Dyslipidemia. Pharmacological Options and Considerations for Management

Transcription

1 Dyslipidemia Pharmacological Options and Considerations for Management

2 Table of Contents Dyslipidemia Management Summary 2 Assess Cardiovascular Risk 6 Determine Treatment Targets 12 Implement Treatment Strategy 18 Pharmacological Treatment Options 22 Statins 25 Ezetimibe 34 Fibrates 37 Niacin 41 Bile Acid Resins 43 PCSK9 Inhibitors 48 References 50 CE Questions 54 Notes 56 V 4.0_2017 1

3 Dyslipidemia Management Summary

4 Dyslipidemia Management Summary Learning Objectives: After consulting this counselling guide, pharmacists will be better able to: 1. Assess 10-year cardiovascular risk of patients 2. Individualize treatment for dyslipidemia according to 10-year cardiovascular risk and patient assessment 3. Determine treatment targets for dyslipidemia according to 10-year cardiovascular risk and presence of conditions warranting pharmacological treatment (e.g., clinical atherosclerosis) 4. Educate patients about differences between drugs and classes of drugs used to treat dyslipidemia 5. Counsel patients on potential adverse events and precautions associated with medication(s) used to treat dyslipidemia Summary: The Pharmacist s Role in Recommending Treatment for the Management of Dyslipidemia There are many issues that must be taken into consideration when recommending treatment and counselling patients about dyslipidemia. Following is a brief step-by-step summary: 1 Assess 10-year cardiovascular (CV) risk for men and women 40 years of age or older or at any age if one or more CV risk factors present as outlined in table on p. 8. Requires lipid panel (i.e., measurement of LDL-C, HDL-C, TC, TG). Note: 2016 CCS Dyslipidemia Guidelines state that non-fasting lipid panel is now acceptable unless TG levels > 4.5 mmol/l. Also requires age, blood pressure measurements, smoking status, diabetes status Determine 10-year CV risk as low, intermediate, or high. Risk is determined according to Framingham Risk Score and patient risk factors. Recommend treatment for patients according to recommendations of the 2016 Canadian Dyslipidemia Guidelines. 1 Statins are first-line therapy to reduce LDL-C level. A 50% reduction in LDL-C level is often achievable with single-agent statin therapy (e.g., atorvastatin, rosuvastatin) at moderate to high doses. Ezetimibe is first option as add-on therapy for patients on maximally tolerated statin therapy that have not reached targets. Advise patients of differences in options within each drug class being recommended. Advise patients of side effects, risks, and need for monitoring for each drug being recommended. Ensure the patient understands the exact dose of the drug to be taken, exactly when to take the drug, side effects to expect, and anything that should be reported to a health professional. Address patient concerns that may arise when receiving a generic version of their medication by using simple language to explain processes in place to ensure quality of the generic version. The quality standards for brand name drugs and generic drugs are the same, as the ingredients, manufacturing processes and facilities for all drugs must meet the federal guidelines for Good Manufacturing Practices. 2 In order to be deemed bioequivalent, the generic drug must show that it delivers the same amount of medicinal ingredient at the same rate as the brand name drug in each healthy individual that uses both versions of the drug through studies known as comparative bioavailability studies. 2 Nonmedicinal ingredients, like fillers and ingredients that colour the drug, may be different from those of the brand name product. 2 The generic manufacturer must provide studies showing that the different nonmedicinal ingredients have not changed the quality, safety or effectiveness of the generic drug. 2 List of Acronyms Used LDL-C = Low density lipoprotein cholesterol HDL-C = High density lipoprotein cholesterol TC = Total cholesterol TG = Triglycerides ApoB = Apolipoprotein B CCS = Canadian Cardiovascular Society 4 5

5 Assess Cardiovascular Risk

6 Assess Cardiovascular Risk Step 1. Assess Cardiovascular (CV) Risk for Your Patient Assess risk factors for CV disease in each patient. Screening of plasma lipids is recommended in adult men and women 40 years. 1 Reduction in CV risk factors is enhanced by sharing the risk profile with the patient. 1 Before prescribing medication for dyslipidemia, a thorough history should be taken, including potential contraindications, smoking history, and medications. 1 The 2016 Canadian Dyslipidemia Guidelines recommend that a CV risk assessment using the 10-year risk as provided by the Framingham model (see p. 11) be completed every 3-5 years for men and women age A risk assessment may also be completed whenever a patient s risk status changes or at any age if any of the CV risk factors listed in the table below are present. The percent risk should be doubled when family history of premature CV disease is present (i.e., first-degree relative < 55 years for men and < 65 years for women). CV Risk Factors Include the Following 1 Current cigarette smoking Diabetes Hypertension Family history of premature CV disease Erectile dysfunction Chronic kidney disease Family history of dyslipidemia Hypertensive diseases of pregnancy Determine CV Risk by Framingham Risk Model 3 Inflammatory bowel disease HIV infection COPD Clinical evidence of atherosclerosis or abdominal aneurysm Clinical manifestation of hyperlipidemia Obesity (body mass index > 30 kg/m 2 ) Step 1 In the points column enter the appropriate value according to the patient s age, HDL-C, total cholesterol, systolic blood pressure and if they smoke or have diabetes. Calculate the total points. Risk Factor Risk Points Points Men Women Age (years) HDL-C (mmol/l) > < Total Cholesterol (mmol/l) < > Systolic Blood Pressure (mmhg) Not Treated Treated Not Treated Treated < Yes 3 4 Diabetes No 0 0 Yes 4 3 Smoker No 0 0 Total Points 8 9

7 Assess Cardiovascular Risk Step 2 Using the Total Points from Step 1, determine the 10-year CVD risk (%). Step 3 Total Points 10-Year CVD Risk (%) Men Women -3 or less < 1 < < > > > > 30 > 30 For subjects between 30 and 59 years double cardiovascular disease risk percentage if cardiovascular disease is present in a first-degree relative before 55 years of age for men and 65 years of age for women. Adapted from Anderson TJ, et al Update of the Canadian Cardiovascular Society Guidelines for the Diagnosis and Treatment of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult. Supplementary Material. CV Risk Calculation 1 Determine your patient s 10-year cardiovascular risk percentage. CV Risk Factor Age (Gender) Years HDL Cholesterol mmol/l Total Cholesterol mmol/l Systolic BP mmhg Smoking Status Yes or No Diabetes Status Yes or No Total Points 10-Year CV Risk (Framingham Risk Score) *Double percentage if family history of CV disease exists Low = < 10%, Intermediate = 10-19%, High = 20% Ensure that patients understand that 10-year CV risk refers to the total risk of experiencing a CV event within the next 10 years. 1 The 2016 CCS Dyslipidemia Guidelines recommend that the concept of cardiovascular age be introduced to patients. 1 The rationale is to improve the likelihood that patients will reach lipid targets and that poorly controlled hypertension will be treated. In other words, a patient discovering that his/her cardiovascular age was much higher than his/her chronological age may be more motivated to engage in activities aimed at reducing CV risk. 1 An individual s CV age can be determined online at Points Points %* Low, Intermediate, High One of the most common reasons for stopping lifestyle modification or pharmacological therapies is that the patient remains unconvinced of the need for treatment. 1 Discussing an individual s CV age, which is often higher than his/her actual age, and the reduction associated with ongoing treatment may help patients remain adherent to therapy

8 Determine Treatment Targets

9 Determine Treatment Targets Step 2. Determine Treatment Targets Based on Level of CV Risk PATIENTS AT HIGH RISK 1 High Risk Features One or more of the following: Framingham Risk Score 20% Clinical vascular disease Abdominal aortic aneurysm Diabetes and age 40 years, or > 15 years duration and age 30 years or microvascular disease* Chronic kidney disease (age 50 years) LDL-C 5 mmol/l Start Health Behaviour Modification + Statin Therapy Primary Target of LDL-C < 2 mmol/l or > 50% decrease in LDL-C Alternate Target: ApoB < 0.8 g/l or Non-HDL-C < 2.6 mmol /L *Not all subjects with diabetes are at high 10-year risk PATIENTS AT INTERMEDIATE RISK 1 Both of the following: No high risk features Framingham Risk Score 10-19% If LDL 3.5 mmol/l or Consider if LDL < 3.5 mmol/l and ApoB 1.2 g/l or Non-HDL-C 4.3 mmol/l Start Health Behaviour Modification + Statin Therapy If LDL < 3.5 mmol/l and ApoB < 1.2 g/l and Non-HDL-C < 4.3 mmol/l or men 50 years and women 60 years with one additional risk factor: low HDL-C, impaired fasting glucose, high waist circumference, smoker, hypertension Start Health Behaviour Modification Primary Target of LDL-C < 2 mmol/l or > 50% decrease in LDL-C Alternate Target: ApoB < 0.8 g/l or Non-HDL-C < 2.6 mmol /L 14 15

10 Determine Treatment Targets PATIENTS AT LOW RISK 1 Both of the following: No high risk features Framingham Risk Score < 10% Dyslipidemia Treatment Targets Based on Cardiovascular Risk 1 Risk Level Primary Target LDL-C Alternate Targets When to Initiate Therapy Low FRS <10% >50% reduction in LDL-C LDL-C 5.0 mmol/l Familial hypercholesterolemia If LDL 5.0 mmol/l or Familial Hypercholesterolemia Intermediate FRS 10%-19% <2 mmol/l or >50% reduction in LDL-C ApoB 0.8 g/l Non-HDL-C 2.6 mmol/l LDL-C 3.5 mmol/l and ApoB 1.2 g/l or Non-HDL-C 4.3 mmol/l Start Health Behaviour Modification + Statin Therapy High FRS 20% or CV Risk Factors as outlined <2 mmol/l or >50% reduction in LDL-C ApoB 0.8 g/l Non-HDL-C 2.6 mmol/l Consider treatment in all If LDL < 5.0 mmol/l and Framingham Risk Score < 5% Start Health Behaviour Modification Primary Target of > 50% decrease in LDL-C 16 17

11 Implement Treatment Strategy

12 Implement Treatment Strategy Step 3. Implement Treatment Strategy Summary of Health Behaviour Modification Strategies 1 1. Adopt healthy eating habits: 1 Moderate energy (caloric) intake to achieve and maintain a healthy body weight Emphasize a diet rich in vegetables, fruit, whole-grain cereals, and polyunsaturated and monounsaturated oils, including omega-3 fatty acids particularly from fish Avoid trans fats and limit saturated and total fats to < 7% and < 30% of daily total energy (caloric) intake, respectively Limit cholesterol intake to 200 mg daily for individuals with dyslipidemia or who are at increased CV disease risk Recommendation for the Mediterranean, portfolio, or dietary approaches to stop hypertension (DASH) diets to improve lipid profiles or decrease CV disease risk (see next column) For cholesterol-lowering, consider increasing phytosterols, soluble fibre, soy, and nut intake 2. Increase physical activity Accumulate at least 150 minutes of moderate-vigorous intensity aerobic physical activity per week, in bouts of 10 minutes or more to reduce CV disease risk 3. Quit smoking and limit alcohol intake to no more than 1-2 standard drinks per day Some health professionals suggest a approach to counselling patients on lifestyle modifications. This refers to 0 cigarettes, 5 servings of vegetables/fruits, and 30 minutes of exercise daily. 1 Mediterranean Diet 1 Eating primarily plant-based foods, such as fruit and vegetables, whole grains, legumes and nuts Replacing butter with healthy fats, such as olive oil Using herbs and spices instead of salt to flavour foods Limiting red meat to no more than a few times a month Eating fish and poultry at least twice a week Drinking red wine in moderation (optional) Study of almost 7,500 people (age years) Risk of MI, stroke or death from CV causes over 4.8 years reduced by 30% in group adding extra virgin olive oil and 28% in group eating extra nuts Profile Diet 1 Substitutes soy-based foods for meat Soy milk as dairy substitute Replaces butter with plant-sterol enriched margarines Includes plenty of fibre (e.g., psyllium to thicken soy milk) Preferred vegetables include eggplant and okra Study about 1/3 achieved >20% LDL reduction, another 1/3 about 15% reduction and about another 1/3 unable to follow diet Dietary Approaches to Stop Hypertension (DASH) Diet 1 Similar to Canada s Food Guide but recommends lower ranges in number of servings and higher level of vegetable and fruit intake Study resulted in average BP reduction of 11.4/5.5 mm Hg See https//: for diet overview 20 21

13 Pharmacological Treatment Options

14 Pharmacological Treatment Options Pharmacological Treatment Options: Statins Pharmacological Treatment of Dyslipidemia in Canada In Canada, the choice of medication for management of dyslipidemia, for first-time users, is aided by the recommendations of the 2016 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult, and should take into account the prescriber s clinical judgment and the preferences of the patient. Before prescribing pharmacological therapy, a thorough pretreatment assessment, which includes a comprehensive personal and family history, a physical examination, and appropriate laboratory investigations should take place. 4 Review of Available Pharmacological Options for Management of Dyslipidemia: Statins Atorvastatin Fluvastatin Lovastatin Pravastatin Rosuvastatin Simvastatin Ezetimibe Niacin Extended release niacin Resins Cholestyramine Colesevelam Colestipol Fibrates Bezafibrate Fenofibrate Gemfibrozil Relative Potencies of Currently Available Statin Therapies 5 High Intensity Statin Therapy (Lowers LDL-C by 50%) Atorvastatin mg Rosuvastatin mg Modern Intensity Statin Therapy (Lowers LDL-C by ~30% to <50%) Atorvastatin mg Rosuvastatin 5-10 mg Simvastatin mg Pravastatin mg Lovastatin 40 mg Fluvastatin L 80 mg Fluvastatin 40 mg BID Modern Intensity Statin Therapy (Lowers LDL-C by <30%) Simvastatin 10 mg Pravastatin mg Lovastatin 20 mg Fluvastatin mg Ensure that statin therapy is right for your patient See Table 1 for Statin Drug Indications Contraindications: 6-11 All Statins Patients who are hypersensitive to the statin drug or to any ingredient in the formulation. For a complete listing, see the Dosage Forms, Composition and Packaging section of the individual product monographs. Active liver disease or unexplained clinically relevant persistent elevations of serum transaminases. During pregnancy and in nursing mothers. Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). Statins should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the possible harm. (If the patient becomes pregnant while taking a statin, the drug should be discontinued immediately and the patient apprised of the potential harm to the fetus. Atherosclerosis being a chronic process, discontinuation of lipid metabolism regulating drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Contraindications listed in product monographs for particular statins Fluvastatin, Pravastatin Children under 9 years of age (fluvastatin) 7 In adolescents and children (pravastatin) 9 Lovastatin 8 Concomitant administration of potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin). In patients using concomitant cyclosporine. Rosuvastatin In patients using concomitant cyclosporine

15 Pharmacological Treatment Options: Statins Rosuvastatin 40 mg is contraindicated in: 10 Asian patients Patients with pre-disposing factors for myopathy/rhabdomyolysis such as: Personal or family history of hereditary muscular disorders Previous history of muscle toxicity with another HMG-CoA reductase inhibitor Concomitant use of a fibrate or niacin Severe hepatic impairment Severe renal impairment (CrCl < 30 ml/min/1.73 m 2 ) Hypothyroidism Alcohol abuse Situations where an increase in rosuvastatin plasma levels may occur. Simvastatin 11 Concomitant administration of gemfibrozil, cyclosporine, or danazol. Concomitant administration of potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin) Inform about possible warnings and precautions associated with statins. Advise your patients to inform their physician or pharmacist before they start taking their medication if they (as per product monographs for all statins unless otherwise indicated): 6-11 are pregnant, or intend to become pregnant. Cholesterol compounds are essential elements for the development of a fetus. Cholesterol-lowering drugs can harm the fetus. Females of childbearing age should discuss with their doctor the potential hazards to the fetus and the importance of birth control methods. Statins should not be used by pregnant women. If the patient does become pregnant, she should discontinue use immediately and discuss with her doctor. are breastfeeding or intend to breastfeed. This medicine may be present in breast milk. have thyroid problems have had a stroke or a mini-stroke (TIA) regularly drink three or more alcoholic drinks daily are taking any other cholesterol-lowering medication such as fibrates (gemfibrozil, fenofibrate, bezafibrate), niacin or ezetimibe have a family history of muscular disorders had any past problems with the muscles (pain, tenderness) after using a statin, or have developed an allergy or intolerance to them. have kidney or liver problems have diabetes (as the dosage of statin may need to be adjusted) have undergone surgery or other tissue injury do excessive physical exercise The following warnings and precautions are included in the fluvastatin product monograph 7 have a serious infection have very low blood pressure have congestive heart failure suffer from seizures are older than 70 years. Your doctor may want to clarify whether you have risk factors for muscular diseases. This may require specific blood tests. The following warning and precaution is included in the simvastatin product monograph 11 Caution should be used when prescribing simvastatin to Asian patients and the lowest dose necessary should be employed. Slightly increased blood sugar can occur when taking a statin. Patients should be advised to discuss risk of developing diabetes with their doctor If any unexplained muscle pain, tenderness or weakness is experienced when starting or changing dose of a statin, the patient should be advised to report this to his/her physician immediately Statins in Children and Adolescents Atorvastatin was studied in boys and girls (girls who already started their period) years of age at a dose of 10 and 20 mg. Atorvastatin has not been studied in prepubertal patients or patients younger than 10 years of age. Adolescent girls should discuss with their doctor the potential hazards to the fetus and the importance of birth control while on atorvastatin therapy. 6 In adolescents and children, the safety of fluvastatin for a prolonged treatment period on their physical, intellectual and sexual maturation has not been established. 7 Safety and effectiveness of simvastatin in patients years of age with heterozygous familial hypercholesterolemia have been evaluated and adverse effect profile was generally similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population

16 Pharmacological Treatment Options: Statins Inform about possible drug interactions with statins. Advise patients to let their healthcare professionals know of ALL medications that are being taken (including prescription, non-prescription and natural health products). In particular, the following products may interact with the particular statin drug listed as indicated: 6-11 Atorvastatin corticosteroids (cortisone-like medicines) cyclosporine gemfibrozil fenofibrate or bezafibrate lipid-modifying doses of niacin (nicotinic acid) erythromycin, clarithromycin or azole antifungal agents (ketoconazole or itraconazole) indinavir sulfate, nelfinavir mesylate, ritonavir, saquinavir mesylate, lopinavir/ ritonavir, telaprevir, tipranavir, darunavir, fosamprenavir, boceprevir fusidic acid digoxin diltiazem efavirenz, rifampin antacids (frequent use) and atorvastatin should be taken 2 hours apart colchicine grapefruit juice - especially if ingesting upwards of 1.2 litres of grapefruit juice at once Pravastatin other cholesterol-lowering medications (e.g., fibrates, niacin or ezetimibe) bile acid-binding resin (cholestyramine, colestipol) cyclosporine excessive alcohol Fluvastatin corticosteroids cholestyramine gemfibrozil/fenofibrate/bezafibrate/ niacin cimetidine/ranitidine/omeprazole digoxin rifampicin warfarin and other coumarin derivatives phenytoin fluconazole oral hypoglycemic agents (e.g., tolbutamide, chlorpropamide, glyburide) non-steroidal anti-inflammatory drugs (NSAIDs) alcohol spironolactone amlodipine cyclosporine Rosuvastatin Any other cholesterol-lowering medications such as fibrates (gemfibrozil, fenofibrate), niacin or ezetimibe Warfarin (or any other drug for thinning the blood) Ritonavir combined with another protease inhibitor (for control of HIV infection) Antacids (frequent use) and rosuvastatin should be taken 2 hours apart. Immunosuppressants (including cyclosporine used after organ transplant) are contraindicated together with rosuvastatin Fusidic acid (temporary suspension of Crestor treatment may be appropriate when the use of fusidic acid is necessary) Lovastatin antifungal agents (such as itraconazole, ketoconazole, posaconazole, or voriconazole) the antibiotics (erythromycin, clarithromycin, telithromycin, and fusidic acid [oral 1 or intravenous]) HIV protease inhibitors (such as indinavir, nelfinavir, ritonavir, and saquinavir) boceprevir or telaprevir (drugs used to treat hepatitis C virus infection) fibric acid derivatives (such as gemfibrozil, bezafibrate and fenofibrate) cyclosporine (immunosuppressant) danazol verapamil or diltiazem amiodarone colchicine grapefruit juice corticosteroids anticoagulants digoxin niacin Simvastatin Inform about side effects associated with statins. Atorvastatin constipation/diarrhea/gas depression (in children) headache skin rash stomach pain or upset vomiting antifungal agents (such as itraconazole, ketoconazole, posaconazole, or voriconazole) HIV protease inhibitors (such as indinavir, nelfinavir, ritonavir, and saquinavir) boceprevir or telaprevir the antibiotics erythromycin, clarithromycin medicines containing cobicistat cyclosporine danazol fibrates/fibric acid derivatives (bezafibrate, fenofibrate and gemfibrozil) amiodarone verapamil, or diltiazem, or amlodipine lomitapide grapefruit juice (which should be avoided while taking simvastatin) corticosteroids anticoagulants colchicine digoxin niacin or niacin-containing products All medicines can cause unwanted side effects. Patients should be advised to check with their physician promptly if any of the following persist or become troublesome*: 6-11 Fluvastatin abdominal pain/indigestion constipation diarrhea nausea headache abnormal blood test values for muscle and liver influenza infections poor memory, confusion and memory loss insomnia dizziness 28 29

17 Pharmacological Treatment Options: Statins Pravastatin abdominal pain constipation diarrhea nausea headache dizziness skin rashes Lovastatin constipation, diarrhea, gas, stomach upset, nausea pain in the abdomen headache, dizziness skin rash poor memory memory loss confusion depression erectile dysfunction Rosuvastatin stomach pain headache constipation dizziness feeling sick less commonly, some people may have other side effects such as a skin rash, itching and hives. Simvastatin constipation, diarrhea, gas, stomach upset, nausea pain in the abdomen headache skin rash poor memory memory loss confusion trouble sleeping depression erectile dysfunction breathing problems, including persistent cough and/or shortness of breath, or fever * These are not complete lists of side effects. For any unexpected effects while taking a statin drug, patients should be advised to contact their physician or pharmacist. For a complete list of known adverse reactions, consult the individual product monographs for each product. Patients should be aware of the symptoms of these serious side effects and what to do about them: 6-11 Symptom/Effect Advise Patient to Speak with Doctor or Pharmacist Only if Severe In All Cases From Atorvastatin Product Monograph 6 Rare Muscle pain that cannot be explained Muscle tenderness or weakness Generalized weakness, especially if not feeling well Unknown Brownish or discoloured urine Increased blood sugar: frequent urination, thirst and hunger Stop Taking the Drug and Seek Immediate Emergency Medical Attention Rare Symptom/Effect Advise Patient to Speak with Doctor or Pharmacist Only if Severe From Fluvastatin Product Monograph 7 Muscle pain that cannot be explained, muscle tenderness or muscle weakness Skin rash, hives, swelling of the face, eyelids and lips In All Cases Very Rare Brownish or discoloured urine Unknown Rare Unknown Generalized weakness, especially if not feeling well Myositis (muscle inflammation), rhabdomyolysis Unusual tiredness or fever, yellowing of the skin and eyes, dark-coloured urine (hepatitis) Severe abdominal pain (inflamed pancreas) Skin swelling, rash, hives, dizziness, sensitivity to light (signs of severe allergic reaction) Difficulty in breathing, swelling of the lips, throat, mouth, tongue or face (signs of severe allergic reaction) Increased blood sugar: frequent urination, thirst and hunger From Lovastatin Product Monograph 8 Allergic reactions: rash, hives, swelling of the face, lips, tongue or throat, difficulty swallowing or breathing Brownish or discoloured urine Liver problems: upper belly pain, nausea, vomiting, loss of appetite, dark/brown urine, yellow skin and eyes, itchy skin, pale stools Generalized weakness, especially if not feeling well Unexplained muscle pain Muscle tenderness or muscle weakness Increased blood sugar: frequent urination, thirst and hunger Stop Taking the Drug and Seek Immediate Emergency Medical Attention 30 31

18 Pharmacological Treatment Options: Statins Symptom/Effect Advise Patient to Speak with Doctor or Pharmacist Only if Severe In All Cases Stop Taking the Drug and Seek Immediate Emergency Medical Attention Symptom/Effect Advise Patient to Speak with Doctor or Pharmacist Only if Severe In All Cases Stop Taking the Drug and Seek Immediate Emergency Medical Attention From Pravastatin Product Monograph 9 Rare Muscle pain that cannot be explained Muscle tenderness or muscle weakness Generalized weakness, especially if not feeling well Brownish or discoloured urine Symptoms of liver problems (upper belly pain, dark urine, itchy skin, nausea or vomiting, loss of appetite, pale stools, yellowing of skin or the whites of eyes) Unknown Increased blood sugar: frequent urination, thirst and hunger From Rosuvastatin Product Monograph 10 Rare Muscle pain that cannot be explained Muscle tenderness or weakness or joint pain Breast enlargement in women and men (gynecomastia) Generalized weakness, especially if not feeling well Jaundice or hepatitis symptoms like brownish or discoloured urine Difficulty in breathing or swallowing Allergic reaction: swelling in the mouth, tongue, face and throat, severe itching, rash, hives, blistering of the skin and mucous membranes of the lips, eyes, mouth, nasal passages or genitals. Liver damage: yellowing of skin or eyes, flu-like symptoms Very rare Unknown Rare Unknown From Rosuvastatin Product Monograph 10 Pancreatitis symptoms such as severe stomach pain Memory loss Increased blood sugar: frequent urination, thirst and hunger Decrease of platelets in the blood (characterized by easy or excessive bleeding such as bruising easily, nosebleed and bleeding gums) From Simvastatin Product Monograph 11 Allergic reactions: swelling of the face, eyelids, lips, tongue or throat, sudden shortness of breath, flushing, sensitivity to light, skin reactions including hives Brownish or discoloured urine Symptoms of liver problems (upper belly pain, dark urine, itchy skin, nausea or vomiting, loss of appetite, pale stools, yellowing of skin or the whites of eyes) Generalized weakness, especially if not feeling well, or fever Unexplained muscle pain Muscle tenderness or muscle weakness Blurred vision Increased blood sugar: frequent urination, thirst and hunger * These are not complete lists of side effects. For any unexpected effects while taking a statin drug, patients should be advised to contact their physician or pharmacist. For a complete list of known adverse reactions, consult the individual product monographs for each product

19 Pharmacological Treatment Options: Ezetimibe Ensure that ezetimibe therapy is right for your patient. See Table 1 for Ezetimibe Indications Contraindications: 12 Advise patients that ezetimibe should not be used under the following circumstances: Patients who are hypersensitive (allergic) to ezetimibe or any of the nonmedicinal ingredients Patients with active liver disease or unexplained increases in liver enzymes should not take ezetimibe together with a statin. Patients who are pregnant should not take ezetimibe together with a statin. Patients who are nursing should not take ezetimibe together with a statin. Inform about possible warnings and precautions associated with ezetimibe. Ezetimibe Serious Warnings and Precautions Liver disease (Hepatitis) Pancreas disease (Pancreatitis) Muscle pain (Myopathy/Rhabdomyolysis, Myalgia) Severe allergic reaction (Anaphylaxis) Advise patients to speak with their doctor before taking Ezetimibe if they: are pregnant, plan to become pregnant or think they might be pregnant are breastfeeding. Ezetimibe may be passed in their milk to their baby. have now or have had in the past any medical problems (including liver disease or liver problems) Inform about possible drug interactions with other medications. Drugs that may interact with ezetimibe include: Cyclosporine Cholestyramine or any other bile acid sequestrant. In that case, ezetimibe should be taken at least 2 hours before or 4 hours after taking the bile acid sequestrant. Fibrates Inform about possible side effects associated with ezetimibe. When used alone, the following common side effects have been reported: 12 abdominal pain diarrhea flatulence tiredness viral infection throat infection (pharyngitis) nose infection (sinusitis) joint pain (arthralgia) back pain coughing When used alone, the following uncommon side effects have been reported: 12 elevations in some laboratory blood tests of liver (transaminases) or muscle (CK) function; indigestion heartburn nausea muscle spasms neck pain decreased appetite hot flush high blood pressure chest pain pain When used with a statin, the following common side effects have been reported: headache; tiredness; abdominal pain; diarrhea; joint pain (arthralgia); muscle pain (myalgia); back pain; throat infection (pharyngitis); nose infection (sinusitis); upper chest infection (respiratory tract); and changes in certain laboratory blood tests. When used with a statin, the following uncommon side effects have been reported: tingling sensation; dry mouth; gastritis; itching; rash; hives; muscular weakness; pain in arms and legs; unusual tiredness or weakness; and swelling, especially in the hands and feet

20 Pharmacological Treatment Options: Ezetimibe Pharmacological Treatment Options: Fibrates When used with fenofibrate, the following side effect was reported: abdominal pain. In general use, the following side effects have been reported: raised red rash, sometimes with target-shaped lesions; dizziness; depression; tingling sensation; constipation; and unusual tiredness or weakness. * These are not complete lists of side effects. For any unexpected effects while taking ezetimibe, patients should be advised to contact their physician or pharmacist. For a complete list of known adverse reactions, consult the individual product monographs for each product. Advise about possible serious side effects, how often they happen and what to do about them. Ezetimibe is generally well tolerated. Patients should be aware of the symptoms of these side effects and what to do about them: 12 Rare Symptom/Effect Muscle aches and pains (Myopathy/ Rhabdomyolysis) Sudden severe allergic reactions (swelling of the face, lips, tongue, and/or throat that may cause difficulty in breathing or swallowing, rash and hives) Symptoms of liver problems (severe abdominal pain, especially if felt on the upper right side below the ribs, dark urine, general itchiness, severe nausea or vomiting, pale stools, yellowing of skin or eyes) Symptoms of gallstones or inflammation of the gallbladder (severe abdominal pain, nausea, vomiting) Symptoms of pancreas problems (severe abdominal pain) Advise Patient to Speak with Doctor or Pharmacist Only if Severe * These are not complete lists of side effects. For any unexpected effects while taking ezetimibe, patients should be advised to contact their physician or pharmacist. For a complete list of known adverse reactions, consult the individual product monographs for each product. In All Cases Stop Taking the Drug and Seek Immediate Emergency Medical Attention Ensure that fibrate therapy is right for your patient. See Table 1 for Fibrate Drug Indications Contraindications Advise patients that bezafibrate should not be used under the following circumstances: 13 Patients who are hypersensitive (allergic) to the drug or any of the nonmedicinal ingredients Patients who have had a sensitivity reaction to any of the fibrates, including sensitivity to the sun Patients with severe liver damage Patients with kidney disease, kidney damage, and those on dialysis Patients with pre-existing gallbladder disease Patients who are pregnant or breastfeeding or planning to have a baby Patients with very high levels of lipids (i.e., Type 1 hyperlipoproteinemia) Patients also taking statins who are predisposed to developing myopathy (e.g., pre-existing renal impairment, severe infection, trauma, surgery, disturbances of the hormonal or electrolyte balance) Advise patients that fenofibrate should not be used under the following circumstances: 14 Patients who are hypersensitive (allergic) to the drug or any of the nonmedicinal ingredients, or to peanuts or arachis oil or soya lecithin Patients who have had a sensitivity reaction to any of the fibrates, including sensitivity to the sun Patients who have liver or kidney problems Patients with gallbladder problems Patients who have pancreatitis Patients who are pregnant or breastfeeding or planning to have a baby Patients also taking statins who are predisposed to developing myopathy Patients under 18 years of age Advise patients that gemfibrozil should not be used under the following circumstances: 15 Patients who are hypersensitive (allergic) to the drug or any of the nonmedicinal ingredients Patients who have liver or kidney problems, including primary biliary cirrhosis Patients with gallbladder problems 36 37

21 Pharmacological Treatment Options: Fibrates Patients who are pregnant or breastfeeding or planning to have a baby Patients with very high levels of lipids (i.e., Type 1 hyperlipoproteinemia) Patients who are also taking the drug repaglinide Patients who are also taking a statin drug Inform about possible warnings and precautions associated with fibrates. Advise your patients to inform their physician or pharmacist before they start taking their medication if they (as per product monographs for all fibrates unless otherwise indicated): have taken a fibrate drug before and it caused an allergy or was otherwise poorly tolerated (e.g., myopathy or elevated creatine kinase levels) are suffering from liver or kidney problems have thyroid problems are over the age of 70 years old drink large amounts of alcohol are pregnant or intend to become pregnant or are breastfeeding are taking other medications prescribed by the doctor, in particular an oral anticoagulant (e.g., warfarin), cyclosporine, statins, cholestyramine or similar drug, estrogens, rosiglitazone or pioglitazone (fenofibrate) 14, or repaglinide (gemfibrozil) 15 are taking any over-the-counter medicines or herbal supplements have ever had any muscle problems when taking any of the fibrates Inform about possible drug interactions with this medication. Drugs that may interact with fibrates include (as per product monographs for all fibrates unless otherwise indicated): Anticoagulants Immunosuppressants Statins Cyclosporine MAO-inhibitors Estrogens Bile acid-binding resins Rosiglitazone, pioglitazone (fenofibrate) Repaglinide (gemfibrozil) For gemfibrozil Drugs affected by Cytochrome P450 2C8 inhibition (e.g., amiodarone, verapamil) For gemfibrozil Drugs affected by Cytochrome P450 2C9 inhibition (e.g., carvedilol, losartan, diazepam, phenytoin) Inform about possible side effects associated with fibrates. Common side effects of bezafibrate are: 13 rash headache diarrhea nausea abdominal pain Common side effects of fenofibrate are: 14 abdominal pain constipation diarrhea flatulence nausea vomiting headache dizziness skin reactions fatigue raised levels of liver enzymes in the blood Common side effects of gemfibrozil are: 15 nausea vomiting abdominal pain epigastric pain rash chest pain * These are not complete lists of side effects. For any unexpected effects while taking fibrate drugs, patients should be advised to contact their physician or pharmacist. For a complete list of known adverse reactions, consult the individual product monographs for each product

22 Pharmacological Treatment Options: Fibrates Pharmacological Treatment Options: Niacin Advise about possible serious side effects, how often they happen and what to do about them. More Common Less Common Frequency Not Listed Symptom/Effect Advise Patient to Speak with Doctor or Pharmacist Only if Severe From Bezafibrate Product Monograph 13 Diarrhea Constipation Abdominal pain Skin reactions Muscular pain, weakness or cramps Dizziness Fast decrease in kidney function (i.e., decreased amount of urine output to almost none) From Fenofibrate Product Monograph 14 Allergic reaction may include swelling of the face, lips, tongue or throat, which may cause difficulty in breathing Chest pain and feeling breathless may be signs of a blood clot in the lung (pulmonary embolism) Pain, redness or swelling in the legs may be signs of a blood clot in the leg (deep vein thrombosis) Yellowing of the skin and whites of the eyes (jaundice), or an increase in liver enzymes these may be signs of an inflamed liver (hepatitis) In All Cases Rare Unexplained muscle pain Stop Taking the Drug and Seek Immediate Emergency Medical Attention * These are not complete lists of side effects. For any unexpected effects while taking fibrate drugs, patients should be advised to contact their physician or pharmacist. For a complete list of known adverse reactions, consult the individual product monographs for each product. Ensure that niacin therapy is right for your patient. See Table 1 for Niacin Indications Contraindications: 16 Advise patients who niacin should not be used under the following circumstances: Patients who are hypersensitive (allergic) to the drug or any of the nonmedicinal ingredients Patients with unexplained persistent elevations of serum transaminases (liver problems) Patients with active peptic ulcer Patients who have active bleeding Patients who are pregnant Inform about possible warnings and precautions associated with niacin. 16 This warning appears in the Consumer Information section of the Niacin Extended-Release product monograph. Serious Warnings and Precautions If you were previously taking another niacin (nicotinic acid) tablet, do not start extended-release niacin at the same dose. You must start with a lower dose of extended-release niacin and gradually move up to a higher dose as directed by your doctor. Never substitute another niacin (nicotinic acid) product for your extended-release niacin; improper substitution can cause severe liver disorders. Advise patients to speak with their doctor before starting niacin therapy if: they have significant or unexplained liver or kidney problems, active peptic ulcer, bleeding, diabetes, unstable angina, heart problems, or if they are at risk for low levels of phosphorus in their blood. they have a past history of jaundice (yellow skin), liver problems, peptic ulcer, or gout. they are pregnant or nursing. they are undergoing surgery. they are hypersensitive to niacin or any component of the medication

23 Pharmacological Treatment Options: Niacin Inform about possible interactions with niacin. 16 Drugs or other products that may interact with niacin include: statins vasoactive drugs (e.g., some antihypertensives, nitrates) acetylsalicylic acid bile acid resins anticoagulant drugs (e.g., warfarin) alcohol (may worsen flushing response) hot drinks (may worsen flushing response) vitamins or other nutritional supplements containing large doses of niacin (> 100 mg) or related compounds such as nicotinamide Inform about possible side effects associated with niacin use. 16 Niacin sometimes causes redness, warmth, itching, and/or a tingling sensation on the face, neck, chest and back (flushing). This is a natural reaction signalling that niacin is in the bloodstream. Most patients on niacin will experience this sensation, usually at the start of therapy or when the dosing is increased. For most patients, the flushing occurs over the first 8 weeks of therapy and will become milder and less frequent as their body adjusts to the drug. If flushing occurs, it usually does so within 2 to 4 hours after taking extended-release niacin and may last for a few hours. In some patients, flushing may be more intense. Additional symptoms, such as rapid or pronounced heartbeat or dizziness, shortness of breath, sweating, chills, and/or swelling may occur; on rare occasions, fainting may occur. If the flushing wakes you up and you wish to get out of bed, take your time and get up slowly especially if you start to feel faint or dizzy, or if you take blood pressure medication. If you are diabetic, inform your doctor if you notice any changes in your blood sugar. If you are taking another cholesterol-lowering drug, you should inform your doctor if you experience any signs of muscle pain or weakness, as this may be a sign of a rare but serious adverse drug reaction. Other than flushing, the side effects most often seen are gastrointestinal in nature, such as stomach upset and diarrhea; rash and itching also are occasionally observed. * These are not complete lists of side effects. For any unexpected effects while taking niacin therapy, patients should be advised to contact their physician or pharmacist. For a complete list of known adverse reactions, consult the individual product monographs for each product. 42 Pharmacological Treatment Options: Bile Acid Resins Ensure that bile acid resin therapy is right for your patient. See Table 1 for Bile Acid Resin Indications Contraindications: Advise patients that bile acid resins should not be used under the following circumstances: Patients who are hypersensitive (allergic) to the drug or any of the nonmedicinal ingredients Complete biliary obstruction (drug unlikely to be effective as no bile products reach the intestine) Colestipol orange granules contain aspartame. This product is contraindicated in people with phenylketonuria, as each 7.5 g colestipol orange granule contains 18.2 mg phenylalanine. 19 Inform about possible warnings and precautions associated with bile acid resins. Advise patients to speak with their doctor before starting bile acid resin therapy if they (for all bile acid resins unless otherwise indicated): have had any allergies to a bile acid resin or to its ingredients or components of the container have or have had in the past any health problems as some conditions can affect cholesterol levels and should be treated before taking bile acid resins have a deficiency of vitamins A, D, E or K are pregnant, or become pregnant, or are planning on becoming pregnant or are breastfeeding are taking other medications (see drug interactions) Warnings and Precautions listed in cholestyramine product monograph 17 suffer from diabetes suffer from renal disease Warnings and Precautions listed in colesevelam product monograph 18 have triglyceride levels greater than 3.4 mmol/l have difficulty in swallowing, or have a major stomach or intestinal disorder are taking antidiabetic treatments are taking cyclosporine are taking oral contraceptive medication are taking anticoagulant therapy suffer from constipation, as bile acid resin therapy can worsen this condition. This is especially important for patients with coronary heart disease and angina pectoris. 43

24 Pharmacological Treatment Options: Bile Acid Resins Warnings and Precautions listed in colestipol product monograph 19 have dysproteinemia, or diabetes, thyroid, gallbladder, kidney or liver disease have irritable bowel syndrome, diverticulosis or diverticulitis, as these conditions can be influenced by the nonmedicinal ingredient colloidal silicon present in the products The elderly may be more likely to experience gastrointestinal side effects. 17 Inform about possible interactions with bile acid-binding resins. Bile Acid- Binding Resin Cholestyramine 17 Colesevelam 18 Colestipol 19 Interacting Drugs (as per PM) thyroid and thyroxine preparations warfarin chlorothiazide phenylbutazone phenobarbital tetracycline penicillin G digitalis drugs that undergo enterohepatic recirculation (e.g., estrogen) statins but cholesterollowering effects are additive anticoagulant therapy thyroid replacement therapy oral contraceptives verapamil antidiabetic medications (e.g., pioglitazone, repaglinide or glyburide) anti-epileptic medicines (e.g., phenytoin) cyclosporine antibiotics beta-blockers digoxin or digitoxin diuretics warfarin mycophenolate mofetil Comments Since cholestyramine resin is an anion-exchange resin, it may have strong affinity for anions other than the bile acids. Drugs that are affected by co-administration of bile acid sequestrants vary widely in pharmacologic effect and mechanisms, magnitude of doses, and chemical characteristics. Therefore, it is not possible to predict a priori whether or not coadministration with cholestyramine will interfere with absorption. It should be assumed that concomitantly administered drugs have the potential of interacting with cholestyramine unless clinical studies have shown otherwise. To ensure that the effectiveness of the interacting medications is not altered, it is important that patients take the medications at least 4 hours before taking colesevelam. Bile acid resins may also interfere with the absorption of vitamins A, D, E and K. If patients have any condition that could cause deficiency in any of these vitamins, vitamin levels may need to be checked periodically. If necessary, supplementation may be recommended. Since colestipol may reduce the effect of other medications taken at the same time, patients should take other drugs at least 1 hour before or 4-6 hours after taking colestipol. Inform about possible side effects associated with bile acid resin use. The following side effects have been reported with cholestyramine: 17 constipation (most common) distention bloating, flatulence nausea, vomiting diarrhea anorexia heartburn and indigestion rash irritation of skin, tongue and perianal area The following side effects have been reported with colesevelam: 18 constipation flatulence diarrhea indigestion muscle pain abdominal pain abnormal stools nausea headache increased levels of triglycerides increased levels of liver enzymes worsening hemorrhoids PM=Product Monograph 44 45

25 Pharmacological Treatment Options: Bile Acid Resins The following side effects have been reported with colestipol: 19 worsened hemorrhoids and bleeding from hemorrhoids nausea bloating and gas heartburn vomiting loss of appetite headache anxiety dizziness drowsiness fatigue weakness insomnia * These are not complete lists of side effects. For any unexpected effects while taking a bile acid resin drug, patients should be advised to contact their physician or pharmacist. For a complete list of known adverse reactions, consult the individual product monographs for each product. Advise about possible serious side effects, how often they happen and what to do about them. Uncommon Symptom/Effect Advise Patient to Speak with Doctor or Pharmacist Only if Severe From Colesevalam Product Monograph 18 Bowel obstruction (abdominal pain, cramps or distension, vomiting, fecal vomiting, constipation) Difficulty swallowing Fecal impaction (chronic constipation [sometimes with overflow diarrhea as liquid stool passes around the obstruction], abdominal pain and bloating, loss of appetite) Pancreatitis (severe upper abdominal pain that radiates to the back, nausea, vomiting) In All Cases Stop Taking the Drug and Seek Immediate Emergency Medical Attention Symptom/Effect Advise Patient to Speak with Doctor or Pharmacist Only if Severe In All Cases From Colestipol Product Monograph 19 Very Constipation Common Stomach pain Common Diarrhea Joint and muscle pain, back pain Blood in feces Shortness of breath Vertigo Ulcers Skin reaction: rash Inflammation of the gallbladder. Gall- stone: symptoms like abdominal pain so intense that patient can t sit still or find a comfortable position Uncommon Elevated liver enzyme levels Allergic reaction: symptoms like hives, swelling of the face, lips, tongue or throat, difficulty swallowing or breathing Chest pain Rapid heartbeat Stop Taking the Drug and Seek Immediate Emergency Medical Attention * These are not complete lists of side effects. For any unexpected effects while taking a bile acid resin drug, patients should be advised to contact their physician or pharmacist. For a complete list of known adverse reactions, consult the individual product monographs for each product