Read all of this leaflet carefully before you start taking this

medicine because it contains important information for you.

* Keep this leaflet. You may need to read it again.

* If you have any further questions, ask your doctor or

pharmacist.

* This medicine has been prescribed for you only.

Do not pass it on to others. It may harm them, even if their

signs of illness are the same as yours.

* If you get any side effects talk to your doctor or pharmacist.

This includes any possible side effects not listed in this leaflet.

See section 4.

Effect of food CLOPISTOP® can be administered with or without

food. In a study in healthy male subjects when CLOPISTOP® 75 mg

per day was given with a standard breakfast, mean inhibition of

ADP-induced platelet aggregation was reduced by less than 9%.

The active metabolite AUC 0–24 was unchanged in the presence

of food, while there was a 57% decrease in active metabolite

Cmax. Similar results were observed when a CLOPISTOP® 300 mg

loading dose was administered with a high-fat breakfast.

Metabolism

Clopidogrel is extensively metabolized by two main metabolic

pathways: one mediated by esterases and leading to hydrolysis

into an inactive carboxylic acid derivative (85% of circulating

metabolites) and one mediated by multiple cytochrome P450

enzymes. Cytochromes first oxidize clopidogrel to a 2-oxo-clopi-

dogrel intermediate metabolite. Subsequent metabolism of the

2-oxo-clopidogrel intermediate metabolite results in formation of

the active metabolite, a thiol derivative of clopidogrel. The active

metabolite is formed mostly by CYP2C19 with contributions from

several other CYP enzymes, including CYP1A2, CYP2B6 and CYP3A.

The active thiol metabolite binds rapidly and irreversibly to platelet

receptors, thus inhibiting platelet aggregation for the lifespan of

the platelet.

The Cmax of the active metabolite is twice as high following a

single 300 mg clopidogrel loading dose as it is after four days of 75

mg maintenance dose. Cmax occurs approximately 30 to 60

minutes after dosing. In the 75 to 300 mg dose range, the

pharmacokinetics of the active metabolite deviates from dose

proportionality: 4-fold the dose results in 2.0-fold and 2.7-fold the

Cmax and AUC, respectively.

Excretion

Following an oral dose of 14C-labeled clopidogrel in humans,

approximately 50% of total radioactivity was excreted in urine and

approximately 46% in feces over the 5 days post dosing. After a

single, oral dose of 75 mg, clopidogrel has a half-life of

approximately 6 hours. The half-life of the active metabolite is

about 30 minutes.

6-CONTRAINDICATIONS

• Active Bleeding: CLOPISTOP® is contraindicated in patients with

active pathological bleeding such as peptic ulcer or intracranial

hemorrhage.

• Hypersensitivity: CLOPISTOP® is contraindicated in patients with

hypersensitivity (e.g., anaphylaxis) to clopidogrel or any

component of the product.

• Patients with significant liver impairment or cholestatic jaundice.

7-POSOLOGY

Recommended Dose and Dosage Adjustment

MI, Stroke or Established Peripheral Arterial Disease The

recommended dose of CLOPISTOP® is 75 mg once daily long term

with or without food.

Acute Coronary Syndrome For patients with non-ST-segment

elevation acute coronary syndrome (unstable

angina/non-Qwave MI), CLOPISTOP® should be initiated with a 300

mg loading dose and continued long term at 75 mg once a day

with ASA (80 mg to 325 mg daily) . For patients with ST-segment

elevation acute myocardial infarction, the recommended dose of

CLOPISTOP® is 75 mg once daily, administered in combination with

ASA, with or without thrombolytics. CLOPISTOP ® may be initiated

with or without a loading dose (300 mg was used in CLARITY

study). No dosage adjustment is necessary for elderly patients or

patients with renal impairment.

Atrial Fibrillation

For patients with atrial fibrillation who have at least one risk factor

for vascular events, who have a low risk of bleeding, and who are

unsuitable for anticoagulation therapy, the recommended dose of

is CLOPISTOP ® 75 mg once daily, administered in combination

with ASA (75 to 100 mg daily).

Pharmacogenetics CYP2C19 poor metabolizer status is

associated with diminished antiplatelet response to clopidogrel.

Although a higher dose regimen in poor metabolizer healthy

subjects increases antiplatelet response, an appropriate dose

regimen for this patient population has not been established in

clinical outcome trials.

Missed Dose If a dose of CLOPISTOP ® is missed, it should be

taken as soon as possible. However, if it is close to the time of the

next dose, disregard the missed dose and return to the regular

dosing schedule. Do not double doses.

8-WARNINGS AND PRECAUTIONS

1-Diminished Antiplatelet Activity in Patients with Impaired

CYP2C19 Function Clopidogrel is a -prodrug. Inhibition of platelet

aggregation by clopidogrel is achieved through an active

metabolite. The metabolism of clopidogrel to its active

metabolite can be impaired by genetic variations in CYP2C19

[see Boxed Warning].

The metabolism of clopidogrel can also be impaired by drugs

that inhibit CYP2C19, such as omeprazole or esomeprazole. Avoid

concomitant use of CLOPISTOP ® with omeprazole or esomepra-

zole because both significantly reduce the antiplatelet activity of

CLOPISTOP ®.

2-General Risk of Bleeding

P2Y12 inhibitors (thienopyridines), including CLOPISTOP®,

increase the risk of bleeding. P2Y12 inhibitors (thienopyridines),

inhibit platelet aggregation for the lifetime of the platelet (7–10

days). Because the half-life of clopidogrel’s active metabolite is

short, it may be possible to restore hemostasis by administering

exogenous platelets; however, platelet transfusions within 4

hours of the loading dose or 2 hours of the maintenance dose

may be less effective.

Use of drugs that induce the activity of CYP2C19 would be

expected to result in increased drug levels of the active

metabolite of clopidogrel and might potentiate the bleeding risk.

As a precaution, avoid concomitant use of strong CYP2C19

inducers. Risk factors for bleeding include concomitant use of

other drugs that increase the risk of bleeding (e.g., anticoagu-

lants, antiplatelet agents, and chronic use of NSAIDs).

3-Discontinuation of CLOPISTOP®

Discontinuation of CLOPISTOP® increases the risk of cardiovas-

cular events. If CLOPISTOP® must be temporarily discontinued

(e.g., to treat bleeding or for surgery with a major risk of

bleeding), restart it as soon as possible. When possible, interrupt

therapy with CLOPISTOP® for five days prior to such surgery.

Resume CLOPISTOP® as soon as hemostasis is achieved.

4-Thrombotic Thrombocytopenic Purpura (TTP)

TTP, sometimes fatal, has been reported following use of

CLOPISTOP®, sometimes after a short exposure (<2weeks). TTP is

a serious condition that requires urgent treatment including

plasmapheresis (plasma exchange). It is characterized by

thrombocytopenia, microangiopathic hemolytic anemia

(schistocytes [fragmented RBCs] seen on

peripheral smear), neurological findings,

renal dysfunction, and fever.

5- Cross-Reactivity among Thienopyri-

dines

Hypersensitivity including rash, angioede-

ma or hematologic reaction has been

reported in patients receiving

CLOPISTOP®, including patients with a

history of hypersensitivity or hematologic

reaction to other thienopyridines.

9-SPECIFIC PATIENT POPULATIONS

Pregnancy

Risk Summary

Available data from cases reported in

published literature and post marketing

surveillance with clopidogrel use in

pregnant women have not identified any

drug-associated risks for major birth

defects or miscarriage. There are risks to

the pregnant woman and fetus

associated with myocardial infarction

and stroke. No evidence of fetotoxicity

was observed when clopidogrel was

administered to pregnant rats and

rabbits during organogenesis at doses

corresponding to 65 and 78 times the

recommended daily human dose.

The estimated background risk of major

birth defects and miscarriage for the

indicated populations is unknown. All

pregnancies have a background risk of

birth defects, loss, or other adverse

outcomes. In the U.S. general population,

the estimated background risk of major

birth defects and miscarriage in clinically

recognized pregnancies is 2% to 4% and

15% to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or

embryo/fetal risk

Myocardial infarction and stroke are

medical emergencies. Therapy for the

pregnant woman should not be withheld

because of potential concerns regarding

the effects of clopidogrel on the fetus.

Labor or delivery Clopidogrel use during

labor or delivery will increase the risk of

maternal bleeding and hemorrhage.

Avoid neuraxial blockade during

clopidogrel use because of the risk of

spinal hematoma. When possible,

discontinue clopidogrel 5 to 7 days prior

to labor, delivery, or neuraxial blockade.

Lactation

There are no data on the presence of

clopidogrel in human milk or the effects

on milk production. No adverse effects on

breastfed infants have been observed

with maternal clopidogrel use during

lactation in a small number of

postmarketing cases. Studies in rats have

shown that clopidogrel and/or its

metabolites are present in the milk. When a drug is present in

animal milk, it is likely that the drug will be present in human milk.

The developmental and health benefits of breastfeeding should

be considered along with mother’s clinical need for CLOPISTOP®

and any potential adverse effects on the breastfed infant from

CLOPISTOP® or from underlying maternal condition.

Pediatric Use

Safety and effectiveness in pediatric populations have not been

established. A randomized, placebo-controlled trial (CLARINET) did

not demonstrate a clinical benefit of clopidogrel in neonates and

infants with cyanotic congenital heart disease palliated with a

systemic-to-pulmonary arterial shunt. Possible factors contribut-

ing to this outcome were the dose of clopidogrel, the concomitant

administration of aspirin, and the late initiation of therapy

following shunt palliation. It cannot be ruled out that a trial with a

different design would demonstrate a clinical benefit in this

patient population.

Geriatric Use

The total number of subjects in the CAPRIE and CURE controlled

clinical studies, approximately 50% of patients treated with

CLOPISTOP® were 65 years of age and older, and 15% were 75

years and older. In COMMIT, approximately 58% of the patients

treated with CLOPISTOP® were 60 years and older, 26% of whom

were 70 years and older. The observed risk of bleeding events with

CLOPISTOP® plus aspirin versus placebo plus aspirin by age

category is provided in Table 1 and Table 2 for the CURE and

COMMIT trials, respectively. No dosage adjustment is necessary in

elderly patients.

Renal Impairment Experience is limited in patients with severe

and moderate renal impairment.

Hepatic Impairment No dosage adjustment is necessary in

patients with hepatic impairment .

10-DRUG INTERACTIONS

CYP2C19 Inducers

Since clopidogrel is metabolized to its active metabolite partly by

CYP2C19, use of drugs that induce the activity of this enzyme

would be expected to result in increased drug levels of the active

metabolite of clopidogrel. Rifampin strongly induces CYP2C19

resulting to both an increase level of clopidogrel active metabolite

and platelet inhibition, which in particular might potentiate the risk

of bleeding. As a precaution, avoid concomitant use of strong

CYP2C19 inducers.

CYP2C19 Inhibitors

Clopidogrel is metabolized to its active metabolite in part by

CYP2C19. Concomitant use of drugs that inhibit the activity of this

enzyme results in reduced plasma concentrations of the active

metabolite of clopidogrel and a reduction in platelet inhibition.

Omeprazole or Esomeprazole Avoid concomitant use of

CLOPISTOP® with omeprazole or esomeprazole. In clinical studies,

omeprazole was shown to reduce significantly the antiplatelet

activity of CLOPISTOP® when given concomitantly or 12 hours

apart. A similar reduction in antiplatelet activity was observed with

esomeprazole when given concomitantly with CLOPISTOP®.

Dexlansoprazole, lansoprazole, and pantoprazole had less effect

on the antiplatelet activity of CLOPISTOP® than did omeprazole or

esomeprazole.

Opioids

As with other oral P2Y12 inhibitors, coadministration of opioid

agonists delay and reduce the absorption of clopidogrel,

presumably because of slowed gastric emptying, resulting in

reduced exposure to its metabolites. Consider the use of a

parenteral antiplatelet agent in acute coronary syndrome

patients requiring coadministration of morphine or other opioid

agonists.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Coadministra-

tion of CLOPISTOP® and NSAIDs increases the risk of gastrointesti-

nal bleeding.

Warfarin (CYP2C9 Substrates) Although the administration of

clopidogrel 75 mg per day did not modify the pharmacokinetics

of S-warfarin (a CYP2C9 substrate) or INR in patients receiving

long-term warfarin therapy, coadministration of CLOPISTOP® with

warfarin increases the risk of bleeding because of independent

effects on hemostasis. However, at high concentrations in vitro,

clopidogrel inhibits CYP2C9.

SSRIs and SNRIs Since selective serotonin reuptake inhibitors

(SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs)

affect platelet activation, the concomitant administration of SSRIs

and SNRIs with clopidogrel may increase the risk of bleeding.

Other Antiplatelet Agents Coadministration of antiplatelet

agents increase the risk of bleeding due to an additive effect.

Promptly evaluate any signs or symptoms of blood loss if patients

are treated concomitantly with other antiplatelet agents.

Repaglinide (CYP2C8 Substrates) The acyl-β-glucuronide

metabolite of clopidogrel is a strong inhibitor of CYP2C8.

CLOPISTOP® can increase the systemic exposure to drugs that are

primarily cleared by CYP2C8, thereby needing dose adjustment

and appropriate monitoring. CLOPISTOP® increased repaglinide

exposures by 3.9-fold to 5.1-fold. Avoid concomitant use of

repaglinide with CLOPISTOP®. If concomitant use cannot be

avoided, initiate repaglinide at 0.5 mg before each meal and do

not exceed a total daily dose of 4 mg. Increased frequency of

glucose monitoring may be required during concomitant use.

11-ADVERSE REACTIONS

The following serious adverse reactions are discussed below and

elsewhere in the labeling:

• Bleeding

• Thrombotic thrombocytopenic purpura

• Hemorrhages, including those with fatal outcome, have been

reported in patients treated with CLOPISTOP®.

• Blood and lymphatic system disorders: Agranulocytosis, aplastic

anemia/pancytopenia, thrombotic thrombocytopenic purpura

(TTP), acquired hemophilia A.

• Gastrointestinal disorders: Colitis (including ulcerative or

lymphocytic colitis), pancreatitis, stomatitis, gastric/duodenal

ulcer, diarrhea.

• General disorders and administration site condition: Fever.

• Hepatobiliary disorders: Acute liver failure, hepatitis (noninfec-

tious), abnormal liver function test.

• Immune system disorders: Hypersensitivity reactions,

anaphylactoid reactions, serum sickness, insulin autoimmune

syndrome, which can lead to severe hypoglycemia.

• Musculoskeletal, connective tissue and bone disorders: Myalgia,

arthralgia, arthritis.

• Nervous system disorders: Taste disorders, headache, ageusia.

• Psychiatric disorders: Confusion, hallucinations.

• Respiratory, thoracic and mediastinal disorders: Bronchospasm,

interstitial pneumonitis, eosinophilic pneumonia.

• Renal and urinary disorders: Increased creatinine levels.

• Skin and subcutaneous tissue disorders: Maculopapular,

erythematous or exfoliative rash, urticaria, bullous dermatitis,

eczema, toxic epidermal necrolysis, Stevens-Johnson syndrome,

acute generalized exanthematous pustulosis (AGEP), angioede-

ma, drug-induced hypersensitivity syndrome, drug rash with

eosinophilia and systemic symptoms (DRESS), erythema

multiforme, lichen planus, generalized pruritus.

• Vascular disorders: Vasculitis, hypotension.

12-STORAGE CONDITIONS

Keep this medicine out of the sight and reach of children.

Store in a dry place below 30°C

Keep your medicine in a cool dry place and away from light in the

original package to protect it from moisture.

Don’t use this medicine after the expiry date which is stated on the

outer packaging. The expiry date refers to the last day of that

month.

Don’t use this medicine if you notice any visible signs of deteriora-

tion.

Don’t throw away any medicines via wastewater. Ask your

pharmacist how to throw away medicines you no longer use.

These measures will help protect the environment.

Manufacturer:

UNIZA LIFECARE PRIVATE LIMITED

kadi-Detroj road, Balasar, Tal.-Kadi,

Dist.-Mehsana, Gujarat-382 715, India.

Marketing Authorization Holder:



Clopidogrel bisulfate 75 mg Film-coated tablet

1-DESCRIPTION

CLOPISTOP® 75mg is a peach colored, round shaped biconvex,

film coated tablets and plain on both sides.

2-COMPOSITION

Each film coated tablet of CLOPISTOP® contains 75mg of

Clopidogrel bisulfate.

Excipients: Microcrystalline cellulose, lactose monohydrate,

HPCLH-21, crospovidone XL-10, colloidal silicone dioxide, PEG4000,

Hydrogenated castor oil, sodium stearyl fumarate.

Colour SC U 3104 Light. Pink

3-THERAPEUTIC INDICATIONS

• Acute coronary syndrome

CLOPISTOP® is indicated to reduce the rate of myocardial

infarction (MI) and stroke in patients with non–ST-segment

elevation ACS (unstable angina [UA]/non–ST-elevation

myocardial infarction [NSTEMI]), including patients who are to be

managed medically and those who are to be managed with

coronary revascularization. CLOPISTOP® should be administered

in conjunction with aspirin.

CLOPISTOP® is indicated to reduce the rate of myocardial

infarction and stroke in patients with acute ST-elevation

myocardial infarction (STEMI) who are to be managed medically.

CLOPISTOP® should be administered in conjunction with aspirin.

• Recent MI, recent stroke, or established peripheral arterial

disease In patients with established peripheral arterial disease or

with a history of recent myocardial infarction (MI) or recent stroke

CLOPISTOP® is indicated to reduce the rate of MI and stroke.

4-PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: P2Y12 platelet inhibitor

ATC code: B01AC04

Mechanism of action

Clopidogrel is an inhibitor of platelet activation and aggregation

through the irreversible binding of its active metabolite to the

P2Y12 class of ADP receptors on platelets.

5-PHARMACOKINETICS

Clopidogrel is a prodrug and is metabolized to a pharmacologi-

cally active metabolite and inactive metabolites.

Absorption

After single and repeated oral doses of 75 mg per day,

clopidogrel is rapidly absorbed. Absorption is at least 50%, based

on urinary excretion of clopidogrel metabolites.

This is a medicament:

- A medicament is a product which

affects your health and its consumption

contrary to instructions is dangerous for

you.

- Follow strictly the doctor's prescription,

the method of use and the instructions of

the pharmacist who sold the

medicament.

- The doctor and the pharmacist are the

experts in medicine, their benefits and

risks.

- Do not by yourself interrupt the period

of treatment prescribed.

- Do not repeat the same prescription

without consulting your doctor.

- Keep all medicaments out of reach of

children.

Council of Arab Health Ministers

Union of Arab pharmacists