PLAXELOR

Ticagrelor, or AZD6140, was first described in the literature in 2003. 4, 5 Ticagrelor is an ADP derivative developed for its P2Y 12 receptor antagonism.

Unlike clopidogrel, ticagrelor is not a prodrug.

It is marketed by Astra Zeneca as Brilinta in the US and Brilique or Possia in the EU, 7.

Ticagrelor was granted

EMA approval on 3 December 2010.

FDA approval on 20 July 2011.

Ticagrelor is indicated to reduce the risk of cardiovascular death, myocardial infarction, and stroke in patients with acute coronary syndrome or a history of myocardial infarction.

Ticagrelor is also indicated to reduce the risk of a first myocardial infarction or stroke in high risk patients with coronary artery disease.

Ticagrelor is a

P2Y 12 receptor antagonist that inhibits the formation of thromboses to reduce the risk of myocardial infarction and ischemic stroke. 1, 3 It has a moderate duration of action as it is given twice daily, and a wide therapeutic index as high single doses are well tolerated. 6, 7 Patients should be counselled regarding the risk of bleeding, dyspnea, and bradyarrhythmias.

Ticagrelor is 36% Oral bioavailable.

A single 200 mg oral dose of ticagrelor reaches a C max of 923ng/mL, with a T max of 1.5 hours and an AUC of 6675ng*h/mL.

The active metabolite of ticagrelor reaches a C max of 264ng/mL, with a T max of 3.0 hours and an AUC of 2538ng*h/mL.

The steady state volume of distribution of ticagrelor is 88 L.

The complete structure of all ticagrelor metabolites are not well defined.

Ticagrelor can be dealkylated at postition of the cyclopentane ring to form the active AR-C124910XX.

AR-C124910XX's cyclopentane ring can be further glucuronidated or the alkyl chain attached to the sulfur can be hydroxylated.

Ticagrelor can also be glucuronidated or hydroxylated.

Ticagrelor can also be N-dealkylated to form AR-C133913XX, which is further glucuronidated or hydroxylated.

Hover over products below to view reaction partners Ticagrelor AR-C124910XX AR-C133913XX.

A radiolabelled dose of ticagrelor is 57.8% recovered in feces and 26.5% recovered in urine. 1, 6 Less than 1% of the dose is recovered as the unmetabolized parent drug.

The active metabolite

AC-C124910XX makes up 21.7% of the recovery in the feces.

The metabolite

AR-C133913XX makes up 9.2% of the recovery in the urine and 2.7% of the recovery in the feces.

Other minor metabolites are predominantly recovered in the urine.

Ticagrelor has a plasma half life of approximately 8 hours, while the active metabolite has a plasma half life of approximately 12 hours.

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Patients experiencing an overdose may present with bleeding, nausea, vomiting, diarrhea, and ventricular pauses.

Overdose can be managed through symptomatic and supportive treatment, including ECG monitoring. 6, 7 Dialysis is not expected to remove ticagrelor from the blood due to it being highly protein bound.

• History of intracranial hemorrhage.

• Active pathological bleeding.

• Hypersensitivity to ticagrelor or any component of the product. 4.1 History of Intracranial Hemorrhage Ticagrelor tablets are contraindicated in patients with a history of intracranial hemorrhage (ICH) because of a high risk of recurrent ICH in this population. 4.2 Active Bleeding Ticagrelor tablets are contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage. 4.3 Hypersensitivity Ticagrelor tablets are contraindicated in patients with hypersensitivity (e.g., angioedema) to ticagrelor or any component of the product.

or History of MI Initiate treatment with 180 mg oral loading dose of ticagrelor tablets.

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 ticagrelor tablets twice daily.

Initiate treatment with a 180 mg loading dose of ticagrelor tablets then continue with 90 mg twice daily for up to 30 days.

Use ticagrelor tablets with a daily maintenance dose of aspirin of to 100 mg. However, in patients who have undergone PCI, consider single antiplatelet therapy with ticagrelor tablets based on the evolving risk for thrombotic versusbleeding events. 2.1 General Instructions Advise patients who miss a dose of ticagrelor tablets to take their next dose at its scheduled time.

For patients who are unable to swallow tablets whole, ticagrelor tablets can be crushed, mixed with water, and drunk.

The mixture can also be administered via a nasogastric tube (CH8 or greater) .

Do not administer ticagrelor tablets with another oral P2Y 12 platelet inhibitor.

Avoid aspirin at doses higher than recommended. 2.2 Acute Coronary Syndrome or a History of Myocardial Infarction Initiate treatment with a 180 mg loading dose of ticagrelor tablets.

Administer the first 90 mg maintenance dose of ticagrelor tablets, 6 to 12 hours after the loading dose.

Administer 90 mg of ticagrelor tablets twice daily during the first year after an ACS event.

After one year, administer 60 mg of ticagrelor tablets twice daily.

Initiate ticagrelor tablets with a daily maintenance dose of aspirin of 75 mg to 100 mg. However, in patients who have undergone percutaneous coronary intervention (PCI), consider single antiplatelet therapy with ticagrelor tablets based on the evolving risk for thrombotic versus bleeding events. 2.3 Coronary Artery Disease but No Prior Stroke or Myocardial Infarction Administer 60 mg of ticagrelor tablets twice daily.

Generally, use ticagrelor tablets with a daily maintenance dose of aspirin of 75 mg to 100 mg. 2.4 Acute Ischemic Stroke or Transient Ischemic Attack (TIA) Initiate treatment with a 180 mg loading dose of ticagrelor tablets and then continue with 90 mg twice daily for up to 30 days.

Administer the first maintenance dose to 12 hours after the loading dose.

Use ticagrelor tablets with a loading dose of aspirin (300 mg to 325 mg) and a daily maintenance dose of aspirin of 75 mg to 100 mg.

Ticagrelor tablets 90 mg is supplied as a round, biconvex, yellow, film-coated tablet debossed with ' '( logo) on one side and T on the other side.

Free from physical defects.

Bottles of 60 NDC 43598-480-60 Bottles of 180 NDC 43598-480-18 Cartons containing 1 blister card of 10 tablets (1 x 10) NDC 43598-480-79 Cartons containing 100 count Hospital Unit Dose NDC 43598-480-78 Ticagrelor tablets 60 mg is supplied as a round, biconvex, white to off white, film-coated tablet debossed with “T” on one side and plain on the other side.

Bottles of 60 NDC 43598-629-60 Bottles of 180 NDC 43598-629-18 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); .

Available data from case reports with ticagrelor 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 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.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

In reproductive toxicology studies, pregnant rats received ticagrelor during organogenesis at doses from to 300 mg/kg/day. 20 mg/kg/day is approximately the same as the MRHD of 90 mg twice daily for a 60 kg human on a mg/m 2 basis.

Adverse outcomes in offspring occurred at doses of 300 mg/kg/day (16.5 times the MRHD on a mg/m 2 basis) and included supernumerary liver lobe and ribs, incomplete ossification of sternebrae, displaced articulation of pelvis, and misshapen/misaligned sternebrae.

At the mid-dose of 100 mg/kg/day (5.5 times the MRHD on a mg/m 2 basis), delayed development of liver and skeleton was seen.When pregnant rabbits received ticagrelor during organogenesis at doses from 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/m 2 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 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/m 2 basis).

Relatively minor effects such as delays in pinna unfolding and eye opening occurred at doses of and 60 mg/kg (approximately one-half and 3.2 times the MRHD on a mg/m 2 basis).

The safety and effectiveness of ticagrelor tablets have not been established in pediatric patients.

Pediatric use information describing a clinical study in which efficacy was not demonstrated is approved for AstraZeneca Pharmaceuticals LP’s BRILINTA® (ticagrelor) tablets.

However, due to AstraZeneca Pharmaceuticals LP’s marketing exclusivity rights, this drug product is not labeled with that information.

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.