Active ingredients: Ticagrerol
Brilique 90 mg film-coated tablets
Why is Brilique used? What is it for?
What is Brilique
Brilique contains the active substance called ticagrelor, which belongs to a group of medicines called antiplatelet agents.
How Brilique works
Brilique works on cells called "platelets" (also called thrombocytes). These very small blood cells help stop bleeding by clumping together to close the tiny holes in severed or damaged blood vessels.
However, platelets can also form clots in the diseased blood vessels of the heart and brain. This can be very dangerous because:
- the clot can completely cut off the blood supply - this can cause a heart attack (myocardial infarction) or stroke, or
- the clot can partially block the blood vessels that supply the heart - this reduces blood flow to the heart and can cause chest pain that comes and goes (called "unstable angina"). Brilique helps to block the clumping of platelets. This reduces the possibility of a blood clot forming which can reduce blood flow.
What is Brilique for
Brilique in combination with acetylsalicylic acid (another antiplatelet agent) should only be used in adult patients.
She was prescribed Brilique because she had:
- a heart attack, or
- unstable angina (angina or chest pain that is not well controlled).
Brilique reduces the chances of you having another heart attack or stroke or of dying from heart or blood vessel related disease.
Contraindications When Brilique should not be used
Do not take Brilique if:
- You are allergic to ticagrelor or any of the other ingredients of Brilique
- He has ongoing bleeding
- He had a stroke caused by bleeding in the brain.
- You have moderate to severe liver problems.
- You are taking one of the following medicines: ketoconazole (used to treat fungal infections), clarithromycin (used to treat bacterial infections), nefazodone (an antidepressant), ritonavir and atazanavir (used to treat HIV infection and AIDS) ).
Do not take Brilique if any of the above applies to you. If you are not sure, talk to your doctor or pharmacist before taking Brilique
Precautions for use What you need to know before taking Brilique
Before taking Brilique, check with your doctor, pharmacist or dentist if:
- You have an increased risk of bleeding due to:
- a recent serious injury
- recent surgery (including dental surgery)
- a disease affecting blood clotting - recent bleeding from the stomach or intestines (eg due to stomach ulcer or colon "polyps")
- You plan to have surgery (including dental work) at any time while you are taking Brilique. This is because there is an increased risk of bleeding. Your doctor may tell you to stop taking Brilique 7 days before surgery.
- Your heart rate is unusually low (typically less than 60 beats per minute) and you have not already implanted an instrument that regulates the rhythm of the heart (pacemaker).
- You have asthma or another lung problem or breathing difficulty.
- He's already had blood tests that showed more uric acid than normal. If any of the above apply to you (or if you are not sure), talk to your doctor, pharmacist or dentist before taking Brilique.
Children and adolescents
Brilique is not recommended for children and adolescents under the age of 18.
Interactions What medications or foods can change the effect of Brilique
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This is because Brilique can affect the way some medicines work, and some medicines can have an effect on Brilique.
Tell your doctor or pharmacist if you are taking any of the following medicines:
- more than 40 mg per day of simvastatin or lovastatin (drugs used to treat high cholesterol)
- rifampicin (an antibiotic), phenytoin, carbamazepine and phenobarbital (used to control seizures), digoxin (used to treat heart failure), cyclosporine (used to lower the body's defenses), quinidine and diltiazem (used to treat heart failure) abnormal heart rhythm), beta blockers and verapamil (used to treat high blood pressure).
In particular, tell your doctor or pharmacist if you are taking any of the following medicines that increase the risk of bleeding:
- "oral anticoagulants" often referred to as "blood thinners", which include warfarin.
- non-steroidal anti-inflammatory drugs (abbreviated as NSAIDs), often used as pain relievers, such as ibuprofen and naproxen.
- selective serotonin reuptake inhibitors (abbreviated as SSRIs) taken as antidepressants, such as paroxetine, sertraline and citalopram.
- other medicines such as ketoconazole (used to treat fungal infections), clarithromycin (used to treat bacterial infections), nefazodone (an antidepressant), ritonavir and atazanavir (used to treat HIV infection and AIDS), cisapride (used for treat heartburn) or ergot alkaloids (used to treat migraines and headaches).
Also, tell your doctor that because you are taking Brilique you may have an increased risk of bleeding if your doctor prescribes fibrinolytics, often called 'thrombolytics', such as streptokinase or alteplase.
Warnings It is important to know that:
Pregnancy and breastfeeding
The use of Brilique is not recommended if you are pregnant or suspect a pregnancy. Women should use appropriate contraceptive methods to avoid becoming pregnant while taking this medicine. Talk to your doctor before taking Brilique if you are breast-feeding. Your doctor will discuss the benefits and risks of Brilique treatment with you during this time.
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.
Driving and using machines
Brilique is unlikely to affect your ability to drive or use machines. If you feel dizzy while taking Brilique, be careful while driving or using machines
Dose, Method and Time of Administration How to use Brilique: Posology
Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
How much Brilique to take
- The starting dose is two tablets at once (180 mg loading dose). This dose will normally be given to you in the hospital.
- After this starting dose, the usual dose is one 90 mg tablet twice a day for up to 12 months, unless your doctor tells you otherwise. Take Brilique at about the same time each day (for example, one tablet in the morning and one in the evening).
Your doctor will usually tell you to take acetylsalicylic acid as well. This is a substance found in many medicines used to prevent blood clotting. Your doctor will tell you how much to take (usually between 75 and 150 mg per day).
How to take Brilique
- You can take the tablet with or without meals.
- you can check when you have taken your last Brilique tablet by looking on the blister. There is a sun (for the morning) and a moon (for the evening). This will tell you if you have taken the dose.
If you have difficulty swallowing the tablet (s)
If you have difficulty swallowing the tablet (s) you can crush it and mix it with water as follows:
- Crush the tablet (s) into a fine powder
- Pour the powder into half a glass of water
- Stir and drink immediately
- To make sure you have not left any medicine, rinse the empty glass with half a glass of water and drink.
Overdose What to do if you have taken too much Brilique
If you take more Brilique than you should
If you have taken more Brilique than you should, contact your doctor or go to the hospital straight away. Take the medicine pack with you. You may be at increased risk of bleeding.
If you forget to take Brilique
- If you forget to take a dose, just take the next dose as usual.
- Do not take a double dose (two doses at the same time) to make up for a forgotten dose.
If you stop taking Brilique
Do not stop taking Brilique without first talking to your doctor. Take Brilique regularly and for as long as your doctor prescribes it for you.
If you stop taking Brilique, this may increase the chances of you having another heart attack or stroke, or of dying from a disease related to heart or blood vessel problems.
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 Brilique
Like all medicines, this medicine can cause side effects, although not everybody gets them.
The following side effects may occur with this medicine:
See a doctor immediately if you notice any of the following symptoms - you may need urgent medical attention:
- Bleeding in the brain or inside the skull is an uncommon side effect and can cause signs of a stroke, such as:
- sudden numbness or weakness in the arms, legs or face, especially if only on one side of the body
- sudden confusion, difficulty speaking or understanding others
- sudden difficulty walking or loss of balance or coordination - sudden dizziness or sudden intense headache with no known cause
- Bleeding - some bleeding is common. However, severe bleeding is not a common occurrence, but it can be life-threatening. Several types of bleeding can be increased, such as:
- bleeding that is severe or cannot be controlled
- unexpected bleeding or bleeding that lasts a long time
- presence of blood in the urine
- production of black stools or red blood in the stool
- visual disturbances caused by the presence of blood in the eyes
- release of blood clots through coughing or vomiting
- bleeding inside the joints resulting in swelling and pain
Contact your doctor if you notice any of the following symptoms:
- Feeling short of breath - this occurrence is common. It may be due to your heart disease or some other cause, or it could be a side effect of Brilique. If your wheezing gets worse or lasts over time, tell your doctor. Your doctor will decide if you need treatment or proceed with further investigations.
Other possible side effects
Common (may affect up to 1 in 10 people)
- Bruising
- Nose bleeding
- More abundant bleeding from surgery, cuts or wounds
Uncommon (may affect up to 1 in 100 people)
- Allergic reaction - rash, itching, or swelling of the face or lips / tongue may be signs of an allergic reaction
- Headache
- Feeling dizzy or as if the room is spinning
- Abdominal pain
- Diarrhea or indigestion
- Feeling or being unwell
- Rash
- Itching
- Inflammation of the stomach (gastritis)
- Vaginal bleeding that is more intense or occurs at times other than normal period (menstrual) bleeding
- Bleeding from the stomach walls (ulcer)
- Bleeding from the gums
Rare (may affect up to 1 in 1,000 people)
- Constipation
- Tingling sensation
- confusion
- Blood in the ears
- Internal bleeding
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
Do not use this medicine after the expiry date which is stated on the blister and carton after the abbreviation EXP / EXP. The expiry date refers to the last day of that month. 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.
Contents of the pack and other information
What Brilique contains
- The active ingredient is ticagrelor. Each film-coated tablet contains 90 mg of ticagrelor.
- The other ingredients are:
Core of the tablet: mannitol (E421), calcium hydrogen phosphate dihydrate, sodium starch glycolate, hydroxypropylcellulose (E463), magnesium stearate (E470b)
Tablet coating: hypromellose (E464), titanium dioxide (E171), talc, polyethylene glycol 400 and yellow iron oxide (E172).
Description of what Brilique looks like and contents of the pack
Film-coated tablet (tablet): The tablets are round, biconvex, yellow, film-coated, debossed with "90" over a "T" on one side.
Brilique is available in:
- standard blister (with sun / moon symbols) in cartons of 60 and 180 tablets
- calendar blister (with sun / moon symbols) in cartons of 14, 56 and 168 tablets
- single-dose perforated blisters in a carton of 100x1 tablets.
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
BRILIQUE 90 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 90 mg of ticagrelor.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet (tablet).
Round, biconvex, yellow tablets debossed with "90" over a "T" on one side, and plain on the other side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Brilique, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with acute coronary syndrome (unstable angina, non-ST segment elevation myocardial infarction [NSTEMI] or ST segment elevation myocardial infarction [STEMI]), including pharmacologically treated patients and those undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG).
For further information, please refer to paragraph 5.1.
04.2 Posology and method of administration
Dosage
Treatment with Brilique should be started with a single 180 mg loading dose (two 90 mg tablets) and then continued with 90 mg twice daily.
Patients being treated with Brilique should also take ASA daily, unless specifically contraindicated. Following an initial dose of ASA, Brilique should be taken with a maintenance dose of ASA between 75 and 150 mg (see section 5.1).
Treatment is recommended for up to 12 months unless discontinuation of Brilique therapy is clinically indicated (see section 5.1). Experience beyond 12 months is limited.
In patients with acute coronary syndrome (ACS), premature discontinuation of any antiplatelet therapy, including that with Brilique, could result in an increased risk of cardiovascular death or myocardial infarction due to the patient's underlying disease. Therefore premature discontinuation of treatment should be avoided.
Interruptions in continuity of treatment should also be avoided. The patient who misses a dose of Brilique should only take one 90 mg tablet (the next dose) at the scheduled time.
If necessary, patients treated with clopidogrel can be switched directly to Brilique (see section 5.1). Switching from prasugrel to Brilique has not been studied.
Special populations
Senior citizens
No dose adjustment is required in elderly patients (see section 5.2).
Patients with impaired renal function
No dose adjustment is required in patients with impaired renal function (see section 5.2). No information is available regarding the treatment of patients on dialysis and therefore Briliquen is not recommended in these patients.
Patients with impaired hepatic function
Brilique has not been studied in patients with moderate or severe hepatic impairment. Therefore, in patients with moderate to severe hepatic impairment, its use is contraindicated (see sections 4.3, 4.4 and 5.2). No dose adjustment is required in patients with mildly impaired hepatic function.
Pediatric population
The safety and efficacy of Brilique in children below the age of 18 for the approved indications in adults have not been established. No data are available.
Method of administration
For oral use.
Brilique can be given with meals or between meals.
For patients who are unable to swallow the tablet (s) whole, Brilique tablets can be crushed into a fine powder, mixed in half a glass of water and drunk immediately. The glass should be rinsed with an additional half glass. d "water and the content drunk. The mixture can also be administered through a nasogastric tube (CH8 or larger). After administration of the mixture it is important to irrigate the nasogastric tube with water.
04.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see section 4.8).
• Pathological bleeding in progress.
• History of intracranial haemorrhage (see section 4.8).
• Moderate to severe hepatic impairment (see sections 4.2, 4.4 and 5.2).
• Co-administration of ticagrelor with strong CYP3A4 inhibitors (eg, ketoconazole, clarithromycin, nefazodone, ritonavir and atazanavir) is contraindicated as co-administration may lead to a substantial increase in ticagrelor exposure (see section 4.5). .
04.4 Special warnings and appropriate precautions for use
Risk of bleeding
In the pivotal phase 3 clinical trial (PLATO [PLATelet Inhibition and Patient Outcomes], 18,624 patients), the main exclusion criteria included an increased risk of bleeding, clinically relevant thrombocytopenia or anemia, prior intracranial bleeding, gastrointestinal bleeding within the previous 6 months or major surgery within the previous 30 days. Acute coronary syndrome patients treated with Brilique and ASA showed an increased risk of non-CABG-related major bleeding and more generally of bleeding that required medical supervision i.e. Major + Minor bleeds according to PLATO criteria, but not Fatal bleeds or those that were life-threatening (see section 4.8).
Therefore, the use of Brilique in patients with known increased risk of bleeding should be balanced against the benefit in terms of prevention of atherothrombotic events. If clinically indicated, Brilique should be used with caution in the following patient groups:
• Patients with a predisposition to bleeding (eg due to recent trauma, recent surgery, bleeding disorders, active or recent gastrointestinal bleeding). The use of Brilique is contraindicated in patients with active pathological bleeding, in those with a history of intracranial haemorrhage and in patients with moderate to severe hepatic impairment (see section 4.3).
• Patients with concomitant administration of medicinal products that may increase the risk of bleeding (eg non-steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants and / or fibrinolytics) within 24 hours of the dose of Brilique.
There are no data with ticagrelor regarding a hemostatic benefit of platelet transfusions; the circulating amount of ticagrelor can inhibit transfused platelets. Since co-administration of ticagrelor and desmopressin did not decrease standard bleeding time, it is unlikely that desmopressin will be effective in the clinical treatment of bleeding events (see section 4.5).
Antifibrinolytic therapy (aminocaproic acid or tranexamic acid) and / or recombinant factor VIIa may increase haemostasis. Ticagrelor can be resumed once the cause of the bleeding has been identified and controlled.
Surgical interventions
Patients should be advised to inform doctors and dentists that they are taking Brilique before scheduling any surgery and before taking any new medicine.
Among the PLATO patients undergoing coronary artery bypass grafting (CABG) surgery, the Brilique arm had more bleeding than clopidogrel when therapy was stopped within 1 day before surgery, but a similar rate of major bleeding compared to clopidogrel when therapy was stopped 2 or more days before surgery (see section 4.8). If a patient is about to undergo elective surgery and an antiplatelet effect is not desired, Brilique should be discontinued 7 days prior to surgery (see section 5.1).
Patients at risk for bradycardia events
Following observations of mostly asymptomatic ventricular pauses in a previous clinical study, patients with increased risk of bradycardia events (e.g., patients without a pacemaker with sick sinus syndrome, 2nd or 3rd degree AV block or bradycardia-related syncope) were excluded from the pivotal PLATO study evaluating the safety and efficacy of ticagrelor. Therefore, given the limited clinical experience, ticagrelor should be used with caution in these patients (see section 5.1).
In addition, caution should be used when administering ticagrelor concomitantly with medicinal products known to induce bradycardia. However, no clinically relevant evidence of adverse reactions was observed in the PLATO study following concomitant administration with one or more medicinal products known to induce bradycardia (e.g. 96% beta blockers, 33% calcium channel blockers diltiazem and verapamil, and 4% digoxin ) (see section 4.5).
During the PLATO Holter monitoring substudy, more patients experienced ventricular pauses ≥3 seconds with ticagrelor than with clopidogrel during the acute phase of ACS. The increase in ventricular pauses observed on Holter with ticagrelor was greater in patients with chronic heart failure (CHF) than in the total study population during the acute phase of ACS, but not after one month on ticagrelor or in comparison with clopidogrel. There were no adverse clinical consequences associated with this imbalance (including syncope or pacemaker application) in this patient population (see section 5.1).
Dyspnea
Episodes of dyspnoea were reported by 13.8% of patients treated with Brilique and 7.8% of patients treated with clopidogrel. In 2.2% of patients, the investigators considered dyspnea to be causally related to treatment with Brilique. Dyspnoea is usually mild to moderate in intensity and often resolves without requiring treatment interruption. Patients with asthma / COPD may have an absolute increased risk of developing dyspnoea with Brilique (see section 4.8). Ticagrelor should be used with caution in patients with a history of asthma and / or COPD. The mechanism has not been elucidated. If a patient develops new, prolonged or aggravated dyspnoea, this should be thoroughly investigated and, if not tolerated, treatment with Brilique should be interrupted.
Elevation of creatinine
Creatinine levels may increase during treatment with ticagrelor (see section 4.8). The mechanism has not been clarified. Renal function should be monitored after one month and thereafter according to standard clinical practice, with particular attention to patients ≥ 75 years, to patients with moderate / severe renal impairment and to those receiving concomitant treatment with angiotensin II antagonists.
Increased uric acid
In the PLATO study, patients taking ticagrelor had a higher risk of hyperuricaemia than those receiving clopidogrel (see section 4.8). Caution should be used when ticagrelor is administered to patients with a history of hyperuricaemia or gouty arthritis. As a precautionary measure, the use of ticagrelor in patients with uric acid nephropathy is not recommended.
Other
Based on the relationship observed in the PLATO study between maintenance dose of ASA and relative efficacy of ticagrelor compared to clopidogrel, co-administration of ticagrelor and high maintenance doses of ASA (> 300 mg) is not recommended (see section 5.1 ).
04.5 Interactions with other medicinal products and other forms of interaction
Ticagrelor is primarily a substrate of CYP3A4 and a mild inhibitor of CYP3A4. Ticagrelor is also a substrate of P-glycoprotein (P-gp) and a weak inhibitor of P-gp and may increase exposure to P-gp substrates.
Effects of other medicinal products on Brilique
Medicinal products metabolised by CYP3A4
CYP3A4 inhibitors
• Strong CYP3A4 inhibitors - Co-administration of ketoconazole and ticagrelor increased ticagrelor Cmax and AUC by 2.4 and 7.3-fold, respectively. Cmax and AUC of the active metabolite were reduced by 89% and 56%, respectively. Other strong inhibitors of CYP3A4 (clarithromycin, nefazodone, ritonavir and atazanavir) may produce similar effects and therefore concomitant use of strong CYP3A4 inhibitors with Brilique is contraindicated (see sections 4.3).
• Moderate CYP3A4 inhibitors - Co-administration of diltiazem and ticagrelor increased the Cmax of ticagrelor by 69% and AUC by 2.7-fold and decreased the Cmax of the active metabolite by 38%, while the AUC was unchanged. . There is no effect of ticagrelor on the plasma levels of diltiazem. Other moderate CYP3A4 inhibitors (e.g. amprenavir, aprepitant, erythromycin and fluconazole) can produce a similar effect and can be administered together with Brilique.
CYP3A inducers
Co-administration of rifampicin and ticagrelor decreased the Cmax and AUC of ticagrelor by 73% and 86%, respectively. The Cmax of the active metabolite was unchanged and the AUC was reduced by 46%, respectively. Other CYP3A inducers (eg phenytoin, carbamazepine and phenobarbital) may reduce ticagrelor exposure. Co-administration of ticagrelor with potent CYP3A inducers may decrease ticagrelor exposure and efficacy therefore their concomitant use with Brilique it is not recommended.
Ciclosporin (inhibitor of P-gp and CYP3A)
Co-administration of cyclosporine (600 mg) and ticagrelor increased the Cmax and AUC of ticagrelor by 2.3-fold and 2.8-fold, respectively. The AUC of the active metabolite increased by 32% and the Cmax decreased. 15% in the presence of cyclosporine.
There are no data on the concomitant use of ticagrelor with other active substances which are also potent inhibitors of P-glycoprotein (P-gp) and moderate inhibitors of CYP3A4 (eg verapamil, quinidine) which also may cause increased exposure to ticagrelor. If this association cannot be avoided, their concomitant use should be made with caution.
Others
Clinical drug interaction studies have shown that co-administration of ticagrelor with heparin, enoxaparin and ASA or desmopressin had no effect on the pharmacokinetic profile of ticagrelor or the active metabolite or on ADP-induced platelet aggregation compared to ticagrelor alone. Clinically indicated, medicinal products that alter haemostasis should be used with caution in combination with ticagrelor.
A two-fold increase in exposure to ticagrelor has been observed after the daily consumption of large quantities of grapefruit juice (3 x 200 ml) per day. This magnitude of the increase in exposure is not thought to be clinically relevant in most patients. patients.
Effects of Brilique on other medicinal products
Medicinal products metabolised by CYP3A4
• Simvastatin - Co-administration of ticagrelor and simvastatin increased simvastatin Cmax by 81% and AUC by 56%, and resulted in an increase in simvastatin-acid Cmax by 64% and AUC by 52%, with some individual increments greater than 2 to 3 times. Co-administration of ticagrelor and simvastatin doses greater than 40 mg daily may cause adverse effects due to simvastatin, and should be weighed against the potential benefits. There were no effects of simvastatin on the plasma levels of ticagrelor. Ticagrelor may induce similar effects on lovastatin. Concomitant use of ticagrelor with doses of simvastatin or lovastatin greater than 40 mg is not recommended.
• Atorvastatin - Co-administration of atorvastatin and ticagrelor increased the Cmax of atorvastatin-acid by 23% and the AUC by 36%. Similar increases in AUC and Cmax were observed for all metabolites of atorvastatin acid. These increases are not considered clinically significant.
• A similar effect on other statins metabolised by CYP3A4 cannot be excluded. The PLATO patients who received ticagrelor were taking a variety of statins, with no problem of an association with statin safety in 93% of the PLATO cohort of patients taking these medicines.
Ticagrelor is a mild inhibitor of CYP3A4. Co-administration of ticagrelor and CYP3A4 substrates with low therapeutic indices (ie cisapride or ergot alkaloids) is not recommended, as ticagrelor may increase exposure to these medicinal products.
P-glycoprotein (P-gp) substrates (including digoxin, cyclosporine)
Co-administration of Brilique increased digoxin Cmax by 75% and "AUC by 28%. The mean" downstream "digoxin levels were increased by approximately 30% with co-administration of ticagrelor, with 2-fold maximum individual increases In the presence of digoxin, the Cmax and AUC of ticagrelor and its active metabolite were not affected.
Therefore, appropriate clinical and / or laboratory monitoring is recommended when administering medicinal products with a low therapeutic index dependent on P-gp, such as digoxin, concomitantly with ticagrelor.
There was no effect of ticagrelor on the blood levels of cyclosporine. The effect of ticagrelor on other P-gp substrates has not been studied.
Medicinal products metabolised by CYP2C9
Concomitant administration of ticagrelor with tolbutamide resulted in no change in the plasma levels of either medicinal product, indicating that ticagrelor is not a CYP2C9 inhibitor and is unlikely to affect the CYP2C9 mediated metabolism of medicinal products such as warfarin and tolbutamide.
Oral contraceptives
Co-administration of ticagrelor and levonorgestrel and ethinyl estradiol increased the exposure to ethinyl estradiol by approximately 20%, but did not alter the pharmacokinetic profile of levonorgestrel. A clinically relevant effect on the efficacy of the oral contraceptive is not expected following the concomitant use of levonorgestrel and ethinylestradiol and ticagrelor.
Medicines known to induce bradycardia
Following observation of mostly asymptomatic ventricular pauses and bradycardia, caution should be exercised when administering Brilique concomitantly with other bradycardia-inducing medicinal products (see section 4.4). However, no evidence of clinically adverse reactions was observed in the PLATO study. significant following concomitant administration with one or more medicinal products known to induce bradycardia (e.g. 96% beta blockers, 33% calcium channel blockers diltiazem and verapamil, and 4% digoxin).
Other concomitant therapies
In the PLATO study, Brilique was commonly administered with ASA, proton pump inhibitors, statins, beta blockers, angiotensin converting enzyme inhibitors and angiotensin receptor antagonists, as required by concomitant clinical conditions, for a long time. term and also with heparin, low molecular weight heparin and short-term intravenous GpIIb / IIIa inhibitors (see section 5.1) No evidence of clinically relevant adverse interactions was observed with these medicinal products.
Co-administration of ticagrelor and heparin, enoxaparin or desmopressin has no effect on activated partial thromboplastin time (aPTT), activated clotting time (ACT), or factor Xa dosages. However, due to potential pharmacodynamic interactions, caution should be used when co-administering Brilique with medicinal products known to impair haemostasis.
Following reports of skin bleeding abnormalities with SSRIs (e.g. paroxetine, sertraline and citalopram) caution should be exercised when administering SSRIs with ticagrelor as this may lead to an increased risk of bleeding.
04.6 Pregnancy and lactation
Women of childbearing potential
Women of childbearing potential must take appropriate contraceptive measures to avoid possible pregnancy during therapy with Brilique.
Pregnancy
There are no or limited data on the use of ticagrelor in pregnant women.
Animal studies have shown reproductive toxicity (see section 5.3). Brilique is not recommended during pregnancy.
Feeding time
Pharmacodynamic / toxicological data in animals have shown excretion of ticagrelor and its active metabolites in milk (see section 5.3). A risk to the newborns / infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or breastfeeding. discontinue / abstain from Brilique therapy taking into account the benefit of breastfeeding for the baby and the benefit of therapy for the mother.
Fertility
Ticagrelor has no effect on male or female fertility in animals (see section 5.3).
04.7 Effects on ability to drive and use machines
Brilique has no or negligible influence on the ability to drive or use machines. Dizziness has been reported during treatment of acute coronary syndrome. For this reason, patients who experience dizziness should exercise caution while driving or operating machinery.
04.8 Undesirable effects
Summary of the safety profile
The most commonly reported adverse reactions in patients treated with ticagrelor were dyspnoea, contusion and epistaxis, which occurred at a higher incidence than in the clopidogrel group.
Table of adverse reactions
The safety of Brilique in patients with acute coronary syndrome (unstable angina, NSTEMI and STEMI) was evaluated in the large pivotal phase 3 study PLATO ([PLATelet Inhibition and Patient ORutcomes], 18,624 patients), who compared patients treated with Brilique (180 mg loading dose of Brilique and maintenance dose of 90 mg twice daily) and patients treated with clopidogrel (300-600 mg loading dose followed by 75 mg once daily as a maintenance dose), both given in combination with acetylsalicylic acid (ASA) and other standard therapies.
The following adverse reactions have been identified following studies performed with Brilique or have been reported in post-marketing experience (Table 1).
Adverse reactions are classified according to frequency and system organ class. Frequency classes are defined according to the following conventions: Very common (≥1 / 10), Common (≥1 / 100,
Multiple correlated adverse reaction terminologies have been grouped together in Table e
include medical terms as described below:
to hyperuricemia, increased serum uric acid
b cerebral haemorrhage, intracranial haemorrhage, haemorrhagic stroke
c dyspnoea, dyspnoea from exertion, dyspnoea at rest, nocturnal dyspnoea
d gastrointestinal haemorrhage, rectal haemorrhage, intestinal haemorrhage, melaena, occult blood
and gastrointestinal ulcer haemorrhage, gastric ulcer haemorrhage, duodenal ulcer haemorrhage, peptic ulcer haemorrhage
f subcutaneous hematoma, cutaneous haemorrhage, subcutaneous haemorrhage, petechiae
g contusion, hematoma, bruising, increased tendency to bruise, traumatic hematoma
h haematuria, blood in urine, urinary tract haemorrhage
puncture site haemorrhage, vascular puncture site hematoma, injection site haemorrhage, puncture site haemorrhage, catheter site haemorrhage
# No ADRs of haemarthrosis were reported in the ticagrelor arm (n = 9,235) in the PLATO study; frequency was calculated using the upper bound of the 95% confidence interval for the point estimate (based on 3 / X, where X represents the total sample, i.e. 9,235 patients). This is calculated as 3 / 9,235, which equals to the "rare" frequency class
## Fatal intracranial haemorrhages have been reported in post marketing experience
Description of selected adverse reactions
Bleeding
The overall outcomes of the PLATO study bleeding rates are shown in Table 2.
Table 2 - Kaplan-Meier assessment of bleeding rates as a function of treatment
Definitions of bleeding categories:
Fatal / Life-threatening Major Bleeding: Clinically apparent with decreased hemoglobin> 50 g / l or transfusion ≥ 4 units of red blood cells; or fatal; or intracranial; o intrapericardial with cardiac tamponade; or with hypovolemic shock or severe hypotension requiring hypertensive treatment or surgery.
Other Major bleeding: Clinically apparent with hemoglobin decrease of 30-50 g / l or transfusion of 2-3 units of red blood cells; orsignificantly disabling.
Minor Bleeding: Requires medical intervention to stop or treat the bleeding.
TIMI Major Bleeding: Clinically apparent with decreased hemoglobin> 50 g / l or intracranial haemorrhage.
TIMI Minor Bleeding: Clinically apparent with 30-50 g / l decrease in hemoglobin.
Brilique and clopidogrel do not differ in the rates of Major Fatal / Life-threatening bleeding according to the PLATO criteria, Major total bleeding according to the PLATO criteria, Major bleeding according to the TIMI scale or Minor according to the TIMI scale (Table 2). However, more PLATO combined Major + Minor bleeds occurred with ticagrelor than with clopidogrel. Few patients in the PLATO study experienced fatal bleeding: 20 (0.2%) for ticagrelor and 23 (0.3%) for clopidogrel (see section 4.4).
Factors such as age, gender, weight, race, geographic region, concomitant physical condition, concomitant therapy and medical history, including previous stroke or transient ischemic attack, were not predictive of either Total or non-procedure related Major bleeding, defined according to the PLATO criteria. Consequently, no particular group was identified at risk for a specific bleeding category.
CABG-related bleeding: In the PLATO study, 42% of 1,584 patients (12% of the cohort) undergoing coronary artery bypass grafting (CABG) surgery had Fatal / Life-threatening Major bleeding according to the PLATO criteria, with no difference between treatment groups. CABG-related fatal bleeding occurred in 6 patients in each treatment group (see section 4.4).
Bleeding not related to CABG and bleeding not related to any procedure: Brilique and clopidogrel do not differ in non-CABG-related Major Fatal / Life-threatening bleeding, defined according to PLATO criteria, while Total Major bleeding according to PLATO criteria, Major according to TIMI scale and Major + Minor according to TIMI scale , were more common with ticagrelor. Similarly, when eliminating procedure-related bleeds, more bleeds were observed with ticagrelor than with clopidogrel (Table 2). Discontinuation of treatment due to non-procedural bleeding was more common for ticagrelor (2.9%) than for clopidogrel (1.2%; p
Intracranial hemorrhage: More non-procedural intracranial bleeds occurred with ticagrelor (n = 27 bleeds in 26 patients, 0.3%) than with clopidogrel (n = 14 bleeds, 0.2%), including 11 bleeds with ticagrelor and 1 with clopidogrel had a fatal outcome. There were no differences in overall fatal bleeding.
Dyspnea
Dyspnoea, a feeling of shortness of breath, has been reported in patients treated with Brilique. Dyspnoic adverse events (EAs) (dyspnoea, dyspnoea at rest, dyspnoea on exertion, paroxysmal nocturnal dyspnea, and nocturnal dyspnoea), when associated, were reported by 13.8% of patients treated with ticagrelor and by 7.8% of patients treated with clopidogrel. In 2.2% of patients who took ticagrelor and 0.6% of patients treated with clopidogrel, investigators considered dyspnoea to be causally related to treatment in the PLATO study, and a few cases were severe (0.14 % for ticagrelor; 0.02% for clopidogrel), (see section 4.4). The most frequently reported symptoms of dyspnoea were mild to moderate in intensity, and most were reported as a single episode soon after initiation of treatment.
Compared to clopidogrel, asthma / COPD patients treated with ticagrelor may have an increased risk of non-severe dyspnoea (3.29% for ticagrelor versus 0.53% for clopidogrel) and severe dyspnoea (0.38%). for ticagrelor versus 0.00% for clopidogrel). In absolute terms, this risk was greater than the overall population of the PLATO study. Ticagrelor should be administered with caution to patients with a history of asthma and / or COPD (see section 4.4).
About 30% of all episodes of dyspnoea resolved within 7 days. The PLATO study included patients who had congestive heart failure, chronic obstructive pulmonary disease, or asthma at baseline; these patients, and the elderly, were more likely to report episodes of dyspnoea. In the Brilique group, 0.9% of patients discontinued the active substance under study due to dyspnoea compared with 0.1% of patients receiving clopidogrel. The higher incidence of dyspnoea observed with Brilique is not associated with the onset or worsening of heart or lung disease (see section 4.4). Brilique does not affect lung function tests.
Diagnostic tests
Elevations in creatinine: In the PLATO study, serum creatinine concentration increased significantly by more than 30% in 25.5% of patients taking ticagrelor compared with 21.3% of patients taking clopidogrel, and more than 50% in patients taking ticagrelor. 8.3% of patients on ticagrelor compared with 6.7% of patients on clopidogrel. Elevations in creatinine> 50% were more pronounced in patients over 75 years of age (ticagrelor 13.6% versus clopidogrel 8 , 8%), in patients with severe renal impairment at baseline (ticagrelor 17.8% versus clopidogrel 12.5%) and in patients concomitantly receiving angiontensin II receptor antagonists (ticagrelor 11.2% versus clopidogrel 7 , 1%). Within these subgroups, severe renal adverse events and adverse events leading to study drug discontinuation were similar in the two treatment groups. The totality of renal adverse events reported was 4.9% for ticagrelor versus 3.8% for clopidogrel, however a similar percentage of patients reported events considered by investigators to be directly causal to treatment: 54 (0.6% ) for ticagrelor and 43 (0.5%) for clopidogrel.
Uric acid elevations: In the PLATO study, serum uric acid concentrations increased above the upper limit of normal in 22% of patients treated with ticagrelor compared with 13% of patients taking clopidogrel. The mean serum uric acid concentration was increased by approximately 15% with ticagrelor compared to 7.5% with clopidogrel and decreased to approximately 7% with ticagrelor after treatment discontinuation, while no reduction was observed with clopidogrel. The hyperuricaemia adverse event was reported in 0.5% for ticagrelor versus 0.2% for clopidogrel. Of these adverse events, 0.05% for ticagrelor versus 0.02% for clopidogrel were considered to be related to investigator-directed causality. For gouty arthritis, adverse events reported were 0.2% for ticagrelor versus 0.1% for clopidogrel; none of these adverse events were considered causally related to treatment by the investigators.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address" www.agenziafarmaco.gov.it/it/responsabili ".
04.9 Overdose
Ticagrelor is well tolerated in single doses up to 900 mg. Gastrointestinal toxicity was dose-limiting in a single dose escalation study. Other clinically relevant adverse reactions that may occur following overdose include dyspnoea and ventricular pauses (see section 4.8).
In the event of an overdose, the above potential adverse reactions may occur and ECG monitoring should be considered.
To date, there is no known antidote to counter the effects of ticagrelor, and it is assumed that ticagrelor is not dialysable (see section 4.4). Treatment of overdose should follow the standards of local medical practice. The expected effect of too much Brilique is the prolongation of the bleeding risk associated with platelet inhibition. If bleeding occurs, appropriate supportive medical measures should be instituted.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antiplatelet agents, excluding heparin.
ATC code: B01AC24.
Mechanism of action
Brilique contains ticagrelor, which belongs to the chemical class of cyclopentyltriazolopyrimidines
(CPTP), which is an oral, direct, selective and reversible P2Y12 receptor antagonist and prevents adenosine diphosphate (ADP) - mediated P2Y12-dependent platelet activation and aggregation.
Ticagrelor does not prevent ADP binding, but when it binds to the P2Y12 receptor it prevents ADP-induced signal transduction. Since platelets play a role in the onset and / or evolution of thrombotic complications of atherosclerotic disease, inhibition of platelet function has been shown to reduce the risk of cardiovascular events such as death, myocardial infarction or stroke.
Ticagrelor also increases local endogenous levels of adenosine through inhibition of the equilibrative nucleoside transporter -1 (ENT-1).
Ticagrelor has been shown to increase the following adenosine-induced effects in healthy subjects and in patients with ACS: vasodilation (measured as increased coronary blood flow in healthy volunteers and in ACS patients; headache), inhibition of platelet function (in whole human blood in vitro) and dyspnea. However, the link between the observed increase in adenosine and clinical outcomes (eg morbidity-mortality) has not been elucidated.
Pharmacodynamic effects
Onset of action (Onset)
In patients with stable coronary artery disease treated with ASA, ticagrelor induces a rapid onset of pharmacological effect, as demonstrated by a mean "platelet aggregation inhibition (PAH) for ticagrelor, 0.5 hours after a 180 mg loading dose. approximately 41% with a maximal effect on PAH of 89% within 2-4 hours post dose, and maintained between 2 and 8 hours. 90% of patients had final PAH> 70% within 2 hours after dose.
Reversibility of the action (Offset)
If a CABG procedure was planned, the risk of bleeding with ticagrelor is increased compared with clopidogrel when stopped less than 96 hours before surgery.
Data relating to the change of therapy
Switching from clopidogrel to ticagrelor results in an absolute increase in PAH of 26.4%, while switching from ticagrelor to clopidogrel results in an absolute decrease in PAH of 24.5%. Patients can be switched from clopidogrel to ticagrelor therapy without interrupting the antiplatelet effect (see section 4.2).
Clinical efficacy and safety
The PLATO study included 18,624 patients who presented within 24 hours of onset of symptoms of unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), or ST-segment elevation myocardial infarction (STEMI), and had been initially treated pharmacologically with either percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) (see section 4.1).
At the same daily dose of ASA, ticagrelor 90 mg twice daily was superior to clopidogrel 75 mg / day in the prevention of the composite endpoint of cardiovascular death [CV], myocardial infarction [MI] or stroke, with the difference guided by the reduction of CV and MI deaths Patients received either a 300 mg loading dose of clopidogrel (600 mg dose possible for PCI) or 180 mg ticagrelor.
The result was achieved early (absolute risk reduction [ARR] 0.6% and relative risk reduction [RRR] by 12% at 30 days), with a treatment effect that remained constant over 12 months, obtaining a "ARR of" 1.9% per year and an RRR of 16%. These data suggest that it is appropriate to treat patients with ticagrelor for up to 12 months (see section 4.2). Treatment of 54 ACS patients with ticagrelor instead that with clopidogrel it would avoid the onset of 1 atherothrombotic event; treatment of 91 patients would avoid 1 CV death (Table 3).
The effect of ticagrelor treatment compared to clopidogrel is consistent across all subgroups of patients by characteristics including weight, sex, history of diabetes mellitus, transient ischemic attack or non-haemorrhagic stroke, revascularization, concomitant therapies including heparins, GpIIb / IIIa inhibitors and proton pump inhibitors (see section 4.5), final diagnosis of the event (STEMI, NSTEMI or UA) and treatment path assigned to randomization (invasive or medical).
A weakly significant interaction was observed between treatment and geographic region, whereby the Hazard Ratio (HR) for the primary endpoint favors ticagrelor in the rest of the world, while it favors clopidogrel in North America, which accounts for approximately 10%. of the global population studied (p-value of the interaction = 0.045).
Exploratory analyzes suggest a possible association with ASA dose, since reduced efficacy was observed with ticagrelor associated with increasing doses of ASA. The daily chronic dose of ASA, given together with Brilique, should be between 75 and 150 mg (see sections 4.2 and 4.4).
Figure 1 shows the estimated risk of first occurrence of any event assessed in the composite efficacy endpoint.
Brilique reduced the onset of the primary composite endpoint compared to clopidogrel in both the UA / NSTEMI and STEMI populations (Table 3).
Table 3 - Clinical outcomes in the PLATO study
a ARR = absolute risk reduction; RRR = relative risk reduction = (1-Hazard ratio) x 100%. A negative RRR indicates an increased relative risk.
b excluding silent myocardial infarction.
c SRI = severe recurrent ischaemia; RI = recurrent ischemia; TIA = transient ischemic attack; ATE = atherothrombotic event. Total MI includes silent MI, with event date set as date of diagnosis.
d value of nominal significance; all other values are formally statistically significant based on a predefined hierarchical test.
Holter substudy
In order to study the onset of ventricular pauses and other episodes of arrhythmia during the PLATO study, the investigators performed Holter monitoring in a subgroup of nearly 3,000 patients, of which about 2,000 had records relating to both the acute phase of Coronary Syndrome. Acute, either after one month. The primary variable of interest was the onset of ventricular pauses ≥3 seconds. More patients experienced ventricular pauses with ticagrelor (6.0%) than with clopidogrel (3.5%) in the acute phase; and 2.2% and 1.6% after 1 month, respectively (see section 4.4). The increase in ventricular pauses in the acute phase of ACS was more pronounced in ticagrelor-treated patients with a history of CHF (9.2% versus 5.4% in patients without a history of CHF; for clopidogrel-treated patients, 4, 0% in patients with a history of CHF versus 3.6% in those without a history of CHF). This difference was not observed after one month: 2.0% versus 2.1% for ticagrelor-treated patients with and without history of CHF respectively; and 3.8% versus 1.4% with clopidogrel.No adverse clinical consequences associated with this difference (including pacemaker applications) were found in this patient population.
Genetics substudy from the PLATO study
The genotyping of CYP2C19 and ABCB1 of 10,285 patients from the PLATO study allowed to associate the clinical results of the study with the genotypic distribution. The superiority of ticagrelor over clopidogrel in reducing major cardiovascular events was not affected by the patient's CYP2C19 or ABCB1 genotype. Similar to the overall data from the PLATO study, the incidence of Total Major Bleeds by PLATO criteria did not differ between ticagrelor and clopidogrel, regardless of the CYP2C19 or ABCB1 genotype. The incidence of PLATO Non-CABG related major bleeding was increased with ticagrelor compared to clopidogrel in patients with one or more CYP2C19 reduced function alleles, but similar to clopidogrel in patients without reduced function alleles.
Composite association of efficacy and safety
The composite combination of efficacy and safety (CV death, MI, stroke, or PLATO Total Major Bleeding) indicates that the efficacy benefit of Brilique over clopidogrel is not offset by Major bleeding events (ARR 1, 4%; RRR 8%; HR 0.92; p = 0.0257) in the 12 months following SCA.
Pediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Brilique in all subsets of the pediatric population in the authorized indication (see sections 4.2 and 5.2).
05.2 Pharmacokinetic properties
Ticagrelor exhibits linear pharmacokinetics and exposure to ticagrelor and the active metabolite (AR-C124910XX) are approximately dose proportional up to 1,260 mg.
Absorption
Absorption of ticagrelor is rapid, with a mean t of approximately 1.5 hours. The formation of the major circulating metabolite, AR-C124910XX (also active), derived from ticagrelor, is rapid, with a t
median of about 2.5 hours. Following oral administration of 90 mg ticagrelor in fasted conditions, Cmax is 529 ng / mL and AUC is 3,451 ng xh / mL. The precursor metabolite ratio is 0.28 for Cmax and 0.42 for the AUC.
The mean absolute bioavailability of ticagrelor was estimated to be 36%. Ingestion of a high-fat meal caused a 21% increase in the AUC of ticagrelor and a 22% decrease in the Cmax of the active metabolite, but had no effect on the Cmax of ticagrelor or the AUC of ticagrelor. active metabolite.These slight changes are considered of minimal clinical relevance, therefore ticagrelor can be administered both with and without meals.Ticagrelor and its active metabolite are substrates of P-gp.
Ticagrelor as crushed tablets mixed in water, administered orally or through a nasogastric tube in the stomach, has a comparable bioavailability to whole tablets for AUC and Cmax for both ticagrelor and the active metabolite. Initial exposure (0 , 5 and 1 hour post dose) to crushed ticagrelor tablets mixed in water was higher than to whole tablets, with a concentration profile from then on generally identical (2 to 48 hours).
Distribution
The steady-state volume of distribution of ticagrelor is 87.5 L. Ticagrelor and its active metabolite are extensively bound to plasma proteins (> 99.0%).
Biotransformation
CYP3A4 is the major enzyme responsible for the metabolism of ticagrelor and the formation of the active metabolite, and their interactions with other CYP3A substrates range from activation to inhibition.
The major metabolite of ticagrelor is AR-C124910XX, which also has pharmacological activity, as demonstrated in vitro by binding to the platelet P2Y12 receptor of ADP. Systemic exposure to the active metabolite is approximately 30-40% of that observed with ticagrelor.
Elimination
The primary route of elimination of ticagrelor is via hepatic metabolism. When radiolabelled ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (57.8% in faeces, 26.5% in urine). The recovered amounts of both ticagrelor and the active metabolite, present in the urine, were less than 1% of the dose.
The primary route of elimination of the active metabolite is likely to be biliary secretion. The mean t1 / 2 was approximately 7 hours for ticagrelor and 8.5 hours for the active metabolite.
Special populations
Senior citizens
Higher exposures to ticagrelor (approximately 25% for both Cmax and AUC) and the active metabolite were observed in elderly patients (≥75 years) with ACS compared to younger patients, via a "population pharmacokinetic analysis. are considered clinically significant (see section 4.2).
Pediatric population
Ticagrelor has not been evaluated in the pediatric population (see sections 4.2 and 5.1).
Sex
Higher exposures of ticagrelor and the active metabolite were observed in women than in men. These differences are not considered clinically significant.
Impaired renal function
Exposure to ticagrelor was approximately 20% lower and active metabolite exposure was approximately 17% higher in patients with severe renal impairment (creatinine clearance
Impaired liver function
Cmax and AUC of ticagrelor were 12% and 23% higher in patients with mild hepatic impairment compared to a comparable sample of healthy subjects (see section 4.2). Ticagrelor has not been studied in patients with moderate or severe hepatic impairment, and its use in these patients is contraindicated (see sections 4.3 and 4.4).
Ethnicity
Patients of Asian descent show a mean bioavailability that is 39% higher than Caucasian patients. Patients self-identified as black had an 18% lower bioavailability of ticagrelor than Caucasian patients. In clinical pharmacology studies, exposure (Cmax and AUC) to ticagrelor in Japanese patients was approximately 40% (20% after adjustment for body weight) higher than in Caucasian patients.
05.3 Preclinical safety data
Preclinical data of ticagrelor and its major metabolite did not demonstrate an unacceptable risk of adverse effects for humans based on conventional studies of safety pharmacology, single or repeated dose toxicity and genotoxic potential.
Gastrointestinal irritation was observed in several animal species for clinically relevant exposure levels (see section 4.8).
In female rats, ticagrelor at high doses showed an increased incidence of uterine tumors (adenocarcinomas) and an increased incidence of hepatic adenomas. The mechanism of onset of uterine tumors is probably related to a hormonal imbalance that can lead to tumor formation in rats. The mechanism underlying the formation of hepatic adenomas is probably due to a rodent-specific hepatic enzyme induction. Therefore the observations relating to the carcinogenic potential are considered to be of unlikely relevance for humans.
Minor developmental abnormalities were observed in rats at a maternally toxic dose (safety margin 5.1). In rabbits, a slight delay in hepatic maturity and skeletal development was observed in fetuses from mothers exposed to high doses, with no signs of maternal toxicity (safety margin 4.5).
Studies in rats and rabbits have shown reproductive toxicity, with slight decrease in maternal body weight gain, reduced neonatal viability and decrease in birth weight, with growth retardation. Ticagrelor caused irregular cycles (predominantly longer cycles) in female rats, but did not affect overall fertility in male and female rats Pharmacokinetic studies performed with radiolabelled ticagrelor showed that the parent compound and its metabolites are excreted in the milk of rats (see section 4.6).
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Core of the tablet
Mannitol (E421)
Calcium hydrogen phosphate dihydrate
Magnesium stearate (E470b)
Sodium starch glycolate
Hydroxypropylcellulose (E463)
Tablet coating
Talc
Titanium dioxide (E171)
Yellow iron oxide (E172)
Polyethylene glycol 400
Hypromellose (E464)
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
• Transparent blister (with sun / moon symbols) in PVC-PVDC / Al of 10 tablets; cartons of 60 tablets (6 blisters) and 180 tablets (18 blisters).
• Transparent calendar blister (with sun / moon symbols) in PVC-PVDC / Al of 14 tablets; cartons of 14 tablets (1 blister), 56 tablets (4 blisters) and 168 tablets (12 blisters).
• Transparent single-dose perforated blister in PVC-PVDC / Al of 10 tablets; cartons of 100x1 tablets (10 blisters).
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
AstraZeneca AB
SE-151 85
Södertälje
Sweden
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/10/655 / 001-006
040546018
040546020
040546032
040546044
040546057
040546069
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 03 December 2010
Date of most recent renewal: July 17, 2015
10.0 DATE OF REVISION OF THE TEXT
July 2015
