Active ingredients: Clopidogrel, Acetylsalicylic acid
DuoPlavin 75 mg / 75 mg film-coated tablets
Duoplavin package inserts are available for pack sizes:- DuoPlavin 75 mg / 75 mg film-coated tablets
- DuoPlavin 75 mg / 100 mg film-coated tablets
Indications Why is Duoplavin used? What is it for?
DuoPlavin contains clopidogrel and acetylsalicylic acid (ASA), and belongs to a group of medicines called antiplatelet agents. Platelets are microscopic-sized elements of the blood that clump together during blood clotting. By preventing this clumping in certain types of blood vessels (called arteries), antiplatelet agents decrease the possibility of blood clots (a phenomenon called atherothrombosis).
DuoPlavin is taken by adults to prevent blood clots from forming in hardened arteries which can cause atherothrombotic events (such as stroke, heart attack, or death).
DuoPlavin has been prescribed to you instead of two separate medicines, clopidogrel and ASA, to help prevent blood clots because you have previously suffered from a severe type of chest pain known as 'unstable angina' or heart attack (heart attack myocardial). To treat this condition, your doctor may have placed a stent in your blocked or narrowed artery to restore blood flow.
Contraindications When Duoplavin should not be used
Do not take DuoPlavin
- If you are allergic to clopidogrel, acetylsalicylic acid (ASA) or any of the other ingredients of this medicine
- If you are allergic to other medicines called non-steroidal anti-inflammatory drugs, generally used to treat painful and / or inflammatory conditions of muscles or joints.
- If you have a medical condition which includes a combination of asthma, nasal discharge (runny nose) and nasal polyps (a type of growth in the nose).
- If you have active bleeding, such as a "stomach ulcer or bleeding in an area of the brain.
- If you have severe liver disease.
- If you have severe kidney disease.
- If you are in the last trimester of pregnancy
Precautions for use What you need to know before taking Duoplavin
If any of the situations mentioned below occur, tell your doctor before taking DuoPlavin:
if you have a bleeding risk such as:
- a medical condition that puts you at risk for internal bleeding (such as a "stomach ulcer)
- a blood disorder that makes you prone to internal bleeding (bleeding inside any tissue, organ or joint in your body)
- a recent serious injury
- recent surgery (including dental surgery)
- scheduled surgery (including dental surgery) in the next 7 days if you have had a clot in an "artery of the brain (ischemic stroke) that has occurred in the past 7 days
- if you have kidney or liver disease
- if you have previously suffered from asthma or had any allergic reactions including a reaction to any medicine used to treat your disease
- if you have gout,
- if you have a condition known as glucose-6-phosphate dehydrogenase (G6PD) deficiency, due to the risk of a particular form of anemia (low red blood cell count).
While you are taking DuoPlavin:
You must inform your doctor
- in case you need to have surgery (including dental surgery)
- if you suffer from stomach or abdominal pain or "bleeding in the stomach or intestines" (red or black stools)
- You must tell your doctor immediately if you develop a medical condition known as thrombotic thrombocytopenic purpura or PTT which includes fever and bruising under the skin which appear as red pinpoint dots, with or without unexplained extreme fatigue, confusion, yellowing of the skin or eyes (jaundice).
- If you cut or injure yourself, it may take longer than usual for the bleeding to stop. This is due to the way the medicine works as it prevents blood clots from forming. For minor cuts and injuries, such as cutting yourself or shaving, this usually isn't a problem. However, if you are concerned by your bleeding, you should contact your doctor straightaway (see section "Possible side effects").
- Your doctor may order blood tests.
Children and adolescents
The use of DuoPlavin is not recommended in children and adolescents under the age of 18. There is a possible association between acetylsalicylic acid (ASA) and Reye's syndrome when medicines containing ASA are taken by children or adolescents with a viral infection. . Reye's Syndrome is a very rare disease that can be fatal.
Interactions Which drugs or foods can modify the effect of Duoplavin
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Some medicines may influence the use of DuoPlavin or vice versa.
You should especially tell your doctor if you are taking:
- oral anticoagulants, medicines used to reduce blood clotting
- ASA or another non-steroidal anti-inflammatory medicine, usually used to treat painful and / or inflammatory conditions of muscles or joints
- heparin or any other injectable medicine used to reduce blood clotting
- omeprazole, esomeprazole or cimetidine, medicines used to treat stomach problems methotrexate, a medicine used to treat severe joint disease (rheumatoid arthritis) or skin disease (psoriasis)
- probenecid, benzbromarone or sulfinpyrazone, medicines used to treat gout
- fluconazole, voriconazole, ciprofloxacin, or chloramphenicol, medicines used to fight bacterial and fungal infections
- carbamazepine or oxcarbazepine, medicines to treat some forms of epilepsy
- ticlopidine, other antiplatelet agents,
- a selective serotonin reuptake inhibitor (including, but not limited to, fluoxetine or fluvoxamine), medicines normally used to treat depression,
- moclobemide, a medicine used to treat depression.
You should stop any other clopidogrel treatment while taking DuoPlavin.
Occasional use of ASA (not exceeding 1,000 mg in 24 hours) should generally not cause problems, but prolonged use of ASA in other circumstances should be discussed with your doctor or pharmacist.
Warnings It is important to know that:
Pregnancy and breastfeeding
Do not use this medicine during the third trimester of pregnancy.
It is preferable not to use this medicine during the first and second trimester of pregnancy.
If you are pregnant or suspect that you are pregnant, tell your doctor or pharmacist before taking DuoPlavin. If you become pregnant while taking DuoPlavin, consult your doctor immediately, as it is recommended not to take DuoPlavin during pregnancy.
You should not breastfeed while using this medicine.
If you are breast-feeding, or planning to breast-feed, consult your doctor before taking this medicine.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
DuoPlavin is unlikely to affect the ability to drive or use machines.
DuoPlavin contains lactose
If you have been told by your doctor that you have an "intolerance to some sugars (eg lactose), consult your doctor before taking this medicine.
DuoPlavin contains hydrogenated castor oil
This can cause stomach upset and diarrhea.
Dose, Method and Time of Administration How to use Duoplavin: Posology
Always take this medicine exactly as your doctor or pharmacist has told you. If you are unsure, consult your doctor or pharmacist.
The recommended dose is one DuoPlavin tablet per day, to be taken orally with a glass of water during or between meals.
You must take the medicine at the same time every day.
Based on your condition, your doctor will determine the duration of treatment with DuoPlavin. If you have had a heart attack, this medicine should be prescribed for at least 4 weeks. In any case, DuoPlavin must be taken for as long as the doctor deems necessary.
Overdose What to do if you have taken too much Duoplavin
If you take more DuoPlavin than you should
Contact your doctor or the emergency room of the nearest hospital for an increased risk of bleeding.
If you forget to take DuoPlavin
If you forget to take a dose, but remember within 12 hours of your usual time, take one tablet straight away and then take the next one at the usual time.
If it has been more than 12 hours, simply take the next dose at the usual time. Do not take a double dose to make up for a forgotten tablet.
For packs of 14, 28 and 84 tablets, you can check the day on which the last DuoPlavin tablet was taken by checking the calendar printed on the blister.
If you stop taking DuoPlavin
Do not stop treatment unless your doctor asks you to. Before stopping or restarting treatment, contact your doctor.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Duoplavin
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Contact your doctor immediately if:
- fever, signs of infection or severe weakness. These effects may be due to a rare decrease in some blood cells
- signs of liver problems such as yellowing of the skin and / or eyes (jaundice), with or without bleeding which appears under the skin as red pinpoints, and / or confusion (see section "Warnings and precautions")
- swelling in the mouth or skin disorders such as rash, itching, blisters. These can be signs of an allergic reaction
The most common side effect reported with DuoPlavin is bleeding. Bleeding may manifest itself as bleeding in the stomach or intestines, bruising, bruising (unusual bleeding or bruising under the skin), nosebleeds, blood in the urine. In a few cases, bleeding in the eye, intracranial have also been reported. (especially in the elderly), in the lungs and joints.
If you experience prolonged bleeding while taking DuoPlavin
If you cut or injure yourself, it may take longer than usual for the bleeding to stop. This is due to the way the medicine works as it prevents blood clots from forming. For minor cuts and injuries, such as cutting yourself or shaving, this usually isn't a problem. However, if you are concerned by your bleeding, you should contact your doctor straightaway (see section 2 'Warnings and precautions').
Other side effects include:
Common side effects (may affect up to 1 in 10 patients):
Diarrhea, abdominal pain, indigestion and heartburn.
Uncommon side effects (may affect up to 1 in 100 patients):
Headache, stomach ulcer, vomiting, nausea, constipation, excess gas in the stomach or intestines, rash, itching, dizziness, tingling sensations and numbness.
Rare side effects (may affect up to 1 in 1000 patients):
Vertigo
Very rare side effects (may affect up to 1 in 10,000 patients):
Jaundice (yellowing of the skin and / or eyes); heartburn and / or esophagus (throat), severe abdominal pain with or without back pain; fever, shortness of breath sometimes associated with cough; generalized allergic reactions (for example; widespread feeling of warmth with sudden general malaise up to fainting); swelling in the mouth; blisters of the skin; skin allergy; burning of the mouth (stomatitis); decrease in blood pressure; confusion; hallucinations; pain in the joints; muscle pain; changes in taste, inflammation of small arterial vessels.
Undesirable effects with frequency not known (frequency cannot be estimated from the available data):
Perforated ulcer, ringing in the ears, hearing loss, sudden life-threatening allergic reactions, kidney disease, hypoglycemia, gout (a condition characterized by joint pain and swelling caused by uric acid crystals), worsening of food allergies, and a particular form of anemia (low number of red blood cells) (see section "Warnings and precautions".
Also, your doctor can identify changes in your blood or urine tests.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of that month.
Store below 25 ° C.
Do not use this medicine if you notice any visible signs of deterioration.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What DuoPlavin contains
The active ingredients are clopidogrel and acetylsalicylic acid (ASA). Each tablet contains 75 mg of clopidogrel (as hydrogen sulfate) and 75 mg of acetylsalicylic acid. The other ingredients are:
- tablet core: mannitol (E421), macrogol 6000, microcrystalline cellulose, low-substituted hydroxypropylcellulose, corn starch, hydrogenated castor oil, (see section "DuoPlavin contains hydrogenated castor oil"), stearic acid and colloidal anhydrous silica
- tablet coating: lactose monohydrate (see section "DuoPlavin contains lactose"), hypromellose (E464), titanium dioxide (E171), triacetin (E1518), yellow iron oxide (E172)
- polishing agent: carnauba wax
What DuoPlavin looks like and contents of the pack
DuoPlavin 75 mg / 75 mg tablets are oval, slightly biconvex, yellow, film-coated, debossed with "C75" on one side and "A75" on the other side. DuoPlavin is supplied in cartons containing:
- 14, 28, 30 and 84 tablets in aluminum / aluminum blisters
- 30x1, 50x1, 90x1 and 100x1 tablet in single-dose perforated aluminum / aluminum blisters.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
DUOPLAVIN 75 MG / 75 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 75 mg of clopidogrel (as hydrogen sulfate) and 75 mg of acetylsalicylic acid (ASA).
Excipients with known effects:
Each film-coated tablet contains 7 mg of lactose and 3.3 mg of hydrogenated castor oil.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet (tablet).
Yellow, oval, slightly biconvex, engraved with "C75" on one side and "A75" on the other side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
DuoPlavin is indicated for the prevention of atherothrombotic events in adult patients already being treated with clopidogrel and acetylsalicylic acid (ASA).
DuoPlavin is a medicine composed of a fixed dose combination indicated for the continuation of therapy in:
• acute coronary syndrome without ST segment elevation (unstable angina or myocardial infarction without Q waves), including patients undergoing stent placement following percutaneous coronary intervention
• acute coronary syndrome with ST segment elevation in drug therapy patients who are candidates for thrombolytic therapy.
For further information see section 5.1.
04.2 Posology and method of administration
Dosage
Adults and the elderly
DuoPlavin is administered as a single daily dose of 75 mg / 75 mg.
DuoPlavin is taken after starting treatment with clopidogrel and ASA given separately.
- In patients with acute coronary syndrome without ST segment elevation (unstable angina or myocardial infarction without Q waves): the optimal duration of treatment has not been formally established. Clinical trial data support use for up to 12 months and maximum benefit was seen at 3 months (see section 5.1). If DuoPlavin is discontinued, patients could benefit from continued single treatment. antiplatelet agent.
- In patients with acute myocardial infarction with ST segment elevation: Therapy should be started as soon as possible after the onset of symptoms and continued for at least 4 weeks. The benefit of combining clopidogrel with ASA beyond four weeks has not been studied in this setting (see section 5.1). If DuoPlavin is discontinued, patients could benefit from continued treatment with a single antiplatelet agent.
If you miss a dose:
• within 12 hours of the regular scheduled time: patients should take the dose immediately and take the next one at the regular scheduled time.
• beyond 12 hours: patients should take their dose at the regular scheduled time and not take two doses at the same time.
Pediatric population
The safety and efficacy of DuoPlavin in children and adolescents under the age of 18 have not yet been established. DuoPlavin is not recommended in this population.
Kidney failure
DuoPlavin must not be used in patients with severe renal impairment (see section 4.3).
Therapeutic experience in patients with mild to moderate renal impairment is limited (see section 4.4). Caution is therefore recommended in the use of DuoPlavin in these patients.
Hepatic insufficiency
DuoPlavin must not be used in patients with severe hepatic impairment (see section 4.3).
Therapeutic experience in patients with moderate hepatic dysfunction who may have haemorrhagic diathesis is limited (see section 4.4). Caution is therefore recommended in the use of DuoPlavin in these patients.
Method of administration
For oral use.
It can be administered with or without meals.
04.3 Contraindications
Due to the presence of both components in the medicine, DuoPlavin is contraindicated in case of:
• Hypersensitivity to the active substances or to one of the excipients listed in section 6.1.
• Severe hepatic insufficiency.
• Pathological bleeding in progress such as eg. in the presence of a peptic ulcer or haemorrhage
intracranial.
Furthermore, due to the presence of ASA, its use is also contraindicated in case of:
• Hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs) and asthmatic syndrome, rhinitis and nasal polyps. Patients with pre-existing mastocytosis, in whom the use of acetylsalicylic acid can induce severe hypersensitivity reactions (including circulatory shock with flushing, hypotension, tachycardia and vomiting).
• Severe renal insufficiency (creatinine clearance
• Third trimester of pregnancy (see section 4.6).
04.4 Special warnings and appropriate precautions for use
Bleeding and haematological disorders
Because of the risk of bleeding and haematological adverse reactions, a complete blood count and / or other appropriate tests should be considered whenever clinical symptoms suggestive of bleeding occur during treatment (see section 4.8). As a combination of two antiplatelet agents, DuoPlavin should be used with caution in patients who may be at risk of increased bleeding following trauma, surgery or other pathological conditions and in patients being treated with other NSAIDs including COX-2 inhibitors. heparin, glycoprotein IIb / IIIa inhibitors, selective serotonin reuptake inhibitors (SSRIs), or thrombolytics. Patients should be followed closely for any signs of bleeding, including occult bleeding, particularly during the first weeks of treatment and / or after invasive cardiac procedures or surgery. Co-administration of DuoPlavin and oral anticoagulants is not recommended as it may result in increased bleeding intensity (see section 4.5).
Before undergoing any surgery and before taking a new medicine, patients should tell their doctor and dentist that they are being treated with DuoPlavin. If a patient is to undergo elective surgery, the need for therapy with two antiplatelet agents should be reviewed and the possibility of using only one antiplatelet agent should be considered. If patients need to temporarily discontinue antiplatelet therapy, administration of DuoPlavin must be discontinued 7 days prior to surgery.
DuoPlavin prolongs bleeding time and should be used with caution in patients with bleeding-prone lesions (particularly gastrointestinal and intraocular).
Patients should also be warned that the use of DuoPlavin could prolong any bleeding and that they should inform their physician of any abnormal bleeding (by location or duration).
Thrombotic thrombocytopenic purpura (PTT)
Thrombotic thrombocytopenic purpura (TTP) has been reported very rarely following the use of clopidogrel, sometimes after short exposure. This is characterized by thrombocytopenia and microangiopathic haemolytic anemia associated with or with neurological problems, renal dysfunction or fever.
TTP is a potentially fatal condition that requires immediate treatment including plasmapheresis.
Acquired hemophilia
Acquired haemophilia has been reported following the use of clopidogrel. In the event of isolated activated Partial Thromboplastin Time (aPTT) prolongation with or without ongoing bleeding, acquired haemophilia should be considered. Patients with a confirmed diagnosis of acquired haemophilia should be managed and treated by medical specialists. Treatment with clopidogrel should be discontinued.
Recent transient ischemic attack or stroke
The combination of ASA with clopidogrel has shown increased major bleeding in patients with recent transient ischemic attack or stroke who are at high risk of recurrence of ischemic events. This combination should therefore be administered with caution outside clinical situations where the association has shown benefits.
Cytochrome P450 2C19 (CYP2C19)
Pharmacogenetics: When clopidogrel is administered at the recommended dose in patients poor metabolisers of CYP2C19, the formation of the active metabolite of clopidogrel is reduced and the effect on platelet function is minor. Tests are available to identify a patient's CYP2C19 genotype.
Since clopidogrel is converted to its active metabolite in part by CYP2C19, the use of drugs that inhibit the activity of this enzyme is expected to lead to a reduction in the pharmacological levels of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged (see section 4.5 for a list of CYP2C19 inhibitors; see also section 5.2).
Cross-reactions between thienopyridines
Patients should be evaluated for clinical history of hypersensitivity to thienopyridines (such as clopidogrel, ticlopidine, prasugrel) as cross-reactivity has been reported among thienopyridines (see section 4.8). Thienopyridines can cause moderate to severe allergic reactions such as rash, angioedema or haematological cross reactions such as thrombocytopenia and neutropenia. Patients who have experienced a previous allergic and / or haematological reaction to one thienopyridine may have an increased risk of developing the same or an "other reaction to" another thienopyridine. Monitoring for signs of hypersensitivity in patients with a known allergy to thienopyridines is advised.
Caution is recommended due to the presence of ASA
• in patients with a history of asthma or allergic disorders, due to the increased risk of hypersensitivity reactions
• in patients with gout, as low doses of ASA increase urate concentrations
• in children and young people under 18 years of age, as there is a possible association between ASA and Reye's syndrome. Reye's syndrome is a very rare disease that can be fatal.
• This medicinal product should be administered under close medical supervision in patients with glucose 6 phosphate dehydrogenase (G6PD) deficiency, due to the risk of haemolysis (see section 4.8).
Gastrointestinal (GI) system
DuoPlavin should be used with caution in patients with a history of peptic ulcer or gastroduodenal haemorrhage or with minor upper gastrointestinal disorders as these could be caused by gastric ulcers which can lead to gastric bleeding. Gastrointestinal (GI) side effects have been reported including stomach pain, burning, nausea, vomiting and gastrointestinal bleeding. Minor disorders of the gastrointestinal tract, such as dyspepsia, are common and can occur at any time during therapy. monitor for signs of gastrointestinal ulceration and bleeding, even in the absence of previous gastrointestinal disturbances Patients should be informed of the signs and symptoms of gastrointestinal side effects and what measures to take if they occur (see section 4.8).
Excipients
DuoPlavin contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp-lactase deficiency or glucose-galactose malabsorption should not take the medicine. This medicine contains hydrogenated castor oil which can cause stomach upset and diarrhea.
04.5 Interactions with other medicinal products and other forms of interaction
Oral anticoagulants
Co-administration of DuoPlavin and oral anticoagulants is not recommended as it may result in increased bleeding intensity (see section 4.4). Though, administration of clopidogrel 75 mg / day did not change the pharmacokinetics of S-warfarin or the International Normalized Ratio (INR) in patients on long-term treatment with warfarin, co-administration of clopidogrel and warfarin increases the risk of bleeding due to the effects independent on hemostasis.
Inhibitors of glycoprotein IIb / IIIa
DuoPlavin should be used with caution in patients taking concomitant glycoprotein IIb / IIIa inhibitors (see section 4.4).
Heparin
In a clinical study conducted in healthy subjects, following administration of clopidogrel no modification of the heparin dose was necessary nor was the effect of heparin on coagulation altered. Co-administration of heparin had no effect on the inhibition of platelet aggregation induced by clopidogrel. A pharmacodynamic interaction is possible between DuoPlavin and heparin, with an increased risk of bleeding. Therefore, concomitant use should be made with caution (see section 4.4).
Thrombolytics
The safety of concomitant administration of clopidogrel, fibrin or nonfibrin specific thrombolytic drugs and heparins has been studied in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed when thrombolytic drugs and heparin were administered together with ASA (see section 4.8). The safety of concomitant administration of DuoPlavin and other thrombolytic drugs has not been formally established and should be performed with caution (see section 4.4).
NSAIDs
In a clinical study conducted in healthy volunteers, the concomitant administration of clopidogrel and naproxen resulted in increased occult gastrointestinal bleeding. Consequently, the concomitant use of NSAIDs including COX-2 inhibitors is not recommended (see section 4.4).
Experimental data suggest that ibuprofen may inhibit the effect of low-dose aspirin on platelet aggregation when administered concomitantly. However, the limitations of this data and the uncertainties surrounding the extrapolation of data ex vivo from the clinical situation imply that no firm conclusions can be drawn on regular use of ibuprofen and that no clinically relevant effects are considered likely for occasional use of ibuprofen (see section 5.1).
Metamizole
Metamizole may reduce the effect of ASA on platelet aggregation when taken concomitantly. Therefore, this combination should be used with caution in patients taking low doses of ASA for cardioprotection.
Selective Serotonin Reuptake Inhibitors (SSRIs)
Since SSRIs affect platelet activation and increase the risk of bleeding, co-administration of SSRIs with clopidogrel should be done with caution.
Other concomitant therapy with clopidogrel
Since clopidogrel is converted to its active metabolite in part by CYP2C19, the use of medicinal products that inhibit the activity of this enzyme is expected to lead to a reduction in the pharmacological levels of the active metabolite of clopidogrel. The clinical relevance of this interaction is not certain. As a precaution, concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged (see sections 4.4 and 5.2).
Medicines that inhibit CYP2C19 include omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine and chloramphenicol.
Proton pump inhibitors (PPIs):
Administration of omeprazole, single dose of 80 mg / day, and of clopidogrel both concomitantly and 12 hours apart, decreased exposure to the active metabolite by 45% (loading dose) and by 40% (maintenance dose). The decrease was associated with a reduction in inhibition of platelet aggregation by 39% (loading dose) and 21% (maintenance dose). similar interaction. Contradictory data on the clinical implications of this pharmacokinetic (PK) / pharmacodynamic (PD) interaction in terms of major cardiovascular events have been reported in both clinical and observational studies. As a precaution, concomitant use of omeprazole or esomeprazole should be discouraged (see section 4.4).
Less marked reductions in metabolite exposure were observed with pantoprazole and lansoprazole.
Plasma concentrations of the active metabolite were reduced by 20% (loading dose) and 14% (maintenance dose) during concomitant treatment with pantoprazole 80 mg once daily. This was associated with a reduction in mean platelet aggregation inhibition of 15% and 11%, respectively. These results indicate that clopidogrel can be administered with pantoprazole.
There is no evidence that other gastric acid lowering drugs such as H2 blockers (except cimetidine which is a CYP2C19 inhibitor) or antacids interfere with the antiplatelet activity of clopidogrel.
Other Medicines
Many other clinical studies have been conducted with clopidogrel and other concomitant therapies to investigate potential pharmacodynamic and pharmacokinetic interactions. No relevant pharmacodynamic interactions were observed when clopidogrel was administered with atenolol or nifedipine alone or in combination. Furthermore, the pharmacodynamic activity of clopidogrel was not significantly affected by the concomitant administration of phenobarbital or estrogen.
The pharmacokinetics of digoxin and theophylline were not affected by co-administration with clopidogrel. Antacids did not alter the absorption of clopidogrel.
Data from the CAPRIE study indicate that phenytoin and tolbutamide which are metabolised by CYP2C9 can be safely administered concurrently with clopidogrel.
Other concomitant therapies with ASA
Interactions with the following medicinal products have been reported with ASA:
Uricosurics (benzbromarone, probenecide, sulfinpyrazone)
Caution is advised as ASA may inhibit the effect of uricosuric drugs through competitive elimination of uric acid.
Methotrexate
Due to the presence of ASA, methotrexate used at doses above 20 mg / week should be administered with caution concomitantly with DuoPlavin as the latter may inhibit renal elimination of methotrexate, which can lead to bone marrow toxicity.
Other interactions with ASA
Interactions between the following medicines and higher (anti-inflammatory) doses of ASA have also been reported: angiotensin converting enzyme (ACE) inhibitors, acetazolamide, antiepileptics (phenytoin and valproic acid), beta blockers, diuretics and hypoglycemic agents oral.
Other interactions with clopidogrel and ASA
More than 30,000 patients were included in clinical trials with clopidogrel + ASA at maintenance doses less than or equal to 325 mg and received several concomitant medicinal products including diuretics, beta blockers, ACE inhibitors, calcium channel blockers, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptics and glycoprotein IIb / IIIa antagonists without evidence of clinically significant negative interactions.
In addition to the information described above on interactions with specific medicinal products, interaction studies with DuoPlavin and some medicinal products commonly administered to patients with atherothrombotic disease have not been conducted.
04.6 Pregnancy and lactation
Pregnancy
No clinical data on exposure to DuoPlavin during pregnancy are available. DuoPlavin should not be used during the first two trimesters of pregnancy unless the clinical condition of the woman requires treatment with clopidogrel / ASA.
Due to the presence of ASA, DuoPlavin is contraindicated during the third trimester of pregnancy.
Clopidogrel:
As no clinical data on exposure to clopidogrel during pregnancy are available, it is preferable to avoid the use of diclopidogrel during pregnancy as a precautionary measure.
Animal studies do not indicate direct or indirect harmful effects on pregnancy, embryonal / fetal development, parturition or postnatal development (see section 5.3).
ASA:
Low doses (up to 100 mg / day):
Clinical studies indicate that doses up to 100 mg / day limited to obstetric use, requiring specialist monitoring, appear safe.
Doses of 100-500 mg / day:
There is insufficient clinical experience on the use of doses above 100 mg / day and up to 500 mg / day.
Therefore, the recommendations below for doses of 500 mg / day and above are also valid for this dose range.
Doses of 500 mg / day and higher:
Inhibition of prostaglandin synthesis can adversely affect pregnancy and / or embryo-fetal development. Data from epidemiological studies indicate that there is an increased risk of miscarriages, cardiac malformations and gastroschisis after the use of a synthesis inhibitor. prostaglandins in early pregnancy. The absolute risk of heart malformation is increased from less than 1% to approximately 1.5%. The risk is believed to increase with dose and duration of therapy.
In animals, administration of prostaglandin synthesis inhibitors has been shown to cause reproductive toxicity (see section 5.3). Until the 24th week of amenorrhea (5th month of pregnancy), acetylsalicylic acid should not be given unless strictly necessary. In case of administration of acetylsalicylic acid to a woman trying to become pregnant, or until the 24th week of amenorrhea (5th month of pregnancy), the dose should be as low as possible and the duration of treatment as short as possible.
From the beginning of the sixth month of pregnancy, all prostaglandin synthesis inhibitors can expose the fetus to:
• cardiopulmonary toxicity (with premature closure of the arterial duct and pulmonary hypertension);
• renal dysfunction, which can develop into renal failure with oligo-hydroamnios;
the mother and the newborn, at the end of pregnancy, to:
• possible prolongation of bleeding time, an antiplatelet effect which can occur even at very low doses;
• inhibition of uterine contractions with consequent delay or prolongation of labor.
Pregnancy
It is unknown whether clopidogrel is excreted in human milk. Animal studies have shown that clopidogrel is excreted in milk. ASA is known to be excreted in limited quantities in human milk.
Breastfeeding should be discontinued during treatment with DuoPlavin.
Fertility
There are no known fertility data with DuoPlavin. Clopidogrel has not been shown to alter fertility in animal studies. It is not known whether the dose of ASA in DuoPlavin alters fertility.
04.7 Effects on ability to drive and use machines
DuoPlavin has no or negligible influence on the ability to drive or use machines.
04.8 Undesirable effects
Summary of the safety profile
Clopidogrel has been evaluated for safety in more than 42,000 patients who participated in clinical studies, including over 30,000 patients treated with clopidogrel + ASA, and over 9,000 patients treated for 1 year or more. Clinically relevant adverse reactions observed in four main studies, the CAPRIE study (comparison study between clopidogrel and ASA) and the CURE, CLARITY and COMMIT studies (studies comparing clopidogrel in combination with ASA vs ASA alone) are discussed below. . In the CAPRIE study, clopidogrel 75 mg / day was, overall, comparable to ASA 325 mg / day regardless of age, gender and race of the patients. In addition to the experience of clinical trials, other adverse reactions have been spontaneously reported.
Bleeding is the most commonly reported reaction in both clinical trials and post-marketing experience, where it was mainly reported during the first month of treatment. In the CAPRIE study in both clopidogrel and ASA-treated patients, the "overall incidence of any type of bleeding was 9.3%. The incidence of severe cases was similar for clopidogrel and ASA.
In the CURE study there was no excess major bleeding with clopidogrel + ASA in the 7 days following coronary artery bypass grafting in patients who stopped therapy more than 5 days before surgery. days prior to bypass surgery, the incidence was 9.6% for clopidogrel + ASA and 6.3% for ASA alone.
In the CLARITY study, there was an overall increase in bleeding in the clopidogrel + ASA group compared to the ASA alone group. The incidence of major bleeding was similar across groups. This finding was consistent across patient subgroups defined by baseline characteristics and by type of fibrinolytic or heparin therapy. In the COMMIT study, the overall rate of non-cerebral or non-cerebral major bleeding of cerebral bleeding was low and similar in the two groups.
Table of adverse reactions
The table below lists clinically relevant adverse reactions observed in clinical trials or which were spontaneously reported with clopidogrel alone, with ASA alone or with clopidogrel in combination with ASA. Their frequency is defined using the following conventions: common (≥1 / 100,
* Information reported in literature for ASA with frequency "not known".
** Information related to clopipdogrel with frequency "not known".
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicine is important. It allows continuous monitoring of the benefit / risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
04.9 Overdose
Clopidogrel
Overdose of clopidogrel can lead to prolonged bleeding time and consequent bleeding complications. If bleeding is observed, appropriate therapy should be considered.
There is no known antidote to the pharmacological activity of clopidogrel. If rapid correction of prolonged bleeding time is required, a transfusion of platelets may reverse the effects of clopidogrel.
ASA
The following symptoms are associated with moderate intoxication: dizziness, headache, tinnitus, confusion and gastrointestinal symptoms (nausea, vomiting and stomach pain).
In case of severe intoxication, serious disturbances of the acid-base balance occur. An initial hyperventilation causes respiratory alkalosis. Respiratory acidosis then occurs due to the depressing effect on the respiratory center. A metabolic acidosis is also caused by the presence of salicylates. As children and infants are often seen only at an advanced stage of intoxication, they usually have already reached the stage of acidosis.
The following symptoms may also occur: hyperthermia and sweating, leading to dehydration, restlessness, seizures, hallucinations and hypoglycemia. A nervous system depression can lead to coma, cardiovascular collapse, and respiratory arrest. The lethal dose of acetylsalicylic acid is 25-30 g. Concentrations of salicylates in plasma above 300 mg / l (1.67 mmol / l) indicate intoxication.
Overdose of the fixed dose combination of clopidogrel / ASA may be associated with increased bleeding and consequent bleeding complications due to the pharmacological activity of clopidogrel and ASA.
Non-cardiogenic pulmonary edema may occur with acute and chronic overdose of acetylsalicylic acid (see section 4.8).
If a toxic dose has been ingested, hospitalization is required. In case of moderate intoxication, one can try to induce vomiting; in case of failure, gastric lavage is indicated. Activated charcoal (adsorbent) and sodium sulfate (laxative) are then administered. Urine alkalinization (250 mmol sodium bicarbonate for 3 hours) with urine pH monitoring is indicated. In case of severe intoxication, treatment with hemodialysis is preferred. Other signs of intoxication should be treated based on symptoms.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antithrombotics, antiplatelet agents excluding heparin, ATC code: B01AC30.
Mechanism of action
Clopidogrel is a prodrug, one of its metabolites is an inhibitor of platelet aggregation. Clopidogrel must be metabolised by CYP450 enzymes to produce the active metabolite which inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor, and consequently inhibits ADP-mediated activation of the glycoprotein GPIIb-IIIa complex, and therefore platelet aggregation is inhibited. Due to the irreversible binding, platelets exposed to clopidogrel are affected for the rest of their life (approximately 7-10 days) and the recovery of normal platelet function occurs with a course dependent on platelet turnover. Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation due to released ADP.
Because the active metabolite is produced by the activity of CYP450 enzymes, some of which are polymorphic or subject to inhibition by other drugs, not all patients will have adequate platelet inhibition.
Pharmacodynamic properties
Repeated doses of 75 mg per day of clopidogrel produced marked inhibition of ADP-induced platelet aggregation from day one; inhibition progressively increased to stabilize between day three and seventh. In this steadystate condition, the mean inhibition level observed with a dose of 75 mg per day ranged from 40 to 60%. Platelet aggregation and bleeding time gradually returned to baseline usually within 5 days of stopping treatment.
Acetylsalicylic acid inhibits platelet aggregation by irreversible blockade of prostaglandin cyclooxygenase and thus inhibits the synthesis of thromboxane A2, an inducer of platelet aggregation and vasoconstriction. This effect lasts for the entire life cycle of the platelets.
Experimental data suggest that ibuprofen may inhibit the effect of low-dose aspirin on platelet aggregation when administered concomitantly. A study found that when a single dose of 400 mg ibuprofen was taken within 8 hours preceding or 30 minutes following immediate-release aspirin (81 mg), there was a reduction in the effect of ASA on thromboxane formation or platelet aggregation. However, the limitations of these data and the uncertainties regarding extrapolation of the data ex vivo to the clinical situation imply that no firm conclusions can be drawn on regular use of ibuprofen and that no effects of clinical relevance are considered likely for occasional use of ibuprofen.
Clinical efficacy and safety
The safety and efficacy of clopidogrel + ASA were evaluated in three double-blind studies involving more than 61,900 patients: the CURE, CLARITY and COMMIT study, comparing clopidogrel + ASA vs ASA alone, both administered in combination. with other standard therapies. The CURE study was conducted in 12,562 patients with acute coronary syndrome without ST segment elevation (unstable angina or non-Q wave myocardial infarction), who had experienced the onset of their most recent episode of chest pain or symptoms consistent with ischemia in the previous 24 hours. Patients were required to have either ECG changes consistent with new ischemia or elevation of cardiac enzymes or troponin I or T at least 2 times the upper limit of normal. Patients were randomized to clopidogrel (300 mg loading dose followed by 75 mg / day, N = 6,259) + ASA (75-325 mg once daily) or ASA alone (N = 6,303) (75- 325 mg once daily), and other standard therapies.Patients were treated for up to one year. In the CURE study, 823 patients (6.6%) received concomitant therapy with GPIIb / IIIa receptor antagonists. Heparin was administered to more than 90% of patients and the relative bleeding rate for clopidogrel + ASA and ASA alone was not significantly affected by concomitant heparin therapy.
The number of patients experiencing the primary endpoint [cardiovascular death, myocardial infarction (MI), or stroke] was 582 (9.3%) in the clopidogrel + ASA group and 719 (11.4%) in the group treated with ASA alone, with a 20% relative risk reduction (RRR) (95% CI 10% to 28%; p = 0.00009) for the clopidogrel + ASA group (17% risk reduction relative when patients were treated conservatively, 29% when undergoing percutaneous transluminal coronary angioplasty (PTCA) with or without stent and 10% when undergoing coronary artery bypass grafting (CABG). New events were prevented. cardiovascular (primary endpoint) with a relative risk reduction of 22% (CI: 8.6 to 33.4), 32% (CI: 12.8 to 46.4), 4% (CI: -26 , 9 to 26.7), 6% (CI: -33.5 to 34.3) and 14% (CI: -31.6 to 44.2), during study intervals 0-1, 1 -3, 3-6, 6-9 and 9-12 months, respectively. Therefore, in addition to 3 months of treatment, the benefit observed in the clopidogrel + ASA group was not further increased while the risk of haemorrhage persisted (see section 4.4).
The use of clopidogrel in CURE was associated with a decrease in the need for thrombolytic treatment (RRR = 43.3%; CI: 24.3% to 57.5%) and GPIIb / IIIa inhibitors (RRR = 18, 2%; CI: 6.5%, 28.3%).
The number of patients experiencing the co-primary endpoint (cardiovascular death, myocardial infarction, stroke or refractory ischaemia) was 1,035 (16.5%) in the clopidogrel + ASA group and 1,187 (18.8%) ) in the group treated with ASA alone, with a relative risk reduction of 14% (95% CI 6% to 21%, p = 0.0005) for the group treated with clopidogrel + ASA. This benefit was mainly determined by a statistically significant reduction in the incidence of myocardial infarction [287 (4.6%) in the clopidogrel + ASA group and 363 (5.8%) in the ASA alone group]. No effect was observed. on the rate of re-hospitalization for unstable angina.
The results obtained in populations with different characteristics (e.g. unstable angina or myocardial infarction without Q waves, low or high risk levels, diabetes, need for revascularization, age, sex, etc.) were found to be consistent with the results of the " Primary analysis. In particular, in a post-hoc analysis of 2,172 patients (17% of the total population of the CURE study) who had undergone stent placement (Stent-CURE), the data showed a significant RRR of 26.2 % in favor of clopidogrel for the co-primary endpoint (cardiovascular death, myocardial infarction, stroke) and a significant RRR of 23.9% for the second co-primary endpoint (cardiovascular death, myocardial infarction, stroke or refractory ischemia). Furthermore, the safety profile of clopidogrel in this subgroup of patients did not reveal any particular problems, therefore the results obtained by this subgroup are in line with the overall results of the study.
In patients with acute ST-segment elevation MI, the safety and efficacy of clopidogrel were evaluated in 2 randomized, double-blind, placebo-controlled studies, CLARITY and COMMIT.
The CLARITY study enrolled 3,491 patients who presented within 12 hours of onset of an ST-segment elevation MI and were candidates for thrombolytic therapy. Patients received clopidogrel (300 mg loading dose, followed by 75 mg / day). , n = 1,752) + ASA or ASA alone (n = 1,739) (150 to 325 mg loading dose, followed by 75-162 mg / day), a fibrinolytic drug and, where necessary, heparin. observed for 30 days. The primary endpoint was the occurrence of one of the following events: infarct-related artery occlusion, found on pre-discharge angiography, or death, or recurrence of MI before coronary angiography. for patients who did not undergo coronary angiography, the primary endpoint was death or recurrence of MI by day 8 or by hospital discharge. The patient population included 19.7% women and 29, 2% of patients aged ≥ 65 years . Overall 99.7% of patients received fibrinolytics (specific fibrin: 68.7%, non-specific fibrin: 31.1%), 89.5% heparin, 78.7% beta blockers, 54.7 % ACE inhibitors and 63% statins. The incidence of the primary endpoint was 15.0% in patients in the clopidogrel + ASA group and 21.7% in patients in the ASA alone group, with a 6.7% absolute reduction and 36% risk reduction in favor of clopidogrel (95% CI: 24, 47%; heart attack related parteries. This benefit was consistent across all prespecified subgroups including age-related subgroups. and gender, location of the heart attack, and type of fibrinolytic or heparin used.
The COMMIT study with 2x2 factorial design enrolled 45,852 patients who presented within 24 hours of onset of suspected MI symptoms, with support for ECG abnormalities (eg, ST segment elevation, ST segment lowering, or blockage). left branch). Patients received clopidogrel (75 mg / day, n = 22,961) in combination with ASA (162 mg / day), or ASA alone (162 mg / day) (n = 22,891) for 28 days or until discharge from hospital. The co-primary endpoints were death from any cause and first occurrence of reinfarction, stroke, or death. The population included 27.8% women, 58.4% patients ≥ 60 years of age (26% ≥ 70 years) and 54.5% of patients received fibrinolytics.
Clopidogrel + ASA significantly reduced the relative risk of death from any cause by 7% (p = 0.029), and the relative risk of the combination of reinfarction, stroke or death by 9% (p = 0.002), with an absolute reduction 0.5% and 0.9%, respectively. This benefit was consistent with age, sex and use or otherwise of fibrinolytics and was seen as early as the first 24 hours.
Pediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with DuoPlavin in all subsets of the pediatric population in the treatment of coronary atherosclerosis (see section 4.2 for information on pediatric use).
05.2 Pharmacokinetic properties
Clopidogrel:
Absorption
After single and repeated oral doses of 75 mg / day, clopidogrel is rapidly absorbed. The peak mean plasma levels of unchanged clopidogrel (approximately 2.2-2.5 ng / ml after a single oral dose of 75 mg) occur approximately 45 minutes after dosing. Absorption is at least 50% based on urinary excretion of clopidogrel metabolites.
Distribution:
In vitror, clopidogrel and its major (inactive) metabolite bind reversibly to human plasma proteins (98% and 94%, respectively). The bond is not saturable in vitro over a wide range of concentrations.
Biotransformation
Clopidogrel is mainly metabolised by the liver. In vitro And in vivo, clopidogrel is metabolised by two major metabolic pathways: one esterase mediated leading to hydrolysis into its inactive carboxylic acid derivative (85% of the circulating metabolites), and one mediated by multiple P450 cytochromes. Clopidogrel is first metabolised to the intermediate metabolite 2- oxo-clopidogrel Subsequent transformation of the 2-oxo-clopidogrel intermediate metabolite leads to the formation of the active metabolite, a thiol derivative of clopidogrel. In vitro this metabolic pathway is mediated by CYP3A4, CYP2C19, CYP1A2, CYP2B6. The active thiol metabolite that was isolated in vitror, it binds rapidly and irreversibly to platelet receptors, with consequent inhibition of platelet aggregation.
Following administration of a single 300 mg loading dose of clopidogrel, the Cmax of the active metabolite was twice as high as after administration of the 75 mg maintenance dose for 4 days. Cmax is observed approximately 30 to 60 minutes after administration.
Elimination
In humans, following an oral dose of 14C-labeled clopidogrel, approximately 50% is excreted in the urine and approximately 46% in the faeces within 120 hours of dosing. After a single 75 mg dose, clopidogrel has a half-life of approximately 6 hours. The elimination half-life of the major circulating (inactive) metabolite is 8 hours after both single and repeated dose administration.
Pharmacogenetics
CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite. Pharmacokinetics of the active metabolite of clopidogrel and antiplatelet effects as measured by platelet aggregation methods ex vivo, vary according to the CYP2C19 genotype.
The CYP2C19 * 1 allele is responsible for fully functional metabolism while the CYP2C19 * 2 and CYP2C19 * 3 alleles correspond to non-functional metabolism. CYP2C19 * 2 and CYP2C19 * 3 alleles make up the majority of impaired alleles in metabolisers Caucasian (85%) and Asians (99%). Other alleles associated with absent or reduced metabolism are less frequent and include CYP2C19 * 4, * 5, * 6, * 7 and * 8. A poor metaboliser will possess two nonfunctioning alleles as noted above. Published frequencies for CYP2C19 genotypes belonging to poor metabolisers are approximately 2% for Caucasians, 4% for Blacks and 14% for Chinese. Tests are available to identify the CYP2C19 genotype of a patient.
A cross-over study of 40 healthy subjects, 10 subjects for each of the 4 CYP2C19 metabolising groups (ultra-rapid, extensive, intermediate and slow), evaluated the pharmacokinetic and antiplatelet response using clopidogrel 300 mg followed by 75 mg / day and 600 mg followed by 150mg / day for a duration of 5 days (steady state) for each group. There was no substantial difference in active metabolite exposure and mean inhibition of platelet aggregation (PAH) between ultra-rapid, extensive, and intermediate metabolisers. In poor metabolisers, exposure to the active metabolite decreased by 63%. 71% compared to extensive metabolisers. Antiplatelet response following a 300 mg / 75 mg clopidogrel dosing regimen was decreased in poor metabolisers with mean PAH (5 μM ADP) by 24% (24 hours) and 37% (day 5) compared to " PAH found in extensive metabolisers by 39% (24 hours) and 58% (day 5) and that observed in intermediate metabolisers by 37% (24 hours) and 60% (day 5). dose of 600 mg / 150mg, the exposure to the active metabolite was higher than the exposure found in the clopidogrel 300 mg / 75mg group. In addition, the PAH was 32% (24 hours) and 61% ( day 5), a value higher than that observed in the group of poor metabolisers treated with the 300mg / 75mg dose regimen and was similar to that of the other CYP2C19 metabolisers treated with the 300mg / 75mg dose regimen. Results from clinical trials did not establish an appropriate dosage for this patient population.
Consistent with the above results, a meta-analysis including 6 studies with a total of 335 subjects treated with clopidogrel at steady state, showed a decrease in exposure to the active metabolite of 28% for intermediate metabolisers and 72% for intermediate metabolisers. poor metabolisers while inhibition of platelet aggregation (5 μM ADP) was decreased with differences in PAH of 5.9% and 21.4% respectively compared to extensive metabolisers.
The influence of the CYP2C19 genotype on clinical outcomes in clopidogrel-treated patients has not been evaluated in prospective, randomized, controlled clinical trials. However, a number of retrospective analyzes exist to evaluate this effect in clopidogrel-treated patients for whom there are genotype results: CURE (n = 2721), CHARISMA (n = 2428), CLARITY-TIMI 28 (N = 227), TRITON-TIMI 38 (N = 1477) and ACTIVE-A (n = 601), and a number of published cohort studies.
In the TRITON-TIMI 38 study and in 3 cohort studies (Collet, Sibbing, Giusti) the combined group of patients with both intermediate and slow metabolisers reported a higher incidence of cardiovascular events (death, myocardial infarction and stroke) or stent thrombosis. compared to extensive metabolisers.
In the CHARISMA study and in a cohort study (Simon), an increased incidence of events was observed only in poor metabolisers compared to extensive metabolisers.
In studies CURE, CLARITY, ACTIVE-A and in one of the cohort studies (Trenk) no increase in the incidence of events was observed based on metaboliser status.
None of these analyzes were adequately sized to detect differences in results in poor metabolisers.
Special populations
The pharmacokinetics of the active metabolite of clopidogrel are unknown in these special populations.
Kidney failure
After repeated daily doses of 75 mg / day of clopidogrel in subjects with severe renal dysfunction (creatinine clearance 5 to 15 ml / min) the inhibition of ADP-induced platelet aggregation was lower (25%) than that observed in healthy subjects, however, the bleeding time prolongation was similar to that seen in healthy subjects who received clopidogrel 75 mg / day. In addition, clinical tolerability was good in all patients.
Hepatic insufficiency
After repeated doses of clopidogrel 75 mg / day for 10 days in patients with severe hepatic impairment, the inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects.
The mean prolongation of bleeding time was also similar between the two groups.
Race
The prevalence of CYP2C19 alleles leading to reduced and intermediate CYP2C19 metabolic activity varies by race / ethnicity (see Pharmacogenetics). From the literature, limited data are available in Asian populations to evaluate the clinical implication of genotyping of this CYP on clinical events.
Acetylsalicylic acid (ASA):
Absorption
Following absorption, the ASA contained in DuoPlavin is hydrolyzed to salicylic acid with a plasma peak of salicylic acid which occurs within 1 hour of administration; these plasma levels of ASA are no longer detectable 1.5-3 hours after administration.
Distribution:
Plasma protein binding of ASA is low and its apparent volume of distribution is low (10 l). Its metabolite, salicylic acid, is strongly bound to plasma proteins, but its binding is concentration-dependent (non-linear). At low concentrations (albumin. Salicylic acid is widely distributed in all tissues and fluids of the body. organism, including the central nervous system, human milk, and fetal tissues.
Biotransformation and elimination
The ASA contained in DuoPlavin is rapidly hydrolyzed in plasma to salicylic acid, with a half-life of 0.3-0.4 hours at doses of ASA between 75 and 100 mg. Salicylic acid is conjugated mainly in the liver to form salicyluric acid, a phenolic glucuronide, an acyl glucuronide and other minor metabolites. The salicylic acid contained in DuoPlavin has a plasma half-life of approximately 2 hours. The metabolism of salicylates is saturable and total body clearance decreases at higher serum concentrations due to the liver's limited ability to form both salicyluric acid and phenolic glucuronide. After toxic doses (10-20 g), the plasma half-life may increase beyond 20 hours. At high doses of ASA, the elimination of salicylic acid follows zero-order kinetics (i.e. the elimination rate is constant in relation at plasma concentration), with an apparent half-life of 6 hours or more. The renal excretion of the unchanged active substance is dependent on the urinary pH. When the urinary pH increases above 6.5, the renal clearance of free salicylate increases by 80%. After administration of therapeutic doses, approximately 10% is eliminated in the urine as salicylic acid, 75% as salicyluric acid, 10% as phenolic glucuronide and 5% as acyl glucuronide of salicylic acid. Based on the pharmacokinetic and metabolic characteristics of both compounds, clinically relevant pharmacokinetic interactions are unlikely to occur.
05.3 Preclinical safety data
Clopidogrel
In non-clinical studies in rats and baboons, modification of liver parameters was the most frequently observed effect. This occurred for doses at least 25 times higher than the corresponding clinical dose of 75 mg / day. administered to humans and resulted from an effect on hepatic metabolic enzymes. No effect of clopidogrel on hepatic metabolic enzymes was observed in humans at therapeutic doses.
At very high doses, poor gastric tolerability (gastritis, gastric erosions and / or vomiting) has been reported in the rat and baboon.
No carcinogenic effect was observed following administration of clopidogrel in mice for 78 weeks and in rats for 104 weeks up to a dose of 77 mg / kg / day (representing at least 25 times the exposure occurring at the clinical dose. of 75 mg / day in humans).Clopidogrel tested in a series of genotoxicity studies in vitro and in vivor, it did not show any genotoxic activity.
Clopidogrel did not show any effect on fertility in male and female rats and did not show any teratogenic effects in either the rat or the rabbit. When administered to lactating rats clopidogrel caused a slight delay in the development of the offspring. Specific pharmacokinetic studies conducted with labeled clopidogrel have shown that the main compound and its metabolites are excreted in milk. Consequently, a direct (mild toxicity) or indirect (poor palatability) effect cannot be excluded.
Acetylsalicylic acid
Single dose studies have shown that the oral toxicity of ASA is low. Repeated dose toxicity studies have shown that doses up to 200 mg / kg / day are well tolerated in the rat; the dog appears to be more sensitive, probably due to the high sensitivity of canines to the ulcerogenic effects of NSAIDs. No significant issues were highlighted on the genotoxicity or clastogenicity of ASA. Although formal carcinogenicity studies with ASA have not been conducted, it has not been shown to be a promoter of cancer.
Reproductive toxicity data showed that ASA is teratogenic in several laboratory animals.
In animals, administration of a prostaglandin synthesis inhibitor has been shown to increase pre- and post-implantation loss and embryo-fetal lethality. Furthermore, an increased incidence of various malformations, including cardiovascular ones, was also found in animals administered a prostaglandin synthesis inhibitor during the organogenetic period.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Nucleus
Mannitol (E421)
Macrogol 6000
Microcrystalline cellulose
Low-substitution hydroxypropylcellulose
Cornstarch
Hydrogenated castor oil
Stearic acid
Anhydrous colloidal silica
Coating
Lactose monohydrate
Hypromellose (E464)
Titanium dioxide (E171)
Triacetin (E1518)
Yellow iron oxide (E172)
Polishing agent
Carnauba wax
06.2 Incompatibility
Not relevant.
06.3 Period of validity
2 years
06.4 Special precautions for storage
Store below 25 ° C.
06.5 Nature of the immediate packaging and contents of the package
Aluminum blisters in cardboard carton containing 14, 28, 30 and 84 film-coated tablets.
Perforated aluminum single-dose blisters in cardboard box containing 30x1, 50x1, 90x1 and 100x1 film-coated tablet.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Sanofi Clir SNC
54, rue La Boétie
F-75008 Paris
France
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/10/619/001 - Carton of 14 film-coated tablets in aluminum blisters
EU / 1/10/619/002 - Carton of 28 film-coated tablets in aluminum blisters
EU / 1/10/619/003 - Carton of 30x1 film-coated tablets in aluminum blisters
EU / 1/10/619/004 - Carton of 50x1 film-coated tablets in aluminum blisters
EU / 1/10/619/005 - Carton of 84 film-coated tablets in aluminum blisters
EU / 1/10/619/006 - Carton of 90x1 film-coated tablets in aluminum blisters
EU / 1/10/619/007 - Carton of 100x1 film-coated tablets in aluminum blisters
EU / 1/10/619/015 - Carton of 30 film-coated tablets in aluminum blisters
039763014
039763026
039763038
039763040
039763053
039763065
039763077
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 15 March 2010
Date of the last renewal:
10.0 DATE OF REVISION OF THE TEXT
D.CCE November 2014
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