Clopidogrel

What is Clopidogrel (Plavix)?

  • Clopidogrel is an oral, thienopyridine-class drug that is used to inhibit blood clots formation.

What is the generic and brand name of the drug?

  • The drug is available under generic name Clopidogrel and marketed by Bristol-Myers Squibb and Sanofi under brand names Plavix

What is the source of the drug (natural or synthetic)?

  • Clopidogrel is a synthetic (man-made) pharmaceutical anti platelet agent or platelet aggregation inhibitor. 

Why is this medication prescribed?

  • Clopidogrel is an antiplatelet agent (pharmaceuticals agent that decreases platelet aggregation) that is chemically and pharmacologically similar to ticlopidine (Ticlid).
  • The drug is used to prevent or inhibit the formation of blood clots in a variety of medical conditions i.e. coronary artery disease, peripheral vascular disease, and cerebrovascular disease.
  • The drug is used to reduce the risk of stroke and myocardial infarction (heart attack) in people who have already had a history of myocardial infarction, other forms of acute coronary syndrome, unstable angina, stroke, and peripheral artery disease.
  • Clopidogrel is also used in combination with acetylsalicylic acid (ASA, aspirin), to prevent thrombosis (blood clotting) following placement of a coronary stent (a tube shaped appliance that is used to keep the arteries open in the treatment of coronary heart disease).
  • Clopidogrel is also used in combination with acetylsalicylic acid as an alternative antiplatelet drug in people with a history of gastric ulceration or when aspirin cannot be used (Aspirin intolerant).
  • As per the norms of American Heart Association and the American College of Cardiology, Clopidogrel or a related drug is recommended for patients with myocardial infarction with ST-elevation, percutaneous coronary intervention (PCI, fibrinolytic therapy, non-ST elevation myocardial infarction or unstable angina and stable ischemic heart disease.

Pharmacophore structure: Information about the chemical structure of the drug.

Clopidogrel chemically belongs to the class of organic compounds which are known as alpha amino acid esters. The alpha amino acid esters are chemically characterized as ester derivatives of alpha amino acids .The detailed chemical classification of Clopidogrel  is described below:

Kingdom Organic compounds 
Super Class Organic acids and derivatives
Class Carboxylic acids and derivatives
Sub Class Amino acids, peptides, and analogues
Direct Parent Alpha amino acid esters

Chemical information of the drug.

  • Clopidogrel is a synthetic pharmaceutical organic compound named as methyl (2S)-2-(2-chlorophenyl)-2-{4H,5H,6H,7H-thieno[3,2-c]pyridin-5-yl}acetate.
  • The compound has molecular formula C16H16ClNO2S and the molecular weight of 822 Da.
  • The melting point of Clopidogrel is 158 °C.
  • Clopidogrel is available as bisulfate salt and is white to off-white in color.
  • Clopidogrel is almost insoluble in water at neutral pH (pH-7.0), however solubility is increased dramatically at pH 1.

 What is the available strength of the drug?

  • The medication is supplied as either pink, round, biconvex, or pink, oblong film-coated tablets for oral administration by mouth.
  • Clopidogrel tablet is usually recommended to be taken once a day and with or without food.
  • Clopidogrel tablet is available in two strengths-(75 mg and 300 mg).
  • Each 75 mg Clopidogrel tablet is embossed with “75” on one side and “1171” on the other and contains 97.875 mg of Clopidogrel bisulfate molar equivalent of 75 mg of Clopidogrel.
  • Each 300 mg Clopidogrel tablet is embossed with “300” on one side and “1332” on the other side and contains 391.5 mg of Clopidogrel bisulfate molar equivalent of 300 mg of Clopidogrel.
  • Besides Clopidogrel, each tablet contain other inactive ingredients such as mannitol, hydrogenated castor oil, microcrystalline cellulose, hydroxypropylcellulose, and polyethylene glycol 6000 as inactive ingredients.
  • The film coating of tablet contains hypromellose 2910, ferric oxide, titanium dioxide, lactose monohydrate, and triacetin. The tablets are polished with carnauba wax.

How the medicine works (mode of action)?

  • Clopidogrel is an antiplatelet agent that prevents the formation of blood clots.
  • When metabolized by the body, the active metabolite of the drug binds irreversibly to the P2Y12 subtype of adenosine diphosphate (ADP) receptor on the platelets.
  • The occupancy of the platelet receptor (involved in the aggregation of platelets and cross-linking by fibrin protein) by the drug impairs the binding of ADP to the receptor and thus, the activation of the glycoprotein GPIIb/IIIa complex.
  • GPIIb/IIIa complex is the major receptor for fibrinogen whose impaired activation prevents binding of fibrinogen to platelets and inhibits platelets from sticking to each other.
  • Clopidogrel interference with the platelet function prevents blot clots formation inside of the blood vessels.
Clopidogrel : Mode of action.
Clopidogrel : Mode of action.

What are the recommended doses of Clopidogrel?

The Clopidogrel is available in tablet form to be administered by mouth once a day. It can be taken with or without food. The dosage depends upon the diseased state of the patient and medical history.

  • Acute Coronary Syndrome: For patients with non-ST-elevation (NSTEMI):
    • The initial dose is a single 300 mg oral loading dose followed by 75 mg dose once daily.
    • Aspirin (75–325 mg once daily) is also recommended in combination with Clopidogrel.
  • Acute Coronary Syndrome: For patients with STEMI:
    • Clopidogrel may be initiated with or without a loading dose.
    • The recommended dose of Clopidogrel is 75 mg once a day to be administered orally, in combination with aspirin (75–325 mg once daily), in presence or absence of thrombolytics (medicines that dissolve blood clots).
  • Peripheral arterial disease, or  recent MI (myocardial infarction) or  stroke:
    • The recommended dose of Clopidogrel is 75 mg once a day orally, with or without food.

This medicine should not be stopped abruptly. If there is an urgency to stop it, it should be done under the supervision of the doctor.

When should I discontinue, withhold or modify the dose of Clopidogrel?

  • The dose of Clopidogrel should be adjusted based on the patient’s clinical status, and medical history.
  • The drug is contraindicated in case of pregnancy or breastfeeding.
  • The use of the drug is restricted in patients who are hypersensitive to any component of the drug.
  • Clopidogrel is contraindicated in case of peptic ulcer or intracranial hemorrhage.
  • The use of Clopidogrel has not been evaluated in case of severe or moderate renal impairment.
  • Safety and effectiveness of the drug has not been evaluated in case of pediatric populations.
  • No dosage adjustment is necessary in elderly people and hepatic impairment patients.

What are the pharmacokinetic properties of the drug?                                          

  • Following administration (single or repeated multiple doses of 75 mg per day), Clopidogrel is rapidly absorbed (approximately 50 %) by the body.
  • Bioavailability of Clopidogrel is not affected by the food.
  • The peak plasma concentration of unchanged Clopidogrel is achieved approximately 45 minutes after dosing (single 75 mg oral dose).
  • Following absorption, the majority of the drug (98 %) is bound to human plasma proteins.
  • The drug is mainly metabolized by the hepatic system.
  • Pharmacokinetic studies with Clopidogrel have shown that the excretion of the drug is 50 % renal (urine) and 46 % biliary (feces).
  • The details regarding average steady state volume of distribution of the drug is not available.
  • The biological half-life of Clopidogrel is 7-8 hours (inactive metabolite).

Which pregnancy category (A; B; C; D; X) has been assigned to Clopidogrel?

  • The Clopidogrel is classified by US FDA pregnancy category: B.
  • Due to lack of adequate and well-controlled studies, the use and safety of Clopidogrel in pregnant women is contraindicated and recommended only if clearly needed.
  • No adequate data is available on excretion of Clopidogrel into human breast milk. However, the use of drug is not recommended in nursing mothers.
  • Due to these facts caution should be exercised when taking Clopidogrel during pregnancy.

How to use the drug?

  • Follow the instructions carefully as directed on prescription leaflet and take Clopidogrel exactly as directed by your health care professional.
  • Clopidogrel is available in tablet form for oral administration.
  • Clopidogrel can be taken with or without food once a day.
  • The drug should be taken with a full glass of water.
  • It is also recommended to take drug at almost the same time every day.
  • Take the medication regularly, even if you feel well.
  • Try to take the medicine at the same time every day.
  • Do not stop taking the medication abruptly without consulting your doctor.
  • Do not change the dose of the drug as prescribed by your doctor. Since, dosage and duration of treatment are based on your medical condition and response to treatment.
  • In case of surgery, tell your doctor beforehand that you are taking Clopidogrel.
  • If you have any queries about the drug immediately consult your doctor.

How to store the drug?

  • Clopidogrel is stored at room temperature 25°C (77°F).
  • Brief excursion period is permitted at temperature 15–30°C (59–86°F).
  • The drug should be kept away from excess heat, direct sun light, moisture and reach of children.
  • The drug should not be stored in bathroom.

How to dispose the medicine?

  • Throw away unused and opened, outdated or no longer used drug.
  • Also dispose the old medicine after the expiration date.
  • Talk to your pharmacist about the proper disposal of your medication.

Does Clopidogrel has approval from government / FDA /or any other related agencies?

  • Clopidogre has received its official approval from US Food and Drug Administration (FDA) in 1997 for the treatment of acute coronary syndrome (ACS), which is defined as unstable angina and myocardial infarction (mild heart attack).
  • The drug has also received official approval from FDA for its use in the prevention of blood clot formation in patients who recently have stroke, myocardial infarction, or peripheral arterial disease.

Other uses of the drug.

  • Clopidogrel also finds an implication in the prevention of blood clot formation in patients with atrial fibrillation (a condition in which the heart beats irregularly).
  • Clopidogrel may also be used for other uses not listed here. It is advisable to ask your doctor or pharmacist for more detailed information regarding its use.

What special dietary precautions should I follow?

  • A high fat and standard meal is usually not recommended as it reduces inhibition of platelet
  • Avoid grape juice and alcoholic beverages.
  • Drink plenty of water when you take the medicine.

What special precautions should I follow?/ What should I avoid while using Clopidogrel?

  • First of all inform your doctor if you are allergic to any Clopidogrel or any of the ingredients present in the Clopidogrel product. Ask your pharmacist or check the prescription leaflet carefully for a list of the ingredients.
  • It is advisable to discuss with your doctor and pharmacist about what prescription and nonprescription medications, vitamins, and nutritional supplements you are taking or plan to take specially aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs); anticoagulants; selective serotonin reuptake inhibitors (SSRIs); and selective serotonin/norepinephrine reuptake inhibitors (SNRIs); esomeprazole (Nexium) etc.
  • Inform your doctor if you are breastfeeding or pregnant or plan to become pregnant. Tell your doctor if you are breastfeeding.
  • Inform your doctor about the use of Clopidogrel if you are having surgery, including dental surgery.
  • Clopidogrel use should be stopped under the supervision of doctor if you have bleeding ulcers, bleeding in the brain or a condition causing excessive bleeding.
  • Inform your doctor about the recent injury and try to avoid cuts or hurting yourself as it may lead to severe bleeding while you are taking Clopidogrel.
  • Before taking Vardenafil, tell your doctor about your medical history preferentially if you have any kind of liver or kidney disease, certain eye disorders, bleeding disorders etc.
  • Consult your doctor in case of any query.
  • It is recommended to avoid consuming alcohol as it may increase the risk of bleeding in stomach or intestines.

What are the possible side effects of this drug?

  • The active ingredient in Clopidogrel may result in some side effects that require medical attention. Check with your doctor immediately if these side effects persist for a long time and become bothersome.
  • Some commonly occurring side effects include:
  • Purple or red spots on the skin
  • Pain in general
  • Chest pain
  • Collection of blood under the skin
  • Deep, dark purple bruise
  • Itching, swelling, pain, or redness
  • There are some side effects that are less common. These include:
  • Vomiting of blood
  • Nosebleed
  • Breath shortness Painful urination
  • Vomiting of material that looks like coffee grounds

Most of the people who take this drug do not develop serious side effects. The symptoms can develop any time after you start taking the medicine.

In rare instances, serious blood disorder (thrombotic thrombocytopenic purpura-TTP) can occur. If any of following symptoms appears get immediate medical help.

  • Extreme skin paleness
  • Bleeding in the eyes, brain, or, stomach, gut
  • Unusual heartbeat
  • Bloody/black stools
  • Severe stomach pain
  • Sudden severe headache
  • Purple skin patches
  • Fainting
  • Uncontrolled bleeding from gums or nose
  • Confusion
    • Yellowing eyes/skin
    • Seizures
    • Change in amount of urine
  • Fever
  • Bloody/red/pink/dark urine
  • Unusual weakness/tiredness
    • Vision changes
    • Slurred speech

Severe allergic reaction on taking this drug is very rare. However, sometimes you may get the symptoms of a very serious allergic reaction to this drug. Get immediate medical help if you notice any of the following symptoms:

  • Severe itching, rash, swelling (especially of the throat /face/tongue)
  • Severe dizziness
  • Trouble breathing

There can be more side effects of the drug not mentioned here. Contact your doctor pharmacist if you notice any other unusual effect after taking this medicine.

What should I do in case of overdose?

  • Overdose usually occurs when someone by mistake or deliberately takes more than the prescribed limit of this medication.
  • Symptoms of overdose include unusual bruising or bleeding.
  • In case of overdose, contact with your doctor or emergency room immediately if the victim is not breathing and has collapsed.
  • Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I do in case of missed a dose?

  • In case of missed dosage, take it as soon as you remember and maintain a regular dosing schedule. Keep in mind that takes the missed dose only on an empty stomach.
  • Skip the missed dose if it is almost time for your next scheduled dose. Keep in mind to not use a double dose to make up a missed dose

Does Clopidogrel have any interaction with drugs?

It has been observed that Clopidogrel may interact with or increase or decrease the effect of following drugs. Caution should be taken when co administrating Clopidogrel with one of the following drugs.

  • CYP2C19 inhibitors:Clopidogrel get metabolized to its active metabolite partly by CYP2C19. Co-administration of Clopidogrel with specific drugs that bring about inhibition of the activity of this enzyme causes reduction in the plasma concentrations of the active metabolite of the drug and a reduction in platelet inhibition.
  • Proton pump inhibitors (PPI): Proton pump inhibitors such as omeprazole and esomeprazole reduce the antiplatelet activity of Clopidogrel when co-administered with it. A higher dose of Clopidogrel is required to increase the antiplatelet activity in presence of omeprazole. Pantoprazole, dexlansoprazole, and lansoprazole exhibit less effect on the antiplatelet activity of Clopidogrel as compared to omeprazole or esomeprazole.
  • Warfarin (CYP2C9 Substrates):There is an increase in the risk of bleeding due to independent effect on hemostasis when Clopidogrel is coadministrated with warfarin.
  • Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs): SSRIs and SNRIs affect platelet activation and increase the risk of bleeding when concomitantly administered with Clopidogrel.
  • Aspirin: Aspirin coadministration with Clopidogrel neither inhibit ADP-induced platelet aggregation nor increases the prolongation of bleeding time induced by Clopidogrel. However, the use of Clopidogrel increases the physiological reaction of aspirin on collagen-induced platelet aggregation.
  • Heparin: Clopidogrel does not modify the effect of heparin on coagulation. Coadministration of heparin shows no effect on inhibition of platelet aggregation induced by Clopidogrel.
  • Other concomitant therapy:
  • No clinically significant adverse interactions are seen in concomitant use of Clopidogrel with nifedipine or/and atenolol.
  • The activity of Clopidogrel is not influenced in presence of phenobarbital or estrogen.
  • Clopidogrel has no effect on the pharmacokinetics of digoxin or theophylline.
  • Clopidogrel when coadministered with a variety of medications (including coronary vasodilators, angiotensin converting enzyme inhibitors, antiepileptic agents, diuretics, thrombolytics, GPIIb/IIIa antagonists, calcium antagonists, cholesterol lowering agents, antidiabetic agents (including insulin), heparins, beta-blocking agents, and hormone replacement therapy exhibits no significant clinical adverse reactions.
  • No data is available on the concomitant use of chronic NSAIDs, oral anticoagulants, and oral anti-platelet drugs with Clopidogrel.
Clopidogrel drug interaction.
Clopidogrel drug interaction.

Does Clopidogrel have any interaction with diseases?

Before you begin to take Clopidogrel, it is necessary to discuss any medical condition or allergies you have or any other significant fact. It has been observed that following medical conditions (disease) may interact with Clopidogrel:

  • Allergy: People who are allergic to other antiplatelet medications like ticlopidine or prasugrel also show allergic reactions to Clopidogrel. Before you start taking Clopidogrel, it is recommended to inform your doctor about any side effect you have experienced on taking medications, especially anti-platelet medications.
  • Bleeding problems:Risk of bleeding increases in presence of Concomitant use of Clopidogrel with other medications (e.g., warfarin, NSAIDs) may further enhance the risk of bleeding. History of bleeding disorders can affect the way the medicine works, the dose and effectiveness of the drug, and whether any special monitoring is required.
  • Kidney function:Impaired kidney function or kidney disease may affect the working of the drug, dosing, drug effectiveness and may require special monitoring.
  • Lactose intolerance: If you suffer from galactose intolerance (glucose-galactose malabsorption, galactosemia, or Lapp lactase deficiency) avoid taking this medicine as it also contain lactose as its ingredient.
  • Liver function:It is not recommended to take this medicine in case of impaired liver function or liver disease as it may affect the working, dosing, and effectiveness of the drug.
  • Stomach ulcers and severe heartburn:Proton pump inhibitors (PPIs) are used to treat the patients with stomach ulcers and severe heartburn. Coadministration of Clopidogrel with proton pump inhibitors in patients of stomach ulcers and severe heart burn make it less effective.
  • Surgery: Use of Clopidogrel need to be stopped a few days prior to any surgery to prevent any unnecessary bleeding.

Where can I get more information?

Your pharmacist can provide more information about Clopidogrel.

Clinical research and current scenario of the drug

  • Clinical studies indicate the effectiveness of Clopidogrel in reduction of the risk of cardiovascular or cerebrovascular events (new myocardial infarction (MI), new ischemic stroke, and vascular death) in patients with a history of recent MI, recent ischemic stroke, or established peripheral arterial disease for treatment of hypercholesterolemia, lipid abnormalities in patients with cardiovascular disease, including Type 2 diabetes and/or metabolic syndromes.
  • Studies with Clopidogrel revealed its use in the secondary prevention of cerebrovascular disease (vascular death, fatal or non-fatal stroke and myocardial infaraction).
  • The use of Clopidogrel / Aspirin combination therapy provides additional protection against cerebrovascular disease particularly in patients who do not respond to aspirin therapy.
  • The ongoing studies in patients with unstable angina and myocardial infarction aim to examine the combination effect of Clopidogrel and aspirin in prevention of coronary thrombosis.
  • Studies indicate the use of Clopidogrel in combination with aspirin for reduction of the rate of ischemic cardiovascular and cerebrovascular events in patients with STEMI (ST-Segment Elevation MI).
  • Clopidogrel/aspirin combination therapy has been recommended as an alternative to warfarin for prevention of stroke and systemic embolism in patients with atrial fibrillation

References from chemical, biological and toxicological databases.

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