1. Buy or Sell Medications Approved in 2015
MaD
MEDS
Buy or Sell Medications Approved in 2015
Angela Thompson, PharmD, BCPS Assistant Professor, Department of Clinical Pharmacy Meghan Jeffres, PharmD Assistant Professor, Department of Clinical Pharmacy

2. Disclosure Statement Angela Thompson
I have no relevant financial relationships with commercial interests pertaining to the content presented in this program.
Meghan Jeffres

3. Objectives
Upon the completion of this presentation, the audience should be able to:
Summarize pharmacokinetic and clinical data for newly approved medications
Identify whether a newly approved medication represents a clinical advantage over existing options
Compare economic differences between newly approved and existing medications

4. BUY SELL 4 Topics Cardiology Infectious diseases Dermatology
Sexual dysfunction
8 medications
MEDS
You will vote to buy or sell each medications
= Green paper
= Pink paper
BUY
SELL

5. Cardiovascular Agents
Lipid lowering medications
Proprotein Convertase Subtilisin-kexin Type 9 (PCSK9) Inhibitors
Heart failure medications
Neprilysin inhibitor/angiotension receptor blocker (ARB)
Cyclic nucleotide-gated channel blocker

6. PCSK9 Inhibitors Alirocumab (Praluent) Sanofi Aventis, July 2015
Evolocumab (Repatha)
Amgen, August 2015

7. PCSK9 Inhibitors Monocolonal antibodies
Mechanism of action: Inhibits proprotein converstase subtilisin-kexin type 9 (PCSK9) to increase LDL-C receptors and reduce circulating LDL-C
Indications
In addition to diet and maximally tolerated statin therapy in patients needing additional LDL-C lowering with:
Primary Hyperlipidemia W/ ASCVD
Heterozygous familial hypercholesterolemia (HeFH)
Homozygous familial hypercholesterolemia (HoFH) (Repatha only)
Praluent (alirocumab) [package insert]. Bridgewater, NJ; Sanofi-Aventis; 2015; Repatha (evolocumab) package [insert]. Thousand Oaks, CA; Amgen; 2015.

8. PCSK9 Inhibitor Dosing Medication Indication Dosing Praluent
(alirocumab)
Primary hyperlipidemia w/ ASCVD and HeFH
mg SubQ q 2 wks
Repatha
(evolocumab)
HoFH
140 mg SubQ q 2 wks OR 420 mg SubQ monthly
420 mg SubQ monthly
Praluent (alirocumab) [package insert]. Bridgewater, NJ; Sanofi-Aventis; 2015; Repatha (evolocumab) package [insert]. Thousand Oaks, CA; Amgen; 2015.

9. PCSK9 Efficacy Studies – Study Design
Study [PSCK9-I]
Design
Intervention
Population Included
ODYSSEY LONG TERM
[alirocumab (Praluent)]
Randomized, double blind, placebo controlled study
Alirocumab 150 mg subq every 2 weeks vs. placebo
-HeFH, established CAD, or CHD risk equivalent
-On max tolerated statin
OSLER 1 & OSLER 2
[evolocumab (Repatha)]
Two randomized, open label controlled studies
Evolucomab 420 mg subq monthly or 140 mg subq q 2 weeks vs. standard therapy
-Successful completion of parent trial without adverse event leading to discontinuation
NEJM ; 372:
NEJM.; 372:

10. PCSK9 Efficacy Studies – Patient Population
ODYSSEY LONG TERM [alirocumab (Praluent)]
OSLER 1 & OSLER 2 [evolocumab (Repatha)]
Average age = 60 years
Sex = 63% male
Mean LDL = 122 mg/dL
>99.9% on statin therapy
Risk:
CHD - 69%
CHD risk equivalent - 41%
Diabetes - 35%
Smokers – 21%
Average age = 58 years
Sex = 50% male
Median LDL = 120 mg/dL
70.1% on statin therapy
Risk:
>1 CV risk factors – 80%
CAD – 20%
Diabetes – 13%
Smokers – 15%
NEJM. 2015; 372: ; NEJM. 2015; 372:

11. PCSK9 Efficacy Studies – Efficacy
Study [PCSK9-I]
% LDL-C change
v. placebo
Cardiovascular Events v. placebo/standard therapy*
Adverse Events
ODYSSEY LONG TERM
[alirocumab (Praluent)]
-61.9%
(p<0.001)
1.7% v. 3.3%
HR = 0.52 (p<0.02)
81.0% v. 82.5%
(p = NS)
OSLER 1 & OSLER 2
[evolocumab (Repatha)]
-60.9%
0.95% v. 2.1%
HR = 0.47 (p = 0.003)
69.2% v. 64.8%
* Data from post-hoc analyses. Effects of alirocumab and evolocumab on CV endpooints have not been established.
NEJM. 2015; 372: ; NEJM. 2015; 372:

12. Cost Data
AWP via LexiComp. Accessed 11/11/ CEPAC

13. Alirocumab and Evolocumab
Buy or Sell?
Alirocumab and Evolocumab
BUY
SELL
Hold

14. Heart Failure Medications
Sacubitril/valsartan (Entresto)
Novartis, July 2015
Neprilysin inhibitor/angiotension receptor blocker (ARB)
Ivabradine (Corlanor)
Amgen, April 2015
Cyclic nucleotide-gated channel blocker
Entresto (sacubitril and valsartan) [package insert]. East Hanover, NJ: Novartis; 2015.; Corlanor (ivabradine) [package insert]. Thousand Oaks, CA: Amgen; 2015.

15. Sacubitril/valsartan (Entresto)
MOA: inhibits neprilysin (neutral endopeptidase) to increase peptides such as natriuretic peptides/inhibits the angiotensin II type-1 receptor
Indications: Reduction in risk of cardiovascular death and hospitalization for patients with chronic heart failure and reduced ejection fraction
Replaces ACE-inhibitor or ARB
Entresto (sacubitril and valsartan) [package insert]. East Hanover, NJ: Novartis; 2015.

16. Sacubitril/valsartan (Entresto) - Dosing
Medication
Sacubitril/valsartan (Entresto)
Dosing
Starting dose
Maximum/target dose
49/51 mg BID
97/103 mg BID
Starting dose Adjustments
Patients naïve to ACE-I or ARBs
Severe renal impairment
Moderate hepatic impairment
24/26 mg BID
Double to dose every 2-4 weeks to targeted dose, as tolerated.
If switching from ACE-inhibitor, allow 36 hour washout period between
administration of 2 agents.
Entresto (sacubitril and valsartan) [package insert]. East Hanover, NJ: Novartis; 2015.

17. Sacubitril/valsartan (Entresto) - Safety
Contraindications
History of angioedema with ACE-inhibitor or ARB
Concomitant use of ACE- inhibitor or aliskiren
Drug interactions
RAAS inhibitors
Potassium sparing diuretics
Lithium
NSAIDs
Adverse reactions
Angioedema
Hypotension
Impaired renal function
Hyperkalemia
Entresto (sacubitril and valsartan) [package insert]. East Hanover, NJ: Novartis; 2015.

18. Sacubitril/valsartan (Entresto) - Efficacy
Endpoint
Sacubitril/valsartan
n (%)
Enalapril
HR (95% CI)
CV death or 1st hospitalization for HF
914 (21.8%)
1117 (26.5%)
0.80 (0.73 to 0.87)
CV death
558 (13.3%)
693 (16.5%)
0.80 (0.71 to 0.89)
Hospitalization for HF
537 (12.8%)
658 (15.6%)
0.79 (0.71 to 0.89)
NEJM. 2014; 371:

19. Sacubitril/valsartan (Entresto) - Safety
Endpoint
Sacubitril/valsartan
200 mg BID
Enalapril
10 mg BID
P-value
Hypotension
558 (14)
388 (9.2)
<0.001
Cough
474 (11.3)
601 (14.3)
Potassium >6 mmol/dL
181 (4.3)
236 (5.6)
0.007
SCr >2.5 mg/dL
139 (3.3)
188 (4.5)
NEJM. 2014; 371:

20. Ivabradine (Corlanor)
MOA: Inhibits If current in sinoatrial node to reduce heart rate
Indication: reduce risk of hospitalization for worsening heart failure in:
Patients with stable, symptomatic chronic heart failure with a reduced ejection fraction (<35%)
AND
Who are in sinus rhythm with resting heart rate > 70 beats per minute
Who are on maximally tolerated beta-blocker therapy or have a contraindication to beta-blocker therapy
Entresto (sacubitril and valsartan) [package insert]. East Hanover, NJ: Novartis; 2015.

21. Ivabradine (Corlanor)- Dosing
Medication
Ivabradine (Corlanor)
Dosing
Starting dose
Maximum dose
5 mg BID
7.5 mg BID
Dosing Adjustments
Conduction defects
Risk for hemodynamic compromise with bradycardia
Start with 2.5 mg BID
Adjust dose after 2 weeks to achieve target heart rate of bpm.
Entresto (sacubitril and valsartan) [package insert]. East Hanover, NJ: Novartis; 2015.

22. Ivabradine (Corlanor)- Safety
Contraindications
Acute decompensated heart failure
BP <90/50 mmHg
AV block/sick sinus syndrome
Resting heart rate <60 bpm
Severe hepatic impairment
Pacemaker dependence
Adverse reactions
Bradycardia
Hypotension
Atrial fibrillation
Luminous phenomena
Drug interactions
CYP3A4 inhibitors
CYP3A4 inducers
Negative chronotropes
Entresto (sacubitril and valsartan) [package insert]. East Hanover, NJ: Novartis; 2015.

23. Ivabradine (Corlanor) - Efficacy
Endpoint
Ivabradine
n (%)
Placebo
HR (95% CI)
CV death or 1st HF hospitalization
793 (24)
937 (29)
0.82 (0.75 to 0.90)
Hospitalization for HF
514 (16)
672 (21)
0.74 (0.66 to 0.83)
CV death
449 (14)
491 (15)
0.91 (0.80 to 1.03)
Death from HF
113 (3)
151 (5)
0.74 (0.58 to 0.94)
Reversible bradycardia and visual disturbances occurred more frequently in
the ivabradine group compared to placebo.
Lancet. 2010; 376:

24. Heart Failure Medication Costs
Heart Failure Agent
Out of Pocket Cost
1 month supply ($)
Sacubitril/valsartan (Entresto)
450
Ivabradine (Corlanor)
AWP via LexiComp. Accessed 11/11/2015.

25. Sacubitril/valsartan (Entresto)
Buy or Sell?
Sacubitril/valsartan (Entresto)
And
Ivabradine
BUY
SELL
Hold

26. Antibacterial Ceftazidime-avibactam (Avycaz) Indications
Forest Pharmaceuticals, February 2015
Combination 3rd generation cephalosporin and beta- lactamase inhibitor
Indications
Complicated intra-abdominal infection
Complicated urinary tract infection

27. Basics – PK, dosing, etc Indication Dosing Spectrum cIAI cUTI
2.5 g Q8 plus metronidazole
2.5 g Q8
Renal dosing
CrCl mL/min: 1.25 g Q8
CrCl mL/min: 0.94 g Q12
CrCl 6-15 mL/min: 0.94 g Q24
CrCl ≤5 mL/min: 0.94 g Q 48
Limited gram positive
Gram negative
P. aeruginosa
AmpC producing organisms (ESCPM)
ESBL producing organisms
Carbapenemase producing organisms
No NDM coverage
NDM = New Delhi Metallo-beta-lactamase-1
Int J Antimicrob Ag. 2015;46:483–493

28. cUTI ceftazidime-avibactam vs imipenem
EOT = end of IV therapy; TOC = test of cure; LFU = late follow-up
Curr Med Res Opin 2012;28:

29. cIAI ceftazidime-avibactam vs meropenem
TOC = test of cure
J Antimicrob Chemother 2013;68:1183–1192

30. Cost data vs competitors
Antibiotic
Cost ($)/day
Piperacillin/tazobactam
48-64
Cefepime
15-30
Imipenem/cilastatin 40
Meropenem
40-60
Ceftolozane/tazobactam
100
Ceftazidime/avibactam
1026
Lexicomp

31. Ceftazidime-avibactam (Avycaz)
Buy or Sell?
Ceftazidime-avibactam (Avycaz)
BUY
SELL
Hold

32. Antifungal Isavuconazole (Cresemba) Indications
Prodrug - Isavuconazonium sulfate
Astellas and Basilea Pharmaceutica, March 2015
Triazole antifungal
Indications
Invasive aspergillus infections
Pulmonary, sinus
Invasive mucor infections
Sinus, brain, eye

33. Basics – PK, dosing, etc Dosing Spectrum Drug interactions
Load: 372 mg Q8 x 6 doses;
Maintenance: 372 mg Q day
*isavuconazole 200 mg
No cyclodextrin in IV solution
Yeast
Candida spp
Cryptococcus spp
Others
Mold
Aspergillus spp
Fusarium spp
Scedosprorium spp
Mucorales family
Dimorphic fungi
Decrease concentration
Rifampin
Carbamazepine
Increased concentration
Sirolimus/tacrolimus
Cyclosporine
Mycophenolate
Digoxin
Colchicine
Dabigatran
Atorvastatin

34. Isavuconazole vs voriconazole - Aspergillus
FDA Advisory Committee Briefing
Document 2015

35. Isavuconazole for Mucormycosis
IDWeek 2014 Abstract 829

36. Cost data vs competitors
Antifungal
Cost ($)/day
Amphotericin B
,470
Voriconazole 94
Posaconazole
418 x 1, 209
Isavuconazole IV
858 x 2 days, 268
Isavuconazole PO
504 x 2 days, 168
Lexicomp

37. Isavuconazonium (Cresemba)
Buy or Sell?
Isavuconazonium (Cresemba)
BUY
SELL
Hold

38. Medication and Indication
Deoxycholic acid (Kybella)
Kythera Biopharmaceuticals Inc, April 2015
Marketed by Allergan
Indications
Improving the appearance of moderate-to-severe convexity or fullness associated with submental fat in adults
AKA double chin
Accessed Nov 22, 2015

39. Origin and Mechanism of Action
Synthetically derived from bile acid deoxycholate
Disrupts adipocyte membranes, causes irreversible cell breakdown (adipocytolysis)

40. Basics
Dosing
Safety
SubQ: Inject into submental subcutaneous fat tissue – max: 2 mg/cm2
Up to 50 injections spaced 1 cm apart (0.2 mL each; total 10 mL vial)
2 – 6 treatments, 1 month apart
Does not accumulate in adipose tissue
Rapid clearance – fecal excretion
“Should not” affect nonlipid-rich tissues such as muscle and bone
Brit J of Derm. 2014;170:445–453

41. Deoxycholic acid vs Placebo
AE % difference from placebo
Pain ± burning
55%
Numbness
49%
Swelling
36%
Induration ± fibrosis
24%
Erythema
14%
Bruising ± bleeding
13%
Treatment responders
1 mg/cm2 = 59%; 2 mg/cm2 = 65%; placebo 23%
Brit J of Derm. 2014;170:445–453

42. Cost data vs competitors
Site
Cost estimates
Happy Clinic Denver
$600/vial
2-3 vials per treatment
Wall Street Journal
$300 per vial
WebMD per American Society of Plastic Surgeons
$560 per treatment
Chin liposuction $

43. Deoxycholic acid (Kybella)
Buy or Sell?
Deoxycholic acid (Kybella)
BUY
SELL
Hold

44. Medication and Indication
Flibanserin (Addyi)
Sprout Pharmaceuticals, August 2015
Indications
Generalized hypoactive sexual desire disorder (HSDD) in premenopausal women
Mechanism
Centrally acting serotonin 1A receptor agonist and 2A antagonist
Results in transient decreases in serotonin and increases in dopamine and norepinephrine in prefrontal coretex of the brain

45. Hypoactive Sexual Desire Disorder
6-43% of US women affected
FDA accepts HSDD is an unmet need (2011)
Flibanserin approved for HSDD after two prior attempts (2009, 2010)
In development
Phase III
Bremelanotide – melanocortin receptor agonist
Lybrido – testosterone-coated sildenafil
Phase II
Lybridos – testosterone-coated buspirone
Lorexys – combination trazodone and bupropion
Cell. 2015;163(3):533.

46. Basics Dosing Adverse effects Interactions 100 mg QPM
Discontinue if no improvement at 8 weeks
Contraindicated in hepatic impairment
ADDYI REMS program required
CNS depression
Hypotension
Syncope
Contraindicated with CYP3A4 inhibitors and inducers
Contradicted with EtOH

47. Satisfying sexual events per month
J Sex Med 2012;3: ; J Sex Med 2012;9: ; J Sex Med 2013;10: ; Menopause 2014;21:

48. Cost data vs competitors
Treatment
Cost ($), day/month
Testosterone patch*
8/240
Testosterone ointment compound
3/90
Bupropion
4/120
Flibanserin
32/960
*Intrinsa patch not FDA approved, no longer manufactured
Lexicomp

49. Buy or Sell?
Flibanserin (Addyi)
BUY
SELL
Hold

50. SELL NOT FEMALE VIAGRA Why Efficacy is minimal
Significant safety concerns
Contraindicated with alcohol
NOT FEMALE VIAGRA

51. Buy or Sell Medications Approved in 2015
MaD
MEDS
Buy or Sell Medications Approved in 2015
Angela Thompson, PharmD, BCPS Assistant Professor, Department of Clinical Pharmacy Meghan Jeffres, PharmD Assistant Professor, Department of Clinical Pharmacy