Ticagrelor

Ticagrelor is used along with aspirin to prevent serious or life-threatening problems with the heart and blood vessels in people who have had a heart attack or severe chest pain. It is also used to prevent blood clots from forming in people with coronary stents (metal tubes surgically placed in clogged blood vessels to improve blood flow) who have had a heart attack or severe chest pain. Ticagrelor is in a class of medications called antiplatelet medications. It works by preventing platelets (a type of blood cell) from collecting and forming clots that may cause a heart attack or stroke.

CYP2C19 is an enzyme in the blood that is responsible for breaking down ticagrelor and other drugs in the body. Some patients have less of this protein in their bodies, affecting how much of the drug gets eliminated. Levels of CYP2C19 can vary greatly between individuals, and those having less of this protein are known as "poor metabolizers." 

CYP2C19 testing is done to determine whether you are a poor metabolizer. If you are a poor metabolizer, the levels of ticagrelor in your blood can become too high. As a result you may be at an increased risk of having more side effects from ticagrelor. 

Your doctor may adjust your dose of ticagrelor if you are a poor metabolizer.

Ticagrelor can cause bleeding that can be serious and sometimes lead to death. In cases of serious bleeding, such as internal bleeding, the bleeding may result in the need for blood transfusions or surgery. Call your doctor right away if you:

• bruise and bleed more easily
• have nose bleeds
• are having bleeding that is severe or that you cannot control
• have pink, red or brown urine
• are vomiting blood or your vomit looks like “coffee grounds”
• have red or black stools (looks like tar)
• are coughing up blood or blood clots

Do not stop taking ticagrelor without talking to the doctor who prescribes it for you. People who are treated with a stent, and stop taking ticagrelor too soon, have a higher risk of getting a blood clot in the stent, having a heart attack, or dying. If you stop ticagrelor because of bleeding, or for other reasons, your risk of a heart attack or stroke may increase.

When instructed by your doctor, you should stop taking ticagrelor 5 days before you have elective surgery. This will help to decrease your risk of bleeding with your surgery or procedure. Your doctor should tell you when to start taking ticagrelor again, as soon as possible after surgery.

Ticagrelor is taken with aspirin. You should not take a dose of aspirin higher than 100 mg daily because it can affect how well ticagrelor works. Do not take doses of aspirin higher than what your doctor tells you to take.

Do not take ticagrelor if you:

• are bleeding now
• have a history of bleeding in the brain
• have bleeding from your stomach or intestine now (an ulcer)
• have severe liver problems

Before you take ticagrelor, tell your doctor about all of your medical conditions including if you:

• have had bleeding problems in the past
• have had any recent serious injury or surgery
• plan to have surgery or a dental procedure
• have a history of stomach ulcers or colon polyps
• have lung problems, such as COPD or asthma
• have liver problems
• have a history of stroke
• are pregnant, or are plan to become pregnant
• are breastfeeding

Tell all of your doctors and dentists that you are taking ticagrelor. They should talk to the doctor who prescribed ticagrelor for you before you have any surgery or invasive procedure.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Ticagrelor helps to prevent platelets in your blood from sticking together and forming a blood clot. An unwanted blood clot can occur with certain heart or blood vessel conditions.

Ticagrelor is used to lower your risk of having a stroke or serious heart problems after you have had a heart attack or severe chest pain (angina).

Ticagrelor may also be used for purposes not listed in this medication guide.

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Take ticagrelor exactly as directed by your doctor. Ticagrelor will not work properly if you take less of it than directed. Taking more ticagrelor than directed may increase the chance of serious side effects without increasing the helpful effects.

ticagrelor comes with a Medication Guide. It is very important that you read and understand this information. Be sure to ask your doctor about anything you do not understand.

You may take ticagrelor with or without food.

If you are unable to swallow the tablets whole:

• You may crush and mix the tablets in a glass of water and swallow it right away.
• Refill the glass with more water, stir, and swallow the mixture again.
• This mixture may also be given through a nasogastric tube. Flush the tube with more water to rinse all of the medicine into the stomach.

If you are using ticagrelor for a condition called acute coronary syndrome, your doctor may tell you to take aspirin while you are using ticagrelor. In this case, do not change the dose or stop taking the aspirin without talking to your doctor first.

Dosing

The dose of ticagrelor will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of ticagrelor. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For prevention of blood clots after unstable angina (chest pain), non-ST-elevation myocardial infarction (a type of heart attack), or ST-elevation myocardial infarction or STEMI:
    • Adults—At first, 180 milligrams (mg) or 2 tablets taken as a single dose. Then, 90 mg two times a day. Your doctor may also give you a loading dose of aspirin 325 mg once a day, then 75 to 100 mg once a day to be taken together with ticagrelor.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of ticagrelor, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
• If you fall or hurt yourself, or if you hit your head, call your doctor right away. Talk with your doctor even if you feel fine.
• If you are taking digoxin, talk with your doctor. You may need to have your blood work checked more closely while you are taking it with ticagrelor.
• Some drugs may look the same as this medicine or may have names that sound like ticagrelor. Always check to make sure you have the right product. If you see any change in the way this medicine looks like shape, color, size, or wording, check with your pharmacist.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using ticagrelor while you are pregnant.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take ticagrelor at the same time of day.
• Take with or without food.
• If you cannot swallow the tablet whole, the tablet can be crushed and mixed with water. Drink right away after mixing. Refill the glass with water, stir, and drink.
• Those who have feeding tubes may use the tablet. Crush the tablet and mix it with water. Flush the feeding tube after this medicine is given.
• To gain the most benefit, do not miss doses.
• Keep taking ticagrelor as you have been told by your doctor or other health care provider, even if you feel well.

What do I do if I miss a dose?

• Skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
• Very bad headache.
• Shortness of breath.
• Slow heartbeat.
• A heartbeat that does not feel normal.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Inhibition of platelet aggregation (IPA): 180 mg loading dose: ~41% within 30 minutes (similar to clopidogrel 600 mg at 8 hours); Peak effect: Time to maximal IPA: 180 mg loading dose: IPA ~88% at 2 hours post administration

Time to Peak

Whole tablets: Parent drug: 1.5 hours (median; range: 1 to 4 hours); Active metabolite (AR-C124910XX): 2.5 hours (median; range: 1.5 to 5 hours)

Crushed tablets: Oral or nasogastric tube administration: Parent drug: ~1 hour (median; range: 1 to 4 hours); Active metabolite (AR-C124910XX): 2 hours (median; range: 1 to 8 hours). Note: Significantly higher concentrations of both ticagrelor and AR-C124910XX may appear at earlier time points (0.5 and 1 hour, respectively) when administered as crushed tablets (Teng 2015).

IPA: 180 mg loading dose: 87% to 89% maintained from 2 to 8 hours; 24 hours after the last maintenance dose, IPA is 58% (similar to maintenance clopidogrel)

Time after discontinuation when IPA is 30%: ~56 hours; IPA 10%: ~110 hours (Gurbel, 2009). Mean IPA observed with ticagrelor at 3 days post-discontinuation was comparable to that observed with clopidogrel at 5 days post discontinuation.

Half-Life Elimination

Parent drug: ~7 hours; active metabolite: ~9 hours

Protein Binding

>99% (parent drug and active metabolite)

Non-ST-elevation acute coronary syndrome, aspirin intolerant patients

Based on the American Heart Association/American College of Cardiology (AHA/ACC) guidelines for the management of patients with non-ST-elevation acute coronary syndromes (NSTE-ACS), ticagrelor is a reasonable alternative to aspirin in aspirin intolerant patients even though it has not been studied in the absence of aspirin.

Hypersensitivity (eg, angioedema) to ticagrelor or any component of the formulation; active pathological bleeding (eg, peptic ulcer, intracranial hemorrhage); history of intracranial hemorrhage

Canadian labeling: Additional contraindications (not in US labeling): Moderate to severe hepatic impairment; concomitant use of strong CYP3A4 inhibitors (eg, ketoconazole, clarithromycin, ritonavir, atazanavir, nefazodone)

Concerns related to adverse effects:

• Bleeding: [US Boxed Warning]: Ticagrelor increases the risk of bleeding including significant and sometimes fatal bleeding. Use is contraindicated in patients with active pathological bleeding (eg, peptic ulcer bleeding, intracranial hemorrhage) or history of intracranial hemorrhage. Additional risk factors for bleeding include propensity to bleed (eg, recent trauma or surgery, recent or recurrent GI bleeding, active PUD, moderate-severe hepatic impairment), CABG or other surgical procedure, concomitant use of medications that increase risk of bleeding (eg, warfarin, NSAIDs), and advanced age. Bleeding should be suspected if patient becomes hypotensive after undergoing recent coronary angiography, PCI, CABG, or other surgical procedure even if overt signs of bleeding do not exist. Where possible, manage bleeding without discontinuing ticagrelor as the risk of cardiovascular events is increased upon discontinuation. If discontinuation of ticagrelor is necessary, resume as soon as possible after the bleeding source is identified and controlled. Hemostatic benefits of platelet transfusions are not known; may inhibit transfused platelets.

• Bradyarrhythmias: Ventricular pauses and bradyarrhythmias, including AV block, have been reported. Use with caution in patients with second- or third-degree AV block, sick sinus syndrome, bradycardia-related syncope not protected by a pacemaker, or patients taking other bradycardic-inducing agents (eg, beta blockers, nondihydropyridine calcium channel blockers). Ventricular pauses ≥3 seconds were noted more frequently with ticagrelor than with clopidogrel during the first week after hospitalization for ACS in a substudy of the PLATO trial; however, most ventricular pauses were asymptomatic and transient (Scirica, 2011).

• Hyperuricemia: Use with caution in patients with a history of hyperuricemia or gouty arthritis. Renal uptake and transport of uric acid are inhibited by ticagrelor and its active metabolite and the risk of hyperuricemia may be increased (Butler, 2012; Zhang, 2015). However, reports of gout did not differ between treatment groups in Platelet Inhibition and Patient Outcomes (PLATO) trial.

• Respiratory: Dyspnea (often mild to moderate and transient) was observed more frequently in patients receiving ticagrelor compared to clopidogrel or aspirin alone during clinical trials (14% to 19% vs 6% to 8%) (Bonaca, 2015; Wallentin, 2009). Resolution of dyspnea was observed within 1 week in most patients (Wallentin, 2009). Patients with new, prolonged, or worsening dyspnea should be evaluated to rule out underlying disease. Ticagrelor-related dyspnea does not require specific treatment nor does it warrant therapy interruption; however, therapy should be discontinued in patients unable to tolerate ticagrelor-related dyspnea.

Disease-related concerns:

• Bleeding disorders: Use with caution in patients with platelet disorders, bleeding disorders, and/or at increased risk for bleeding (eg, PUD, trauma, or surgery).

• Hepatic impairment: Use with caution in patients with moderate hepatic impairment (limited experience); avoid use in severe hepatic impairment (has not been studied).

• Renal impairment: Creatinine levels may rise during therapy (mechanism undetermined); monitor renal function.

Concurrent drug therapy issues:

• Aspirin/other NSAIDs: [US Boxed Warning]: Maintenance doses of aspirin greater than 100 mg/day reduce the efficacy of ticagrelor and should be avoided. Use of higher maintenance doses of aspirin (ie, >100 mg/day) was associated with relatively unfavorable outcomes for ticagrelor versus clopidogrel in the PLATO trial (Gaglia, 2011; Wallentin, 2009).

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Lower GI bleed patients: An individualized and multidisciplinary approach should be utilized to determine therapy discontinuation and management in patients with acute lower GI bleed (LGIB) who are on antiplatelet medications; risk of ongoing bleeding should be weighed with risk of thromboembolic events. In patients receiving dual antiplatelet therapy (aspirin plus P2Y12 receptor blocker [eg, clopidogrel, prasugrel, ticagrelor, ticlopidine]) or thienopyridine monotherapy, the thienopyridine should generally be resumed as soon as possible and at least within 7 days, taking into account control of bleeding and cardiovascular risk (aspirin should not be discontinued); however, dual antiplatelet therapy should not be discontinued in the 90 days post-acute coronary syndrome or 30 days post-coronary stenting (Strate 2016).

• Surgical patients: [US Boxed Warning]: Avoid initiation of ticagrelor when urgent CABG surgery is planned; when possible, discontinue use at least 5 days before any surgery. Discontinue therapy 5 days before elective surgery (except in patients with cardiac stents who have not completed their full course of dual antiplatelet therapy; patient-specific situations need to be discussed with cardiologist) (ACCF/AHA [Hillis 2011]). The ACCF/AHA STEMI guidelines recommend discontinuation for at least 24 hours prior to on-pump CABG if possible; off-pump CABG may be performed within 24 hours of ticagrelor administration if the benefits of prompt revascularization outweigh the risks of bleeding (ACCF/AHA [O’Gara 2013]).

Other warnings/precautions:

• Discontinuation of therapy: Premature discontinuation of therapy will increase the risk of MI, stroke, and death. If ticagrelor must be discontinued (eg, treatment of bleeding or for significant surgery), restart ticagrelor as soon as possible. Duration of therapy, in general, is determined by the type of stent placed (bare metal or drug eluting) and whether an ACS event was ongoing at the time of placement.

Applies to ticagrelor: oral tablet

Along with its needed effects, ticagrelor may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking ticagrelor:

• Difficult or labored breathing
• tightness in the chest

• Blurred vision
• chest pain or discomfort
• confusion
• dizziness
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• fainting
• fast or irregular heartbeat
• headache
• lightheadedness, dizziness, or fainting
• loss of consciousness
• nervousness
• pounding in the ears
• slow or fast heartbeat
• sweating
• unusual tiredness or weakness

• Bleeding gums
• bruising
• coughing up blood
• difficulty with swallowing
• headache, sudden and severe
• increased menstrual flow or vaginal bleeding
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• nausea or vomiting
• nosebleeds
• paralysis
• prolonged bleeding from cuts
• rash
• red or black, tarry stools
• red or dark brown urine
• weakness

Some side effects of ticagrelor may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Back pain
• cough
• diarrhea

• Swelling of the breasts or breast soreness in both females and males