BRILINTA® (ticagrelor)

BRILINTA® (ticagrelor) tablet

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BRILINTA® (ticagrelor) tablet

BRILINTA contains ticagrelor, a cyclopentyltriazolopyrimidine, inhibitor of platelet activation and aggregation mediated by the P2Y12 ADP-receptor. Chemically it is (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5- (propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol. The empirical formula of ticagrelor is C23H28F2N6O4S and its molecular weight is 522.57.

Ticagrelor is a crystalline powder with an aqueous solubility of approximately 10 μg/mL at room temperature.

BRILINTA 90 mg tablets for oral administration contain 90 mg of ticagrelor and the following ingredients: mannitol, dibasic calcium phosphate, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, talc, polyethylene glycol 400, and ferric oxide yellow.

BRILINTA 60 mg tablets for oral administration contain 60 mg of ticagrelor and the following ingredients: mannitol, dibasic calcium phosphate, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol 400, ferric oxide black, and ferric oxide red.

Indications and usage

BRILINTA is a P2Y12 platelet inhibitor indicated

  • to reduce the risk of cardiovascular (CV) death, myocardial infarction (MI), and stroke in patients with acute coronary syndrome (ACS) or a history of MI. For at least the first 12 months following ACS, it is superior to clopidogrel. BRILINTA also reduces the risk of stent thrombosis in patients who have been stented for treatment of ACS.
  • to reduce the risk of a first MI or stroke in patients with coronary artery disease (CAD) at high risk for such events. While use is not limited to this setting, the efficacy of BRILINTA was established in a population with type 2 diabetes mellitus (T2DM).
  • to reduce the risk of stroke in patients with acute ischemic stroke (NIH Stroke Scale score ≤5) or high-risk transient ischemic attack (TIA)

Mechanism of Action

Ticagrelor and its major metabolite reversibly interact with the platelet P2Y12 ADP-receptor to prevent signal transduction and platelet activation. Ticagrelor and its active metabolite are approximately equipotent.

Pharmacokinetics

Ticagrelor demonstrates dose proportional pharmacokinetics, which are similar in patients and healthy volunteers.

Absorption: BRILINTA can be taken with or without food. Absorption of ticagrelor occurs with a median tmax of 1.5 h (range 1.0–4.0). The formation of the major circulating metabolite AR-C124910XX (active) from ticagrelor occurs with a median tmax of 2.5 h (range 1.5-5.0).

The mean absolute bioavailability of ticagrelor is about 36% (range 30%-42%). Ingestion of a high-fat meal had no effect on ticagrelor Cmax, but resulted in a 21% increase in AUC. The Cmax of its major metabolite was decreased by 22% with no change in AUC.

BRILINTA as crushed tablets mixed in water, given orally or administered through a nasogastric tube into the stomach, is bioequivalent to whole tablets (AUC and Cmax within 80-125% for ticagrelor and AR-C124910XX) with a median tmax of 1.0 hour (range 1.0 – 4.0) for ticagrelor and 2.0 hours (range 1.0 –8.0) for AR-C124910XX.

Distribution: The steady state volume of distribution of ticagrelor is 88 L. Ticagrelor and the active metabolite are extensively bound to human plasma proteins (>99%).

Metabolism: CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. Ticagrelor and its major active metabolite are weak P-glycoprotein substrates and inhibitors. The systemic exposure to the active metabolite is approximately 30-40% of the exposure of ticagrelor.

Excretion: The primary route of ticagrelor elimination is hepatic metabolism. When radiolabeled ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (58% in feces, 26% in urine). Recoveries of ticagrelor and the active metabolite in urine were both less than 1% of the dose. The primary route of elimination for the major metabolite of ticagrelor is most likely to be biliary secretion. The mean t ½ is approximately 7 hours for ticagrelor and 9 hours for the active metabolite.

Dosage and administration

ACS or History of MI

  • Initiate treatment with 180 mg oral loading dose of BRILINTA. Then administer 90 mg twice daily during the first year. After one year, administer 60 mg twice daily

Patients with CAD and No Prior Stroke or MI

  • Administer 60 mg BRILINTA twice daily.

Acute Ischemic Stroke

  • Initiate treatment with a 180 mg loading dose of BRILINTA then continue with 90 mg twice daily for up to 30 days

Use BRILINTA with a daily maintenance dose of aspirin of 75-100 mg

Contraindications

  • History of intracranial hemorrhage.
  • Active pathological bleeding.
  • Hypersensitivity to ticagrelor or any component of the product.

Warnings and precautions

  • Dyspnea was reported more frequently with BRILINTA than with control agents in clinical trials. Dyspnea from BRILINTA is self-limiting.
  • Severe Hepatic Impairment: Likely increase in exposure to ticagrelor.
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  • Laboratory Test Interference: False negative platelet functional test results have been reported for Heparin Induced Thrombocytopenia (HIT). BRILINTA is not expected to impact PF4 antibody testing for HIT

Side effects

Blood and lymphatic system disorders: Thrombotic Thrombocytopenic Purpura (TTP) has been rarely reported with the use of BRILINTA. TTP is a serious condition which can occur after a brief exposure (<2 weeks) and requires prompt treatment.

Immune system disorders: Hypersensitivity reactions including angioedema

Respiratory Disorders: Central sleep apnea, Cheyne-Stokes respiration

Skin and subcutaneous tissue disorders: Rash

Drug interactions

Strong CYP3A Inhibitors: StrongCYP3A inhibitors substantially increase ticagrelor exposure and so increase the risk of dyspnea, bleeding, and other adverse events. Avoid use of strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir and telithromycin)

Strong CYP3A Inducers: Strong CYP3A inducers substantially reduce ticagrelor exposure and so decrease the efficacy of ticagrelor. Avoid use with strong inducers of CYP3A (e.g., rifampin, phenytoin, carbamazepine and phenobarbital)

Aspirin: Use of BRILINTA with aspirin maintenance doses above 100 mg reduced the effectiveness of BRILINTA

Opioids: As with other oral P2Y12 inhibitors, co-administration of opioid agonists delay and reduce the absorption of ticagrelor and its active metabolite presumably because of slowed gastric emptying. Consider the use of a parenteral anti-platelet agent in acute coronary syndrome patients requiring co-administration of morphine or other opioid agonists.

Simvastatin, Lovastatin: BRILINTA increases serum concentrations of simvastatin and lovastatin because these drugs are metabolized by CYP3A4. Avoid simvastatin and lovastatin doses greater than 40 mg

Digoxin: BRILINTA inhibits the P-glycoprotein transporter; monitor digoxin levels with initiation of or change in BRILINTA therapy

Use in specific populations

Preganancy: Available data from case reports with BRILINTA use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Ticagrelor given to pregnant rats and pregnant rabbits during organogenesis caused structural abnormalities in the offspring at maternal doses about 5 to 7 times the maximum recommended human dose (MRHD) based on body surface area. When ticagrelor was given to rats during late gestation and lactation, pup death and effects on pup growth were seen at approximately 10 times the MRHD.

Lactation: There are no data on the presence of ticagrelor or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Ticagrelor and its metabolites were present in rat milk at higher concentrations than in maternal plasma. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Breastfeeding is not recommended during treatment with BRILINTA.

Pediatric Use: The safety and effectiveness of BRILINTA in pediatric patients have not been established.

Geriatric Use: About half of the patients in PLATO, PEGASUS, THEMIS, and THALES were ≥65 years of age and at least 15% were ≥75 years of age. No overall differences in safety or effectiveness were observed between elderly and younger patients.

Hepatic Impairment: Ticagrelor is metabolized by the liver and impaired hepatic function can increase risks for bleeding and other adverse events. Avoid use of BRILINTA in patients with severe hepatic impairment. There is limited experience with BRILINTA in patients with moderate hepatic impairment; consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor. No dosage adjustment is needed in patients with mild hepatic impairment

Renal Impairment: No dosage adjustment is needed in patients with renal impairment

Overdosage

There is currently no known treatment to reverse the effects of BRILINTA, and ticagrelor is not dialyzable. Treatment of overdose should follow local standard medical practice. Bleeding is the expected pharmacologic effect of overdosing. If bleeding occurs, appropriate supportive measures should be taken.

Platelet transfusion did not reverse the antiplatelet effect of BRILINTA in healthy volunteers and is unlikely to be of clinical benefit in patients with bleeding.

Other effects of overdose may include gastrointestinal effects (nausea, vomiting, diarrhea) or ventricular pauses. Monitor the ECG.

Storage and Handling

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP controlled room temperature].

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