Brilinta, 90 mg 56 pcs.

Pharmacotherapeutic group: anti-aggregant

ATX code: B01AC24

Indications

Active ingredient

Composition

How to take, the dosage

To be taken orally. The drug Brilinta® can be taken regardless of the time of food intake.

The use of Brilinta® should be started with a single loading dose of 180 mg (two 90 mg tablets) and then continued at 90 mg twice daily.

For patients with difficulty swallowing, the tablet (or 2 tablets if taking a loading dose) should be crushed to a fine powder, stirred in half a glass of drinking water, and the resulting suspension should be drunk immediately. Mix the remainder with an additional half glass of drinking water and drink the resulting suspension. The suspension can also be injected through a nasogastric tube (CH8 or larger). After the suspension is administered, the nasogastric tube should be flushed with water to ensure that the dose of the drug reaches the patient’s stomach completely.

Patients taking Brilinta® should take daily ASA (75 mg to 150 mg when taken continuously) unless there are specific contraindications.

The therapy with Brilinta® is recommended for 12 months unless there is a clinical need for early withdrawal of the drug (see Pharmacological properties). After 12 months of therapy, patients taking Brilinta® 90 mg twice daily may be switched to Brilinta® 60 mg twice daily without interruption of therapy.

Missing a dose

Breaks in therapy should be avoided. A patient who misses a dose of Brilinta® should only take one 90 mg tablet (next dose) at the scheduled time.

Early withdrawal of therapy

In patients with ACS, early withdrawal of any antiplatelet therapy, including Brilinta

sup>® may increase the risk of cardiovascular death, myocardial infarction, or stroke due to the underlying disease (see See “Special Precautions”). Premature discontinuation of the drug should be avoided.

Transfer to therapy

Patients with ACS should be given a loading dose of Brilinta® 180 mg as soon as possible regardless of any prior antiplatelet therapy.

When transferring ACS patients to Brilinta® the first dose should be administered within 24 hours of the last dose of another antiplatelet drug.

Elderly patients

Dose adjustment is not required (see section on Pharmacological properties).

Patients with renal impairment

There is no need to adjust the dose of the drug in patients with renal impairment (see section on “Pharmacological properties”).

Patients with hepatic impairment

There is no need to adjust the dose of the drug in patients with mild to moderate hepatic impairment. There have been no studies of Brilinta® in patients with severe hepatic impairment; therefore, its use in these patients is contraindicated (see sections “Pharmacological properties” and “Contraindications”).

Children

The safety and effectiveness of Brilinta® in children under 18 years of age for the approved indication in adults has not been established.

Interaction

Effects of other drugs on Brilinta® Effects of other drugsDrugs metabolized by CYP3A4 isoenzyme CYP3A4 inhibitors

Cyclosporine (P-gp and CYP3A4 inhibitor)

The combined use of cyclosporine (600 mg) with ticagrelor increases Cmax and AUC of ticagrelor 2.3 and 2.8 times, respectively. At the same time, there is a 32% increase in AUC of the active metabolite and a 15% decrease in Cmax. Ticagrelor has no effect on the plasma concentration of cyclosporine.

CYP3A4 inducers

The co-administration of rifampicin with ticagrelor reduces Cmax and AUC of ticagrelor by 73% and 86%, respectively. The Cmax of the active metabolite does not change, and the AUC is reduced by 46%. Other CYP3A4 inducers (e.g., phenytoin, carbamazepine and phenobarbital) are likely to reduce the exposure of Brilinta®. Powerful CYP3A4 inducers may decrease the exposure and effectiveness of Brilinta®.

Other

. According to the results of pharmacological interaction studies, concomitant use of ticagrelor with heparin, enoxaparin and ASA or desmopressin has no effect on the pharmacokinetics of ticagrelor, its active metabolite and ADP-dependent platelet aggregation. If there are clinical indications for the administration of drugs affecting hemostasis, they should be used with caution in combination with Brilinta® (see section “Caution”).

There are no data on co-administration of Brilinta® with potent glycoprotein P inhibitors and moderate CYP3A4 inhibitors (such as verapamil and quinidine) that may increase ticagrelor exposure. If co-administration cannot be avoided, it should be used with caution (see sections “Caution”, “Special Precautions”).

There has been evidence of delayed and decreased exposure to oral P2Y12 inhibitors, including ticagrelor and its active metabolite, in patients receiving morphine therapy (approximately 35% reduction in exposure to ticagrelor). This interaction may be associated with decreased gastrointestinal motility and is therefore applicable to other opioids. The clinical relevance is unknown, but data indicate that the efficacy of ticagrelor may be reduced in patients receiving ticagrelor and morphine concomitantly. In ACS patients in whom the use of morphine cannot be delayed and rapid inhibition of P2Y12 is considered critical, a parenteral P2Y12 inhibitor may be considered.

The effects of Brilinta® on other medications

em>Drugs metabolized by CYP3A4 isoenzyme

Ticagrelor is a weak CYP3A4 inhibitor. Co-administration of Brilinta® and CYP3A4 substrates with a narrow therapeutic index (e.g., cisapride or ergot alkaloids) is not recommended, because ticagrelor may increase exposure to these drugs.

Drugs metabolized by CYP2C9 isoenzyme

Concomitant use of ticagrelor and tolbutamide did not alter plasma concentrations of either drug, suggesting that ticagrelor is not a CYP2C9 isoenzyme inhibitor and that it is unlikely to affect CYP2C9-mediated metabolism of drugs like warfarin and tolbutamide.

Oral contraceptives

The co-administration of ticagrelor, levonorgestrel and ethinylestradiol increases ethinylestradiol exposure by approximately 20%, but does not affect levonorgestrel pharmacokinetics. No clinically significant effect on contraceptive efficacy is expected with concomitant use of levonorgestrel, ethinylestradiol and Brilinta®.

P-gp substrates (including digoxin and cyclosporine)

The concomitant use of digoxin with ticagrelor increased Cmax and AUC of digoxin by 75% and 28%, respectively. When co-administered with ticagrelor, the mean value of the lowest concentration of digoxin increased by 30%, in some individual cases doubling. Cmax and AUC of ticagrelor did not change with digoxin administration. Therefore, appropriate clinical and/or laboratory monitoring is recommended when Brilinta® and P-gp-dependent drugs with a narrow therapeutic index, such as digoxin and cyclosporine, are used concomitantly.

Ticagrelor has no effect on the blood concentration of cyclosporine. The effect of ticagrelor on other P-gp substrates has not been studied.

Drugs that may cause bradycardia

Caution should be exercised when co-administering Brilinta® with drugs that may cause bradycardia. However, in PLATO study there were no clinically significant adverse events when concomitant use with one or more drugs that can cause bradycardia (for example, 96% of patients concomitantly took beta-adreno-blockers, 33% – slow calcium channel blockers, including diltiazem and verapamil, and 4% – digoxin).

Other concomitant therapy

In clinical trials, Brilinta® was predominantly administered with ASA, proton pump inhibitors, statins, beta-adrenoblockers, angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists as part of long-term therapy, and with heparin, low molecular weight heparins, glycoprotein IIb/IIIa receptor inhibitors for intravenous administration as part of short-term therapy. According to the results of these studies, no clinically significant adverse interactions were found.

The co-administration of Brilinta® with heparin, enoxaparin or desmopressin had no effect on activated partial thromboplastin time (APT), activated clotting time (ABC) and factor Xa study, but due to potential pharmacodynamic interaction, caution is required when using together with drugs that affect hemostasis.

Because of reports of subcutaneous hemorrhage with selective serotonin reuptake inhibitors (e.g., paroxetine, sertraline and citalopram), caution is recommended when they are combined with Brilinta®.

A 2-fold increase in exposure to ticagrelor has been noted with daily consumption of large amounts of grapefruit juice (200 ml 3 times daily). This increase in ticagrelor exposure is not expected to be clinically significant in most patients.

Special Instructions

Risk of bleeding

When prescribing Brilinta®, the ratio of benefit from prevention of atherothrombotic events to risk in patients at increased risk of bleeding should be evaluated.

When clinically indicated, Brilinta® should be used with caution in the following patient groups:

In a study involving healthy volunteers, platelet transfusion did not terminate the antiplatelet effect of Brilinta® and is likely to have no clinical effect in patients with bleeding. Since the concomitant use of Brilinta® and desmopressin did not decrease the standardized bleeding time, it is unlikely that desmopressin will effectively stop bleeding (see section “Interaction with other medicinal products”).

Antifibrinolytic therapy (aminocaproic acid or tranexamic acid) and/or recombinant factor VIIa may enhance hemostasis. Once the cause of the bleeding has been established and it has resolved, therapy with Brilinta® may be resumed.

Surgical surgeries

Patients should inform their physician that they are taking Brilinta® before any planned surgery or starting new medications.

In the PLATO study, patients who underwent a CABG undergoing Brilinta® had more bleeding compared with clopidogrel when therapy was discontinued one day before surgery, but the incidence of major bleeding when therapy was discontinued 2 or more days before surgery was similar in the ticagrelor and clopidogrel groups (see See section “Side effects”). If a patient undergoes elective surgery and no antithrombotic effect is desired, therapy with Brilinta® should be discontinued 5 days before surgery (see section “Pharmacological properties”).

Patients with previous ischemic stroke

Patients with ACS with previous ischemic stroke may take Brilinta® up to 12 months (PLATO study).

The PEGASUS study did not include patients with a history of myocardial infarction with prior ischemic stroke. Therefore, in the absence of data, therapy of more than 1 year should be used with caution.

Patients with hepatic impairment

The use of Brilinta® is contraindicated in patients with severe hepatic impairment (see

The use of Brilinta® is contraindicated in patients with severe hepatic impairment (see sections “Contraindications” and “Dosage and administration”). Caution should be exercised in patients with moderate hepatic impairment given the limited experience with the drug in this group of patients (see sections “Pharmacokinetics” and “Dosage and administration”).

Bradyarrhythmia

In daily ECG Holter monitoring, an increased frequency of mostly asymptomatic ventricular pauses was noted during ticagrelor therapy compared to clopidogrel. In phase 3 studies evaluating the safety and efficacy of Brilinta® bradyarrhythmia events were recorded with similar frequency for ticagrelor and comparison drugs (placebo, clopidogrel and ASA). Patients at increased risk of bradycardia (e.g., patients without a pacemaker diagnosed with sinus node weakness syndrome, grade 2 or 3 atrioventricular heart block, or bradycardia-related syncope) were excluded from Brilinta® outcome studies. Therefore, due to limited clinical experience with these patients, it is recommended that Brilinta® be used with caution (see also section “Pharmacological properties”).

Cautious use of Brilinta® with drugs that may cause bradycardia should also be observed. However, in PLATO study there were no clinically significant adverse effects when used together with one or more drugs which can cause bradycardia (for example, 96% of patients concomitantly used beta-adreno-blockers, 33% – slow calcium channel blockers, including diltiazem and verapamil, and 4% – digoxin) (see section “Interaction with other medicinal products”). In a substudy using daily ECG Holter monitoring in ticagrelor group compared to clopidogrel, more patients in the acute phase of ACS had ventricular pauses ≥ 3 seconds. Increased number of ventricular pauses registered by daily Holter monitoring during ticagrelor administration was observed more often in patients with chronic heart failure compared to the general population in the acute phase of ACS, but not during the first month of therapy and not compared to clopidogrel. Pauses in these patients were not accompanied by subsequent adverse clinical consequences (syncope and pacemaker placement).

In post-marketing use of Brilinta®, cases of bradyarrhythmia and atrioventricular block (see section “Adverse effects”) were noted, primarily in patients with ACS in which myocardial ischemia and concomitant administration of drugs that reduce heart rate or affect conduction could potentially have an effect. The patient’s clinical condition and concomitant medications should be evaluated as potential causes before adjusting therapy.

Dyspnea

The development of dyspnea has been reported in patients taking Brilinta®. Dyspnea with Brilinta® is usually mild to moderate in intensity and often subsides as therapy with the drug continues. Patients with bronchial asthma/COPD may have an increased absolute risk of dyspnea when taking Brilinta® (see section “Side effects”). In patients with bronchial asthma/COPD, ticagrelor should be used with caution. The mechanism of dyspnea on ticagrelor administration has not been elucidated. If a patient develops a new episode of dyspnea, persists or worsens dyspnea while using Brilinta®, a full evaluation should be performed and if intolerance occurs, the drug should be discontinued.

Central sleep apnea

Cases of central sleep apnea, including Cheyne-Stokes breathing, have been reported during post-marketing use of Brilinta®. If central sleep apnea is suspected, the need for further clinical evaluation should be evaluated.

Elevated creatinine concentration

Creatinine concentration may increase during therapy with Brilinta® (see section “Adverse effects”). The mechanism of this effect is unknown. In patients with ACS, renal function should be evaluated one month after the start of the drug, and thereafter in accordance with routine clinical practice, paying special attention to patients aged 75 years and older, patients with moderate or severe renal insufficiency and those receiving therapy with angiotensin II receptor antagonists.

Elevated uric acid concentration

Urea acid concentration may increase during therapy with Brilinta® (see section “Adverse effects”). Caution should be exercised in patients with a history of hyperuricemia or gouty arthritis. As a preventive measure, ticagrelor should be avoided in patients with hyperuricemic nephropathy.

Trombotic thrombocytopenic purpura (TTP)

TTP with Brilinta® has rarely been reported. TTP is a serious condition and requires immediate treatment.

Influence on laboratory results

Analysis of platelet function as part of the diagnosis of heparin-induced thrombocytopenia (HIT)

Synopsis

Contraindications

Side effects

Safety Profile Overview

The safety profile of Brilinta® has been studied in two large outcome studies (PLATO and PEGASUS) involving over 39,000 patients (see section on Pharmacodynamics).

In the PLATO study, patients receiving Brilinta® were more likely to discontinue therapy due to adverse events than patients receiving clopidogrel (7.4% versus 5.4%). In PEGASUS study patients treated with Brilinta® had higher rate of therapy withdrawal due to adverse events than patients receiving ASA monotherapy (16.1% in ticagrelor 60 mg group in combination with ASA and 8.5% in ASA monotherapy group). The most frequent adverse events in patients receiving ticagrelor were bleeding and dyspnea (see also section “Special Precautions”). Below are the adverse reactions reported in these studies.

List of adverse reactions

The adverse reactions noted in clinical studies or in post-marketing use of Brilinta® are categorized by organ system class and frequency of development. The incidence of adverse reactions is determined using the following categories: very common (≥1/10), common (≥1/100, < 1/10), infrequent (≥1/1000, < 1/100), rare (≥1/10000, < 1/1000), very rare (< 1/10000), unspecified frequency (cannot be estimated from data obtained).

Class of systems

bodies

both benign, malignant and unspecified neoplasms

(including cysts and

polips

Tumor bleeding

sup>2

Blood and lymphatic system disorders

Bleeding related to diseases

blood3

Trombotic thrombocytic thrombopenic purpura13

immune system disorders

Hypersensitivity, including angio-

hypersensitivity, including angioedema13

Disorders of metabolism

substances and nutrition

Hyperuricemia1

Gout/gouty-

Overdose

Pregnancy use