Film-coated tablet

Each film-caoted tablet contains:

Clopidogrel bisulfate

equivalent to clopidogrel 75 mg

Clopidogrel is an inhibitor of platelet aggregation. A variety of drugs that inhibit platelet function have been shown to decrease morbid events in people with established atherosclerotic cardiovascular disease as evidenced by stroke or transient ischemic attacks, myocardial infarction, or need for bypass or angioplasty. This indicates that platelets participate in the initiation and/or evolution of these events and that inhibiting them can reduce the event rate.

Clopidogrel is a prodrug. The active metabolite, a thiol derivative, is formed by oxidation of clopidogrel to 2-oxo-clopidogrel and subsequent hydrolysis.

Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Biotransformation of clopidogrel is necessary to produce inhibition of platelet aggregation, but an active metabolite responsible for the activity of the drug has not been isolated. Clopidogrel also inhibits platelet aggregation induced by agonists other than ADP by blocking the amplification of platelet activation by released ADP. Clopidogrel does not inhibit phosphodiesterase activity.

Clopidogrel acts by irreversibly modifying the platelet ADP receptor. Consequently, platelets exposed to clopidogrel are affected for the remainder of their lifespan.

Dose dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of Clopidogrel. Repeated doses of 75 mg Clopidogrel per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg Clopidogrel per day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days.

Effect of food

Administration of clopidogrel with meals did not significantly modify the bioavailability of clopidogrel as assessed by the pharmacokinetics of the main circulating metabolite.

Absorption and distribution

Clopidogrel is rapidly absorbed after oral administration of repeated doses 75 mg clopidogrel (base), with peak plasma levels (@3 mg/L) of the main circulating metabolite occurring approximately 1 hour after dosing. The pharmacokinetics of the main circulating metabolite are linear (plasma concentration increased in proportion to dose) in the dose range of 50 to 150 mg of clopidogrel. Absorption is at least 50% based on urinary excretion of clopidogrel-related metabolites.

Clopidogrel and the main circulating metabolite bind reversibly in vitro to human plasma protein (98% and 94%, respectively). The binding is nonsaturable in vitro up to a concentration of 100 µg/mL.

Metabolism dan eliminasi

In vitro and in vivo, clopidogrel undergoes rapid hydrolysis into its carboxylic acid derivative. In plasma and urine, the glucuronide of the carboxylic acid derivative is also observed.

The use of Clopidogrel is contraindicated in the following conditions:

• Hypersensitivity to the drug substance or any component of the product
• Active pathological bleeding such as peptic ulcer or intracranial hemorrhage

• Autonomic nervous system disorders: Syncope, palpitation. Body as a whole-general disorders: Arthenia, hernia. Rarely reported (<1%): Allergic reaction, necrosis ischemic.
• Cardiovascular disorders: Cardiac failure, edema generalized rarely reported (<1%).
• Central and pheripheral nervous system disorders: Cramps legs, hypoaesthesia, neuralgia, paraesthesia, vertigo.
• Gastrointestinal system disorders: Constipation, vomiting. Rarely reported (<1%): gastric ulcer perforated, gastritis hemorrhagic, upper GI ulcer hemorrhagic.
• Heart rate and rhythm disorders: Fibrillation atrial.
• Liver and biliary system disorders: Hepatic enzymes increased. Rarely reported (<1%): Billirubinemia, hepatitis infectious, liver fatty.
• Metabolic and nutritional disorders: Gout, hyperuricemia, non-protein nitrogen (NPN) increased.
• Musculo-skeletal system disorders: Arthritis, arthrosis.
• Platelet, bleeding and clotting disorders: GI hemorrhage, hematoma, platelets decrease. Rarely reported (<1%): Hemarthrosis, hematuria, hemoptysis, hemorrhage of operative wound, ocular hemorrhage, pulmonary hemorrhage, purpura allergic, thrombocytopenia.
• Psychiatric disorders: Anxiety, insomnia.
• Red blood cell disorders: anemia. Rarely reported (<1%): Anemia aplastic, anemia hypochromic.
• Respiratory system disorders: Pneumonia, sinusitis. Rarely reported (<1%): Hemothorax.
• Skin and appendage disorders: eczema, skin ulceration. Rarely reported (<1%): Bullous eruption, rash erythematous, rash maculopapular, urticaria.
• Urinary system disorders: cystitis.
• Vision disorders: Cataract, conjunctivitis.

Other potentially serious adverse events which may be of clinical interest but were rarely reported (<1%):

• Reproductive disorders, female: Menorrhagia
• White cell and reticuloendothelial system disorders: Agranulocytosis, granulocytopenia, leukemia, leukopenia, neutrophils decreased.

• In patients with acute myocardial infarction, clopidogrel therapy should not be initiated within the first few days following myocardial infarction.
• As with other anti-platelet agents, clopidogrel should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions and in patients receiving treatment with ASA, NSAID, heparin, glycoprotein Iib/IIIa inhibitors or thrombolytics. Patients should be followed carefully for any signs of bleeding including occult bleeding, especially during the first weeks of treatment and/or after invasive cardiac procedures of surgery. If a patient is to undergo elective surgery and an antiplatelet effect is not desired, clopidogrel should be discontinued 7 days prior to surgery.
• Clopidogrel prolongs bleeding time and should be used with caution in patients who have lesions with a propensity to bleed (particulary gastrointestinal and intraocular). Patients should be told that it may take longer than usual to stop bleeding when they take clopidogrel (alone or in combination with ASA), and that they should report any unusual bleeding (site or duration) to their physician. Patients should inform physicians and dentists that they are taking clopidogrel before any surgery is scheduled and before any new drug is taken.
• Therapeutic experience with clopidogrel is limited in patients with renal impairment. Therefore clopidogrel should be used with caution in these patients.
• Experience is limited in patients with moderate hepatic disease who may have bleeding diatheses. Clopidogrel should therefore be used with caution in this population.
• Due to the risk of bleeding and haematological undesirable effects, blood cell count determination and/or other appropriate testing should be promptly considered whenever clinical symptoms suggestive of bleeding arise during the course of treatment.

Pregnancy: Reproduction studies performed in rats and in rabbits revealed no evidence of impaired fertility or harm to the foetus due to clopidogrel. There are, however, no adequate and well-controlled studies in pregnant women. In view of the lack of date, clopidogrel is not recommended during pregnancy.

Lactation: Studies in rats shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether this medical product is excreted in human milk.

• The concomitant administration of clopidogrel with warfarin is not recommended since it may increase the intensity of bleedings.
• Drugs that might induce gastrointestinal lesions (such as Non-Steroidal Anti-Inflammatory Drugs) should be used with caution in patients taking clopidogrel.
• In a clinical study conducted in healthy subjects, clopidogrel did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Co-administration of heparin had no effect on the inhibition of platelet aggregation induced by clopidogrel. However, the safety pf this combination has not been established and concomitant use should be undertaken with caution.
• The safety of concomitant administration of clopidogrel, rt-PA and heparin was assessed in patients with recent myocardial infarction. The incidence of clinically significant bleeding was similar to that observed when rt-PA and heparin was assessed in patients with recent myocarial infarction. The incidence of administration of clopidogrel with other thrombolytic agents has not been establised and should be undertaken with caution.
• The pharmacokinetics of digoxin or theophylline were not modified by the co-administration of clopidogrel.
• Antacids did not modify the extent of clopidogrel absorption.
• Glycoprotein IIb/IIIa inhibitors: clopidogrel should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions that receive concomitant glycoprotein IIb/IIIa inhibitors.
• Acetylsalicylic (ASA): ASA did not modify the clopidogrel mediated inhibition of ADP-induced platelet agregation, but clopidogrel potentiated the effect of ASA on collagen-induced platelet aggregation
• Thrombolytics: The safety of the concomitant administration of clopidogrel, rt-PA and heparin was assessed in patients with recent myocardial infarction. The incidence of clinically significant bleeding was similar to that observed when rt-PA and heparin are co-administered with ASA. The safety of the concomitant administration of clopidogrel with other thrombolytic agents has not been formally established and should undertaken with caution.

VACLO film-coated tablet, Box, 5 strips @ 6 film-coated tablets; No. Reg. : DKL0834607717A1

Manufactered by
PT DEXA MEDICA
JL. LETJEN BAMBANG UTOYO 138
PALEMBANG – INDONESIA
for
PT FERRON PAR PHARMACEUTICALS
CIKARANG - INDONESIA