 0.07).

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In patients with acute myocardial infarction (AMI) and multivessel disease, along with additional cardiovascular
risk factors, the administration of four weekly infusions of CSL112 apoA-1 compared to placebo did not lead
to a reduction of major adverse cardiovascular events (CV death, MI, or stroke) within the initial 90 days.
However, the suggestion of potential benefit observed among individuals with elevated baseline LDL-C levels
is considered hypothesis-generating.

Safety findings
» Overall, adverse event rates were comparable with CSL112 compared to placebo.
» There were no notable disparities in all hypersensitivity events, including both serious and non-serious
cases.
» While the number of immune system disorder events leading to discontinuation from investigational
product was low, it was higher in the CSL112 group compared with the placebo group (14 vs 4 events,
p=0.02).
» Acute kidney injury events were fewer in the CSL112 arm, defined by changes in creatinine through the
active treatment period: 570 (6.3%) vs 650 (7.2%) (p=0.02).
» No significant imbalances were observed in potential hepatic injury events (defined as ALT >3x ULN with
Tbili >2x ULN or ALT >5x ULN), or new or worsening heart failure events based on adjudication.

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Secondary and exploratory hypothesis generating analyses

» Primary MACE endpoint lower in patients with baseline hyperlipidemia (LDL-C ≥ 100, all on statins)

» Benefits seen in the hyperlipidemic group

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Conclusion
» In acute myocardial infarction (AMI) patients with multivessel disease and additional cardiovascular risk
factors on guideline-directed background therapies, four weekly infusions of CSL112 compared with
placebo did not result in a significant reduction in the primary endpoint of cardiovascular (CV) death,
myocardial infarction (MI), or stroke through 90 days.
» Consistency in the primary endpoint was observed across pre-specified subgroups.
» The drug was well tolerated.
» Secondary and exploratory hypothesis generating analyses revealed
• The potential treatment effect of ApoA-1 infusion increased significantly as baseline LDL-C levels
increased, analyzed as a continuous variable.
• A positive interaction term indicated that the treatment effect was statistically significant in patients
with LDL-C ≥ 100 mg/dL, while it was not in those with LDL < 100 mg/dL.
• The observed benefit of ApoA-1 infusions in hyperlipidemic patients aligns with biological plausibility,
yet this observation is hypothesis-generating and requires prospective validation.
• Trends observed for the individual components of cardiovascular (CV) death and myocardial infarction
(MI) are consistent with the proposed biological effect of plaque stabilization, as pre-determined.

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2. A double-blind, randomized placebo procedure-controlled trial

of an interatrial shunt in patients with HfrEF and HfpEF: Principal
results from the RELIEVE-HF trial
(Presenter: Gregg Stone (New York, NY), ACC Conference 2024)

The study examined individuals with advanced heart failure (HF) and differing left ventricular ejection fractions
(LVEF), identified as being at a heightened risk for cardiovascular morbidity and mortality occurrences.

Results showed:
» The annual occurrence rate of cardiovascular events, which includes all-cause mortality, the need for LVAD/
heart transplantation, all hospitalizations due to heart failure, and instances of outpatient deterioration in
heart failure, was 55.7% in the shunt group and 56.0% in the placebo group (P=0.96).

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In the predefined analysis categorizing patients based on LVEF (≤40% and >40%), notable variations in
treatment response were reported.
» For individuals with HFrEF, the yearly rate of all cardiovascular events was 49.0% among patients receiving
the shunt compared to 88.6% in the placebo group.
» This advantage was attributed to significant decreases in heart failure hospitalizations and a slightly reduced
necessity for LVAD/heart transplantation.

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In individuals with HFpEF, the event rates displayed an inverse pattern: the annualized rate was 60.2% in those
treated with a shunt compared to 35.9% in the placebo group.
» Shunt-treated patients with HFpEF exhibited a higher risk of all-cause mortality (16.4% versus 5.2% in the
placebo arm), a statistically significant difference.
» Additionally, the risk of all heart failure hospitalizations was 37.0% per year in the shunt arm versus 19.0%
per year in the placebo group, indicating a 50% reduction in all heart failure hospitalizations.
» Unlike patients with preserved ejection fraction, there was a doubling of events and a tripling of all-
cause mortality, which was exacerbated by shunt treatment in patients with preserved ejection fraction,
escalating from 5.2% to 60.2% over 2 years, with a difference of only nine patients succumbing to death.

In general, there was no notable improvement observed with the shunt compared to the placebo. Moreover,
when patients were categorized by LVEF, there was no apparent disparity in quality of life between the two
groups.

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Among individuals with HFrEF, both the shunt- and placebo-treated patients initially exhibited an increase
in the KCCQ overall summary score. However, the change from baseline to one year showed no divergence
between the two groups. Similarly, in patients with HFpEF, there were no discernible differences observed in
the KCCQ score at the one-year mark between the treatments.

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Limitations of the study

» These findings are specific to patients enrolled and treated with the Ventura inter-atrial shunt.
» Although the reduced and preserved LVEF groups were pre-specified randomized strata, they were not
individually powered for effectiveness; therefore, the results within each stratum should be considered
exploratory.
» However, the significant interaction (P<0.0001) and spline curve analysis for cardiovascular events suggest
that these findings are not merely due to chance.
» The substantial and comparable increase in KCCQ-OSS in both the device and control groups underscores
the significance of the placebo effect and underscores the need for blinded trials.
» Furthermore, the similar magnitude of improvement in KCCQ-OSS and the absence of between-group
differences in this measure, despite a significant decrease in heart failure hospitalizations in shunt-treated
patients with reduced LVEF and a considerable increase in heart failure hospitalizations and mortality in
shunt-treated patients with preserved LVEF, complicates its interpretation in both blinded and open-label
trials.
Conclusions
» Transcatheter implantation of the Ventura inter-atrial shunt was deemed safe, yet it did not alleviate
symptoms or enhance prognosis over a span of 2 years in patients with heart failure across the entire
spectrum of left ventricular ejection fraction (LVEF).
» Results derived from a pre-defined stratified analysis indicate that inter-atrial shunt implantation confers
benefits to patients with reduced LVEF but may be detrimental to those with preserved LVEF.

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3. Empagliflozin after acute myocardial infarction: Results of the

EMPACT-MI trial
(Presenter: Javed Butler (Atlanta, GA), ACC Conference 2024)

Despite advancements in acute myocardial infarction (AMI) management, post-MI patients still face a
significant risk of developing heart failure, with rates reaching up to 30% within the first year. Prognosis is
notably poor for individuals who experience congestion or left ventricular dysfunction alongside AMI. SGLT2
inhibitors have consistently demonstrated efficacy in reducing the risk of heart failure events, both in patients
at high risk of HF development, such as those with chronic kidney disease (CKD) or type 2 diabetes (T2D), and
in those with established heart failure, regardless of left ventricular ejection fraction (LVEF) or T2D status.

The EMPACT-Mi trial was designed to be streamlined, incorporating inclusion and exclusion criteria easily
applicable in routine clinical practice.

The trial predominantly relied on remote follow-up visits, which made patient engagement simpler. Data
collection was also streamlined, emphasizing focused gathering of safety information. Rather than central
adjudication, blinded investigator review was utilized alongside structured data collection methods. The
primary endpoint of the trial was defined as the time until the first heart failure hospitalization or occurrence
of all-cause mortality.

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EMPACT- MI trial is a large-scale, global clinical trial

Key trial parameters encompassed the randomization of 6522 patients, among whom 565 reached the primary
endpoint, with a median follow-up duration of 17.9 months and 99.2% completeness in vital status follow-up.
EMPACT-MI: Patient population
Out of the enrolled patients, 3715 individuals (57.0%) required treatment for signs and symptoms of
congestion. Additionally, 2323 patients (35.6%) exhibited both signs of congestion and had a left ventricular
ejection fraction (LVEF) less than 45%. Moreover, a significant majority, totaling 5112 patients (78.4%), had an
LVEF below 45%.

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Revascularization and medications at discharge

Medical management of these patients, approximately 90% of the patients were revascularized for their index
AMI.

The hazard ratio (HR) for the primary endpoint was 0.90 (95% CI: 0.76, 1.06), with a corresponding p-value of
0.21.
» Regarding the individual components comprising the primary endpoint, an initial hospitalization for heart
failure occurred in 118 patients (3.6%) within the empagliflozin group and 153 patients (4.7%) within the
placebo group (hazard ratio, 0.77; 95% CI, 0.60 to 0.98).
» Additionally, death from any cause occurred in 169 individuals (5.2%) in the empagliflozin group and 178
individuals (5.5%) in the placebo group (hazard ratio, 0.96; 95% CI, 0.78 to 1.19).

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No noticeable differences were observed between groups across various secondary endpoints or within key
subgroups, such as patients with chronic kidney disease (CKD) or diabetes. Furthermore, no safety concerns
were identified with the treatment.

The incidence of both the first heart failure (HF) event (3.6% vs. 4.7%; hazard ratio [HR] 0.77, 95% CI 0.60-0.98)
and total HF hospitalizations (148 events vs. 207 events; relative risk [RR] 0.67, 95% CI: 0.51-0.89) showed
favorable outcomes for the SGLT2 inhibitor group compared to the placebo group.

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The total heart failure burden included heart failure adverse events, reflecting a rising trend in diagnosing and
treating heart failure on an outpatient basis. These adverse events encompassed hospitalizations, fatal heart
failure events, and outpatient incidents. The identification of heart failure adverse events was predefined as
serious adverse events, and all serious adverse events were reported as per protocol.

Patients receiving SGLT2 inhibitors experienced a significantly reduced duration until the initial use of heart
failure medication, including an ARNI, RAAS inhibitor, MRA, or diuretic, compared to those in the placebo

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Consistent with the established safety profile of empagliflozin, it’s noteworthy that there was no significant
difference in the risk of kidney adverse events.

Conclusion
» Empagliflozin did not yield a significant reduction in the risk of time to first hospitalization for heart failure
(HHF) or all-cause death following acute myocardial infarction (AMI).
» Empagliflozin exhibited a relative risk reduction of 23% and 33% for the occurrence of first HHF and total
HHF, respectively, which are components of the primary and first key secondary endpoints.
» The risk reduction for HHF remained consistent across subgroup and sensitivity analyses.
» The safety profile observed was in line with the known safety profile of empagliflozin.

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Featured Clinical Research

4. Using Inclisiran as a First-Line Approach Safe and Effective
for Controlling LDL-C in Patients with ASCVD: Results From The
VICTORION-INITIATE Randomized Trial
Presenter: Jorge Plutzky, ACC Conference 2024

New data from a phase 3b trial presented at ACC.24 underlines the potential of inclisiran
in reducing LDL-C levels among patients with ASCVD.
Extensive evidence supports the importance of intensive lowering of LDL-C levels to improve cardiovascular
outcomes in patients diagnosed with atherosclerotic cardiovascular disease (ASCVD), with guidelines
recommending risk-based LDL-C goals of less than 55 mg/dL and less than 70 mg/dL.
Inclisiran, a novel small interfering RNA (siRNA) medication, functions by inhibiting hepatic production of
PCSK9, thereby increasing LDL receptor expression and enhancing LDL-C clearance from circulation. Clinical
studies have demonstrated that biannual administration of inclisiran by healthcare providers can lead to an
additional reduction of approximately 50% in LDL-C levels, with a majority of patients successfully meeting
LDL-C goals.
“Inclisiran first” implementation strategy involved promptly incorporating inclisiran if patients do not attain
LDL-C levels below 70 mg/dL despite receiving maximally tolerated statins. This assessment aimed to
determine whether the efficacy observed with twice-yearly inclisiran administration translates effectively into
real-world clinical settings in the United States, where practical challenges often impact treatment adherence
and outcomes.
Study Design:
The trial leveraged a prospective, randomized, parallel-group, open-label design and randomized 450 patients
from 45 sites across the US in a 1:1 ratio to an inclisiran first strategy or usual care. For inclusion in the trial,
patients needed to be at least 18 years of age and have a history of coronary heart disease, cerebrovascular
disease, or peripheral artery disease, with an LDL-C of 70 mg/dL or greater or a non-HDL-C of 100 mg/dL or
greater, and fasting triglycerides less than 500 mg/dL.

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The cohort of 450 patients had a median age of 67.0 years (27, 89), 30.9% were female, 12.4% were Black, and
15.3% were Hispanic or Latino. Investigators pointed out 97.1% had health insurance at baseline and 58.4%
reported an annual income of $50,000 or less.
The cohort had a mean baseline LDL-C of 97.4 mg/dL and 91.8% reported prior or current coronary heart
disease. Investigators also pointed out 25.8% were considered statin intolerant and 90.0% of the overall
cohort took statins at baseline.

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Results:
» Mean percentage change from baseline to day 330 in LDL-C was −60.0% (97.5% CI, −64.7 to −55.2) with the
inclisiran first strategy and −7.0% (97.5% CI, −12.0 to −1.9) with usual care, which yielded a between-group
difference of −53.0 percentage points (97.5% CI, −60.0 to −46.0; P < .001).
» Discontinuation of statin therapy was observed among 6.0% of the inclisiran first arm compared to 16.7%
of the usual care arm.
» Further analysis indicated a greater proportion of patients in the inclisiran first arm achieved an LDL-C of
less than 70 mg/dL relative to placebo therapy (81.8% vs 22.2%; P < .001).
» This trend was also observed when assessing the proportion of patients who achieved an LDL-C of less than
55 mg/dL (71.6% vs 8.9%; P < .001).
» When assessing safety, investigators found treatment-emergent adverse events occurred at a similar rate
for those randomized to an inclisiran first strategy relative to usual care (62.8% vs 53.7%).

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Conclusions:
» Data from V-INITIATE illustrate that earlier initiation of innovative non-statin therapies, like Leqvio, presents
a real opportunity to do better for ASCVD patients and improve the way we approach LDL-C lowering,” said
David Soergel, MD, global head of Cardiovascular, Renal and Metabolic Drug Development at Novartis.2
“This study adds data from a real-world setting to the growing body of evidence for Leqvio being generated
through our robust VictORION program, and further reinforces the clinical value of this twice-yearly HCP-
administered therapy.”

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5. Remote Acute Assessment Of Patients With High Cardiovascular

Risk Post-acute Coronary Syndrome (TELE-ACS)
Presenter: Nasser Alshsrani, ACC Conference 2024

A robust telemedicine intervention across six months following an acute coronary syndrome (ACS) was
associated with a reduction in hospital readmission, emergency department (ED) visits, unplanned coronary
revascularization and patient-reported symptoms, according to a randomized study presented during a
Featured Clinical Research session during ACC.
A large tertiary center in London, UK, involved randomized 337 participants (mean age 58.1 years, 86.1% men,
46% White, 36% Asian, 11% Black) presenting with an ACS and at least one cardiovascular risk factor before
discharge to either standard care or standard care plus telemedicine.
Patients in the telemedicine arm were given a user-applied 12-lead electrocardiogram (EKG) belt that linked
to their smart device and automatically transferred a copy of their EKG to the research team, as well as an
automated blood pressure monitor and a pulse oximeter. If the patient reported symptoms, a cardiologist
would perform a remote clinical assessment before referring them to the ED, their primary care physician or
elsewhere. Data were collected at three, six and nine months.
Study Outcomes:
» Primary Outcome: All Hospital readmission rate (time to readmission) at 6 months of follow up
» Secondary Outcomes
• Total length of stay (LOS) at 3, 6, and 9 months
• All-cause mortality
• Major adverse cardiovascular events (myocardial infarction, stroke, cardiovascular death)
• Medical intervention
• Emergency room visits not requiring admission or further intervention
• 9 months readmission rates
• Patient-reported quality of life outcome measures

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Results:
» The primary outcome of time to first readmission at six months was lower in the telemedicine arm than
the standard care arm (13 patients vs. 48 patients, respectively; hazard ratio [HR], 0.24; 95% CI, 0.13-0.44;
p<0.001), using an intention-to-treat analysis.

» Looking at secondary endpoints, ED admission was also lower in the telemedicine arm vs. standard care arm
(40 vs. 62 patients; HR, 0.59; 95% CI, 0.40-0.89; p=0.01), Specifically, there were fewer unplanned coronary
revascularizations (3% vs. 9%), fewer occurrences of chest pain (9% vs. 24%), and less breathlessness (21%
vs. 39%) and dizziness (6% vs. 18%).

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» A sustained benefit was found at nine months, with an HR of 0.35 for event-free survival, compared with
0.24 at six months.
Conclusions:
» “These results highlight the potential of telemedicine to improve post-ACS patient care by enhancing clinical
decision-making and reducing the need for hospital care,” Alshahrani, et al., concluded. Furthermore, they
note, “it is also important for this protocol to be robust enough to prevent inappropriate readmissions and
avoid in-person assessment.”

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ROZUCOR 5/10/20/40
For the use of a Registered Medical Practitioner or Hospital or a Laboratory only Abbreviated Prescribing information for Rozucor (Rosuvastatin Tablets 5/10/20/40 mg) [Please refer the complete prescribing information available at www.torrentpharma.com] PHARMACOLOGICAL PROPERTIES: Rosuvastatin is a 3-hydroxy-3-methyl glutaryl coenzyme A (HMGCoA) reductase inhibitor indicated for the
treatment of hyperlipidemia. INDICATION: Treatment of hypercholesterolemia, as an adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia, as an adjunctive therapy to diet to slow the progression of atherosclerosis in adult patients as part of a treatment strategy to lower Total-C and LDL-C to target levels. DOSAGE AND ADMINISTRATION: Before treatment initiation the patient should
be placed on a standard cholesterol-lowering diet that should continue during treatment. The dose should be individualized according to the goal of therapy and patient response, using current consensus guidelines. Rosuvastatin may be given at any time of day, with or without food. CONTRAINDICATION: Contraindicated in patients with a known hypersensitivity to any component of this product. Hypersensitivity
reactions includes rash, pruritus, urticaria, and angioedema have been reported with Rosuvastatin, Patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels. Rosuvastatin may cause fetal harm when administered to pregnant women, nursing mothers, because another drug in this class passes into breast milk, and because HMG-Co reductase inhibitors
have the potential to cause serious adverse reactions in nursing infants, women who require Rosuvastatin treatment should be advised not to nurse their infants. WARNINGS & PRECAUTIONS: Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including Rosuvastatin, caution should be exercised when anticoagulants
are given in conjunction with rosuvastatin because of its potentiation of the effect of coumarin-type anticoagulants in prolonging the prothrombin time/INR, In the Rosuvastatin clinical trial program, dipstick-positive proteinuria and microscopic hematuria were observed among Rosuvastatin treated patients. Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors,
including Rosuvastatin. DRUG INTERACTION: Cyclosporine, Gemfibrozil, Protease Inhibitors, Coumarin Anticoagulants, Niacin, Fenofibrate and Colchicine.
ADVERSE REACTIONS: Rhabdomyolysis with myoglobinuria and acute renal failure, myopathy (including myositis), liver enzyme abnormalities, headache, myalgia, abdominal pain, asthenia and nausea.

UNISTAR GOLD / ROZUCOR GOLD

For the use of a Registered Medical Practitioner or Hospital or a Laboratory only. Abbreviated Prescribing information for UNISTAR GOLD / ROZUCOR GOLD (Rosuvastatin, Aspirin and Clopidogrel Capsules) [Please refer the complete prescribing information available at www.torrentpharma.com] PHARMACOLOGICAL PROPERTIES: Mechanism of action: Rosuvastatin: Rosuvastatin is a selective and
competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor for cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for cholesterol lowering. Rosuvastatin increases the number of hepatic LDL receptors on the cell-surface, enhancing uptake and catabolism of LDL and it inhibits the hepatic synthesis
of VLDL, thereby reducing the total number of VLDL and LDL particles. Acetylsalicylic acid: Acetylsalicylic acid inhibits the platelet activation: blocking the platelet cyclooxygenase by acetylation, it inhibits thromboxane A2 synthesis, a physiological activating substance released by the platelets and which would play a role in the complications of the atheromatosic lesions. Clopidogrel is a prodrug, one of whose
metabolites is an inhibitor of platelet aggregation. Clopidogrel must be metabolised by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet
aggregation. Due to the irreversible binding, platelets exposed are affected for the remainder of their lifespan (approximately 7-10 days) and recovery of normal platelet function occurs at a rate consistent with platelet turnover. Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP. Because the active metabolite is formed by CYP450
enzymes, some of which are polymorphic or subject to inhibition by other medicinal products, not all patients will have adequate platelet inhibition. DOSAGE AND ADMINISTRATION: As directed physician. CONTRAINDICATION: In patients with hypersensitivity to Rosuvastatin, Clopidogrel and salicylic acid or to any of the excipients, in patients with active liver disease, severe renal and hepatic impairment, myopathy,
concomitant combination of sofosbuvir/velpatasvir/voxilaprevir, suffering from gout, Hypothyroidism. [Refer Prescribing information for more details] WARNINGS & PRECAUTIONS: Rosuvastatin: Renal Effects: Proteinuria, detected by dipstick testing, Skeletal Muscle Effects: myalgia, myopathy and, rarely, rhabdomyolysis, Liver Effects: In patients with secondary hypercholesterolaemia caused by hypothyroidism
or nephrotic syndrome, the underlying disease should be treated prior to initiating therapy with Rosuvastatin, Lactose Intolerance, Interstitial Lung Disease, Diabetes Mellitus. Aspirin may also precipitate bronchospasm or induce attacks of asthma in susceptible subjects or promote other hypersensitivity reactions. Steven-Johnsons syndrome. Clopidogrel: Bleeding and haematological disorders, Thrombotic
Thrombocytopenic Purpura (TTP), Acquired haemophilia, Recent ischaemic stroke, Cytochrome P450 2C19 (CYP2C19), CYP2C8 substrates, Renal and hepatic impairment. [Refer Prescribing information for more details] DRUG INTERACTION: Effect of co-administered medicinal products on rosuvastatin: it is a substrate for certain transporter proteins including the hepatic uptake transporter OATP1B1 and efflux
transporter BCRP, Ciclosporin: During concomitant treatment with Rosuvastatin and ciclosporin, rosuvastatin: During concomitant treatment with Rosuvastatin and ciclosporin, rosuvastatin AUC values were on average 7 times higher than also have interaction with Protease inhibitors, Gemfibrozil and other lipid-lowering products, Cytochrome P450 enzymes, Methotrexate, impairs the renal excretion of digoxin and
lithium, should be used with caution in patients who receive concomitant glycoprotein IIb/IIIa inhibitors. Aspirin: Methotrexate, Uricosuric agents, Anticoagulants, Anti-platelet, Antidiabetics, Diuretics and antihypertensive, Digoxin and lithium, NSAIDs, Carbonic anhydrase inhibitors, Antacids and adsorbents, Antiemetics, Leukotriene antagonists. Clopidogrel: Oral anticoagulants, Thrombolytics, SSRIs, PPI. [Refer
Prescribing information for more details] ADVERSE REACTIONS: Thrombocytopenia, Hypersensitivity reactions including Angioedema, Pancreatitis, Myopathy (including myositis). Rhabdomyolysis, Lupus-like syndrome, Muscle rupture, Increased bleeding tendencies, Hyperuricemia. Intracranial haemorrhage. Reduced hearing ability. Rhinitis, dyspnoea, Bronchospasm, asthma attacks. Gastric or duodenal ulcers
and perforation, diarrhoea, Steven-Johnsons syndrome, Eye bleeding (conjunctival, ocular, retinal). [Refer Prescribing information for more details]

ROZUPLATT
For the use of a Registered Medical Practitioner or Hospital or a Laboratory only. Abbreviated Prescribing information for ROZUPLATT (Rosuvastatin Calcium I.P. and Clopidogrel hard gelatin capsules) [Please refer the complete prescribing information available at www.torrentpharma.com] PHARMACOLOGICAL PROPERTIES: Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the
rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor for cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for cholesterol lowering. Rosuvastatin increases the number of hepatic LDL receptors on the cell-surface, enhancing uptake and catabolism of LDL and it inhibits the hepatic synthesis of VLDL, thereby reducing the total number of
VLDL and LDL particles. Clopidogrel is a prodrug, one of whose metabolites is an inhibitor of platelet aggregation. Clopidogrel must be metabolised by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the
glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Due to the irreversible binding, platelets exposed are affected for the remainder of their lifespan (approximately 7-10 days) and recovery of normal platelet function occurs at a rate consistent with platelet turnover. Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released
ADP. DOSAGE AND ADMINISTRATION: Dosage should be taken as directed by your Physician. CONTRAINDICATION: 1. Known hypersensitivity to Rosuvastatin or Clopidogrel or to any of the excipients. 2. In patients with pre-disposing factors for myopathy/rhabdomyolysis such as alcohol abuse, Hypothyroidism, moderate renal impairment, pathological bledding etc. 3. In patients with active liver disease, severe
renal impairment, myopathy, receiving concomitant ciclosporin and during pregnancy and lactation. WARNINGS & PRECAUTIONS: ROZUPLATT has effects on skeletal muscle and can cause myalgia, myopathy and, rarely, rhabdomyolysis and bleeding related issues, immediately stop taking medicine and seek doctor advise. DRUG INTERACTION: It can interact with Ciclosporin, Protease inhibitors, Gemfibrozil
and other lipid-lowering products, Ezetimibe, Antacid, Erythromycin, Cytochrome P450 enzymes, Vitamin K antagonists, Oral contraceptive/hormone replacement therapy (HRT), Digoxin, Fusidic Acid, Oral anticoagulants, Glycoprotein IIb/IIIa inhibitors, Acetylsalicylic acid, Heparin, Thrombolytics, NSAIDs, SSRIs Proton Pump Inhibitors (PPI) etc. ADVERSE REACTIONS: Rash, itching or other skin reactions,
vomiting, nausea, constipation, excessive gas in stomach or intestines, extreme tiredness/ feeling weak, headache, stomach pain, constipation, feeling sick, muscle pain, dizziness, increase in the amount of protein in the urine, diabetes and bleeding.

APIXATOR
For the use only of a Registered Medical Practitioner or a Hospital or a Laboratory abbreviated prescribing information for APIXATOR (Apixaban 2.5 mg and 5 mg film coated tablet) [Please refer the complete prescribing information available at www.torrentpharma.com ] PHARMACOLOGICAL PROPERTIES: Apixaban is a potent, oral, reversible, direct and highly selective active site inhibitor of factor Xa. It does
not require antithrombin III for antithrombotic activity. Apixaban inhibits free and clot-bound factor Xa, and prothrombinase activity. Apixaban has no direct effects on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting factor Xa, apixaban prevents thrombin generation and thrombus development. Preclinical studies of apixaban in animal models have demonstrated
antithrombotic efficacy in the prevention of arterial and venous thrombosis at doses that preserved haemostasis. INDICATION: Apixator used for Prevention of stroke and systemic embolism in adult patients with non-valvular artrial fibrillation (NVAF), including those with one or more risk factors, such as prior stroke or transient ischemic attack. Treatment of deep vein thrombosis (DVT) and pulmonary Embolism (PE),
and prevention of Recurrent DVT and PE in adult patients. DOSAGE AND ADMINISTRATION: Dosage: Apixator 2.5 mg and 5 mg film coated tablet. Administration: As directed by the Physician. Tablets should be taken orally. CONTRAINDICATION: Hypersensitivity to the active substance or to any of the excipients. Active clinically significant bleeding. Hepatic disease associated with coagulopathy and clinically
relevant bleeding risk. Lesion or condition if considered a significant risk factor for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or
major intraspinal or intracerebral vascular abnormalities. Concomitant treatment with any other anticoagulant agent e.g., unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, rivaroxaban, dabigatran, etc.) except under specific circumstances of switching anticoagulant therapy, when UFH is given at doses
necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation. WARNINGS & PRECAUTIONS: Haemorrhage risk: As with other anticoagulants, patients taking apixaban are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. Interaction with other medicinal
products affecting haemostasis: Care is to be taken if patients are treated concomitantly with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs), or non-steroidal anti-inflammatory medicinal products (NSAIDs), including acetylsalicylic acid. Use of thrombolytic agents for the treatment of acute ischemic stroke, prosthetic heart valves: the use of apixaban is not
recommended in this setting. Antiphospholipid syndrome: Direct acting Oral Anticoagulants (DOACs) including apixaban are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome. Surgery and invasive procedures: Apixaban should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of bleeding.
Temporary discontinuation: Discontinuing anticoagulants, including apixaban, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of thrombosis. Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy: Apixaban is not recommended as an alternative to unfractionated heparin in patients with pulmonary embolism who are
haemodynamically unstable. Patients with active cancer: can be at high risk of both venous thromboembolism and bleeding events. Renal impairment: In patients with creatinine clearance < 15 mL/min, or in patients undergoing dialysis, there is no clinical experience therefore apixaban is not recommended. Elderly patients, Body weight may increase haemorrhagic risk. Hepatic impairment: Apixaban is contraindicated
in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Interaction with inhibitors of both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp): The use of apixaban is not recommended in patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp, such as azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole and
posaconazole) and HIV protease inhibitors (e.g., ritonavir). DRUG INTERACTIONS: Inhibitors of CYP3A4 and P-gp: Coadministration of apixaban with ketoconazole (400 mg once a day), a strong inhibitor of both CYP3A4 and P-gp, led to a 2-fold increase in mean apixaban AUC and a 1.6-fold increase in mean apixaban Cmax. The use of apixaban is not recommended in patients receiving concomitant systemic
treatment with strong inhibitors of both CYP3A4 and P-gp, such as azole-antimycotics and HIV protease inhibitors. Inducers of CYP3A4 and P-gp: Coadministration of apixaban with rifampicin, a strong inducer of both CYP3A4 and P-gp, led to an approximate 54% and 42% decrease in mean apixaban AUC and Cmax, respectively. Apixaban is not recommended for the treatment of DVT and PE in patients receiving
concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp since efficacy may be compromised. Anticoagulants, platelet aggregation inhibitors, SSRIs/SNRIs and NSAIDs: Due to an increased bleeding risk co-administration of these medicinal products with apixaban is not recommended. apixaban on other medicinal products: apixaban did not meaningfully alter the pharmacokinetics of digoxin,
naproxen, or atenolol. ADVERSE REACTIONS: Blood and lymphatic system disorders: Common: Anaemia, uncommon: Thrombocytopenia. Immune system disorders: Uncommon: Hypersensitivity, allergic oedema and Anaphylaxis, Pruritus, Not known: Angioedema. Nervous system disorders: Uncommon: Brain haemorrhage. Eye disorders: Eye haemorrhage (including conjunctival haemorrhage). Vascular
disorders: Common: Haemorrhage, haematoma, Hypotension (including procedural hypotension), Intra-abdominal haemorrhage. Respiratory, thoracic and mediastinal disorders: Common: Epistaxis, Uncommon: Haemoptysis, Rare: Respiratory tract haemorrhage. Gastrointestinal disorders: Common: Nausea, Gastrointestinal haemorrhage. Uncommon: Haemorrhoidal haemorrhage, Mouth haemorrhage,
Haematochezia. Rare: Retroperitoneal haemorrhage. Hepatobiliary disorders: Common: Gamma-glutamyltransferase increased. Uncommon: Liver function test abnormal, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood bilirubin increased,Alanine aminotransferase increased. Skin and subcutaneous tissue disorders: Uncommon: Skin rash. Alopecia. Very rare: Erythema
multiforme. Not known: Cutaneous vasculitis. Musculoskeletal and connective tissue disorders: Rare: Muscle haemorrhage. Renal and urinary disorders: Common: Haematuria. Reproductive system and breast disorders: Abnormal vaginal haemorrhage, urogenital haemorrhage. General disorders and administration site conditions: Uncommon: Application site bleeding Investigations: Uncommon: Occult blood
positive. Injury, poisoning and procedural complications: Common: Contusion. Uncommon: Post procedural haemorrhage (including post procedural haematoma, wound haemorrhage, vessel puncture site haematoma and catheter site haemorrhage), wound secretion, incision site haemorrhage (including incision site haematoma), operative haemorrhage. Uncommon: Traumatic haemorrhage.