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Effient

Effient(prasugrel) – Daiichi Sankyo/Eli Lilly

BOXED WARNING

May cause significant, sometimes fatal, bleeding; risk factors include <60kg body weight, propensity to bleed, and concomitant use of medications that increase risk bleeding (eg, warfarin, heparin, fibrinolytic therapy, chronic use of NSAIDs). Do not use in patients with active pathological bleeding or a history of transient ischemic attack (TIA) or stroke. Not recommended in patients ≥75 yrs due to increased risk of fatal and intracranial bleeding and uncertain benefit, except in high-risk situations (diabetes or history of prior myocardial infarction [MI]) where the effect appears to be greater and use may be considered. Do not start in patients likely to undergo urgent coronary artery bypass graft surgery (CABG); d/c at least 7 days prior to any surgery, when possible. Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures. If possible, manage bleeding without d/c. Discontinuing, particularly in the 1st few weeks after acute coronary syndrome (ACS), increases the risk of subsequent cardiovascular (CV) events.

View FDA-Approved Full Prescribing Information for Effient

THERAPEUTIC CLASS

Platelet aggregation inhibitor

INDICATIONS

To reduce the rate of thrombotic CV events (including stent thrombosis) in patients with ACS who are to be managed with percutaneous coronary intervention (PCI) as follows: patients with unstable angina (UA) or non-ST-elevation myocardial infarction (NSTEMI) or patients with ST-elevation myocardial infarction (STEMI) when managed with primary or delayed PCI.

ADULT DOSAGE

Adults: LD: 60mg as a single dose. Maint: 10mg qd. <60kg: Consider lowering the maint dose to 5mg qd. Take with aspirin (ASA) (75-325mg/day).

HOW SUPPLIED

Tab: 5mg, 10mg

CONTRAINDICATIONS

Active pathological bleeding (eg, peptic ulcer, intracranial hemorrhage), history of prior TIA or stroke.

WARNINGS/PRECAUTIONS

Withholding a dose will not be useful in managing a bleeding event or the risk of bleeding associated with an invasive procedure. D/C for active bleeding, elective surgery, stroke, or TIA. Avoid therapy lapses; if need to temporarily d/c because of adverse events, restart as soon as possible. Thrombotic thrombocytopenic purpura (TTP) reported; may occur after a brief exposure (<2 weeks) and requires urgent treatment (eg, plasmapheresis). Hypersensitivity, including angioedema, reported.

ADVERSE REACTIONS

Bleeding, HTN, hypercholesterolemia/hyperlipidemia, headache, back pain, dyspnea, nausea, dizziness, cough, hypotension, fatigue, noncardiac chest pain.

DRUG INTERACTIONS

See Boxed Warning. ASA may increase bleeding time.

PREGNANCY

Category B, caution in nursing.

MECHANISM OF ACTION

Platelet aggregation inhibitor (thienopyridine class); inhibits platelet activation and aggregation through irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets.

PHARMACOKINETICS

Absorption: Rapid; Tmax=30 min. Distribution: Plasma protein binding (98%, albumin); Vd=44-68L (active metabolite). Metabolism: Hydrolysis; converted to active metabolite via CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19. Elimination: Urine (68%), feces (27%); T1/2=7 hrs (active metabolite).

ASSESSMENT

Assess for active pathological bleeding, history of prior TIA or stroke, other risk factors for bleeding, hypersensitivity, pregnancy/nursing status, and possible drug interactions.

MONITORING

Monitor for signs/symptoms of bleeding, TTP, hypersensitivity, and other adverse reactions. Monitor for cardiac events in patients who require premature d/c.

PATIENT COUNSELING

Inform about the benefits and risks of treatment. Instruct to take exactly as prescribed and not to d/c without consulting the prescribing physician. Inform that may bruise and bleed more easily and that bleeding will take longer than usual to stop. Advise to report to physician any unanticipated, prolonged, or excessive bleeding, or blood in stool/urine. Inform that TTP, a rare but serious condition, has been reported; instruct to seek prompt medical attention if experiencing unexplained fever, weakness, extreme skin paleness, purple skin patches, yellowing of skin/eyes, or neurological changes. Inform that hypersensitivity reactions may occur. Instruct to notify physicians and dentists about therapy before scheduling any invasive procedure.

ADMINISTRATION/STORAGE

Administration: Oral route. Take with or without food. Do not break the tab. Storage: 25°C (77°F); excursions permitted to 15-30°C (59-86°F).


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    Effient

    Effient

    Pronunciation Generic Name: prasugrel (PRA soo grel)

    Brand Name: Effient

    OverviewSide EffectsInteractionsFor ProfessionalsMore…

    What is prasugrel?

    Prasugrel keeps the platelets in your blood from coagulating (clotting) to prevent unwanted blood clots that can occur with certain heart or blood vessel conditions.

    Prasugrel is used to prevent blood clots in people with acute coronary syndrome who are undergoing a procedure after a recent heart attack or stroke, and in people with certain disorders of the heart or blood vessels.

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

    What is the most important information I should know about prasugrel?

    Prasugrel keeps your blood from coagulating (clotting) to prevent unwanted blood clots that can occur with certain heart or blood vessel conditions. Because of this drug action, prasugrel can make it easier for you to bleed, even from a minor injury. Contact your doctor or seek emergency medical attention if you have bleeding that will not stop.

    You may also have bleeding on the inside of your body, such as in your stomach or intestines. Call your doctor at once if you have black or bloody stools, or if you cough up blood or vomit that looks like coffee grounds. These could be signs of bleeding in your digestive tract.

    If you need to have any type of surgery or dental work, tell the surgeon or dentist ahead of time that you are using prasugrel. You may need to stop using the medicine for at least 7 days before surgery to prevent excessive bleeding.

    While you are taking prasugrel, do not take NSAIDs (non-steroidal anti-inflammatory drugs) without your doctor’s advice. NSAIDs include ibuprofen (Motrin, Advil), naproxen (Aleve, Naprosyn), diclofenac (Voltaren), diflunisal (Dolobid), etodolac (Lodine), flurbiprofen (Ansaid), indomethacin (Indocin), ketoprofen (Orudis), ketorolac (Toradol), mefenamic acid (Ponstel), meloxicam (Mobic), nabumetone (Relafen), piroxicam (Feldene), and others.

    What should I discuss with my healthcare provider before taking prasugrel?

    Do not use this medication if you are allergic to prasugrel, or if you have any active bleeding such as a stomach ulcer or bleeding in the brain (such as from a head injury), or a history of stroke, including TIA (“mini-stroke”).

    If you have any of these other conditions, you may need a dose adjustment or special tests to safely take this medication:

    • a bleeding or blood clotting disorder, such as hemophilia;

    • a stomach ulcer;
    • severe liver disease; or
    • just before or after heart bypass surgery (coronary artery bypass graft, or CABG).

    FDA pregnancy category B. This medication is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

    It is not known whether prasugrel passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

    How should I take prasugrel?

    Take this medication exactly as it was prescribed for you. Do not take the medication in larger amounts, or take it for longer than recommended by your doctor. Follow the directions on your prescription label.

    Take this medication with a full glass of water.

    Prasugrel can be taken with or without food.

    Do not crush or break a prasugrel tablet. Swallow the pill whole.

    Because prasugrel keeps your blood from coagulating (clotting) to prevent unwanted blood clots, it can also make it easier for you to bleed, even from a minor injury. Contact your doctor or seek emergency medical attention if you have bleeding that will not stop.

    You may also have bleeding on the inside of your body, such as in your stomach or intestines. Call your doctor at once if you feel very weak or dizzy, or if you have black or bloody stools, or if you cough up blood or vomit that looks like coffee grounds. These could be signs of bleeding in your digestive tract.

    If you need to have any type of surgery or dental work, tell the surgeon or dentist ahead of time that you are using prasugrel. You may need to stop using the medicine for at least 7 days before surgery to prevent excessive bleeding.

    Do not stop taking this medication without first talking to your doctor. Stopping suddenly may make your condition worse.

    Store prasugrel at room temperature away from moisture and heat. Keep the tablets in their original container, along with the packet of moisture-absorbing preservative that comes with prasugrel tablets.

    What happens if I miss a dose?

    Take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at your next regularly scheduled time. Do not take extra medicine to make up the missed dose.

    What happens if I overdose?

    Seek emergency medical attention if you think you have used too much of this medicine.

    Overdose symptoms may include vomiting, feeling exhausted or short of breath, blurred vision, watery eyes, trouble walking, and blood in your stools or vomit.

    What should I avoid while taking prasugrel?

    While you are taking prasugrel, do not take NSAIDs (non-steroidal anti-inflammatory drugs) without your doctor’s advice. NSAIDs include ibuprofen (Motrin, Advil), naproxen (Aleve, Naprosyn), diclofenac (Voltaren), diflunisal (Dolobid), etodolac (Lodine), flurbiprofen (Ansaid), indomethacin (Indocin), ketoprofen (Orudis), ketorolac (Toradol), mefenamic acid (Ponstel), meloxicam (Mobic), nabumetone (Relafen), piroxicam (Feldene), and others.

    Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth.

    Prasugrel side effects

    Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

    Call your doctor at once if you have any of these serious side effects:

    • unusual bleeding such as nosebleeds, bleeding gums, or any bleeding that will not stop;

    • pale skin, fever, easy bruising, purple or red spots under your skin;
    • jaundice (yellowing of the skin or eyes);
    • unexpected vaginal bleeding;
    • feeling very weak or dizzy;
    • blood in your urine or stools, black or tarry stools;
    • coughing up blood or vomit that looks like coffee grounds;
    • chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling;
    • sudden numbness or weakness, especially on one side of the body; or
    • sudden headache, confusion, problems with vision, speech, or balance.

    Less serious side effects may include:

    • mild headache or dizziness;

    • back pain, minor chest pain;
    • cough;
    • nausea; or
    • tired feeling.

    This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    See also: Effient side effects (in more detail)

    What other drugs will affect prasugrel?

    Before taking prasugrel, tell your doctor if you are taking a blood thinner such as warfarin (Coumadin).

    This list is not complete and there may be other drugs that can interact with prasugrel. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

    Next Page → Side Effects

    More Effient resources

    • Side Effects
    • Pregnancy Warnings
    • Drug Images
    • Drug Interactions
    • Support Group
    • 7 Reviews - Add your own review/rating
    • Effient Prescribing Information (FDA)
    • Effient Monograph (AHFS DI)
    • Effient Advanced Consumer (Micromedex) – Includes Dosage Information
    • Effient Consumer Overview
    • Effient MedFacts Consumer Leaflet (Wolters Kluwer)
    • Prasugrel Professional Patient Advice (Wolters Kluwer)

    Compare Effient with other medications

    • Acute Coronary Syndrome

    Where can I get more information?

    • Your pharmacist can provide more information about prasugrel.

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    Effient

    Effient

    Pronunciation Generic Name: prasugrel (Oral route)

    PRA-soo-grel

    OverviewSide EffectsInteractionsFor ProfessionalsMore… Oral route(Tablet) Prasugrel can cause significant, sometimes fatal, bleeding in patients with active pathological bleeding or a propensity to bleed, a history of transient ischemic attack or stroke, a body weight of less than 60 kg, or concomitant use of medications that increase the risk of bleeding (eg, warfarin, heparin, fibrinolytics, chronic use of NSAIDs). Prasugrel is not recommended in patients 75 years of age and older, except for high-risk situations (diabetes, history of prior myocardial infarction). Do not start prasugrel in patients likely to undergo urgent CABG and discontinue at least 7 days prior to any surgery. If possible, manage bleeding without discontinuing prasugrel, as discontinuation in the first few weeks after acute coronary syndrome may increase risk for subsequent cardiovascular events .

    Commonly used brand name(s)

    In the U.S.

    • Effient

    Available Dosage Forms:

    • Tablet

    Therapeutic Class: Platelet Aggregation Inhibitor

    Pharmacologic Class: ADP-Induced Aggregation Inhibitor

    Uses For Effient

    Prasugrel is used to prevent strokes, heart attacks, or other serious problems with your heart or blood vessels. It is given to patients before they have a heart procedure called percutaneous coronary intervention (PCI).

    A heart attack or stroke may occur when a blood vessel in the heart or brain is blocked by a blood clot. Prasugrel reduces the chance that a harmful blood clot will form by preventing certain cells in the blood from clumping or sticking together. Prasugrel may also increase the chance for serious bleeding in some people.

    This medicine is available only with your doctor’s prescription.

    Before Using Effient

    In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

    Allergies

    Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

    Pediatric

    Appropriate studies have not been performed on the relationship of age to the effects of prasugrel in the pediatric population. Safety and efficacy have not been established.

    Geriatric

    Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of prasugrel in the elderly. Because of prasugrel’s toxicity, use in elderly patients 75 years of age and older is not recommended.

    Pregnancy

    Pregnancy Category Explanation
    All Trimesters B Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus.

    Breast Feeding

    There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

    Interactions with Medicines

    Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

    Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

    • Alteplase, Recombinant
    • Aspirin
    • Cilostazol
    • Citalopram
    • Dabigatran Etexilate
    • Desirudin
    • Dipyridamole
    • Escitalopram
    • Fluoxetine
    • Fluvoxamine
    • Nefazodone
    • Paroxetine
    • Rivaroxaban
    • Sertraline
    • Warfarin

    Interactions with Food/Tobacco/Alcohol

    Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

    Other Medical Problems

    The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

    • Bleeding (eg, head, stomach, or bowel bleeding), active or
    • Stroke, history of or
    • Transient ischemic attack (TIA) or “mini-stroke”, history of—Should not be used in patients with these conditions.
    • Hypersensitivity reaction to clopidogrel (Plavix®) or ticlopidine (Ticlid®), history of or
    • Liver disease, severe or
    • Low body weight (less than 60 kilograms or 132 pounds) or
    • Stomach or bowel bleeding, recurrent or
    • Stomach ulcer or
    • Surgery or other procedures (eg, heart bypass surgery, coronary angiography, PCI), recent or
    • Trauma, recent—Use with caution. May increase risks for more serious side effects.

    Proper Use of Effient

    Take this medicine exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance of side effects.

    Do not stop taking this medicine without checking with your doctor first. To do so may increase your risk for clots.

    This medicine should come with a medication guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.

    You may take this medicine with or without food.

    Dosing

    The dose of this medicine 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 this medicine. 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 heart attacks or strokes:
        • Adults weighing 60 kilograms (kg) and above—At first, 60 milligrams (mg) taken as a single loading dose, and then 10 mg once a day. You may take this medicine with aspirin (75 to 325 mg) once a day.
        • Adults weighing less than 60 kilograms (kg)—At first, 60 milligrams (mg) taken as a single loading dose, and then 5 mg once a day.
        • Children—Use and dose must be determined by your doctor.

    Missed Dose

    If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, 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.

    Precautions While Using Effient

    It is very important that your doctor check your progress at regular visits. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to take it. Blood tests may be needed to check for unwanted effects.

    Tell all of your medical doctors, dentists, and nurses that you are taking this medicine. Prasugrel may increase the risk of serious bleeding during an operation or some dental procedures. Treatment may have to be stopped about 7 days before the operation or dental procedure.

    Check with your doctor right away if you have the following symptoms: change in mental status, dark or bloody urine, difficulty with speaking, fever, pale color of the skin, pinpoint red spots on the skin, seizures, weakness, yellow eyes or skin. These may be symptoms of a serious condition called thrombotic thrombocytopenic purpura (TTP).

    This medicine may cause serious allergic reactions, including angioedema. Angioedema can be life-threatening and requires immediate medical attention. Stop using this medicine and tell your doctor right away if you have chest pain; a rash; itching; swelling of the face, lips, tongue, or throat; or trouble with swallowing or breathing while you are using the medicine.

    Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

    Effient Side Effects

    Along with its needed effects, a medicine 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:

    More common

    • Blurred vision
    • dizziness
    • headache
    • nervousness
    • pounding in the ears
    • slow or fast heartbeat

    Less common

    • Black, tarry stools
    • bloating or swelling of the face, arms, hands, lower legs, or feet
    • chest pain or discomfort
    • chills
    • cough
    • difficult or labored breathing
    • fainting
    • fever
    • irregular heartbeat
    • lightheadedness, dizziness, or fainting
    • painful or difficult urination
    • rapid weight gain
    • shortness of breath
    • sore throat
    • sores, ulcers, or white spots on the lips or in the mouth
    • swollen glands
    • tightness in the chest
    • tingling of the hands or feet
    • unusual bleeding or bruising
    • unusual tiredness or weakness
    • unusual weight gain or loss
    • wheezing

    Incidence not known

    • Change in mental status
    • dark or bloody urine
    • difficulty with speaking
    • fever
    • pale color of the skin
    • pinpoint red spots on the skin
    • seizures
    • weakness
    • yellow eyes or skin

    Some side effects 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:

    Less common

    • Back pain
    • diarrhea
    • nausea
    • pain in the arms or legs
    • rash

    Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

    Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

    See also: Effient side effects (in more detail)

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    Effient

    Effient

    Pronunciation Generic Name: prasugrel (PRA-soo-grel)

    Brand Name: Effient

    Effient can cause severe and sometimes fatal bleeding. It should not be used in patients who have an active bleeding problem or a history of stroke or transient ischemic attack (TIA) (“mini-stroke”). The risk of severe side effects may be increased in patients older than 74 years old. Effient is usually not recommended in these patients, except in certain situations (eg, diabetes, history of heart attack).

    Do not use Effient if you will be having bypass heart surgery (coronary artery bypass graft [CABG]). Tell your doctor that you take Effient if you have recently had or will be having any type of surgery. If possible, Effient should be stopped for at least 7 days before surgery.

    Tell your doctor if you have risk factors for bleeding, including a body weight of less than 132 lbs (60 kg) or a history of easy or persistent bleeding. Tell your doctor if you take a medicine that may increase your risk of bleeding, such as warfarin, heparin, nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, ibuprofen), or fibrinolytic agents (eg, alteplase).

    Tell your doctor if dizziness or fainting occurs while you take Effient. Do not suddenly stop Effient without checking with your doctor. This may increase the risk of severe heart problems or death.

    OverviewSide EffectsInteractionsFor ProfessionalsMore…

    Effient is used for:

    Reducing the risk of having another serious heart or blood vessel problem (eg, heart attack, stroke, blood clots in your stent, death). It is intended for use in patients who have had a heart attack, angina, or a procedure called angioplasty.

    Effient is a platelet aggregation inhibitor. It works by slowing or stopping platelets from clumping together to form clots.

    Do NOT use Effient if:

    • you are allergic to any ingredient in Effient
    • you have an active bleeding problem (eg, ulcer, bleeding in the brain) or a history of stroke or TIA (“mini-stroke”)
    • you will be having bypass heart surgery (CABG)

    Contact your doctor or health care provider right away if any of these apply to you.

    Before using Effient:

    Some medical conditions may interact with Effient. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

    • if you are pregnant, planning to become pregnant, or are breast-feeding
    • if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement
    • if you have allergies to medicines, foods, or other substances
    • if you have had a severe allergic reaction (eg, severe rash, hives, difficulty breathing, dizziness) to any other thienopyridine (eg, clopidogrel)
    • if you have diabetes, liver problems, or kidney problems
    • if you have a history of heart attack, stomach or bowel problems (eg, bleeding, ulcers, polyps, diverticulosis), easy or persistent bleeding, or recent injury or surgery
    • if you will be having surgery (including dental surgery)
    • if you weigh less than 132 lbs (60 kg)

    Some MEDICINES MAY INTERACT with Effient. Tell your health care provider if you are taking any other medicines, especially any of the following:

    • Anticoagulants (eg, heparin, warfarin), apixaban, dabigatran, desirudin, fibrinolytic agents (eg, alteplase), NSAIDs (eg, ibuprofen), rivaroxaban, or other medicines to prevent or treat blood clots because the risk of bleeding may be increased

    This may not be a complete list of all interactions that may occur. Ask your health care provider if Effient may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

    How to use Effient:

    Use Effient as directed by your doctor. Check the label on the medicine for exact dosing instructions.

    • Effient comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Effient refilled.
    • Take Effient by mouth with or without food.
    • Swallow Effient whole. Do not break, crush, or chew before swallowing.
    • You will also need to take aspirin while you take Effient, as directed by your doctor.
    • If you miss a dose of Effient, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once unless your doctor tells you to.

    Ask your health care provider any questions you may have about how to use Effient.

    Important safety information:

    • Dizziness may occur while you are taking Effient. This effect may be worse if you take it with alcohol or certain medicines. Use Effient with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.
    • Do not suddenly stop Effient without checking with your doctor. This may increase the risk of severe heart problems or death.
    • Effient may reduce the number of clot-forming cells (platelets) in your blood. Avoid activities that may cause bruising or injury. Tell your doctor if you have unusual bruising or bleeding. Tell your doctor if you have dark, tarry, or bloody stools.
    • Effient may cause a serious and sometimes fatal condition called thrombotic thrombocytopenic purpura (TTP). Contact your doctor right away if you develop purple patches on the skin or mouth, fever, unusual bruising or bleeding, unusual tiredness or weakness, unusually pale skin, yellowing of the skin or eyes, or change in the amount of urine produced. Discuss any questions with your doctor.
    • Call your doctor right away if you fall or injure yourself, especially if you hit your head. You may need to be checked by your doctor.
    • Tell your doctor or dentist that you take Effient before you receive any medical or dental care, emergency care, or surgery. If possible, Effient should be stopped for at least 7 days before surgery as directed by your doctor.
    • Lab tests, including blood pressure, may be performed while you use Effient. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.
    • Use Effient with caution in the ELDERLY; they may be more sensitive to its effects, especially the risk of serious and sometimes fatal bleeding (including bleeding in the brain). Effient is usually not recommended in patients older than 74 years old except in certain situations (eg, diabetes, history of heart attack).
    • Effient should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed.
    • PREGNANCY and BREAST-FEEDING: If you think you may be pregnant, contact your doctor. You will need to discuss the benefits and risks of using Effient while you are pregnant. It is not known if Effient is found in breast milk. If you are or will be breast-feeding while you use Effient, check with your doctor. Discuss any possible risks to your baby.

    Possible side effects of Effient:

    All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

    Back pain; cough; diarrhea; headache; mild bruising or bleeding; nausea; nosebleeds; tiredness.

    Seek medical attention right away if any of these SEVERE side effects occur:

    Severe allergic reactions (rash; hives; itching; difficulty breathing or swallowing; tightness in the chest; swelling of the mouth, face, lips, throat, or tongue; unusual hoarseness); black, tarry stools; change in the amount of urine produced; chest pain; confusion; coughing up blood; dark or bloody urine; dizziness; fainting; fast, slow, or irregular heartbeat; fever, chills, or persistent sore throat; one-sided weakness; pale skin; purple spots on the skin or mouth; seizure; severe or persistent headache; severe or persistent nausea, vomiting, or diarrhea; severe or persistent nosebleeds; shortness of breath; speech problems; stomach pain; swelling of the hands, ankles, or feet; unusual bruising; unusual or severe bleeding (eg, excessive bleeding from cuts, increased menstrual bleeding, unexplained vaginal bleeding, unusual bleeding from the gums when brushing); unusual tiredness or weakness; vision changes (eg, blurred vision); vomit that contains blood or looks like coffee grounds; yellowing of the skin or eyes.

    This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

    If OVERDOSE is suspected:

    Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

    Proper storage of Effient: Store Effient at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store in the original container with the lid tightly closed. Do not remove the desiccant (gray cylinder) from the bottle. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Effient out of the reach of children and away from pets.

    General information:

    • If you have any questions about Effient, please talk with your doctor, pharmacist, or other health care provider.
    • Effient is to be used only by the patient for whom it is prescribed. Do not share it with other people.
    • If your symptoms do not improve or if they become worse, check with your doctor.
    • Check with your pharmacist about how to dispose of unused medicine.

    This information should not be used to decide whether or not to take Effient or any other medicine. Only your health care provider has the knowledge and training to decide which medicines are right for you. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Effient. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Effient. This information is not specific medical advice and does not replace information you receive from your health care provider. You must talk with your healthcare provider for complete information about the risks and benefits of using Effient.

    Issue Date: March 6, 2013 Database Edition 13.1.1.003 Copyright © 2013 Wolters Kluwer Health, Inc.

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    Effient

    Effient

    Generic Name: prasugrel hydrochloride

    Dosage Form: tablet, film coated

    WARNING: BLEEDING RISK Effient can cause significant, sometimes fatal, bleeding [see Warnings and Precautions (5.1 and 5.2) and Adverse Reactions (6.1)].

    Do not use Effient in patients with active pathological bleeding or a history of transient ischemic attack or stroke [see Contraindications (4.1 and 4.2)].

    In patients ≥75 years of age, Effient is generally not recommended, because of the increased risk of fatal and intracranial bleeding and uncertain benefit, except in high-risk situations (patients with diabetes or a history of prior MI) where its effect appears to be greater and its use may be considered [see Use in Specific Populations (8.5)].

    Do not start Effient in patients likely to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue Effient at least 7 days prior to any surgery.

    Additional risk factors for bleeding include:

    • body weight <60 kg
    • propensity to bleed
    • concomitant use of medications that increase the risk of bleeding (e.g., warfarin, heparin, fibrinolytic therapy, chronic use of non-steroidal anti-inflammatory drugs [NSAIDs])

    Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in the setting of Effient.

    If possible, manage bleeding without discontinuing Effient. Discontinuing Effient, particularly in the first few weeks after acute coronary syndrome, increases the risk of subsequent cardiovascular events [see Warnings and Precautions (5.3)].

    Indications and Usage for Effient

    Acute Coronary Syndrome

    Effient® is indicated to reduce the rate of thrombotic cardiovascular (CV) events (including stent thrombosis) in patients with acute coronary syndrome (ACS) who are to be managed with percutaneous coronary intervention (PCI) as follows:

    • Patients with unstable angina (UA) or non-ST-elevation myocardial infarction (NSTEMI).
    • Patients with ST-elevation myocardial infarction (STEMI) when managed with primary or delayed PCI.

    Effient has been shown to reduce the rate of a combined endpoint of cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke compared to clopidogrel. The difference between treatments was driven predominantly by MI, with no difference on strokes and little difference on CV death [see Clinical Studies (14)].

    It is generally recommended that antiplatelet therapy be administered promptly in the management of ACS because many cardiovascular events occur within hours of initial presentation. In the clinical trial that established the efficacy of Effient, Effient and the control drug were not administered to UA/NSTEMI patients until coronary anatomy was established. For the small fraction of patients that required urgent CABG after treatment with Effient, the risk of significant bleeding was substantial [see Warnings and Precautions (5.2)]. Because the large majority of patients are managed without CABG, however, treatment can be considered before determining coronary anatomy if need for CABG is considered unlikely. The advantages of earlier treatment with Effient must then be balanced against the increased rate of bleeding in patients who do need to undergo urgent CABG.

    Effient Dosage and Administration

    Initiate Effient treatment as a single 60-mg oral loading dose and then continue at 10 mg orally once daily. Patients taking Effient should also take aspirin (75 mg to 325 mg) daily [see Drug Interactions (7) and Clinical Pharmacology (12.3)]. Effient may be administered with or without food [see Clinical Pharmacology (12.3) and Clinical Studies (14)].

    Dosing in Low Weight Patients

    Compared to patients weighing ≥60 kg, patients weighing <60 kg have an increased exposure to the active metabolite of prasugrel and an increased risk of bleeding on a 10 mg once daily maintenance dose. Consider lowering the maintenance dose to 5 mg in patients <60 kg. The effectiveness and safety of the 5 mg dose have not been prospectively studied.

    Dosage Forms and Strengths

    Effient 5 mg is available as a yellow, elongated hexagonal, film-coated, non-scored tablet:

    • debossed with “5 MG” on one side and “4760” on the other side (original formulation) OR

    • debossed with “5121” on one side and 3 parallel arched lines followed by a “5” on the other side (revised formulation)

    Effient 10 mg is available as a beige, elongated hexagonal, film-coated, non-scored tablet:

    • debossed with “10 MG” on one side and with “4759” on the other side (original formulation) OR

    • debossed with “5123” on one side and 3 parallel arched lines followed by a “10” on the other side (revised formulation)

    Contraindications

    Active Bleeding

    Effient is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

    Prior Transient Ischemic Attack or Stroke

    Effient is contraindicated in patients with a history of prior transient ischemic attack (TIA) or stroke. In TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel), patients with a history of TIA or ischemic stroke (>3 months prior to enrollment) had a higher rate of stroke on Effient (6.5%; of which 4.2% were thrombotic stroke and 2.3% were intracranial hemorrhage [ICH]) than on clopidogrel (1.2%; all thrombotic). In patients without such a history, the incidence of stroke was 0.9% (0.2% ICH) and 1.0% (0.3% ICH) with Effient and clopidogrel, respectively. Patients with a history of ischemic stroke within 3 months of screening and patients with a history of hemorrhagic stroke at any time were excluded from TRITON-TIMI 38. Patients who experience a stroke or TIA while on Effient generally should have therapy discontinued [see Adverse Reactions (6.1) and Clinical Studies (14)].

    4.3 Hypersensitivity

    Effient is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to prasugrel or any component of the product [see Adverse Reactions (6.2)].

    Warnings and Precautions

    General Risk of Bleeding

    Thienopyridines, including Effient, increase the risk of bleeding. With the dosing regimens used in TRITON-TIMI 38, TIMI (Thrombolysis in Myocardial Infarction) Major (clinically overt bleeding associated with a fall in hemoglobin ≥5 g/dL, or intracranial hemorrhage) and TIMI Minor (overt bleeding associated with a fall in hemoglobin of ≥3 g/dL but <5 g/dL) bleeding events were more common on Effient than on clopidogrel [see Adverse Reactions (6.1)]. The bleeding risk is highest initially, as shown in Figure 1 (events through 450 days; inset shows events through 7 days).

    Figure 1: Non-CABG-Related TIMI Major or Minor Bleeding Events.

    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 overt signs of bleeding.

    Do not use Effient in patients with active bleeding, prior TIA or stroke [see Contraindications (4.1 and 4.2)].

    Other risk factors for bleeding are:

    • Age ≥75 years. Because of the risk of bleeding (including fatal bleeding) and uncertain effectiveness in patients ≥75 years of age, use of Effient is generally not recommended in these patients, except in high-risk situations (patients with diabetes or history of myocardial infarction) where its effect appears to be greater and its use may be considered [see Adverse Reactions (6.1), Use in Specific Populations (8.5), Clinical Pharmacology (12.3), and Clinical Trials (14)].
    • CABG or other surgical procedure [see Warnings and Precautions (5.2)].
    • Body weight <60 kg. Consider a lower (5 mg) maintenance dose [see Dosage and Administration (2), Adverse Reactions (6.1), Use in Specific Populations (8.6)].
    • Propensity to bleed (e.g., recent trauma, recent surgery, recent or recurrent gastrointestinal (GI) bleeding, active peptic ulcer disease, severe hepatic impairment, or moderate to severe renal impairment) [see Adverse Reactions (6.1) and Use in Specific Populations (8.7 and 8.8)].
    • Medications that increase the risk of bleeding (e.g., oral anticoagulants, chronic use of non-steroidal anti-inflammatory drugs [NSAIDs], and fibrinolytic agents). Aspirin and heparin were commonly used in TRITON-TIMI 38 [see Drug Interactions (7), Clinical Studies (14)].

    Thienopyridines inhibit platelet aggregation for the lifetime of the platelet (7-10 days), so withholding a dose will not be useful in managing a bleeding event or the risk of bleeding associated with an invasive procedure. Because the half-life of prasugrel’s active metabolite is short relative to the lifetime of the platelet, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 6 hours of the loading dose or 4 hours of the maintenance dose may be less effective.

    Coronary Artery Bypass Graft Surgery-Related Bleeding

    The risk of bleeding is increased in patients receiving Effient who undergo CABG. If possible, Effient should be discontinued at least 7 days prior to CABG.

    Of the 437 patients who underwent CABG during TRITON-TIMI 38, the rates of CABG-related TIMI Major or Minor bleeding were 14.1% in the Effient group and 4.5% in the clopidogrel group [see Adverse Reactions (6.1)]. The higher risk for bleeding events in patients treated with Effient persisted up to 7 days from the most recent dose of study drug. For patients receiving a thienopyridine within 3 days prior to CABG, the frequencies of TIMI Major or Minor bleeding were 26.7% (12 of 45 patients) in the Effient group, compared with 5.0% (3 of 60 patients) in the clopidogrel group. For patients who received their last dose of thienopyridine within 4 to 7 days prior to CABG, the frequencies decreased to 11.3% (9 of 80 patients) in the prasugrel group and 3.4% (3 of 89 patients) in the clopidogrel group.

    Do not start Effient in patients likely to undergo urgent CABG. CABG-related bleeding may be treated with transfusion of blood products, including packed red blood cells and platelets; however, platelet transfusions within 6 hours of the loading dose or 4 hours of the maintenance dose may be less effective.

    Discontinuation of Effient

    Discontinue thienopyridines, including Effient, for active bleeding, elective surgery, stroke, or TIA. The optimal duration of thienopyridine therapy is unknown. In patients who are managed with PCI and stent placement, premature discontinuation of any antiplatelet medication, including thienopyridines, conveys an increased risk of stent thrombosis, myocardial infarction, and death. Patients who require premature discontinuation of a thienopyridine will be at increased risk for cardiac events. Lapses in therapy should be avoided, and if thienopyridines must be temporarily discontinued because of an adverse event(s), they should be restarted as soon as possible [see Contraindications (4.1 and 4.2) and Warnings and Precautions (5.1)].

    Thrombotic Thrombocytopenic Purpura

    Thrombotic thrombocytopenic purpura (TTP) has been reported with the use of Effient. TTP can occur after a brief exposure (<2 weeks). TTP is a serious condition that can be fatal and requires urgent treatment, including plasmapheresis (plasma exchange). TTP is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragment red blood cells] seen on peripheral smear), neurological findings, renal dysfunction, and fever [see Adverse Reactions (6.2)].

    Hypersensitivity Including Angioedema

    Hypersensitivity including angioedema has been reported in patients receiving Effient, including patients with a history of hypersensitivity reaction to other thienopyridines [see Contraindications (4.3), Adverse Reactions (6.2)].

    Adverse Reactions

    Clinical Trials Experience

    The following serious adverse reactions are also discussed elsewhere in the labeling:

    • Bleeding [see Boxed Warning and Warnings and Precautions (5.1, 5.2)]
    • Thrombotic thrombocytopenic purpura [see Warnings and Precautions (5.4)]

    Safety in patients with ACS undergoing PCI was evaluated in a clopidogrel-controlled study, TRITON-TIMI 38, in which 6741 patients were treated with Effient (60-mg loading dose and 10 mg once daily) for a median of 14.5 months (5802 patients were treated for over 6 months; 4136 patients were treated for more than 1 year). The population treated with Effient was 27 to 96 years of age, 25% female, and 92% Caucasian. All patients in the TRITON-TIMI 38 study were to receive aspirin. The dose of clopidogrel in this study was a 300-mg loading dose and 75 mg once daily.

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

    Drug Discontinuation

    The rate of study drug discontinuation because of adverse reactions was 7.2% for Effient and 6.3% for clopidogrel. Bleeding was the most common adverse reaction leading to study drug discontinuation for both drugs (2.5% for Effient and 1.4% for clopidogrel).

    Bleeding

    Bleeding Unrelated to CABG Surgery – In TRITON-TIMI 38, overall rates of TIMI Major or Minor bleeding adverse reactions unrelated to coronary artery bypass graft surgery (CABG) were significantly higher on Effient than on clopidogrel, as shown in Table 1.

    Table 1: Non-CABG-Related Bleedinga (TRITON-TIMI 38)
    a Patients may be counted in more than one row.

    b See 5.1 for definition.

    Effient

    (%)

    (N=6741)

    Clopidogrel

    (%)

    (N=6716)

    p-value
    TIMI Major or Minor bleeding 4.5 3.4 p=0.002
    TIMI Major bleedingb 2.2 1.7 p=0.029
        Life-threatening 1.3 0.8 p=0.015
              Fatal 0.3 0.1
              Symptomatic intracranial hemorrhage (ICH) 0.3 0.3
              Requiring inotropes 0.3 0.1
              Requiring surgical intervention 0.3 0.3
              Requiring transfusion (≥4 units) 0.7 0.5
    TIMI Minor bleedingb 2.4 1.9 p=0.022

    Figure 1 demonstrates non-CABG related TIMI Major or Minor bleeding. The bleeding rate is highest initially, as shown in Figure 1 (inset: Days 0 to 7) [see Warnings and Precautions (5.1)].

    Bleeding rates in patients with the risk factors of age ≥75 years and weight <60 kg are shown in Table 2.

    Table 2: Bleeding Rates for Non-CABG-Related Bleeding by Weight and Age (TRITON-TIMI 38)
    Major/Minor Fatal
    Effient

    (%)

    Clopidogrel

    (%)

    Effient

    (%)

    Clopidogrel

    (%)

    Weight <60 kg (N=308 Effient, N=356 clopidogrel) 10.1 6.5 0.0 0.3
    Weight ≥60 kg (N=6373 Effient, N=6299 clopidogrel) 4.2 3.3 0.3 0.1
    Age <75 years (N=5850 Effient, N=5822 clopidogrel) 3.8 2.9 0.2 0.1
    Age ≥75 years (N=891 Effient, N=894 clopidogrel) 9.0 6.9 1.0 0.1

    Bleeding Related to CABG – In TRITON-TIMI 38, 437 patients who received a thienopyridine underwent CABG during the course of the study. The rate of CABG-related TIMI Major or Minor bleeding was 14.1% for the Effient group and 4.5% in the clopidogrel group (see Table 3). The higher risk for bleeding adverse reactions in patients treated with Effient persisted up to 7 days from the most recent dose of study drug.

    Table 3: CABG-Related Bleedinga (TRITON-TIMI 38)
    a Patients may be counted in more than one row.

    Effient (%)

    (N=213)

    Clopidogrel (%)

    (N=224)

    TIMI Major or Minor bleeding 14.1 4.5
    TIMI Major bleeding 11.3 3.6
              Fatal 0.9 0
              Reoperation 3.8 0.5
              Transfusion of ≥5 units 6.6 2.2
              Intracranial hemorrhage 0 0
    TIMI Minor bleeding 2.8 0.9

    Bleeding Reported as Adverse Reactions – Hemorrhagic events reported as adverse reactions in TRITON-TIMI 38 were, for Effient and clopidogrel, respectively: epistaxis (6.2%, 3.3%), gastrointestinal hemorrhage (1.5%, 1.0%), hemoptysis (0.6%, 0.5%), subcutaneous hematoma (0.5%, 0.2%), post-procedural hemorrhage (0.5%, 0.2%), retroperitoneal hemorrhage (0.3%, 0.2%), pericardial effusion/hemorrhage/tamponade (0.3%, 0.2%), and retinal hemorrhage (0.0%, 0.1%).

    Malignancies

    During TRITON-TIMI 38, newly-diagnosed malignancies were reported in 1.6% and 1.2% of patients treated with prasugrel and clopidogrel, respectively. The sites contributing to the differences were primarily colon and lung. It is unclear if these observations are causally-related or are random occurrences.

    Other Adverse Events

    In TRITON-TIMI 38, common and other important non-hemorrhagic adverse events were, for Effient and clopidogrel, respectively: severe thrombocytopenia (0.06%, 0.04%), anemia (2.2%, 2.0%), abnormal hepatic function (0.22%, 0.27%), allergic reactions (0.36%, 0.36%), and angioedema (0.06%, 0.04%). Table 4 summarizes the adverse events reported by at least 2.5% of patients.

    Table 4: Non-Hemorrhagic Treatment Emergent Adverse Events Reported by at Least 2.5% of Patients in Either Group
    Effient (%)

    (N=6741)

    Clopidogrel (%)

    (N=6716)

    Hypertension 7.5 7.1
    Hypercholesterolemia/Hyperlipidemia 7.0 7.4
    Headache 5.5 5.3
    Back pain 5.0 4.5
    Dyspnea 4.9 4.5
    Nausea 4.6 4.3
    Dizziness 4.1 4.6
    Cough 3.9 4.1
    Hypotension 3.9 3.8
    Fatigue 3.7 4.8
    Non-cardiac chest pain 3.1 3.5
    Atrial fibrillation 2.9 3.1
    Bradycardia 2.9 2.4
    Leukopenia (<4 x 109 WBC/L) 2.8 3.5
    Rash 2.8 2.4
    Pyrexia 2.7 2.2
    Peripheral edema 2.7 3.0
    Pain in extremity 2.6 2.6
    Diarrhea 2.3 2.6

    Postmarketing Experience

    The following adverse reactions have been identified during post approval use of Effient. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

    Blood and lymphatic system disorders — Thrombocytopenia, Thrombotic thrombocytopenic purpura (TTP) [see Warnings and Precautions (5.4) and Patient Counseling Information (17.3)]

    Immune system disorders — Hypersensitivity reactions including anaphylaxis [see Contraindications (4.3)]

    Drug Interactions

    Warfarin

    Coadministration of Effient and warfarin increases the risk of bleeding [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

    Non-Steroidal Anti-Inflammatory Drugs

    Coadministration of Effient and NSAIDs (used chronically) may increase the risk of bleeding [see Warnings and Precautions (5.1)].

    Other Concomitant Medications

    Effient can be administered with drugs that are inducers or inhibitors of cytochrome P450 enzymes [see Clinical Pharmacology (12.3)].

    Effient can be administered with aspirin (75 mg to 325 mg per day), heparin, GPIIb/IIIa inhibitors, statins, digoxin, and drugs that elevate gastric pH, including proton pump inhibitors and H2 blockers [see Clinical Pharmacology (12.3)].

    USE IN SPECIFIC POPULATIONS

    Pregnancy

    Pregnancy Category B – There are no adequate and well-controlled studies of Effient use in pregnant women. Reproductive and developmental toxicology studies in rats and rabbits at doses of up to 30 times the recommended therapeutic exposures in humans (based on plasma exposures to the major circulating human metabolite) revealed no evidence of fetal harm; however, animal studies are not always predictive of a human response. Effient should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

    In embryo fetal developmental toxicology studies, pregnant rats and rabbits received prasugrel at maternally toxic oral doses equivalent to more than 40 times the human exposure. A slight decrease in pup body weight was observed; but, there were no structural malformations in either species. In prenatal and postnatal rat studies, maternal treatment with prasugrel had no effect on the behavioral or reproductive development of the offspring at doses greater than 150 times the human exposure [see Nonclinical Toxicology (13.1)].

    Nursing Mothers

    It is not known whether Effient is excreted in human milk; however, metabolites of Effient were found in rat milk. Because many drugs are excreted in human milk, prasugrel should be used during nursing only if the potential benefit to the mother justifies the potential risk to the nursing infant.

    Pediatric Use

    Safety and effectiveness in pediatric patients have not been established [see Clinical Pharmacology (12.3)].

    Geriatric Use

    In TRITON-TIMI 38, 38.5% of patients were ≥65 years of age and 13.2% were ≥75 years of age. The risk of bleeding increased with advancing age in both treatment groups, although the relative risk of bleeding (Effient compared with clopidogrel) was similar across age groups.

    Patients ≥75 years of age who received Effient had an increased risk of fatal bleeding events (1.0%) compared to patients who received clopidogrel (0.1%). In patients ≥75 years of age, symptomatic intracranial hemorrhage occurred in 7 patients (0.8%) who received Effient and in 3 patients (0.3%) who received clopidogrel. Because of the risk of bleeding, and because effectiveness is uncertain in patients ≥75 years of age [see Clinical Studies (14)], use of Effient is generally not recommended in these patients, except in high-risk situations (diabetes and past history of myocardial infarction) where its effect appears to be greater and its use may be considered [see Warnings and Precautions (5.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

    Low Body Weight

    In TRITON-TIMI 38, 4.6% of patients treated with Effient had body weight <60 kg. Individuals with body weight <60 kg had an increased risk of bleeding and an increased exposure to the active metabolite of prasugrel [see Dosage and Administration (2), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)]. Consider lowering the maintenance dose to 5 mg in patients <60 kg. The effectiveness and safety of the 5 mg dose have not been prospectively studied.

    Renal Impairment

    No dosage adjustment is necessary for patients with renal impairment. There is limited experience in patients with end-stage renal disease, but such patients are generally at higher risk of bleeding [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

    Hepatic Impairment

    No dosage adjustment is necessary in patients with mild to moderate hepatic impairment (Child-Pugh Class A and B). The pharmacokinetics and pharmacodynamics of prasugrel in patients with severe hepatic disease have not been studied, but such patients are generally at higher risk of bleeding [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

    Metabolic Status

    In healthy subjects, patients with stable atherosclerosis, and patients with ACS receiving prasugrel, there was no relevant effect of genetic variation in CYP2B6, CYP2C9, CYP2C19, or CYP3A5 on the pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation.

    Overdosage

    Signs and Symptoms

    Platelet inhibition by prasugrel is rapid and irreversible, lasting for the life of the platelet, and is unlikely to be increased in the event of an overdose. In rats, lethality was observed after administration of 2000 mg/kg. Symptoms of acute toxicity in dogs included emesis, increased serum alkaline phosphatase, and hepatocellular atrophy. Symptoms of acute toxicity in rats included mydriasis, irregular respiration, decreased locomotor activity, ptosis, staggering gait, and lacrimation.

    Recommendations about Specific Treatment

    Platelet transfusion may restore clotting ability. The prasugrel active metabolite is not likely to be removed by dialysis.

    Effient Description

    Effient contains prasugrel, a thienopyridine class inhibitor of platelet activation and aggregation mediated by the P2Y12 ADP receptor. Effient is formulated as the hydrochloride salt, a racemate, which is chemically designated as 5-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate hydrochloride. Prasugrel hydrochloride has the empirical formula C20H20FNO3S•HCl representing a molecular weight of 409.90. The chemical structure of prasugrel hydrochloride is:

    Prasugrel hydrochloride is a white to practically white solid. It is soluble at pH 2, slightly soluble at pH 3 to 4, and practically insoluble at pH 6 to 7.5. It also dissolves freely in methanol and is slightly soluble in 1- and 2-propanol and acetone. It is practically insoluble in diethyl ether and ethyl acetate.

    Effient is available for oral administration as 5 mg or 10 mg elongated hexagonal, film-coated, non-scored tablets, debossed on each side. Each yellow 5 mg tablet is manufactured with 5.49 mg prasugrel hydrochloride, equivalent to 5 mg prasugrel and each beige 10 mg tablet with 10.98 mg prasugrel hydrochloride, equivalent to 10 mg of prasugrel.

    Original Formulation

    During manufacture and storage, partial conversion from prasugrel hydrochloride to prasugrel free base may occur. Other ingredients include mannitol, hypromellose, croscarmellose sodium, microcrystalline cellulose, and vegetable magnesium stearate. The color coatings contain lactose, hypromellose, titanium dioxide, triacetin, iron oxide yellow, and iron oxide red (only in Effient 10 mg tablet).

    Revised Formulation

    Other ingredients include mannitol, hypromellose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, sucrose stearate, and glyceryl behenate. The color coatings contain lactose, hypromellose, titanium dioxide, triacetin, iron oxide yellow, and iron oxide red (only in Effient 10 mg tablet).

    Effient – Clinical Pharmacology

    Mechanism of Action

    Prasugrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets.

    Pharmacodynamics

    Prasugrel produces inhibition of platelet aggregation to 20 μM or 5 μM ADP, as measured by light transmission aggregometry. Following a 60-mg loading dose of Effient, approximately 90% of patients had at least 50% inhibition of platelet aggregation by 1 hour. Maximum platelet inhibition was about 80% (see Figure 2). Mean steady-state inhibition of platelet aggregation was about 70% following 3 to 5 days of dosing at 10 mg daily after a 60-mg loading dose of Effient.

    Figure 2: Inhibition (Mean±SD) of 20 μM ADP-induced Platelet Aggregation (IPA) Measured by Light Transmission Aggregometry after Prasugrel 60 mg.

    Platelet aggregation gradually returns to baseline values over 5-9 days after discontinuation of prasugrel, this time course being a reflection of new platelet production rather than pharmacokinetics of prasugrel. Discontinuing clopidogrel 75 mg and initiating prasugrel 10 mg with the next dose resulted in increased inhibition of platelet aggregation, but not greater than that typically produced by a 10-mg maintenance dose of prasugrel alone. The relationship between inhibition of platelet aggregation and clinical activity has not been established.

    Pharmacokinetics

    Prasugrel is a prodrug and is rapidly metabolized to a pharmacologically active metabolite and inactive metabolites. The active metabolite has an elimination half-life of about 7 hours (range 2-15 hours). Healthy subjects, patients with stable atherosclerosis, and patients undergoing PCI show similar pharmacokinetics.

    Absorption and Binding – Following oral administration, ≥79% of the dose is absorbed. The absorption and metabolism are rapid, with peak plasma concentrations (Cmax) of the active metabolite occurring approximately 30 minutes after dosing. The active metabolite’s exposure (AUC) increases slightly more than proportionally over the dose range of 5 to 60 mg. Repeated daily doses of 10 mg do not lead to accumulation of the active metabolite. In a study of healthy subjects given a single 15 mg dose, the AUC of the active metabolite was unaffected by a high fat, high calorie meal, but Cmax was decreased by 49% and Tmax was increased from 0.5 to 1.5 hours. Effient can be administered without regard to food. The active metabolite is bound about 98% to human serum albumin.

    Metabolism and Elimination – Prasugrel is not detected in plasma following oral administration. It is rapidly hydrolyzed in the intestine to a thiolactone, which is then converted to the active metabolite by a single step, primarily by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19. The estimates of apparent volume of distribution of prasugrel’s active metabolite ranged from 44 to 68 L and the estimates of apparent clearance ranged from 112 to 166 L/hr in healthy subjects and patients with stable atherosclerosis. The active metabolite is metabolized to two inactive compounds by S-methylation or conjugation with cysteine. The major inactive metabolites are highly bound to human plasma proteins. Approximately 68% of the prasugrel dose is excreted in the urine and 27% in the feces as inactive metabolites.

    Specific Populations

    Pediatric – Pharmacokinetics and pharmacodynamics of prasugrel have not been evaluated in a pediatric population [see Use in Specific Populations (8.4)].

    Geriatric – In a study of 32 healthy subjects between the ages of 20 and 80 years, age had no significant effect on pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation. In TRITON-TIMI 38, the mean exposure (AUC) of the active metabolite was 19% higher in patients ≥75 years of age than in patients <75 years of age [see Warnings and Precautions (5.1), Adverse Reactions (6.1), and Use in Specific Populations (8.5)].

    Body Weight – The mean exposure (AUC) to the active metabolite is approximately 30 to 40% higher in subjects with a body weight of <60 kg than in those weighing ≥60 kg [see Dosage and Administration (2), Warnings and Precautions (5.1), Adverse Reactions (6.1), and Use in Specific Populations (8.6)].

    Gender – Pharmacokinetics of prasugrel’s active metabolite are similar in men and women.

    Ethnicity – Exposure in subjects of African and Hispanic descent is similar to that in Caucasians. In clinical pharmacology studies, after adjusting for body weight, the AUC of the active metabolite was approximately 19% higher in Chinese, Japanese, and Korean subjects than in Caucasian subjects.

    Smoking – Pharmacokinetics of prasugrel’s active metabolite are similar in smokers and nonsmokers.

    Renal Impairment – Pharmacokinetics of prasugrel’s active metabolite and its inhibition of platelet aggregation are similar in patients with moderate renal impairment (CrCL=30 to 50 mL/min) and healthy subjects. In patients with end-stage renal disease, exposure to the active metabolite (both Cmax and AUC (0-tlast)) was about half that in healthy controls and patients with moderate renal impairment [see Warnings and Precautions (5.1) and Use in Specific Populations (8.7)].

    Hepatic Impairment – Pharmacokinetics of prasugrel’s active metabolite and inhibition of platelet aggregation were similar in patients with mild to moderate hepatic impairment compared to healthy subjects. The pharmacokinetics and pharmacodynamics of prasugrel’s active metabolite in patients with severe hepatic disease have not been studied [see Warnings and Precautions (5.1) and Use in Specific Populations (8.8)].

    Drug Interactions

    Potential for Other Drugs to Affect Prasugrel

    Inhibitors of CYP3A – Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A4 and CYP3A5, did not affect prasugrel-mediated inhibition of platelet aggregation or the active metabolite’s AUC and Tmax, but decreased the Cmax by 34% to 46%. Therefore, CYP3A inhibitors such as verapamil, diltiazem, indinavir, ciprofloxacin, clarithromycin, and grapefruit juice are not expected to have a significant effect on the pharmacokinetics of the active metabolite of prasugrel [see Drug Interactions (7.3)].

    Inducers of Cytochromes P450 – Rifampicin (600 mg daily), a potent inducer of CYP3A and CYP2B6 and an inducer of CYP2C9, CYP2C19, and CYP2C8, did not significantly change the pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation. Therefore, known CYP3A inducers such as rifampicin, carbamazepine, and other inducers of cytochromes P450 are not expected to have significant effect on the pharmacokinetics of the active metabolite of prasugrel [see Drug Interactions (7.3)].

    Drugs that Elevate Gastric pH – Daily coadministration of ranitidine (an H2 blocker) or lansoprazole (a proton pump inhibitor) decreased the Cmax of the prasugrel active metabolite by 14% and 29%, respectively, but did not change the active metabolite’s AUC and Tmax. In TRITON-TIMI 38, Effient was administered without regard to coadministration of a proton pump inhibitor or H2 blocker [see Drug Interactions (7.3)].

    Statins – Atorvastatin (80 mg daily), a drug metabolized by CYP450 3A4, did not alter the pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation [see Drug Interactions (7.3)].

    Heparin – A single intravenous dose of unfractionated heparin (100 U/kg) did not significantly alter coagulation or the prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared with either drug alone [see Drug Interactions (7.3)].

    Aspirin – Aspirin 150 mg daily did not alter prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared with either drug alone [see Drug Interactions (7.3)].

    Warfarin – A significant prolongation of the bleeding time was observed when prasugrel was coadministered with 15 mg of warfarin [see Drug Interactions (7.1)].

    Potential for Prasugrel to Affect Other Drugs

    In vitro metabolism studies demonstrate that prasugrel’s main circulating metabolites are not likely to cause clinically significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A, or induction of CYP1A2 or CYP3A.

    Drugs Metabolized by CYP2B6 — Prasugrel is a weak inhibitor of CYP2B6. In healthy subjects, prasugrel decreased exposure to hydroxybupropion, a CYP2B6-mediated metabolite of bupropion, by 23%, an amount not considered clinically significant. Prasugrel is not anticipated to have significant effect on the pharmacokinetics of drugs that are primarily metabolized by CYP2B6, such as halothane, cyclophosphamide, propofol, and nevirapine.

    Effect on Digoxin – The potential role of prasugrel as a Pgp substrate was not evaluated. Prasugrel is not an inhibitor of Pgp, as digoxin clearance was not affected by prasugrel coadministration [see Drug Interactions (7.3)].

    Pharmacogenomics

    There is no relevant effect of genetic variation in CYP2B6, CYP2C9, CYP2C19, or CYP3A5 on the pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation.

    Nonclinical Toxicology

    Carcinogenesis, Mutagenesis, Impairment of Fertility

    Carcinogenesis – No compound-related tumors were observed in a 2-year rat study with prasugrel at oral doses up to 100 mg/kg/day (>100 times the recommended therapeutic exposures in humans (based on plasma exposures to the major circulating human metabolite). There was an increased incidence of tumors (hepatocellular adenomas) in mice exposed for 2 years to high doses (>250 times the human metabolite exposure).

    Mutagenesis – Prasugrel was not genotoxic in two in vitro tests (Ames bacterial gene mutation test, clastogenicity assay in Chinese hamster fibroblasts) and in one in vivo test (micronucleus test by intraperitoneal route in mice).

    Impairment of Fertility – Prasugrel had no effect on fertility of male and female rats at oral doses up to 300 mg/kg/day (80 times the human major metabolite exposure at daily dose of 10 mg prasugrel).

    Clinical Studies

    The clinical evidence for the effectiveness of Effient is derived from the TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel) study, a 13,608-patient, multicenter, international, randomized, double-blind, parallel-group study comparing Effient to a regimen of clopidogrel, each added to aspirin and other standard therapy, in patients with ACS (UA, NSTEMI, or STEMI) who were to be managed with PCI. Randomization was stratified for UA/NSTEMI and STEMI.

    Patients with UA/NSTEMI presenting within 72 hours of symptom onset were to be randomized after undergoing coronary angiography. Patients with STEMI presenting within 12 hours of symptom onset could be randomized prior to coronary angiography. Patients with STEMI presenting between 12 hours and 14 days of symptom onset were to be randomized after undergoing coronary angiography. Patients underwent PCI, and for both UA/NSTEMI and STEMI patients, the loading dose was to be administered anytime between randomization and 1 hour after the patient left the catheterization lab. If patients with STEMI were treated with thrombolytic therapy, randomization could not occur until at least 24 hours (for tenecteplase, reteplase, or alteplase) or 48 hours (for streptokinase) after the thrombolytic was given.

    Patients were randomized to receive Effient (60-mg loading dose followed by 10 mg once daily) or clopidogrel (300-mg loading dose followed by 75 mg once daily), with administration and follow-up for a minimum of 6 months (actual median 14.5 months). Patients also received aspirin (75 mg to 325 mg once daily). Other therapies, such as heparin and intravenous glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, were administered at the discretion of the treating physician. Oral anticoagulants, other platelet inhibitors, and chronic NSAIDs were not allowed.

    The primary outcome measure was the composite of cardiovascular death, nonfatal MI, or nonfatal stroke in the UA/NSTEMI population. Success in this group allowed analysis of the same endpoint in the overall ACS and STEMI populations. Nonfatal MIs included both MIs detected solely through analysis of creatine kinase muscle-brain (CK-MB) changes and clinically apparent (investigator-reported) MIs.

    The patient population was 92% Caucasian, 26% female, and 39% ≥65 years of age. The median time from symptom onset to study drug administration was 7 hours for patients with STEMI and 30 hours for patients with UA/NSTEMI. Approximately 99% of patients underwent PCI. The study drug was administered after the first coronary guidewire was placed in approximately 75% of patients.

    Effient significantly reduced total endpoint events compared to clopidogrel (see Table 5 and Figure 3). The reduction of total endpoint events was driven primarily by a decrease in nonfatal MIs, both those occurring early (through 3 days) and later (after 3 days). Approximately 40% of MIs occurred peri-procedurally and were detected solely by changes in CK-MB. Administration of the clopidogrel loading dose in TRITON-TIMI 38 was delayed relative to the placebo-controlled trials that supported its approval for ACS. Effient produced higher rates of clinically significant bleeding than clopidogrel in TRITON-TIMI 38 [see Adverse Reactions (6.1)]. Choice of therapy requires balancing these differences in outcome.

    The treatment effect of Effient was apparent within the first few days, and persisted to the end of the study (see Figure 3). The inset shows results over the first 7 days.

    Figure 3: Time to first event of CV death, MI, or stroke (TRITON-TIMI 38).

    The Kaplan-Meier curves (see Figure 3) show the primary composite endpoint of CV death, nonfatal MI, or nonfatal stroke over time in the UA/NSTEMI and STEMI populations. In both populations, the curves separate within the first few hours. In the UA/NSTEMI population, the curves continue to diverge throughout the 15 month follow-up period. In the STEMI population, the early separation was maintained throughout the 15 month follow-up period, but there was no progressive divergence after the first few weeks.

    Effient reduced the occurrence of the primary composite endpoint compared to clopidogrel in both the UA/NSTEMI and STEMI populations (see Table 5). In patients who survived an on-study myocardial infarction, the incidence of subsequent events was also lower in the Effient group.

    Table 5: Patients with Outcome Events (CV Death, MI, Stroke) in TRITON-TIMI 38
    a RRR = (1-Hazard Ratio) x 100%. Values with a negative relative risk reduction indicate a relative risk increase.

    Patients with events From Kaplan-Meier analysis
    Effient

    (%)

    Clopidogrel

    (%)

    Relative Risk Reduction (%)a

    (95% CI)

    p-value
    UA/NSTEMI N=5044 N=5030
        CV death, nonfatal MI, or nonfatal stroke 9.3 11.2 18.0 (7.3, 27.4) 0.002
              CV death 1.8 1.8 2.1 (-30.9, 26.8) 0.885
              Nonfatal MI 7.1 9.2 23.9 (12.7, 33.7) <0.001
              Nonfatal Stroke 0.8 0.8 2.1 (-51.3, 36.7) 0.922
    STEMI N=1769 N=1765
         CV death, nonfatal MI, or nonfatal stroke 9.8 12.2 20.7 (3.2, 35.1) 0.019
              CV death 2.4 3.3 26.2 (-9.4, 50.3) 0.129
              Nonfatal MI 6.7 8.8 25.4 (5.2, 41.2) 0.016
              Nonfatal Stroke 1.2 1.1 -9.7 (-104.0, 41.0) 0.77

    The effect of Effient in various subgroups is shown in Figures 4 and 5. Results are generally consistent across pre-specified subgroups, with the exception of patients with a history of TIA or stroke [see Contraindications (4.2)]. The treatment effect was driven primarily by a reduction in nonfatal MI. The effect in patients ≥75 years of age was also somewhat smaller, and bleeding risk is higher in these individuals [see Adverse Reactions (6.1)]. See below for analyses of patients ≥75 years of age with risk factors.

    Figure 4: Subgroup analyses for time to first event of CV death, MI, or stroke (HR and 95% CI; TRITON-TIMI 38) – UA/NSTEMI Patients.

    Figure 5: Subgroup analyses for time to first event of CV death, MI, or stroke (HR and 95% CI; TRITON-TIMI 38) – STEMI Patients.

    Effient is generally not recommended in patients ≥75 years of age, except in high-risk situations (diabetes mellitus or prior MI) where its effect appears to be greater and its use may be considered. These recommendations are based on subgroup analyses (see Table 6) and must be interpreted with caution, but the data suggest that Effient reduces ischemic events in such patients.

    Table 6: Subgroup Analyses for Time to First Event of CV Death, MI, or Stroke: Patients < or ≥75 Years of Age, ± Diabetes, ± Prior History of MI, All ACS Patient Population
    Effient Clopidogrel
    N % with events N % with events Hazard Ratio

    (95% CI)

    p-value
    Age ≥75
         Diabetes – yes 249 14.9 234 21.8 0.64 (0.42, 0.97) 0.034
         Diabetes – no 652 16.4 674 15.3 1.1 (0.83, 1.43) NS
    Age <75
         Diabetes – yes 1327 10.8 1336 14.8 0.72 (0.58, 0.89) 0.002
         Diabetes – no 4585 7.8 4551 9.5 0.82 (0.71, 0.94) 0.004
     
    Age ≥75
         Prior MI – yes 220 17.3 212 22.6 0.72 (0.47, 1.09) 0.12
         Prior MI – no 681 15.6 696 15.2 1.05 (0.80, 1.37) NS
    Age <75
         Prior MI – yes 1006 12.2 996 15.4 0.78 (0.62, 0.99) 0.04
         Prior MI – no 4906 7.7 4891 9.7 0.78 (0.68, 0.90) <0.001

    There were 50% fewer stent thromboses (95% C.I. 32% – 64%; p<0.001) reported among patients randomized to Effient (0.9%) than among patients randomized to clopidogrel (1.8%). The difference manifested early and was maintained through one year of follow-up. Findings were similar with bare metal and drug-eluting stents.

    In TRITON-TIMI 38, prasugrel reduced ischemic events (mainly nonfatal MIs) and increased bleeding events [see Adverse Reactions (6.1)] relative to clopidogrel. The findings are consistent with the intended greater inhibition of platelet aggregation by prasugrel at the doses used in the study [see Clinical Pharmacology (12.2)]. There is, however, an alternative explanation: both prasugrel and clopidogrel are pro-drugs that must be metabolized to their active moieties. Whereas the pharmacokinetics of prasugrel’s active metabolite are not known to be affected by genetic variations in CYP2B6, CYP2C9, CYP2C19, or CYP3A5, the pharmacokinetics of clopidogrel’s active metabolite are affected by CYP2C19 genotype, and approximately 30% of Caucasians are reduced-metabolizers. Moreover, certain proton pump inhibitors, widely used in the ACS patient population and used in TRITON-TIMI 38, inhibit CYP2C19, thereby decreasing formation of clopidogrel’s active metabolite. Thus, reduced-metabolizer status and use of proton pump inhibitors may diminish clopidogrel’s activity in a fraction of the population, and may have contributed to prasugrel’s greater treatment effect and greater bleeding rate in TRITON-TIMI 38. The extent to which these factors were operational, however, is unknown.

    How Supplied/Storage and Handling

    Effient (prasugrel) is available as elongated hexagonal, film-coated, non-scored tablets in the following strengths, colors, imprints, and presentations:

    * Identi Dose®, unit dose medication, Lilly

    Features Strengths
    5 mg 10 mg
    Tablet color yellow beige
    Formulation Original Revised Original Revised
    Tablet imprint 5 MG 5 10 MG 10
    Tablet imprint 4760 5121 4759 5123
    Presentations and NDC Codes
    Bottles of 7 0002-4760-76 NA NA NA
    Bottles of 30 0002-4760-30 0002-5121-30 0002-4759-30 0002-5123-30
    Blisters ID*24 NA 0002-5121-52 NA NA
    Blisters ID*90 NA NA 0002-4759-77 0002-5123-77

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

    Dispense and keep product in original container. Keep container closed and do not remove desiccant from bottle. Do not break the tablet.

    Patient Counseling Information

    See Medication Guide

    Benefits and Risks

    • Summarize the effectiveness features and potential side effects of Effient.
    • Tell patients to take Effient exactly as prescribed.
    • Remind patients not to discontinue Effient without first discussing it with the physician who prescribed Effient.
    • Recommend that patients read the Medication Guide.

    Bleeding

    Inform patients that they:

    • will bruise and bleed more easily.
    • will take longer than usual to stop bleeding.
    • should report any unanticipated, prolonged, or excessive bleeding, or blood in their stool or urine.

    Other Signs and Symptoms Requiring Medical Attention

    • Inform patients that TTP is a rare but serious condition that has been reported with Effient.
      • Instruct patients to get prompt medical attention if they experience any of the following symptoms that cannot otherwise be explained: fever, weakness, extreme skin paleness, purple skin patches, yellowing of the skin or eyes, or neurological changes.
    • Inform patients that they may have hypersensitivity reactions including rash, angioedema, anaphylaxis, or other manifestations. Patients who have had hypersensitivity reactions to other thienopyridines may have hypersensitivity reactions to Effient.

    Invasive Procedures

    Instruct patients to:

    • inform physicians and dentists that they are taking Effient before any invasive procedure is scheduled.
    • tell the doctor performing the invasive procedure to talk to the prescribing health care professional before stopping Effient.

    Concomitant Medications

    Ask patients to list all prescription medications, over-the-counter medications, or dietary supplements they are taking or plan to take so the physician knows about other treatments that may affect bleeding risk (e.g., warfarin and NSAIDs).

    Literature Revised: November 30, 2012

    Effient® is a registered trademark of Eli Lilly and Company.

    Manufactured by Eli Lilly and Company, Indianapolis, IN, 46285

    Marketed by Daiichi Sankyo, Inc. and Lilly USA, LLC

    Copyright ©2009, 2012 Daiichi Sankyo, Inc. and Eli Lilly and Company. All rights reserved.

    PV 7802 AMP

    MEDICATION GUIDE

    Effient® (Ef′-fee-ent)

    (prasugrel) tablets

    Read this Medication Guide before you start taking Effient and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or your treatment.

    What is the most important information I should know about Effient?

    • Effient is used to lower your chance of having a heart attack or other serious problems with your heart or blood vessels. But, Effient can cause bleeding, which can be serious, and sometimes lead to death. You should not start to take Effient if it is likely that you will have heart bypass surgery (coronary artery bypass graft surgery or CABG) right away. You have a higher risk of bleeding if you take Effient and then have heart bypass surgery.
    • Do not take Effient if you:
      • currently have abnormal bleeding, such as stomach or intestinal bleeding, or bleeding in your head
      • have had a stroke or “mini-stroke” (also known as transient ischemic attack or TIA)
      • are allergic to prasugrel or any of the ingredients in Effient. See the end of this Medication Guide for a list of ingredients in Effient.
    • Get medical help right away if you think you may be having a stroke or TIA. Symptoms that you may be having a stroke or TIA include:
      • sudden slurring of speech,
      • sudden weakness or numbness in one part of your body,
      • sudden blurry vision, or sudden severe headache.
    • If you have a stroke or TIA while taking Effient, your doctor will probably stop your Effient. Follow your doctor’s instructions about stopping Effient. Do not stop taking Effient unless your doctor tells you to.
    • Before having any surgery you should talk to your doctor about stopping Effient. If possible, Effient should be stopped at least 1 week (7 days) before any surgery, as instructed by the doctor who prescribed Effient for you.

    Your risk of bleeding while taking Effient may be higher if you also:

    • have had trauma, such as an accident or surgery
    • have stomach or intestine bleeding that is recent or keeps coming back, or you have a stomach ulcer
    • have severe liver problems
    • have moderate to severe kidney problems
    • weigh less than 132 pounds
    • take other medicines that increase your risk of bleeding, including:
      • warfarin sodium (Coumadin*, Jantoven*)
      • a medicine that contains heparin
      • other medicines to prevent or treat blood clots
      • regular daily use of non-steroidal anti-inflammatory drugs (NSAIDs)

    Tell your doctor if you take any of these medicines. Ask your doctor if you are not sure if your medicine is one listed above.

    • Effient increases your risk of bleeding because it lessens the ability of your blood to clot. While you take Effient:
      • you will bruise and bleed more easily
      • you are more likely to have nose bleeds
      • it will take longer for any bleeding to stop
    • Call your doctor right away if you have any of these signs or symptoms of bleeding:
      • unexpected bleeding or bleeding that lasts a long time
      • bleeding that is severe or you cannot control
      • pink or brown urine
      • red or black stool (looks like tar)
      • bruises that happen without a known cause or get larger
      • cough up blood or blood clots
      • vomit blood or your vomit looks like “coffee grounds”
    • Do not stop taking Effient without talking to the doctor who prescribes it for you. People who are treated with angioplasty and have a stent, and stop taking Effient too soon, have a higher risk of a blood clot in the stent, having a heart attack, or dying. If you must stop Effient because of bleeding, your risk of a heart attack may be higher. See “What are the possible side effects of Effient?” for more information about side effects.

    What is Effient?

    Effient is a prescription medicine used to treat people who:

    • have had a heart attack or severe chest pain that happens when your heart does not get enough oxygen, and
    • have been treated with a procedure called “angioplasty” (also called balloon angioplasty).

    Effient is used to lower your chance of having another serious problem with your heart or blood vessels, such as another heart attack, a stroke, blood clots in your stent, or death.

    Platelets are blood cells that help with normal blood clotting. Effient helps prevent platelets from sticking together and forming a clot that can block an artery or a stent.

    It is not known if Effient is safe and works in children.

    What should I tell my doctor before taking Effient?

    Effient may not be right for you. Tell your doctor about all of your medical conditions, including if you:

    • have any bleeding problems
    • have had a stroke or “mini-stroke” (also known as transient ischemic attack or TIA)
    • are allergic to any medicines, including clopidogrel (Plavix*) or ticlopidine hydrochloride (Ticlid*)
    • have a history of stomach ulcers, colon polyps, diverticulosis
    • have liver problems
    • have kidney problems
    • have had any recent severe injury or surgery
    • plan to have surgery or a dental procedure. See “What is the most important information I should know about Effient?”
    • pregnant, or are planning to get pregnant. It is not known if Effient will harm your baby.
    • if you are breast-feeding. It is not known if Effient passes into your breast-milk. You and your doctor should decide if you will take Effient or breast-feed. You should not do both without talking with your doctor.

    Tell all of your doctors and dentists that you are taking Effient. They should talk to the doctor who prescribed Effient 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. Certain medicines may increase your risk of bleeding. See “What is the most important information I should know about Effient?”

    Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine.

    How should I take Effient?

    • Take Effient exactly as prescribed by your doctor.
    • Take Effient one time each day.
    • You can take Effient with or without food.
    • Take Effient with aspirin as instructed by your doctor.
    • Your doctor will decide how long you should take Effient. Do not stop taking Effient without first talking to the doctor who prescribed it for you. See “What is the most important information I should know about Effient?”
    • If you miss a dose, take Effient as soon as you remember. If it is almost time for your next dose, skip the missed dose. Just take the next dose at your regular time. Do not take two doses at the same time unless your doctor tells you to.
    • If you take too much Effient, call your local emergency room or poison control center right away.
    • Call your doctor or healthcare provider right away if you fall or injure yourself, especially if you hit your head. Your doctor or healthcare provider may need to check you.

    What are the possible side effects of Effient?

    Effient can cause serious side effects, including:

    • See “What is the most important information I should know about Effient?”
    • A blood clotting problem called Thrombotic Thrombocytopenic Purpura (TTP). TTP can happen with Effient, sometimes after a short time (less than 2 weeks). TTP is a blood clotting problem where blood clots form in blood vessels and can happen all over the body. TTP needs to be treated in a hospital right away, because you may die. Get medical help right away if you have any of these symptoms and they cannot be explained by another medical condition:
      • purplish spots called purpura on the skin or mucous membranes (such as on the mouth) due to bleeding under the skin
      • paleness or jaundice (a yellowish color of the skin or eyes)
      • feeling tired or weak
      • fever
      • fast heart rate or feeling short of breath
      • headache, speech changes, confusion, coma, stroke, or seizure
      • low amount of urine or urine that is pink-tinged or has blood in it
      • stomach area (abdominal) pain, nausea, vomiting, or diarrhea
      • visual changes
    • Serious allergic reactions. Serious allergic reactions can happen with Effient, or if you have had a serious allergic reaction to the medicine clopidogrel (Plavix*) or ticlopidine (Ticlid*). Get medical help right away if you get any of these symptoms of a severe allergic reaction while taking Effient.
      • swelling or hives of your face, lips, in or around your mouth, or throat
      • trouble breathing or swallowing
      • chest pain or pressure
      • dizziness or fainting

    Tell your doctor if you have any side effect that bothers you or that does not go away.

    These are not all of the possible side effects of Effient. For more information, ask your doctor or pharmacist.

    Call your doctor for medical advice about side effects.

    You may report side effects to FDA at 1-800-FDA-1088.

    How should I store Effient?

    • Keep Effient at room temperature between 59°F to 86°F (15°C to 30°C).
    • Keep Effient in the container it comes in.
    • Keep the container closed tightly with the gray cylinder inside.
    • Protect Effient from moisture.

    Keep Effient and all medicines out of the reach of children.

    General Information about Effient

    Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Effient for a condition for which it was not prescribed. Do not give your Effient to other people, even if they have the same symptoms you have. It may harm them.

    This Medication Guide summarizes the most important information about Effient. If you would like more information about Effient, talk with your doctor or pharmacist. For more information, call 1-800-545-5979 or go to the following website: www.Effient.com

    What are the ingredients in Effient?

    Active Ingredient: prasugrel

    Original Formulation

    Inactive Ingredients: mannitol, hypromellose, croscarmellose sodium, microcrystalline cellulose, and vegetable magnesium stearate. The color coatings contain lactose, hypromellose, titanium dioxide, triacetin, iron oxide yellow, and iron oxide red (only in Effient 10 mg tablet).

    Revised Formulation

    Inactive Ingredients: mannitol, hypromellose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, sucrose stearate, and glyceryl behenate. The color coatings contain lactose, hypromellose, titanium dioxide, triacetin, iron oxide yellow, and iron oxide red (only in Effient 10 mg tablet).

    Effient® is a registered trademark of Eli Lilly and Company.

    Revised: November 30, 2012

    Manufactured by Eli Lilly and Company, Indianapolis, IN, 46285

    Marketed by Daiichi Sankyo, Inc. and Lilly USA, LLC

    This Medication Guide has been approved by the U.S. Food and Drug Administration.

    *The brands listed are trademarks of their respective owners and are not trademarks of Daiichi Sankyo, Inc. or Eli Lilly and Company.

    Copyright © 2009, 2012 Daiichi Sankyo, Inc. and Eli Lilly and Company. All rights reserved.

    PV 7812 AMP

    PACKAGE LABEL – Effient 5 mg 30 Tablets.

    NDC 0002-4760-30

    30 Tablets

    Effient TM

    (prasugrel) tablets

    5 mg

    Rx only

    Each tablet contains prasugrel hydrochloride* equivalent to 5 mg prasugrel

    *see package insert section 11

    Dispense accompanying Medication Guide to each patient.

    Effient.com

    Daiichi Sankyo/Lilly

    PACKAGE LABEL – Effient 10 mg 30 Tablets

    NDC 0002-4759-30

    30 Tablets

    Effient ®

    (prasugrel) tablets

    10 mg

    Rx only

    Each tablet contains prasugrel hydrochloride* equivalent to 10 mg prasugrel

    *see package insert section 11

    Dispense accompanying Medication Guide to each patient.

    Effient.com

    Daiichi Sankyo/Lilly

    PACKAGE LABEL – Effient 5 mg 30 Tablets

    NDC 0002-5121-30

    30 Tablets

    Effient ®

    (prasugrel) tablets

    5 mg

    Rx only

    Each tablet contains prasugrel hydrochloride equivalent to 5 mg prasugrel

    Dispense accompanying Medication Guide to each patient.

    Effient.com

    Daiichi Sankyo/Lilly

    PACKAGE LABEL – Effient 10 mg 30 Tablets

    NDC 0002-5123-30

    30 Tablets

    Effient ®

    (prasugrel) tablets

    10 mg

    Rx only

    Each tablet contains prasugrel hydrochloride equivalent to 10 mg prasugrel

    Dispense accompanying Medication Guide to each patient.

    Effient.com

    Daiichi Sankyo/Lilly

    Effient 

    prasugrel hydrochloride tablet, film coated

    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0002-4760
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    Prasugrel hydrochloride (Prasugrel) Prasugrel 5 mg
    Inactive Ingredients
    Ingredient Name Strength
    MANNITOL  
    HYPROMELLOSES  
    CROSCARMELLOSE SODIUM  
    CELLULOSE, MICROCRYSTALLINE  
    MAGNESIUM STEARATE  
    LACTOSE  
    TITANIUM DIOXIDE  
    TRIACETIN  
    FERRIC OXIDE YELLOW  
    Product Characteristics
    Color YELLOW Score no score
    Shape HEXAGON (6 sided) ( double-arrow ) Size 10mm
    Flavor Imprint Code 5;mg;4760
    Contains         
    Packaging
    # Item Code Package Description
    1 NDC:0002-4760-76 7 TABLET, FILM COATED (7 TABLET) in 1 BOTTLE
    2 NDC:0002-4760-30 30 TABLET, FILM COATED (30 TABLET) in 1 BOTTLE
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA022307 07/10/2009
    Effient 

    prasugrel hydrochloride tablet, film coated

    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0002-4759
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    Prasugrel hydrochloride (Prasugrel) Prasugrel 10 mg
    Inactive Ingredients
    Ingredient Name Strength
    MANNITOL  
    HYPROMELLOSES  
    CROSCARMELLOSE SODIUM  
    CELLULOSE, MICROCRYSTALLINE  
    MAGNESIUM STEARATE  
    LACTOSE  
    TITANIUM DIOXIDE  
    TRIACETIN  
    FERRIC OXIDE YELLOW  
    FERRIC OXIDE RED  
    Product Characteristics
    Color BROWN ( beige ) Score no score
    Shape HEXAGON (6 sided) ( double-arrow ) Size 11mm
    Flavor Imprint Code 10;mg;4759
    Contains         
    Packaging
    # Item Code Package Description
    1 NDC:0002-4759-30 30 TABLET, FILM COATED (30 TABLET) in 1 BOTTLE
    2 NDC:0002-4759-77 90 BLISTER PACK (90 BLISTER PACK) in 1 CARTON
    2 NDC:0002-4759-01 1 TABLET, FILM COATED (1 TABLET) in 1 BLISTER PACK
    3 NDC:0002-4759-61 7 TABLET, FILM COATED (7 TABLET) in 1 BOTTLE
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA022307 07/10/2009
    Effient 

    prasugrel hydrochloride tablet, film coated

    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0002-5121
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    Prasugrel hydrochloride (Prasugrel) Prasugrel 5 mg
    Inactive Ingredients
    Ingredient Name Strength
    MANNITOL  
    HYPROMELLOSES  
    HYDROXYPROPYL CELLULOSE, LOW SUBSTITUTED  
    CELLULOSE, MICROCRYSTALLINE  
    SUCROSE STEARATE  
    GLYCERYL BEHENATE  
    LACTOSE  
    TITANIUM DIOXIDE  
    TRIACETIN  
    FERRIC OXIDE YELLOW  
    Product Characteristics
    Color YELLOW Score no score
    Shape HEXAGON (6 sided) (double-arrow) Size 7mm
    Flavor Imprint Code 5;5121
    Contains         
    Packaging
    # Item Code Package Description
    1 NDC:0002-5121-30 30 TABLET, FILM COATED (30 TABLET) in 1 BOTTLE
    2 NDC:0002-5121-52 24 BLISTER PACK (24 BLISTER PACK) in 1 CARTON
    2 NDC:0002-5121-01 1 TABLET, FILM COATED (1 TABLET) in 1 BLISTER PACK
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA022307 03/01/2012
    Effient 

    prasugrel hydrochloride tablet, film coated

    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0002-5123
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    Prasugrel hydrochloride (Prasugrel) Prasugrel 10 mg
    Inactive Ingredients
    Ingredient Name Strength
    MANNITOL  
    HYPROMELLOSES  
    HYDROXYPROPYL CELLULOSE, LOW SUBSTITUTED  
    CELLULOSE, MICROCRYSTALLINE  
    SUCROSE STEARATE  
    GLYCERYL BEHENATE  
    LACTOSE  
    TITANIUM DIOXIDE  
    TRIACETIN  
    FERRIC OXIDE YELLOW  
    FERRIC OXIDE RED  
    Product Characteristics
    Color BROWN (beige ) Score no score
    Shape HEXAGON (6 sided) (double-arrow) Size 11mm
    Flavor Imprint Code 10;5123
    Contains         
    Packaging
    # Item Code Package Description
    1 NDC:0002-5123-30 30 TABLET, FILM COATED (30 TABLET) in 1 BOTTLE
    2 NDC:0002-5123-77 90 BLISTER PACK (90 BLISTER PACK) in 1 CARTON
    2 NDC:0002-5123-01 1 TABLET, FILM COATED (1 TABLET) in 1 BLISTER PACK
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA022307 03/01/2012
    Labeler - Eli Lilly and Company (006421325)
    Establishment
    Name Address ID/FEI Operations
    Ube Industries, Ltd. 695266288 API MANUFACTURE(0002-4759, 0002-4760, 0002-5121, 0002-5123), ANALYSIS(0002-4759, 0002-4760, 0002-5121, 0002-5123)
    Establishment
    Name Address ID/FEI Operations
    Eli Lilly and Company (Indianapolis) 006421325 MANUFACTURE(0002-4759, 0002-4760, 0002-5121, 0002-5123), ANALYSIS(0002-4759, 0002-4760, 0002-5121, 0002-5123), PACK(0002-4759, 0002-4760, 0002-5121, 0002-5123), LABEL(0002-4759, 0002-4760, 0002-5121, 0002-5123)
    Establishment
    Name Address ID/FEI Operations
    Sharp Corporation-Conshohocken 002346625 PACK(0002-4759, 0002-4760, 0002-5121, 0002-5123), LABEL(0002-4759, 0002-4760, 0002-5121, 0002-5123)
    Establishment
    Name Address ID/FEI Operations
    Anderson Packaging, Inc. 053217022 PACK(0002-5121, 0002-5123), LABEL(0002-5121, 0002-5123)

    Revised: 11/2012   Eli Lilly and Company

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    Effient

    Effient

    Pronunciation Generic Name: Prasugrel
    Class: Platelet-Aggregation Inhibitors

    For ProfessionalsSide EffectsInteractionsMore…

    Warning(s)

    • Bleeding
    • Potential risk of serious (including fatal) bleeding.1 2 6 10 (See Bleeding under Cautions.)
    • Avoid use in patients with active pathological bleeding, history of stroke/ TIA, or in those likely to undergo CABG.1
    • Generally not recommended in patients ≥75 years of age because of increased risk of fatal and intracranial bleeding, except in certain high-risk patients (e.g., those with diabetes, history of MI) who may experience a greater net clinical benefit.1 5 18 70 (See Geriatric Use under Cautions.)
    • Consider additional risk factors for bleeding such as body weight <60 kg, concomitant use of drugs that increase risk of bleeding, or other underlying conditions that may increase risk of bleeding.1
    • Discontinue prasugrel at least 7 days prior to any surgery when possible.1
    • Suspect bleeding in any patient receiving prasugrel who is hypotensive and has recently undergone an invasive (e.g., PCI, coronary angiography) or surgical (e.g., CABG) procedure.1
    • If bleeding occurs, attempt to manage without discontinuing therapy; increased risk of subsequent cardiovascular events possible with premature discontinuance, particularly in first few weeks following an acute coronary event or in patients with intracoronary stents.1 43 44 45 46 47 48 49 54 70 (See Discontinuance of Therapy under Cautions.)

    REMS:

    FDA approved a REMS for prasugrel to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of prasugrel and consists of the following: medication guide and communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

    Introduction

    Platelet-activation and aggregation inhibitor; thienopyridine P2Y12 platelet adenosine diphosphate (ADP)-receptor antagonist.1 2 3 4 5 6 8 13 14 15 28 30

    Uses for Effient

    Acute Coronary Syndromes: Patients Undergoing PCI

    Used in conjunction with aspirin to reduce the risk of thrombotic cardiovascular events (e.g., stent thrombosis, MI) in patients with acute coronary syndromes (ACS) undergoing PCI.1 2

    Used in patients with unstable angina or non-ST-segment-elevation MI (NSTEMI) undergoing PCI and in patients with ST-segment elevation MI (STEMI) managed with primary or delayed (after medical treatment) PCI.1 2

    Dual-drug antiplatelet therapy with a P2Y12-receptor antagonist and aspirin is considered part of the current standard of care in patients with ACS.991 992 993 994 1010 The American College of Cardiology Foundation (ACCF), AHA, and other experts recommend antiplatelet therapy with a P2Y12-receptor antagonist (clopidogrel, prasugrel, or ticagrelor) in conjunction with aspirin for treatment and secondary prevention in patients with ACS, including those undergoing PCI.992 993 994 1010 Continue treatment with a P2Y12-receptor antagonist for at least 12 months following placement of a coronary artery stent; continue aspirin therapy indefinitely.992 993 994 1010

    Unlike clopidogrel, genetic polymorphism of the CYP2C19 isoenzyme does not appear to affect pharmacodynamic or clinical response to prasugrel;140 142 143 144 145 therefore, some experts recommend prasugrel as an alternative to clopidogrel in patients identified as poor metabolizers of clopidogrel.140 143

    Produces more rapid and potent inhibition of platelet aggregation than standard dosages of clopidogrel; prasugrel therapy also associated with greater reductions in ischemic outcomes (e.g., stent thrombosis, MI); however, such benefits have been accompanied by an increased risk of bleeding.1 3 5 6 7 8 9 11 13 14 15 17 18

    Some evidence suggests that certain patient populations (e.g., those with diabetes, previous MI) may be more likely to benefit from prasugrel’s greater inhibition of platelet aggregation, while others (e.g., patients ≥75 years, those weighing <60 kg, or with previous TIA/stroke) may experience harm;2 5 14 16 17 19 additional studies needed to confirm these findings.2 5 13 19

    When selecting an appropriate antiplatelet regimen, consider individual patient (e.g., ischemic and bleeding risk) and drug-related (e.g., adverse effects, drug interaction potential) factors.140 141 When considering use of prasugrel over other P2Y12-receptor antagonists, balance anticipated greater benefits against increased risk of bleeding.1 2 8 9 13 14 17 70

    Effient Dosage and Administration

    General

    • It is generally recommended that antiplatelet agents be administered promptly upon presentation or diagnosis in patients with ACS.1 2 993

    • Pretreatment with prasugrel may be considered prior to determining coronary anatomy in patients who are not likely to undergo CABG surgery; weigh benefits of pretreatment against risk of surgical bleeding in patients who may require urgent CABG.1 Temporarily discontinue prasugrel at least 7 days prior to CABG, if possible.1
    • In patients with STEMI who will undergo primary PCI, ACC and AHA currently recommend administration of the loading dose of prasugrel as early as possible before PCI or at the time of the procedure.70

    Administration

    Oral Administration

    Administer orally without regard to meals.1

    Dosage

    Available as prasugrel hydrochloride; dosage expressed in terms of prasugrel.1

    Adults

    Acute Coronary Syndromes
    Patients Undergoing PCI

    Oral 60-mg initial loading dose followed by maintenance dosage of 10 mg daily; give in conjunction with aspirin (75–325 mg daily).1

    ACC and AHA recommend administering loading dose as soon as possible in patients with STEMI undergoing primary PCI.70 In patients with STEMI undergoing nonprimary/delayed PCI who have not received thrombolytic therapy and in whom coronary anatomy has been determined and PCI is planned, ACC and AHA recommend administering loading dose of prasugrel promptly and no later than 1 hour after PCI.70 Majority of patients in pivotal efficacy study (TRITON-TIMI 38) received loading dose after first coronary guidewire was placed or within 1 hour of PCI.1 2 3

    Consider reduced maintenance dosage in patients weighing <60 kg.1 6 18 (See Low Body Weight under Dosage and Administration: Special Populations.)

    Optimum duration of maintenance therapy not known; premature discontinuance of antiplatelet therapy in patients with intracoronary stents associated with thrombotic events, sometimes fatal.1 43 44 45 46 47 48 49 54 70 (See Discontinuance of Therapy under Cautions.) Therefore, experts recommend administering prasugrel for at least 12 months in those undergoing PCI with stent placement unless bleeding risk outweighs anticipated benefit; continue aspirin therapy indefinitely.992 993 994 1010

    Special Populations

    Hepatic Impairment

    No dosage adjustments required in patients with mild to moderate hepatic impairment (Child-Pugh class A or B).1 Not studied in patients with severe hepatic disease.1

    Renal Impairment

    No dosage adjustments required.1

    Low Body Weight

    May reduce maintenance dosage to 5 mg daily in patients who weigh <60 kg, although safety and efficacy of such lower dosages not established.1 6 18 (See Bleeding under Cautions.)

    Cautions for Effient

    Contraindications

    • Active pathological bleeding (e.g., peptic ulcer, intracranial hemorrhage).1

    • History of stroke or TIA.1

    Warnings/Precautions

    Warnings

    Bleeding

    Risk of serious, sometimes fatal bleeding.1 2 6 10 Major and minor bleeding events, including life-threatening and fatal bleeding reported more frequently in patients receiving prasugrel than those who received clopidogrel in pivotal clinical study.1 2 6 10

    Greater risk of bleeding observed in patients ≥75 years of age, those weighing < 60 kg, and those with prior stroke or TIA.1 2 Additional risk factors include recent trauma, recent surgery (e.g., CABG), recent or recurrent GI bleeding, active peptic ulcer disease, severe hepatic impairment, and concurrent use of drugs that increase risk of bleeding (e.g., oral anticoagulants, NSAIAs, thrombolytic agents).1

    Do not use in patients who are actively bleeding and/or who have a history of stroke or TIA.1 17 18 Not recommended in patients likely to undergo emergent CABG.1 (See Coronary Artery Bypass Grafting Surgery under Cautions.)

    Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or any other surgical procedure, even if there are no overt manifestations of bleeding.1

    If possible, manage bleeding without discontinuing prasugrel; premature discontinuance is associated with an increased risk of subsequent cardiovascular events.1 (See Discontinuance of Therapy under Cautions.) May treat bleeding with platelet transfusions; however, transfusions within 6 hours of a loading dose or 4 hours of a maintenance dose may be less effective.1 Withholding a dose not likely to resolve or prevent bleeding.1

    Cerebrovascular Events

    Higher incidence of stroke (thrombotic and hemorrhagic) and no evidence of clinical benefit reported among patients with a history of stroke or TIA receiving prasugrel compared with clopidogrel in TRITON-TIMI 38 study.1 2 Use not recommended in patients with a history of stroke or TIA; in general, discontinue prasugrel in those who experience such cerebrovascular events during therapy.1 18

    Coronary Artery Bypass Grafting Surgery

    Increased risk of bleeding in patients who undergo CABG surgery.1 2 (See Bleeding under Cautions.) CABG-related major and minor bleeding events occurred substantially more frequently in patients who received prasugrel versus clopidogrel in pivotal clinical study.1 2

    Discontinue prasugrel at least 7 days prior to CABG.1 Do not initiate in patients who are likely to undergo urgent CABG.1 May treat CABG-related bleeding with blood product transfusions (e.g., packed RBCs, platelets).1

    Discontinuance of Therapy

    Discontinue prasugrel in patients who develop active bleeding, stroke, or TIA during therapy.1 Temporarily discontinue drug at least 7 days prior to elective surgery.1 70

    In general, avoid premature discontinuance of thienopyridine treatment because of the subsequent increased risk of ischemic complications.1 6 45 Premature discontinuance of antiplatelet therapy in patients with intracoronary stents has been associated with an increased risk of stent thrombosis, MI, and/or death.43 44 45 46 47 48 49 54 Advise patients to never discontinue such therapy without first consulting their prescribing clinician, even if instructed to do so by another health-care professional.1 45 (See Advice to Patients.) If prasugrel must be temporarily discontinued because of an adverse event, reinstitute therapy as soon as possible.1

    Thrombotic Thrombocytopenic Purpura (TTP)

    Reported rarely with use of other thienopyridine derivatives, sometimes after brief exposure (<2 weeks); potentially fatal.1 31 Characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes on peripheral blood smear), neurologic findings, renal dysfunction, and fever.1 31 Requires urgent treatment (e.g., plasmapheresis).1

    Specific Populations

    Pregnancy

    Category B.1

    Lactation

    Distributed into milk in rats; not known whether distributed into human milk.1 Use during nursing only if potential benefits outweigh risks.1

    Pediatric Use

    Safety and efficacy not established in pediatric patients.1

    Geriatric Use

    Geriatric patients, particularly those ≥75 years of age, appear to be at greater risk of bleeding (including fatal bleeding) with prasugrel therapy compared with younger patients.1 Fatal bleeding and symptomatic intracranial hemorrhage occurred more often in patients ≥75 years of age receiving prasugrel compared with that in clopidogrel-treated patients in a large clinical study.1

    In general, avoid use in patients ≥75 years of age, but may consider use in certain geriatric patients with high-risk conditions (e.g., diabetes, previous MI) in whom a greater net clinical benefit has been demonstrated.1 5 18 70

    Hepatic Impairment

    In patients with mild to moderate hepatic impairment (Child-Pugh class A or B), inhibition of platelet aggregation was similar to that of healthy individuals.1 Not specifically studied in patients with severe hepatic impairment; such patients generally are at higher risk of bleeding.1

    Renal Impairment

    Inhibition of platelet aggregation similar in patients with moderate renal impairment (Clcr of 30–50 mL/minute) and healthy individuals.1

    Low Body Weight

    Patients with low body weight (< 60 kg) have increased exposure to the active metabolite of prasugrel and appear to be at increased risk of bleeding.1 (See Bleeding under Cautions.)

    Common Adverse Effects

    Bleeding, including life-threatening and fatal bleeding events.1 2

    Interactions for Effient

    Metabolized principally by CYP3A4 and CYP2B6; to a lesser extent by CYP2C9 and CYP2C19.1 13 14 22 23 30 Not likely to inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2D6 or 3A4 nor induce isoenzymes 1A2 or 3A4.1 13 Weak inhibitor of CYP2B6.1 25

    Does not inhibit P-glycoprotein (Pgp) transport system.1

    Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

    Clinically important interactions mediated by CYP enzymes unlikely.1 13 25

    CYP3A4 inhibitors: No substantial effect on systemic exposure or antiplatelet activity of prasugrel’s active metabolite.1 22

    CYP3A4 inducers: Not expected to substantially alter pharmacokinetic or pharmacodynamic response to prasugrel.1 25

    Drugs metabolized by CYP2B6: Potential for increased plasma concentrations and exposure to concomitantly administered drug; however, clinically important interactions not expected because of weak inhibition of CYP2B6.1 25

    Other Antiplatelet or Antithrombotic Agents

    Manufacturer states that prasugrel may be administered concomitantly with aspirin, heparin, and GP IIb/IIIa-receptor inhibitors.1 While evidence from drug interaction studies with other antiplatelet or antithrombotic agents generally is lacking, increased risk of bleeding likely with concomitant use of such agents.13 14

    Specific Drugs or Foods

    Drug

    Interaction

    Comments

    Aspirin

    Possible increased bleeding time and greater levels of platelet inhibition1 26

    May be administered concomitantly1

    Carbamazepine

    Pharmacokinetic/pharmacodynamic response to prasugrel not expected to be substantially altered1 25

    Ciprofloxacin

    Systemic exposure and antiplatelet activity of prasugrel active metabolite not affected1 22

    Clarithromycin

    Systemic exposure and antiplatelet activity of prasugrel active metabolite not affected1 22

    Cyclophosphamide

    Possible increased plasma concentrations and exposure to concomitant drug; clinically important interaction not expected1 25

    Digoxin

    Concurrent administration not expected to affect digoxin clearance1

    May be administered concomitantly1

    Diltiazem

    Systemic exposure and antiplatelet activity of prasugrel active metabolite not affected1 22

    Grapefruit juice

    Systemic exposure and antiplatelet activity of prasugrel active metabolite not affected1 22

    Halothane

    Possible increased plasma concentrations and exposure to concomitant drug; clinically important interaction not expected1

    Heparin

    Possible increased bleeding time, but no associated changes in coagulation or platelet inhibition1

    May be administered concomitantly1

    HMG-CoA reductase inhibitors (e.g., atorvastatin)

    Minor effect on exposure to active prasugrel metabolite, but no effect on inhibition of platelet aggregation1 17 23

    May be used concomitantly; no dosage adjustments necessary1 23

    Histamine H2-receptor antagonists (e.g., ranitidine)

    Decreased plasma concentrations of active prasugrel metabolite by approximately 14%, but systemic exposure unaffected

    May be administered concomitantly1

    Indinavir

    Systemic exposure and antiplatelet activity of prasugrel active metabolite not affected1 22

    Ketoconazole

    Decreased plasma concentrations of prasugrel’s active metabolite by 34–46%; no change in systemic exposure or platelet inhibition1 14 17 22

    Nevirapine

    Possible increased plasma concentrations and exposure to concomitant drug; clinically important interaction not expected1 25

    NSAIAs

    Increased risk of bleeding with concomitant long-term use of NSAIAs1

    Propofol

    Possible increased plasma concentrations and exposure to concomitant drug; clinically important interaction not expected1 25

    Proton-pump inhibitors (e.g., lansoprazole)

    Possible decreased systemic exposure and peak plasma concentrations of prasugrel’s active metabolite, but no effect on platelet inhibition1 13 17 24

    May be administered concomitantly1

    Rifampin

    Pharmacokinetic/pharmacodynamic response to prasugrel not expected to be substantially altered1 25

    Thrombolytic agents

    Increased risk of bleeding1

    Warfarin

    Increased risk of bleeding; prolonged bleeding time observed with concomitant use1

    Effient Pharmacokinetics

    Absorption

    Bioavailability

    Rapidly and completely absorbed following oral administration.1 13 27 28

    Onset

    Peak plasma concentrations of active metabolite attained approximately 30 minutes following oral administration; no evidence of accumulation with repeated administration.1 13 25 28

    Following a 60-mg loading dose, approximately 90% of patients achieve at least 50% inhibition of platelet aggregation by 1 hour; maximum platelet inhibition was approximately 80%.1 Steady-state platelet inhibition (70%) occurs within 3–5 days following maintenance therapy with repeated dosages of 10 mg daily.1

    Duration

    Following discontinuance, platelet aggregation gradually returns to baseline values in about 5–9 days.1

    Food

    In healthy individuals, food (high-fat or high-caloric meal) decreased peak plasma concentrations by 49% but did not alter exposure to active metabolite.1

    Special Populations

    In patients with end-stage renal impairment, exposure to active metabolite was decreased to approximately half that in healthy individuals and those with moderate renal impairment.1

    In low-weight individuals (weight <60 kg), increased exposure to active metabolite observed.1 Clearance of active metabolite appears to increase exponentially with increasing body weight.30

    In patients ≥75 years of age, mean exposure to active metabolite increased by 19% compared with younger patients.1

    Distribution

    Plasma Protein Binding

    Approximately 98% for active metabolite.1

    Elimination

    Metabolism

    Rapidly hydrolyzed by esterases to an inactive thiolactone; subsequently metabolized to active metabolite by CYP isoenzymes (primarily by 3A4 and 2B6, and to a lesser extent by 2C9 and 2C19).1 13 14 22 23 28 30 Requires a single step for metabolic activation compared with clopidogrel, which undergoes a 2-step oxidative process.13 14 22 29 30 31

    Elimination Route

    Excreted in urine (68%) and feces (27%) as inactive metabolites.1 14 28 Active metabolite not expected to be removed by dialysis.1

    Half-life

    Manufacturer reports half-life of active metabolite about 7 hours (range 2–15 hours);1 half-life of about 3.7 hours also reported.13 14

    Stability

    Storage

    Oral

    Tablets

    25°C (may be exposed to 15–30°C).1 Dispense and store in original container; keep container closed and do not remove dessicant from bottle.1

    Actions

    • Prodrug; platelet inhibitory activity is dependent on hepatic transformation to an active metabolite.1 2 14 22 30 31

    • Active metabolite binds irreversibly to P2Y12 class of ADP receptors on platelet surfaces, thereby inhibiting ADP-dependent platelet activation and aggregation.1 13 14 15
    • ADP receptor is irreversibly modified; platelets exposed to prasugrel remain affected for the remainder of their lifespan (about 7–10 days).1 22
    • Prasugrel is a thienopyridine derivative that is structurally and pharmacologically related to clopidogrel.1 2 3 4 5 6 8 13 14 15 28 30 Exhibits more rapid, consistent, and greater inhibition of ADP-mediated platelet aggregation than clopidogrel.2 3 8 9 11 12 13 14 15 27 Increased potency appears to be a result of more efficient conversion of the prodrug to its active metabolite.2 3 9 14 15 22 27 30

      Genetic polymorphisms of CYP isoenzymes (e.g., CYP2B6, CYP2C9, CYP2C19, CYP3A5) do not appear to affect pharmacologic or clinical response to prasugrel.1 29

    Advice to Patients

    • Importance of counseling patients about potential risks versus benefits of prasugrel.1

    • Importance of informing patients that they will bruise and/or bleed more easily and that a longer than usual time will be required to stop bleeding when taking prasugrel.1 Importance of informing clinicians about any unexpected, prolonged, or excessive bleeding, or blood in urine or stool.1
    • Importance of patients taking prasugrel exactly as prescribed and not discontinuing therapy without first consulting the prescribing clinician.1
    • Importance of informing clinicians (e.g., physicians, dentists) about prasugrel therapy before any invasive procedure or surgery is scheduled.1 45 Clinician performing invasive procedure should consult with prescribing clinician before discontinuing prasugrel.1 45
    • Risk of thrombotic thrombocytopenic purpura (TTP); importance of advising patients to immediately seek medical attention if they experience manifestations such as fever, weakness, extreme skin paleness, purple skin patches, yellowing of the skin or eyes, or otherwise unexplained neurologic changes.1
    • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, particularly drugs that affect bleeding (e.g., warfarin, NSAIAs).1
    • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1
    • Importance of informing patients of other important precautionary information.1 (See Cautions.)

    Preparations

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

    Prasugrel Hydrochloride
    Routes

    Dosage Forms

    Strengths

    Brand Names

    Manufacturer

    Oral

    Tablets

    5 mg (of prasugrel)

    Effient

    Eli Lilly and Company (also promoted by Daiichi Sankyo, Inc.)

    10 mg (of prasugrel)

    Effient

    Eli Lilly and Company (also promoted by Daiichi Sankyo, Inc.)

    Comparative Pricing

    This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2013. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

    Effient 10MG Tablets (LILLY): 30/$215.26 or 90/$608.03

    Effient 5MG Tablets (LILLY): 30/$218.00 or 90/$622.00

    Disclaimer

    This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

    The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug’s actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

    AHFS Drug Information. © Copyright, 1959-2013, Selected Revisions February 15, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

    References

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