vorapaxar (Zontivity)

Dosing and uses of Zontivity (vorapaxar)

• Adult
• Pediatric

 

Adult dosage forms and strengths

tablet

• 2.08mg

 

Thromboembolism

Indicated to reduce thrombotic cardiovascular events in patients with a history of MI or with peripheral arterial disease

2.08 mg PO qDay in combination with either aspirin and/or clopidogrel (according to their indications or standard of care); there is limited clinical experience with other antiplatelet drugs and none with vorapaxar as the only antiplatelet agent

 

Dosage modifications

Renal impairment: No dose adjustment required

Mild-to-moderate hepatic impairment: No dose adjustment required

Severe hepatic impairment: Not recommended; based on the increased inherent risk of bleeding in patients with severe hepatic impairment

 

Dosing Considerations

Results from clinical trials have shown vorapaxar reduces the rate of a combined endpoint of cardiovascular death, MI, stroke, and urgent coronary

 

Administration

May take with or without food

 

Pediatric dosage forms and strengths

Safety and efficacy not established

 

Zontivity (vorapaxar) adverse (side) effects

Bleeding

Non-CABG-Related Bleeds in Post-MI or PAD Patients without a History of Stroke or TIA

• Severe (1%)
• Moderate or severe (3%)
• Any bleeding (25%)
• Fatal bleeding (0.2%)
• Intracranial hemorrhage (0.4%)
• Clinically significant bleeding (15.5%)
• GI bleeding (4.7%)

 

1-10%

Anemia (5%)

Depression (2.4%)

Rashes, eruptions, exanthemas (2.2%)

 

<1%

Diplopia (0.2%)

 

Warnings

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 and lactation

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.

 

Pharmacology of Zontivity (vorapaxar)

Mechanism of action

Reversible antagonist of the protease-activated receptor-1 (PAR-1) expressed on platelets, but its long half-life makes it effectively irreversible; inhibits thrombin-induced and thrombin receptor agonist peptide (TRAP)-induced platelet aggregation in in vitro studies

 

Absorption

Bioavailability: 100%

Peak plasma time: 1 hr (fasting); 45 min (nonfasting)

 

Distribution

Protein bound: ≥99%; highly bound to albumin and does not preferentially distribute into RBCs

Vd: 424 L

Steady-state: 21 days

 

Metabolism

Metabolism via CYP3A4 and CYP2J2

Major active circulating metabolite is M20 (monohydroxy metabolite) and the predominant metabolite identified in excreta is M19 (amine metabolite)

Systemic exposure of M20 is ~20% of the exposure to vorapaxar

 

Elimination

Half-life: 3-4 days (disposition); 8 days (terminal elimination)

Excretion (as metabolites): 58% feces; 25% urine