DuoPlavin

The European Medicines Agency noted that DuoPlavin is comparable to clopidogrel and acetylsalicylic acid tablets taken separately, and concluded that combining both active substances in a single tablet simplifies treatment for patients as they will need to take fewer tablets. The Agency therefore decided that DuoPlavin’s benefits are greater than its risks and it can be authorised for use in the EU.

DuoPlavin is available as a tablet and can only be obtained with a prescription.

DuoPlavin is taken once a day as one tablet containing 75 mg clopidogrel and either 75 mg or 100 mg acetylsalicylic acid and is taken in place of the clopidogrel and acetylsalicylic acid tablets that the patient has already been taking separately. The medicine can be taken for up to 12 months.

For more information about using DuoPlavin, see the package leaflet or contact your doctor or pharmacist.

Both active substances in DuoPlavin, clopidogrel and acetylsalicylic acid, are antiplatelet medicines. This means that they help to prevent blood cells called platelets from sticking together and forming clots, thus helping to prevent heart problems, such as heart attack.

Clopidogrel stops the platelets sticking together by blocking a substance called ADP from attaching to a receptor on their surface. This stops the platelets becoming ‘sticky’, reducing the risk of a blood clot forming. Acetylsalicylic acid stops the platelets sticking together by blocking an enzyme called prostaglandin cyclo-oxygenase. This reduces the production of a substance called thromboxane, which normally helps clots to form by attaching platelets together. The combination of the two active substances has an additive effect, reducing the risk of blood clots forming, more than either medicine alone.

Both active substances have been available in the EU for a number of years. Clopidogrel has been authorised since 1998 and is often used in combination with acetylsalicylic acid. Acetylsalicylic acid has been used for over 100 years.

Bleeding reactions are the most common side effects reported with DuoPlavin. The most common of these (which may affect up to 1 and 10 people) are haematoma (a collection of blood under the skin), epistaxis (nosebleeds), gastrointestinal haemorrhage (bleeding in the stomach or gut), bruising and bleeding where the skin is punctured.

Other side effects (which may affect up to 1 in 10 people) are diarrhoea, abdominal pain (stomach ache) and dyspepsia (heartburn).

For the full list of side effects of DuoPlavin, see the package leaflet.

DuoPlavin must not be used in people who are hypersensitive (allergic) to clopidogrel, non-steroidal anti-inflammatory drugs (such as acetylsalicylic acid) or any of the other ingredients in DuoPlavin. It must not be used in patients who have a disease that is causing bleeding, such as stomach ulcer or bleeding in the brain or in patients with mastocytosis (high blood levels of certain white blood cells called mast cells). It must not be used in patients who have severely reduced liver or kidney function, or who have a medical condition that includes a combination of asthma, rhinitis (stuffy and runny nose) and nasal polyps (growths in the lining of the nose). DuoPlavin must not be used during the last three months of pregnancy.

Recommendations and precautions to be followed by healthcare professionals and patients for the safe and effective use of DuoPlavin have been included in the summary of product characteristics and the package leaflet.

As for all medicines, data on the use of DuoPlavin are continuously monitored. Suspected side effects reported with DuoPlavin are carefully evaluated and any necessary action taken to protect patients.

DuoPlavin received a marketing authorisation valid throughout the EU on 14 March 2010.

Because the two active substances have been used together for a number of years, the company presented the results of studies showing that the active substances in DuoPlavin are absorbed in the body in the same way when taken in a single tablet as when taken separately.

DuoPlavin was shown to be comparable to clopidogrel and acetylsalicylic acid taken separately, and can therefore be used in place of the clopidogrel and acetylsalicylic acid tablets that the patients have already been taking.

In addition, the company presented the results from 3 previous studies in 61,000 patients with unstable angina or who had had a heart attack, which showed that the combination of clopidogrel and acetylsalicylic acid taken as separate tablets was more effective at preventing events such as heart attacks than acetylsalicylic acid alone.

A further study also showed that DuoPlavin was effective at reducing the occurrence of heart attack, stroke or death in patients undergoing percutaneous coronary intervention.

DuoPlavin is a medicine containing the active substances clopidogrel and acetylsalicylic acid in one tablet. It was to be available as tablets containing 75 mg clopidogrel plus 75 mg acetylsalicylic acid, and as tablets containing 75 mg clopidogrel plus 100 mg acetylsalicylic acid.

DuoPlavin was expected to be used in adult patients already taking clopidogrel and acetylsalicylic acid as separate tablets. It was expected to be used to prevent atherothrombotic events (problems caused by blood clots and hardening of the arteries) in patients who have a condition known as 'acute coronary syndrome'. This included patients who were having an acute myocardial infarction (heart attack) with an 'ST segment elevation' (an abnormal reading on the electrocardiogram or ECG) when the doctor thought that they would have benefited from the treatment. It was also expected to be used in patients who did not have this abnormal reading on the ECG, if they had unstable angina (a severe type of chest pain) or a 'non-Q-wave' myocardial infarction and who had a stent inserted (a short tube placed in an artery to prevent it closing up).

The active substances in DuoPlavin, clopidogrel and acetylsalicylic acid, are combined into one tablet in DuoPlavin to reduce the number of tablets the patients need to take every day. It was hoped that this would make it easier for patients to stick to their treatment.

Acetylsalicylic acid is a well-known medicine, commonly known as aspirin, that has been used for a long time as a blood-thinning agent.

Clopidogrel is an inhibitor of platelet aggregation. This means that it helps to prevent blood clots from forming. When the blood clots, this is due to special cells in the blood, the platelets, sticking together (aggregating). Clopidogrel stops the platelets aggregating by blocking a substance called ADP from binding to a special receptor on their surface. This stops the platelets becoming 'sticky', reducing the risk of a blood clot forming and helping to prevent another heart attack or stroke.

Clopidogrel on its own has been approved by the EU under the names Iscover and Plavix, for prevention of atherothrombotic events, in combination with acetylsalicylic acid, in patients with acute coronary syndrome. To support the application for DuoPlavin the company carried out 'bioequivalence' studies to establish whether the combined tablet was absorbed in the body in the same way as the two medicines given separately.

Furthermore, the studies of Iscover and Plavix used with acetylsalicylic acid as separate tablets were used to support the use of DuoPlavin in the same indication.

The application was at day 206 when the company withdrew.

After the CHMP had assessed the responses from the company to a list of questions, there were still some unresolved issues outstanding.

The CHMP normally takes up to 210 days to evaluate a new application. Based on the review of the initial documentation, the CHMP prepares a list of questions at day 120, which is sent to the company. Once the company has supplied responses to the questions, the CHMP reviews them and may, before giving an opinion, ask any remaining questions at day 180. Following the CHMP's opinion, it usually takes around two months for the European Commission to grant a licence.

Based on the review of the data and the company's responses to the CHMP list of questions at the time of the withdrawal, the CHMP had some concerns. However the CHMP thought that the company could have addressed these concerns and was of the provisional opinion that DuoPlavin could have been approved for the prevention of atherothrombotic events.

The CHMP was concerned that the bioequivalence studies that were carried out did not use the recommended methods and did not provide sufficient evidence that the combined tablet was absorbed in the body in the same way as the two medicines given separately. Therefore, at the time of the withdrawal, the CHMP's view was that the company had not fully addressed their concerns and the benefit of DuoPlavin combined tablet compared with the separate medicines had not been sufficiently demonstrated.

The letter from the company notifying the EMEA of the withdrawal of the application is available under the tab 'All documents'.

The company informed the CHMP that there are no consequences for patients who are planned to be included in clinical trials with DuoPlavin or patients currently included in clinical trials with clopidogrel and acetylsalicylic acid as separate medicines. If you are in a clinical trial or compassionate use programme and need more information about your treatment, contact the doctor who is giving it to you.

There are no consequences on the use of Iscover/Plavix with acetylsalicylic acid in the authorised indications, for which the balance of benefits and risks remains unchanged.