Aspirin/atorvastatin/clopidogrel

Prevention of Cardiovascular Disease: Encourage aspirin use in men (45-79 years) and women (55-79 years) when potential benefit (ie, prevention of myocardial infarction in men and prevention of ischemic stroke in women) outweighs potential harm of gastrointestinal hemorrhage.

Primary Prevention of Thromboembolic Disorders and Cardiovascular Events: Ischemic stroke; transient ischemic attack (TIA); prevention of recurrent myocardial infarction (MI); unstable angina pectoris; chronic stable angina pectoris.

Secondary Prevention of Cardiovascular Disease in Persons with Diabetes Mellitus Especially in the Following Subgroups: History of MI, vascular bypass procedure, stroke or transient ischemic attack and angina. Persons with additional risk factors: Hypertension, smoking, dyslipidemia and family history of cardiovascular disease.

Revascularization Procedures: Patients who have undergone revascularization procedures eg, coronary artery bypass graft (CABG), percutaneous transluminal coronary angioplasty (PTCA) and carotid endarterectomy when there is a preexisting condition for which aspirin is already indicated.

Pregnancy-Induced Hypertension: Primary prevention of pregnancy-induced hypertension, preeclampsia and intrauterine growth retardation particularly in pregnant women with preexisting chronic hypertension, auto-immune disorders like systemic lupus erythematosus (SLE), positive cardiolipin antibody test, history of recurring toxemia in successive pregnancies, and hypotension developing before the 20th week of gestation.

Atorvastatin is indicated as an adjunct to diet for the treatment of patients with elevated total cholesterol (total-C), low density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo B), and triglycerides (TG) and to increase high density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia (heterozygous familial and non-familial hypercholesterolemia), combined (mixed) hyperlipidemia (Fredrickson Types IIa and IIb), elevated serum TGlevels (Fredrickson Type IV), and for patients with dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet.

Atorvastatin is also indicated for the reduction of total-C and LDL-C in patients with homozygous familial hypercholesterolemia.

Prevention of Cardiovascular Complications: In patients without clinically evident cardiovascular disease (CVD), and with or without dyslipidemia, but with multiple risk factors for coronary heart disease (CHD), such as smoking, hypertension, diabetes, low HDL-C, or a family history of early CHD, atorvastatin is indicated to: Reduce the risk of fatal CHD and non-fatal myocardial infarction (MI); reduce the risk of stroke; reduce the risk of revascularization procedures and angina pectoris.

In patients with clinically evident CHD, atorvastatin is indicated to: Reduce the risk of non-fatal MI; reduce the risk of fatal and non-fatal stroke; reduce the risk for revascularization procedures; reduce the risk of hospitalization for congestive heart failure (CHF); reduce the risk of angina.

As adjunct to lifestyle changes, such as proper diet and exercise, intensive atorvastatin treatment has been shown to halt the progression of atherosclerosis (total atheroma or plaque volume) in patients with coronary artery disease and other individuals who are at high risk for cardiovascular disease.

Chronic Kidney Disease: In patients with diabetes with moderately decreased eGFR, Atorvastatin is indicated to reduce the risk for cardiovascular disease.

In patients with clinically evident coronary heart disease and CKD not requiring dialysis, atorvastatin is indicated to reduce the risk of major cardiovascular events including stroke.

In patients with clinically evident coronary heart disease and/or diabetes with microalbuminuria, atorvastatin is indicated to reduce the rate of GFR decline and progression of CKD.

Pediatric Patients (10-17 Years of Age): Atorvastatin is indicated as an adjunct to diet to reduce total-C, LDL-C, and apo B levels in boys and post-menarchal girls, 10 to 17 years of age, with heterozygous familial hyperchlolesterolemia if, after an adequate trial of diet therapy, the following findings are present: LDL-C remains ≥190 mg/dL or, LDL-C remains ≥160 mg/dL and there is a positive family history of premature CVD or, two or more other CVD risk factors are present in the pediatric patient.

Prevention of atherothrombotic events in: Recent MI, Recent Stroke or Established Peripheral Arterial Disease: For patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease, Clopidogrel has been shown to reduce the rate of a combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death.

Acute Coronary Syndrome: For patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave MI) including patients who are to be managed medically and those who are to be managed with percutaneous coronary intervention (with or without stent) or coronary artery bypass graft (CABG), Clopidogrel has been shown to decrease the rate of a combined endpoint of cardiovascular death, MI or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke or refractory ischemia.

For patients with ST-segment elevation acute MI, Clopidogrel has been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, reinfarction or stroke.

Atrial Fibrillation: In patients with atrial fibrillation (AF) at increased risk of vascular events who can take vitamin K antagonist (VKA) therapy, VKA has been shown to be associated with a better clinical benefit than acetylsalicylic acid (Clopidogrel) alone or the combination of clopidogrel and Clopidogrel for the reduction of stroke.

In patients with atrial fibrillation who have at least 1 risk factor for vascular events and who cannot take VKA therapy [eg, specific risk of bleeding, physician assessment that patient is unable to comply with international normalized ratio (INR) monitoring or that VKA use is inappropriate], clopidogrel is indicated in combination with Clopidogrel for the prevention of atherothrombotic and thromboembolic events, including stroke. Clopidogrel in combination with Clopidogrel has been shown to reduce the rate of the combined endpoint of stroke, myocardial infarction (MI), non-CNS systemic embolism, or vascular death, largely through a reduction in stroke.

Aspirin may also be used to lessen the chance of heart attack, stroke, or other problems that may occur when a blood vessel is blocked by blood clots. Aspirin helps prevent dangerous blood clots from forming. However, this effect of aspirin may increase the chance of serious bleeding in some people. Therefore, aspirin should be used for this purpose only when your doctor decides, after studying your medical condition and history, that the danger of blood clots is greater than the risk of bleeding. Do not take aspirin to prevent blood clots or a heart attack unless it has been ordered by your doctor.

Salicylates may also be used for other conditions as determined by your doctor.

The caffeine present in some of these products may provide additional relief of headache pain or faster pain relief.

Some salicylates are available only with your medical doctor's or dentist's prescription. Others are available without a prescription; however, your medical doctor or dentist may have special instructions on the proper dose of these medicines for your medical condition.

Atorvastatin is in a group of drugs called HMG CoA reductase inhibitors, or "statins." Atorvastatin reduces levels of "bad" cholesterol (low-density lipoprotein, or LDL) and triglycerides in the blood, while increasing levels of "good" cholesterol (high-density lipoprotein, or HDL).

Atorvastatin is used to treat high cholesterol, and to lower the risk of stroke, heart attack, or other heart complications in people with type 2 diabetes, coronary heart disease, or other risk factors.

Atorvastatin is used in adults and children who are at least 10 years old.

Atorvastatin may also be used for purposes not listed in this medication guide.

Clopidogrel is used alone or together with Clopidogrel to lessen the chance of a heart attack or stroke. It is given to patients who have already had a heart attack, severe chest pain, or a stroke, or to patients with other circulation problems that could cause a stroke or heart attack.

A heart attack or stroke may occur when a blood vessel is blocked by a blood clot. Clopidogrel is a platelet inhibitor. It reduces the chance that a harmful blood clot will form by preventing platelets from clumping together in the blood. Clopidogrel may also increase the chance of serious bleeding in some people.

clopidogrel is available only with your doctor's prescription.

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Caplet, oral: 500 mg

Bayer Aspirin Extra Strength: 500 mg

Bayer Genuine Aspirin: 325 mg

Bayer Women's Low Dose Aspirin: 81 mg [contains elemental calcium 300 mg]

Caplet, oral [buffered]:

Ascriptin Maximum Strength: 500 mg [contains aluminum hydroxide, calcium carbonate, magnesium hydroxide] [DSC]

Bayer Plus Extra Strength: 500 mg [contains calcium carbonate]

Caplet, enteric coated, oral:

Bayer Aspirin Regimen Regular Strength: 325 mg

Capsule Extended Release, oral:

Aspirin: 162.5 mg

Suppository, rectal: 300 mg (12s); 600 mg (12s)

Tablet, oral: 325 mg

Aspercin: 325 mg

Aspirtab: 325 mg

Bayer Genuine Aspirin: 325 mg

Tablet, oral [buffered]: 325 mg

Ascriptin Regular Strength: 325 mg [contains aluminum hydroxide, calcium carbonate, magnesium hydroxide]

Buffasal: 325 mg [contains magnesium oxide]

Bufferin: 325 mg [contains calcium carbonate, magnesium carbonate, magnesium oxide]

Bufferin Extra Strength: 500 mg [contains calcium carbonate, magnesium carbonate, magnesium oxide]

Buffinol: 324 mg [sugar free; contains magnesium oxide]

Tri-Buffered Aspirin: 325 mg [contains calcium carbonate, magnesium carbonate, magnesium oxide]

Tablet, chewable, oral: 81 mg

Bayer Aspirin Regimen Children's: 81 mg [cherry flavor]

Bayer Aspirin Regimen Children's: 81 mg [orange flavor]

St Joseph Adult Aspirin: 81 mg

Tablet, delayed release, oral: 81 mg, 325 mg

Aspirin Adult Low Dose: 81 mg

Aspirin Adult Low Strength: 81 mg

Aspirin EC Low Strength: 81 mg

Bayer Aspirin: 325 mg

Bayer Aspirin EC Low Dose: 81 mg

GoodSense Low Dose: 81 mg

Tablet, enteric coated, oral: 81 mg, 325 mg, 650 mg

Aspir-low: 81 mg

Bayer Aspirin Regimen Adult Low Strength: 81 mg

Aspirin: 325 mg

Aspirin Arthritis Strength: 500 mg

Aspirin Low Strength: 81 mg

Halfprin: 81 mg [DSC]

St Joseph Adult Aspirin: 81 mg

Dosing: Adult

Note: Ibuprofen, naproxen, and possibly other nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the cardioprotective effects of aspirin (Capone 2005; Catella-Lawson 2001; MacDonald 2003). Avoid regular or frequent use of NSAIDs in patients receiving aspirin for cardiovascular protection. An ER formulation exists (162.5 mg capsule); however, it should not be used in situations when a rapid onset of action is necessary (eg, ST-elevation myocardial infarction [MI]); dosing information provided is based on the IR formulations.

Analgesic and antipyretic: Immediate release:

Oral: 325 mg to 1 g every 4 to 6 hours as needed; usual maximum daily dose: 4 g/day (Abramson 2019). Note: If patient cannot take orally, rectal suppositories (300 or 600 mg) are available.

Anti-inflammatory for arthritis associated with rheumatic disease: Immediate release:

Oral: 4 to 8 g/day in 4 to 5 divided doses as needed; titrate dose based on response and tolerability. Continue treatment until symptoms resolve (typically 1 to 2 weeks, but potentially up to 8 weeks). Use of aspirin at these high doses (4 to 8 g/day) may be limited by adverse effects (tinnitus, diminished auditory acuity, GI intolerance) (Abramson 2019; Carapetis 2012; Steer 2019).

Atherosclerotic cardiovascular disease:

Acute coronary syndrome: Note: For rapid onset, non-enteric-coated IR tablet(s) should be chewed and swallowed upon identification of clinical and ECG findings suggesting an acute coronary syndrome. Enteric-coated aspirin is not preferred since onset of action may be delayed. If it is the only product available, enteric-coated IR tablet(s) may be chewed and swallowed (ACCP [Eikelboom 2012]; Sai 2011). For maintenance therapy, any oral formulation is acceptable for use.

Non–ST-elevation acute coronary syndromes or ST-elevation myocardial infarction: Note: For initial therapy, administer aspirin in combination with an IV anticoagulant and a P2Y12 inhibitor (ACC/AHA [Amsterdam 2014]; ACCF/AHA [O'Gara 2013]).

Initial:

Immediate release (non-enteric-coated):

Oral: 162 to 325 mg administered once (chew and swallow) at the time of diagnosis (ACC/AHA [Amsterdam 2014]; ACCF/AHA [O'Gara 2013]).

Rectal (alternative route): 600 mg administered once at the time of diagnosis if an IR oral formulation is unavailable or oral route is not feasible (Maalouf 2009).

Maintenance (secondary prevention): Immediate release:

Oral: 75 to 100 mg once daily (ACC/AHA [Levine 2016]; Hennekens 2019; Mehta 2001).

Duration of therapy: Aspirin plus a P2Y12 inhibitor (dual antiplatelet therapy [DAPT]) should be continued for ≥12 months unless bleeding risk is a concern. If there have been no major bleeding complications after 12 months, continuation of DAPT may be considered. Re-evaluate the need for DAPT at regular intervals based on bleeding and thrombotic risks. When DAPT is complete, discontinue the P2Y12 inhibitor and continue aspirin indefinitely (ACC/AHA [Levine 2016]; Bonaca 2015; Cutlip 2019a; Lincoff 2019; Mauri 2014; Mehta 2001; Wallentin 2009; Wiviott 2007; Yusuf 2001).

Percutaneous coronary intervention for stable ischemic heart disease (off-label use):

Initial: Note: For initial therapy, non-enteric-coated IR tablet(s) should be administered. Enteric-coated aspirin is not preferred since onset of action is delayed. For patients who receive a coronary stent during percutaneous coronary intervention, administer aspirin in combination with an IV anticoagulant and clopidogrel (ACCF/AHA/SCAI [Levine 2011]).

Patients chronically taking aspirin ≥325 mg/day prior to percutaneous coronary intervention: Immediate release (non-enteric-coated):

Oral: 75 to 100 mg prior to the procedure (Cutlip 2020); some experts recommend doses up to 325 mg (ACCF/AHA/SCAI [Levine 2011]).

Patients not chronically taking aspirin or chronically taking aspirin <325 mg/day prior to percutaneous coronary intervention: Immediate release (non-enteric-coated):

Oral: 300 to 325 mg given ≥2 hours (preferably 24 hours) before the procedure (ACCF/AHA/SCAI [Levine 2011]; Cutlip 2020).

Maintenance: Immediate release:

Oral: 75 to 100 mg once daily in combination with clopidogrel (DAPT); upon completion of the recommended duration of DAPT, continue aspirin indefinitely (ACC/AHA [Levine 2016]; Cutlip 2019c). Refer to Clopidogrel monograph for information on duration of DAPT.

Atherosclerotic cardiovascular disease, primary prevention (off-label use): Note: Use should be a shared decision between health care professionals and patients after weighing the cardiovascular disease risk versus benefits (ACC/AHA [Arnett 2019]).

Immediate release:

Oral: 75 to 100 mg once daily (ACC/AHA [Arnett 2019]).

Atherosclerotic cardiovascular disease, secondary prevention:

Carotid artery atherosclerosis, asymptomatic or symptomatic (off-label use): Immediate release:

Oral: 75 to 325 mg once daily (ACCP [Alonso-Coello 2012]; Walker 1995).

Coronary artery bypass graft surgery: Immediate release:

Oral: 75 to 81 mg once daily beginning preoperatively; continue indefinitely following surgery (AHA [Kulik 2015]; Aranki 2019).

Off-pump coronary artery bypass graft surgery: Following surgery, consider adding clopidogrel in combination with aspirin for 12 months then discontinue clopidogrel and continue aspirin indefinitely (AHA [Kulik 2015]).

Patients with acute coronary syndrome followed by coronary artery bypass graft surgery: Administer aspirin in combination with a P2Y12 inhibitor for 12 months then continue aspirin indefinitely (AHA [Kulik 2015]). Some experts do not use P2Y12 inhibitors postoperatively in these patients (Aranki 2019).

Ischemic stroke/Transient ischemic attack:

Cardioembolic stroke (alternative agent): Note:

Oral anticoagulation is preferred. For patients who cannot take an oral anticoagulant, may consider aspirin as an alternative (AHA/ASA [Kernan 2014]).

Immediate release:

Oral: 75 to 100 mg once daily (AHA/ASA [Kernan 2014]).

Intracranial atherosclerosis (50% to 99% stenosis of a major intracranial artery), secondary prevention: Immediate release:

Oral: 325 mg once daily; for patients with recent stroke or transient ischemic attack (within 30 days) may consider short-term use of clopidogrel (for 21 or 90 days depending on degree of stenosis) in combination with aspirin (AHA/ASA [Kernan 2014]; Chimowitz 2011) followed by single-agent antiplatelet therapy with aspirin, clopidogrel, or aspirin/ER dipyridamole indefinitely (ACCP [Lansberg 2012]; AHA/ASA [Kernan 2014]; Cucchiara 2019).

Noncardioembolic ischemic stroke/transient ischemic attack: Note: For patients with a minor stroke (National Institutes of Health Stroke Scale score ≤3) or high-risk transient ischemic attack (ABCD/ of 81 mg tablet):

Analgesic:

Oral, rectal:

Infants, Children, and Adolescents weighing <50 kg: Limited data available: 10 to 15 mg/kg/dose every 4 to 6 hours; maximum daily dose: 90 mg/kg/day or 4,000 mg/day whichever is less (APS 2016)

Children ≥12 years and Adolescents weighing ≥50 kg: 325 to 650 mg every 4 to 6 hours; maximum daily dose: 4,000 mg/day

Anti-inflammatory: Limited data available: Infants, Children, and Adolescents:

Oral: Initial: 60 to 90 mg/kg/

Maintenance: 80 to 100 mg/kg/day divided every 6 to 8 hours; monitor serum concentrations (Levy 1978)

Antiplatelet effects: Limited data available: Infants, Children, and Adolescents:

Oral: Adequate pediatric studies have not been performed; pediatric dosage is derived from adult studies. Usual adult maximum daily dose for antiplatelet effects is 325 mg/day.

Acute ischemic stroke (AIS):

Noncardioembolic: 1 to 5 mg/kg/dose once daily for ≥2 years; patients with recurrent AIS or TIAs should be transitioned to clopidogrel, LMWH, or warfarin (ACCP [Monagle 2012])

Secondary to Moyamoya and non-Moyamoya vasculopathy: 1 to 5 mg/kg/dose once daily; Note: In non-Moyamoya vasculopathy, continue aspirin for 3 months, with subsequent use guided by repeat cerebrovascular imaging (ACCP [Monagle 2012]).

Prosthetic heart valve:

Bioprosthetic aortic valve (with normal sinus rhythm): 1 to 5 mg/kg/dose once daily for 3 months (AHA [Giglia 2013]; ACCP [Guyatt 2012]; ACCP [Monagle 2012])

Mechanical aortic and/or mitral valve: 1 to 5 mg/kg/dose once daily combined with vitamin K antagonist (eg, warfarin) is recommended as first-line antithrombotic therapy (ACCP [Guyatt 2012]; ACCP [Monagle 2012]). Alternative regimens: 6 to 20 mg/kg/dose once daily in combination with dipyridamole (Bradley 1985; el Makhlouf 1987; LeBlanc 1993; Serra 1987; Solymar 1991)

Shunts: Blalock-Taussig; Glenn; postoperative; primary prophylaxis: 1 to 5 mg/kg/dose once daily (ACCP [Monagle 2012]; AHA [Giglia 2013])

Norwood, Fontan surgery, postoperative; primary prophylaxis: 1 to 5 mg/kg/dose once daily (ACCP [Monagle 2012]; AHA [Giglia 2013])

Transcatheter Atrial Septal Defect (ASD) or Ventricular Septal Defect (VSD) devices, postprocedure prophylaxis: 1 to 5 mg/kg/dose once daily starting one to several days prior to implantation and continued for at least 6 months. For older children and adolescents, after device closure of ASD, an additional anticoagulant may be given with aspirin for 3 to 6 months, but the aspirin should continue for at least 6 months (AHA [Giglia 2013]).

Ventricular assist device (VAD) placement: 1 to 5 mg/kg/dose once daily initiated within 72 hours of VAD placement; should be used with heparin (initiated between 8 to 48 hours following implantation) and with or without dipyridamole (ACCP [Monagle 2012])

Kawasaki disease: Limited data available; optimal dose not established: Note: Patients with Kawasaki disease and presenting with influenza or viral illness should not receive aspirin; acetaminophen is suggested as an antipyretic in these patients and an alternate antiplatelet agent suggested for a minimum of 2 weeks (AHA [McCrindle 2017]).

Infants, Children, and Adolescents:

Oral:

Initial therapy (acute phase): Recommended dosing regimens vary. Use in combination with IV immune globulin (within first 10 days of symptom onset) and corticosteroids in some cases.

High dose: 80 to 100 mg/kg/day divided every 6 hours for up to 14 days until fever resolves for at least 48 to 72 hours (AAP [Red Book 2015]; ACCP [Monagle 2012]; AHA [Giglia 2013]; AHA [McCrindle 2017])

Moderate dose: 30 to 50 mg/kg/day divided every 6 hours for up to 14 days until fever resolves for at least 48 to 72 hours (AHA [McCrindle 2017])

Subsequent therapy (low-dose; antiplatelet effects): 3 to 5 mg/kg/day once daily; reported dosing range: 1 to 5 mg/kg/day; initiate after fever resolves for at least 48 to 72 hours (or after 14 days). In patients without coronary artery abnormalities, administer the lower dose for 6 to 8 weeks. In patients with coronary artery abnormalities, low-dose aspirin should be continued indefinitely (in addition to therapy with warfarin) (AAP [Red Book 2015]; ACCP [Monagle 2012]; AHA [Giglia 2013]; AHA [McCrindle 2017]).

Rheumatic fever: Limited data available: Infants, Children, and Adolescents:

Oral: Initial: 100 mg/kg/

Migratory polyarthritis, with carditis without cardiomegaly or congestive heart failure: Initial: 100 mg/kg/day in 4 divided doses for 3 to 5 days, followed by 75 mg/kg/day in 4 divided doses for 4 weeks

Carditis and cardiomegaly or congestive heart failure: At the beginning of the tapering of the prednisone dose, aspirin should be started at 75 mg/kg/day in 4 divided doses for 6 weeks

Always take Atorvastatin exactly as prescribed.

The following instructions may apply only if the doctor has not prescribed a different regimen for administering Atorvastatin. Observe the instructions closely, otherwise the medicine cannot be effective.

Before the start of treatment, the physician will prescribe a low-cholesterol diet and should be strictly observe throughout the treatment with Atorvastatin.

Usual Starting Dose: Adults and Children ≥10 years: 10 mg once daily. The physician will determine further doses to achieve the desired blood cholesterol levels. Thereafter, the dose will be adjusted individually every ≤4 weeks frequently. Maximum Daily Dose: 80 mg for adults and 20 mg once daily for children.

Elevated Blood Cholesterol Levels (Hypercholesterolemia) or Concurrent Elevation of Blood Cholesterol and Triglyceride Levels (Mixed Hyperlipidemia): In the majority of patients, the effective daily dose of atorvastatin is 20 mg. The effect of treatment can be seen after 2 weeks; it is usually greatest after 4 weeks. This therapeutic effect is then maintained with long-term administration of Atorvastatin.

Hereditary Increase of Blood Cholesterol Levels (Familial Hypercholesterolemia): Heterozygous Familial Hypercholesterolemia: Starting Dose: 10 mg once daily. The dose should be determined for each individual patient. The physician will increases the dose up to 80 mg daily every 4 weeks.

Homozygous Familial Hypercholesterolemia: Adults: In the majority of patients (taking atorvastatin 80 mg daily), blood cholesterol levels (LDL cholesterol) decreased by 17-31% in clinical trials.

Patients with Renal Insufficiency and the

Elderly:

In clinical trials, it was ascertained that no dosage adjustment is necessary in elderly patients.

Administration: Take Atorvastatin with some liquid at any time of the day and regardless of food intake.

Atorvastatin are designated for long-term administration.

Missed Dose: Do not take a double dose, but only the normal dose.

Acute Coronary Syndrome

Clopidogrel can be administered with or without food.

• For patients with non-ST-elevation ACS (UA/NSTEMI), initiate Clopidogrel with a single 300 mg oral loading dose and then continue at 75 mg once daily. Initiate Clopidogrel (75-325 mg once daily) and continue in combination with Clopidogrel.
• For patients with STEMI, the recommended dose of Clopidogrel is 75 mg once daily orally, administered in combination with Clopidogrel (75-325 mg once daily), with or without thrombolytics. Clopidogrel may be initiated with or without a loading dose.

Recent MI, Recent Stroke, Or Established Peripheral Arterial Disease

The recommended daily dose of Clopidogrel is 75 mg once daily orally, with or without food.

CYP2C19 Poor Metabolizers

CYP2C19 poor metabolizer status is associated with diminished antiplatelet response to clopidogrel. Although a higher dose regimen in poor metabolizers increases antiplatelet response, an appropriate dose regimen for this patient population has not been established.

Use With Proton Pump Inhibitors (PPI)

Avoid using omeprazole or esomeprazole with Clopidogrel. Omeprazole and esomeprazole significantly reduce the antiplatelet activity of Clopidogrel. When concomitant administration of a PPI is required, consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite.

How supplied

Dosage Forms And Strengths

• 75 mg tablets: Pink, round, biconvex, film-coated tablets debossed with “75” on one side and “1171” on the other
• 300 mg tablets: Pink, oblong, film-coated tablets debossed with “300” on one side and “1332” on the other

Storage And Handling

Clopidogrel (clopidogrel bisulfate) 75 mg tablets are available as pink, round, biconvex, film-coated tablets debossed with “75” on one side and “1171” on the other. Tablets are provided as follows:

NDC 63653-1171-6 Bottles of 30

NDC 63653-1171-1 Bottles of 90

NDC 63653-1171-5 Bottles of 500

NDC 63653-1171-3 Blisters of 100

Clopidogrel (clopidogrel bisulfate) 300 mg tablets are available as pink, oblong, film-coated tablets debossed with “300” on one side and “1332” on the other. Tablets are provided as follows:

NDC 63653-1332-2 Unit-dose packages of 30

NDC 63653-1332-3 Unit-dose packages of 100

Store at 25° C (77° F); excursions permitted to 15°–30° C (59°–86° F).

Distributed by: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, Bridgewater, NJ 08807. Revised: July 2015

See also:
What is the most important information I should know about Aspirin?

This medicine is contraindicated in the following situations:

hypersensitivity to acetylsalicylic acid or any of the excipients history of asthma provoked by the administration of salicylates or substances of similar activity, including anti-inflammatory drugs, PUD evolving any constitutional or acquired bleeding disorder, risk of bleeding, severe hepatic, severe renal insufficiency, uncontrolled severe heart failure, pregnancy beyond 24 weeks of gestation (5 months of age) at doses above 100 mg per day: beyond 24 weeks of gestation (5 months old), all inhibitors of prostaglandin synthesis may explain the fetus: a cardiopulmonary toxicity (ductus arteriosus and pulmonary hypertension), renal dysfunction may progress to renal failure associated with oligohydramniosIn late pregnancy, the mother and the newborn may have: a prolonged bleeding time due to an anti-platelet aggregation may occur even after administration of low doses of medication inhibiting uterine contractions leading to a delay term or prolonged laborConsequently, aspirin is not recommended cons beyond 24 weeks of gestation (5 months old), in combination with methotrexate in doses above 20 mg / week, in combination with oral anticoagulants for anti-inflammatory doses of acetylsalicylic acid (> 1 g per dose and / or ? 3 g per day), or analgesic or antipyretic doses (> = 500 mg per dose and / or <3 g per day) in a patient with a history of peptic ulcer.

Due to the presence of lactose, the drug is contraindicated for congenital galactosemia, malabsorption of glucose and galactose deficiency or lactase.

The use of this drug is not recommended during lactation: acetylsalicylic acid passing into breast milk, this medicine is not recommended during breastfeeding.

Concomitant use of acetylsalicylic acid, with anti-inflammatory doses (> 1 g per dose and / or ? 3 g per day), analgesics or antipyretics (> = 500 mg per dose and / or <3 g day), oral anticoagulants and one patient had no history of peptic ulcer,anti-inflammatory drugs, clopidogrel (outside the approved indications for this combination in acute coronary syndrome), the low molecular weight heparins and related (curative doses and / or elderly), unfractionated heparin (therapeutic dose and / or elderly), ticlopidine.

See also:
What is the most important information I should know about Atorvastatin?

Active liver disease, which may include unexplained persistent elevations in Hepatic Transaminase Levels

Hypersensitivity to any Component of this Medication

Pregnancy

Women who are pregnant or may become pregnant. Atorvastatin calcium may cause fetal harm when administered to a pregnant woman. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of Atorvastatin calcium use during pregnancy; however in rare reports, congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, Atorvastatin revealed no evidence of teratogenicity. Atorvastatin CALCIUM SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING AGE ONLY WHEN SUCH PATIENTS ARE HIGHLY UNLIKELY TO CONCEIVE AND HAVE BEEN INFORMED OF THE POTENTIAL HAZARDS. If the patient becomes pregnant while taking this drug, Atorvastatin calcium should be discontinued immediately and the patient apprised of the potential hazard to the fetus.

Nursing Mothers

It is not known whether Atorvastatin is excreted into human milk; however a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require Atorvastatin calcium treatment should not breastfeed their infants.

See also:
What is the most important information I should know about Clopidogrel?

Clopidogrel should not be used whenever stimulation of gastrointestinal motility might be dangerous, e.g., in the presence of gastrointestinal hemorrhage, mechanical obstruction, or perforation.

Clopidogrel is contraindicated in patients with pheochro-mocytoma because the drug may cause a hypertensive crisis, probably due to release of catecholamines from the tumor. Such hypertensive crises may be controlled by phen-tolamine.

Clopidogrel is contraindicated in patients with known sensitivity or intolerance to the drug.

Clopidogrel should not be used in epileptics or patients receiving other drugs which are likely to cause extrapyramidal reactions, since the frequency and severity of seizures or extrapyramidal reactions may be increased.

Use Aspirin as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Aspirin by mouth with or without food. If stomach upset occurs, take with food to reduce stomach irritation.
• Take Aspirin with a full glass of water (8 oz/240 mL). Do not lie down for 30 minutes after taking Aspirin.
• Swallow Aspirin whole. Do not break, crush, or chew before swallowing.
• Use Aspirin exactly as directed on the package, unless instructed differently by your doctor. If you are taking Aspirin without a prescription, follow any warnings and precautions on the label.
• If you miss a dose of Aspirin and you are taking it regularly, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Aspirin.

Use atorvastatin as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with atorvastatin. Talk to your pharmacist if you have questions about this information.
• Take atorvastatin by mouth with or without food.
• Swallow atorvastatin whole. Do not break, crush, or chew before swallowing.
• Taking atorvastatin at the same time each day will help you remember to take it.
• Eating grapefruit or drinking grapefruit juice may increase the amount of atorvastatin in your blood, which may increase your risk for serious side effects. The risk may be greater with large amounts of grapefruit or grapefruit juice. Avoid large amounts of grapefruit or grapefruit juice (eg, more than 1 quart daily). Talk with your doctor or pharmacist if you have questions about including grapefruit or grapefruit juice in your diet while you are taking atorvastatin.
• Continue to take atorvastatin even if you feel well. Do not miss any doses.
• If you miss a dose of atorvastatin, take it as soon as possible if you remember within 12 hours of the missed dose. If it is more than 12 hours since the missed dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use atorvastatin.

Use clopidogrel as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take clopidogrel by mouth with or without food.
• Take clopidogrel on a regular schedule to get the most benefit from it.
• Do not stop taking clopidogrel without talking to your doctor. This may increase the risk of heart problems.
• If you miss a dose of clopidogrel, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use clopidogrel.

Aspirin is used to reduce fever and relieve mild to moderate pain from conditions such as muscle aches, toothaches, common cold, and headaches. It may also be used to reduce pain and swelling in conditions such as arthritis. Aspirin is known as a salicylate and a nonsteroidal anti-inflammatory drug (NSAID). It works by blocking a certain natural substance in your body to reduce pain and swelling. Consult your doctor before giving this drug to a child younger than 12 years. It is very important to keep this and all medication out of the reach of children. Aspirin is a common cause of poisoning in children.

Your doctor may direct you to take a low dose of aspirin to prevent blood clots. This effect reduces the risk of stroke and heart attack. If you have recently had surgery on clogged arteries (such as bypass surgery, carotid endarterectomy, coronary stent), your doctor may direct you to use aspirin in low doses as a "blood thinner" to prevent blood clots. Aspirin prevents blood clots by stopping certain blood cells (platelets) from clumping together.

How to use Aspirin

If you are taking this medication for self-treatment, follow all directions on the product package. If you are uncertain about any of the information, consult your doctor or pharmacist. If your doctor has directed you to take this medication, take it exactly as prescribed.

Chew the tablet thoroughly before swallowing. This medication may also be crushed or swallowed whole. If stomach upset occurs while you are taking this medication, you may take it with food or milk.

The dosage and length of treatment are based on your medical condition and response to treatment. Read the product label to find recommendations on how many tablets you can take in a 24-hour period and how long you may self-treat before seeking medical advice. Do not take more medication or take it for longer than recommended unless directed by your doctor. Use the smallest effective dose. Consult your doctor or pharmacist if you have any questions.

If you are taking this medication for self-treatment of headache, seek immediate medical attention if you also have slurred speech, weakness on one side of the body, or sudden vision changes. Before using this drug, consult a doctor or pharmacist if you have headaches caused by head injury, coughing, or bending, or if you have a headache with persistent/severe vomiting, fever, and stiff neck. These may be signs of serious medical conditions.

If you are taking this medication as needed (not on a regular schedule), remember that pain medications work best if they are used as the first signs of pain occur. If you wait until the pain has worsened, the medicine may not work as well.

You should not take this medication for self-treatment of pain for longer than 10 days. You should not use this drug to self-treat a fever that lasts longer than 3 days. In these cases, consult a doctor because you may have a more serious condition. Tell your doctor promptly if you develop ringing in the ears or difficulty hearing.

If your condition persists or worsens (such as new or unusual symptoms, redness/swelling of the painful area, pain/fever that does not go away or gets worse) or if you think you may have a serious medical problem, tell your doctor promptly.

Use: Labeled Indications

Heterozygous familial hypercholesterolemia: To reduce elevated total cholesterol (total-C), LDL cholesterol (LDL-C), apolipoprotein B (apo B), and triglyceride levels, and to increase HDL cholesterol in patients with primary hypercholesterolemia.

Heterozygous familial hypercholesterolemia (pediatrics): To reduce total-C, LDL-C, and apo B levels in pediatric patients 10 to 17 years of age with heterozygous familial hypercholesterolemia with LDL-C ≥190 mg/dL, LDL-C ≥160 mg/dL with positive family history of premature cardiovascular disease (CVD), or LDL-C ≥160 mg/dL with 2 or more other CVD risk factors.

Homozygous familial hypercholesterolemia: To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) or if such treatments are unavailable.

Prevention of atherosclerotic cardiovascular disease:

Primary prevention of atherosclerotic cardiovascular disease (ASCVD): To reduce the risk of myocardial infarction (MI), stroke, revascularization procedures, and angina in adult patients without a history of coronary heart disease (CHD) but who have multiple CHD risk factors.

Secondary prevention in patients with established ASCVD: To reduce the risk of MI, stroke, revascularization procedures, and angina in patients with a history of CHD.

Off Label Uses

Transplantation, post heart or post kidney

Based on the 2010 International Society of Heart and Lung Transplantation guidelines for the care of heart transplant recipients, atorvastatin is effective and recommended following heart transplant, regardless of cholesterol levels, to reduce cardiac allograft vasculopathy and improve long-term outcomes.

Based on the 2013 Kidney Disease: Improving Global Outcomes clinical practice guideline for lipid management in chronic kidney disease, atorvastatin is suggested following kidney transplant to reduce cardiovascular events (eg, myocardial infarction, stroke, cardiovascular death).

Use: Labeled Indications

Acute coronary syndrome:

ST-segment elevation myocardial infarction: To reduce the rate of myocardial infarction (MI) and stroke in conjunction with Clopidogrel in patients with acute ST-elevation MI who are to be managed medically.

Non-ST-segment elevation acute coronary syndromes: To decrease the rate of MI and stroke in conjunction with Clopidogrel in patients with non-ST-segment elevation acute coronary syndromes (unstable angina/non-ST-elevation MI), including patients who are to be managed medically and those who are to be managed with coronary revascularization.

Myocardial infarction, ischemic stroke, or peripheral atherosclerotic disease: To reduce the rate of MI and stroke in patients with a history of recent MI, recent stroke, or established peripheral atherosclerotic disease.

Off Label Uses

Carotid artery atherosclerosis, symptomatic

Based on the American College of Chest Physicians guidelines for antithrombotic therapy in peripheral artery disease, clopidogrel is effective and recommended for patients with symptomatic carotid artery atherosclerosis.

Carotid artery stenting

A randomized, controlled trial with blinded end point adjudication evaluated carotid artery stenting versus carotid endarterectomy in patients with carotid artery stenosis. In this trial, Clopidogrel in combination with clopidogrel was used for patients who underwent carotid artery stenting, which suggests that this antiplatelet combination is effective.

See also:
What other drugs will affect Aspirin?

Alcohol: Do not take Aspirin 2 hours before or 1 hour after consuming alcohol. Alcohol can interfere with the controlled release properties of Aspirin.

Renin-angiotensin system (RAS) inhibitors: In patients who are elderly, volume-depleted (including those on diuretic therapy), or who have compromised renal function, coadministration of NSAIDs, including Aspirin, with RAS inhibitors may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving RAS inhibitors and Aspirin.

NSAIDs, including Aspirin may attenuate the antihypertensive effects of RAS inhibitors.

Anticoagulant and antiplatelets: Increased risk of bleeding

Anticonvulsants: Salicylate can displace protein-bound phenytoin and valproic acid, leading to a decrease in the total concentration of phenytoin and an increase in serum valproic acid levels.

Methotrexate: Salicylate can inhibit renal clearance of methotrexate, leading to bone marrow toxicity, especially in the elderly or renal impaired.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs): The concurrent use of Aspirin with other NSAIDs increases the risk of bleeding and may result in renal impairment.

Ibuprofen can interfere with the anti-platelet effect of low dose aspirin. Patients who use Aspirin and take a single dose of ibuprofen 400 mg should dose the ibuprofen at least 2-4 hours or longer after ingestion of Aspirin. Wait 8 hours after ibuprofen dosing, before giving aspirin, to avoid significant interference.

Nonselective NSAIDs may interfere with the antiplatelet effect of low-dose aspirin.

See also:
What other drugs will affect Atorvastatin?

The risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or strong CYP 3A4 inhibitors (e.g., clarithromycin, HIV protease inhibitors, and itraconazole).

Strong Inhibitors of CYP 3A4

Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of Atorvastatin with strong inhibitors of CYP 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depend on the variability of effect on CYP 3A4.

Clarithromycin

Atorvastatin AUC was significantly increased with concomitant administration of Atorvastatin 80 mg with clarithromycin (500 mg twice daily) compared to that of Atorvastatin alone. Therefore, in patients taking clarithromycin, caution should be used when the Atorvastatin dose exceeds 20 mg.

Combination of Protease Inhibitors

Atorvastatin AUC was significantly increased with concomitant administration of Atorvastatin 40 mg with ritonavir plus saquinavir (400 mg twice daily) or Atorvastatin 20 mg with lopinavir plus ritonavir (400 mg + 100 mg twice daily) compared to that of Atorvastatin alone. Therefore, in patients taking HIV protease inhibitors, caution should be used when the Atorvastatin dose exceeds 20 mg.

Itraconazole

Atorvastatin AUC was significantly increased with concomitant administration of Atorvastatin 40 mg and itraconazole 200 mg. Therefore, in patients taking itraconazole, caution should be used when the Atorvastatin dose exceeds 20 mg.

Grapefruit Juice

Contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption ( > 1.2 liters per day).

Cyclosporine

Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g., cyclosporine) can increase the bioavailability of atorvastatin. Atorvastatin AUC was significantly increased with concomitant administration of Atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day compared to that of Atorvastatin alone. In cases where co-administration of Atorvastatin with cyclosporine is necessary, the dose of Atorvastatin should not exceed 10 mg.

Rifampin or other Inducers of Cytochrome P450 3A4

Concomitant administration of Atorvastatin with inducers of cytochrome P450 3A4 (e.g., efavirenz, rifampin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, simultaneous co-administration of Atorvastatin with rifampin is recommended, as delayed administration of Atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.

Digoxin

When multiple doses of Atorvastatin and digoxin were coadministered, steady state plasma digoxin concentrations increased by approximately 20%. Patients taking digoxin should be monitored appropriately.

Oral Contraceptives

Co-administration of Atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol. These increases should be considered when selecting an oral contraceptive for a woman taking Atorvastatin.

Warfarin

Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.

See also:
What other drugs will affect Clopidogrel?

Oral Anticoagulants:

Glycoprotein IIb/IIIa Inhibitors: As a pharmacodynamic interaction between clopidogrel and glycoprotein IIb/IIIa inhibitors is possible, concomitant use should be undertaken with caution.

Acetylsalicylic Acid: Acetylsalicylic acid did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation, but clopidogrel potentiated the effect of ASA on collagen-induced platelet aggregation. However, concomitant administration of ASA 500 mg twice daily for 1 day did not significantly increase the prolongation of bleeding time induced by clopidogrel intake. As a pharmacodynamic interaction between clopidogrel and ASA is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution. However, clopidogrel and ASA have been administered together for up to 1 year.

Injectable Anticoagulants: In a clinical study conducted in healthy subjects, clopidogrel did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Co-administration of heparin had no effect on the IPA induced by clopidogrel. As a pharmacodynamic interaction between clopidogrel and heparin is possible, concomitant use should be undertaken with caution.

Thrombolytics: The safety of the concomitant administration of clopidogrel, thrombolytic agents and heparins was assessed in patients with acute MI. The incidence of clinically significant bleeding was similar to that observed when thrombolytic agents and heparins are co-administered with ASA.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): In a clinical study conducted in healthy volunteers, the concomitant administration of clopidogrel and naproxen increased occult gastrointestinal blood loss. However, due to the lack of interaction studies with other NSAIDs, it is presently unclear whether there is an increased risk of gastrointestinal bleeding with all NSAIDs. Consequently, NSAIDs including COX-2 inhibitors and clopidogrel should be co-administered with caution.

Selective Serotonin Reuptake Inhibitors (SSRIs): Since SSRIs affect platelet activation and increase the risk of bleeding, the concomitant administration of SSRIs with clopidogrel should be undertaken with caution.

Other Concomitant Therapy: Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of drugs that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. Concomitant use of strong or moderate CYP2C19 inhibitors (eg, omeprazole) should be discouraged. If a proton-pump inhibitor is to be used concomitantly with clopidogrel, consider using one with less CYP2C19 inhibitory activity eg, pantoprazole.

Proton-Pump Inhibitors (PPI): In a crossover clinical study, clopidogrel (300-mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg at the same time as clopidogrel) were administered for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 45% (day 1) and 40% (day 5) when clopidogrel and omeprazole were administered together. Mean IPA with 5 mM ADP was diminished by 39% (24 hrs) and 21% (day 5) when clopidogrel and omeprazole were administered together.

In a 2nd interaction study with omeprazole 80 mg administered 12 hrs apart from the clopidogrel standard regimen, the results were similar, indicating that administering clopidogrel and omeprazole at different times does not prevent their interaction that is likely to be driven by the inhibitory effect of omeprazole on CYP2C19.

In a 3rd interaction study with omeprazole 80 mg administered with a higher dose regimen of clopidogrel (600-mg loading dose followed by 150 mg/day), a degree of interaction was observed similar to that noted in the other omeprazole interaction studies. However, active metabolite formation and platelet aggregation were at the same level as clopidogrel administered alone at the standard dose regimen.

In a crossover clinical study, healthy subjects were administered clopidogrel (300-mg loading dose followed by 75 mg/day) alone and with pantoprazole (80 mg at the same time as clopidogrel) for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 20% (day 1) and 14% (day 5) when clopidogrel and pantoprazole were administered together. Mean IPA was diminished by 15% (24 hrs) and 11% (day 5) when clopidogrel and pantoprazole were administered together. These results indicate that clopidogrel can be administered with pantoprazole.

The CURRENT trial compared 2 dosing regimens of clopidogrel (600-mg loading dose, then 150 mg/day for 6 days followed by 75 mg/day up to 30 days vs 300-mg loading dose followed by 75 mg/day up to 30 days). A subanalysis (n=18,432) correlated PPI use (mainly omeprazole and pantoprazole) at randomization and hospital discharge and demonstrated no interaction between clopidogrel and PPI use for the primary endpoint (CV death, MI or stroke) or any secondary endpoints, including stent thrombosis.

A number of other clinical studies have been conducted with clopidogrel and other concomitant medications to investigate the potential for pharmacodynamic and pharmacokinetic interactions. No clinically significant pharmacodynamic interactions were observed when clopidogrel was co-administered with atenolol, nifedipine or both atenolol and nifedipine. Furthermore, the pharmacodynamic activity of clopidogrel was not significantly influenced by the co-administration of phenobarbital, or oestrogen.

The pharmacokinetics of digoxin or theophylline were not modified by the co-administration of clopidogrel. Antacids did not modify the extent of clopidogrel absorption.

Although the administration of clopidogrel 75 mg/day did not modify the pharmacokinetics of S-warfarin (a CYP2C9 substrate) or INR in patients receiving long-term warfarin therapy, co-administration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on hemostasis. However, at high concentrations in vitro, clopidogrel inhibits CYP2C9. It is unlikely that clopidogrel may interfere with the metabolism of drugs eg, phenytoin and tolbutamide and the NSAIDs, which are metabolised by cytochrome P-450 2C9. Data from the CAPRIE study indicate that phenytoin and tolbutamide can be safely co-administered with clopidogrel.

Apart from the specific drug interaction information described previously, interaction studies with clopidogrel and some drugs commonly administered in patients with atherothrombotic disease have not been performed. However, patients entered into clinical trials with clopidogrel received a variety of concomitant medications including diuretics, β-blockers, ACE inhibitors, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents, hormone replacement therapy and GP IIb/IIIa antagonists without evidence of clinically significant adverse interactions.

Incompatibilities: Not applicable.

See also:
What are the possible side effects of Aspirin?

Adverse Reactions

As with all drugs which may affect hemostasis, bleeding is associated with aspirin. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables including dosage, concurrent use of multiple agents which alter hemostasis, and patient susceptibility. Many adverse effects of aspirin are dose related, and are rare at low dosages. Other serious reactions are idiosyncratic, related to allergy or individual sensitivity. Accurate estimation of frequencies is not possible. The reactions listed below have been reported for aspirin.

Cardiovascular: Cardiac arrhythmia, edema, hypotension, tachycardia

Central nervous system: Agitation, cerebral edema, coma, confusion, dizziness, fatigue, headache, hyperthermia, insomnia, lethargy, nervousness, Reye's syndrome

Dermatologic: Skin rash, urticaria

Endocrine & metabolic: Acidosis, dehydration, hyperglycemia, hyperkalemia, hypernatremia (buffered forms), hypoglycemia (children)

Gastrointestinal: Gastrointestinal ulcer (6% to 31%), duodenal ulcer, dyspepsia, epigastric distress, gastritis, gastrointestinal erosion, heartburn, nausea, stomach pain, vomiting

Genitourinary: Postpartum hemorrhage, prolonged gestation, prolonged labor, proteinuria, stillborn infant

Hematologic & oncologic: Anemia, blood coagulation disorder, disseminated intravascular coagulation, hemolytic anemia, hemorrhage, iron deficiency anemia, prolonged prothrombin time, thrombocytopenia

Hepatic: Hepatitis (reversible), hepatotoxicity, increased serum transaminases

Hypersensitivity: Anaphylaxis, angioedema

Neuromuscular & skeletal: Acetabular bone destruction, rhabdomyolysis, weakness

Otic: Hearing loss, tinnitus

Renal: Increased blood urea nitrogen, increased serum creatinine, interstitial nephritis, renal failure (including cases caused by rhabdomyolysis), renal insufficiency, renal papillary necrosis

Respiratory: Asthma, bronchospasm, dyspnea, hyperventilation, laryngeal edema, noncardiogenic pulmonary edema, respiratory alkalosis, tachypnea

Miscellaneous: Low birth weight

Postmarketing and/or case reports: Anorectal stenosis (suppository), atrial fibrillation (toxicity), cardiac conduction disturbance (toxicity), cerebral infarction (ischemic), cholestatic jaundice, colitis, colonic ulceration, coronary artery vasospasm, delirium, esophageal obstruction, esophagitis (with esophageal ulcer), hematoma (esophageal), macular degeneration (age-related) (Li 2015), periorbital edema, rhinosinusitis

See also:
What are the possible side effects of Atorvastatin?

The following serious adverse reactions are discussed in greater detail in other sections of the label:

Rhabdomyolysis and myopathy

Liver enzyme abnormalities

Clinical Trial Adverse Experiences

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

In the Atorvastatin placebo-controlled clinical trial database of 16,066 patients (8755 Atorvastatin vs. 7311 placebo; age range 10–93 years, 39% women, 91% Caucasians, 3% Blacks, 2% Asians, 4% other) with a median treatment duration of 53 weeks, 9.7% of patients on Atorvastatin and 9.5% of the patients on placebo discontinued due to adverse reactions regardless of causality. The five most common adverse reactions in patients treated with Atorvastatin that led to treatment discontinuation and occurred at a rate greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), alanine aminotransferase increase (0.4%), and hepatic enzyme increase (0.4%).

The most commonly reported adverse reactions (incidence ≥ 2% and greater than placebo) regardless of causality, in patients treated with Atorvastatin in placebo controlled trials (n=8755) were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), pain in extremity (6.0%), and urinary tract infection (5.7%).

Table 2 summarizes the frequency of clinical adverse reactions, regardless of causality, reported in ≥ 2% and at a rate greater than placebo in patients treated with Atorvastatin (n=8755), from seventeen placebo-controlled trials.

Other adverse reactions reported in placebo-controlled studies include:

Body as a whole: malaise, pyrexia; Digestive system: abdominal discomfort, eructation, flatulence, hepatitis, cholestasis; Musculoskeletal system: musculoskeletal pain, muscle fatigue, neck pain, joint swelling; Metabolic and nutritional system: transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creatine phosphokinase increase, hyperglycemia; Nervous system: nightmare; Respiratory system: epistaxis; Skin and appendages: urticaria; Special senses: vision blurred, tinnitus; Urogenital system: white blood cells urine positive.

Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

In ASCOT involving 10,305 participants (age range 40–80 years, 19% women; 94.6% Caucasians, 2.6% Africans, 1.5% South Asians, 1.3% mixed/other) treated with Atorvastatin 10 mg daily (n=5,168) or placebo (n=5,137), the safety and tolerability profile of the group treated with Atorvastatin was comparable to that of the group treated with placebo during a median of 3.3 years of follow-up.

Collaborative Atorvastatin Diabetes Study (CARDS)

In CARDS involving 2,838 subjects (age range 39–77 years, 32% women; 94.3% Caucasians, 2.4% South Asians, 2.3% Afro-Caribbean, 1.0% other) with type 2 diabetes treated with Atorvastatin 10 mg daily (n=1,428) or placebo (n=1,410), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between the treatment groups during a median follow-up of 3.9 years. No cases of rhabdomyolysis were reported.

Treating to New Targets Study (TNT)

In TNT involving 10,001 subjects (age range 29–78 years, 19% women; 94.1% Caucasians, 2.9% Blacks, 1.0% Asians, 2.0% other) with clinically evident CHD treated with Atorvastatin 10 mg daily (n=5006) or Atorvastatin 80 mg daily (n=4995), there were more serious adverse reactions and discontinuations due to adverse reactions in the high-dose atorvastatin group (92, 1.8%; 497, 9.9%, respectively) as compared to the low-dose group (69, 1.4%; 404, 8.1%, respectively) during a median follow-up of 4.9 years. Persistent transaminase elevations (≥3 × ULN twice within 4–10 days) occurred in 62 (1.3%) individuals with atorvastatin 80 mg and in nine (0.2%) individuals with atorvastatin 10 mg. Elevations of CK (≥ 10 × ULN) were low overall, but were higher in the high-dose atorvastatin treatment group (13, 0.3%) compared to the low-dose atorvastatin group (6, 0.1%).

Incremental Decrease in Endpoints through Aggressive Lipid Lowering Study (IDEAL)

In IDEAL involving 8,888 subjects (age range 26–80 years, 19% women; 99.3% Caucasians, 0.4% Asians, 0.3% Blacks, 0.04% other) treated with Atorvastatin 80 mg/day (n=4439) or simvastatin 20–40 mg daily (n=4449), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between the treatment groups during a median follow-up of 4.8 years.

Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)

In SPARCL involving 4731 subjects (age range 21–92 years, 40% women; 93.3% Caucasians, 3.0% Blacks, 0.6% Asians, 3.1% other) without clinically evident CHD but with a stroke or transient ischemic attack (TIA) within the previous 6 months treated with Atorvastatin 80 mg (n=2365) or placebo (n=2366) for a median follow-up of 4.9 years, there was a higher incidence of persistent hepatic transaminase elevations (≥ 3 × ULN twice within 4–10 days) in the atorvastatin group (0.9%) compared to placebo (0.1%). Elevations of CK (>10 × ULN) were rare, but were higher in the atorvastatin group (0.1%) compared to placebo (0.0%). Diabetes was reported as an adverse reaction in 144 subjects (6.1%) in the atorvastatin group and 89 subjects (3.8%) in the placebo group.

In a post-hoc analysis, Atorvastatin 80 mg reduced the incidence of ischemic stroke (218/2365, 9.2% vs. 274/2366, 11.6%) and increased the incidence of hemorrhagic stroke (55/2365, 2.3% vs. 33/2366, 1.4%) compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17 Atorvastatin vs. 18 placebo). The incidence of non-fatal hemorrhagic strokes was significantly greater in the atorvastatin group (38 non-fatal hemorrhagic strokes) as compared to the placebo group (16 non-fatal hemorrhagic strokes). Subjects who entered the study with a hemorrhagic stroke appeared to be at increased risk for hemorrhagic stroke [7 (16%) Atorvastatin vs. 2 (4%) placebo].

There were no significant differences between the treatment groups for all-cause mortality: 216 (9.1%) in the Atorvastatin 80 mg/day group vs. 211 (8.9%) in the placebo group. The proportions of subjects who experienced cardiovascular death were numerically smaller in the Atorvastatin 80 mg group (3.3%) than in the placebo group (4.1%). The proportions of subjects who experienced non-cardiovascular death were numerically larger in the Atorvastatin 80 mg group (5.0%) than in the placebo group (4.0%).

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Atorvastatin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions associated with Atorvastatin therapy reported since market introduction, that are not listed above, regardless of causality assessment, include the following: anaphylaxis, angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), rhabdomyolysis, myositis, fatigue, tendon rupture, fatal and non-fatal hepatic failure, dizziness, depression, peripheral neuropathy, and pancreatitis.

There have been rare reports of immune-mediated necrotizing myopathy associated with statin use.

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

Pediatric Patients (ages 10–17 years)

In a 26-week controlled study in boys and postmenarchal girls (n=140, 31% female; 92% Caucasians, 1.6% Blacks, 1.6% Asians, 4.8% other), the safety and tolerability profile of Atorvastatin 10 to 20 mg daily was generally similar to that of placebo.

See also:
What are the possible side effects of Clopidogrel?

Clopidogrel has been evaluated for safety in more than 44,000 patients who have participated in clinical studies, including >12,000 patients treated for ≥1 year. Overall, clopidogrel 75 mg/day was comparable to ASA 325 mg/day in CAPRIE regardless of age, gender and race. The clinically relevant adverse reactions observed in the CAPRIE, CURE, CLARITY, COMMIT and ACTIVE-A studies are discussed as follows. In addition to clinical studies experience, adverse reactions have been spontaneously reported.

Bleeding is the most common reaction reported both in clinical studies as well as in post-marketing experience where it was mostly reported during the 1st month of treatment.

In CAPRIE, in patients treated with either clopidogrel or ASA, the overall incidence of any bleeding was 9.3%. The incidence of severe cases was similar for clopidogrel and ASA.

In CURE, there was no excess in major bleeds with clopidogrel + ASA within 7 days after coronary bypass graft surgery in patients who stopped therapy >5 days prior to surgery. In patients who remained on therapy within 5 days of bypass graft surgery, the event rate was 9.6% for clopidogrel + ASA, and 6.3% for placebo + ASA.

In CLARITY, there was an overall increase in bleeding in the clopidogrel + ASA group versus the placebo + ASA group. The incidence of major bleeding was similar between groups. This was consistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytic or heparin therapy.

In COMMIT, the overall rate of noncerebral major bleeding or cerebral bleeding was low and similar in both groups.

In ACTIVE-A, the rate of major bleeding was greater in the clopidogrel + ASA group than in the placebo + ASA group (6.7% vs 4.3%). Major bleeding was mostly of extracranial origin in both groups (5.3% in the clopidogrel + ASA group; 3.5% in the placebo + ASA group), mainly from the gastrointestinal tract (3.5% vs 1.8%). There was an excess of intracranial bleeding in the clopidogrel + ASA treatment group compared to the placebo + ASA group (1.4% vs 0.8%, respectively). There was no statistically significant difference in the rates of fatal bleeding (1.1% in the clopidogrel + ASA group and 0.7% in the placebo + ASA group) and haemorrhagic stroke (0.8% and 0.6%, respectively) between groups.

Adverse reactions that occurred either during clinical studies or that were spontaneously reported are presented in Table 2. Their frequency is defined using the following conventions: Common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000). Within each system organ class, adverse reactions are presented in order of decreasing seriousness.

The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. (From Martindale, The Extra Pharmacopoeia, 30th ed, p5)

Atorvastatin 10: Each tablet contains atorvastatin calcium equivalent to 10 mg atorvastatin.

Atorvastatin 20 mg: Each tablet contains atorvastatin calcium equivalent to 20 mg atorvastatin.

Atorvastatin 40 mg: Each tablet contains atorvastatin calcium equivalent to 40 mg atorvastatin.

Atorvastatin 80 mg: Each tablet contains atorvastin calcium equivalent to 80 mg atorvastatin.

Atorvastatin is a white, elliptical film coated tablet containing atorvastatin calcium. Atorvastatin calcium is a synthetic lipid-lowering agent, which is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis.

The empirical formula of atorvastatin calcium is (C₃₃H₃₄FN₂O₅)₂Ca·3H₂O and its molecular weight is 1209.42.

Atorvastatin calcium is a white to off-white crystalline powder, practically insoluble in aqueous solutions of pH 4 and below. It is very slightly soluble in distilled water, pH 7.4 phosphate buffer, and acetonitrile; slightly soluble in ethanol; and freely soluble in methanol.

Each film-coated tablet contains clopidogrel hydrogen sulphate 97.875 mg (molar equivalent of clopidogrel base 75 mg) or clopidogrel hydrogen sulphate 391.5 mg (molar equivalent of clopidogrel base 300 mg).

Clopidogrel also contains the following excipients: Hydrogenated castor oil, hydroxypropyl cellulose, mannitol E421, microcrystalline cellulose and polyethylene glycol 6000 as inactive ingredient. The pink film coating contains ferric oxide E172, hypromellose 2910, lactose, titanium dioxide and triacetin. The tablets are polished with carnauba wax.

Clopidogrel hydrogen sulfate is methyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulfate (1:1). It has an empirical formula of C₁₆H₁₆CINO₂S·H₂SO₄ and a molecular weight of 419.9.

Clopidogrel hydrogen sulfate is an inhibitor of ADP-induced platelet aggregation acting by direct inhibition of adenosine diphosphate (ADP) binding to its receptor and of the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex.

Clopidogrel hydrogen sulfate is a white to off-white powder. It is practically insoluble in water at neutral pH but freely soluble at pH 1. It also dissolves freely in methanol, dissolves slightly in methylene chloride, and is practically insoluble in ethyl ether. It has a specific optical rotation of about +56°.