Belinta Tablet

Belinta, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with acute coronary syndromes (ACS) or a history of myocardial infarction (MI) and a high risk of developing an atherothrombotic event.

Ticagrelor is a P2Y₁₂ receptor antagonist. The P2Y₁₂ receptor couples with Gα_i2 and other G_i proteins which inhibit adenylyl cyclase. G_i mediated signalling also activates PI3K, Akt, Rap1b, and potassium channels. The downstream effects of these activities mediate hemostasis and lead to platelet aggregation. Antagonism of the P2Y₁₂ receptor reduces development of occlusive thromboses, which can reduce the risk of myocardial infarction and ischemic stroke.

Patients taking Ticagrelor should also take a daily low maintenance dose of acetylsalicylic acid (ASA) 75-150 mg unless specifically contraindicated.

Acute coronary syndromes: Ticagrelor treatment should be initiated with a single 180 mg loading dose (two tablets of 90 mg) and then continued at 90 mg twice daily. Treatment with Ticagrelor twice daily is recommended for 12 months in ACS patients unless discontinuation is clinically indicated.

History of myocardial infarction: Ticagrelor 60 mg twice daily is the recommended dose when an extended treatment is required for patients with a history of MI of at least one year and a high risk of an atherothrombotic event. Treatment may be started without interruption as continuation therapy after the initial one-year treatment with ticagrelor or another adenosine diphosphate (ADP) receptor inhibitor therapy in ACS patients with a high risk of an atherothrombotic event. Treatment can also be initiated up to 2 years from the MI, or within one year after stopping previous ADP receptor inhibitor treatment. There are limited data on the efficacy and safety of ticagrelor beyond 3 years of extended treatment.

Switch therapy: If a switch is needed, the first dose of ticagrelor should be administered 24 hours following the last dose of the other antiplatelet medication.

Missed dose: A patient who misses a dose of ticagrelor should take only one tablet (their next dose) at its scheduled time.

Elderly: No dose adjustment is required in the elderly.

Renal impairment: No dose adjustment is necessary for patients with renal impairment. No information is available concerning the treatment of patients on renal dialysis and therefore ticagrelor is not recommended in these patients.

Hepatic impairment: Ticagrelor has not been studied in patients with severe hepatic impairment and its use in these patients is therefore contraindicated. Only limited information is available in patients with moderate hepatic impairment. Dose adjustment is not recommended, but ticagrelor should be used with caution. No dose adjustment is necessary for patients with mild hepatic impairment.

Pediatric population: The safety and efficacy of ticagrelor in hildren below the age of 18 years have not been established. No data are available. Ticagrelor can be administered with or without food. Contra-indications, warnings etc.

Effects of medicinal and other products on Belinta;

CYP3A4 inhibitors: Concomitant use of strong CYP3A4 clarithromycin, nefazodone, ritonavir, and atazanavir) inhibitors with Belinta is contraindicated.

CYP3A inducers: Co-administration of Belinta with potent CYP3A inducers (rifampicin)may decrease exposure and efficacy of Belinta, therefore, their concomitant use with Belinta is discouraged.

Cyclosporine (P-gp and CYP3A inhibitor): No data are available on concomitant use of Belinta with other active substances that also are potent P-gp inhibitors and moderate CYP3A4 inhibitors (e.g. verapamil, quinidine) that also may increase Belinta exposure. If the association cannot be avoided, their concomitant use should be made with caution.

Effects of Belinta on other medicinal products: Medicinal products metabolised by CYP3A4: The concomitant use of Belinta with doses of simvastatin or lovastatin greater than 40 mg is not recommended. Atorvastatin: Co-administration of atorvastatin and Belinta increased atorvastatin acid Cmax by 23% and AUC by 36%. Similar increases in AUC and Cmax were observed for all atorvastatin acid metabolites. These increases are not considered clinically significant. Belinta is a mild CYP3A4 inhibitor. Co-administration of Belinta and CYP3A4 substrates with narrow therapeutic indices (i.e. cisapride or ergot alkaloids) is not recommended, as Belinta may increase the exposure to this medicinal products.

P-gp substrates (including digoxin, cyclosporine): Appropriate clinical and/or laboratory monitoring is recommended when giving narrow therapeutic index P-gp dependent medicinal products like digoxin concomitantly with Belinta.

Medicinal products metabolised by CYP2C9: Co-administration of Belinta with tolbutamide resulted in no change in the plasma levels of either medicinal product, which suggests that Belinta is not a CYP2C9 inhibitor and unlikely to alter the CYP2C9 mediated metabolism of medicinal products like warfarin and tolbutamide.

Oral contraceptives: No clinically relevant effect on oral contraceptive efficacy is expected when levonorgestrel and ethinyl estradiol is co-administered with Belinta.

Medicinal products known to induce bradycardia: No evidence of clinically significant adverse reactions were observed in the PLATO trial after 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 therapy: No evidence of clinically significant adverse interactions with these medicinal products (acetylsalicylic acid, proton pump inhibitors, statins, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers) was observed. Due to potential pharmacodynamic interactions, caution should be exercised with the concomitant administration of Belinta with medicinal products (heparin, enoxaparin or desmopressin) known to alter haemostasis. Due to reports of cutaneous bleeding abnormalities with SSRIs (e.g. paroxetine, sertraline and citalopram), caution is advised when administering SSRIs with Belinta as this may increase the risk of bleeding.

Hypersensitivity to the active substance or to any of the excipients, active pathological bleeding, history of intracranial haemorrhage, severe hepatic impairment.

Very Common: Blood disorder bleedings, Hyperuricaemia, Dyspnoea. Common: Gout/Gouty Arthritis, Dizziness, Syncope, Headache, Vertigo, Hypotension, Respiratory system bleedings, Gastrointestinal haemorrhage, Diarrhoea, Nausea, Dyspepsia, Constipation, Subcutaneous or dermal bleeding, Rash, Pruritus, Urinary tract bleeding, Blood creatinine increased, Postprocedural haemorrhage, Traumatic bleedings. Uncommon: Tumour bleedings, Hypersensitivity including angioedema, Confusion, Intracranial haemorrhage, Eye haemorrhage, Ear haemorrhage, Retroperitoneal haemorrhage, Muscular bleedings.

Ticagrelor is not recommended during pregnancy. Available pharmacodynamic/toxicological data in animals have shown excretion of ticagrelor and its active metabolites in milk. A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ticagrelor therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Bleeding risk: The use of Belinta in patients at known increased risk for bleeding should be balanced against the benefit in terms of prevention of atherothrombotic events. If clinically indicated, Belinta should be used with caution in the following patient groups; Patients with a propensity to bleed (e.g. due to recent trauma, recent surgery, coagulation disorders, active or recent gastrointestinal bleeding). Antifibrinolytic therapy (aminocaproic acid or tranexamic acid) and/or recombinant factor VIIa therapy may increase haemostasis. Belinta may be resumed after the cause of bleeding has been identified and controlled.

Surgery: Patients should be advised to inform  physicians and dentists that they are taking Belinta before any surgery is scheduled and before any new medicinal product is taken. If a patient is to undergo elective surgery and the antiplatelet effect is not desired, Belinta should be discontinued 5 days prior to surgery.

Patients with prior ischaemic stroke: ACS patients with prior ischaemic stroke can be treated with Belinta for up to 12 months. Patients at risk for bradycardic events: Due to the limited clinical experience, Belinta should be used with caution in these patients.

Dyspnoea: Patients with asthma/chronic obstructive pulmonary disease (COPD) may have an increased absolute risk of experiencing dyspnoea with Belinta. Belinta should be used with caution in patients with a history of asthma and/or COPD. Creatinine elevations: Creatinine levels may increase during treatment with Belinta. In patients with ACS, it is recommended that renal function is also checked one month after initiating the treatment with Belinta, paying special attention to patients ≥75 years, patients with moderate/severe renal impairment and those receiving concomitant treatment with an angiotensin receptor blocker (ARB). Uric acid increase: Hyperuricaemia may occur during treatment with Belinta. Caution is advised in patients with a history of hyperuricaemia or gouty arthritis. Other: Based on a relationship observed in PLATO between maintenance dose of acetylsalicylic acid (ASA) and relative efficacy of Belinta compared to clopidogrel, co-administration of Belinta and high maintenance dose of acetylsalicylic acid (ASA) (>300 mg) is not recommended.

Premature discontinuation: Premature discontinuation with any antiplatelet therapy, including Belinta, could result in an increased risk of cardiovascular (CV) death or MI due to the patient’s underlying disease. Therefore, premature discontinuation of treatment should be avoided.

Belinta is well tolerated in single doses up to 900 mg. Gastrointestinal toxicity was dose-limiting in a single ascending dose study. Other clinically meaningful adverse reactions which may occur with overdose include dyspnoea and ventricular pauses.

Anti-platelet drugs

Store in a cool and dry place, protected from light.