Plavix | HealthClot

plavix
is an oral, thienopyridine class antiplatelet agent used to inhibit blood clots
in coronary artery disease, peripheral vascular disease, and cerebrovascular
disease. It is marketed by Bristol-Myers Squibb and Sanofi-Aventis. The drug
works by irreversibly inhibiting a receptor called P2Y12, an adenosine
diphosphate ADP chemoreceptor. Adverse effects include hemorrhage, severe
neutropenia, and Thrombotic thrombocytopenic purpura (TTP).

Contents

1
Pharmacology

2
Clinical use

3
Indications

4
Dosage forms

5
Pharmacokinetics and metabolism

6
Pharmacogenetics

7
Adverse effects

8
Interactions

9
Marketing and litigation

10
References

11
External links

Pharmacology

Clopidogrel
is a pro-drug whose action may be related to an adenosine diphosphate (ADP)
receptor on platelet cell membranes. The drug specifically and irreversibly
inhibits the P2Y12 subtype of ADP receptor, which is important in aggregation
of platelets and cross-linking by the protein fibrin. The blockade of this
receptor inhibits platelet aggregation by blocking activation of the
glycoprotein IIb/IIIa pathway. The IIb/IIIa complex functions as a receptor
mainly for fibrinogen and vitronectin but also for fibronectin and von
Willebrand factor. Activation of this receptor complex is the “final
common pathway” for platelet aggregation, and is important in the
cross-linking of platelets by fibrin.

Platelet
inhibition can be demonstrated two hours after a single dose of oral
clopidogrel, but the onset of action is slow, so that a loading-dose of
300600mg is usually administered.

Clinical
use

Indications

Clopidogrel
is indicated for

Prevention
of vascular ischaemic events in patients with symptomatic atherosclerosis

Acute
coronary syndrome without ST-segment elevation (NSTEMI),

ST
elevation MI (STEMI)

It
is also used, along with aspirin, for the prevention of thrombosis after
placement of intracoronary stent or as an alternative antiplatelet drug for
patients who are intolerant to aspirin.

International
guidelines granted the highest grade of recommendation for NSTE-ACS, PCI and
stent,for clopidogrel in addition to aspirin. Consensus-based therapeutic
guidelines recommend also the use of clopidogrel, instead of aspirin, in
patients requiring antiplatelet therapy but with a history of gastric
ulceration, as inhibition of the synthesis of prostaglandins by aspirin
(acetylsalicylic acid) can exacerbate this condition. A study has shown that in
patients with healed aspirin-induced ulcers, however, patients receiving
aspirin plus the proton pump inhibitor esomeprazole had a lower incidence of
recurrent ulcer bleeding than patients receiving clopidogrel.However, a more
recent study suggested that prophylaxis with proton pump inhibitors along with
clopidogrel following acute coronary syndrome may increase adverse cardiac
outcomes, possibly due to inhibition of CYP2C19 which is required for the
conversion of clopidogrel to its active form.

Dosage
forms

Clopidogrel
is marketed as clopidogrel bisulfate (clopidogrel hydrogen sulfate), most commonly
under the trade names Plavix, as 75 mg oral tablets.

Pharmacokinetics
and metabolism

The
active metabolite of clopidogrel

After
repeated 75-mg oral doses of clopidogrel (base), plasma concentrations of the
parent compound, which has no platelet inhibiting effect, are very low and are
generally below the quantification limit (0.000258 mg/L) beyond two hours after
dosing.

Clopidogrel
is a pro-drug activated in the liver by cytochrome P450 enzymes, including
CYP2C19. The active metabolite has an elimination half-life of about eight
hours and acts by forming a disulfide bridge with the platelet ADP receptor.
Patients with a variant allele of CYP2C19 are 1.5 to 3.5 times more likely to
die or have complications than patients with the high-functioning allele.

Following
an oral dose of 14C-labeled clopidogrel in humans, approximately 50% was
excreted in the urine and approximately 46% in the feces in the five days after
dosing.

Effect
of Food: Administration of clopidogrel bisulfate with meals did not significantly
modify the bioavailability of clopidogrel as assessed by the pharmacokinetics
of the main circulating metabolite.

Absorption
and Distribution: Clopidogrel is rapidly absorbed after oral administration of
repeated doses of 75 mg clopidogrel (base), with peak plasma levels (appx. 3
mg/L) of the main circulating metabolite occurring approximately one hour after
dosing. The pharmacokinetics of the main circulating metabolite are linear
(plasma concentrations increased in proportion to dose) in the dose range of 50
to 150 mg of clopidogrel. Absorption is at least 50% based on urinary excretion
of clopidogrel-related metabolites. Clopidogrel and the main circulating
metabolite bind reversibly in vitro to human plasma proteins (98% and 94%,
respectively). The binding is nonsaturable in vitro up to a concentration of
110 ¼g/mL.

Metabolism
and Elimination: In vitro and in vivo, clopidogrel undergoes rapid hydrolysis
into its carboxylic acid derivative. In plasma and urine, the glucuronide of
the carboxylic acid derivative is also observed.

In
March 2010, the U.S. Food and Drug Administration (FDA) added a boxed warning
to Plavix alerting that the drug can be less effective in people who cannot
metabolize the drug to convert it to its active form

Pharmacogenetics

CYP2C19
is an important drug-metabolizing enzyme that catalyzes the biotransformation
of many clinically useful drugs including antidepressants, barbiturates, proton
pump inhibitors, antimalarial and antitumor drugs. Clopidogrel is one of the
drugs metabolized by this enzyme.

Several
recent landmark studies have proven the importance of 2C19 genotyping in
treatment using clopidogrel or Plavix. In March of 2010, the FDA put a black
box warning on Plavix to make patients and healthcare providers aware that CYP2C19
poor metabolizers, representing up to 14% of patients, are at high risk of
treatment failure and that testing is available.Researchers have found that
patients with variants in cytochrome P-450 2C19 (CYP2C19) have lower levels of
the active metabolite of clopidogrel, less inhibition of platelets, and a 3.58
times greater risk for major adverse cardiovascular events such as death, heart
attack, and stroke; the risk was greatest in CYP2C19 poor metabolizers.

Adverse
effects

Serious
adverse drug reactions associated with clopidogrel therapy include:

Severe
neutropenia (low white blood cells) (Incidence: 1/2,000)

Thrombotic
thrombocytopenic purpura (TTP) (Incidence: 4/1,000,000 patients treated)

Hemorrhage
– The annual incidence of hemorrhage may be increased by the co-administration
of aspirin.

Gastrointestinal
Hemorrhage (Incidence: 2.0% annually)

Cerebral
Hemorrhage (Incidence: 0.1 to 0.4% annually)

Use
of non-steroidal anti-inflammatory drugs is discouraged in those taking
clopidogrel due to increased risk of digestive tract hemorrhage

Interactions

Clopidogrel
interacts with the following drugs: proton pump inhibitors (except
pantoprazole), phenytoin (Dilantin); tamoxifen (Nolvadex); tolbutamide
(Orinase); torsemide (Demadex); fluvastatin (Lescol); a blood thinner such as
warfarin (Coumadin), heparin, ardeparin (Normiflo), dalteparin (Fragmin),
danaparoid (Orgaran), enoxaparin (Lovenox), or tinzaparin (Innohep);
(Activase), anistreplase (Eminase), dipyridamole (Persantine), streptokinase
(Kabikinase, Streptase), ticlopidine (Ticlid), and urokinase (Abbokinase). If
you are using any of these drugs, you may not be able to take Plavix, or you
may need dosage adjustments or special tests during treatment.

In
November 2009, the FDA announced that clopidogrel should not be taken with PPIs
such as Prilosec (omeprazole) and Nexium (esomeprazole).

Marketing
and litigation

A
box of Plavix

Plavix
is marketed worldwide in nearly 110 countries, with sales of US$6.6 billion in
2009.It had been the 2nd top selling drug in the world for a few years as of
2007and was still growing by over 20% in 2007. U.S. sales were US$3.8 billion in
2008[

In
2006, generic clopidogrel was briefly marketed by Apotex, a Canadian generic
pharmaceutical company before a court order halted further production until
resolution of a patent infringement case brought by Bristol-Myers Squibb.The
court ruled that Bristol-Myers Squibb’s patent was valid and provided
protection until November 2011.

Generic
clopidogrel is also produced by several pharmaceutical companies in India.
Clopidogrel is marketed by Sun Pharmaceuticals under the trade name Clopilet,
by Ranbaxy Laboratories under the trade name Ceruvin, and under the name
“Clavix” by Intas Pharmaceuticals and under the name
“deplatt” by torrent pharmaceuticals. In India, it is sold as Clopigrel,
Clopitab, Clopijoy, and Clasprin (mixed with aspirin).

Counterfeit
Plavix is in circulation, as with many popular medicines.