Statin Muscle Symptoms: Managing Statin Intolerance

PL Detail-Document #311003 This PL Detail-Document gives subscribers additional insight related to the Recommendations published in PHARMACIST S LETTER / PRESCRIBER S LETTER October 2015 Statin Muscle Symptoms: Managing Statin Intolerance Muscle symptoms are commonly reported by statin users; however, over 70% of these patients end up tolerating a statin. 3,5,8 Statin-associated muscle symptoms are usually not serious. Although rhabdomyolysis has a mortality rate of almost 8%, it is rare. 3 The chart below provides information to help clinicians prevent and manage statin-associated muscle symptoms. Also download the ACC Statin Intolerance App at http://www.acc.org/statin IntoleranceApp. Abbreviations: ACC = American College of Cardiology; AHA = American Heart Association; BMI = body mass index; CK = creatine kinase; CoQ10 (coenzyme Q10; ubiquinol); CV = cardiovascular; NLA = National Lipid Association; SCr = serum creatinine; ULN = upper limit of normal Clinical Question Suggested Approach/Pertinent Information What adverse muscle effects Patients may complain of pain, tenderness, stiffness, cramps, weakness, or fatigue. 1 can statins cause? Symptoms usually involve large, proximal muscle groups (e.g., legs, back) symmetrically. 4 Symptoms usually occur within 4 to 6 weeks after starting the statin, but can occur after years of treatment. 4 Examples of terminology commonly used in the context of statin muscle symptoms (definitions used in literature/guidelines vary): Myopathy: general term for muscle disease (Canada), 3 or used to denote muscle weakness not due to pain, and which may or may not be associated with elevated CK (NLA) 8 Myalgia: muscle symptoms with CK <ULN 3,8 Myositis: muscle symptoms with CK >ULN (Canada); 3 muscle inflammation (NLA) 8 Myonecrosis: CK >3 times baseline or ULN adjusted for age, sex, and race (NLA). 8 Further divided into mild, moderate, and severe. Rhabdomyolysis: muscle symptoms plus myoglobinuria and CK >10 x ULN (CK >10,000 units/l; Canada); 3 myonecrosis with myoglobinuria or acute renal failure (increase in SCr 0.5 mg/dl; NLA) 8 How common are statinassociated muscle symptoms? In clinical trials, low- or moderate-intensity statins a did not increase the risk of muscle symptoms. 1 However, in practice, up to about 30% of patients complain of muscle symptoms. 4 In clinical trials, rhabdomyolysis occurred in <0.06% of patients over about a five-year period. 1 In a real life unselected population, rhabdomyolysis may occur in as many as 0.2% of statin users. 3

(PL Detail-Document #311003: Page 2 of 5) Clinical Question What are some risk factors for statin-associated muscle adverse effects? Suggested Approach/Pertinent Information Multiple disease states (e.g., renal or hepatic insufficiency) or polypharmacy 1,4 History of musculoskeletal symptoms or CK elevation, neuromuscular disease, or personal or family history of statin or other myopathy 1,3 Use of medications or foods (e.g., grapefruit) that increase statin levels 1 Age over 75 to 80 years 1,3 Asian ancestry 1,3 Being female 3 Low BMI or small frame 3 Frailty 3 Physical activity 4 Alcohol or drug abuse 3 Are certain statins more commonly associated with muscle symptoms? The vast majority of patients who do not tolerate one statin can tolerate the same or a different statin. 3,5 Almost half can tolerate the same statin upon rechallenge, usually at the same or higher dose. 3 When choosing a different statin, consider one with fewer drug interactions (e.g., rosuvastatin, pravastatin, fluvastatin), or one that a family member can tolerate. 8 Evidence that lipophilicity/hydrophilicity directly affects muscle symptoms is lacking in humans. 8 What can be done to prevent statin-associated muscle symptoms? Before starting a statin, document current or previous muscle symptoms. 1 This information may help prevent unnecessary statin discontinuation in the future. 1 Do not use gemfibrozil with a statin. 1 Screen for drug interactions. 1 Adjust dose or use a different statin accordingly. 1 Ensure dose is appropriate for renal function. Our PL Chart, Characteristics of the Various Statins, has information on drug interactions and renal dosing. Ensure the statin dose is appropriate based on cardiovascular risk. 1 Consider a moderate-intensity statin a instead of a high-intensity statin a for patients with risk factors for statin muscle symptoms. 1 Avoid simvastatin 80 mg daily. 1,3 Before starting, set patient expectations that side effects can be managed if they occur. 4

(PL Detail-Document #311003: Page 3 of 5) Clinical Question When should a creatine kinase be checked? What is the general approach to take when a patient complains of muscle symptoms? Continued Suggested Approach/Pertinent Information Consider baseline measurement in patients with risk factors. 1 Do not check routinely. 1 Elevations >3x the ULN occur in patients with heart disease at a similar rate regardless of statin treatment. 1 The clinical importance of an elevated CK without symptoms is unclear. 4 Exercise can also cause increased CK. 4 Check in the event of muscle symptoms. 1 Example approach based on ACC/AHA guidelines, NLA panel, and European consensus panel: Hold statin for 2 to 4 weeks in the event of intolerable symptoms, weakness, or CK >3 times ULN. If patient reports weakness, evaluate muscle strength by physical exam, and consider additional testing (e.g., biopsy) if weakness persists despite statin discontinuation. 8 Consider rhabdomyolysis in the event of severe muscle pain or fatigue, generalized weakness, or dark urine. 1,4 Check CK, urine for myoglobin, and SCr. 1 If rhabdomyolysis is confirmed, treat and do not restart statin at any point in the future. 4 Look for other causes of muscle symptoms (e.g., hypothyroidism, vitamin D deficiency, rheumatologic or musculoskeletal disease, exercise, steroid myopathy, antipsychotics, immunosuppressants, bisphosphonates, alcohol or drug abuse, drug or food interactions [e.g., fibrates, macrolides, immunosuppressives, protease inhibitors]). 1,3,4,9 Also consider alternate causes of leg cramps. Check renal and hepatic function. 1 Assuming no contraindications: 1 rechallenge with same statin at the same or lower dose once symptoms resolve to establish a causal relationship. If symptoms return, discontinue statin. Once symptoms resolve, start a different statin at a lower dose, then increase as tolerated. 1 OR start a low or target dose of a different statin once symptoms improve. 8 Increase as tolerated. 8 If not tolerated, try extending the dosing frequency, such as every other day or twice a week. 3,6,8 (See more about alternate dosing options in the next sections.) OR for patients at low CV risk, consider lifestyle interventions in lieu of a statin 4 Consider adding ezetimibe for certain high-risk patients who can t tolerate a high-intensity statin, such as those with a prior cardiovascular event. Ezetimibe is the only non-statin with evidence of improving cardiovascular outcomes when added to a statin. See our PL Chart, Non-Statin Lipid-Lowering Agents, for considerations when deciding to start a non-statin, and a comparison of their lipid effects, outcomes, and cost. Save PCSK9 inhibitors (Praluent, Repatha) as an add-on to statins for familial hypercholesterolemia. Do not routinely use these agents in other high-risk patients with or without a statin, due to high cost and lack of long-

(PL Detail-Document #311003: Page 4 of 5) Clinical Question General approach, continued When should I stop a statin due to muscle symptoms? Can I give statins less often than once daily to reduce symptoms? What is the role of coenzyme Q10 (ubiquinol)? Suggested Approach/Pertinent Information term outcome and safety data. If symptoms/ck elevation does not improve in 2 to 4 weeks, or do not normalize after two months, evaluate for non-statin cause. 1,8 If non-statin cause is found, or predisposing condition has been treated, restart original statin at original dose. 1 Use a take your time approach and be persistent. Help patients understand the benefits and risks of continued statin therapy. See our PL Patient Education Handout, What You Should Know About Statins. In the event of symptoms, hold statin temporarily pending evaluation. 1 (See General Approach section above for more information.) European guidelines recommend permanent discontinuation in patients who experience rhabomyolysis. 4 Rosuvastatin is most often used in this strategy because of its long-half life, high potency, and favorable drug interaction profile. 5 Intermittent dosing of rosuvastatin (i.e., 5 mg 2 to 3 times weekly) can reduce LDL by over 30%. 3 Rosuvastatin 5 to 10 mg weekly may reduce LDL by 10%. 10 Atorvastatin also has a long half-life. 8 Atorvastatin 20 mg every other day may be as effective as 20 mg daily in regard to LDL reduction. 6 Intermittent dosing has not been prospectively studied in regard to cardiovascular morbidity or mortality. 5 In patients with a history of statin muscle symptoms, confirmed by placebo-controlled crossover rechallenge, CoQ10 600 mg daily did not affect pain, muscle strength, or aerobic performance vs placebo in patients taking simvastatin 20 mg daily [Evidence level B; lower-quality RCT]. 2 Canadian and European consensus panels advise against use of dietary supplements (including vitamin D) for statin muscle symptoms. 3,10 Coenzyme Q10 is well-tolerated if patients insist on trying it. 7 However, it can be expensive. The suggested dose for statin muscle pain is 100 to 200 mg daily (in divided doses if >100 mg/day). a. See our PL Chart, 2013 ACC/AHA Cholesterol Guidelines, for a list of high- and moderate-intensity statins. Users of this PL Detail-Document are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and internet links in this article were current as of the date of publication.

(PL Detail-Document #311003: Page 5 of 5) Levels of Evidence In accordance with the trend towards Evidence-Based Medicine, we are citing the LEVEL OF EVIDENCE for the statements we publish. Level Definition A High-quality randomized controlled trial (RCT) High-quality meta-analysis (quantitative systematic review) B Nonrandomized clinical trial Nonquantitative systematic review Lower quality RCT Clinical cohort study Case-control study Historical control Epidemiologic study C Consensus Expert opinion D Anecdotal evidence In vitro or animal study Adapted from Siwek J, et al. How to write an evidence-based clinical review article. Am Fam Physician 2002;65:251-8. Project Leader in preparation of this PL Detail- Document: Melanie Cupp, Pharm.D., BCPS References 1. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129(25 Suppl 2):S1-45. 2. Taylor BA, Lorson L, White M, Thompson PD. A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy. Atherosclerosis 2015;238:329-35. 3. Mancini GB, Tashakkor AY, Baker S, et al. Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Working Group Consensus update. Can J Cardiol 2013;29:1553-68. 4. Stroes ES, Thompson PD, Corsini A, et al. Statinassociated muscle symptoms: impact on statin therapy-european Atherosclerosis Society consensus panel statement of assessment etiology and management. Eur Heart J 2015;36:1012-22. 5. Mampuya WM, Frid D, Rocco M, et al. Treatment strategies in patients with statin intolerance: the Cleveland Clinic experience. Am Heart J 2013;166:597-603. 6. Pramanik S, Das AK, Chakrabarty M, et al. Efficacy of alternate-day versus everyday dosing of atorvastatin. Indian J Pharmacol 2012;44:362-5. 7. Jellin JM, Gregory PJ, et al. Natural Medicines Comprehensive Database. www.naturaldatabase.com. (Accessed September 3, 2015). 8. Rosenson RS, Baker SK, Jacobson TA, et al. An assessment by the statin muscle safety task force: 2014 update. J Clin Lipidol 2014;8(Suppl 3):S58-71. 9. FDA. Information for healthcare professionals: bisphosphonates (marketed as Actonel, Actonel+Ca, Aredia, Boniva, Didronel, Fosamax, Fosamax+D, Reclast, Skelid, and Zometa). January 7, 2008. (Last updated August 15, 2013). http://www.fda.gov/drugs/drugsafety/postmarketdru gsafetyinformationforpatientsandproviders/ucm1241 65.htm. (Accessed September 16, 2015). 10. Anderson TJ, Gregoire J, Hegele RA, et al. 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol 2013;29:151-67. Cite this document as follows: PL Detail-Document, Statin Muscle Symptoms: Managing Statin Intolerance. Pharmacist s Letter/Prescriber s Letter. October 2015. Evidence and Recommendations You Can Trust 3120 West March Lane, Stockton, CA 95219 ~ TEL (209) 472-2240 ~ FAX (209) 472-2249 Copyright 2015 by Therapeutic Research Center Subscribers to the Letter can get PL Detail-Documents, like this one, on any topic covered in any issue by going to www.pharmacistsletter.com, www.prescribersletter.com, or www.pharmacytechniciansletter.com

What It Is Repatha (evolocumab) is a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor, one of only two agents available in this new class of cholesterol lowering drugs. 1 PCSK9 inhibitors have shown impressive results in lowering LDL cholesterol levels. This article will provide an overview of evolocumab and its role in the treatment of hypercholesterolemia. How It Works PCSK9 is an enzyme that binds with high affinity and specificity to LDL cholesterol receptors. 2 This bound complex then promotes the degradation of the LDL cholesterol receptors and prevents them from recycling themselves. 2 The result is decreased receptor activity, which lowers the liver s ability to remove circulating LDL cholesterol from the blood. 2 Repatha is a human monoclonal antibody that inhibits the PCSK9 enzyme, stopping it from binding to the LDL cholesterol receptors. 2 This increases the number of receptors that are available to bind to and clear LDL cholesterol, increases the recycling of receptors, and results in increased LDL cholesterol clearance and lower LDL cholesterol plasma levels. 2 Indications Repatha is indicated as an adjunct to diet and maximally tolerated doses of statin therapy in adults with heterozygous familial hypercholesterolemia (HeFH) or with clinical atherosclerotic cardiovascular disease who need further lowering of LDL cholesterol. And, also as an adjunct to diet and other LDL-lowering therapies in adults with homozygous familial hypercholesterolemia (HoFH) who need further LDL cholesterol lowering. 1 How Supplied Repatha is a clear to opalescent, colorless to pale yellow, preservative-free solution available in PL Detail-Document #311003 This PL Detail-Document gives subscribers additional insight related to the Recommendations published in PHARMACIST S LETTER / PRESCRIBER S LETTER October 2015 New Drug: Repatha (Evolocumab) 140 mg/ml single-use pre-filled syringes or autoinjectors. 1 Syringes are available individually and the autoinjectors come in packs of one, two, or three. 1 Each dose of 140 mg costs $542 (WAC), giving an annual cost per patient of about $14,100 for the every two weeks administration. 3 Amgen is offering copay reductions and financial support assistance that may help reduce the outof-pocket cost to patients, see http://www.repatha.com for more information. 3 Dosage The recommended dose of Repatha is 140 mg subcutaneously every two weeks or 420 mg monthly for patients with HeFH or clinical atherosclerotic cardiovascular disease. Patients with HoFH should receive 420 mg subcutaneously monthly. For administration of a 420 mg dose, give three 140 mg injections within 30 minutes. 1 In patients with HoFH, LDL-cholesterol levels should be measured four to eight weeks after starting Repatha to assess efficacy. 1 If a dose is missed on either the every two week or monthly schedule, but given within seven days, the patient can resume their original schedule. If the dose cannot be administered within seven days, the patient should wait and administer on the next scheduled dose of the original schedule. 1 Storage and Administration Repatha should be kept in the refrigerator at 2 C to 8 C (36 F to 46 F) in the original, outer carton to protect it from light. Repatha can also be stored at room temperature (up to 25 C [77 F]), in the original carton, but then must be used within 30 days. 1 To minimize discomfort and ensure the entire dose is administered, instruct patients to allow Repatha to warm to room temperature for at least 30 minutes prior to administration. Do not heat Repatha or leave it in direct sunlight to warm it

(PL Detail-Document #311003: Page 2 of 4) up. Patients also need to protect Repatha from freezing as well as from any extreme heat. 1 Before each administration the patient must check the expiration date and inspect the solution for any visible particles or discoloration, ensure the device is not cracked or broken, and that the orange or gray cap is intact. For the autoinjector, also ensure that the window of the device is not yellow. In any of these cases, the product should be discarded. Instruct the patient on proper aseptic technique for administration of this subcutaneous injection, such as to wash their hands prior to administration, clean the injection site with an alcohol wipe, and not to touch the needle. The injection site should be rotated with each injection and can be in the thigh, abdomen, or upper arm. The skin at the injection site should be healthy and intact, free of any damage (e.g., tender, bruised, red, etc). It also should not be injected into an area with stretch marks or scars. Avoid giving any other injections at the same site. Let the patient know to safely dispose of their used needles and syringes in a sharps container, or a household container that is heavy-duty plastic and can be sealed. 1 For more information on the safe disposal of medical sharps, go to http://www.epa.gov/wastes/nonhaz/industrial/med ical/disposal.htm. Other important administration information for Repatha: 1 Do not shake Do not try to remove any air bubbles before injecting, these are normal Plunger may be harder to depress than other injectables It can take up to 15 seconds to inject the full dose The window of the autoinjector must be yellow before removing the needle from the skin to ensure a complete dose is given Don t rub the injection site after giving the injection For detailed administration information, including diagrams, go to http://pi.amgen.com /united_states/repatha/repatha_ifu_hcp_pt_english.pdf. And, for additional questions and assistance, patients can call 844-REPATHA (844-737-2842) or go to http://www.repatha.com. Adverse Effects The most commonly reported adverse reactions (>5% and more common than placebo) in clinical trials are nasopharyngitis, upper respiratory tract infections, back pain, injection site reactions, and influenza. 1 Other adverse effects reported with Repatha include myalgia, cough, diarrhea, musculoskeletal pain, and rarely neurocognitive impairment. 4 Some studies have reported elevated creatine kinase levels and myalgias more often in PCSK9- treated groups than in placebo groups. One study reported elevated creatine kinase levels to more than five times normal in seven patients (1.2%) taking evolocumab compared to one patient (0.3%) in the placebo group. 5 And, myalgia was reported in 24 patients (4%) in the evolocumab group compared to nine patients (3%) in the placebo group. 5 In addition to the liver, the PCSK9 enzyme is also expressed in pancreatic islets. Because of this, there is the potential that inhibiting PCSK9 will have an effect on glucose homeostasis with an increased risk for the development of type 2 diabetes. Current studies with evolocumab, of up to one year in duration, have not shown an increased risk of type 2 diabetes. 5 There are ongoing long-term safety outcomes studies that will offer more information on this potential for increased risk of the development of diabetes in patients taking Repatha. Drug Interactions There have been no drug-drug interactions reported with Repatha. 1 Contraindications Repatha is contraindicated in patients who have had a serious hypersensitivity reaction to this medication. 1 Precautions If any signs or symptoms of an allergic reaction occur (e.g., pruritus, rash, urticaria, etc), Repatha should be discontinued immediately and the reactions treated. 1 The needle covers of Repatha s syringes and autoinjectors contain dry natural rubber and may cause allergic reactions in patients who are sensitive to latex. 1

(PL Detail-Document #311003: Page 3 of 4) Use In Pregnancy There is no data available on the use of Repatha in pregnant women. Animal studies have shown that evolocumab does cross the placental barrier. 1 Manufacturer Amgen Inc. Thousand Oaks, CA 91320 805-447-1000 www.amgen.com Commentary Despite currently available cholesterol lowering therapy (e.g., statins), there are certain patient groups who would benefit from additional options to better manage their hyperlipidemia. 6 These patients include those with familial hyperlipidemia, statin-intolerant patients, those with a poor response to statins, and patients with contraindications to statins. 6 Repatha significantly reduces LDL cholesterol levels in patients with high cholesterol [Evidence Level A; high quality RCT]. 7 It has shown efficacy when used as monotherapy, as well as when added to statins and/or other lipid lowering therapy, in patients with familial hypercholesterolemia and in patients who are intolerant to statin therapy. 8 Repatha has shown a reduction in LDL cholesterol levels ranging from 42% to 65% in patients with different types of dyslipidemia. 5,7 And, the effects were maintained for the duration of the studies. 8 Data from four phase 3 evolocumab studies were pooled to analyze 3152 patients. 8 Within these studies, evolocumab was compared to placebo, ezetimibe, or to standard lipid-lowering therapy. 8 The OSLER 1 and 2 trials were open-label, randomized trials that were analyzed together. 7 They enrolled 4465 patients who had completed previous evolocumab phase 2 or 3 studies, so called parent trials. 7 Patients were randomized to receive evolocumab 140 mg every two weeks or 420 mg every month by subcutaneous injection (added to their existing standard therapy) or standard therapy alone. 7 At one year, there was a 61% reduction in LDL cholesterol levels in the evolocumab group, from a mean of 120 mg/dl (6.8 mmol/l) to 48 mg/dl (2.7 mmol/l), compared to those not treated with evolocumab (p=<0.001). 7 While some studies are reporting beneficial effects of PCSK9 inhibitors on cardiovascular events, these studies are preliminary and only suggestive for benefit on cardiovascular outcomes. 2,9 There are four large, ongoing randomized controlled trials that have been designed to assess long-term cardiovascular outcomes with PCSK9 inhibitors. Results from these studies are expected by 2017. 2 Caution should be used to avoid the overuse of Repatha at the risk of not optimizing/maximizing statins, the only LDL cholesterol-lowering drugs proven to improve cardiovascular outcomes in dyslipidemic patients. Be cautious of the label statin-intolerant put on some patients. Statins are commonly discontinued, often due to adverse events such as muscle pain, but it is important to know that most patients who are rechallenged are often on the same statin 12 months later at the same or a higher dose. 10 There are also some strategies that can be used with statins, such as alternate day dosing, to increase the tolerability of these agents. 11 For more about managing statin intolerance, see our PL Chart, Statin Muscle Symptoms: Managing Statin Intolerance. Also see our PL Chart, 2013 ACC/AHA Cholesterol Guidelines, for information on using proven interventions for reducing CV risk in patients with dyslipidemia. Clinical trials with Repatha and other PCSK9 inhibitors show that they are relatively well tolerated. 12 However, studies have been of two years duration or less, so long-term effects are still unknown. 12 As we have seen with statins, it can take decades to identify some adverse effects, such as neurocognitive events and effects on glycemic control. For more information on evolocumab and PCSK9 inhibitors, including Praluent (alirocumab), another recently released PCSK9 inhibitor, see our PL Detail-Documents, PCSK9 Inhibitors for High Cholesterol and New Drug: Praluent (Alirocumab). Conclusion Statins, at target doses, are the only lipidlowering drugs proven to improve cardiovascular outcomes, the primary treatment goal in dyslipidemic patients. While Repatha significantly lowers LDL cholesterol levels, it is important to note that its long-term safety and

(PL Detail-Document #311003: Page 4 of 4) effect on cardiovascular outcomes is still undetermined. For now, this injectable, costly medication should be reserved for high-risk, hardto-treat patients with familial hypercholesterolemia where lifestyle changes and optimized statins have not been able to adequately control their hypercholesterolemia. Users of this PL Detail-Document are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and internet links in this article were current as of the date of publication. Levels of Evidence In accordance with the trend towards Evidence-Based Medicine, we are citing the LEVEL OF EVIDENCE for the statements we publish. Level Definition A High-quality randomized controlled trial (RCT) High-quality meta-analysis (quantitative systematic review) B Nonrandomized clinical trial Nonquantitative systematic review Lower quality RCT Clinical cohort study Case-control study Historical control Epidemiologic study C Consensus Expert opinion D Anecdotal evidence In vitro or animal study Adapted from Siwek J, et al. How to write an evidence-based clinical review article. Am Fam Physician 2002;65:251-8. Project Leader in preparation of this PL Detail- Document: Annette Murray, BScPharm 2. Navarese SP, Kolodziejczak M, Schulze V, et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia. Ann Intern Med 2015;163:40-51. 3. Amgen. FDA approves Amgen s new cholesterollowering medication Repatha (evolocumab). August 27, 2015. http://www.amgen.com/media/media_pr_detail.jsp? releaseid=2082837. (Accessed September 4, 2015). 4. Toth PP, Sattar N, Genest J, et al. A comprehensive safety analysis of 6026 patients from phase 2 and 3 short and long term clinical trials with evolocumab [abstract]. J Am Coll Cardiol 2015;65. doi: 10.1016/s0735-1097(15)61351-1. 5. Blom DJ, Hala T, Bolognese M, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med 2014;370:1809-19. 6. Koren MJ, Lundqvist P, Bolognese M, et al. Anti- PCSK9 monotherapy for hypercholesterolemia. J Am Coll Cardiol 2014;63:2531-40. 7. Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500-9. 8. FDA. FDA Briefing document Repatha. June 10, 2015. http://www.fda.gov/downloads/advisorycommittees /CommitteesMeetingMaterials/Drugs/Endocrinologi candmetabolicdrugsadvisorycommittee/ucm4500 72.pdf. (Accessed September 3, 2015). 9. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489-99. 10. Zhang H, Plutzky J, Skentzos S, et al. Discontinuation of statins in routine care settings. Ann Intern Med 2013;158:526-34. 11. Mampuya W, Frid D, Rocco M, et al. Treatment strategies in patients with statin intolerance: the Cleveland Clinic experience. Am Heart J 2013;166:597-603. 12. Stone NJ, Lloyd-Jones DM. Lowering LDL cholesterol is good, but how and in whom? N Engl J Med 2015;372:1564-5. References 1. Product information for Repatha. Amgen Inc. Thousand Oaks, CA 91320. August 2015. Cite this document as follows: PL Detail-Document, New Drug: Repatha (Evolocumab). Pharmacist s Letter/Prescriber s Letter. October 2015. Evidence and Recommendations You Can Trust 3120 West March Lane, Stockton, CA 95219 ~ TEL (209) 472-2240 ~ FAX (209) 472-2249 Copyright 2015 by Therapeutic Research Center Subscribers to the Letter can get PL Detail-Documents, like this one, on any topic covered in any issue by going to www.pharmacistsletter.com, www.prescribersletter.com, or www.pharmacytechniciansletter.com

PL Detail-Document #311003 This PL Detail-Document gives subscribers additional insight related to the Recommendations published in PHARMACIST S LETTER / PRESCRIBER S LETTER October 2015 Repatha and Praluent Comparison Abbreviations: HeFH=heterozygous familial hypercholesterolemia; HoFH=homozygous familial hypercholesterolemia REPATHA (Evolocumab) 1 PRALUENT (Alirocumab) 2 Subcutaneous Dose HeFH or clinical atherosclerotic cardiovascular disease: 140 mg every two weeks or 420 mg monthly 75 mg every two weeks, can be increased to 150 mg every two weeks HoFH: 420 mg monthly Indication Adjunct to diet and maximally tolerated doses of statin therapy in adults with HeFH or clinical atherosclerotic cardiovascular disease. Adjunct to diet and other LDL cholesterol-lowering therapies in adults with HoFH. Adjunct to diet and maximally tolerated statin therapy in adults with HeFH or clinical atherosclerotic cardiovascular disease. Efficacy 42% to 65% reduction in LDL-cholesterol 3,4 40% to 60% reduction in LDL-cholesterol 5 Availability Pre-filled syringes and autoinjectors of 140 mg/ml Pre-filled syringes and pens of 75 and 150 mg/ml Administration Storage Can take up to 15 seconds to administer entire dose. For the 420 mg dose, give three injections of 140 mg within 30 minutes. For more details on the administration of Repatha, see our PL Detail- Document, New Drug: Repatha (Evolocumab). Refrigerate. Can also be stored at room temperature, but must be used within 30 days. Can take up to 20 seconds to administer entire/full dose. For more details on the administration of Praluent, see our PL Detail-Document, New Drug: Praluent (Alirocumab). Refrigerate. Must be discarded if left at room temperature more than 24 hours. Cost $542 per dose; about $14,100 per year for every two week dosing $1120 for 2 doses; $14,600 per year Allergy Alert The needle covers of both the syringe and autoinjector contain latex. Avoid in patients who are allergic to latex. Devices do not contain latex.

(PL Detail-Document #311003: Page 2 of 2) Users of this PL Detail-Document are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and internet links in this article were current as of the date of publication. Project Leader in preparation of this PL Detail- Document: Annette Murray, BScPharm References 1. Product information for Repatha. Amgen Inc. Thousand Oaks, CA 91320. August 2015. 2. Product information for Praluent. Sanofi-Aventis. Bridgewater, NJ 08807. July 2015. 3. Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500-9. 4. Blom DJ, Hala T, Bolognese M, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med 2014;370:1809-19. 5. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489-99. Cite this document as follows: PL Detail-Document, Repatha and Praluent Comparison. Pharmacist s Letter/Prescriber s Letter. October 2015. Evidence and Recommendations You Can Trust 3120 West March Lane, Stockton, CA 95219 ~ TEL (209) 472-2240 ~ FAX (209) 472-2249 Copyright 2015 by Therapeutic Research Center Subscribers to the Letter can get PL Detail-Documents, like this one, on any topic covered in any issue by going to www.pharmacistsletter.com, www.prescribersletter.com, or www.pharmacytechniciansletter.com