Brilinta, 90 mg, film-coated tablets, 56 pcs.

Release form and composition

Brilinta is produced in the form of film-coated tablets: round, biconvex; 90 mg – yellow, on one side with an engraving “90” above the letter T; 60 mg – pink, on one side with an engraving “60” (14 pcs. in a blister made of Al/PVC/PVDC; 90 mg – 1, 4 or 12 blisters, 60 mg – 4 or 12 blisters in a cardboard pack with first opening control);

Composition of 1 tablet:

• active ingredient: ticagrelor – 60 or 90 mg;
• additional components: sodium carboxymethyl starch, mannitol, magnesium stearate, calcium hydrogen phosphate, hyprolose;
• film shell: titanium dioxide (E171), macrogol 400, talc, hypromellose, 90 mg - yellow iron oxide dye, 60 mg - red iron oxide dye and black oxide.

Pharmacological properties

Pharmacodynamics

The active substance of the drug, ticagrelor, is an oral, selective and reversible direct-acting P2Y12 receptor antagonist, part of the chemical class of cyclopentyltriazolopyrimidines and preventing ADP (adenosine diphosphate)-mediated P2Y12-dependent platelet aggregation and activation. The interaction of ticagrelor with the P2Y12 platelet receptor prevents ADP-induced signal transduction. By inhibiting platelet function, the drug helps reduce the risk of cardiovascular events such as stroke, myocardial infarction, and death.

Ticagrelor also has an additional mechanism of action by increasing local concentrations of endogenous adenosine through inhibition of the endogenous equilibrium nucleoside transporter type I (ENT-1).

In patients with acute coronary syndrome (ACS) and healthy volunteers, ticagrelor increased the effects of adenosine such as vasodilation, suppression of platelet function, and dyspnea. However, the relationship between morbidity and mortality rates and elevated local adenosine concentrations has not been proven.

Against the background of the use of acetylsalicylic acid (ASA) in patients with stable coronary heart disease (CHD), a rapid effect of ticagrelor is observed: ½ hour after taking a loading dose of 180 mg, the average value of inhibition of platelet aggregation (IAT) is about 41%, and its maximum value (89%) is achieved after 2–4 hours and is maintained for 2–8 hours.

When planning coronary artery bypass surgery, if ticagrelor is discontinued less than 96 hours before the procedure, the risk of bleeding increases.

During the entire study period, in combination with ASA, ticagrelor with a frequency of use of 2 times a day Brilinta 60 mg, as well as 90 mg, demonstrated effectiveness in preventing atherothrombotic complications, namely: 60 mg - absolute risk reduction (AR) by 1.27% and relative risk (RR) by 16%, 90 mg – reduction in RAR by 1.19% and RRR by 15%.

Ticagrelor 60 mg showed better tolerability and safety profile regarding the risk of bleeding and dyspnea when compared with the effectiveness of the 90 mg dose. As a result, in case of a history of myocardial infarction (1 year or more after surgery), 60 mg of ticagrelor in combination with ASA is recommended to prevent atherothrombotic complications.

Pharmacokinetics

Ticagrelor is characterized by a linear dependence of changes in pharmacokinetic parameters; exposure to ticagrelor and its active metabolite (AR-C124910XX) is almost proportional to the dose received, up to 1260 mg.

Ticagrelor is rapidly absorbed with an average Tmax (time to reach maximum plasma concentration) of about 1.5 hours. The formation of the main active metabolite circulating in the blood occurs with an average Tmax of approximately 2.5 hours. The maximum plasma concentration (Cmax) of ticagrelor after administration on an empty stomach at a dose of 90 mg is 529 ng/ml, and the total concentration during observation time (AUC) is 3451 ng×h/ml.

The average absolute bioavailability of ticagrelor is 36%. Intake of fatty foods does not affect the AUC of the active metabolite and Cmax of ticagrelor. The drug taken orally or introduced into the stomach through a nasogastric tube in the form of a suspension of tablets crushed in drinking water is bioequivalent to ticagrelor taken orally in tablet form.

The main route of elimination of ticagrelor is metabolism in the liver. When isotope-labeled ticagrelor is administered, approximately 57.8% of the radioactivity is excreted in feces and 26.5% in urine. Excretion of the active metabolite and drug in urine corresponds to less than 1% of the dose. The active metabolite is predominantly excreted in bile.

The average half-life of ticagrelor and the active metabolite is 7 and 8.5 hours, respectively.

pharmachologic effect

Ticgrelor belongs to the class of cyclopentyltriazolopyrimidines and is part of the group of reversible P2Y12 receptor antagonists. Acts on ADP-mediated platelet activation. The binding of ADP by Brilinta does not stop, however, due to the effect on P2Y12 receptors, signal transduction becomes impossible. Thus, the drug has an inhibitory effect on platelet function, reduces the risk of strokes, heart attacks, and sudden death syndrome.

The second mechanism of action of ticagrelor is an increase in angiotensin concentrations. Main effects:

• Cardioprotection.
• Vasodilation.
• Modulation of inflammation.
• Decreased platelet aggregation.

This affects Brilinta's clinical profile. According to studies, in patients with manifestations of acute coronary syndrome, there was increased vasodilation and decreased platelet function. But the connection of these conditions with angiotensin has not been proven.

Brilinta exhibits linear pharmacokinetics and is rapidly absorbed. The time to reach the maximum concentration of the substance is 2 hours. The formation of active metabolites occurs no later than after 3 hours. After taking it on an empty stomach, I note the following indicators:

• The maximum concentration of the substance is 530 ng/ml.
• The area of ​​the concentration-time curve is 3450 ng*h/ml.

The bioavailability of the drug is 36%. Concentration levels are affected by fatty foods. In this case, the maximum concentration will decrease by 23%.

Ticagrelor, like its metabolites, is highly bound to plasma proteins. The main route for removing breakdown products is metabolic processes in the liver. No more than 1% of the substance is excreted in the urine. Other components are excreted in bile.

Indications for use

The use of Brilinta is recommended in combination with ASA for the prevention of atherothrombotic events in adults:

• 90 mg – in the presence of acute coronary syndrome (myocardial infarction with or without ST segment elevation, unstable angina), including patients receiving drug therapy and patients after percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG);
• 60 mg – in case of myocardial infarction one year or more ago and a high risk of developing an atherothrombotic complication.

Reviews and recommendations from doctors and patients

According to reviews, Brilinta is an effective remedy that rarely exhibits side effects. The only drawback of the product is the high cost and the need for long-term use.

The effectiveness of the drug is confirmed by a number of studies:

PLATO. The study included patients who developed symptoms of a heart attack or unstable angina. With daily use of acetylsalicylic acid, patients were also prescribed the drug Brilinta 2 times a day, 90 mg. After 30 days, a therapeutic effect was noted. The relative risk decreased by 12%.

PEGASUS. According to the study results, the use of Brilinta twice a day in combination with acetylsalicylic acid prevents atherothrombic events and reduces the relative and absolute risk of death in 16 and 1.27 percent of cases.

Contraindications

Absolute:

• moderate (for 90 mg) and severe liver failure;
• indications in the anamnesis of intracranial hemorrhage;
• active phase of pathological bleeding;
• age under 18 years;
• pregnancy and lactation;
• hemodialysis;
• combined use with strong CYP3A4 inhibitors such as ketoconazole, ritonavir, nefazodone, clarithromycin and atazanavir (due to a significant increase in ticagrelor exposure);
• hypersensitivity to any of the components of the drug.

The combined use of Brilinta with ASA in a high maintenance dose exceeding 300 mg is not recommended.

Relative (ticagrelor is taken with extreme caution):

• predisposition to bleeding (including active/recent gastrointestinal bleeding, recent injury or surgery, bleeding disorders);
• functional liver disorders of moderate severity (for 60 mg);
• concomitant treatment with drugs that increase the risk of bleeding, such as oral anticoagulants and/or fibrinolytics, nonsteroidal anti-inflammatory drugs (NSAIDs) for 24 hours before taking ticagrelor;
• increased risk of developing bradycardia, including the presence of atrioventricular block (AV block) of the second or third degree, sick sinus syndrome (patients without a pacemaker), fainting caused by bradycardia;
• combined use of drugs that cause bradycardia;
• history of myocardial infarction with previous ischemic stroke, with a course of treatment of more than one year (for 60 mg);
• a history of bronchial asthma and/or chronic obstructive pulmonary disease (COPD) (if shortness of breath worsens, prolonged shortness of breath occurs, or a new episode occurs, an examination should be performed and discontinuation in case of intolerance);
• severe or moderate renal failure, due to the risk of increased creatinine levels;
• history of hyperuricemia or gouty arthritis (avoid ticagrelor in hyperuricemic nephropathy);
• age over 75 years (for 90 mg);
• combination with digoxin [requires careful laboratory and clinical monitoring of plasma concentrations of digoxin, electrocardiogram (ECG), heart rate (HR)];
• combined use with powerful P-glycoprotein inhibitors (quinidine, cyclosporine, verapamil), due to the lack of clinical observation data;
• combined use with drugs that affect hemostasis (desmopressin, enoxaparin, heparin);
• combination with selective serotonin reuptake inhibitors (sertraline, paroxetine, citalopram) due to the possible development of subcutaneous hemorrhages.

Directions for use and dosage

Brilinta is taken orally. Eating does not affect the effectiveness of the drug.

Therapy with ticagrelor 90 mg must be started with a single loading dose of 180 mg (two tablets of 90 mg), and subsequently used 2 times a day, 90 mg (1 tablet). Treatment with the drug at this dose should be carried out for 1 year, except in cases in which early discontinuation of the drug is necessary. Information on the use of ticagrelor 90 mg beyond this period is limited.

If necessary, it is possible to switch from therapy with clopidogrel 75 mg once a day to ticagrelor 90 mg twice a day; in this case, the antithrombotic effect is not interrupted.

Patients who received Brilinta 90 mg twice daily for 1 year (during an acute condition) can continue treatment with the drug at a dose of 60 mg without interruption at the same dosage frequency.

One year after myocardial infarction, ticagrelor 60 mg is recommended to be taken 2 times a day, regardless of the presence of breaks in treatment or previous use of antiplatelet drugs. It is not necessary to start using ticagrelor with a loading dose. After completing previous therapy, the interval between the last dose of the antiplatelet drug and the first dose of Brilinta 60 mg should be 24 hours.

Simultaneously with ticagrelor (90 or 60 mg), in the absence of specific contraindications, it is necessary to use ASA daily in a low maintenance dose of 75 to 150 mg.

Therapy with Brilinta 60 mg should be carried out for a long time; there is no experience of using the drug for more than 3 years in patients with a history of myocardial infarction.

It is necessary to avoid missing doses, but if the next dose is missed, at the appointed time you need to take only the next tablet (90 or 60 mg), without using a double dose.

Premature cessation of antiplatelet therapy (including ticagrelor) should also be avoided, as in the setting of ACS this may exacerbate the threat of myocardial infarction or cardiovascular death.

For patients who have difficulty swallowing the tablet, it is recommended that it be crushed to a fine powder and then diluted in ½ glass of water. The prepared suspension should be taken immediately, the remainder should be filled with the same amount of water and drunk again. The suspension can also be administered through a nasogastric tube, which must be rinsed with water after administration to obtain the full dose.

Use of the drug

Brilint tablets are intended for oral administration. Does not depend on food intake. If it is difficult for a patient to swallow a tablet, it can be crushed to a powder state and dissolved in 100 ml of water.

In severe cases, the drug can be administered through a tube in the form of a suspension.

If the patient suffered an acute myocardial infarction a year ago or more, do not use a loading dose. It is recommended to take 60 mg 2 times a day. Therapy begins regardless of the use of antiplatelet agents before this case.

The instructions assume long-term use of the drug. The exception is patients with absolute contraindications to the use of Brilinta. When treating acute coronary syndrome, therapy begins with a loading dose of 180 mg. After this, they switch to a two-time dose of 90 mg using 75 mg of acetylsalicylic acid. Early discontinuation of the drug increases the risk of a new episode of acute coronary syndrome. The recommended course of treatment is 1 year. Patients taking clopidogrel switch to Brilinta without the risk of side effects.

Side effects

Brilinta 90 mg:

• nervous system: uncommon – dizziness, headache, intracranial/cerebral hemorrhage, hemorrhagic stroke; rarely – confusion, paresthesia;
• digestive system: often - gastrointestinal bleeding (positive test for occult blood, intestinal bleeding, rectal bleeding, melena); uncommon – bleeding in the oral cavity (including gingival), hemorrhoidal bleeding, gastritis, abdominal pain, diarrhea, vomiting, dyspepsia, nausea, bleeding from ulcers (stomach, peptic ulcer, duodenum, digestive tract); rarely – constipation, retroperitoneal bleeding;
• organ of hearing: rarely – vertigo, hemorrhage in the ear;
• organ of vision: infrequently – hemorrhages (conjunctival, intraocular, retinal);
• respiratory system: often – shortness of breath (at rest, during exertion, at night), nosebleeds; infrequently – hemoptysis;
• metabolism: rarely – hyperuricemia, increased plasma concentration of uric acid;
• musculoskeletal system: rarely - hemarthrosis;
• skin and subcutaneous tissues: often - subcutaneous or cutaneous hemorrhages (petechiae, subcutaneous hematoma), bruises (ecchymosis, hematoma, contusion, traumatic hematoma, increased tendency to bruise); uncommon – itching, rash;
• reproductive system: infrequently – vaginal bleeding (including metrorrhagia);
• urinary system: uncommon – bleeding from the urinary tract, hematuria;
• laboratory tests: rarely - increased creatinine concentration in the blood;
• other: often - bleeding from the injection/puncture site, hematoma at the puncture site, bleeding from the catheterization site; uncommon – bleeding after the procedure; rarely – traumatic bleeding, bleeding from a wound.

Brilinta 60 mg:

• nervous system: often – headache, dizziness, fainting; uncommon: intracranial hemorrhage;
• digestive system: often - bleeding from stomach ulcers, rectal bleeding, gingival bleeding, nausea, constipation, diarrhea, dyspepsia; uncommon – retroperitoneal bleeding;
• malignant, benign and unspecified neoplasms (including cysts and polyps): uncommon – bleeding from a tumor (including colon, stomach, bladder);
• immune system: uncommon – hypersensitivity reactions (including angioedema);
• organ of hearing and labyrinthine disorders: often - vertigo, infrequently - hemorrhage in the ear;
• organ of vision: infrequently – hemorrhages (conjunctival, intraocular, retinal);
• respiratory system: very often - shortness of breath, often - bleeding from the organs of the respiratory system (including nosebleeds, hemoptysis);
• metabolism and nutrition: very often – hyperuricemia; often – gouty arthritis/gout;
• musculoskeletal system and connective tissue: infrequently - muscle bleeding (hemorrhage into the muscle, hemarthrosis);
• mental disorders: infrequently – confusion;
• lymphatic system and blood: very often - bleeding caused by blood diseases (spontaneous hematoma, increased tendency to bruise, hemorrhagic diathesis);
• skin and subcutaneous tissues: often – subcutaneous or skin bleeding (skin hemorrhage, ecchymosis, petechiae), itching, rash;
• vessels: often – arterial hypotension;
• reproductive system: uncommon – bleeding from the genitals (postmenopausal bleeding, hematospermia, vaginal bleeding);
• kidneys and urinary tract: often – hemorrhagic cystitis, hematuria;
• intoxication, trauma, and complications of manipulation: often - traumatic bleeding (traumatic hematoma or bleeding, bruise), bleeding after manipulation;
• laboratory and instrumental data: often - increased creatinine levels in the blood.

Side effects

The use of the drug is accompanied by side effects. Common: shortness of breath, increased frequency of nosebleeds, and bruising.

Rarely (in one patient out of 10,000) possible:

• increased concentration of uric acid in plasma;
• hemorrhagic stroke;
• vertigo;
• hemarthrosis;
• increased creatinine levels;
• traumatic bleeding.

Infrequently (in one patient out of 1000) the following occur:

• ulcerative, vaginal and rectal bleeding;
• bleeding in the mouth;
• vomit;
• constipation;
• hematuria.

When the drug is used correctly, the risk of side effects is reduced.

Overdose

Brilinta was well tolerated when taking a single dose of up to 900 mg. Adverse effects from the digestive tract during the single study were dose-limiting, and ventricular pauses and shortness of breath were also observed with overdose. Suspected pharmacologic actions may include prolongation of bleeding time.

For this condition, symptomatic therapy is recommended under the control of clinical symptoms and ECG. The drug is not excreted by hemodialysis, the antidote is unknown. If bleeding occurs, appropriate supportive measures are prescribed.

special instructions

Before starting Brilinta therapy, a careful assessment of the balance between the benefits of preventing atherothrombotic events and the possible threat of bleeding is required.

There is no data confirming the hemostatic effectiveness of platelet transfusions during the use of ticagrelor. Brilinta is capable of inhibiting transfused platelets in the blood.

The use of recombinant activated factor VIIa and/or antifibrinolytic treatment (aminocaproic or tranexamic acid) can lead to increased hemostasis. After determining the cause of bleeding and stopping it, it is possible to resume taking Brilinta.

Before undergoing elective surgery or using new medications, the attending physician must be informed about ticagrelor therapy. If a surgical procedure is scheduled for which an antithrombotic effect is not desired, Brilinta should be discontinued 7 days before surgery.

During CABG, the incidence of major bleeding with ticagrelor was the same as with clopidogrel on all days after discontinuation of therapy, with the exception of the first day, when the likelihood of major bleeding was higher with Brilinta.

The shortness of breath that occurs during treatment is usually mild or moderate in nature and resolves during therapy.

During Brilinta therapy, an increase in creatinine levels is possible, and therefore it is recommended to use the drug with extreme caution (assessing renal function) during concomitant treatment with angiotensin receptor antagonists.

Impact on the ability to drive vehicles and complex mechanisms

The effect of Brilinta on the ability to drive vehicles and other complex mechanisms has not been studied.

Given the likelihood of developing dizziness and confusion during ACS therapy, it is recommended to exercise caution when driving vehicles and operating any machinery.

Drug interactions

• carbamazepine, rifampicin, phenobarbital, phenytoin (CYP3A4 inducers) - may reduce the exposure and effectiveness of ticagrelor;
• ethinyl estradiol, levonorgestrel (oral contraceptives) - no clinically significant effect on the effectiveness of contraception was noted;
• lovastatin, simvastatin - when taking ticagrelor at a dose exceeding 40 mg per day, the adverse reactions of these drugs may worsen; combined use is not recommended;
• ergot alkaloids, cisapride (CYP3A4 substrates with a narrow therapeutic index) – increased exposure of these drugs is possible;
• proton pump inhibitors, beta-blockers, ASA, angiotensin-converting enzyme inhibitors, statins, angiotensin receptor antagonists (with long-term use), glycoprotein IIb/IIIa receptor inhibitors for intravenous administration (with a short course of therapy), low molecular weight heparins - no undesirable clinically significant interactions were identified ;
• grapefruit juice (with daily consumption of 200 ml 3 times a day) – the exposure to ticagrelor increases by 2 times, which is clinically insignificant for most patients.

Compatibility with other drugs

CYP3A4 inducers and inhibitors. With the combined use of Brilinta and rifampicin, the concentration of ticagrelor in the blood decreases by 73%.

The use of ticagrelor with cyclomporine increases the concentration of Brilinta by 2 times. But at the same time, the levels of the active metabolite of ticagrelor decrease.

According to recent studies, the use of heparin, desmopressin or encosaparin during therapy with ticagrelor does not affect the pharmacokinetics of the drug. But be careful when using the products.

Ticagrelor affects the following drugs:

• Simvastine and atorvastine. The maximum concentration of drugs increases. When used in combination, side effects are possible (in cases where the dose of simvastine exceeds 40 mg).
• Oral contraceptives. Acts on ethinyl estradiol, increasing its exposure.