Ticagrelor

Synonyms and keywords: Brilinta

To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY or FDA at 1-800-FDA-1088 or the FDA Medwatch site.

Overview
Ticagrelor (previously known as AZD6140) is a member of a new generation of P2Y12 inhibitors. Chemically, this is a first-in-class member of the cyclo-pentyl-triazolo-pyrimidine (CPTP) family with a mean terminal half-life of approximately 7 h and a median Tmax of 2.6 h. Ticagrelor’s steady-state volume of distribution (87.5 L) indicates it does not extensively distribute into or bind to tissues.

Indications
Ticagrelor is a P2Y12 platelet inhibitor indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) (unstable angina, non-ST elevation myocardial infarction, or ST elevation myocardial infarction). Ticagelor has been shown to reduce the rate of a combined endpoint of cardiovascular death, myocardial infarction, or stroke compared to clopidogrel. The difference between treatments was driven by CV death and MI with no difference in stroke. In patients treated with PCI, it also reduces the rate of stent thrombosis.

Ticagrelor has been studied in ACS in combination with aspirin. Maintenance doses of aspirin above 100 mg decreased the effectiveness of Ticagrelor. Avoid maintenance doses of aspirin above 100 mg daily.

Method of action
Like thienopyridines, ticagrelor is only orally available, but in contrast with these pro-drugs, ticagrelor is direct acting, i.e. does not require metabolic activation. In addition, ticagrelor is a reversible P2Y12 inhibitor with more rapid onset and off set of action compared with clopidogrel. Ticagrelor has 2 metabolites. The major ticagrelor metabolite (AR-C124910XX) has a P2Y12 inhibiting activity comparable to the parent compound while a second metabolite (AR-C133913XX) is inactive. Ticagrelor is rapidly and extensively metabolized in the liver by CYP3A4. The P2Y12 receptor is targeted by ticagrelor via a mechanism that is non-competitive with ADP, suggesting the existence of an independent receptor-binding site. Compared with clopidogrel, ticagrelor provides greater and more consistent platelet inhibition.

Dosing
Initiate Ticagrelor treatment with a 180 mg (two 90 mg tablets) loading dose and continue treatment with 90 mg twice daily After the initial loading dose of aspirin (usually 325 mg), use Ticagrelor with a daily maintenance dose of aspirin of 75-100 mg.

ACS patients who have received a loading dose of clopidogrel may be started on Ticagrelor.

Ticagrelor can be administered with or without food.

A patient who misses a dose of Ticagrelor should take one 90 mg tablet (their next dose) at its scheduled time.

Dosage Forms and Strengths
Ticagrelor 90 mg is supplied as a round, biconvex, yellow, film-coated tablet marked with a “90” above “T” on one side.

History of Intracranial Hemorrhage
Ticagrelor is contraindicated in patients with a history of intracranial hemorrhage (ICH) because of a high risk of recurrent ICH in this population.

Active Bleeding
Ticagrelor is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage.

Severe Hepatic Impairment
Ticagrelor is contraindicated in patients with severe hepatic impairment because of a probable increase in exposure, and it has not been studied in these patients. Severe hepatic impairment increases the risk of bleeding because of reduced synthesis of coagulation proteins.

General Risk of Bleeding
Drugs that inhibit platelet function including Ticagrelor increase the risk of bleeding. Ticagrelor increased the overall risk of bleeding (Major + Minor) to a somewhat greater extent than did clopidogrel. The increase was seen for non-CABG-related bleeding, but not for CABG-related bleeding. Fatal and life-threatening bleeding rates were not increased.

In general, risk factors for bleeding include older age, a history of bleeding disorders, performance of percutaneous invasive procedures, and concomitant use of medications that increase the risk of bleeding (e.g., anticoagulant and fibrinolytic therapy, higher doses of aspirin, and chronic nonsteroidal anti-inflammatory drugs [NSAIDS]).

When possible, discontinue Ticagrelor five days prior to surgery. Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or other surgical procedures, even if the patient does not have any signs of bleeding.

If possible, manage bleeding without discontinuing Ticagrelor. Stopping Ticagrelor increases the risk of subsequent cardiovascular events.

Concomitant Aspirin Maintenance Dose
In PLATO, use of Ticagrelor with maintenance doses of aspirin above 100 mg decreased the effectiveness of Ticagrelor. Therefore, after the initial loading dose of aspirin (usually 325 mg), use Ticagrelor with a maintenance dose of aspirin of 75-100 mg.

Moderate Hepatic Impairment
Ticagrelor has not been studied in patients with moderate hepatic impairment. Consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor.

Dyspnea
Dyspnea was reported in 14% of patients treated with Ticagrelor and in 8% of patients taking clopidogrel. Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment. If a patient develops new, prolonged, or worsened dyspnea during treatment with Ticagrelor, exclude underlying diseases that may require treatment. If dyspnea is determined to be related to Ticagrelor, no specific treatment is required; continue Ticagrelor without interruption.

In a substudy, 199 patients from PLATO underwent pulmonary function testing irrespective of whether they reported dyspnea. There was no significant difference between treatment groups for FEV1. There was no indication of an adverse effect on pulmonary function assessed after one month or after at least 6 months of chronic treatment.

Discontinuation of Ticagrelor
Avoid interruption of Ticagrelor treatment. If Ticagrelor must be temporarily discontinued (e.g., to treat bleeding or for elective surgery), restart it as soon as possible. Discontinuation of Ticagrelor will increase the risk of myocardial infarction, stent thrombosis, and death.

Strong Inhibitors of Cytochrome CYP3A
Ticagrelor is metabolized by CYP3A4/5. Avoid use with strong CYP3A inhibitors, such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole.

Cytochrome CYP3A Potent Inducers
Avoid use with potent CYP3A inducers, such as rifampin, dexamethasone, phenytoin, rbamazepine, and phenobarbital.

Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Ticagrelor has been evaluated for safety in more than 10000 patients, including more than 3000 patients treated for more than 1 year.

Bleeding
PLATO used the following bleeding severity categorization:


 * Major bleed – fatal/life-threatening. Any one of the following: fatal; intracranial; intrapericardial bleed with cardiac tamponade; hypovolemic shock or severe hypotension due to bleeding and requiring pressors or surgery; clinically overt or apparent bleeding associated with a decrease in hemoglobin (Hb) of more than 5 g/dL; transfusion of 4 or more units (whole blood or packed red blood cells ((PRBCs)) for bleeding.
 * Major bleed – other. Any one of the following: significantly disabling (e.g., intraocular with permanent vision loss); clinically overt or apparent bleeding associated with a decrease in Hb of 3 g/dL; transfusion of 2-3 units (whole blood or PRBCs) for bleeding.
 * Minor bleed. Requires medical intervention to stop or treat bleeding (e.g., epistaxis requiring visit to medical facility for packing).
 * Minimal bleed. All others (e.g., bruising, bleeding gums, oozing from injection sites, etc.) not requiring intervention or treatment.

Drug Discontinuation
In PLATO, the rate of study drug discontinuation attributed to adverse reactions was 7.4% for Ticagrelor and 5.4% for clopidogrel. Bleeding caused permanent discontinuation of study drug in 2.3% of Ticagrelor patients and 1.0% of clopidogrel patients. Dyspnea led to study drug discontinuation in 0.9% of Ticagrelor and 0.1% of clopidogrel patients.

Bradycardia
In clinical studies Ticagrelor has been shown to increase the occurrence of Holterdetected bradyarrhythmias (including ventricular pauses). PLATO excluded patients at increased risk of bradycardic events (e.g., patients who have sick sinus syndrome, 2nd or 3rd degree AV block, or bradycardic-related syncope and not protected with a pacemaker). In PLATO, syncope, pre-syncope and loss of consciousness were reported by 1.7% and 1.5% of Ticagrelor and clopidogrel patients, respectively.

In a Holter substudy of about 3000 patients in PLATO, more patients had ventricular pauses with Ticagrelor (6.0%) than with clopidogrel (3.5%) in the acute phase; rates were 2.2% and 1.6% respectively after 1 month.

Gynecomastia
In PLATO, gynecomastia was reported by 0.23% of men on Ticagrelor and 0.05% on clopidogrel.

Other sex-hormonal adverse reactions, including sex organ malignancies, did not differ between the two treatment groups in PLATO.

Lab abnormalities

 * Serum Uric Acid: Serum uric acid levels increased approximately 0.6 mg/dL from baseline on Ticagrelor and approximately 0.2 mg/dL on clopidogrel in PLATO. The difference disappeared within 30 days of discontinuing treatment. Reports of gout did not differ between treatment groups in PLATO (0.6% in each group).


 * Serum Creatinine: In PLATO, a >50% increase in serum creatinine levels was observed in 7.4% of patients receiving Ticagrelor compared to 5.9% of patients receiving clopidogrel. The increases typically did not progress with ongoing treatment and often decreased with continued therapy. Evidence of reversibility upon discontinuation was observed even in those with the greatest on treatment increases. Treatment groups in PLATO did not differ for renal-related serious adverse events such as acute renal failure, chronic renal failure, toxic nephropathy, or oliguria.

Drug Interactions
Ticagrelor is predominantly metabolized by CYP3A4 and to a lesser extent by CTP3A5.

Ticagrelor is an inhibitor of CYP3A4/5 and the P-glycoprotein tranporter.

CYP3A inhibitors
Avoid use of strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir and telithromycin).

CYP3A inducers
Avoid use with potent inducers of CYP3A (e.g., rifampin, dexamethasone, phenytoin, carbamazepine and phenobarbital).

Aspirin
Use of Ticagrelor with aspirin maintenance doses above 100 mg reduced the effectiveness of Ticagrelor.

Simvastatin, Iovastatin
Ticagrelor will result in higher serum concentrations of simvastatin and lovastatin because these drugs are metabolized by CYP3A4. Avoid simvastatin and lovastatin doses greater than 40 mg.

Digoxin
Because Ticagrelor inhibits the P-glycoprotein transporter, monitor digoxin levels with initiation of or any change in Ticagrelor therapy

Other Concomitant Therapy
Ticagrelor can be administered with unfractionated or low-molecular-weight heparin, GPIIb/IIIa inhibitors, proton pump inhibitors, beta-blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers.

Pregnancy
There are no adequate and well-controlled studies of Ticagrelor use in pregnant women. In animal studies, Ticagrelor caused structural abnormalities at maternal doses about 5 to 7 times the maximum recommended human dose (MRHD) based on body surface area. Ticagrelor should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In reproductive toxicology studies, pregnant rats received Ticagrelor during organogenesis at doses from 20 to 300 mg/kg/day. The lowest dose was approximately the same as the MRHD of 90 mg twice daily for a 60 kg human on a mg/m2 basis. Adverse outcomes in offspring occurred at doses of 300 mg/kg/day (16.5 times the MRHD on a mg/m2 basis) and included supernumerary liver lobe and ribs, incomplete ossification of sternebrae, displaced articulation of pelvis, and misshapen/misaligned sternebrae. When pregnant rabbits received ticagrelor during organogenesis at doses from 21 to 63 mg/kg/day, fetuses exposed to the highest maternal dose of 63 mg/kg/day (6.8 times the MRHD on a mg/m2 basis) had delayed gall bladder development and incomplete ossification of the hyoid, pubis] and [[sternebrae occurred.

In a prenatal/postnatal study, pregnant rats received Ticagrelor at doses of 10 to 180 mg/kg/day during late gestation and lactation. Pup death and effects on pup growth were observed at 180 mg/kg/day (approximately 10 times the MRHD on a mg/m2 basis). Relatively minor effects such as delays in pinna unfolding and eye opening occurred at doses of 10 and 60 mg/kg (approximately one-half and 3.2 times the MRHD on a mg/m2 basis).

Nursing Mothers
It is not known whether Ticagrelor or its active metabolites are excreted in human milk. Ticagrelor is excreted in rat milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Ticagrelor, a decision should be made whether to discontinue nursing or to discontinue drug, taking into account the importance of the drug to the mother.

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

Geriatric Use
In PLATO, 43% of patients were ≥65 years of age and 15% were ≥75 years of age. The relative risk of bleeding was similar in both treatment and age groups.

No overall differences in safety or effectiveness were observed between these patients and younger patients. While this clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.

Hepatic Impairment
Ticagrelor has not been studied in the patients with moderate or severe hepatic impairment. Ticagrelor is metabolized by the liver and impaired hepatic function can increase risks for bleeding and other adverse events. Hence, Ticagrelor is contraindicated for use in patients with severe hepatic impairment and its use should be considered carefully in patients with moderate hepatic impairment. No dosage adjustment is needed in patients with mild hepatic impairment.

Renal Impairment
No dosage adjustment is needed in patients with renal impairment. Patients receiving dialysis have not been studied.