Atorvastatin + Clopidogrel

Atorvastatin + Clopidogrel is a cardiovascular agent belonging to “lipid-lowering agents" and "antiplatelet agents."

Atorvastatin + Clopidogrel is approved for treating cardiovascular conditions such as heart attack and stroke prevention.

It decreases cholesterol levels and inhibits platelet aggregation, lowering the risk of blood clots and associated complications.

Atorvastatin + Clopidogrel involve absorption in the gastrointestinal tract, liver metabolism, and bile and urine excretion. Atorvastatin has a half-life of approximately 14 hours. Clopidogrel is absorbed rapidly and undergoes hepatic metabolism, with a half-life of about 6 hours.

The common side effects of Atorvastatin + Clopidogrel include nausea, abdominal pain, headache, and constipation.

Atorvastatin + Clopidogrel is available as tablets or capsules for convenient administration.

Atorvastatin + Clopidogrel is available in Canada, Australia, the United States, the United Kingdom, and India.

Atorvastatin + Clopidogrel is a cardiovascular agent belonging to lipid-lowering and antiplatelet agents.

Atorvastatin: HMG-CoA reductase, an enzyme that catalyses the conversion of HMG-CoA to mevalonate, is specifically and competitively inhibited by atorvastatin. By stimulating LDL catabolism and increasing LDL receptor expression as a result of an inhibition in mevalonate synthesis, LDL cholesterol levels are lowered.

The Onset of Action of Atorvastatin is within (Initial effect) 3-5 days.

The Duration of Action of Atorvastatin is within 20 to 30 hours.

The Tmax of Atorvastatin is approximately 1-2 hours, and Cmax is within 1.95–252 μg/ml.

Clopidogrel: Carboxylesterase-1 transforms clopidogrel into its active form. Irreversible binding to the P2Y12 ADP receptors on platelets characterizes the active form of this platelet inhibitor. The glycoprotein GPIIb/IIIa complex activation, platelet aggregation, and ADP binding to P2Y12 receptors are all inhibited by this interaction.

The Onset of action of Clopidogrel is found to be 2 hours.

The Duration of Action of Clopidogrel is approximately 12 hours.

Synergistic Benefits: Atorvastatin and Clopidogrel combination have synergistic benefits on cardiovascular health. Atorvastatin decreases LDL cholesterol, lowering the risk of atherosclerosis; Clopidogrel inhibits platelet aggregation, reducing the risk of blood clot formation and heart attacks and strokes. Together, they prevent atherosclerotic plaque rupture and associated cardiovascular events by stabilising the plaques. When taken separately, the benefits of each medicine are outweighed by the help of this combination, which effectively treats acute coronary syndrome and post-stent insertion.

Data Onset of action of Atorvastatin + Clopidogrel is not specified.

Data duration of action of Atorvastatin + Clopidogrel is not specified.

The Data of Tmax and Cmax Atorvastatin + Clopidogrel are not established.

Atorvastatin + Clopidogrel is available in tablets and capsules.

Tablets/ Capsules: To be swallowed whole with water/liquid.

Atorvastatin + Clopidogrel can treat cardiovascular conditions, reducing cholesterol levels and preventing blood clots in individuals at high risk of heart attacks and strokes, particularly those with a history of coronary artery disease.

Atorvastatin + Clopidogrel is a cardiovascular agent belonging to lipid-lowering and antiplatelet agents.

Atorvastatin: The HMG-CoA reductase enzyme is competitively inhibited by Atorvastatin. Statin drugs lower hepatic cholesterol synthesis by inhibiting HMG-CoA from being converted to mevalonate. The amount of LDL receptors on the surface of hepatic cells also rises when Atorvastatin is taken.

Clopidogrel: Clopidogrel selectively and irreversibly inhibits adenosine diphosphate (ADP) from binding to its platelet P2Y12 receptor and subsequent ADP-mediated activation of glycoprotein IIb/IIIa complex, thus reducing platelet aggregation.

Atorvastatin and Clopidogrel combination have beneficial effects on cardiovascular health. A statin drug called Atorvastatin decreases LDL (bad) cholesterol levels, minimising the risk of atherosclerosis and heart disease. An antiplatelet drug called Clopidogrel prevents platelet aggregation, which lessens the risk of blood clots that can cause heart attacks and strokes. When used together, they provide complete prevention against cardiovascular events, including heart attacks and strokes. This combination lowers the chance of recurrent episodes and improves overall heart health, making it particularly beneficial for people with a history of cardiovascular events. Medical professionals prescribe and monitor it to ensure that patients benefit the most from this combination.

Atorvastatin + Clopidogrel is approved for use in the following clinical indications:

• Atherosclerotic Cardiovascular Disease (ASCVD): To lower the risk of cardiovascular events, including strokes and heart attacks, this combination is recommended for patients with established ASCVD, like coronary artery disease (CAD) and peripheral artery disease (PAD).
• Post-Percutaneous Coronary Intervention (PCI): Patients may be administered Atorvastatin and Clopidogrel after undergoing procedures like coronary stent insertion or angioplasty to avoid clotting around the stent and preserve open blood arteries.
• Management of Post-Myocardial Infarction (Post-MI): To stop future cardiac events and enhance long-term results, patients with a heart attack (myocardial infarction) may be given Atorvastatin and Clopidogrel.
• Secondary stroke prevention reduces the risk of repeat strokes in those with an ischemic stroke or a transient ischemic attack (TIA).

Orally: Atorvastatin + Clopidogrel are available as tablets and capsules that can be taken orally. Atorvastatin + Clopidogrel should be taken with food to prevent stomach upset. It is advisable to follow the physician's prescribed schedule for regular and evenly spaced intervals because the dose and duration of therapy are individualized per specific conditions to achieve the most effective and successful treatment outcome.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Atorvastatin + Clopidogrel is available in the form of Oral tablets and capsules.

Dosage Adjustment for Adult Patients

Prophylaxis

One single dose of Atorvastatin + Clopidogrel orally, once a day as directed by the physician.

Atorvastatin + Clopidogrel should be used in treating cardiovascular and bleeding disorders, along with appropriate dietary restrictions.

While taking this combination, it is advised to maintain a rich- balanced diet low in saturated fats and cholesterol—consuming plenty of vegetables, whole grains, fruits, and lean proteins in meals. Avoid excessive consumption of grapefruit, grapefruit juice, or alcohol, as it may interact with the medication.

The dietary restriction should be individualized as per patient requirements.

Atorvastatin + Clopidogrel may be contraindicated in patients with the following conditions:

• Intracranial haemorrhage or active pathological bleeding such as a stomach ulcer.
• Active liver disease, unexplained persistent serum transaminase elevation.
• Pregnancy and lactation.
• Intracranial haemorrhage or active pathological bleeding such as a stomach ulcer.
• Anaphylaxis or other hypersensitivity to the product's ingredients, including Clopidogrel.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows.

• This combination may raise the risk of bleeding, particularly in individuals with a history of bleeding problems, recent surgeries, or concurrent use of drugs that influence blood coagulation. Use with caution.
• Patients with pre-existing liver conditions should undergo regular liver function monitoring. If liver enzyme levels significantly increase, discontinue the medication. It is advisable to alter the dosage and ensure routine kidney function test is done in cases of severe renal impairment.
• Do not use Atorvastatin + Clopidogrel if you are a breastfeeding mother since it may pass into the breast milk.
• Do not use Atorvastatin + Clopidogrel if you plan to conceive or are pregnant.

There is no sufficient scientific evidence traceable regarding the use and safety of Atorvastatin + Clopidogrel for breastfeeding populations.

Avoid or minimize the consumption of red yeast rice, grapefruit or grapefruit juice.

The clinically relevant drug interactions of Atorvastatin and Clopidogrel are briefly summarized here.

• CYP3A4 inhibitors: May increase risk of myopathy and rhabdomyolysis with moderate to potent CYP3A4 inhibitors (e.g. HIV and HCV protease inhibitors, itraconazole, ketoconazole, clarithromycin, erythromycin, verapamil, diltiazem), Atorvastatin, gemfibrozil, ezetimibe, niacin, colchicine, fixed combination of lopinavir/ritonavir. Concomitant use with CYP3A4 inducers (e.g. rifampicin, efavirenz, phenytoin), Al or Mg antacids, and colestipol may reduce plasma concentrations of Atorvastatin. It may increase serum digoxin levels and oral contraceptives (e.g., norethindrone, Ethinyl estradiol).
• CYP2C19 Inducers: Since CYP2C19 plays a role in the partial metabolism of Clopidogrel to produce its active metabolite, medications that do so are likely to boost blood levels of Clopidogrel's active metabolite. Rifampin has a significant impact on CYP2C19, which leads to a rise in Clopidogrel's active metabolite and platelet inhibition, which may increase the risk of bleeding. Avoid using potent CYP2C19 inducers simultaneously as a safety measure.
• CYP2C19 Inhibitors: CYP2C19 acts in the process of transforming clopidogrel into its active metabolite. Reduced plasma concentrations of Clopidogrel's active metabolite and decreased platelet inhibition are caused by concurrent use of medications that block the action of this enzyme.
• Proton Pump Inhibitors (PPIs): PPIs like omeprazole Or Esomeprazole can reduce the antiplatelet effects of Clopidogrel. Avoid the concomitant use of Clopidogrel with omeprazole or esomeprazole.
• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Taking NSAIDs and Clopidogrel together increases the risk of gastrointestinal bleeding.
• Warfarin (CYP2C9 Substrates): The coadministration of Clopidogrel with warfarin increases the risk of bleeding due to separate effects on hemostasis. However, it did not affect the pharmacokinetics of S-warfarin (a CYP2C9 substrate) or INR in those patients undergoing long-term warfarin treatment. However, Clopidogrel inhibits CYP2C9 at excessive doses in vitro.

• Pain in the stomach
• Diarrhoea
• Indigestion
• Constipation
• Headache
• Dizziness
• Weakness
• Muscle pain
• Increased blood glucose
• Increased liver enzymes

The use of Atorvastatin + Clopidogrel should be prudent in the following group of special populations

• Pregnancy

Atorvastatin + Clopidogrel should not be used during pregnancy unless the potential benefits outweigh the risks. It may cause harm to the fetus, and alternative treatments should be considered. Pregnant individuals should consult their healthcare provider for a thorough evaluation and discussion of potential risks and benefits before using this medication. Animal studies have shown significant harmful effects on the developing baby.

• Lactating Mothers

It is vital to exercise caution while using Atorvastatin and Clopidogrel in lactating women. Both medications can potentially enter breast milk, and how they will affect a nursing newborn is unknown. Based on limited human evidence, the medicine does not appear to pose any significant risk to the developing foetus.

• Pediatric Use

As per FDA, safety and effectiveness in the pediatric population have not been established.

• Geriatric Use

Geriatric people should have their use of Atorvastatin and Clopidogrel closely monitored. Elderly people may be more vulnerable to adverse drug reactions and drug interactions. It is essential to closely monitor liver and kidney function and any possible medication interactions. Depending on the individual's medical situation and drug regimen, dosage modifications may be required. It's crucial to monitor patients and consult with medical professionals regularly.

Dosage Adjustment in Kidney Patient

Mild to severe impairment: No dosage adjustment necessary.

Dosage Adjustment in Hepatic Impairment Patient

It is contraindicated in persons with active liver disease or those with persistently elevated serum transaminases without a known reason.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Atorvastatin + Clopidogrel. Overconsumption of Atorvastatin + Clopidogrel could lead to symptoms such as excessive bleeding, difficulty breathing, loss of consciousness, severe gastrointestinal disturbances, and muscle-related issues.

There is no specific antidote or treatment for excessive intake of Atorvastatin + Clopidogrel. However, immediate medical attention is essential.

Atorvastatin + Clopidogrel should be terminated immediately when an overdose is suspected or experience any unusual symptoms after its intake. Management typically involves supportive measures and symptomatic treatment. Supportive therapy should also be given, addressing any symptoms that persist or worsen. Activated charcoal may be considered if the overdose is detected shortly after ingestion to reduce absorption. Monitoring of vital signs and the patient's clinical condition is crucial. In severe cases, gastric lavage may be performed if ingestion occurs within the previous hour. Physical treatment might be added if necessary.

Pharmacodynamic of Atorvastatin + Clopidogrel

Atorvastatin: Humans can be pharmacologically affected by Atorvastatin and some of its metabolites. Cholesterol production and LDL clearance occur mainly in the liver, also the site of action. More closely correlated with LDL-C lowering is medication dose than systemic drug concentration. Depending on the therapeutic response, pharmacological dosages should be individualized.

Clopidogrel: Clopidogrel is a prodrug of platelet inhibitor used to reduce the risk of myocardial infarction and stroke. It has a long duration of action as it is taken once daily and has a large therapeutic window.

Pharmacokinetics of Atorvastatin + Clopidogrel

• Absorption:

Atorvastatin: Atorvastatin is well absorbed from the gastrointestinal tract, with peak blood levels occurring within 1-2 hours after oral administration. It is efficiently absorbed in the small intestine.

Clopidogrel: After oral administration of Clopidogrel once or more during the day, the drug is rapidly absorbed. After a single 75-mg oral dosage, mean peak plasma levels of unaltered Clopidogrel increased 45 minutes later at about 2.2–2.5 ng/mL. Based on the urine excretion of clopidogrel metabolites, the absorption is at least 50%.

• Distribution

Atorvastatin: Atorvastatin's average volume of distribution is 381 litres. About 98% of Atorvastatin is bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor penetration of the drug into red blood cells. According to findings in rats, Atorvastatin is likely to be released in human milk.

Clopidogrel: Human plasma proteins bind reversibly to Clopidogrel (98% and 94%, respectively) and the primary circulating inactive metabolite in vitro. Up to a 100 mcg/mL concentration, the binding is in vitro nonsaturable.

• Metabolism

Atorvastatin: Atorvastatin undergoes extensive metabolism to produce a variety of beta-oxidation compounds and ortho- and parahydroxylated derivatives. In vitro, ortho- and para-hydroxylated metabolites inhibit HMG-coa reductase to the same extent as Atorvastatin. Active metabolites are responsible for around 70% of the circulating inhibitory activity for hmg-coa reductase.

Clopidogrel: Clopidogrel undergoes extensive liver metabolism through two main pathways. The first involves esterases, producing an inactive carboxylic acid derivative (accounting for 85% of circulating metabolites). The second pathway is mediated by multiple cytochrome P450 enzymes, where Clopidogrel is initially oxidized to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of this intermediate leads to the formation of the active thiol metabolite, which inhibits platelet aggregation by binding rapidly and irreversibly to platelet receptors.

• Excretion

Atorvastatin: Atorvastatin and its metabolites are mainly eliminated through bile after hepatic and extra-hepatic metabolism. Although there's no enterohepatic recirculation, Atorvastatin has a plasma elimination half-life of about 14 hours in humans. However, the inhibitory activity on HMG-CoA reductase, which includes active metabolites, has a longer half-life of 20 to 30 hours. Urine excretion accounts for less than 2% of an orally administered dose of Atorvastatin.

Clopidogrel: Clopidogrel has a half-life of around 6 hours following a single oral 75 mg dose. The inactive acid metabolite has an elimination half-life of 8 hours following single and repeated dosing. 2% of the radiolabel with an 11-day half-life was covalently bound to platelets. The carboxylic acid derivative's glucuronide is also seen in plasma and urine.

Therapeutic benefits of Atorvastatin and Clopidogrel combination

• Combining Atorvastatin with Clopidogrel decreases the risk of heart attacks and strokes by reducing cholesterol levels and inhibiting the development of blood clots.
• It enhances cardiac blood flow by treating or preventing problems, including angina (chest discomfort) and coronary artery disease.
• A combination of atorvastatin and Clopidogrel provides complete cardiovascular protection through synergistic effects.
• Combining atorvastatin with Clopidogrel lowers low-density lipoprotein (LDL) cholesterol levels, minimising the risk of atherosclerosis and coronary heart disease.

• Sasha P. Suarez Ferreira, Ryan P. Hall, Monica Majumdar, Guillaume Goudot, Samuel Jessula, Tiffany Bellomo, Ivy Lee, Navi Kukreja, Gaurav Parmar, Ana E. Boada, Anahita Dua, Atorvastatin Effect on Clopidogrel Efficacy in the Patients with Peripheral Artery Disease, Annals of Vascular Surgery, Volume 95,2023, Pages 74-79, ISSN 0890-5096, https://doi.org/10.1016/j.avsg.2023.05.023.
• An, K., Huang, R., Tian, S. et al. Statins significantly reduce mortality in those patients receiving Clopidogrel without affecting the platelet activation and aggregation: a systematic review and meta-analysis. Lipids Health Dis 18, 121 (2019). https://doi.org/10.1186/s12944-019-1053-0
• Kreutz, Rolf P et al. “Simultaneous administration of high-dose atorvastatin and clopidogrel does not interfere with platelet inhibition during percutaneous coronary intervention.” Clinical pharmacology: advances and applications vol. 8 45-50. 3 Jun. 2016, doi:10.2147/CPAA.S98790

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