Zontivity

Black Box Warnings

Do not use in patients with a history of stroke, TIA, or intracranial hemorrhage (ICH)

Increases risk of bleeding, including ICH and fatal bleeding

Contraindications

History of stroke, TIA, or ICH because of an increased risk of ICH in this population (see Black Box Warnings)

Active pathologic bleeding

Cautions

Discontinue in patients who experience a stroke, TIA, or ICH

Antiplatelet agents, including vorapaxar, increase the risk of bleeding, including ICH and fatal bleeding (see Black Box Warnings)

Strong CYP3A inhibitors increase and inducers decrease vorapaxar exposure; avoid coadministration

Pregnancy Category: B

Lactation: Unknown if distributed in human breast milk; because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in breastfed infants from vorapaxar, discontinue nursing or discontinue breastfeeding

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

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

Vorapaxar is used to lower the risk of stroke or serious heart problems in people who have had a heart attack or a blood vessel disorder affecting circulation in the arms and legs.

Vorapaxar is sometimes used together with aspirin or clopidogrel (Plavix).

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

Vorapaxar is usually taken once per day. Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

You may take vorapaxar with or without food.

You may also need to take aspirin or clopidogrel (Plavix). Follow your doctor's instructions very carefully.

If you need surgery or any dental work, tell the surgeon or dentist ahead of time that you are using vorapaxar. You may need to stop using the medicine for a short time to prevent bleeding.

Do not stop using vorapaxar without your doctor's advice. Stopping suddenly may make your condition worse.

Vorapaxar can have long lasting effects in your body. You may still bleed more easily for as long as 4 weeks after you stop using this medicine.

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

• Importance of advising patients to read the manufacturer's patient information (medication guide).1 2

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

• Importance of taking vorapaxar exactly as prescribed and not discontinuing therapy without first consulting the prescribing clinician.1 2

• Importance of informing patients that they may bruise and/or bleed more easily when taking vorapaxar; such effects may last for 4 weeks after drug discontinued.1 2 Patients should be advised to report to their clinician any unexpected, prolonged, or excessive bleeding.1 2

• Importance of informing clinicians (e.g., physicians, dentists) about vorapaxar therapy before any invasive procedure or surgery is scheduled.1 Clinicians performing invasive procedures should consult with prescribing clinician before discontinuing vorapaxar.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription drugs, dietary supplements, and OTC drugs, particularly drugs that affect bleeding risk (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.)

It is very important that your doctor check your progress at regular visits to make sure that this medicine is working properly. Blood tests may be needed to check for unwanted effects.

This medicine may increase your risk of serious bleeding problems. Call your doctor right away if you have bleeding that is severe or that you cannot control, coughing up blood, pink, red, or brown urine, red or black stools, or vomiting blood or material that looks like coffee grounds.

This medicine can cause you to bleed and bruise more easily. Take precautions to avoid injury. Brush and floss your teeth gently, do not play rough sports, and be careful with sharp objects.

Do not stop taking this medicine without checking first with your doctor.

Make sure any doctor or dentist who treats you knows that you are using this medicine. You may need to stop using this medicine several days before having surgery.

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 (eg, St. John's wort) or vitamin supplements.

Effects of Other Drugs on Zontivity

Vorapaxar is eliminated primarily by metabolism, with contributions from CYP3A4 and CYP2J2.

Strong CYP3A Inhibitors

Avoid concomitant use of Zontivity with strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, posaconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin and conivaptan) [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

Strong CYP3A Inducers

Avoid concomitant use of Zontivity with strong inducers of CYP3A (e.g., rifampin, carbamazepine, St. John's Wort and phenytoin) [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

There is no known treatment to reverse the antiplatelet effect of Zontivity, and neither dialysis nor platelet transfusion can be expected to be beneficial if bleeding occurs after overdose. Inhibition of platelet aggregation can be expected for weeks after discontinuation of normal dosing [see Clinical Pharmacology (12.2)]. There is no standard test available to assess the risk of bleeding in an overdose situation.

Zontivity contains vorapaxar sulfate, a tricyclic himbacine-derived selective inhibitor of platelet aggregation mediated by PAR-1.

The chemical name of vorapaxar sulfate is ethyl [(1R,3aR,4aR,6R,8aR,9S,9aS)-9-{(1E)-2-[5-(3-fluorophenyl)pyridin-2-yl]ethen-1-yl}-1-methyl-3-oxododecahydronaphtho[2,3-c]furan-6-yl]carbamate sulfate. The empirical formula is C29H33FN2O4∙H2SO4, and its molecular weight is 590.7. The structural formula is:

Vorapaxar sulfate is a white to off-white solid. Vorapaxar sulfate is freely soluble in methanol and slightly soluble in ethanol, acetone, 2-propanol, and acetonitrile. In aqueous solution, it is slightly soluble in pH 1; its solubility decreases with increasing pH. Zontivity tablets are formulated with vorapaxar sulfate, but during manufacture and storage, partial conversion from vorapaxar sulfate to vorapaxar free base may occur.

Zontivity is available for oral use as tablets containing 2.08 mg of vorapaxar, which is equivalent to 2.5 mg of vorapaxar sulfate.

Each film-coated tablet of Zontivity contains the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone, and magnesium stearate. In addition, the film coating contains the following inactive ingredients: lactose monohydrate, hypromellose, titanium dioxide, triacetin (glycerol triacetate), and iron oxide yellow.

Zontivity tablets, 2.08 mg vorapaxar, are yellow, oval-shaped, film-coated tablets with "351" on one side and the Merck logo on the other side.

They are supplied as follows:

• NDC 70347-208-30 bottles of 30 tablets
• NDC 70347-208-90 bottles of 90 tablets

Storage of bottles

Store at 20-25°C (68-77°F), excursions permitted between 15-30°C (between 59-86°F). [See USP Controlled Room Temperature.] Store tablets in the original package with the bottle tightly closed. Keep the desiccant in the bottle to protect from moisture.

Storage of blisters

Store at 20-25°C (68-77°F), excursions permitted between 15-30°C (between 59-86°F). [See USP Controlled Room Temperature.] Store in the original package until use.