Elements for a public summary. VI.2.1 Overview of disease epidemiology

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1 VI.2 Elements for a public summary VI.2.1 Overview of disease epidemiology Coronary artery disease and as anticoagulant (inhibiting the clotting of the blood) in patients undergoing surgery to treat blockages in the heart blood vessels: Coronary artery disease happens when the arteries that supply blood to heart muscle (named as coronary artery) become hardened and narrowed due to the build-up of cholesterol and other material known as plaque. As a result, the heart muscle can't get the blood or oxygen it needs. This can lead to chest pain (angina) or a heart attack (myocardial infarction). Most heart attacks happen when a blood clot suddenly cuts off the hearts' blood supply, causing permanent heart damage. Coronary artery disease is responsible for the deaths of approximately one in five men and one in six women. Up to 50% of people who have heart attack die within 30 days of the event, and over half of these deaths occur before medical assistance arrives or the patient reaches hospital. A heart surgery called as Percutaneous coronary intervention (also known as angioplasty) is performed to open blocked coronary arteries. Bivalirudin is a specific and direct inhibitor of thrombin (enzyme in blood) which is used along with other medications aspirin and clopidogrel (the medicines that stop blood cells from sticking together and forming a blood clot) in the patients undergoing such intervention. VI.2.2 Summary of treatment benefits Bivalirudin Accord used to prevent blood clots in adults who are undergoing percutaneous coronary intervention (PCI), a non-surgical procedure used to unblock the heart s blood vessels. In PCI, Bivalirudin has been compared with another type of anticoagulant, a heparin, in two studies involving a total of almost 10,000 adults. Heparin was given in combination with a glycoprotein IIb/IIIa inhibitor (GPI, another type of medicine that helps to prevent blood clots) and some patients receiving Bivalirudin were also given a GPI where appropriate. Almost 4,000 of the patients were having PCI to treat myocardial infarction with ST segment elevation. In patients with unstable angina or myocardial infarction without ST segment elevation waiting for further treatment, the main study involved almost 14,000 adults and compared Bivalirudin taken alone or with a GPI, with the combination of heparin and a GPI.

2 In all three studies, the patients also received other medicines to prevent blood clots, such as aspirin and clopidogrel. In all the studies of patients undergoing PCI, Bivalirudin (alone or with a GPI where appropriate) was as effective as heparin in combination with a GPI at preventing new ischaemic events. When used to treat unstable angina or myocardial infarction without ST segment elevation, Bivalirudin, given with or without a GPI, was as effective as the combination of heparin and a GPI in preventing deaths, heart attacks and revascularisations. It was most effective in patients who also took aspirin and clopidogrel. Major bleeding was less common with Bivalirudin alone than with heparin plus GPI. VI.2.3 Unknowns relating to treatment benefits Safety and the ability to produce the desired result of Bivalirudin in pregnancy and lactation have not been established. There is no relevant indication for use of Bivalirudin in children less than 18 years old in all indications and the safety and efficacy of bivalirudin have not been specifically studied in patients with hepatic impairment. VI.2.4 Summary of safety concerns Important identified risks: Medication error Activated clotting time (ACT) (a Doctor need to properly (including reports blood test) may be used as an monitor this test and adjust the describing patients indication that a patient has dose accordingly. receiving bivalirudin received bivalirudin. Where Administration should be as per bolus without insufficient ACT increase is the product label. subsequent infusion) observed, the possibility of

3 medication error should be considered, for example inadequate mixing of Bivalirudin or intravenous (infusion directly into vein) equipment failures. Administration errors may lead to death from thrombosis (formation of a blood clot in blood vessel). Serious bleeding Like all medicines, this medicine Do not use Bivalirudin Accord events can cause side effects: if you have, or have recently The common, (may affect up to 1 in 10 people) serious side effect of treatment with Bivalirudin Accord, is major bleeding which could occur anywhere inside the body (e.g. stomach, digestive system (including vomiting blood or passing blood with the stools), abdomen, lungs, groin, bladder, heart, eye, ear, nose or brain). This may, rarely, result in a stroke or be fatal. Swelling or pain in the groin or the arm, back pain, bruising, headache, coughing blood, pink or red urine, sweating, feeling faint or sick or dizzy due to low blood had, any bleeding from your stomach, intestines, bladder or other organs, for example, if you have noticed abnormal blood in your stools or urine (except from menstrual bleeding). Tell your doctor or pharmacist if you are taking blood thinners or medicines to prevent blood clots (anticoagulants or antithrombotics e.g. warfarin, dabigatran, apixaban, rivaroxaban, acetylsalicylic acid, clopidogrel, prasugrel, ticagrelor) pressure may be signs of internal

4 bleeding. Bleeding is more likely to occur when Bivalirudin is used in combination with other anticoagulant or antithrombotic (drugs that reduces the formation of blood clots) medicines. Serious hypersensitivity reactions (allergic reactions) Hypersensitivity, including anaphylactic reaction and shock (serious, potentially lifethreatening allergic reaction to a substance), including reports with fatal outcome is uncommon side effect which affects more than one patient in 1000 to less than one in 100. The patient who are having known hypersensitivity to the active substance or to any of the excipients, or to hirudins should not take bivalirudin. Necessary preparations should be made to deal with this. Patients should be informed of the early signs of hypersensitivity reactions (over sensitivity) including generalised urticaria (hives), tightness of chest, wheezing (whistling sound while breathing), hypotension (low blood pressure) and anaphylaxis (serious, potentially lifethreatening allergic reaction to a substance). In the case of shock (a life-threatening condition

5 that occurs when the body is not getting enough blood flow which can lead to organ damage) and the current medical standards for shock treatment should be applied. Blood clot within a stent in patients with STEMI {heart attack (= ST-segment elevation myocardial infarction) undergoing primary PCI (= percutaneous coronary intervention (Acute stent thrombosis) Like all medicines, this medicine can cause side effects: Patients may rarely experience (which affects more than one patient in 10,000 to less than one in 1,000) blood clot in the heart arteries or within a stent being felt as a heart attack which can also be fatal Please tell your doctor immediately if you experience these events. Warfarin blood test result (INR) increase following coadministration of warfarin and Bivalirudin Like all medicines, this medicine can cause side effects: Rare side effects (may affect up to 1 in 1,000 people): INR test (warfarin blood test result) increased. Tell your doctor or pharmacist if you are taking blood thinners or medicines to prevent blood clots (anticoagulants or antithrombotics e.g. warfarin,). These medicines may increase the risk of side effects such as bleeding when given at the same time as Bivalirudin.

6 Your warfarin blood test result (INR test) may be affected by Bivalirudin. Heart disorders (cardiac disorders) Angina or chest pain, Slow heartbeat, Rapid heartbeat rare side effects which affects up to 1 patient in 1000 patients. Do not use Bivalirudin Accord if they have an infection of the heart tissue. After being treated with Bivalirudin Accord for a cardiac (heart) event, you should stay in the hospital for at least 24 hours and the you should be monitored for any symptoms or signs similar to the ones that remind the your cardiac (heart) event and resulted in the your hospitalization. Increased pressure within one of the body's compartments which contains muscles and nerves (Compartment Syndrome) Compartment syndrome is very rare side effects which affects less than 1 patient in 10,000. Compartment syndrome (increased pressure within one of the body's compartments which contains muscles) has been reported as a complication of forearm haematoma (Pocket of blood Please tell your doctor immediately if you experience these events

7 caused by bleeding from a broken blood vessel) following administration of bivalirudin. Important potential risks Risk Use in patients with severe renal (kidney) impairment What is known Do not use Bivalirudin Accord: If you have severe kidney problems or if you need kidney dialysis. If you have kidney problems, the dose of Bivalirudin Accord may need to be reduced. In older people, if their kidney function is decreased, the dose may need to be reduced. The doctor will decide for how long you should be treated. A condition caused by bleeding or a lack of blood in the brain. (Stroke) The common, (may affect up to 1 in 10 people) serious side effect of treatment with Bivalirudin Accord, is major bleeding which could occur anywhere inside the body (e.g. stomach, digestive system (including vomiting blood or passing blood with the stools), abdomen, lungs, groin, bladder, heart, eye, ear, nose or brain). This may, rarely, result in a stroke (a condition caused by bleeding or a lack of blood in the brain) or be fatal.

8 Missing information: Risk Bivalirudin exposure in pregnant or lactating (breast feeding) patients What is known Bivalirudin Accord should not be used during pregnancy, unless clearly necessary. Your doctor will decide whether or not this treatment is appropriate for you. If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. If you are breast-feeding, the doctor will decide whether Bivalirudin Accord should be used. Use of bivalirudin in paediatric patients Use in patients with hepatic (liver) impairment There is no relevant indication for use of Bivalirudin Accord in children less than 18 years old in all indications Pharmacokinetic studies (the studies of how a drug enters and leaves the blood and tissues over time) indicate that hepatic (liver) metabolism of bivalirudin is limited; therefore the safety and efficacy of bivalirudin have not been specifically studied in patients with hepatic (liver) impairment. VI.2.5 Summary of additional risk minimisation measures by safety concern All medicines have a Summary of Product Characteristics (SmPC) which provides physicians, pharmacists and other health care professionals with details on how to use the medicine, the risks and recommendations for minimising them. An abbreviated version of this in lay language is provided in the form of the package leaflet (PL). The measures in these documents are known as routine risk minimisation measures. This medicine has a special conditions and restrictions for its safe and effective use. Hence additional risk minimisation measures would be implemented for the risk of medication errors. How this additional risk minimisation measure would be implemented in each country

9 will depend upon agreement between the manufacturer and the national authorities. Educational material to healthcare professional for the risk of occurrence of medication error including reports describing patients receiving bivalirudin bolus without subsequent infusion and the appropriate management of this risk to minimise its occurrence and its severity is proposed as below- Medication error (including reports describing patients receiving bivalirudin bolus without subsequent infusion Education Material including DHCP (Dear HealthCare Professional) letter Objective and rationale: HCPs to understand the risk of occurrence of medication error including reports describing patients receiving bivalirudin bolus without subsequent infusion and the appropriate management of this risk to minimise its occurrence and its severity. Proposed actions: HCP educational materials to be provided to prescribing physicians and pharmacists including advice on: - for the correct administration of the drug - for dosing in renal (kidney) impairment - for correct reconstitution of the lyophilised drug - for Intravenous (IV) line incompatibilities e.g. Diazepam, Alteplase - on drug stability e.g. as lyophilised powder, as reconstituted and diluted solution This communication through DHPC letter would be done prior to launch. VI.2.6 Planned post authorisation development plan No studies planned.

10 VI.2.7 Summary of changes to the risk management plan over time Version Date Safety Concern Comment December 2015 No change in safety concerns RMP has been updated as per APHV comments on pharmacovigilance system Aug Safety concerns are aligned with the most recent version of the originator s RMP Angiox as per the following safety concerns : Below mentioned safety concerns have been included Important identified risks: Serious hypersensitivity reactions Cardiac Disorders Compartment Syndrome Important potential risks: Additional Risk minimisation measures have been proposed for safety concern Medication error (including reports describing patients receiving bivalirudin bolus without subsequent infusion. RMP has been updated as per RMS Day 70 and Day 100 comments. Use in patients with severe

11 Version Date Safety Concern Comment renal impairment Stroke Missing information Use of bivalirudin in paediatric patients Use in patients with hepatic impairment Below mentioned safety concerns have been deleted Important potential risks: Thrombocytopenia with Bivalirudin given concomitantly with GPI Below mentioned safety concerns have been updated Important identified risk Medication error have been updated as Medication error (including reports describing patients receiving bivalirudin bolus without subsequent infusion