INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo MISTRO (tablet)
SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

MISTRO (tablet)

COMPOSITION
MISTRO: Each film-coated tablet contains clopidogrel bisulfate 97,875 mg equivalent to 75 mg clopidogrel base.
Sugar free.

PHARMACOLOGICAL CLASSIFICATION
A 8.2 Anticoagulants

PHARMACOLOGICAL ACTION
Pharmacodynamics
Clopidogrel is a specific and potent inhibitor of platelet aggregation. It acts by irreversibly modifying the platelet ADP-receptors. It inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor and subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Consequently platelets exposed to clopidogrel are affected for the remainder of their lifespan and recovery of normal platelet function occurs at a rate consistent with platelet turnover (of about 7 days).
Clopidogrel also inhibits platelet aggregation induced by other agonists by blocking the amplification of platelet activation by released ADP.
Biotransformation of clopidogrel is necessary to produce inhibition of platelet aggregation.
Repeated doses of 75 mg per day may produce inhibition of ADP-induced platelet aggregation from the first day; this may increase progressively and reach steady state between day 3 and day 7. At steady state the average inhibition level observed with a dose of 75 mg per day may be between 40% and 60%. Platelet aggregation and bleeding time gradually returns to baseline values, generally within 7 days after treatment has been discontinued.
Pharmacokinetics
After oral doses clopidogrel is rapidly absorbed. Absorption is at least 50%. Clopidogrel is extensively metabolized by the liver and the main metabolite which is inactive, is the carboxylic acid derivative which represents about 85% of the circulating compound in the plasma.
Clopidogrel and the main metabolite bind in vitro reversibly to human plasma proteins (98% and 94% respectively).
The elimination half-life of the main circulating metabolite may reach 8 hours after administration. Clopidogrel and the main metabolite are excreted in urine (50%) and faeces (46%).

INDICATIONS
MISTRO is indicated for:
• Reduction of atherosclerotic events (myocardial infarction, stroke, death due to vascular causes) in patients with a history of symptomatic atherosclerotic disease defined by ischaemic stroke (from 7 days until less than 6 months), myocardial infarction (from a few days until less than 35 days) or established peripheral arterial disease

CONTRAINDICATIONS
MISTRO is contraindicated in:
• hypersensitivity to the active substance or any component of the product
• active bleeding such as peptic ulcer and intracranial haemorrhage
• safety and efficacy in patients below the age of 18 have not been established
• pregnancy and lactation
• severe liver impairment
• thrombocytopenia
• platelet dysfunction

WARNINGS
THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP) HAS BEEN REPORTED TO OCCUR WITH MISTRO DURING POST-MARKETING EXPERIENCE. MOST CASES WERE REPORTED IN THE FIRST TWO WEEKS OF TREATMENT. IN ADDITIONPRESCRIBERS SHOULD ALSO WARN PATIENTS ABOUT THE SIGNS AND SYMPTOMS OF THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP).
The clinical diagnosis of TTP is characterized by the presence of thrombocytopenia, haemolytic anaemia, neurological symptoms, renal dysfunction and fever.
Due to the risk of fatal outcome in the event of suspected TTP, MISTRO should be stopped and a specialist team should be contacted. The management of a patient with TTP is complex. Early treatment with plasmapharesis is indicated in TTP.
Risk of increased blood loss during dental and surgical procedures
Active pathological bleeding such as peptic ulcer and intracranial haemorrhage
Use with caution in patients receiving other drugs that increase the risk of bleeding (anticoagulants, NSAIDs and other anticoagulants)

INTERACTIONS
Acetylsalicylic acid (aspirin)
MISTRO potentiates the effect of acetylsalicylic acid on collagen-induced platelet aggregation. A pharmacodynamic interaction between clopidogrel and acetylsalicylic acid (aspirin) is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution. The safety of the chronic concomitant administration of acetylsalicylic acid (aspirin) and MISTRO has not been established (see Special Precautions).
Heparin
The safety of this combination has not been established and concomitant use should be undertaken with caution.A pharmacodynamic interaction between clopidogrel and heparin is possible, leading to increased risk of bleeding.
Thrombolytics
The safety of the concomitant co-administration of MISTRO with other thrombolytic agents has not been established and concomitant administration should be undertaken with caution.
Warfarin
The safety of the co-administration of MISTRO with warfarin has not been established. Consequently, concomitant administration of these two agents should be undertaken with caution.
Non-Steroidal Anti-Inflammatory Agents (NSAIDs) including aspirin
There is a potential risk of gastrointestinal bleeding and NSAIDs, including aspirin, and MISTRO should be co-administered with caution (see Special Precautions). NSAIDs, including COX-2 inhibitors and clopidogrel should be co-administered with caution.
Glycoprotein IIb/IIIa inhibitors
MISTRO should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other conditions/disorders that may require glycoprotein IIb/IIIa inhibitors intake.
Other concomitant therapy
No clinically significant pharmacodynamic interactions were observed when MISTRO was administered with atenolol, nifedipine or both atenolol and nifedipine. The pharmacodynamic activity of MISTRO was not significantly influenced by the co-administration of phenobarbital, cimetidine, or oestrogen. The pharmacokinetics of digoxin or theophylline were not modified by the co-administration of MISTRO.
MISTRO inhibits the activity of one of the Cytochrome P450 enzymes: (CYP 2C9). This leads to increased plasma levels of medicines such as phenytoin, tolbutamide, warfarin, tamoxifen, fluvastatin and many NSAIDs which are metabolized by CYP 2C9.

PREGNANCY AND LACTATION
(See CONTRA-INDICATIONS)
The use of MISTRO during pregnancy and lactation is not recommended as safety and efficacy have not been established.

DOSAGE AND DIRECTIONS FOR USE
Adults:
MISTRO should be given as a single daily dose of 75 mg with or without food.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side-effects
Very common (>1/10), Common ((>1/100 and <1/10), Uncommon ((>1/1000 and <1/100), Rare ((> 1/10 000 and < 1/1000), Very rare (< 1/10 000)
Blood and lymphatic system disorders
Common: Purpura, bruising, epistaxis, gastrointestinal haemorrhage
Uncommon: Severe neutropenia including agranulocytosis
Rare: Intracranial haemorrhage
Very rare: Aplastic anaemia, pancytopenia, severe thrombocytopenia (including thrombotic thrombocytopenic purpura)
Incidence unknown: Haematuria, eye bleeding (conjunctival, ocular, retinal), respiratory tract bleeding (including haemothorax), musculoskeletal bleeding (including haemarthrosis), haemorrhagic ulcer, haemorrhage of operative wound, retroperitoneal haemorrhage
Immune system disorders
Very rare: Bronchospasm, angioedema, anaphylactoid reactions
Psychiatric disorders
Very rare: Confusion, hallucinations
Common: Anxiety, mental depression
Nervous system disorders
Common: Syncope, insomnia, hypoesthesia
Uncommon: Headache, dizziness, paraesthesia
Rare: Vertigo, intracranial haemorrhage
Very rare: Taste disturbances
Cardiac disorders
Common: Chest pain, atrial fibrillation, palpitations
Vascular disorders
Common: Oedema, hypertension
Very rare: Hypotension, vasculitis
Respiratory, thoracic and mediastinal disorders
Common: Bronchitis, dyspnoea, upper respiratory tract infection, cough, rhinitis
Very rare: Interstitial pneumonitis
Gastrointestinal disorders
Common: Abdominal pain, dyspepsia, gastrointestinal haemorrhage, diarrhoea
Uncommon: Gastric and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence
Incidence unknown: Tooth disorder
Hepato-biliary disorders
Very rare: Abnormal liver function tests, hepatitis, acute liver failure
Skin and subcutaneous tissue disorders
Uncommon: Rash, pruritus
Very rare: Severe skin reactions (including bullous eruption), erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, lichen planus, urticaria, eczema
Renal and urinary disorders
Common: Urinary tract infection
Very rare: Glomerulonephritis, increased creatinine levels
Musculoskeletal system disorders
Common: Back pain, gout, leg cramps
Very rare: Arthralgia, myalgia, arthritis
Other
Common: Generalised pain, flu-like symptoms, fatigue, asthenia
Special Precautions
MISTRO 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 acetylsalicylic acid (aspirin), NSAIDs (including COX-2 inhibitors), heparin or glycoprotein IIb/IIIa inhibitors. Patients should be monitored carefully for any signs of bleeding, including occult bleeding, especially during the first week of treatment and/or after invasive cardiac procedures or surgery. The concomitant administration of clopidogrel with warfarin is not recommended since it may increase the intensity of bleedings. If a patient is to undergo elective surgery and an anti-platelet effect is not desired, MISTRO should be discontinued 7 days prior to surgery. MISTRO prolongs bleeding time and should be used with caution in patients who have lesions with a propensity to bleed (such as ulcers). Medicines that might induce such lesions (such as acetylsalicylic acid and NSAIDs) should be used with caution in patients taking MISTRO.
Patients should be told that it may take longer than usual to stop bleeding when they take MISTRO and that they should report any unusual bleeding to their medical practitioner. Patients should inform medical practitioners and dentists that they are taking MISTRO before any surgery is scheduled and before any new medicine is taken.
In view of the possible increased risk of bleeding, the concomitant administration of MISTRO with acetylsalicylic acid (aspirin), heparin, warfarin or thrombolytics should be undertaken with caution (see INTERACTIONS).
In patients with recent transient ischaemic attack (TIA) or stroke, who are at high risk of recurrent ischaemic events, the combination of aspirin and MISTRO has not been shown to be more effective than MISTRO alone, but the combination has been shown to increase major bleeding. It is therefore recommended that such addition should be undertaken with caution. In patients with acute myocardial infarction, MISTRO therapy should not be initiated within the first few days following the myocardial infarction.
In view of the lack of data MISTRO cannot be recommended in coronary artery by-pass graft (CABG) and acute ischaemic stroke (less than 7 days). Clinical experience is limited in patients with renal impairment and moderate hepatic disease with bleeding diatheses. MISTRO should be used in caution in these patients.
Thrombocytopenia, neutropenia, aplastic anaemia and pancytopenia have been reported in patients takingclopidogrel (seeSide-effects).
Therapeutic experience is limited in patients with renal impairment and moderate hepatic disease with bleeding diatheses. MISTRO should be used with caution in these patients.
Effects on ability to drive and use machines:
No impairment of driving or psychometric performance was observed following MISTRO administration.

KNOWN SYMPTOMS OF OVER-DOSAGE AND PARTICULARS OF ITS TREATMENT
(See SIDE-EFFECTS AND SPECIAL PRECAUTIONS)
Overdosing following MISTRO administration may lead to prolonged bleeding time and subsequent bleeding complications. Treatment is symptomatic and supportive.

IDENTIFICATION
MISTRO: White film-coated, round biconvex tablets embossed “R”on one side and “196”on other side

PRESENTATION
MISTRO: Pack sizes of 30 tablets in white HDPE plastic bottles.

STORAGE INSTRUCTIONS       
Store below 25°C. Protect from light.
Keep the tablets in the original pack in which it was received until you are ready to take a dose.
KEEP OUT OF THE REACH OF CHILDREN

REGISTRATION NUMBER
41/8.2/0146

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
Dr. Reddy’s Laboratories (Pty) Limited
381 Rossouw Street
Murrayfield
Pretoria
0184

DATE OF PUBLICATION OF THE PACKAGE INSERT
December 2008

New addition to this site: March 2010
Source: Pharmaceutical Industry

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