Platelet inhibition by Nabratin is irreversible and will last for the life of the platelet. Overdose following clopidogrel administration may result in bleeding complications. A single oral dose of clopidogrel at 1500 or 2000 mg/kg was lethal to mice and to rats and at 3000 mg/kg to baboons. Symptoms of acute toxicity were vomiting, prostration, difficult breathing, and gastrointestinal hemorrhage in animals.
Based on biological plausibility, platelet transfusion may restore clotting ability.
The following serious adverse reactions are discussed below and elsewhere in the labeling:
Because clinical trials are conducted under widely varying conditions and durations of follow-up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Nabratin has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for one year or more. The clinically important adverse reactions observed in trials comparing Nabratin plus aspirin to placebo plus aspirin and trials comparing Nabratin alone to aspirin alone are discussed below.
Bleeding CUREIn CURE, Nabratin use with aspirin was associated with an increase in major bleeding (primarily gastrointestinal and at puncture sites) compared to placebo with aspirin (see Table 1). The incidence of intracranial hemorrhage (0.1%) and fatal bleeding (0.2%) were the same in both groups. Other bleeding events that were reported more frequently in the clopidogrel group were epistaxis, hematuria, and bruise.
The overall incidence of bleeding is described in Table 1.
Table 1: CURE Incidence of Bleeding Complications (% patients)
| Event | Nabratin (+ aspirin) (n=6259) | Placebo (+ aspirin) (n=6303) |
| Major bleeding* | 3.7 | 2.7 |
| Life-threatening bleeding | 2.2 | 1.8 |
| Fatal | 0.2 | 0.2 |
| 5 g/dL hemoglobin drop | 0.9 | 0.9 |
| Requiring surgical intervention | 0.7 | 0.7 |
| Hemorrhagic strokes | 0.1 | 0.1 |
| Requiring inotropes | 0.5 | 0.5 |
| Requiring transfusion (≥ 4 units) | 1.2 | 1.0 |
| Other major bleeding | 1.6 | 1.0 |
| Significantly disabling | 0.4 | 0.3 |
| Intraocular bleeding with significant loss of vision | 0.05 | 0.03 |
| Requiring 2-3 units of blood | 1.3 | 0.9 |
| Minor bleeding† | 5.1 | 2.4 |
| * Life-threatening and other major bleeding. † Led to interruption of study medication. |
In COMMIT, similar rates of major bleeding were observed in the Nabratin and placebo groups, both of which also received aspirin (see Table 2).
Table 2: Incidence of Bleeding Events in COMMIT (% patients)
| Type of Bleeding | Nabratin (+ aspirin) (n=22961) | Placebo (+ aspirin) (n=22891) | p-value |
| Major* noncerebral or cerebral bleeding | 0.6 | 0.5 | 0.59 |
| Major noncerebral | 0.4 | 0.3 | 0.48 |
| Fatal | 0.2 | 0.2 | 0.90 |
| Hemorrhagic stroke | 0.2 | 0.2 | 0.91 |
| Fatal | 0.2 | 0.2 | 0.81 |
| Other noncerebral bleeding (nonmajor) | 3.6 | 3.1 | 0.005 |
| Any noncerebral bleeding | 3.9 | 3.4 | 0.004 |
| * Major bleeds were cerebral bleeds or noncerebral bleeds thought to have caused death or that required transfusion. |
In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2.0% in those taking Nabratin versus 2.7% in those taking aspirin; bleeding requiring hospitalization occurred in 0.7% and 1.1%, respectively. The incidence of intracranial hemorrhage was 0.4% for Nabratin compared to 0.5% for aspirin.
Other bleeding events that were reported more frequently in the Nabratin group were epistaxis and hematoma.
Other Adverse EventsIn CURE and CHARISMA, which compared Nabratin plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between Nabratin and placebo.
In CAPRIE, which compared Nabratin to aspirin, pruritus was more frequently reported in those taking Nabratin. No other difference in the rate of adverse events (other than bleeding) was reported.
Postmarketing ExperienceThe following adverse reactions have been identified during postapproval use of Nabratin. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hemorrhages, including those with fatal outcome, have been reported in patients treated with Nabratin.
Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible. Consequently, platelets exposed to clopidogrel's active metabolite are affected for the remainder of their lifespan (about 7 to 10 days). Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP.
Dose-dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of Nabratin. Repeated doses of 75 mg Nabratin per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg Nabratin per day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days.
Geriatric PatientsElderly (≥ 75 years) and young healthy subjects had similar effects on platelet aggregation.
Renally Impaired PatientsAfter repeated doses of 75 mg Nabratin per day, patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min) and moderate renal impairment (creatinine clearance from 30 to 60 mL/min) showed low (25%) inhibition of ADP-induced platelet aggregation.
Hepatically Impaired PatientsAfter repeated doses of 75 mg Nabratin per day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects.
GenderIn a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women.
Clopidogrel is a prodrug and is metabolized to a pharmacologically active metabolite and inactive metabolites.
AbsorptionAfter single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.
Effect Of Food
Nabratin can be administered with or without food. In a study in healthy male subjects when Nabratin 75 mg per day was given with a standard breakfast, mean inhibition of ADP-induced platelet aggregation was reduced by less than 9%. The active metabolite AUC0-24 was unchanged in the presence of food, while there was a 57% decrease in active metabolite Cmax. Similar results were observed when a Nabratin 300 mg loading dose was administered with a high-fat breakfast.
MetabolismClopidogrel is extensively metabolized by two main metabolic pathways: one mediated by esterases and leading to hydrolysis into an inactive carboxylic acid derivative (85% of circulating metabolites) and one mediated by multiple cytochrome P450 enzymes. Cytochromes first oxidize clopidogrel to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxoclopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. The active metabolite is formed mostly by CYP2C19 with contributions from several other CYP enzymes, including CYP1A2, CYP2B6 and CYP3A. The active thiol metabolite binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation for the lifespan of the platelet.
The Cmax of the active metabolite is twice as high following a single 300 mg clopidogrel loading dose as it is after four days of 75 mg maintenance dose. Cmax occurs approximately 30 to 60 minutes after dosing. In the 75 to 300 mg dose range, the pharmacokinetics of the active metabolite deviates from dose proportionality: 4-fold the dose results in 2.0-fold and 2.7-fold the Cmax and AUC, respectively.
EliminationFollowing an oral dose of 14C-labeled clopidogrel in humans, approximately 50% of total radioactivity was excreted in urine and approximately 46% in feces over the 5 days post dosing. After a single, oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The half-life of the active metabolite is about 30 minutes.
