vorapaxar (Zontivity)
Classes: Protease Activated Receptor-1 (PAR-1) Inhibitors; Thrombin Inhibitors; Antiplatelet Agents, Cardiovascular
Dosing and uses of Zontivity (vorapaxar)
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