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additional insight related to the Recommendations published in−

PHARMACIST’S LETTER / PRESCRIBER’S LETTER October 2015

More. . . Copyright © 2015 by Therapeutic Research Center

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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

can statins cause? Patients may complain of pain, tenderness, stiffness, cramps, weakness, or fatigue.

1

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 <ULN3,8

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 statin-

associated muscle

symptoms?

In clinical trials, low- or moderate-intensity statinsa 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)




What are some risk factors

for statin-associated muscle

adverse effects?

Multiple disease states (e.g., renal or hepatic insufficiency) or polypharmacy1,4

History of musculoskeletal symptoms or CK elevation, neuromuscular disease, or personal or family history of

statin or other myopathy1,3

Use of medications or foods (e.g., grapefruit) that increase statin levels1

Age over 75 to 80 years1,3

Asian ancestry1,3

Being female3

Low BMI or small frame3

Frailty3

Physical activity4

Alcohol or drug abuse3

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 statina 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





When should a creatine

kinase be checked? 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

What is the general approach

to take when a patient

complains of muscle

symptoms?

Continued…

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 statin4

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-





General approach,

continued

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.

When should I stop a statin

due to muscle symptoms? 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

Can I give statins less often

than once daily to reduce

symptoms?

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

What is the role of coenzyme

Q10 (ubiquinol)? 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.


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. Statin-associated 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/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124165.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

http://pharmacistsletter.therapeuticresearch.com/?s=ND






New Drug: Repatha (Evolocumab)

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

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 out-

of-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

http://www.pharmacistsletter.com/




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





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 lipid-

lowering 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




effect on cardiovascular outcomes is still

undetermined. For now, this injectable, costly

medication should be reserved for high-risk, hard-

to-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.


Document: Annette Murray, BScPharm

References 1. Product information for Repatha. Amgen Inc.

Thousand Oaks, CA 91320. August 2015.

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 cholesterol-lowering 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/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM450072.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.

Cite this document as follows: PL Detail-Document, New Drug: Repatha (Evolocumab). 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

HoFH: 420 mg monthly

75 mg every two weeks, can be increased to 150 mg

every two weeks

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-cholesterol3,4

40% to 60% reduction in LDL-cholesterol5

Availability

Pre-filled syringes and autoinjectors of 140 mg/mL

Pre-filled syringes and pens of 75 and 150 mg/mL

Administration 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).

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).

Storage Refrigerate. Can also be stored at room temperature, but must be

used within 30 days.

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.


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.


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.


