PCSK9 INHIBITORS, ARNIS, FUNNY CHANNEL INHIBITORS:ARE YOU SURE THESE ARE
REALLY CARDIAC DRUGS?ALLORIE SMITH, PHARM.D.
CARDIOVASCULAR UPDATE CONFERENCE
FEBRUARY 9, 2012
OBJECTIVES
• Explain the pharmacology of Repatha™, Praluent®,
Entresto™, and Corlanor®.
• Learn the indications and doses for each of the
medications listed above.
• Discuss the literature behind the approval of the drugs
above
EVOLOCUMAB (REPATHA™)ALIROCUMAB (PRALUENT®)
PCSK9 INHIBITORS
PCSK9 INHIBITORS: CLASSIFICATION AND MOA
• Class: Proprotien convertase subtilisin kexin type 9
inhibitor (PCSK-9) antibody
• MOA: Binds to the PCSK-9 and prevents it from binding
and degradation the the LDL receptors. This allows for
the LDL receptors to return to the liver cell surface and
clear LDL from the blood, lowering LDL-C levels
Normal Activity
With Repatha
PCSK9 INHIBITORS: INDICATIONS AND DOSING
REPATHA™
• Adjunct to diet and maximum statin
dose in primary hyperlipidemia
• 140 mg subQ every 2 weeks
• 420 mg subQ monthly
• Adjunct to diet and other LDL
lowering therapies for homozygous
familial hypercholesterolemia
• 420 mg subQ monthly
PRALUENT®
• Adjunct to diet and
maximum statin dose in
primary hyperlipidemia
• 75 mg subQ every 2 weeks
• May increase to 150 mg
subQ every 2 weeks if
needed to achieve LDL
lowering goals
PCSK9 INHIBITORS : SIDE EFFECTS
REPATHA™• Nasopharyngitis (11%)
• URI (9%)
• Flu (9%)
• Gastreoenteritis (6%)
• Injection side reaction (6%)
• UTI (5%)
• Less than 5%
• Dizziness (4%), Myalgia (4%), Hypertension (3%),
Fatigue (2%), Nausea (2%), Bruise (1%)
PRALUENT®
• Injection site reactions (7%)
• Influenza (6%)’
• Diarrhea (5%)
• Less than 5%
• Increased liver enzymes (3%), Myalgia
(4%), Spasms (3%), cough(3%)
• Post marketing data/case reports:
confusion, memory impairment
PCSK9 INHIBITORS : DRUG INTERACTIONS/ CONTRAINDICATIONS
REPATHA™
• Interactions
• Belimumab
• Contraindications
• Hypersensitivity
PRALUENT®
• Interactions
• Belimumab
• Contraindications
• Hypersensitivity
PCSK9 INHIBITORS : PRICING
REPATHA™
• ~$650 per 140 mg
injection
• $5 copay coupon for
commercial insurance
PRALUENT®
• ~$670 per 75mg or 150mg
injection
• $0 copay for 6 months then
$10 thereafter coupon for
commercial insurance
REPATHA™: PHASE III STUDY RESULTS
• MENDEL 2: J Am Coll Cardiol. 2014 Jun 17;63(23):2531-40
• LAPLACE-2: JAMA. 2014 May 14;311(18):1870-82.
• DESCARTES : N Engl J Med. 2014 May 8;370(19):1809-19.
• GAUSS-2 : J Am Coll Cardiol. 2014 Jun 17;63(23):2541-8.
• RUTEHRFORD-2: Lancet. 2015 Jan 24;385(9965):331-40.
• TESLA PART B: Lancet. 2015 Jan 24;385(9965):341-50.
• OSLER 1: Circulation. 2014 Jan 14;129(2):234-43.
PRALUENT™: PHASE III STUDY RESULTS
• ODYSSEY MONO : Future Cardiol. 2015;11(1):27-37.
• ODYSSEY COMBO 1: Am Heart J. 2015 Jun;169(6):906-915
• ODYSSEY COMBO 2 : Eur Heart J. 2015 May 14;36(19):1186-94.
• ODYSSEY ALTERNATIVE : J Clin Lipidol. 2014 Nov-Dec;8(6):554-61.
• ODYSSEY FH 1 AND 2 : Eur Heart J. 2015 Nov 14;36(43):2996-
3003
• ODYSEEY LONG TERM : N Engl J Med. 2015 Apr 16;372(16):1489-
99.
SACUBITRIL / VALSARTAN (ENTRESTO™)
ENTRESTO™: INDICATION AND DOSAGE
• Heart failure
• Patients previously taking the
equivalent of >10 mg/day of
enalapril or >160 mg of
Valsartan
• Start 49mg/51 mg BID, double
the dose every 2-4 weeks to the
target dose of 97 mg/ 103 mg
BID
• Patients previously taking the
equivalent of <10 mg/day of
enalapril or <160 mg of
Valsartan
• Start 24mg/26 mg BID, double
the dose every 2-4 weeks to the
target dose of 97 mg/ 103 mg
BID
ENTRESTO™ CLASSIFICATION AND MOA
• Class: Angiotensin Receptor
Blocker (ARB) and Neprilysin
Inhibitor
• MOA:
• ARB: Blocks angiotensin
receptors
• Neprilysin inhibitor:
prodrug that inhibits
neprilysin and increase
levels of naturetic peptides
ENTRESTO™ : SIDE EFFECTS
• Hypotension (~18%)
• Hyperkalemia (up to 16%)
• Increase in SCR (up to 16%)
• Cough (9%)
• Less than 5%:
• Hypotension, Dizziness, Decreased H/H, Angioedema, Renal
failure
ENTRESTO™ : DRUG INTERACTIONS / CONTRAINDICATION
DRUG INTERACTIONS
• ACEI
• Aliskiren
• Lithium
• Trimethoprim
• Simeprevir
CONTRAINDICATIONS
• History of angioedema
Plavix [package insert]
Lexi-comp
Micromedex
ENTRESTO™ : PHASE III STUDY
• PARADIGM-HF
• N Engl J Med. 2014 Sep 11; 371(11): 993-1004
Pharmacotherapy. 2012;32(12):e348-e386
ENTRESTO™ : PRICING
• All strengths: ~$450 for 60 tablets
• 30 days free coupon valid for all insurances (commercial and
government)
• $10 copay card for commercial insurance
IVABRADINE (CORLANOR®)
CORLANOR®: INDICATIONS AND DOSAGE
• Heart failure
• Initial dose: 5 mg BID
• Adjustments after two weeks
• Resting HR > 60 – increase to 7.5 mg BID (max dose)
• Resting HR between 50-60 – maintain dose
• Resting heart rate <60 or Symptoms of bradycardia – reduce to
2.5 mg BID
CORLANOR®: CLASSIFICATION AND MOA
• Class: MISC Cardiovascular agent
• NO FUN!!! I think we should call them funny channel inhibitors
• MOA:
• Selective and specific inhibition of the hyperpolarization-
activated cyclin nucleotide-gated channels (If channels or funny
channels) within the SA node of the cardiac tissue
• Slows diastolic depolarization and firing of the SA node which
reduces heart rate
Corlanor Website https://www.corlanorhcp.com/~/media/amgen/full/www-corlanorhcp-com/diagram-
moa3.ashx?la=en&hash=89DD72F9A1AC0E2F6A32D9AB4E30F6A77073AB05
CORLANOR®: SIDE EFFECTS
• Bradycardia (10%)
• Hypertension (8.9%)
• A Fib (8.3%)
• Phosphene (2.8%)
CORLANOR®: DRUG INTERACTIONS / CONTRAINDICATION
DRUG INTERACTIONS
• QT prolongating agents
• CYP 3A4 drugs
CONTRAINDICATIONS
• Decompensated CHF
• Pacemaker dependent
• Baseline bradycardia
• Hepatic impairment
• Hypotension
• Heart block
CORLANOR®: STUDY
• BEAUTIFUL: Lancet. 2008 Sep 6;372(9641):807-16.
• SHIFT: Lancet. 2010 Sep 11;376(9744):875-85.
• SIGNIFY: N Engl J Med. 2014 Sep 18; 371:1091-1099
Pharmacotherapy. 2012;32(12):e348-e386
CORLANOR®: PRICING
• $375 for 60 tablets
• $20 copay coupon for commercial insurance
REFERENCE
• Corlanor [package insert]. Thousand Oaks, CA: Amgen; 2015.
• Entresto [package insert]. East Hanover, NJ: Novartis; 2015.
• Lexi-Comp Online. Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc.;
2016. http://online.lexi.com. Accessed January 25, 2016.
• Micromedex Healthcare Series. DRUGDEX System. Greenwood
Village, CO: Thomson Healthcare; 2016.
http://www.thomsonhc.com/. Accessed January 25, 2016.
• Praluent [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2015.
• Repatha [package insert]. Thousand Oaks, CA: Amgen; 2015.
PCSK9 INHIBITORS, ARNIS, FUNNY CHANNEL INHIBITORS:
ARE YOU SURE THESE ARE REALLY
CARDIAC DRUGS?ALLORIE SMITH, PHARMD
CARDIOVASCULAR UPDATE CONFERENCE
FEBRUARY 9, 2012
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