What are the key differences between Atorvastatin and Lipitor. How do these medications work to lower cholesterol levels. What are the potential side effects and drug interactions to be aware of. Who should consider taking these medications and what precautions should be taken.

Understanding Atorvastatin and Lipitor: An Overview

Atorvastatin and Lipitor are essentially the same medication, with Lipitor being the brand name version and atorvastatin the generic form. Both are part of a class of drugs known as statins, which are prescribed to lower cholesterol levels in the blood. These medications work by blocking an enzyme in the liver responsible for producing cholesterol, thereby reducing the amount of LDL (“bad”) cholesterol and triglycerides in the bloodstream while potentially increasing HDL (“good”) cholesterol levels.

Are atorvastatin and Lipitor interchangeable? In most cases, yes. The active ingredient in both medications is identical, and they are equally effective in treating high cholesterol. The main difference lies in their cost, with generic atorvastatin typically being more affordable than brand-name Lipitor.

Indications and Uses of Atorvastatin/Lipitor

Atorvastatin and Lipitor are primarily prescribed to manage high cholesterol levels, particularly in cases where lifestyle changes alone haven’t been sufficient. Their uses extend beyond simply lowering cholesterol, however. These medications can also:

• Reduce the risk of heart attack and stroke in patients with heart disease or risk factors such as age, smoking, high blood pressure, low HDL-C, or family history of heart disease
• Lower the risk of certain types of heart surgery
• Decrease the likelihood of chest pain in patients with heart disease
• Reduce the risk of heart attack or stroke in patients with diabetes and additional risk factors

Can atorvastatin/Lipitor be used preventatively? While primarily used to treat existing high cholesterol, these medications may be prescribed as a preventive measure for individuals at high risk of cardiovascular events, even if their cholesterol levels are not significantly elevated.

Dosage and Administration Guidelines

The appropriate dosage of atorvastatin or Lipitor varies depending on individual factors such as the patient’s cholesterol levels, medical history, and risk factors. Typically, the starting dose is 10 or 20 mg once daily, which can be adjusted by a healthcare provider based on the patient’s response to treatment.

Key Dosage Information:

• Dosages range from 10 mg to 80 mg daily
• The medication should be taken at the same time each day
• It can be taken with or without food
• Patients should not adjust their dosage without consulting their healthcare provider

How long does it take for atorvastatin/Lipitor to work? While some improvement in cholesterol levels may be seen within 2 weeks, it typically takes about 4 weeks to see the full effect of the medication.

Potential Side Effects and Risks

Like all medications, atorvastatin and Lipitor can cause side effects. While many people tolerate these drugs well, it’s important to be aware of potential adverse reactions.

Common Side Effects:

• Diarrhea
• Upset stomach
• Muscle and joint pain
• Changes in some blood test results

Serious Side Effects:

• Muscle problems (myopathy) that can lead to kidney issues
• Liver problems
• Elevated blood sugar levels

What should patients do if they experience side effects? If side effects are bothersome or persistent, patients should consult their healthcare provider. In case of severe muscle pain or weakness, or symptoms of liver problems (such as fatigue, loss of appetite, upper belly pain, dark urine, or jaundice), medical attention should be sought immediately.

Drug Interactions and Precautions

Atorvastatin and Lipitor can interact with various medications and substances, potentially affecting their efficacy or increasing the risk of side effects. It’s crucial for patients to inform their healthcare providers about all medications, supplements, and herbal products they are taking.

Notable Interactions:

• Other cholesterol-lowering medications
• Certain antibiotics
• Some antifungal medications
• HIV protease inhibitors
• Cyclosporine
• Grapefruit juice

Why is grapefruit juice a concern? Grapefruit juice can increase the concentration of atorvastatin in the blood, potentially leading to an increased risk of side effects. Patients taking these medications should avoid consuming large quantities of grapefruit or grapefruit juice.

Special Considerations for Specific Populations

While atorvastatin and Lipitor are widely prescribed, certain groups require special consideration when using these medications.

Pregnancy and Breastfeeding:

The FDA has recently revised its recommendations regarding statin use during pregnancy. While previously contraindicated for all pregnant women, the current guidance allows for more individualized decision-making, particularly for high-risk patients. However, in most cases, statin therapy should be discontinued during pregnancy and breastfeeding.

Elderly Patients:

Older adults may be more susceptible to certain side effects and may require closer monitoring when taking atorvastatin or Lipitor.

Patients with Liver Disease:

These medications are not recommended for individuals with active liver disease. Liver function tests should be performed before starting treatment and as clinically indicated thereafter.

How do these considerations impact treatment decisions? Healthcare providers must weigh the potential benefits and risks for each individual patient, taking into account their overall health status, risk factors, and specific circumstances.

Monitoring and Follow-up Care

Regular monitoring is essential for patients taking atorvastatin or Lipitor to ensure the medication is effective and to detect any potential side effects or complications.

Recommended Monitoring:

• Lipid profile tests to assess cholesterol levels
• Liver function tests
• Blood glucose levels, particularly in patients with or at risk for diabetes
• Creatine kinase levels if muscle symptoms develop

How often should patients have follow-up appointments? Initially, follow-up may be more frequent, typically every 4-12 weeks. Once the patient’s response to the medication is established, appointments may be scheduled less frequently, usually every 3-12 months, depending on individual circumstances.

Lifestyle Modifications to Complement Medication

While atorvastatin and Lipitor are effective in managing cholesterol levels, they work best when combined with healthy lifestyle choices. Patients are encouraged to adopt heart-healthy habits to maximize the benefits of their medication and improve overall cardiovascular health.

Recommended Lifestyle Changes:

• Following a balanced, low-fat diet rich in fruits, vegetables, and whole grains
• Engaging in regular physical activity
• Maintaining a healthy weight
• Quitting smoking
• Limiting alcohol consumption

Can lifestyle changes reduce the need for medication? In some cases, adopting healthy lifestyle habits may allow patients to lower their medication dosage or even discontinue use, under the guidance of their healthcare provider. However, for many individuals, particularly those at high risk of cardiovascular events, medication remains an important part of their treatment plan.

Atorvastatin and Lipitor have revolutionized the treatment of high cholesterol and the prevention of cardiovascular events. While these medications are generally well-tolerated and effective, they require careful consideration and monitoring. Patients should work closely with their healthcare providers to determine the most appropriate treatment plan, taking into account their individual risk factors, medical history, and lifestyle. By combining medication with heart-healthy habits, patients can significantly improve their cardiovascular health and reduce their risk of serious complications.

Cholesterol Treatment | LIPITOR® (atorvastatin calcium)

LIPITOR tablets are not for everyone, including anyone who has previously had an allergic reaction to LIPITOR. It is not for those with liver problems. And it is not for women who are nursing, pregnant, or may become pregnant. If you get pregnant, stop taking LIPITOR and call your doctor right away.

If you take LIPITOR tablets, tell your doctor if you feel any new muscle pain or weakness. This could be a sign of rare but serious muscle problems that can lead to kidney problems, including kidney failure.

Tell your doctor about all your medical conditions and all medications you take. This may help avoid serious drug interactions. Your doctor should do blood tests to check your liver function before starting LIPITOR and during your treatment if you have symptoms of liver problems. Call your doctor right away if you have the following symptoms of liver problems – feel tired or weak or have a loss of appetite, upper belly pain, dark amber colored urine, or yellowing of your skin or the whites of your eyes.

Tell your doctor if you have diabetes. Elevated blood sugar levels have been reported with statins, including LIPITOR.

Common side effects are diarrhea, upset stomach, muscle and joint pain, and changes in some blood tests.

Talk to your healthcare provider if you have side effects that bother you or that will not go away.

INDICATIONS

LIPITOR is a prescription medicine that lowers cholesterol in the blood. It lowers the LDL-C (“bad” cholesterol) and triglycerides in your blood. It can raise your HDL-C (“good” cholesterol) as well. LIPITOR is for adults and children over 10 whose cholesterol does not come down enough with exercise and a low-fat diet alone.

LIPITOR can lower the risk for heart attack, stroke, certain types of heart surgery, and chest pain in patients who have heart disease or risk factors for heart disease such as age, smoking, high blood pressure, low HDL-C, or heart disease in the family. LIPITOR can lower the risk for heart attack or stroke in patients with diabetes and risk factors such as eye problems, kidney problems, smoking, or high blood pressure.

Limitations of Use: LIPITOR has not been studied in people who have an increase of chylomicrons (Fredrickson Types I and V).

Please see Full Prescribing Information and Patient Information.

Atorvastatin: MedlinePlus Drug Information

[Posted 07/20/2021]

AUDIENCE: Patient, Health Professional, OBGYN, Cardiology, Endocrinology, Pharmacy

ISSUE: The FDA is requesting revisions to the information about use in pregnancy in the prescribing information of the entire class of statin medicines. These changes include removing the contraindication against using these medicines in all pregnant patients. A contraindication is FDA’s strongest warning and is only added when a medicine should not be used because the risk clearly outweighs any possible benefit. Because the benefits of statins may include prevention of serious or potentially fatal events in a small group of very high-risk pregnant patients, contraindicating these drugs in all pregnant women is not appropriate.

FDA expects removing the contraindication will enable health care professionals and patients to make individual decisions about benefit and risk, especially for those at very high risk of heart attack or stroke. This includes patients with homozygous familial hypercholesterolemia and those who have previously had a heart attack or stroke.

BACKGROUND: Statins are a class of prescription medicines that have been used for decades to lower low-density lipoprotein (LDL-C or “bad”) cholesterol in the blood. Medicines in the statin class include atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

RECOMMENDATIONS:

• Patients: Patients taking statins should notify their health care professionals if they become pregnant or suspect they are pregnant. Your health care professional will be able to advise whether you should stop taking the medicine during pregnancy and whether you may stop your statin temporarily while breastfeeding. Patients who are at high risk of heart attack or stroke who require statins after giving birth should not breastfeed and should use alternatives such as infant formula.
• Health Care Professionals: Health care professionals should discontinue statin therapy in most pregnant patients, or they can consider the ongoing therapeutic needs of the individual patient, particularly those at very high risk for cardiovascular events during pregnancy. Because of the chronic nature of cardiovascular disease, treatment of hyperlipidemia is not generally necessary during pregnancy. Discuss with patients whether they may discontinue statins temporarily while breastfeeding. Advise those who require a statin because of their cardiovascular risk that breastfeeding is not recommended because the medicine may pass into breast milk

The FDA hopes the revised language in the prescribing information will help reassure health care professionals that statins are safe to prescribe in patients who can become pregnant, and help them reassure patients with unintended statin exposure in early pregnancy or before pregnancy is recognized that the medicine is unlikely to harm the unborn baby.

For more information visit the FDA website at: http://www.fda.gov/Safety/MedWatch/SafetyInformation and http://www.fda.gov/Drugs/DrugSafety.

Statin side effects: Weigh the benefits and risks

Statin side effects: Weigh the benefits and risks

Statins are effective at lowering cholesterol and protecting against a heart attack and stroke, although they may lead to side effects for some people.

By Mayo Clinic Staff

Doctors often prescribe statins for people with high cholesterol to lower their total cholesterol and reduce their risk of a heart attack or stroke. While statins are highly effective and safe for most people, they have been linked to muscle pain, digestive problems and mental fuzziness in some people who take them and may rarely cause liver damage.

Statins include atorvastatin (Lipitor), fluvastatin (Lescol XL), lovastatin (Altoprev), pitavastatin (Livalo), pravastatin (Pravachol), rosuvastatin (Crestor, Ezallor) and simvastatin (Zocor, FloLipid).

Having too much cholesterol in your blood increases your risk of heart attacks and strokes. Statins block a substance your liver needs to make cholesterol. This causes your liver to remove cholesterol from your blood.

If you think you’re experiencing side effects from statins, don’t just stop taking the pills. Talk to your doctor to see if a change of dosage or even a different type of medication might be helpful.

What are statin side effects?

Muscle pain and damage

One of the most common complaints of people taking statins is muscle pain. You may feel this pain as a soreness, tiredness or weakness in your muscles. The pain can be a mild discomfort, or it can be severe enough to make your daily activities difficult.

However, researchers have found a “nocebo” effect when it comes to perceived muscle pain and statins. A “nocebo” effect means people who have negative expectations about a medication report experiencing the potential side effect at higher rates than the drug should cause.

The actual risk of developing muscle pain as a result of taking statins is about 5 percent or less compared with taking a pill that doesn’t contain medication (placebo). However, studies have found that nearly 30 percent of people stopped taking the pills because of muscle aches even when they were taking a placebo.

A strong predictor you’ll experience muscle aches when taking statins could be whether or not you read about the potential side effect.

Very rarely, statins can cause life-threatening muscle damage called rhabdomyolysis (rab-doe-my-OL-ih-sis). Rhabdomyolysis can cause severe muscle pain, liver damage, kidney failure and death. The risk of very serious side effects is extremely low, and calculated in a few cases per million people taking statins. Rhabdomyolysis can occur when you take statins in combination with certain drugs or if you take a high dose of statins.

Liver damage

Occasionally, statin use could cause an increase in the level of enzymes that signal liver inflammation. If the increase is only mild, you can continue to take the drug. Rarely, if the increase is severe, you may need to try a different statin.

Although liver problems are rare, your doctor may order a liver enzyme test before or shortly after you begin to take a statin. You wouldn’t need any additional liver enzyme tests unless you begin to have signs or symptoms of trouble with your liver.

Contact your doctor immediately if you have unusual fatigue or weakness, loss of appetite, pain in your upper abdomen, dark-colored urine, or yellowing of your skin or eyes.

Increased blood sugar or type 2 diabetes

It’s possible your blood sugar (blood glucose) level may increase when you take a statin, which may lead to developing type 2 diabetes. The risk is small but important enough that the Food and Drug Administration (FDA) has issued a warning on statin labels regarding blood glucose levels and diabetes.

The increase generally occurs when blood sugar levels are already higher than normal and fall in the prediabetes or diabetes range when you begin taking a statin.

Statins prevent heart attacks in people with diabetes, so the relevance of the mild increase in sugar values with statins observed in some people is unclear. The benefit of taking statins likely outweighs the small risk to have the blood sugar level go up. Talk to your doctor if you have concerns.

Neurological side effects

The FDA warns on statin labels that some people have developed memory loss or confusion while taking statins. These side effects reverse once you stop taking the medication. There is limited evidence to prove a cause-effect relationship, but talk to your doctor if you experience memory loss or confusion while taking statins.

There has also been evidence that statins may help with brain function — in people with dementia, for example. This is still being studied. Don’t stop taking your statin medication before talking to your doctor.

Who’s at risk of developing statin side effects?

Not everyone who takes a statin will have side effects, but some people may be at a greater risk than are others. Risk factors include:

• Taking multiple medications to lower your cholesterol
• Being female
• Having a smaller body frame
• Being age 80 or older
• Having kidney or liver disease
• Drinking too much alcohol
• Having certain conditions such as hypothyroidism or neuromuscular disorders including amyotrophic lateral sclerosis (ALS)

Drugs and food that interact with statins

Grapefruit juice contains a chemical that can interfere with the enzymes that break down (metabolize) the statins in your digestive system. While you won’t need to eliminate grapefruit entirely from your diet, ask your doctor about how much grapefruit you can have.

Some drugs that may interact with statins and increase your risk of side effects include:

• Amiodarone (Cordarone, Pacerone), a medication for irregular heart rhythms
• Gemfibrozil (Lopid), another variety of cholesterol drug
• HIV treatments called protease inhibitors such as saquinavir (Invirase) and ritonavir (Norvir)
• Some antibiotic and antifungal medications, such as clarithromycin and itraconazole (Onmel, Sporanox)
• Some immunosuppressant medications, such as cyclosporine (Gengraf, Neoral, Sandimmune)

There are many drugs that may interact with statins, so be sure your doctor is aware of all the medicines you take when being prescribed with statins.

How to relieve statin side effects

To relieve side effects believed to be caused by statins, your doctor may recommend several options. Discuss these steps with your doctor before trying them:

• Take a brief break from statin therapy. Sometimes it’s hard to tell whether the muscle aches or other problems you’re having are statin side effects or just part of the aging process. Taking a break can help you determine whether your aches and pains are due to statins instead of something else.
• Switch to another statin drug. It’s possible, although unlikely, that one particular statin may cause side effects for you while another statin won’t. It’s thought that simvastatin (Zocor) may be more likely to cause muscle pain as a side effect than other statins when it’s taken at high doses.
• Change your dose. Lowering your dose may reduce some of your side effects, but it may also reduce some of the cholesterol-lowering benefits your medication has. Another option is to take the medication every other day, especially if you take a statin that stays in the blood for several days. Talk to your doctor to determine if this is appropriate for you.
• Take it easy when exercising. Unaccustomed vigorous exercise might increase the risk of muscle injury. It’s best to make changes in your exercise routine more gradually. Exercise causes muscle pain too, so it is sometimes difficult to know if the pain comes from the statin or the exercise in someone who just started an exercise program.
• Consider other cholesterol-lowering medications. Although statins are the most effective oral medications for lowering your cholesterol, other types of drugs also are available. Sometimes, taking a combination of cholesterol drugs can provide the same result with lower doses of statins.
• Try coenzyme Q10 supplements. Coenzyme Q10 supplements may help prevent statin side effects in some people, though more studies are needed to determine any benefits of taking it. Talk to your doctor first to make sure the supplement won’t interact with any of your other medications.

Weigh the risks and benefits

Although side effects believed to be caused by statins can be annoying, consider the benefits of taking a statin before you decide to stop taking your medication. Remember that statin medications can reduce your risk of a heart attack or stroke, and the risk of life-threatening side effects from statins is very low.

If you have read about the potential side effects of statins, you may be more likely to blame your symptoms on the medication, whether or not they’re truly caused by the drug.

Even if your side effects are frustrating, don’t stop taking your statin medication for any period of time without talking to your doctor first. Your doctor may be able to come up with an alternative treatment plan that can help you lower your cholesterol without uncomfortable side effects.

Jan. 14, 2020

Show references

1. Controlling cholesterol with statins. Food and Drug Administration. https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm293330.htm. Accessed Jan. 24, 2019.
2. Rosenson RS. Statins: Actions, side effects and administration. https://www.uptodate.com/contents/search. Accessed Jan. 24, 2019.
3. Rosenson RS, et al. Statin muscle-related adverse events. https://www.uptodate.com/contents/search. Accessed Jan. 25, 2019.
4. Ferri FF. Statin-induced muscle syndromes. In: Ferri’s Clinical Advisor 2019. Philadelphia, Pa.: Elsevier; 2019. https://www.clinicalkey.com. Accessed Jan. 24, 2019.
5. Adhyaru BB, et al. Safety and efficacy of statin therapy. Nature Reviews Cardiology. 2018;12:757.
6. Alonso R, et al. Diagnosis and management of statin intolerance. Journal of Atherosclerosis and Thrombosis. 2019;26:e000.
7. Mach F, et al. Adverse effects of statin therapy: Perception vs. the evidence — focus on glucose homeostasis, cognitive, renal and hepatic function, haemorrhagic stroke and cataract. European Heart Journal. 2018;39:2526.
8. About cholesterol. American Heart Association. http://www.heart.org/HEARTORG/Conditions/Cholesterol/AboutCholesterol/About-Cholesterol_UCM_001220_Article.jsp#.VpbEathIiic. Accessed Jan. 29, 2019.
9. AskMayoExpert. Statin intolerance. Rochester, Minn.: Mayo Foundation for Medical Education and Research; 2018.
10. Anyanwagu U, et al. Drug-induced diabetes mellitus: Evidence for statins and other drugs affecting glucose metabolism. Clinical Pharmacology and Therapeutics.2016;99:390.
11. Lopez-Jimenez F (expert opinion). Mayo Clinic, Rochester, Minn. March 18, 2019.

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Comparative Effectiveness of Generic Atorvastatin and Lipitor® in Patients Hospitalized with an Acute Coronary Syndrome

J Am Heart Assoc. 2016 Apr; 5(4): e003350.

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²Institute for Clinical Evaluative Sciences, Toronto Ontario, Canada

³Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA

⁴Institute of Health Policy, Management and Evaluation, Faculty of Medicine, University of Toronto Ontario, Canada

⁶University Health Network, Toronto, Ontario, Canada

Jack V.

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²Institute for Clinical Evaluative Sciences, Toronto Ontario, Canada

⁴Institute of Health Policy, Management and Evaluation, Faculty of Medicine, University of Toronto Ontario, Canada

⁵Division of Cardiology, Schulich Heart Center, Sunnybrook Health Sciences Center, University of Toronto Ontario, Canada

Harlan M. Krumholz

⁷Section of Cardiovascular Medicine, Department of Medicine, Yale University, New Haven, CT

⁸Yale University School of Medicine, Center for Outcomes Research and Evaluation, Yale New Haven Hospital, New Haven, CT

⁹Section of Health Policy and Administration, Department of Epidemiology and Public Health, Yale University, New Haven, CT

¹⁰Robert Wood Johnson Clinical Scholars Program, New Haven, CT

Peter C. Austin

²Institute for Clinical Evaluative Sciences, Toronto Ontario, Canada

⁴Institute of Health Policy, Management and Evaluation, Faculty of Medicine, University of Toronto Ontario, Canada

Joseph S.

Ross

⁸Yale University School of Medicine, Center for Outcomes Research and Evaluation, Yale New Haven Hospital, New Haven, CT

¹¹Section of General Internal Medicine, Department of Medicine, Yale University, New Haven, CT

Therese A. Stukel

²Institute for Clinical Evaluative Sciences, Toronto Ontario, Canada

⁴Institute of Health Policy, Management and Evaluation, Faculty of Medicine, University of Toronto Ontario, Canada

Maria Koh

²Institute for Clinical Evaluative Sciences, Toronto Ontario, Canada

Alice Chong

²Institute for Clinical Evaluative Sciences, Toronto Ontario, Canada

Dennis T. Ko

²Institute for Clinical Evaluative Sciences, Toronto Ontario, Canada

⁴Institute of Health Policy, Management and Evaluation, Faculty of Medicine, University of Toronto Ontario, Canada

⁵Division of Cardiology, Schulich Heart Center, Sunnybrook Health Sciences Center, University of Toronto Ontario, Canada

¹Department of Pharmacy Practice and Administration, College of Pharmacy, Western University of Health Sciences, Pomona, CA

²Institute for Clinical Evaluative Sciences, Toronto Ontario, Canada

³Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA

⁴Institute of Health Policy, Management and Evaluation, Faculty of Medicine, University of Toronto Ontario, Canada

⁵Division of Cardiology, Schulich Heart Center, Sunnybrook Health Sciences Center, University of Toronto Ontario, Canada

⁶University Health Network, Toronto, Ontario, Canada

⁷Section of Cardiovascular Medicine, Department of Medicine, Yale University, New Haven, CT

⁸Yale University School of Medicine, Center for Outcomes Research and Evaluation, Yale New Haven Hospital, New Haven, CT

⁹Section of Health Policy and Administration, Department of Epidemiology and Public Health, Yale University, New Haven, CT

¹⁰Robert Wood Johnson Clinical Scholars Program, New Haven, CT

¹¹Section of General Internal Medicine, Department of Medicine, Yale University, New Haven, CT

Corresponding author. ^*Correspondence to: Cynthia A. Jackevicius, BScPhm, PharmD, MSc, BCPS Western University of Health Sciences, College of Pharmacy, 309 E. Second St, Pomona, CA 91766. E‐mail: ude.unretsew@suicivekcajc

Received 2016 Feb 11; Accepted 2016 Mar 12.

Copyright © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.This article has been cited by other articles in PMC.

Supplementary Materials

Table S1. ICD‐10 Codes of Secondary Outcomes

Table S2. Baseline and Treatment Characteristics of the Cohort Before Propensity Matching

Table S3. Unadjusted and Adjusted Primary and Secondary Outcomes Using Drug (Brand or Generic) as a Time‐Varying Covariate

Figure S1. Cumulative incidence of secondary endpoints according to study group.

GUID: D88BCEE6-852B-431C-903F-183D4545E032

Abstract

Background

Although generic medications are approved based on bioequivalence with brand‐name medications, there remains substantial concern regarding their clinical effectiveness and safety. Lipitor^®, available as generic atorvastatin, is one of the most commonly prescribed statins. Therefore, we compared the effectiveness of generic atorvastatin products and Lipitor^®.

Methods and Results

We conducted a population‐based cohort study, using propensity score matching to minimize potential confounding of patients ≥65 years, discharged alive after acute coronary syndrome (ACS) hospitalization between 2008 and 2012 in Ontario, Canada, who were prescribed Lipitor^® or generic atorvastatin within 7 days of discharge. The primary outcome was 1‐year death/recurrent ACS hospitalization. Secondary outcomes included hospitalization for heart failure, stroke, new‐onset diabetes, rhabdomyolysis, and renal failure. In the 7863 propensity‐matched pairs (15 726 patients), mean age was 76.9 years, 56.3% were male, 87.6% had myocardial infarction, and all patients had complete follow‐up. At 1 year, 17.7% of those prescribed generic atorvastatin and 17.7% of those prescribed Lipitor^® experienced death or recurrent ACS (hazard ratio, 1.00; 95% CI, 0.93–1.08; P=0.94). No significant differences in rates of secondary outcomes between groups were observed. Prespecified subgroup analyses by age, sex, diabetes, atorvastatin dose, or admission diagnosis found no outcome difference between groups.

Conclusions

Among older adults discharged alive after ACS hospitalization, we found no significant difference in cardiovascular outcomes or serious, infrequent side effects in patients prescribed generic atorvastatin compared with those prescribed Lipitor^® at 1 year. Our findings support the use of generic atorvastatin in ACS, which could lead to substantial cost saving for patients and health care plans without diminishing population clinical effectiveness.

Keywords: acute coronary syndrome, comparative effectiveness, statin

Subject Categories: Atrial Fibrillation, Quality and Outcomes

Introduction

Atorvastatin is a top‐selling medication, with over 80 million prescriptions dispensed in the United States in 2014. In Canada, over 17 million prescriptions were filled for atorvastatin in 2012, totaling nearly $0.5 billion in sales.1, 2 Generic atorvastatin was approved in Canada in June 2010, providing health care plans with an opportunity to save millions in medication costs.3 Once available in generic form in Canada, Ontario’s public prescription benefit program mandated universal substitution of any of the available generic atorvastatin products for all Lipitor^® prescriptions. After this mandatory generic policy was implemented, Ontario’s public formulary atorvastatin costs dropped 74%, reducing atorvastatin expenditures from $316 million in 2009–2010 to $83 million in 2012–2013. 4

Whereas most clinicians and patients welcome decreased generic drug costs, it is essential that safety and effectiveness is not compromised.5 Although generic drugs have identical active ingredients as brand‐name drugs, they are not exact replicas because their inactive ingredients (excipients) differ.6 Health Canada, like the US Food and Drug Administration (FDA), requires bioequivalence studies for generic drug approval. Bioequivalence studies typically enroll a small number of healthy volunteers (minimum, 12) who are usually given one dose of brand‐name and generic drug, and focus on drug absorption, only needing to show that a similar amount of the generic drug was absorbed at a similar rate as the brand‐name drug.7, 8, 9, 10 Statin efficacy was originally demonstrated with brand‐name statins versus placebo in large, secondary prevention trials with thousands of patients, reducing major coronary events by 27% to 44%, mortality by 13% to 30%, and coronary death by 18% to 42% in those with heart disease. 11, 12, 13 Given that generic medications are approved on the basis of bioequivalence with brand‐name medications in healthy volunteers, rather than the target population with or at risk of cardiovascular disease, there remains a substantial uncertainty regarding their clinical effectiveness and safety, as well as the mandatory substitution policies that ensue following their approval.11, 14, 15

The few studies that have directly compared brand and generic atorvastatin in patients have evaluated lipid values rather than clinical outcomes.16, 17, 18, 19, 20 It is crucial to be able to provide strong clinical outcomes evidence regarding generic products in order to address concerns about their effectiveness and safety. The Ontario policy change affords a unique opportunity to compare clinical outcomes between generic atorvastatin preparations and Lipitor^® in those with acute coronary syndromes (ACS), a population at the highest risk for adverse cardiac outcomes, at a time when Lipitor^® was the most commonly prescribed statin, and during a period without other major competing health policy changes.

Methods

Design and Data Sources

We conducted a population‐based observational study, creating a propensity‐score–matched cohort by linking administrative health care databases for hospitalizations, prescription claims, and vital status using unique, encoded identifiers and analyzed at the Institute for Clinical Evaluative Sciences (Toronto, Ontario, Canada). Data on diagnosis were from the Canadian Institute for Health Information’s (CIHI) Discharge Abstract Database, outpatient medications dispensed were from the Ontario Drug Benefit prescription claims database, procedures were from the Ontario Health Insurance Plan and CIHI databases, vital status was from the Ontario Registered Persons Database, and neighborhood income was from Statistics Canada census data.

Study Population

Our cohort was comprised of patients 65 years and older, discharged alive and surviving at least 7 days after an ACS hospitalization between June 1, 2008 and June 30, 2012 in Ontario, Canada. ACS diagnosis was identified using International Classification of Disease, 10th Revision (ICD‐10) codes I20, I21, I22, I24.0, I24.8, and I24.9. We excluded patients age >105 years, those with an invalid Ontario health card, with an index ACS coded as an in‐hospital complication, or those hospitalized with ACS within the year preceding the index ACS. Patients who had multiple ACS admissions in the study period were identified based on their first ACS hospitalization. We categorized patients into 2 exposure groups based on receipt of a prescription of either generic atorvastatin or Lipitor^® within 7 days of index discharge. From June 1, 2008 to June 30, 2012, eligible patients were included in the brand drug group, and after the mandatory generic automatic substitution policy change in June 2010, those eligible patients between June 1, 2010 and June 30, 2012 were included in the generic drug group (Figure  shows patient accrual). There were 9 generic atorvastatin products dispensed during our study (Apo‐Atorvastatin, Co‐Atorvastatin, Gd‐Atorvastatin, Mylan‐Atorvastatin, Novo‐Atorvastatin, PMS‐Atorvastatin, Ran‐Atorvastatin, Ratio‐Atorvastatin, and Sandoz‐Atorvastatin).

Distribution of patient accrual from June 2008 to June 2012.

Outcomes

The primary outcome was death or recurrent ACS hospitalization within 1 year. Secondary outcomes included hospitalization for heart failure, stroke, myopathy/rhabdomyolysis, renal insufficiency, and new‐onset diabetes. ACS hospitalization and secondary outcomes were from discharge abstract data. Death was from the Ontario Registered Persons Database. Diabetes was ascertained using the Ontario Diabetes Mellitus Database (Table S1).21 Follow‐up for ascertainment of outcomes began 7 days post‐ACS discharge. Subjects who did not experience the event of interest were censored at the first occurrence of: switch from brand to generic (or vice versa) or after 1 year postindex date.

Statistical Analysis

To reduce potential confounding between treatment groups, we constructed a propensity‐matched cohort as our primary analysis. The propensity score (the probability of receiving generic atorvastatin conditional on relevant baseline characteristics) was estimated using a multivariable logistic regression model. Variables in the propensity score model included those listed in Table .

Table 1

Baseline and Treatment Characteristics of the Propensity‐Matched Cohort

Characteristics	All Patients	Brand	Generic	Standardized Difference
	N=15 726	N=7863	N=7863
Agea, mean±SD, y	76.87±7.66	76.88±7.66	76. 87±7.67	0.00
Malea (%)	8858 (56.3)	4429 (56.3)	4429 (56.3)	0.00
Income quintilesa (%)
1 (lowest)	3361 (21.4)	1670 (21.2)	1691 (21.5)	0.01
2	3272 (20.8)	1645 (20.9)	1627 (20.7)	0. 01
3	3161 (20.1)	1601 (20.4)	1560 (19.8)	0.01
4	3003 (19.1)	1498 (19.1)	1505 (19.1)	0.00
5 (highest)	2929 (18.6)	1449 (18.4)	1480 (18.8)	0.01
Rurala (%)	2325 (14.8)	1151 (14. 6)	1174 (14.9)	0.01
Most responsible diagnosisa (%)
Acute myocardial infarction	13 778 (87.6)	6889 (87.6)	6889 (87.6)	0.00
Angina	1948 (12.4)	974 (12.4)	974 (12.4)
Most responsible diagnosis STEMIa (%)	3776 (24.0)	1894 (24. 1)	1882 (23.9)	0.00
Total length of stay, mean±SD, days	8.34±11.22	8.40±11.06	8.29±11.38	0.01
Median (IQR)	5 (3–9)	5 (4–10)	5 (3–9)	0.01
Cardiovascular comorbiditiesa (%)
Angina	667 (4.2)	354 (4.5)	313 (4. 0)	0.03
Atrial fibrillation/flutter	1073 (6.8)	544 (6.9)	529 (6.7)	0.01
Diabetes	5308 (33.8)	2654 (33.8)	2654 (33.8)	0.00
Heart failure	2909 (18.5)	1461 (18.6)	1448 (18.4)	0.00
Hypertension	12 235 (77. 8)	6107 (77.7)	6128 (77.9)	0.01
Dyslipidemia	5686 (36.2)	2843 (36.2)	2843 (36.2)	0.00
Peripheral vascular disease	599 (3.8)	308 (3.9)	291 (3.7)	0.01
Past myocardial infarction	1424 (9.1)	730 (9.3)	694 (8.8)	0. 02
Cerebrovascular disease	764 (4.9)	374 (4.8)	390 (5.0)	0.01
Shock	160 (1.0)	82 (1.0)	78 (1.0)	0.01
Medical comorbiditiesa (%)
Renal disease	758 (4.8)	383 (4.9)	375 (4.8)	0.00
Cancer	1294 (8. 2)	646 (8.2)	648 (8.2)	0.00
Chronic obstructive pulmonary disease	4422 (28.1)	2209 (28.1)	2213 (28.1)	0.00
Liver disease	61 (0.4)	30 (0.4)	31 (0.4)	0.00
Peptic ulcer disease	582 (3.7)	286 (3.6)	296 (3.8)	0. 01
Anemia/blood disease	1365 (8.7)	689 (8.8)	676 (8.6)	0.01
Cardiac invasive proceduresa (%)
Coronary catheterization	1691 (10.8)	857 (10.9)	834 (10.6)	0.01
PCI	693 (4.4)	359 (4.6)	334 (4.2)	0.02
Coronary artery bypass grafting	187 (1. 2)	98 (1.2)	89 (1.1)	0.01
Cardiac invasive procedures during hospitalizationa (%)
Coronary catheterization	10 920 (69.4)	5447 (69.3)	5473 (69.6)	0.01
PCI	6921 (44.0)	3475 (44.2)	3446 (43.8)	0.01
Coronary artery bypass grafting	1383 (8. 8)	685 (8.7)	698 (8.9)	0.01
Most responsible physician annual volume of AMI/anginaa
Mean±SD	34.05±32.05	34.20±31.70	33.91±32.40	0.01
Median (IQR)	26 (9–48)	26 (9–48)	26 (9–47)	0.01
Most responsible physician typea (%)
Family physician	3197 (20. 3)	1588 (20.2)	1609 (20.5)	0.01
General internist	5042 (32.1)	2509 (31.9)	2533 (32.2)	0.01
Cardiologist	6893 (43.8)	3473 (44.2)	3420 (43.5)	0.01
Other	594 (3.8)	293 (3.7)	301 (3.8)	0. 01
Hospital annual volume of AMI/anginaa
Mean±SD	464.27±328.43	463.60±327.83	464.94±329.04	0.00
Median (IQR)	371 (214–757)	385 (212–757)	371 (214–757)	0.00
Teaching hospitala (%)	4590 (29.2)	2288 (29.1)	2302 (29.3)	0.00
Hospital facilitiesa (%)
None	8990 (57. 2)	4505 (57.3)	4485 (57.0)	0.01
Cath only or cath and PCI (%)	1648 (10.5)	805 (10.2)	843 (10.7)	0.02
Cath, PCI, and OHS	5088 (32.4)	2553 (32.5)	2535 (32.2)	0.00
Medication use within 100 days before admission (%)
Antiplatelet agents (Plavix)a	1014 (6. 4)	494 (6.3)	520 (6.6)	0.01
Any statina	6293 (40.0)	3104 (39.5)	3189 (40.6)	0.02
Beta‐adrenoreceptor antagonista	5062 (32.2)	2538 (32.3)	2524 (32.1)	0.00
ACEI/ARBa	8012 (50.9)	3991 (50.8)	4021 (51. 1)	0.01
Nitratesa	1508 (9.6)	771 (9.8)	737 (9.4)	0.01
Calcium‐channel blockersa	4948 (31.5)	2467 (31.4)	2481 (31.6)	0.00
Furosemidea	2382 (15.1)	1189 (15.1)	1193 (15.2)	0.00
Spironolactonea	397 (2. 5)	199 (2.5)	198 (2.5)	0.00
Medication use within 7 days after dischargea (%)
Antiplatelet agents (Plavix)	10 227 (65.0)	5112 (65.0)	5115 (65.1)	0.00
Beta‐adrenoreceptor antagonist	12 568 (79.9)	6269 (79.7)	6299 (80.1)	0.01
ACEI/ARB	12 972 (82. 5)	6491 (82.6)	6481 (82.4)	0.00
Nitrates	3268 (20.8)	1639 (20.8)	1629 (20.7)	0.00
Calcium‐channel blockers	5415 (34.4)	2682 (34.1)	2733 (34.8)	0.01
Furosemide	4129 (26.3)	2049 (26.1)	2080 (26.5)	0. 01
Spironolactone	698 (4.4)	340 (4.3)	358 (4.6)	0.01
Dose per day within 7 days after index dischargea
Dose per day (mg), mean±SD	47.43±24.09	47.69±24.15	47.16±24.03	0.02
Median (IQR)	40 (30–80)	40 (30–80)	40 (30–80)	0.02

To ensure balance between groups on key variables that may be associated with outcomes of interest and perform subgroup analysis, greedy nearest neighbor caliper matching without replacement was used to match each generic atorvastatin patient with a Lipitor^® patient using the logit of the propensity score, and on age (±1 year), sex, diabetes, most responsible diagnosis at index admission (acute myocardial infarction [AMI] or angina), and statin daily dosage category (0–19, 20–39, and ≥40 mg). 22 A caliper width of 0.2 of the SD of the logit of the propensity score in the overall sample was used.23 Generic atorvastatin patients without a suitable match were excluded from the cohort. To determine the degree of balance between the 2 groups in the matched cohort, we calculated standardized differences between groups for each of the measured baseline covariates, with a standardized difference of <0.1 indicative of good balance between groups for that covariate (Table ).

In the propensity‐score–matched cohort, Kaplan–Meier curves were estimated to compare survival between the treatment groups. Hazard ratios (HRs) and 95% CIs were calculated for the outcomes, including drug side effects, using Cox proportional hazard models with a robust sandwich‐type variance estimator to account for the matched nature of the sample.24, 25 Subgroup analyses, adjusted for covariates in the propensity score, were conducted for age (<75, ≥75 years), sex (male, female), past diabetes, Lipitor^®/atorvastatin dose (<40 mg and ≥40 mg), and most responsible diagnosis (AMI or unstable angina). Pairs mismatched on age were excluded from the age subgroup analysis.

As a secondary analysis in the overall (nonpropensity score matched) cohort, we compared the primary outcome between generic atorvastatin preparations. We conducted a sensitivity analysis with the exposure of generic atorvastatin versus Lipitor^® as a time‐varying covariate, which allowed patients to switch between generic and brand atorvastatin without defining the grouping within 7 days of their ACS. To address concerns about the effect of secular trends in event rates, we reanalyzed our cohort limited to 1 year before and after the policy change. We also estimated mortality for the entire cohort at 7, 14, 30, and 365 days and examined for temporal trends by year. We estimated that with 7800 patients per group and a Lipitor^® event rate of 17.7%, we would have 83% power to detect a 10% relative difference. SAS software (version 9.3; SAS Institute Inc., Cary, NC) was used to conduct statistical analyses. A 2‐sided P<0.05 was considered statistically significant. Patient consent is not required for this retrospective study under the privacy rules of Ontario, Canada. The Sunnybrook Health Sciences Center Research Ethics Board (Toronto, Ontario, Canada) approved this study.

Results

Study Cohort

Of 52 278 patients who met the eligibility criteria, were >65 years old, and were discharged alive after an ACS, we excluded 30 959 patients who within 7 days postindex discharge did not have a prescription for generic atorvastatin or Lipitor^®, had both brand and generic atorvastatin dispensed, or died or were readmitted with ACS (Figure ). In the final cohort of 21 319 patients, 9666 patients received generic atorvastatin and 11 653 received Lipitor^®. Of 9666 patients who received generic atorvastatin, 7863 (81%) were successfully matched to a patient who received Lipitor^® using the matching and propensity score variables, creating 7863 matched pairs in the cohort.

Study participant selection. AMI indicates acute myocardial infarction; MI, myocardial infarction.

Propensity‐Matched Cohort

The mean age of the propensity‐score–matched cohort was 76.9 years, 56.3% were male, and 87.6% had a myocardial infarction (MI) as the index ACS diagnosis (Table ). Common comorbidities included cardiovascular risk factors, such as diabetes (33.8%), hypertension (77.8%), and dyslipidemia (36.2%). Mean Lipitor^®/atorvastatin dose was 47.7 mg and 47.2 mg/day, respectively. Mean 1‐year medication possession ratio (adherence) was 88.4±23.3 for brand and 88.4±23.0 for generic atorvastatin. The most common generic atorvastatin product used in our study was Apo‐atorvastatin (77.2%) followed by Ran‐atorvastatin (7.8%), Ratio‐atorvastatin (4.6%), Co‐atorvastatin (3.8%), and Novo‐atorvastatin (3.4%), with the remaining products each <2%. A comparison of the baseline characteristics of the treatment groups in the propensity‐score–matched sample showed that the 2 groups were well balanced, with the standardized differences <0. 1 (Table ). Baseline characteristics of the unmatched cohort are presented in Table S2.

Primary and Secondary Outcomes

At 1 year, the rate of death or recurrent ACS hospitalization in the propensity‐score–matched sample was 17.7% among those prescribed generic atorvastatin and 17.7% for Lipitor^® (HR, 1.00; 95% CI, 0.93–1.08; P=0.94; Table ; Figure ). There were also no differences in the 30‐day rates of death or recurrent ACS between generic atorvastatin (3.7%) and Lipitor^® (4.2%) (HR, 0.89; 95% CI, 0.76–1.04; P=0.16). No significant differences in rates of heart failure or stroke between treatment groups were observed at 30 days or 1 year (Table ; Figure S1). No differences were found in the primary outcome between the 9 different generic atorvastatin products (Figure ).

Cumulative incidence of primary endpoint and death according to study group. Cumulative incidence of the primary endpoint and death in brand and generic groups are displayed in Kaplan–Meier curves, reported as event‐free rates as a percentage shown over time in days.

Adjusted primary outcome compared between generic atorvastatin products.

Table 2

Primary and Secondary Outcomes in the Propensity‐Matched Cohort

Outcomes	Brand	Generic	Hazard Ratio (95% CI) Brand as reference group	P Value
30 days after index discharge, n (%)a
Death	168 (2.2)	153 (1.9)	0.91 (0.73–1.12)	0. 36
Death/hospitalization for MI or angina	324 (4.2)	292 (3.7)	0.89 (0.76–1.04)	0.16
Hospitalization for myocardial infarction or angina	173 (2.2)	155 (2.0)	0.89 (0.71–1.10)	0.29
Hospitalization for heart failure	159 (2.2)	149 (1.9)	0.93 (0.75–1.16)	0.53
Hospitalization for ischemic/hemorrhagic stroke/TIA	14 (0. 2)	23 (0.3)	1.64 (0.84–3.13)	0.15
365 days after index discharge, n (%)a
Death	788 (11.6)	898 (11.6)	0.99 (0.90–1.09)	0.84
Death/hospitalization for MI or angina	1218 (17.7)	1376 (17.7)	1.00 (0.93–1.08)	0.94
Hospitalization for MI or angina	573 (8. 6)	643 (8.6)	1.00 (0.89–1.12)	0.96
Hospitalization for heart failure	436 (6.3)	491 (6.6)	1.03 (0.91–1.16)	0.67
Hospitalization for ischemic/hemorrhagic stroke/TIA	100 (1.6)	139 (1.9)	1.20 (0.93–1.56)	0.14

As secondary outcomes, we also examined serious statin adverse events and found low 1‐year rates for newly diagnosed diabetes (2.0% vs 1.9%; P=0.37) and rhabdomyolysis (P=0. 39) in patients receiving generic atorvastatin and Lipitor^®, respectively, with no difference between groups at 30 days or 1 year.

Sensitivity analysis using the exposure of generic atorvastatin or Lipitor^® as a time‐varying covariate in the overall cohort also found similar results for primary and secondary outcomes (Table S3). For example, there was no difference in the primary outcome of death or recurrent ACS (HR, 0.99 [0.93–1.05]; P=0.668). The 1‐year sensitivity analysis found consistent results for all outcomes. One‐year mortality rates, adjusted for variables in the propensity score, did not show a declining trend over the study period: 11.7% for 2008; 8.9% for 2009; 11.6% for 2010; 12.0% for 2011; and 11.7% for 2012.

Subgroup Analyses

Prespecified subgroup analyses by age, sex, diabetes, atorvastatin dose, or admission diagnosis also found consistent results for the primary and secondary outcomes (Tables  and ). For example, whereas absolute event rates were higher in the older age group at 1 year, no difference was found between generic atorvastatin and Lipitor^® for the primary outcome of death or recurrent ACS in either the younger age group or the older age group (<75 years: HR, 0. 97 [0.83–1.15]; ≥75 years: 1.00 [0.92–1.09]; P=0.90).

Table 3

Prespecified Subgroup Analysis of Primary Outcome and Death From Baseline to 1 Year

Subgroup	N Pairs	Brand	Generic	HR (95% CI) Brand vs Generic	P Value for Interaction
		No. of Events (%)
Age
Death
<75 years	N=3233	137 (5. 0)	140 (4.4)	0.88 (0.70–1.12)	0.36
≥75 years	N=4529	640 (16.4)	748 (16.7)	1.01 (0.91–1.12)
Death/hospitalization for MI or angina
<75 years	N=3233	284 (10.1)	315 (9.9)	0.97 (0.83–1.15)	0.90
≥75 years	N=4529	917 (23. 2)	1041 (23.2)	1.00 (0.92–1.09)
Sex
Death
Female	N=3434	408 (13.7)	454 (13.4)	0.97 (0.85–1.10)	0.61
Male	N=4429	380 (9.9)	444 (10.2)	1.02 (0.89–1.16)
Death/hospitalization for MI or angina
Female	N=3434	601 (20. 0)	666 (19.6)	0.98 (0.88–1.09)	0.63
Male	N=4429	617 (15.9)	710 (16.2)	1.02 (0.92–1.12)
Past diabetes
Death
Diabetic	N=2654	354 (15.6)	431 (16.5)	1.05 (0.92–1.20)	0.21
Nondiabetic	N=5209	434 (9. 6)	467 (9.1)	0.93 (0.83–1.06)
Death/hospitalization for MI or angina
Diabetic	N=2654	534 (23.3)	651 (24.8)	1.08 (0.96–1.19)	0.07
Nondiabetic	N=5209	684 (14.9)	725 (14.1)	0.93 (0.85–1.03)
Dose of brand or generic atorvastatin
Death
<40 mg	N=2113	293 (16. 2)	353 (16.9)	1.04 (0.90–1.20)	0.37
≥40 mg	N=5750	495 (9.9)	545 (9.6)	0.96 (0.85–1.08)
Death/hospitalization for MI or angina
<40 mg	N=2113	404 (22.1)	494 (23.6)	1.09 (0.95–1.23)	0.11
≥40 mg	N=5750	814 (16. 0)	882 (15.5)	0.95 (0.87–1.04)
Primary diagnosis
Death
MI	N=6889	720 (12.0)	829 (12.2)	1.00 (0.91–1.10)	0.49
Angina	N=974	68 (8.3)	69 (7.2)	0.87 (0.63–1.20)
Death/hospitalization for MI or angina
MI	N=6889	1090 (18. 0)	1238 (18.2)	1.00 (0.93–1.09)	0.77
Angina	N=974	128 (15.3)	138 (14.4)	0.96 (0.76–1.22)

Table 4

Prespecified Subgroup Analysis of Primary Outcome and Death From Baseline to 30 Days

Subgroup	N Pairs	Brand	Generic	HR (95% CI) Brand vs Generic	P Value for Interaction
Age
Death
<75 years	N=3233	137 (5. 0%)	140 (4.4%)	0.88 (0.70–1.12)	0.36
≥75 years	N=4529	640 (16.4%)	748 (16.7%)	1.01 (0.91–1.12)
Death/hospitalization for MI or angina
<75 years	N=3233	284 (10.1%)	315 (9.9%)	0.97 (0.83–1.15)	0.90
≥75 years	N=4529	917 (23. 2%)	1041 (23.2%)	1.00 (0.92–1.09)
Sex
Death
Female	N=3434	408 (13.7%)	454 (13.4%)	0.97 (0.85–1.10)	0.61
Male	N=4429	380 (9.9%)	444 (10.2%)	1.02 (0.89–1.16)
Death/hospitalization for MI or angina
Female	N=3434	601 (19. 9%)	666 (19.6%)	0.98 (0.88–1.09)	0.63
Male	N=4429	617 (15.9%)	710 (16.2%)	1.02 (0.92–1.12)
Past diabetes
Death
Diabetic	N=2654	354 (15.6%)	431 (16.5%)	1.05 (0.92–1.20)	0.21
Nondiabetic	N=5209	434 (9.6%)	467 (9.1%)	0.93 (0.83–1.06)
Death/hospitalization for MI or angina
Diabetic	N=2654	534 (23.3%)	651 (24.8%)	1.08 (0.96–1.19)	0.07
Nondiabetic	N=5209	684 (14.9%)	725 (14.1%)	0.93 (0.85–1.03)
Dose of brand or generic atorvastatin
Death
<40 mg	N=2113	293 (16.2%)	353 (16.9%)	1.04 (0.90–1.20)	0.37
≥40 mg	N=5750	495 (9.9%)	545 (9.6%)	0.96 (0.85–1.08)
Death/hospitalization for MI or angina
<40 mg	N=2113	404 (22.1%)	494 (23.6%)	1.09 (0.95–1.23)	0.11
≥40 mg	N=5750	814 (16.0%)	882 (15.5%)	0.95 (0.87–1.04)
Primary diagnosis
Death
MI	N=6889	720 (12.0%)	829 (12.2%)	1.00 (0.91–1.10)	0.49
Angina	N=974	68 (8.3%)	69 (7.2%)	0.87 (0.63–1.20)
Death/hospitalization for MI or angina
MI	N=6889	1090 (18.0%)	1238 (18.2%)	1.00 (0.93–1.09)	0.77
Angina	N=974	128 (15.3%)	138 (14.4%)	0.96 (0.76–1.22)

Discussion

Concerns about the effectiveness and safety of generic medications have led to the reluctance of prescribers and patients to use these medications.11, 14, 15 Our study, comparing Lipitor^® and generic atorvastatin, one of the most common generic medications in use today, found no significant difference in clinical outcomes, with nearly 18% of patients in each group experiencing recurrent ACS or death within 1 year of drug initiation. Given the absence of a difference in major cardiovascular events between brand and generic atorvastatin in our large, population‐based study, our study provides objective support that the benefits demonstrated by brand‐name Lipitor^® in clinical trials may indeed extrapolate to generic atorvastatin in clinical practice, offering patients and clinicians reassurance regarding the effectiveness of generic atorvastatin products as used in routine clinical practice in an ACS population.

Our study capitalized on a natural experiment within a large universal health system that was undergoing a mandatory policy change from Lipitor^® to generic atorvastatin. We used this population‐wide intervention to compare drug effectiveness in a high‐risk ACS population who were prescribed an atorvastatin product within 7 days postdischarge. Lipitor^® was automatically substituted to generic atorvastatin, as dictated by policy for the entire population. This policy mandate minimizes the chance of selection bias Comparability between groups in our large cohort was also strengthened by use of a propensity‐matched cohort that was well balanced for baseline prognostic characteristics. Additional strengths include the discrete intervention, patient‐important clinical endpoints, and long‐term follow‐up. We conducted 2 sensitivity analyses, 1 that examined mortality in our cohort over the study period and 1 that restricted our analysis to 1‐year pre‐ and postpolicy change to address potential secular trends in mortality over time and found no difference between groups, further strengthening our findings.

Our findings are important because bioequivalence studies are not designed to test clinical efficacy or effectiveness, given their samples sizes of typically <50 patients, single‐dose administration, investigation of drug absorption properties rather than clinical outcomes, and use of healthy volunteers.5, 8, 9, 26 Meta‐analyses of studies comparing brand‐name and generic cardiovascular medications have found no difference between statins for lipid‐level endpoints.16 Direct comparison of clinical outcomes with brand and generic statins is limited to 1 study with simvastatin that found no difference in cardiovascular outcomes.16, 17, 18, 19, 20, 27, 28, 29 As such, our study is the first to compare the effectiveness of clinical outcomes between generic atorvastatin and Lipitor^®.

Quality control in generic manufacturing facilities has recently been questioned as drug recall notices have risen.30, 31 Generic drug recalls, continued expansion of, and limited regulatory oversight for, overseas generic drug manufacturing facilities have raised public concern about the perceived safety and effectiveness of generic products. Reassuringly, we found no outcome differences between the 9 generic products, including some of the most common generic atorvastatin products used worldwide, Apo‐atorvastatin and Ran‐atorvastatin.30, 31, 32, 33

A robust generic drug industry, producing effective therapies, coupled with a sufficient number of manufacturers to induce competitive pricing, is essential to support a sustainable health care system.34, 35 We previously projected that the introduction of generic atorvastatin in the United States would reduce expenditures by $4.5 billion in 2014, a 77% savings.36 Comparable savings were found for Ontario’s public prescription benefit program, where total atorvastatin costs declined by 74% after the mandatory generic atorvastatin policy was instituted.4

High drug costs are also an essential consideration in selecting drug therapy given that they may pose a barrier to medication adherence.37, 38 Gagne recently found that Medicare patients initiating a generic statin (lovastatin, pravastatin, or simvastatin) were more likely to adhere, which may have translated into improved clinical outcomes.39 Our study, demonstrating the effectiveness of generic atorvastatin versus Lipitor^®, may reassure patients and clinicians about these generic products, potentially improving medication adherence, and may also support policy makers in their promotion of generic substitution policies.

Limitations

Our study has some limitations. We were able to create a well‐balanced cohort through the use of propensity score methods. However, some risk factors (eg, smoking, physical activity) were not available. It is unlikely these factors were imbalanced enough in our cohort to impact our results. Because most in the brand group were from 2008 to 2010, and in the generic group from 2010 to 2012, there is possible confounding attributed to a temporal improvement in outcomes. In our propensity‐matched cohort, baseline patient characteristics, medications within 7 days of index ACS discharge, and interventional cardiovascular procedures occurring during the ACS hospitalization were well balanced between groups, reducing the likelihood of confounding. In addition, our sensitivity analysis restricted to 1 year pre‐ and postpolicy change found similar results. Furthermore, analysis of mortality rates indicated no significant changes during our study’s 4‐year time frame. Our study is limited to an older cohort of patients ≥65 years. Smaller between‐group differences are likely in younger patients. Although we found no significant difference in severe side effects, such as rhabdomyolysis and diabetes between the generic atorvastatin and Lipitor^® groups, we were unable to evaluate common side effects, such as myalgias and gastrointestinal symptoms associated with statins given that they are not captured adequately in our data sources. We also do not have data on race/ethnicity. Our study did not evaluate the impact of generic versus brand drug copay because the generic copay does not differ in Ontario.

In conclusion, our large, population‐based study found that there is no difference in major adverse cardiovascular outcomes at 1 year in older ACS patients prescribed generic atorvastatin products after hospitalization compared with those prescribed Lipitor^®. Our findings support the use of generic atorvastatin in ACS, which could lead to substantial cost saving without diminishing population clinical effectiveness.

Sources of Funding

This study was funded by a grant (G‐14‐0005977) from the Heart and Stroke Foundation (HSF). The Institute for Clinical Evaluative Sciences (ICES) is funded by an annual grant from the Ontario Ministry of Health and Long‐Term Care (MOHLTC). The opinions, results, and conclusions reported in this article are those of the authors and are independent from the funding sources. Furthermore, design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication were also independent from the funding sources. No endorsement by ICES, the MOHLTC, or the HSF is intended or should be inferred.

Disclosures

Dr Ko is supported by a Clinician Scientist Award from the HSF, Ontario Provincial Office. Dr J. Tu is funded by a Tier 1 Canada Research Chair in Health Services Research and a Career Investigator Award from the HSF. Dr Austin is supported by a Career Investigator Award from the HSF, Ontario Provincial Office. Drs Ross and Krumholz receive support from Medtronic, Johnson & Johnson, and the US Food and Drug Administration to develop methods to enhance postmarket surveillance of medical devices and the Centers for Medicare and Medicaid Services to develop and maintain performance measures that are used for public reporting. Dr Ross is supported by the National Institute on Aging (Grant No.: K08 AG032886) and by the American Federation for Aging Research through the Paul B. Beeson Career Development Award Program. Dr Krumholz is supported by a National Heart, Lung, and Blood Institute Cardiovascular Outcomes Center Award (1U01HL105270‐04). Dr Krumholz chairs a scientific advisory board for UnitedHealthcare. No other disclosures are reported. The other authors report no disclosures or conflicts.

Supporting information

Table S1. ICD‐10 Codes of Secondary Outcomes

Table S2. Baseline and Treatment Characteristics of the Cohort Before Propensity Matching

Table S3. Unadjusted and Adjusted Primary and Secondary Outcomes Using Drug (Brand or Generic) as a Time‐Varying Covariate

Figure S1. Cumulative incidence of secondary endpoints according to study group.

Acknowledgments

Parts of this material are based on data and information compiled and provided by Canadian Institute for Health Information (CIHI). However, the analyses, conclusions, opinions, and statements expressed herein are those of the author, and not necessarily those of CIHI.

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a cross-sectional retrospective cohort study

BMC Res Notes. 2017; 10: 291.

,¹,¹,²,¹,¹ and ¹

Alexander Loch

¹Department of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia

Jan Philipp Bewersdorf

¹Department of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia

Daniel Kofink

²Laboratory of Experimental Cardiology, Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands

Dzafir Ismail

¹Department of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia

Imran Zainal Abidin

¹Department of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia

Ramesh Singh Veriah

¹Department of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia

¹Department of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia

²Laboratory of Experimental Cardiology, Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands

Corresponding author.

Received 2016 Sep 22; Accepted 2017 Jul 10.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.This article has been cited by other articles in PMC.

Data Availability Statement

The datasets analysed during the current study are available from the corresponding author on reasonable request.

Abstract

Background

In a world of ever increasing health care costs, generic drugs represent a major opportunity to ensure access to essential medicines for people who otherwise would be unable to afford them. However, some clinicians and patients are still questioning the safety and effectiveness of generic formulations compared to the proprietary drugs necessitating further systematic research analyzing the generic drugs’ efficacy. Our objective was to compare the lipid lowering effects of generic and branded atorvastatin.

Methods

This cross-sectional, retrospective cohort study was conducted at the University of Malaya Medical Centre from 1 May 2013 until 30 May 2013. We analyzed the lipid profiles (total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides) of 629 patients before and at least 3 months after switching them from proprietary atorvastatin (Lipitor^®) to generic atorvastatin (atorvastatin calcium from Ranbaxy Laboratories, Inc.). We also investigated if there was any difference in the effectiveness of both atorvastatin formulations in various ethnic groups.

Results

266 patients were included in this study. When comparing the median values we found no statistically significant differences (Wilcoxon signed-rank test; p < 0.05) between proprietary and generic atorvastatin in lowering total cholesterol (4.60 mmol/l pre-transition vs. 4.50 mmol/l post-transition; p = 0.583), LDL-cholesterol (2.42 mmol/l vs. 2.41 mmol/l; p = 0.923) and triglycerides (1.50 mmol/l vs. 1.50 mmol/l; p = 0.513). While there was a statistically significant (p = 0.009) difference in HDL-cholesterol levels favouring proprietary atorvastatin, the extent of this change (1.26 mmol/l vs. 1.25 mmol/l) was deemed not to be clinically relevant. There was no statistically significant difference when analyzing the effects on various ethnic groups.

Conclusions

Substituting proprietary atorvastatin for its generic formulation atorvastatin calcium does not result in a less effective management of hyperlipidemia. Our findings lend support to the approach of lowering health care costs by switching patients from branded drugs to their less expensive generic analogues.

Keywords: Generic medication, Lipid lowering drugs, Atorvastatin, Lipitor^®, Hypercholesterolaemia, Efficacy

Background

In a world of ever increasing health care costs, generic drugs represent a major opportunity to cut health care costs and to ensure access to essential medicines for people who otherwise would be unable to afford them.

A generic drug must contain the same active ingredients and must be identical or within an acceptable bioequivalent range to the brand-name counterpart with respect to pharmacokinetic and pharmacodynamic properties. Generic manufacturers solely develop bioequivalent versions to existing drugs without having to prove the safety and efficacy of the drugs through clinical trials. In the United States the Drug Price Competition and Patent Term Restoration Act, also informally known as the Hatch–Waxman Act, states that pre-clinical and clinical testing does not have to be repeated for generics. A generic drug is considered to be bioequivalent to the brand name drug if the rate and extent of absorption do not show a significant difference from the listed drug [1].

There is however a perception among some patients and physicians that generics are inferior drugs. Patients are accustomed to their branded drugs and are often unwilling to change, particularly in the face of company sponsored advertising negating the benefits of generic drugs. Physicians commonly have negative perceptions of generic drugs, attitudes created and cemented by company marketing and information policies [2].

Atorvastatin, a lipid lowering agent marketed under the trade name Lipitor^® by Pfizer Inc. entered the market in 1996 and became the world’s best-selling drug of all time. Pfizer’s patent on atorvastatin expired in November 2011. Other manufacturers began to supply the generic versions of the drug by May 2012. The first company to develop a generic atorvastatin (known as atorvastatin calcium) and to introduce it to the market was Ranbaxy Laboratories, India’s largest pharmaceutical company [3]. Both the patient’s and the physician’s perception of Ranbaxy’s generic atorvastatin have been shaken by various quality control issues resulting in recalls and fines [4, 5]. Negative perceptions based on quality control issues invariably will result in negative assumptions about the therapeutic efficacy of generic drugs as well.

It is difficult to dispel negative perceptions regarding generic atorvastatin in general, as there are only very few studies available analysing the efficacy of non-proprietary atorvastatin [6, 7]. The data interpretation of these studies is limited for various reasons: low number of study subjects, the absence of reference groups and the fact that a multitude of generic and proprietary statins were examined.

The objective of our study was to analyse the lipid lowering effects of generic atorvastatin calcium (Ranbaxy) compared with the original brand-name drug (Lipitor^®) in a real life population.

Methods

Study design

This cross-sectional retrospective study was conducted at the University of Malaya Medical Centre from 1 May 2013 until 30 May 2013. The hospital pharmacy started dispensing generic, non-proprietary atorvastatin (Ranbaxy Laboratories) on 3 July 2012 as part of a general policy to switch all drugs to generics if possible in order to reduce costs. Prior to this, all patients with a prescription for atorvastatin were issued Lipitor^®. All patients switched from proprietary to generic atorvastatin were identified from the pharmacy’s electronic drug prescription system. Lipid levels before and after the transition were compared. Figure  outlines the study flow chart.

Data collection

The Medical Ethics Committee at the University Malaya Medical Centre approved the study and waived the necessity for informed consent to be obtained from each patient included (MEC ID No. 20152-1019). The data collected for this study included patient demographics, date of onset of branded atorvastatin therapy, date of first issuance of generic atorvastatin and adjunctive lipid-lowering medications. The date of the first issuance of the generic atorvastatin was considered the “transition date”. Low density lipoprotein (LDL)-cholesterol, total cholesterol, high density lipoprotein (HDL)-cholesterol and triglyceride levels were extracted from the electronic blood investigation reporting system for the time before and after the transition. When multiple blood tests existed for a patient, the blood test closest to the transition date, but not later than the transition date was analysed as the pre-transition test. Post-transition blood testing had to be at least 3 months after the transition date. For patients with multiple blood tests following the transition, the first blood test after the 3 month period after switching was utilised for data analysis.

Inclusion and exclusion criteria

All patients with a record of transition from proprietary to generic atorvastatin were included. Patients had to be on atorvastatin therapy for at least 3 months to be included. Exclusion criteria were as follows: patients with missing pre- or post-transition blood results, patients who were started on concurrent lipid-modifying medications during the transition period and patients with atorvastatin dose changes during the transition period.

Study outcomes

This study assessed the differences between pre-transition and post-transition lipid levels.

Statistical methods

Differences between pre- and post-transition lipid levels were tested for normality by Shapiro–Wilk tests (p < 0.05) and were found to significantly deviate from normality. Changes in lipid levels were therefore analysed with the use of the non-parametric Wilcoxon signed-rank test. Two-sided p values <0.05 were considered statistically significant. Statistical analyses were performed in R (version 3.2.4).

Results

Study population

A total of 629 patients were switched from Lipitor^® to the generic drug. 363 patients had to be excluded from analysis for various reasons (missing lipid values pre- and post-transition, dose changes between pre-and post-transition or introduction of other lipid lowering medications). The mean age of the study population was 64.3 (±9.5) years. Male and female patients were equally represented. Patients were divided according to ethnicity to allow analysis for inter-ethnic differences. 63 patients were on lipid-lowering medications other than atorvastatin. These were exclusively fenofibrate and ezetimibe. The dose of the lipid-lowering medication was stable throughout the study period. Pre-transition blood tests were done 99.5 days (median) before the transition date. Post-transition blood tests were done 180 days (median) after the transition date. A description of the study population is shown in Table .

Table 1

Demographic details of the study population

Lipid levels pre and post transition

The median triglyceride pre-transition value was 1.50 mmol/l (mean 1.71 mmol/l; range 0.40–7.00 mmol/l) and the post-transition value was 1.50 mmol/l (mean 1.72 mmol/l; range 0.40–7.70 mmol/l) with p = 0.513. The median LDL pre-transition value was 2.42 mmol/l (mean 2.64 mmol/l; range 0.47–6.34 mmol/l) and the post-transition value was 2.41 mmol/l (mean 2.64 mmol/l; range 1.01–7.30 mmol/l) with p = 0.923. The median HDL pre-transition value was 1.26 mmol/l (mean 1.29 mmol/l; range 0.12–2.51 mmol/l) and the post-transition value was 1.25 mmol/l (mean 1.26; mmol/l range 0.15–2.39 mmol/l) with p = 0.009. The median total cholesterol pre-transition value was 4.60 mmol/l (mean 4.71 mmol/l; range 1.76–8.40 mmol/l) and the post-transition value was 4.50 mmol/l (mean 4.68 mmol/l; range 2.30–9.90 mmol/l) with p = 0.583.

There were no statistical differences between pre- and post-transition levels (Wilcoxon signed-rank test) for triglycerides, LDL-cholesterol, and total cholesterol. The statistical analysis for HDL-cholesterol yielded a significant p value, however in practical terms, it is obvious that a mean HDL of 1.29 mmol/l pre-transition vs. 1.26 mmol/l post-transition is of little clinical relevance.

There were no differences when analysed according to ethnicity. Figure  and Table  visualize the presented data.

Box- and whisker plot of mean blood concentrations of LDL-cholesterol (LDL), HDL-cholesterol (HDL), total cholesterol (total chol) and triglycerides (TG) with boxes indicating the upper and lower quartiles. Tukey method was used to plot whiskers. Outliers are not shown in the diagram. Asterisk represents a statistically significant difference in HDL-cholesterol levels before and after the transition (p < 0.05; Wilcoxon signed-rank test)

Table 2

Lipid values before and after transition from branded to generic atorvastatin

Discussion

We could demonstrate in this cross-sectional cohort study, that the lipid lowering properties of generic atorvastatin calcium (Ranbaxy Laboratories, Inc.) are comparable to those of Lipitor^® (Pfizer, Inc.). Negative perceptions about generic atorvastatin with regards to efficacy appear to be unfounded.

Our findings are in keeping with other studies comparing branded and generic atorvastatin. A retrospective study by Rahalkar et al. showed no differences in plasma levels of total or LDL-cholesterol, or triglycerides, but was associated with a small but significant increase in HDL-cholesterol [7]. Kim et al. studied 211 Korean patients for the purpose of marketing a Korean generic formulation and demonstrated equal efficacy and tolerability of generic and proprietary atorvastatin [8]. Ong et al. reported good LDL-cholesterol reduction with generic atorvastatin in 85 Malaysian patients without serious drug related adverse events, however without having a control group [9].

Generic drugs are the only option for millions of people to obtain affordable pharmacotherapy, particularly in developing countries. The fact that generic manufacturers do not have to prove the safety and efficacy of the drugs through clinical trials makes it of utmost importance for the manufacturers to uphold highest production standards to avoid loss of confidence in their products and to maintain patient safety. Reports of impurities, contaminations, dosing errors and misrepresentation of generic drug data do not mean that generic substitutions are not equivalent or ineffective. But these reports highlight the importance of regulatory oversight from the US Food and Drugs Administration and other national bodies [4, 5].

There have been numerous studies demonstrating comparable levels of effectiveness and safety for various generic drugs [10–12]. Despite this growing level of evidence, the perception that generic drugs are inferior remains among some patients and physicians. Patients are accustomed to their branded drugs and are often anxious about having to change to generic formulations [13]. Physicians and pharmacists commonly have negative perceptions of generic drugs with one study showing that about a third of pharmacists considers generic drugs less effective than their branded analogues [2, 14]. We could demonstrate with our study that negative perceptions with regards to the efficacy of generic atorvastatin seem to be unfounded.

This is a retrospective cohort study with all its associated limitations. Data on drug compliance was not available. However, our hospital pharmacy dispenses a maximum supply of 2 months of medication only. Non-compliance would be detectable by patients not collecting the renewal prescription after that 2 month period. Data were collected by chart abstraction which always poses the possibility for mistakes. It is of note, that only Lipitor^® from Pfizer, Inc. and atorvastatin calcium from Ranbaxy Laboratories, Inc. were investigated. Therefore, the study conclusions might not be fully transferable to other generic atorvastatin formulations. Our study was a cross-sectional retrospective cohort study. We did not attempt to analyse lipid profiles over time. It would have been ideal to follow the patients prospectively over a longer period of time to assess the long-term efficacy of generic atorvastatin in the management of hyperlipidemia. Further studies are warranted to address these questions.

Conclusions

Substituting proprietary atorvastatin for its generic formulation atorvastatin calcium does not result in a less effective management of hyperlipidemia. Our findings lend support to the approach of lowering health care costs by switching patients from branded drugs to their less expensive generic analogues. Further studies in the field of generic medication efficacy are desirable to supply physicians with the data and confidence to prescribe these medications.

Authors’ contributions

AL and RSV conceived and designed the study. AL, IZA and DI developed the study protocol. AL supervised data collection. AL, DK and JPB analysed the data. AL, JPB and DK prepared the manuscript. All authors read and approved the final manuscript.

Acknowledgements

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Availability of data and materials

The datasets analysed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

Approval was obtained prior to commencing the study from the University Malaya Medical Centre Medical Ethics Committee (MEC ID No. 20152-1019). The institutional Ethics Committee waived the need for patient consent as the study was solely observational and non-interventional.

Funding

This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Abbreviations

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Uses, How to Take It, Dietary Tips & Potential Complications

Lipitor is a prescription drug used to lower bad cholesterol and reduce the risk of stroke, heart attack, and other heart and blood vessel problems.

The U.S. Food and Drug Administration approved the medication in 1996. Its active ingredient is atorvastatin calcium.

Lipitor blocks HMG-CoA reductase, a liver enzyme the body needs to produce low-density lipoproteins (LDL), or “bad” cholesterol. By lowering the amount of LDL in the blood, the medication prevents atherosclerosis, a condition in which plaque deposits accumulate on the inner walls of arteries, causing them to stiffen and narrow. In turn, this reduces the risk of atherosclerosis complications like heart attack, stroke, chest pain and aneurysms.

The medicine can also raise levels of high-density lipoproteins (HDL), or “good” cholesterol, which protects against heart attack. Some experts believe HDL can carry plaque away from arteries to the liver, which helps to slow its buildup and prevent dangerous blockages in blood flow.

Lipitor is the most popular and most potent member of the statin family of drugs, which is the most widely prescribed class of medications in the United States. Pfizer Inc. manufacturers the billion-dollar drug.

Approved Uses

Doctors commonly prescribe Lipitor together with diet, weight loss and exercise to lower cholesterol and help stave off cardiovascular disease in people with multiple risk factors other than pre-existing coronary heart disease.

The FDA approved Lipitor for this use based on clinical trials. In one clinical trial called the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), researchers investigated atorvastatin’s ability to prevent heart disease in more than 10,000 at-risk patients. The drug was found to reduce the risk of fatal or nonfatal cardiac events by 36 percent when compared to a placebo.

“Lipitor is for adults and children over 10 whose cholesterol does not come down enough with exercise and a low-fat diet alone.”

Patients already diagnosed with heart disease take the drug to lower their risk of having a cardiac event. For patients diagnosed with coronary heart disease, the drug can reduce the risk of heart attack, stroke and chest pain while also lowering the risk for heart failure surgeries and hospitalization from congestive heart failure.

The medication is also a preventative treatment option for patients with Type 2 diabetes and several risk factors for heart disease and stroke such as high blood pressure, a history of smoking and two diabetes-related conditions called retinopathy and albuminuria, which affect the eyes and kidneys, respectively.

The FDA also approved the drug for use in children and teenagers who are 10 to 17 years old and have heterozygous familial hypercholesterolemia, an inherited condition in which cholesterol cannot be removed from the body normally. If diet therapy fails, Lipitor may be used in these patients to decrease the amount of cholesterol and triglycerides in the blood.

Triglycerides are fats that can clog blood vessels, and high levels in the blood can mean an elevated risk of stroke.

Important Information on Taking Lipitor

Carefully follow your doctor’s instructions on how to take Lipitor and how often. Never adjust your dose or stop taking the drug without first speaking with your doctor.

The medication comes in 10 mg, 20 mg, 40 mg and 80 mg tablets. The tablets are white, oval-shaped and film-coated, and should be swallowed whole.

Doctors may start patients on a low dose and then slowly up the dose, but not more than once every two to four weeks. The recommended starting dose is 10 mg to 20 mg once daily. The medicine takes about two weeks to start working.

EXPAND

Lipitor comes in four strengths: 10 mg, 20 mg, 40 mg and 80 mg.

It’s normal for a doctor to order blood tests to check cholesterol levels during treatment. He or she may adjust the dose based on the test results.

The drug label says patients can take the medication during the day or at night, though it recommends they take it at the same time every day. You do not need to take the medicine with food, but you can if you want to.

If you forget to take a dose at your normal time, take it as soon as you think of it, but don’t take two doses at the same time. If more than 12 hours have passed since you missed your last dose, then wait to take the pill at your scheduled time. If you take too much of the medication, call your doctor or Poison Control Center, or go to the nearest hospital or emergency room.

Dietary Dos and Don’ts

When taking Lipitor, it’s important to follow the exercise and dietary recommendations made by your doctor or dietitian. Typically, patients who take the medication are told to eat a low-fat, low-cholesterol diet.

The U.S. Department of Health and Human Services recommends that people looking to lower their cholesterol have:

• Less than 7 percent of daily calories from saturated fat
• Less than 200 mg a day of cholesterol
• 25 percent to 35 percent of daily calories from total fat

The drug’s label warns users to avoid drinking large amounts of grapefruit juice while taking the drug. This means users should not drink more than 1.2 liters of grapefruit juice per day. Grapefruit juice contains one or more components that inhibit CYP34A, an important enzyme found in the liver, and it can increase plasma concentrations of atorvastatin.

Experts also recommend at least 30 minutes a day of moderate intensity physical activity such as brisk walking, but talk with your doctor to determine what is appropriate for you.

Common and Serious Side Effects

In some people, Lipitor may cause mild side effects such as diarrhea, upset stomach, and muscle and joint pain. Though rare, people have also reported memory loss, forgetfulness, amnesia and confusion associated with statin use.

Serious Lipitor side effects include muscle disease called myopathy and muscle breakdown called rhabdomyolysis, which can lead to kidney damage and kidney failure. The risk of these complications rises when patients take atorvastatin at the same time as certain antibiotics, antivirals and antifungals.

The medication can also cause liver problems, including fatal and non-fatal liver failure. Signs of liver trouble may include: feeling tired or weak; losing your appetite; experiencing belly pain on the right side of your upper abdomen; and developing yellowish skin and eyes.

Studies also link atorvastatin use to an increased risk of developing Type 2 diabetes. Thousands of people filed lawsuits against Pfizer alleging Lipitor caused their Type 2 diabetes. The Lipitor lawsuits claimed Pfizer knew about the risks but didn’t adequately warn patients and doctors.

Many of these complications can occur with all statins, which raises serious safety concerns about the drug class as a whole.

Pregnancy, Breastfeeding, Liver Problems and Allergic Reactions

People who are allergic to Lipitor or any of its ingredients should not take the medication, according to the drug’s label. Neither should people with liver problems.

The label also advises against taking the drug while pregnant or breastfeeding. Atorvastatin may harm an unborn baby, and the medicine can pass into breast milk and may harm a nursing baby.

DID YOU KNOW?

Because Lipitor reduces the synthesis of cholesterol and potentially other biological substances derived from cholesterol, the drug may cause fetal harm if taken by pregnant women.

According to the label, women should stop taking the drug right away if they find out they are pregnant. Studies have not established the safety of the drug in pregnant women, and expectant mothers get no benefit from lipid-reducing drugs, the label states.

Before the FDA replaced its pregnancy risk letter categories in 2015, it had deemed Lipitor as Pregnancy Category X, indicating that the risks involved with use of the drug in pregnant women clearly outweigh the potential benefits. Pregnancy Category X means studies in animals or humans have demonstrated fetal abnormalities and/ or there is evidence of fetal risk based on human experience.

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90,000 Lipitor 40 mg 14 tablets – Russian Pharmacy in Egypt

Trade name:

Lipitor 40 mg

Lipitor 40mg

Ingredients:

Each p / o tablet contains:

Atorvastatin – 40mg.

Auxiliary components:

calcium carbonate, lactose monohydrate, microcrystalline cellulose ph 101, croscarmellose sodium, polysorbate 80, hydroxypropyl cellulose, magnesium stearate, white opadrium, simethicone emulsion, wax.

Properties:

Atorvastatin is a third generation hypolipidemic drug from the statin group. Reduces the level of “bad” cholesterol and triglycerides in the blood, while increasing the level of “good” cholesterol (high density lipoprotein or HDL).

Readings:

Treating high cholesterol levels and reducing the risk of stroke, heart attack, or other heart complications in people with type 2 diabetes, coronary artery disease, or other risk factors.

Application:

Atorvastatin can be taken once at any time of the day, regardless of food intake, a standard cholesterol-lowering diet should be followed before using atorvastatin. Hypercholesterolemia: The recommended starting dose is 10 or 20 mg once a day. Patients who require a significant reduction in LDL-C levels (more than 45%) can start with 40 mg once a day. The dose range for atorvastatin is 10 to 80 mg once a day.The doctor adjusts the dosage according to the individual parameters of the patient. After starting atorvastatin, lipid levels should be analyzed within 2-4 weeks. With heterozygous familial hypercholesterolemia in patients (10–17 years old), the recommended initial dose of atorvastatin is 10 mg / day; the maximum is 20 mg / day. Doses should be selected individually, adjustments are made at intervals of 4 weeks or more. Homozygous familial hypercholesterolemia: The dose is 10 to 80 mg per day.Atorvastatin should be used as an adjunct to other lipid-lowering treatments in patients or if such treatment is not available.

Contraindications:

hypersensitivity to the drug; cases of active liver disease; pregnancy and breastfeeding.

Precautions:

, attempts should be made to control the development of hypercholesterolemia with appropriate diet, exercise, and weight loss in obese patients, and other associated health problems, before initiating atorvastatin therapy.Liver function tests should be performed before and periodically after atorvastatin therapy. Patients with any unexplained muscle pain or muscle weakness, especially if accompanied by malaise or fever, should consult a physician.

Side effects:

are mild, transient, rare and include: constipation, flatulence, dyspepsia, abdominal pain, headache, nausea, myalgia, diarrhea, insomnia, angioedema, muscle cramps, myopathy, peripheral neuropathy, pancreatitis, anorexia, vomiting, itching, rash, impotence, hyperglycemia, or hypoglycemia.

Storage method:

Store at a temperature not exceeding 30C in a dry place out of the reach of children.

Packing:

cardboard box contains blisters of 7 p / o tablets each; paper instructions.

Clinical Study Coronary Arteriosclerosis: Atorvastatin (Lipitor) – Clinical Trials Registry

Statins: serious NDT – FGBU NCESMP of the Ministry of Health

In the UK, based on the analysis of data from clinical trials, spontaneous reports of CPD, literature data, it was concluded that it is necessary to pay special attention to medical workers on the possibility of developing serious CPD, characteristic of all members of the statin group.

Statins are a group of drugs used for the treatment of patients with hypercholesterolemia and for the prevention of cardiovascular diseases. In the UK, based on the analysis of data from clinical trials, spontaneous reports of CPD, literature data, it was concluded that it is necessary to pay special attention to medical workers on the possibility of developing serious CPD, characteristic of all members of the statin group.

New guidelines for healthcare professionals include the following information:

• Patients should be warned that all statins can sometimes cause depression, sleep disturbances, memory loss and sexual dysfunction
• Interstitial lung lesions may be associated with statins in rare cases.Patients should be advised to seek medical attention if they develop symptoms such as respiratory distress, unproductive cough, and worsening general condition (eg, fatigue, weight loss, fever).

In connection with these data, FC MBLS asks all medical and pharmaceutical workers to inform the Federal or Regional Centers for Monitoring the Safety of Medicines in case of detection of such cases of NPD on statins.

Notes:

The following statins are registered in Russia:
simvastatin is registered under the trade name Vasilip, Simvastatin, Simplakor, Simvastatin-Teva, SimvaHeksal, Zokor Forte, Simtin, Zorstat, Simvalimit, Zosta, Simvastatin, Simvastatin Likonsa, Aterostat, Simvastatin, Simplacaloid, Aterostat, Carostatine Alkaloid, Aterostatine , Simvalip, Simvastatin Alkaloid, Simvastatin-Ferein, Aktalipid, Holvasim, Ovenkor, Avestatin, Zokor, Simvor, Simvakol, Levomir, Simgal; rosuvastatin is registered under the trade name Mertenil, Crestor; atorvastatin is registered under the trade name Lipitor, TG-tor, Torvakard, Atomax, Lipona, Atorvox, Atoris, Atorvastatin, Atorvastatin-Teva, Liprimar, Tulip, Liptonorm; Pravastatin is registered under the trade name Pravastatin; lovastatin is registered under the trade name Lovastatin, Holetar, Apextatin, Cardiostatin, Lovastatin, Lovacor, Mevacor, Medostatinr, Rovacor; cerivastatin is registered under the trade name Lipobay.

InScience

That said, according to a comparative analysis of 135 studies, statins do increase the risk of diabetes, cause muscle pain and can be harmful to the liver, but these risks are still quite low. And here atorvastatin was on a par with other statins, and the least side effects were caused by pravastatin and simvastatin. While statin-related muscle pain appears to be underestimated in clinical trials, severe muscle damage occurs in 1 to 2 people per 10,000 people * years of drug use, concludes a systematic review in The Canadian Journal of Cardiology.

Less serious consequences, which the instruction also warns about (nausea, digestive problems, loose stools, pain in muscles and joints) are much more common – in 1-10% of patients. Also, the US Food and Drug Administration (FDA) in 2014 reported forgetfulness and absent-mindedness when taking statins, but these problems stopped after patients refused the medication.

In terms of recommendations for HIV-positive patients and people taking hemofibrozil, atorvastatin may be the least dangerous option than other statins, as patients in these groups are at increased risk of side effects.

Atoris really slows down the development of atherosclerosis and other cardiovascular diseases that increase the likelihood of heart attack and stroke. Its active ingredient is a fairly strong statin and is effective in different dosages: when taken 10 mg per day, it lowers blood cholesterol by 27%, and 80 mg per day by 37.9%, according to another Cochrane review.

And although the side effects of statins are unpleasant, and you cannot expect a dramatic improvement and complete cure from them, you should not stop drinking them without a doctor’s permission. But in reality, the choice is not so hard: according to statistics, health-threatening events (for example, the development of diabetes, serious damage to the liver or muscles) are considered very rare, and more frequent symptoms, such as muscle pain or nausea, are not dangerous. Despite this, while some patients use statins for prophylaxis, being healthy (this is especially common in the USA and Europe), others drop out of therapy that could prolong their life for years.

Here, the truth lies somewhere in between: the benefits of the drug for healthy people are questionable, although statins are unlikely to cause significant harm. However, there is hope for prevention: A 2013 Cochrane Review shows that statins help prevent cardiovascular complications in an average of 18 out of 1000 patients who initially had hypertension, diabetes, or high cholesterol. Therefore, in the case of statins, everything depends on the patient’s condition.

Of course, do not forget about a healthy lifestyle: sometimes it is enough to stop eating fatty foods in order to lower the blood cholesterol level to normal values ​​without the help of medications. And even with medications, eating a healthy diet won’t hurt you either.

Our recommendations cannot be equated with a doctor’s prescription. Before you start taking this or that drug, be sure to consult with a specialist.

instructions for use, dosages, composition, analogs, side effects / Pillintrip

With the simultaneous administration of cyclosporine, fibrates, erythromycin, clarithromycin, immunosuppressive, antifungal drugs (related to azoles) and nicotinamide, the concentration of atorvastatin in the blood plasma (and the risk of myopathy) rises. Antacids reduce the concentration by 35% (the effect on LDL cholesterol does not change). The simultaneous use of atorvastatin with protease inhibitors, known as inhibitors of cytochrome P450 CYP3A4, is accompanied by an increase in the concentration of atorvastatin in the blood plasma.When using digoxin in combination with atorvastatin at a dose of 80 mg / day, the concentration of digoxin increases by about 20%. Increases by 20% the concentration of oral contraceptives containing norethindrone and ethinyl estradiol (when administered with atorvastatin at a dose of 80 mg / day). The hypolipidemic effect of the combination with colestipol is superior to that for each drug separately. When taken simultaneously with warfarin, the PT decreases in the first days, but after 15 days this indicator is normalized.In this regard, patients taking atorvastatin with warfarin should be monitored more often than usual. Drinking grapefruit juice during treatment with atorvastatin can lead to an increase in the concentration of the drug in the blood plasma. In this regard, patients taking the drug should avoid drinking this juice.

During treatment with HMG-CoA reductase inhibitors with the simultaneous use of cyclosporine, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g / day) or inhibitors of the CYP3A4 isoenzyme (for example, erythromycin, clarithromycin, antifungal agents – azole derivatives) cm.”Special instructions”).

CYP3A4 isoenzyme inhibitors. Since atorvastatin is metabolized by the CYP3A4 isoenzyme, the combined use of atorvastatin with inhibitors of the CYP3A4 isoenzyme may lead to an increase in the concentration of atorvastatin in the blood plasma. The degree of interaction and potentiation effect is determined by the variability of the effect on the CYP3A4 isoenzyme.

It was found that potent inhibitors of the isoenzyme CYP3A4 lead to a significant increase in the concentration of atorvastatin in the blood plasma.Concomitant use of potent inhibitors of the CYP3A4 isoenzyme (eg, cyclosporine, telithromycin, clarithromycin, delavirdine, styripenthol, ketoconazole, voriconazole, itraconazole, posaconazole, and HIV protease inhibitors, including ritonavir, lopinavir, davinaviruviru) should be avoided if possible, including ritonavir, lopinavir, davinaviru, atazviru. If the simultaneous administration of these drugs is necessary, the possibility of starting therapy with a minimum dose should be considered, and the possibility of reducing the maximum dose of atorvastatin should be evaluated.Moderate inhibitors of the CYP3A4 isoenzyme (for example, erythromycin, diltiazem, verapamil and fluconazole) can lead to an increase in the concentration of atorvastatin in the blood plasma. Against the background of the simultaneous use of HMG-CoA reductase inhibitors (statins) and erythromycin, an increased risk of myopathy was noted. Interaction studies of amiodarone or verapamil and atorvastatin have not been conducted. It is known that both amiodarone and verapamil inhibit the activity of the isoenzyme CYP3A4, and the simultaneous use of these drugs with atorvastatin can lead to an increase in atorvastatin exposure.In this regard, it is recommended to reduce the maximum dose of atorvastatin and conduct appropriate monitoring of the patient’s condition while using it with moderate inhibitors of the CYP3A4 isoenzyme. Control should be carried out after the initiation of therapy and against the background of a change in the dose of the inhibitor.

Inhibitors of the transport protein OATP1B1. Atorvastatin and its metabolites are substrates for the transport protein OATP1B1. OATP1B1 inhibitors (eg cyclosporin) can increase the bioavailability of atorvastatin.Thus, the combined use of atorvastatin at a dose of 10 mg and cyclosporin at a dose of 5.2 mg / kg / day leads to an increase in the concentration of atorvastatin in the blood plasma by 7.7 times (see “Dosage and Administration”). The effect of inhibition of the function of hepatic uptake transporters on the concentration of atorvastatin in hepatocytes is unknown. If it is impossible to avoid the simultaneous use of such drugs, it is recommended to reduce the dose and monitor the effectiveness of therapy.

Gemfibrozil / fibrates. Adverse reactions (including rhabdomyolysis) related to the musculoskeletal system were periodically observed against the background of the use of fibrates in monotherapy. The risk of such reactions increases with the simultaneous use of fibrates and atorvastatin. If the simultaneous use of these drugs cannot be avoided, the minimum effective dose of atorvastatin should be used, as well as regular monitoring of the patient’s condition.

Ezetimibe. The use of ezetimibe is associated with the development of adverse reactions, incl.including rhabdomyolysis, from the musculoskeletal system. The risk of such reactions increases with the simultaneous use of ezetimibe and atorvastatin. Close monitoring is recommended for these patients.

Erythromycin / clarithromycin. With the simultaneous use of atorvastatin and erythromycin (500 mg 4 times a day) or clarithromycin (500 mg 2 times a day), inhibitors of the isoenzyme CYP3A4, an increase in the concentration of atorvastatin in blood plasma was observed (see “Special instructions”).

Protease inhibitors. The simultaneous use of atorvastatin with protease inhibitors, known as inhibitors of the isoenzyme CYP3A4, is accompanied by an increase in the concentration of atorvastatin in the blood plasma.

Diltiazem. The combined use of atorvastatin at a dose of 40 mg with diltiazem at a dose of 240 mg leads to an increase in the concentration of atorvastatin in the blood plasma.

Cimetidine. No clinically significant interaction of atorvastatin with cimetidine was found.

Itraconazole. The simultaneous use of atorvastatin at doses from 20 to 40 mg and itraconazole at a dose of 200 mg led to an increase in the AUC value of atorvastatin.

Grapefruit juice . Since grapefruit juice contains one or more components that inhibit the isoenzyme CYP3A4, its excessive consumption (more than 1.2 liters per day) can cause an increase in the concentration of atorvastatin in the blood plasma.

CYP3A4 isoenzyme inductors. Concomitant use of atorvastatin with inducers of the CYP3A4 isoenzyme (eg efavirenz, rifampicin, or St. John’s wort preparations) may lead to a decrease in the concentration of atorvastatin in the blood plasma.Due to the dual mechanism of interaction with rifampicin (an inducer of the CYP3A4 isoenzyme and an inhibitor of the transport protein of hepatocytes OATP1B1), the simultaneous use of atorvastatin and rifampicin is recommended, since delayed intake of atorvastatin after taking rifampicin leads to a significant decrease in the concentration of atorvastatin in the blood plasma. However, the effect of rifampicin on the concentration of atorvastatin in hepatocytes is unknown, and if the simultaneous use cannot be avoided, the effectiveness of this combination should be carefully monitored during therapy.

Antacids. Simultaneous ingestion of a suspension containing magnesium hydroxide and aluminum hydroxide reduced the concentration of atorvastatin in blood plasma by about 35%, but the degree of decrease in the concentration of LDL-C did not change.

Phenazone. Atorvastatin does not affect the pharmacokinetics of phenazone, therefore, interaction with other drugs metabolized by the same cytochrome isoenzymes is not expected.

Colestipol. With the simultaneous use of colestipol, the concentration of atorvastatin in the blood plasma decreased by about 25%; however, the hypolipidemic effect of the combination of atorvastatin and colestipol was superior to that of each drug alone.

Digoxin. With repeated administration of digoxin and atorvastatin at a dose of 10 mg C _ss of digoxin in blood plasma did not change. However, when using digoxin in combination with atorvastatin at a dose of 80 mg / day, the concentration of digoxin increased by about 20%. Patients receiving digoxin in combination with atorvastatin require appropriate follow-up.

Azithromycin. With the simultaneous use of atorvastatin at a dose of 10 mg once a day and azithromycin at a dose of 500 mg once a day, the concentration of atorvastatin in the blood plasma did not change.

Oral contraceptives. With the simultaneous use of atorvastatin and oral contraceptives containing norethisterone and ethinyl estradiol, there was a significant increase in the AUC of norethisterone and ethinyl estradiol by about 30 and 20%, respectively. This effect should be considered when choosing an oral contraceptive for a woman taking atorvastatin.

Terfenadine. With the simultaneous use of atorvastatin and terfenadine, no clinically significant changes in the pharmacokinetics of terfenadine were detected.

Warfarin. In a clinical study in patients regularly receiving warfarin therapy, while concomitant use of atorvastatin at a dose of 80 mg / day, resulted in a slight increase in PT by about 1.7 s during the first 4 days of therapy. The indicator returned to normal within 15 days of atorvastatin therapy. Despite the fact that only in rare cases significant interactions affecting anticoagulant function have been noted, PT should be determined before starting therapy with atorvastatin in patients receiving therapy with coumarin anticoagulants, and often enough during therapy to prevent a significant change in PT.Once stable PT numbers are noted, PT control can be performed in the same way as recommended for patients receiving coumarin anticoagulants. When changing the dose of atorvastatin or discontinuing therapy, PT control should be carried out according to the same principles as described above. Atorvastatin therapy was not associated with the development of bleeding or PT changes in patients who did not receive anticoagulant treatment.

Colchicine. Despite the fact that studies of the simultaneous use of colchicine and atorvastatin have not been conducted, there are reports of the development of myopathy with the use of this combination.Caution should be exercised with the simultaneous use of atorvastatin and colchicine.

Amlodipine. With the simultaneous use of atorvastatin at a dose of 80 mg and amlodipine at a dose of 10 mg, the pharmacokinetics of atorvastatin in the equilibrium state did not change.

Fusidic acid. During post-marketing studies, cases of rhabdomyolysis have been reported in patients taking statins at the same time, including atorvastatin and fusidic acid. The mechanism of this interaction is unknown.In patients for whom the use of fusidic acid is considered necessary, statin treatment should be discontinued during the entire period of use of fusidic acid. Statin therapy can be resumed 7 days after the last dose of fusidic acid. In exceptional cases where long-term systemic therapy with fusidic acid is needed, for example, for the treatment of severe infections, the need for the combined use of atorvastatin and fusidic acid should be considered on a case-by-case basis and under the strict supervision of a physician.The patient should seek immediate medical attention if symptoms of muscle weakness, tenderness, or pain appear.

Other concomitant therapy. In clinical studies, atorvastatin has been used in combination with antihypertensive drugs and estrogens as part of hormone replacement therapy. There were no signs of a clinically significant adverse interaction; interaction studies with specific drugs have not been conducted.

In addition, there was an increase in the concentration of atorvastatin when used concomitantly with HIV protease inhibitors (combinations of lopinavir and ritonavir, saquinavir and ritonavir, darunavir and ritonavir, fosamprenavir, fosamprenavir with ritonavir and nelfinavirol hepatase inhibitors) …Caution should be exercised with the simultaneous use of these drugs, and also use the lowest effective dose of atorvastatin.

Statins. Cholesterol medications.

What are statins drugs?

The drugs called statins are intended for such an effect on the body’s metabolism, when the amount of lipoproteins causing atherosclerosis (the so-called “bad cholesterol”) in the blood decreases, and the amount of lipoproteins preventing atherosclerosis (“good cholesterol”) increases.

The therapeutic effect of statins is achieved by affecting the initial stage of cholesterol synthesis in which acetate (acetic acid) is converted to mevalonate (mevalonic acid). An enzyme (biological catalyst) HMG-CoA reductase is involved in this transformation. Statins reduce its activity and thereby reduce the production of mevalonate. Less mevalonate means less cholesterol.

Blocking the synthesis of cholesterol at an early stage does not cause the accumulation of intermediate metabolic products in this multistep reaction, which largely explains the absence of toxic manifestations of the use of statins.The following statins are registered in the Russian Federation: lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, pitavastatin.

Lovastatin. Original manufacturer Merck Sharp & Dohme. The original name is Mevacor. Generics: Cardiostatin, Holetar, Apextatin, Medostatin.

Lovastatin is a fermentation product of the Aspergillus terreus fungus and the very first statin to be approved for use by the American Food and Drug Administration (FDA) in 1987.In the AF / Tex CAPS study on the primary prevention of coronary atherosclerosis, completed in 1998, lovastatin reduced cholesterol and low density lipoprotein (LDL) levels by 19% and 27%, respectively. The incidence of sudden death, myocardial infarction, new cases of angina pectoris decreased by 37% compared with those who received placebo. The study prompted doctors to prescribe statins for the primary prevention of coronary heart disease. The drug is prescribed at a dose of 20-40 mg per day, used after dinner, since cholesterol synthesis occurs most intensively at night.The maximum effect develops in 10 – 14 days from the start of treatment. Now lovastatin is practically not used, which is associated with the emergence of new drugs for statins.

Simvastatin. Original manufacturer Merck Sharp & Dohme. The original name is Zokor. Generics: Aterostat, Vasilip, Vero-Simvastatin, Ovenkor, Simvagexal, Simvacard, Simvakol, Simvalimit, Simvastol, Simvor, Simgal, Simlo, Sincard, Zorstat.

Simvastatin is structurally similar to lovastatin and differs from it by the presence of one methyl group in the molecule.However, simvastatin is almost twice as active as lovastatin. The efficacy of simvastatin in preventing coronary complications in high-risk patients has been proven in numerous studies, of which 4S and HPS are the most famous. The incidence of cardiovascular complications in the 4S study decreased by 34%, in the HPS study by 24%, and regardless of the baseline cholesterol level. Simvastatin is widely used in modern clinical practice and is prescribed at a dose of 20-40 mg per day, taken after dinner.The appointment of simvastatin at a dose of 80 mg per day is not recommended due to the high likelihood of side effects (mainly increased liver function and muscle damage).

Pravastatin Original manufacturer Bristol-Mayer Squibb. The original name is Pravahol. Generics are not sold in the Russian Federation.

Pravastatin, unlike lovastatin and simvastatin, is an active dosage form, that is, it begins to act directly upon absorption into the blood. In studies on primary (WOSCOPS) and secondary (LIPID) prevention, pravastatin therapy was accompanied by a 23-28% reduction in the number of cardiovascular complications.The drug is prescribed at a dose of 20-40 mg per day, the LDL level decreases by 25-26%. Pravastatin compares favorably with other statins in that it is not metabolized through the cytochrome P450 system, so the risk of side effects when combined with other drugs is minimal.

Fluvastatin. Original manufacturer Novartis. The original name is Leskol. Generics are not sold in the Russian Federation.

Fluvastatin is the first synthetic statin. Due to its relatively weak hypolipidemic effect, the drug is prescribed at a dose of 40-80 mg per day.At a dose of 80 mg per day, fluvastatin lowers cholesterol levels by 22-24%, moderately lowers triglycerides and slightly increases the concentration of high density lipoproteins (HDL). Due to the fact that fluvastatin is metabolized through the cytochrome P450 2C9 isoform, it does not enter into a competitive metabolism with cytostatics and does not cause side effects observed with the prescription of statins, which are metabolized through the P450 ZA4 isoform (lovastatin, simvastatin, atorvastatin). However, after the appearance of rosuvastatin, which is also metabolized by cytochrome P450 2C9, it became possible to prescribe rosuvastatin for the treatment of patients taking cytostatics.At the same time, fluvastatin remains the statin with the lowest incidence of complications when taken in combination with other drugs.

Latest generation statins

Atorvastatin. Original manufacturer Pfizer. The original name is Lipitor (Liprimar). Generics: Atomax, Atoris, Vasator, Lipoford, Liptonorm, Novosostat, TG-tor, Torvakard, Torvas, Tulip.

Atorvastatin is a synthetic statin that, in doses of 40-80 mg per day, reduces the amount of LDL by 40-50%.Compared to other statins, it is better at lowering triglyceride levels (by 19-30%). Many studies have been conducted with atorvastatin, among others on the so-called aggressive lipid-lowering therapy (MIRACL, PROVE IT-TIMI 22, TNT, IDEAL). In these studies, the use of atorvastatin at a dose of 80 mg per day led to a pronounced decrease in LDL levels, which led to the entry into routine clinical practice of the target LDL cholesterol for patients at highest risk, equal to 1.8 mmol / L. The researchers observed a significant reduction in the incidence of cardiovascular complications, such as myocardial infarction, ischemic stroke, unstable angina pectoris, and death from coronary heart disease, compared with the groups receiving medium doses of statins.The REVERSAL study was the first to demonstrate the possibility of reducing atherosclerotic plaque in coronary vessels with high-dose atorvastatin therapy using intravascular ultrasound. The medicine is used in doses of 10 to 80 mg per day. High doses of the drug (40-80 mg per day) are prescribed mainly in cases of pronounced increase in cholesterol, in particular, with familial hypercholesterolemia.

Most studies on secondary prevention, treating patients with coronary artery disease, have been performed with the original atorvastatin (Liprimar).The need for its use in patients with diabetes mellitus, ischemic stroke, hypertension and before balloon angioplasty and stenting has been proven. Thus, the ASCOT study, conducted over 5 years, included 5168 patients with arterial hypertension. Atorvastatin reduced the risk of myocardial infarction by 36%, and the risk of all cardiovascular complications and the need for angioplasty by 21%. The SPARCL study is investigating the use of statins in stroke patients.4732 patients were included without coronary artery disease, but with a history of stroke or transient cerebrovascular accident. A decrease in the risk of recurrent ischemic strokes by 22%, coronary events by 35%, and repeated fatal strokes by 43% has been shown. The CARDS study examined the effect of atorvastatin treatment in 2238 patients with type 2 diabetes mellitus without coronary artery disease. In patients treated with atorvastatin, the risk of cardiovascular complications decreased by 37%.

In 2014The UK’s National Institute for Health and Clinical Excellence (NICE) has published clinical guidelines for cardiovascular risk assessment and lipid profile correction for primary and secondary prevention of cardiovascular disease. In 2016, these guidelines were updated. Atorvastatin is designated in the document as a first-line drug for primary and secondary prevention. In particular, atorvastatin at a dose of 20 mg per day is recommended for primary prevention in patients with a 10-year risk of cardiovascular events of more than 10%, including for patients with diabetes mellitus, chronic kidney disease, in the elderly (over 85 years) , and at a dose of 80 mg per day – for secondary prevention in patients with cardiovascular diseases.In low doses, atorvastatin can also be used in the selection of drug therapy and a high risk of side effects.

Rosuvastatin. Original manufacturer AstraZeneca. The original name is Crestor. Generics: Acorta, Mertinil, Ro-statin, Rosart, Rosistark, Rosucard, Rosulip, Roxera, Suvardio, Tevastor.

Rosuvastatin belongs to the latest generation of synthetic statins. The most important results for the prevention of cardiovascular complications with rosuvastatin were obtained in the studies ASTEROID, JUPITER and SATURN.SATURN was the first to show a reduction in atherosclerotic plaque in the coronary arteries with long-term treatment with rosuvastatin at a dose of 40 mg per day. In the JUPITER study, a 42% reduction in cardiovascular complications was observed after 2.5 years of therapy with rosuvastatin at a dose of 20 mg per day in individuals with normal LDL cholesterol, but with an increased level of C-reactive protein (more than 2 mg / L). These results became the basis for the use of rosuvastatin in the United States and several countries of Western Europe for the purpose of primary prevention in patients with a high content of C-reactive protein and the presence of an additional risk factor for cardiovascular disease.The maximum dose of rosuvastatin is 40 mg / day. At a dose of 80 mg / day, rosuvastatin is not prescribed due to the increased likelihood of side effects in the form of muscle damage and an increase in hepatic parameters (ACT, ALT).

Pitavastatin. Original manufacturer of Kowa Pharmaceuticals. The original name is Livazo (Livalo). Generics: not available in the Russian Federation.

Pitavastatin was produced in Japan and went on sale in 2003. Currently, the drug is used in Europe, Asia and America.The pitavastatin molecule is different from other statins. Its structure provides better pharmacokinetics and efficacy for lowering LDL at low doses. Unlike other similar drugs, the transformation of pitavastatin in the body occurs bypassing the cytochrome P450 system, causing a low frequency of interactions with other drugs. Pitavastatin is rapidly excreted from the liver into bile, but is recirculated inside the liver, which causes its long-term action. Pitavastatin has a pronounced effect of increasing HDL (good cholesterol) with minimal effect on glucose metabolism.The main feature of this modern statin is its high efficiency in regulating the lipid profile with low interaction with other drugs, which is extremely beneficial for patients who have to constantly take several drugs. The standard starting dose is 1 mg per day, but most patients need twice the dose. It is recommended to change the dose at intervals of at least 4 weeks. The drug can be used at any time of the day, regardless of food intake.

Is there anything newer for lowering cholesterol?

Yes.And not just anything, but a whole new class of drugs – PCSK9 inhibitors. These are no longer statins, so about them in a separate article “PCSK9 inhibitors: a new era of lipid-lowering therapy”.

In 2018-19 there were data on the high lipid-lowering activity of bempedoic acid. Commercial preparations of bempedoic acid are expected to appear in 2019-2020.

For a deeper understanding of the role and problems of statin use in modern cardiology, read our articles:

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90,000 Atorvastatin (lipitor): warnings to be aware of

Disclaimer

If you have any medical questions or concerns, please contact your doctor.Articles in the Health Guide are based on peer-reviewed research and information gleaned from medical societies and government agencies. However, they are not a substitute for professional medical advice, diagnosis, or treatment.

Anyone who has had a cold or something more serious knows that they will probably do their best to feel better. This is human nature; if there is a tincture, tonic or pill that will help us with pain and problems, we want them.

Give statins.Considered by healthcare professionals as the gold standard treatment for high cholesterol, statins have been shown to significantly reduce the risk of heart attacks, strokes, and death among those at increased risk.

Vitals

• Statins such as atorvastatin are considered the gold standard treatment for high cholesterol and can help prevent heart attacks, strokes and death.
• However, there are potential contraindications for pregnant women and people with kidney, liver, and type 2 diabetes.
• Drinking grapefruit juice while taking atorvastatin (brand name Lipitor) may increase your risk of certain side effects such as liver disease and muscle damage.
• Certain prescription medicines can increase the risk of serious muscle problems when taken with atorvastatin.

Statins are part of a class of drugs called HMG CoA reductase inhibitors. Almost 30% of Americans over 40 use them.Statins are often among the first drugs that healthcare professionals turn to when treating people with high cholesterol or heart disease (Salami, 2017). They are often used in combination with other treatments such as weight loss, smoking cessation, and dietary changes.

One of these statins is atorvastatin calcium. It was first approved in 1996 and marketed by Pfizer under the Lipitor brand; it is now available in both generics and brand-name prescription drugs.While it effectively treats high cholesterol, it has a list of warnings and contraindications.

Let’s learn more about atorvastatin (brand name Lipitor) and its various warnings to see if it is worth studying with your healthcare provider.

Warnings about atorvastatin

Some people living with the following conditions may be more likely to experience side effects. However, the presence of an association does not mean that the reaction will occur in most or even many people.

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Pregnancy and breastfeeding

HMG-CoA reductase inhibitors such as atorvastatin are contraindicated in pregnant women and nursing mothers. The reason is that cholesterol is essential for the development of the fetus. Since atorvastatin reduces the synthesis of cholesterol and possibly cholesterol-derived substances, this drug can harm the fetus.

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To date, there is a limited number of studies linking atorvastatin and an increased risk of serious congenital malformations or miscarriage. However, since there is no conclusive evidence that atorvastatin is truly safe during pregnancy, it is recommended that you stop taking atorvastatin if you become pregnant or are trying to get pregnant.

In addition, there is minimal data on the risk of atorvastatin entering breast milk, so the FDA does not recommend breastfeeding while taking this drug (DailyMed, 2019).

Kidney disease

Research on whether statins are safe for people with kidney disease is controversial; some studies show benefits for the kidneys, while others show an increased risk of kidney failure, muscle damage, or kidney inflammation (Verdoodt, 2018).

For example, a review published by the American Heart Association found that atorvastatin improves kidney function over time (Vogt, 2019). However, another study suggests that statin use increases the risk of kidney disease (Achara, 2016).

Despite controversy, there is insufficient data to prohibit the use of statins in people with kidney disease, as lowering cholesterol is good for the kidneys. However, there may be differences in the choice of statins, dosage, other medications, etc., if you have kidney disease. Therefore, if you have both kidney disease and high cholesterol, check with your doctor to compare the potential benefits and risks of starting atorvastatin treatment.

Liver disease

Healthcare professionals may advise certain people with liver problems not to take statins, including atorvastatin.Atorvastatin is contraindicated in people with active liver disease or unexplained liver dysfunction on blood tests.

Statins such as atorvastatin act on liver enzymes and are broken down by the liver. People with active liver disease or a poorly functioning liver are at a higher risk of toxicity and liver damage from statins.

However, health care providers may be cautious about prescribing statins for people with chronic and stable (inactive) liver disease (Jose, 2016).You should be aware that people with chronic liver disease, like chronic alcoholic liver disease, may have higher than expected amounts of atorvastatin in their bloodstream (DailyMed, 2019).

If you have a history of liver disease or any other problem, discuss it with your doctor. Before you start taking atorvastatin, your doctor may do a blood test for liver enzymes. One of the side effects of atorvastatin is that it can cause abnormal liver blood test results.Call your doctor right away if you experience unusual tiredness or weakness, loss of appetite, upper abdominal pain, dark urine, or yellowing of the skin or eyes.

Grapefruit

Research shows that grapefruit contains a chemical that can interfere with the enzymes that break down statins in your liver (known as the cytochrome P450 system). Health professionals may advise against drinking grapefruit juice if you are taking other statins such as simvastatin or lovastatin.However, they usually say that grapefruit is safe if you are taking atorvastatin, especially if you are consuming only 8 ounces of grapefruit juice or half a grapefruit per day (Rosenson, 2020).

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Drinking grapefruit juice or drinking grapefruit while taking atorvastatin may increase your risk of certain side effects such as liver disease and muscle damage, especially if you consume large amounts of grapefruit juice (more than 1.2 quarts per day).The good news is that the occasional glass is safe (Rosenson, 2020).

Type 2 diabetes

Atorvastatin may increase blood sugar and increase the risk of type 2 diabetes. However, most healthcare professionals agree that the ability of atorvastatin to reduce the risk of heart attacks and strokes outweighs the risk of diabetes.

A review published in The Lancet found that treating 10,000 patients with 40 mg of atorvastatin per day (high-intensity therapy) for five years would result in just 50 to 100 new cases of type 2 diabetes.In contrast, it will prevent 500 major vascular events (such as heart attack or stroke) in people who have never had a vascular event before (Collins 2016).

Allergic reactions

Atorvastatin can cause severe allergic reactions such as difficulty breathing, trouble swallowing, and swelling of the face, lips, tongue or throat (FDA, 2017). You should not take atorvastatin if you have had an allergic reaction to this medicine in the past.

Drug Interactions

Certain drugs when taken concomitantly with atorvastatin may increase the risk of side effects. Examples include (DailyMed, 2019)

• Antibiotics such as clarithromycin.
• Antifungal drugs such as itraconazole or ketoconazole.
• Cyclosporin
• Niacin
• Birth control pills
• Fibrates, such as gemfibrozil
• Cardiac drugs, such as digoxin
• Antiretroviral drugs for HIV / AIDS, such as ritonavir, siprana vosampirenavir.
• Colchicine

Side effects of atorvastatin

Common side effects of Lipitor in placebo-controlled trials: nasopharyngitis (cold symptoms), joint pain (arthralgia), diarrhea, pain in hands or feet, and urinary tract infections (FDA, 2017) …

Other mild side effects include:

• Heartburn
• Nausea
• Muscle aches, pains, or cramps
• Gas
• Headache
• Forgetfulness or memory loss
• Confusion

Sleep problems

Less commonly, atorvastatin can cause more serious side effects.You should seek immediate medical attention if you experience any of the following (UpToDate, NA):

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• Anaphylaxis (severe allergic reaction with swelling and difficulty breathing)
• Severe skin rash (including erythema multiforme and Stevens-Johnson syndrome)
• Rhabdomyolysis
• Liver failure
• Unusual bleeding

or bruising

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One of the most serious side effects of atorvastatin is myopathy or muscle disease in the form of myalgia (muscle aches / pains), myositis (muscle inflammation) or rhabdomyolysis (muscle breakdown) (Tomaszewski, 2011).

Some people (5% or less) will notice muscle pain, muscle soreness, or muscle weakness shortly after starting atorvastatin. Depending on your reaction, the effects may disappear within two to three weeks, or the pain may continue and worsen.

However, you should seek medical attention. If you notice that muscle aches are accompanied by fever, fatigue, or dark urine, this could be a sign of a serious condition called rhabdomyolysis (muscle breakdown).Rhabdomyolysis can lead to kidney failure and even death (Tomaszewski, 2011).

Liver complications

Atorvastatin may cause abnormalities in blood function tests (elevated serum transaminase levels), and your provider will likely perform baseline liver blood tests before starting atorvastatin (McIver, 2020).

Get immediate medical attention if you have any of the following symptoms of liver problems or impaired liver function: fatigue and weakness, dark urine, loss of appetite, abdominal pain, yellowing of the skin or whites of the eyes.These can all be signs of liver problems.

What is atorvastatin used for?

Atorvastatin (brand name Lipitor) is FDA approved for the following uses (DailyMed, 2019):

• Reducing the risk of heart attacks and strokes in people with cardiovascular risk factors such as age, smoking, high blood pressure, diabetes, low HDL (good cholesterol) levels or family history of early heart disease
• Decreases the likelihood of heart surgery and also reduces the risk of heart attacks and strokes in people with heart disease.
• Reducing total cholesterol and low-density lipoprotein (LDL) cholesterol when used with dietary modifications
• Raising good cholesterol (HDL) when using dietary modifications
• Reducing triglycerides when used with adult dietary modifications
• Treat with family hypercholesteritis and primary dysbetalipoproteinemia, disorders that cause abnormal cholesterol levels.
• Reducing the amount of cholesterol and other fatty substances in the blood of pediatric patients (aged 10-17 years) with heterozygous familial hypercholesterolemia (a genetic disorder in which cholesterol cannot be eliminated from the body in the usual way)

Currently, there are several types Prescription statins approved by the US Food and Drug Administration (FDA).In addition to atorvastatin, other available statins include fluvastatin (trademark Lescol), lovastatin (trademark Mevacor), pitavastatin (trademark Livalo), pravastatin (trademark Pravachol), rosuvastatin (trademark Crestor), and simvastatin (trademark Zocor). …

Whichever statin you choose, talk to your doctor and together you can find the treatment option that works best for you.

Recommendations

1. Acharya, T., Huang, J., Tringali, S., Frey, K.R., Mortensen, E.M., & Muncie, I.A. (2016). Statin use and risk of kidney disease in long-term follow-up (8.4-year study). American Journal of Cardiology, 117 (4), 647–655. https://doi.org/10.1016/j.amjcard.2015.11.031
2. American Heart Association (AHA). (2017). Prevention and treatment of high cholesterol (hyperlipidemia). Retrieved October 7, 2020 from https://www.heart.org/en/health-topics/cholesterol/prevention-and-treatment-of-high-cholesterol-hyperlipidemia
3. Bailey, D.Dresser, J. Arnold, J.M. (2013). Grapefruit drug interactions: forbidden fruit or avoidable consequences? CMAJ. DOI: 10.1503 / cmaj.120951. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589309/
4. Collins, R., Wright, K., Amberson, J., Armitage, J., Baigent, K., and Blackwell, L. et al. (2016). Interpreting evidence for the efficacy and safety of statin therapy. Lancet, 388 (10059), 2532-2561. https://doi.org/10.1016/s0140-6736(16)31357-5
5. DailyMed – atorvastatin calcium, film-coated tablets (2019)). Retrieved October 7, 2020 from https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1daa6f20-a032-4541-939d-931f36a020dd#ID95
6. Dormuth, K.R. Hemmelgarn, B. Paterson, J.M. (2013). Use of high-potency statins and hospital admission rates for acute kidney injury: a multicenter retrospective observational analysis of administrative databases. BMJ. Doi: 10.1136 / bmj.f880. Retrieved from https://www.bmj.com/content/346/bmj.f880
7. Jose J. (2016).Statins and their effects on the liver: new evidence, implications and changing recommendations. Journal of Pharmacy and Biological Sciences, 8 (1), 23-28. https://doi.org/10.4103/0975-7406.171699
8. McIver, L.A. Siddiq, M.S. (2020). Atorvastatin. StatPearls. Retrieved October 7, 2020 from https://www.ncbi.nlm.nih.gov/books/NBK430779/
9. Rosenson, RS. (2020). Statins: actions, side effects and uses. Until now. Retrieved October 7, 2020 from https://www.uptodate.com/contents/statins-actions-side-effects-and-administration?search=statins-and-kidney-disease
10. Salami, J., Warrich, H., Valero-Elizondo, J., Spatz, E., Desai, N., & Rana, J., et al. (2017). National Trends in Statin Use and US Adult Costs from 2002 to 2013 JAMA Cardiology, 2 (1), 56.https: //doi.org/10.1001/jamacardio.2016.4700
11. Tomashevsky, M., Stempen, K.M., Tomashevska, Yu., Chuchvar, S. Yu. ). Statin-induced myopathies. Pharmacological reports. PR, 63 (4), 859-866. DOI: 10.1016 / s1734-1140 (11) 70601-6. Retrieved from https: //www.sciencedirect.com / science / article / abs / pii / S1734114011706016
12. UpToDate – Atorvastatin Drug Information (NA). Retrieved October 7, 2020 from https://www.uptodate.com/contents/atorvastatin-drug-information
13. US Food and Drug Administration (FDA).