November 2019 INESSS Quebec’s national medical protocol – Lipid-lowering agents 1

Dose adjustments for lipid-lowering pharmacologic agents (statins and ezetimibe) in cardiovascular risk management

No 628005

Developed in collaboration with an advisory committee consisting of Québec clinicians and experts Validated by the Comité d’excellence clinique en usage optimal du médicament, des protocoles médicaux nationaux et ordonnances of the Institut national d’excellence en santé et en services sociaux (INESSS)

CLINICAL SITUATION OR TARGET POPULATION

Person 18 years of age or older currently on lipid-lowering therapy (statin alone or with ezetimibe) that is part of a cardiovascular risk management strategy.

CONTRAINDICATIONS TO THE APPLICATION OF THIS PROTOCOL

Pregnancy and breastfeeding Familial hypercholesterolemia

INSTRUCTIONS

GENERAL INFORMATION – TREATMENT

► Prescribing the optimum dose of a lipid-lowering agent may be an option for reducing cardiovascular risk, preferably as part of a shared decision-making process that includes:

• an assessment of the patient’s overall cardiovascular risk, based on all information gathered (history, risk factors, physical examination, laboratory tests, calculation of 10-year cardiovascular risk);

• presenting various treatment options to the patient, and discussing risks and benefits o a discussion of lifestyle changes to reduce the patient’s cardiovascular risk before prescribing a

lipid-lowering agent (allowing sufficient time to optimize these changes) or concomitantly with the prescription of a lipid-lowering agent;

• setting treatment goals that are in line with the patient’s values and preferences o determining follow-up values for the effects of lipid-lowering agents and lifestyle changes on the

patient’s lipid profile (Appendix I). ► Once the decision to initiate pharmacological treatment has been made, statins are the treatment of choice

among lipid-lowering agents, but they should not supplant a positive lifestyle change. ! Higher treatment intensities should be a part of secondary prevention (Section 3.2). The other lipid-

lowering drugs or other agents on the market (e.g., anti-PCSK9 antibodies) should be used, if needed, at a subsequent stage of the treatment.

! Prescribing a dose every other day is not advised when initiating statin treatment for primary prevention.

! When deciding to initiate statin treatment in patients over 75 years of age whose health is not compromised, a low to moderate dose (Section 3.2.1) is preferable to a high dose in first-line treatment, especially for primary prevention.

For additional information, refer to the Algorithmes de prévention du risque cardiovasculaire published by INESSS.

November 2019 INESSS Quebec’s national medical protocol – Lipid-lowering drugs 2

1. ASSESS HEALTH STATUS WHEN MAKING THE ADJUSTMENT

Emphasize the importance of optimizing a healthy lifestyle and ask what changes have been made (Section 4.2).

Document any recent changes that could impact the relevance of the treatment or the treatment itself. • Find out if patient is using any new medications and/or natural products that could present a risk of

interaction with statins or ezetimibe (Appendix II). Check other conditions that could raise cardiovascular risk (Section 4.3). Analyze and document any adverse effects that may have occurred (Section 4.5).

2. LABORATORY TESTS RELATED TO DOSE ADJUSTMENT

Review results of laboratory tests performed before treatment was initiated. Schedule laboratory tests needed for dose adjustment.

LABORATORY TESTS

Tests Prior to start of treatment

Once every 4 to 6 weeks until LDL is reduced as expected (target) based on intensity of prescribed

treatment

If symptoms are present

Lipid profile(1) (fasting or non-fasting)

3 m

onth

s(2)

√ (4) √ (4)

ALT √ √ (6)

CK (5) √ (7)

Creatinine (calculation of eGFR)

√

HbA1C

12 m

onth

s(3)

√

TSH √

1. A high-fat, low-carbohydrate diet (e.g., a ketogenic diet) could impact the blood lipid profile (↑HDL, ↑LDL, ↓TG). 2. Results of tests performed in the last 3 months can be used. 3. Results of tests performed in the last 12 months can be used. 4. If TG > 4.5 mmol/L, redo fasting lipid profile (with no alcohol consumption in the previous 48 hours) or use non-HDL or

measure Apo-B to assess treatment. TG ≥ 1.7 mmol/L, combined with abdominal obesity, could result in metabolic syndrome. 5. While CK measured prior to statin treatment provides a baseline value for comparison as needed, too many people are tested

needlessly. Order this test only when muscle symptoms are present, especially since CK is often normal and is not an absolute indicator.

6. Hepatotoxicity: e.g., unusual weakness or fatigue, loss of appetite, abdominal pain, dark urine, jaundice. 7. Myopathy: e.g., pain, sensitivity, cramps, muscle weakness.

Abbreviations: ALT: alanine aminotransferase; CK: creatine kinase; eGFR: estimated glomerular filtration rate; HbA1c: glycosylated hemoglobin; HDL: high-density lipoproteins; LDL: low-density lipoproteins; non-HDL: total – HDL cholesterol; TG: triglycerides; TSH: thyroid-stimulating hormone.

November 2019 INESSS Quebec’s national medical protocol – Lipid-lowering drugs 3

3. RECOMMENDED PROCEDURE FOR DOSE ADJUSTMENT

3.1 General principles

If the statin dose is well tolerated, it does not need to be reduced immediately in patients over 75 years of age who are taking it for secondary prevention.

Work to reach the maximum tolerated dose of a statin rather than introducing another lipid-lowering agent.

3.2 General information about the medication

For additional information on statins or ezetimibe, see Appendix II.

3.2.1 Treatment intensity and risk categories

The intensity of statin treatment determines the potential for LDL reduction (%) expected in a patient who is more than 80% treatment-compliant.

Ezetimibe is generally prescribed in combination with a statin as adjuvant therapy when LDL is not reduced as desired, despite statin and lifestyle optimization, in patients presenting with proven clinical signs of atherosclerosis (secondary prevention)7.

TREATMENT INTENSITY BASED ON RISK CATEGORY(1)

Firs

t-lin

e tre

atm

ent

STAT

INS

Treatment intensity Drug Risk category

HIGH (↓ LDL ≥ 50%)

Atorvastatin 40(2), 80 mg Rosuvastatin 20(3), 40 mg

Secondary prevention(4) and other specific clinical conditions(5)

MODERATE (↓ LDL 30% to 50%)

Atorvastatin 10, 20 mg Fluvastatin 40 mg BID or 80 mg QD (sustained-release preparation) Lovastatin 40(2), 80 mg Pravastatin 40, 80 mg Rosuvastatin 5, 10(2) mg Simvastatin 20, 40 mg

Primary prevention(6) when cardiovascular risk is not raised due to a specific clinical condition(5)

LOW (↓ LDL < 30%)

Fluvastatin 20, 40 mg Lovastatin 20 mg Pravastatin 10, 20 mg Simvastatin 5, 10 mg

When it represents the highest dose tolerated

Adj

uvan

t th

erap

y ( a

dded

)

(↓ LDL up to 23%) Ezetimibe 10 mg Secondary prevention(4) when statin cannot be optimized based on achievement of goals and targets set(7)

1. Except in the case of familial hypercholesterolemia, there is limited evidence linked to cardiovascular benefits for the other classes of lipid-lowering agents (fibrates, bile acid sequestrants, niacin).

2. Maximum recommended dose in cases of serious renal failure (eGFR lower than 30 ml/min./1.73 m2). 3. Maximum recommended dose for patients of Asian origin. 4. Secondary prevention: In patients with previous cardiovascular events. 5. Specific clinical conditions: Familial hypercholesterolemia (FH), clinical evidence of atherosclerosis, chronic kidney disease,

abdominal aortic aneurism, diabetes (40 years and over, 30 years and over and duration of 15 years [Type 1], microvascular complication).

6. Primary prevention: In patients with no previous cardiovascular events. 7. The effectiveness of ezetimibe on cardiovascular events was only reported in an IMPROVE-IT sub-study of people with

diabetes and people who were 75 years of age or over, in secondary prevention (effectiveness statistically significant in secondary prevention, myocardial infarct (24%) and ischemic stroke cases (39%).

November 2019 INESSS Quebec’s national medical protocol – Lipid-lowering drugs 4

3.3 Dose adjustment modalities

Adjust lipid-lowering agents based on laboratory test results, as shown in the table below. Order another lipid profile, to be done 4 to 6 weeks after the lipid-lowering agent has been changed.

DOSE ADJUSTMENT MODALITIES ADJUSTMENT INTERVAL: EVERY 6 TO 8 WEEKS

Drugs Dose adjustment modalities(1)

Firs

t-lin

e tre

atm

ent S

TATI

NS(2

)

Atorvastatin 10 ↔ 20 ↔ 40(3) ↔ 80 mg PO QD

Fluvastatin 20 mg PO QD ↔ 40 mg PO QD ↔ 40 mg PO BID OR 80 mg (sustained-release preparation) PO QD

Lovastatin 20 ↔ 40(3) ↔ 80 mg PO QD

Pravastatin 10 ↔ 20 ↔ 40 ↔ 80 mg PO QD

Rosuvastatin 5 ↔ 10(3) ↔ 20(4) ↔ 40 mg PO QD

Simvastatin 5 ↔ 10 ↔ 20 ↔ 40 mg PO QD

Adj

uvan

t th

erap

y(5) (a

dded

)

Ezetimibe 10 mg PO QD

1. The maximum statin dose is limited for some drug combinations (see Appendix II). 2. Doubling a statin dose or dividing it in two only changes LDL by 6% (avoid intermediate doses that only have a 3% effect). 3. Maximum recommended dosage in cases of serious renal failure (eGFR lower than 30 ml/min./1.73 m2). 4. Maximum recommended dosage for patients of Asian origin. 5. Adding ezetimibe to a statin could lead to a drop in LDL of up to 23%.

4. FOLLOW-UP Set out the modalities of the next follow-up appointment. Follow up and adjust lipid-lowering agents, keeping in mind the management of overall cardiovascular

risk, which should include working with a multidisciplinary team to optimize lifestyle (through an intensive approach when the user’s clinical condition allows) and management of conditions that raise cardiovascular risk. As such:

• Work with the multidisciplinary team to periodically reassess the attainment of goals set (Section 4.1).

• Document lifestyle and changes made (Section 4.2).

• Document recent changes that could impact relevance of treatment or the treatment itself.

• Document any adverse effects that may have occurred. o Order tests related to the presence of adverse effects. o Adjust dose of lipid-lowering agents as needed (Section 4.5.1 ).

• If lipid profile results are abnormal: o Check treatment compliance and persistence (Section 4.4). o Look for causes of secondary dyslipidemia (Section 4.3) and find out if patient has adopted a

high-fat, low-carbohydrate diet (e.g., ketogenic diet). o Adjust lipid-lowering agents as needed (Section 3.3).

November 2019 INESSS Quebec’s national medical protocol – Lipid-lowering drugs 5

4.1 Treatment goals and targets

TREATMENT GOALS AND TARGETS

Treatment goals and targets are personalized in consultation with the patient, in a shared decision-making process. The INESSS shared decision-making tool can be helpful for this process and the tracking sheet can be used to compile choices.

o quit smoking (including street drugs and cannabis) o moderate alcohol consumption o time spent doing physical activity o weight loss o abdominal circumference o 80% compliance and persistence – statin taken continuously for several years o diet includes quantity of fruits and vegetables in line with nutritionist’s recommendations/Canada Food Guide o sleep (duration and quality) o stress level and stress management

4.2 Lifestyle

OPTIMIZE A HEALTHY LIFESTYLE

• Lifestyle changes (including types of foods consumed) have an effect on overall health, above and beyond that achieved through the use of statins or other lipid-lowering agents. It is therefore preferable to target results based on goals set with the patient in the action plan, rather than on an LDL target value.

• Optimization of a healthy lifestyle can take several weeks/months and be achieved by working with various healthcare professionals:

o physician o nurse o pharmacist o dietician/nutritionist o physical activity specialist (e.g., kinesiologist)

• It may be easier to opt for changing one aspect at a time, in order to facilitate treatment compliance and persistence.

• Reassessment of cardiovascular risk is advisable after a certain period of time (with baseline lipid profile values), so the patient can be shown the benefits of his/her lifestyle changes.

• Ask patient about his/her consumption of food and drug-type supplements.

4.3 Conditions that raise cardiovascular risk

OPTIMIZE MANAGEMENT OF CLINICAL CONDITIONS THAT RAISE CARDIOVASCULAR RISK

Monitor causes of secondary dyslipidemia, treated before initiation of lipid-lowering therapy, and exclude de novo comorbidities as needed. Refer to guidelines for treatment plan and monitor various aspects, including:

• hypertension • diabetes

November 2019 INESSS Quebec’s national medical protocol – Lipid-lowering drugs 6

CAUSES* OF SECONDARY DYSLIPIDEMIA (LDL, HDL, TG)

• anorexia • primary or secondary hypothyroidism • obstructive liver disease • poor lifestyle (e.g., foods rich in saturated fats, smoking,

sedentary lifestyle, abdominal obesity) • nephrotic syndrome • certain drugs:

- retinoic acid - atypical antipsychotics - beta-blockers (except carvedilol, nebivolol) - cyclophosphamide - cyclosporin

- diuretics - estrogens - glucocorticoids - interferon - protease inhibitors - L-asparaginase - raloxifene - rosiglitazone - bile acid sequestrants - anabolic steroids - sirolimus - tamoxifen - tacrolimus

* Adapted from Grundy et al, 2018.

4.4 Drug therapy compliance and persistence

COMPLIANCE AND PERSISTENCE

The patient should be asked directly if he/she is taking his/her medications (e.g., how many doses were missed over the past month, and why). If needed, the patient can keep a log of when medication was taken.

The patient should be made aware of the need for drug therapy compliance and persistence over the next several years – even for the rest of his/her life – in order to achieve the desired benefits.

Although LDL values do not have to be followed up regularly once the pre-set follow-up values are attained, these laboratory tests could be incorporated, as needed, into the compliance and persistence tracking, along with reassessment of cardiovascular risk and/or cardiovascular age.

November 2019 INESSS Quebec’s national medical protocol – Lipid-lowering drugs 7

4.5 Adverse Effects

During follow-up visits, list all possible statin-related adverse effects that could interfere with the treatment by preventing optimization or resulting in curtailment, as reported by the patient since treatment was initiated.

• Remain vigilant for muscle symptoms and/or symptoms that are compatible with acute hepatotoxicity.

Remain watchful for adverse effects that occur more frequently in the elderly. Watch for risk factors that could intensify the adverse effects of statins.

ADVERSE EFFECTS

Adverse effects Statins1 Ezetimibe

More frequent Myalgia Fatigue, digestive problems

More rare

↑ liver transaminases

Statin-specific:

• Myositis, ↑ muscle enzymes

• Rhabdomyolysis

↑ liver transaminases

Myalgia2

1. See Appendix II for a more detailed table of statin-related adverse effects and their frequency. 2. Rare cases of myopathy have been reported in patients taking ezetimibe, with or without a statin, independently of the causal

relationship with the drug.

MUSCLE-RELATED SYNDROMES1

Syndrome Definition

Myopathy General term associated with muscle-related syndromes.

Myalgia Condition associated with muscle symptoms (e.g., pain, sensitivity, cramps). CK below upper limit of normal (ULN).

Myositis Condition usually associated with muscle symptoms (e.g., pain, sensitivity, cramps, weakness). CK rises above ULN.

Rhabdomyolysis

Serious, very rare form of myositis.

Characterized by significant muscle pain, muscle necrosis and myoglobinuria.

Possible complication: Acute renal failure. CK rises significantly above ULN.

1. Considered: Other causes of muscle symptoms, such as an underlying neuromuscular disorder, polymyalgia rheumatica, severe vitamin D deficiency or, very rarely, immune-mediated necrotizing myositis.

November 2019 INESSS Quebec’s national medical protocol – Lipid-lowering drugs 8

TYPICAL SYMPTOMS AND SIGNS OF ACUTE HEPATITIS

Symptoms Signs

Late-day fever or sweating

Loss of appetite and weight loss

Nausea

Abdominal discomfort (especially on the right side)

Yellowish skin and conjunctiva

Dark (tea-coloured) urine

Increase in ALT Increase in bilirubin

MAIN RISK FACTORS FOR ADVERSE EFFECTS WITH STATINS

Alcohol abuse

Age > 80 years

History of muscle toxicity related to use of another statin

Personal or family history of hereditary muscle disorders

Surgery or trauma

Diabetes with hepatic steatosis

Statins in high doses

Fragile health

Low BMI (< 18.5 kg/m2), frail constitution/frailty

Excessive physical exercise

Hypothyroidism

Renal failure

Hepatic failure

Drug interaction with statins (Appendix II)

Neuromuscular disease

Patients of Asian origin

Concomitant use of a fibrate (especially gemfibrozil) or niacin

4.5.1 Procedure in case of statin-induced adverse effects

► Check muscle or hepatic symptoms objectively, measuring CK and ALT respectively during statin treatment (Section 3).

► Try stopping treatment for a short time, followed by reintroduction, dose reduction or substitution (a different statin1), in an attempt to establish a causal relationship between symptom presentation and the statin.

o Although one week off the statin is usually enough time to form a general idea, a longer period, or a “stop-start” over a few periods, may be needed to see if the adverse effects disappear.

! Muscle pain is not often associated with elevated CK.

1 Do not make simvastatin a preferred option.

November 2019 INESSS Quebec’s national medical protocol – Lipid-lowering drugs 9

4.5.2 Management of statin intolerance — decisional algorithm

November 2019 INESSS Quebec’s national medical protocol – Lipid-lowering drugs 10

5. SITUATIONS REQUIRING SPECIAL ATTENTION, FURTHER INVESTIGATION OR A REEVALUATION

Special attention or reassessment ► Onset of an allergic reaction to the lipid-lowering agent prescribed ► Deterioration of patient’s state of health ► Pregnancy or breast-feeding while on treatment ► Statin non-compliance regularly noted ► Causes of secondary dyslipidemia are present ► Presence of risk factors for adverse effects while on statin (e.g., personal or family history of hereditary

muscle disorders) ► Presence of adverse effects

Further investigations ► Failure to attain follow-up lipid values (LDL lower than 5 mmol/L)

o LDL equal to or higher than 5 mmol/L, with secondary causes of dyslipidemia excluded (screening for familial hypercholesterolemia if suggested by family history1)

► Alternative markers (non-HDL or ApoB) are off-target, although LDL is within target value limits (residual cardiovascular risk should also be taken into consideration)

► CK elevated to more than 10 times the upper limit of normal (ULN) (or results exceeded 5 times ULN twice): suspicion of rhabdomyolysis

► Serious progressive liver disease or persistent unexplained rise in liver transaminase levels (more than 3 times ULN)

► TG exceeding 4.5 mmol/L (LDL cannot be calculated; refer to non-HDL or Apo B if available): • higher than 5.6 mmol/L: risk of pancreatitis • higher than 10 mmol/L: major risk of pancreatitis

REFERENCES

This national medical protocol is based on the latest scientific data and best practice recommendations, which were enhanced with contextual information and experiential knowledge provided by Québec clinicians and experts. For further details on the process used to develop this protocol and to consult the references, see the report in support of this protocol.

November 2019 INESSS Quebec’s national medical protocol – Lipid-lowering drugs 11

APPENDIX I PHARM ACOLOGICAL TREATMENT INDICATIONS Correlate the lipid profile with a cardiovascular risk assessment, using a risk calculator (e.g., the shared INESSS decision-making tool, Framingham).

! Lipid profile exceeding threshold values: This result should not be considered in isolation when deciding to initiate pharmacological treatment. Consider ordering another lipid profile to corroborate the first result after an intensive approach that enables lifestyle changes.

! Low HDL and high TG are associated with a higher cardiovascular risk. However, the data currently available do not support an indisputable conclusion (sub-group studies only) that pharmacological intervention targeting these parameters reduces cardiovascular risk.

INDICATIONS FOR PHARMACOLOGICAL TREATMENT FOLLOW-UP LIPID VALUES

Prim

ary

prev

entio

n

High risk: Framingham ≥ 20% Moderate risk: Framingham ≥ 10% and < 20% AND LDL ≥ 3.5 mmol/L

OR Non-HDL ≥ 4.3 mmol/L

OR Apo B ≥ 1.2 g/L

OR Male > 50 years, female > 60 years AND presence of one of the following cardiovascular risk factors:

Low HDL, glucose intolerance, large abdominal circumference, smoking, hypertension LDL < 2.0 mmol/L OR

LDL > 50%

Alternative targets:2 Non-HDL < 2.6 mmol/L

OR Apo B < 0.8 g/L

Clin

ical

con

ditio

ns re

quiri

ng s

tatin

trea

tmen

t Clinical signs of atherosclerosis (cardiovascular, cerebrovascular or peripheral vascular disease)

OR Abdominal aortic aneurism (diameter exceeds 3 cm) OR Diabetes AND ≥ 40 years

OR ≥ 30 years AND duration > 15 years (Type 1)

OR Microvascular complications

OR Chronic renal failure (≥ 50 years, duration > 3 months) AND

eGFR < 60 ml/min./1.73 m2 OR

Albumin/creatinine ratio > 3 mg/mmol

LDL ≥ 5.0 mmol/L (including familial hypercholesterolemia excluded from this protocol) LDL > 50%

1. These are the targets recommended by the Canadian Cardiovascular Society in 2016. They may be changed in 2020, in line with other learned societies that are targeting LDL reduction up to 1.8 mmol/L.

2. Since alternative targets include cholesterol contained in non-LDL lipoproteins, they are more sensitive predictors and can be used to update residual cardiovascular risk, especially when LDL cannot be calculated due to high TG rates.

Abbreviations: APO-B: apolipoprotein B; eGFR: estimated glomerular filtration rate; HDL: high-density lipoprotein; LDL: low-density lipoprotein; non-HDL: total – HDL cholesterol.

November 2019 INESSS Quebec’s national medical protocol – Lipid-lowering drugs 12

APPENDIX I I SUPPLEMENTARY INFORMATION ON STATINS AND EZETIMIBE

The information set out below is not exhaustive.

DRUG-SPECIFIC CONTRAINDICATIONS AND PRECAUTIONS

STATINS EZETIMIBE

Contra-indications • History of allergic reaction to statin • Pregnancy or breast-feeding • Serious progressive liver disease or persistent

unexplained rise in liver transaminase levels (> 3 times upper limit of normal)

• History of allergic reaction to ezetimibe • Pregnancy or breast-feeding

Precautions • Regular consumption of alcohol in large quantities • Serious progressive liver disease or persistent unexplained rise in liver transaminase levels (> 3 times upper limit of normal)

November 2019 INESSS Quebec’s national medical protocol – Lipid-lowering drugs 13

MOST FREQUENT ADVERSE EFFECTS OF STATINS

TREATMENT RISKS AND BENEFITS

MOST FREQUENTLY REPORTED ADVERSE EFFECTS

• headache (7.7%) • diarrhea (4.5%) • abdominal pain/cramps (3.3%) • nausea/vomiting (3.3%) • flatulence (3.0%) • rash/pruritus (3.0%) • constipation (2.7%) • vertigo (2.3%)

• heartburn (2.2%) • insomnia (1.9%) • paresthesia (1.0%) • more serious but less than 1%

o myalgia

o hepatic

o rhabdomyolysis

o onset of Type 2 diabetes

Adverse effects – less than 1%

Statin risk expressed as relative risk and absolute risk: statins vs. placebo1

Events Type of risk Statins1

All treatment intensities2 High treatment intensity2

Myalgia RRI 2% - 5%

ARI/1000 0 - 3

Hepatic RRI 90% 57%

ARI/1000 + 3 + 4

Rhabdomyolysis RRI 21% - 36%

ARI/1000 0 0

Onset of Type 2 diabetes RRI 9% 25%

ARI/1000 + 4 + 6

Statin risk expressed as relative risk and absolute risk: High vs. low treatment intensity1

Adverse effect Type of risk Atorvastatin 80 vs. 20 mg2 Simvastatin 80 vs. 20 mg3

Hepatic RRI 762% —

ARI/1000 + 13 (from 1 to 101 more) —

Rhabdomyolysis RRI — 315%

ARI/1000 — + 5 (from 2 to 10 more)

1 From the NICE (National Institute for Health and Care Excellence) systematic review with meta-analysis of randomized controlled trials.

2 5-year follow-up. 3 7-year follow-up.

ARI: Absolute risk increase; RRI: Relative risk increase.

From https://www.inesss.qc.ca/fileadmin/doc/INESSS/Algo_statines/Prevcardioavec/PrevRisqueCV-avec-algo_16.pdf

November 2019 INESSS Quebec’s national medical protocol – Lipid-lowering drugs 14

MOST SIGNIFICANT DRUG INTERACTIONS

The information set out below is not exhaustive.

The potential for drug interaction should be assessed whenever changes are made or items added to a medication profile. Consult the appropriate references and/or a pharmacist as needed.

1Atorvastatin, lovastatin and simvastatin.

MOST IMPORTANT INTERACTIONS

STAT

INS

• Amiodarone • Azole antifungal drugs (e.g., fluconazole, itraconazole, ketoconazole) • Calcium channel blockers (e.g., amlodipine, diltiazem, verapamil) • Cyclosporin • Fibrates (in particular, gemfibrozil) • Protease inhibitors (e.g., lopinavir, nelfinavir, simeprevir) • Macrolides (e.g., clarithromycin, erythromycin) • Niacin • Grapefruit juice in large quantities (> 1 L/day)1

Effect: ↑ in plasma concentration of statins metabolized by cytochrome P450 3A41 or additive myotoxic effect

• Warfarin Effect: ↑ risk of bleeding

EZET

IMIB

E

• Cyclosporin • Fibrates • Niacin

Effect: ↑ plasma concentration of ezetimibe or additive toxicity