Prasugrel

Increased risk of bleeding in patients receiving concomitant therapy with warfarin. Bleeding time substantially prolonged with concomitant administration of a single 15-mg dose of warfarin.

Increased risk of bleeding with concomitant use /of thrombolytic agents/.

Increased risk of bleeding with concomitant long-term use of aspirin or other nonsteroidal anti-inflammatory agents (NSAIAs).

Prasugrel is metabolized by the cytochrome P-450 (CYP) microsomal enzyme system, principally by isoenzymes 3A4 and 2B6, and to a lesser extent by isoenzymes 2C9 and 2C19. In vitro studies indicate that prasugrel is not likely to inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2D6, and 3A or induce CYP isoenzymes 1A2 or 3A. Prasugrel is a weak inhibitor of CYP2B6. Clinically important drug interactions mediated by CYP isoenzymes are considered unlikely with prasugrel. Studies have shown that if one of the CYP isoenzymes involved in the metabolism of prasugrel is inhibited, others remain capable of forming the active metabolite. CYP3A4 inhibitors such as verapamil, diltiazem, indinavir, ciprofloxacin, clarithromycin, and grapefruit juice are not expected to have a substantial effect on the pharmacokinetics of prasugrel's active metabolite. In healthy individuals receiving prasugrel, concomitant administration of ketoconazole (a potent inhibitor of CYP3A4) decreased maximum concentrations of prasugrel's active metabolite by 34-46%, but did not alter systemic exposure or degree of inhibition of platelet aggregation. Similarly, CYP3A4 inducers (e.g., rifampin, carbamazepine) are not expected to substantially alter the pharmacokinetic or pharmacodynamic response to prasugrel; concomitant administration of rifampin, a potent inducer of CYP3A4 and CYP2B6, did not affect formation of the active prasugrel metabolite nor its ability to inhibit platelet aggregation. Concomitant administration of prasugrel and drugs principally metabolized by CYP2B6 (e.g., halothane, cyclophosphamide, propofol, nevirapine) may increase plasma concentrations and exposure of the concomitant drug; however, clinically important interactions are not expected because of weak inhibition of CYP2B6.

May be used concomitantly with proton pump inhibitors and histamine H2-receptor antagonists. Maximum plasma concentrations of the active metabolite of prasugrel are decreased by 14 or 29% with ranitidine or lansoprazole, respectively, but systemic exposure of this metabolite is unaffected. In a pharmacokinetic study in healthy adults, concomitant daily administration of a single loading dose of prasugrel 60 mg with lansoprazole 30 mg decreased systemic exposure and peak plasma concentrations of prasugrel's active metabolite but did not affect inhibition of platelet aggregation.

Prasugrel is associated with low rates of serum enzyme elevations during therapy, which are similar to those with clopidogrel. In premarketing studies, no instances of clinically apparent liver injury were reported. Since marketing and release, there has been several reports of liver injury attributed to prasugrel often as a part of a hypersensitivity reaction. The onset was within a few weeks of switching from clopidogrel to prasugrel, and was accompanied by mild-to-moderate ALT and GGT elevations that resolved rapidly once prasugrel was replaced by clopidogrel. The liver injury was overshadowed by features of a hypersensitivity syndrome with fever, eosinophilia and diarrhea, which also reversed rapidly with stopping prasugrel. Autoantibodies were not reported. There has also been one report of a case of hepatocellular jaundice that resolved only after stopping prasugrel. There have been no reports of chronic injury or acute liver failure reported with prasugrel, although such instances have been reported with clopidogrel and ticlopidine.

Bleeding is the most common adverse effect associated with prasugrel, and the drug carries a black box warning for potentially fatal bleeding. Increased risk of bleeding may occur in patients with a body weight of less than 60 kg, recent trauma, recent surgery, and an active bleeding peptic ulcer. Increased risk of bleeding is also seen in renal impairment, as it is associated with decreased excretion. There is no antidote available for bleeding caused by prasugrel. If bleeding does occur, hemostasis is theoretically achievable with a platelet transfusion. However, platelet transfusion within 4 hours of prasugrel administration may be less effective. If possible, bleeding management should take place without stopping prasugrel, as premature discontinuation of prasugrel is associated with stent thrombosis and increased incidence of adverse cardiovascular outcomes.

Prasugrel causes rapid and irreversible platelet inhibition and can be associated with life-threatening bleeding in case of toxicity. Researchers observed lethality in rats with a dose of 2000 mg/kg. There is no antidote available for use in case of toxicity with prasugrel. The active metabolite of prasugrel is unlikely to be removed by dialysis.

/SIGNS AND SYMPTOMS/ Effient can cause significant, sometimes fatal, bleeding. Do not use Effient in patients with active pathological bleeding or a history of transient ischemic attack or stroke. In patients > or = 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 myocardial infarction (MI)) where its effect appears to be greater and its use may be considered. 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.

/CASE REPORTS/ Therapy with aspirin and/or adenosine diphosphate (ADP) receptor blockers is associated with better outcomes via inhibition of platelet activity, and subsequent reduction of ischemic vascular events. Non-compliance is a well-recognized hazard limiting the clinical utility of antiplatelet agents, and, probably worsening outcomes. ... A 48-year-old male patient ... was among patients enrolled in the platelet sub-study for the /(Joint Utilization of Medication to Block Platelets Optimally (JUMBO)/ trial. He received 325 mg of aspirin daily for 9 months, presented with unstable angina for urgent coronary intervention, and was successfully reperfused with two intracoronary stents. The patient was randomised to a 60 mg prasugrel loading dose, and 10 mg of prasugrel daily for 30 days. Platelets were assessed at baseline, 4 and 24 hr, and at 30 days after acute coronary event utilising ADP-, and collagen-induced conventional aggregometry, rapid cartridge-based analyser and flow cytometry. Loading with prasugrel resulted in significant inhibition of platelet activity during and after stenting. However, after assessing platelet biomarkers at 30 days, voluntary withdrawal from the antiplatelet agents was suspected. Based on the platelet activity characteristics, non-compliance was later confirmed, and the patient admitted that he stopped taking both prasugrel and aspirin shortly after discharge due to minor bleeding episodes after shaving. Major platelet activity biomarkers of the index non-compliant patient were compared with those from compliant prasugrel-, clopidogrel-treated patients, and healthy controls. The platelet tests uniformly revealed rebound activation by all platelet measures (at least twofold increase) while being especially high for ADP-, and collagen-induced aggregation, platelet/endothelial cell adhesion molecule-1 (PECAM-1), glycoprotein (GP)Ib, GPIIb/IIIa activity, P-selectin, protease activated receptor (PAR)-1 thrombin receptor (activated and intact epitopes), and thrombospondin expression. The clinical benefits of antiplatelet agents are not only denied in non-compliant outpatients, but may put them at additional risk for worsened vascular outcomes due to the rebound platelet activation.

/LABORATORY ANIMALS: Acute Exposure/ Prasugrel (30 and 100 mg/kg, ID) showed no major effects on heart rate, blood pressure, respiration rate, carotid blood flow, or pressure response to acetylcholine, norepinephrine or bilateral carotid occlusion in the anesthetized dogs.

/LABORATORY ANIMALS: Acute Exposure/ In an escalating dose study in beagle dogs, platelet aggregation was inhibited, consistent with the pharmacological action of the compound. Emesis was observed after administration at doses > or = 300 mg/kg, and serum ALP was increased following the 2000 mg/kg dose. Slight hepatocellular atrophy and ground glass appearance of hepatocellular cytoplasm were also observed in these dogs.

/LABORATORY ANIMALS: Acute Exposure/ In a comparison single dose rat study of prasugrel base vs prasugrel hydrochloride, no deaths occurred at doses of prasugrel base up to 2000 mg/kg, while 3 out of 5 males and 4 out of 5 females administered 2000 mg/kg prasugrel hydrochloride died. Systemic exposure to prasugrel metabolites in the prasugrel hydrochloride group was 1.2 to 3.5 times higher than that of the prasugrel base group and this difference is believed to account for the difference in mortality.

/LABORATORY ANIMALS: Acute Exposure/ Clinical observations in female rats given 2000 mg/kg included some non-specific signs of irregular respiration, reduced locomotor activity, ptosis, lacrimation, and staggering gait.

For more Non-Human Toxicity Excerpts (Complete) data for Prasugrel (11 total), please visit the HSDB record page.

Geriatric patients, particularly those 75 years of age and older, appear to be at greater risk of bleeding (including fatal bleeding) with prasugrel therapy compared with younger patients. In the TRITON-TIMI 38 trial, about 39% of patients were 65 years of age or older and 13% were 75 years of age or older. Risk of bleeding increased with advancing age in both prasugrel and clopidogrel treatment groups. Among patients 75 years of age or older, fatal bleeding was more common with prasugrel than with clopidogrel (1 or 0.1%, respectively); symptomatic intracranial hemorrhage also was reported more frequently with prasugrel (0.8 or 0.3%, respectively). Mean exposure to the active metabolite of prasugrel is approximately 19% higher in patients 75 years or older compared with younger patients. Prasugrel generally should be avoided in patients 75 years of age or older because of a higher risk of bleeding and uncertain efficacy, but use may be considered in certain patients with high-risk conditions (e.g., diabetes, previous MI) in whom a greater net clinical benefit has been demonstrated.

Effient can cause significant, sometimes fatal, bleeding. Do not use Effient in patients with active pathological bleeding or a history of transient ischemic attack or stroke. In patients > or = 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 myocardial infarction (MI)) where its effect appears to be greater and its use may be considered. 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.

Effient is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including prasugrel hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Prasugrel hydrochloride/

MEDICATION

Use (kg; approx.) in Germany (2009): >10