Download New Drug Update 2015

8/27/2015
Pharmacist Objectives
New Drug Update 2015
Joe Strain, Pharm.D.
SDSU College of Pharmacy
Rapid City Regional Hospital
Following this presentation, pharmacists will be able to:
 Identify therapeutic indications and pharmacological
properties of specific drugs recently approved by the
FDA.
 List side effects, warnings, precautions and significant
drug interactions associated with each medication.
 Identify the normal dose and dosage forms of the drugs
presented.
 Demonstrate an understanding of how to effectively
educate patients who are prescribed each medication.
 Describe how the new drugs presented will be used in
clinical practice.
New Drug Approval Trends
Technician Objectives
NME
NB
33
Following this presentation, pharmacy
technicians will be able to:
 Identify new drugs approved by the FDA and
their classification.
 Identify the major uses for the drugs
presented.
 Identify the usual dose and route of
administration for each medication.
 List the cost associated with each of the
new drugs approved by the FDA.
18
21
18
30
25
24
19
16
15
11
2
4
2
4
7
6
6
6
4
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014
NME: New Molecular Entity
NB: New Biologic
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopeda
ndApproved/DrugandBiologicApprovalReports/NDAandBLAApprovalReports/UCM406851.pdf
Agenda
“I have had no financial relationship
over the past 12 months with any
commercial sponsor with a vested
interest in this presentation”

Edoxaban (Savaysa™)

Ivabradine (Corlanor®)

Sacubitril/valsartan (Entresto™)

Ceftazidime/avibactam (Avycaz ®)

Ceftolozane/tazobactam (Zerbaxa™)

Sofosbuvir & ledipasvir (Harvoni®)

Paritaprevir/ritonovir, ombitasvir, dasabuvir (Viekira®)

Alirocumab (Praluent®)

Evolocumab (Repatha™)

Flibanserin (Addyi™)

Naloxegol (Movantik™)

Eluxadoline (Viberzi™)

Dantrolene (Ryanodex®)
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8/27/2015
Edoxaban should NOT be used in A. fib if:
Edoxaban (Savaysa™)
1. CrCl is < 30ml/min
 Indication
 Reduce stroke and systemic embolism
2. CrCl is < 50 ml/min
in non-valvular atrial fibrillation
 Treatment of DVT & PE AFTER 5-10
3. CrCl is > 95 ml/min
days of a parenteral anticoagulant
 Pharmacology
 Factor Xa inhibitor
Savaysa PI 2015.
Pharmacokinetic comparison of oral Factor Xa
inhibitors
Edoxaban
Apixaban
Rivaroxaban
Peak effect
1-2h
3-4h
2-4h
T½
10-14h
~ 12h
5-9h
Renal
clearance
50%
~ 27%
~ 36%
Metabolism
Minimal
CYP3A4
CYP3A4
Edoxaban (Savaysa™)
 Warnings and precautions
 Not recommended in mechanical
Savaysa PI 2015.
Eliquis PI 2012.
heart valves or moderate to severe
mitral stenosis
 Not recommended for use in nonvalvular atrial fibrillation IF the
creatinine clearance is > 95 ml/min
 Not studied in CrCl < 15 ml/min
Savaysa PI 2015
Xarelto PI 2014.
Bleeding Rates in Atrial Fibrillation with CrCl < 95 ml/min
Edoxaban (Savaysa™)
 Drug interactions
 P-glycoprotein inhibitors
Bleeding Event Edoxaban 60 mg
n = 5417
Warfarin
n = 5485
HR (95%
CI)
 May require reduction for DVT/PE
Major
3.1%
3.7%
0.84
(0.73,0.97)
 P-glycoprotein inducers (i.e. rifampin)
Intracranial
hemorrhage
0.5%
1%
0.44
(0.32, 0.61)
GI bleeding
1.8%
1.3%
1.4
(1.13, 1.73)
Fatal bleeding
0.2%
0.4%
0.51
(0.3, 0.86)
indication
 Avoid due to reduced levels
 Other anticoagulants and antiplatelets
Savaysa PI 2015.
Savaysa PI 2015.
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8/27/2015
Efficacy Data in Atrial Fibrillation vs. Warfarin
Bleeding Rates in VTE
Edoxaban 60 mg
N = 4118
Warfarin
N = 4122
HR
(95% CI)
ENGAGE AF-TIMI
48 Trial
Edoxaban 60 mg
N = 7012
Warfarin
N = 7012
P-value
Clinically Relevant
bleeding
8.5%
10.3%
0.81
(0.71, 0.94)
Stroke or systemic
embolic event
1.18%
1.5%
<0.001
Major bleeding
1.4%
1.6%
0.84
(0.59, 1.21)
Intracranial
hemorrhage
0.1%
0.3%
NR
Hokusai-VTE Trial
< 0.1%
0.2%
NR
1st recurrent VTE or
VTE-related death
Bleeding Event
Fatal bleeding
Efficacy Data in VTE vs. Warfarin
Edoxaban 60 mg
N = 4118
Warfarin
N = 4122
P-value
3.2%
3.5%
<0.001
N Engl J Med 2013;369:2093-104.
N Engl J Med 2013;369:1406-15.
N Engl J Med 2013;369:1406-15.
Edoxaban (Savaysa™)
Edoxaban (Savaysa™)
 Dosing
 Transitioning to edoxaban:
 Atrial fibrillation
 60 mg daily for CrCl 51-95 ml/min
 30 mg daily for CrCl 15-50 ml/min
 DVT/PE treatment
 60 mg daily
 30 mg daily for CrCl 15-50 ml/min
or body weight ≤ 60 kg or on
certain P-gp inhibitors
 From warfarin
 Start when INR < 2.5
 From any other oral anticoagulant or
a LMWH
 Start at next scheduled dose
 From heparin
 Turn off heparin and start 4 hours
later
Savaysa PI 2015.
Savaysa PI 2015.
Edoxaban (Savaysa™)
Edoxaban (Savaysa™)
 Transitioning from edoxaban:
 Bottom line
 To warfarin
 Start warfarin and taper edoxaban
 If on 60 mg decrease to 30 mg
 If on 30 mg decrease to 15 mg
 Draw INR immediately prior to edoxaban
dose--when INR is > 2 stop edoxaban
 To any other oral agent, LMWH, or heparin
 Start alternative agent at time of next
scheduled edoxaban dose
 Non-inferior to warfarin for stroke
prevention in atrial fibrillation and for
DVT/PE treatment
 Use of heparin/LWMH for 5-10 days prior to
DVT/PE tx may limit use
 Watch renal function—high and low!
 No specific reversal agent….yet….
 Additional review
 Mekaj YH et al. Ther Clin Risk Manag
2015;11:967-77.
Savaysa PI 2015.
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8/27/2015
Ivabradine works for heart failure by:
Ivabradine (Corlanor®)
1. Increasing contractility
 Indication
2. Increasing urine output
3. Slowing the heart rate
4. Reducing afterload
 Reduce the risk of hospitalization for
worsening heart failure in patients with:
 Stable, symptomatic chronic heart
failure
 EF ≤ 35%
 Sinus rhythm
 Resting heart rate of ≥ 70 BPM
 On maximum beta-blocker or
contraindication to beta-blocker
Corlanor PI 2015
Ivabradine (Corlanor®)
Ivabradine (Corlanor®)
 Pharmacology
 Pharmacokinetics
 Inhibits the If “funny” current
 Cmax in ~ 1 hour
 Slows heart rate
 Food increases absorption (20-40%)
 Effects more pronounced at higher
 Effective t ½ ~ 6 hours; active
baseline heart rates
 Does not affect contractility or blood
pressure
metabolite ~ 11 hours
 CYP3A4 metabolism
Corlanor PI 2015
Corlanor PI 2015
Ivabradine (Corlanor®)
Ivabradine (Corlanor®)
 Contraindications
 Warnings and precautions
 Resting HR < 60 BPM at initiation
 Fetal toxicity
 BP < 90/50 mmHg
 Risk of atrial fibrillation (5% vs 3.9%
 Acute decompensated heart failure
 Sick sinus syndrome
 Heart block
 Severe hepatic impairment
 Moderate-strong CYP3A4 inhibitors or
placebo per year)
 Bradycardia (6% vs. 1.3% placebo
per year)
 Drug interactions
 CYP3A4 inducers and inhibitors
inducers
Corlanor PI 2015
Corlanor PI 2015
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8/27/2015
Clinical Efficacy from SHIFT trial
Adverse Reactions from the SHIFT trial
Ivabradine
n = 3241
Placebo
n = 3264
HR
(95% CI)
CV death or hospital
admit for worsening HF*
24%
29%
0.82
(0.75-0.90)
Hospital admit for
worsening heart failure
16%
21%
0.74
(0.66-0.83)
3%
5%
0.74
(0.58-0.94)
16%
17%
0.9
(0.80-1.02)
Ivabradine
n = 3232
Placebo
n = 3260
P-value
Outcome
Symptomatic
bradycardia
5%
1%
< 0.0001
Asymptomatic
bradycardia
6%
1%
< 0.0001
Atrial fibrillation
9%
8%
0.012
Phosphenes*
3%
1%
< 0.0001
Reaction
*Transient enhanced brightness in a restricted area of the visual field.
Death from heart failure
All-cause mortality
*primary endpoint
Lancet. 2010 Sep 11;376:875-85
Lancet. 2010 Sep 11;376:875-85
Ivabradine (Corlanor®)
Ivabradine (Corlanor®)
 Dosing
 Bottom line
 5mg PO BID with meals
 If after 2 weeks:
 HR is > 60 BPM increased to 7.5mg BID
 HR 50-60 BPM remain at 5mg BID
 HR < 50 BPM decrease to 2.5mg BID
 May start at 2.5 mg BID if concerned
about bradycardia
 Cost: ~ $375/month
 May be used for heart failure AFTER
beta-blockers optimized
 No effect on blood pressure, monitor
heart rate
 Prevents 1 in 25 patients form being
hospitalized over 2 years
 Additional review
 Cowie MR. Interv Cardiol 2013;5:21-31.
Corlanor PI 2015
Sacubitril should NOT be used with:
Sacubitril/valsartan (Entresto™)
1. HCTZ
 Indication
2. Lisinopril
 NYHA Class II-IV to reduce risk of CV
death and heart failure hospitalization
3. Spironolactone
4. Metoprolol
 Pharmacology
 Neprilysin inhibitor
 Blocks the break down of natriuretic
peptides
Entresto PI 2015
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Sacubitril/valsartan (Entresto™)
Sacubitril/valsartan (Entresto™)
 Pharmacokinetics
 Contraindications
 Peaks in ~ 2 hours
 T ½ ~ 10 hours
 Valsartan has a higher bioavailability in
Entresto vs. other formulations
 History of angioedema due to ACEI or ARB
 Concomitant use with an ACEI
 Avoid within 36 hours
 Concomitant use with aliskiren in diabetics
 Warnings and precautions
 Sacubitril rapidly metabolized by
esterases to active metabolite LBQ657
 Majority excreted via kidneys
 Hyperkalemia
 Pregnancy
 Hypotension
Entresto PI 2015
Entresto PI 2015
Key Outcomes from PARADIGM Trial
Common Adverse Reactions in PARADIGM Trial
Outcome
Adverse
Reaction
Sacubitril/valsartan
N = 4187
Enalapril
N = 4212
P-value
Symptomatic
Hypotension
14%
9.2%
<0.001
Potassium >
5.5 mmol/L
16.1%
17.3%
0.15
Cough
11.3%
14.3%
< 0.001
Scr > 2.5 mg/dl
3.3%
4.5%
0.007
N Engl J Med 2014;37:993-1004
Sacubitril/Valsartan Enalapril
N = 4187
N = 4212
HR
(95% CI)
*Death from
CV cause or
First
hospitalization
for worsening
HF
21.8%
26.5%
0.8
(0.73-0.87)
21
Death from CV
cause
13.3%
16.5%
0.8
(0.71-0.89)
32
First
hospitalization
for worsening
HF
12.8%
15.6%
0.79
(0.71-0.89)
36
* Primary outcome
N Engl J Med 2014;37:993-1004
CV = cardiovascular
HF = heart failure
NNT = number need to treat
Sacubitril/valsartan (Entresto™)
Sacubitril/valsartan (Entresto™)
 Dosing
 Availability
 49/51mg PO BID
 After 2-4 weeks increase to 97/103mg
BID as tolerated
 May start at 24/26mg if:
 Not previously on an ACEI or ARB (or
on very low doses)
 Severe renal impairment (< 30ml/min)
 Moderate hepatic impairment
Entresto PI 2015
NNT
 Tablets
 24-26 mg
 49-51 mg
 97-103 mg
 Cost
 ~ $500 for #60 tabs
 ~ $6000/year
Entresto PI 2015
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Sacubitril/valsartan (Entresto™)
Avycaz will be used for ____ infections
 Bottom line
1. MRSA
 Impressive trial results
 Potential to become new standard for HF
patients but some criticize trial design
 On-going trials will further define role
 Long-term safety?
 Do not use with an ACE inhibitor
2. VRE
3. Gram negative
4. Anaerobic
 Additional review
 Singh JS, Land CC. Vasc Health Risk
Manag. 2015;11:283-95.
Ceftazidime-Avibactam (Avycaz™)
Ceftazidime-Avibactam (Avycaz™)
 Indication
 Complicated intra-abdominal (cIAI) with
metronidazole and complicated urinary tract
infections (cUTI)
 Reserve for use in patients who have limited
or no alternative treatment options
 Avibactam enhances in vitro activity in
presence of some β-lactamases
 Pharmacology
 3rd generation, antipseudomonal
cephalosporin β-lactamase inhibitor
inactivates some β-lactamases and protects
ceftazidime from degradation
Avycaz PI 2015
Core Evidence. 2014;9:13–25
 TEM
 SHV
 CTX-M
 KPCs
 AmpC
 Certain oxacillinases (OXA)
 Not active against all β-lactamases
 Metallo-β-lactamases
 Gram negative bacteria that overexpress
efflux pumps or have porin mutations
Avycaz™ 2015
Adverse Reactions
Phase 2 cIAI Trial
Phase 2 cUTI Trial
Avycaz™ plus
Metronidazole
N=101
Meropenem
N=102
Avycaz™
N=68
ImipenemCilastatin
N=67
Vomiting
14%
5%
0%
0%
Nausea
10%
6%
2%
5%
Constipation
4%
1%
10%
3%
Abdominal
Pain
8%
3%
7%
5%
Upper
Abdominal
Pain
1%
0%
7%
2%
Avycaz™ PI 2015
Ceftazidime-Avibactam (Avycaz™)
 Clinical Studies
 Efficacy supported in part by previous
findings of the efficacy and safety of
ceftazidime for treatment of cIAI and
cUTI
 Contribution of avibactam was
established in vitro and in animal
models of infection
 Limited trial data
Avycaz™ PI 2015
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Renal Dosing Adjustment
Ceftazidime/Avibactam (Avycaz™)
 Dosage
 2.5 g IV q8h
 5-14 days for cIAI
 In combination with metronidazole
 7-14 days for cUTI
 Including pyelonephritis
Estimated CrCl (mL/min)
Recommended Dosage
(infused over 2 hours)
>50
2.5 g IV Q8H
31-50
1.25 g IV Q8H
16-30
0.94 g IV Q12H
6-15
0.94 g IV Q24H
≤5
0.94 g IV Q48H
Avycaz™ PI 2015
Ceftazidime/Avibactam (Avycaz™)
 Bottom line
 Pooled analyses support avibactam as an
effective extender of ceftazidime activity
 Need adequate laboratory analysis to
determine specific β-lactamase—likely
reserved for KPC-producing bacteria
 More research is needed to solidify
efficacy and safety profile
Avycaz™ PI 2015
Zerbaxa will be used for ____ infections
1. MRSA
2. VRE
3. Gram negative
4. Anaerobic
 Additional review
 Lagace-Wiens, et al. Core Evid
2014;9:13-25.
Ceftolozane/tazobactam (Zerbaxa™)
Ceftolozane/tazobactam (Zerbaxa™)
 Indication
 Gram negative
 Complicated intra-abdominal
infections (with metronidazole) and
complicated urinary tract infections
 Pharmacology
 New cephalosporin combined with
tazobactam (beta-lactamase
inhibitor)
 Enterobacter cloacae
 E. coli
 Klebsiella oxytoca, pneumonia
 Proteus mirabilis
 Pseudomonas aeruginosa
 Bacteroides fragilis
 Gram positive
 Streptococcus anginosus, constellatus,
salivarius
Zerbaxa PI 2014
Zerbaxa PI 2014
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8/27/2015
Adverse Reactions
Ceftolozane/tazobactam (Zerbaxa™)
cIAI
Susceptibility Rates (%)
100
Meropenem
N=497
Zerbaxa™
N=533
Nausea
7.9%
5.8%
2.8%
1.7%
Diarrhea
6.2%
5%
1.9%
4.3 %
Vomiting
3.3%
4%
1.1%
1.1%
Headache
2.5%
1.8%
5.8%
4.9%
Rash
1.7%
1.4%
0.9%
0.4%
90
80
70
60
50
Ceftolozane/tazo
40
Levofloxacin
30
Meropenem
20
10
0
MDR
Pseudomonas
K.
Pseudomonas N = 1081
pneumoniae
N = 310
cUTI
Zerbaxa™ +
Metronidazole
N=482
Levofloxacin
N=535
E. coli
N = 1683
N = 659
Zerbaxa PI 2014
Avycaz™ PI 2015
Ceftolozane/tazobactam (Zerbaxa™)
Ceftolozane/tazobactam (Zerbaxa™)
 Dosing
 Bottom line




1.5 gm (1 gm/0.5 gm) IV q8h
Infused over 1 hour
cIAI  4-14 days
cUTI  7 days
 Renal adjustments
 CrCl 30-50 mL/min  750 mg q8h
 CrCl 15-29 mL/min  375 mg q8h
 ESRD on HD  single loading dose of 750 mg,
followed by 150 mg (100 mg/50 mg) maintenance
dose q8h for the remainder of the treatment period
 On HD days, administer dose ASAP following
completion of HD
 Likely reserved for resistant gram-
negative bacteria (i.e. Pseudomonas)
 Anticipate it being restricted to
infectious disease service for approval
 Additional review
 Sorbera M, et al. P & T 2014;39:825-
32.
Zerbaxa [PI] 2014
Compared to the older agents the new
hepatitis C medications:
New Standard of Care for HCV
in 2015 and Beyond
Boceprevir or
Telaprevir +
P/R x 6-12m
SVR ~ 70%
1. Are less expensive
Interferon +
Ribavirin x
12m
SVR ~ 30%
2. Have more side effects
3. Have more drug interactions
GT1
4. Require longer treatment duration
1991
1998
2011
Harvoni®
or Viekira®
x 2-6m
SVR >
90%
2013
2014+
2001
GT2 and 3
Interferon
x 12m
SVR ~
10%
Simeprevir or
Sofosbuvir +
P/R x 2-6m
SVR ~ 90%
Peginterferon/
Ribavirin x 12m
SVR ~50%
2013
Sofosbuvir +
Ribavirin x 3-6m
SVR 55-92%
GT, genotype; P/R, peginterferon/ribavirin
9
8/27/2015
Clinical Significance of Newer Agents
Sofosbuvir & Ledipasvir (Harvoni®)
 Significant adverse effects with current
CHC medications
 Indication
 Genotype 1 hepatitis C
 Ribavirin: hemolytic anemia, fatigue, nausea,
headache
 Interferon and PEG-interferon: flu-like
symptoms
 Mechanism of action
 Sofosbuvir
 Simple combination regimen
 Enables shorter duration of treatment
 U.S. Preventative Services Task Force:
Screen adults born between 1945-1965 for
HCV
 HCV NS5B RNA polymerase
inhibitor
 Ledipasvir
 NS5A protein inhibitor
 Increased identification of CHC genotype 1
positive patients
ION-3. N Engl J Med. 2014 May 15;370(20):1879-88.
CDC. Hepatitis C FAQs for Health Professionals. 2014 Jul.
Sofosbuvir & Ledipasvir (Harvoni®)—
ION-2 Study
Harvoni [PI]. 2014.
Sofosbuvir & Ledipasvir (Harvoni®)—ION-2
Study
100
100
96%
95% CI: 8797%
95% CI: 9199%
95% CI: 95100%
99%
95% CI: 95100%
60
40
20
102/109
107/111
108†/109
110/111
0
LDV/SOF x 12 LDV/SOF + RBV LDV/SOF x 24 LDV/SOF + RBV
wks
x 12 wks
wks
x 24 wks
* = All treatment groups had SVR rates superior to adjusted historical response rate of 25% (p<0.001 for all
comparisons)
† = One patient in LDV/SOF x 24 weeks withdrew consent after four weeks of treatment
N Engl J Med. 2014 Apr 17;370(16):1483-93.
Sofosbuvir & Ledipasvir (Harvoni®)—
ION-3 Study
100
SVR12*, %
80
80
SVR12, %
SVR12*, %
80
99%
94%
94%
93%
95%
95% CI: 9097%
95% CI: 8996%
95% CI: 9298%
202/215
201/216
206/21
6
60
40
20
0
LDV/SOF x 8 wks
LDV/SOF + RBV x 8
wks
LDV/SOF x 12 wks
* = All treatment groups had SVR rates superior to adjusted historical control rate of 60% (p<0.001 for
all comparisons)
N Engl J Med. 2014 May 15;370(20):1879-88.
60
95%
86%*
95% CI: 6597%
95% CI: 8696%
100%*
99%
95% CI: 85100%
95% CI: 94100%
Cirrhosis
No Cirrhosis
40
20
19/22
83/87
22/22
86/87
0
LDV/SOF x 12 wks
LDV/SOF x 24 wks
* = Difference in rates of response between 12 & 24 weeks among cirrhotic patients significant (p = 0.007)
N Engl J Med. 2014 Apr 17;370(16):1483-93.
Sofosbuvir & Ledipasvir (Harvoni®)
 Drug Interactions
 Amiodarone--bradycardia
 Potent P-gp inducers decrease ledipasvir &
sofosbuvir plasma concentrations
 Rifampin, St. John’s wort
 Antacids/H2’s/PPIs decrease ledipasvir
absorption
 Other medications that can decrease
sofosbuvir plasma concentrations
 Carbamazepine
 Phenytoin
 Phenobarbital
Harvoni [PI]. 2013.
10
8/27/2015
Sofosbuvir & Ledipasvir (Harvoni®)
Sofosbuvir & Ledipasvir (Harvoni®)
 Dosage and Administration
 Bottom line
 One tablet (400mg sofosbuvir/90mg
 One tablet, once daily treatment for
ledipasvir) once daily
 With or without food
 May take in evening due to fatigue (1318%) after administration
hepatitis C
 Cure rates of > 90%
 Duration of 8-24 weeks
 No dosage adjustment for hepatic
dysfunction
 Sofosbuvir metabolite may
accumulate in renal impairment
Additional review

 Cada D, et al. Hosp Pharm
2015;50(3):224-34.
Harvoni [PI] 2014.
Paritaprevir/ritonovir, ombitasvir,
dasabuvir +/- ribavirin (Viekira®)
Clinical Results—No cirrhosis
 Indication
100
90
SVR 12 (% of patients)
 Genotype 1 hepatitis C
 Pharmacology
 Ombitasvir: Inhibits NS5A polymerase
 Paritaprevir: Inhibits NS3/4A protease
 Dasabuvir: Inhibits NS5B RNA
polymerase
 Ritonovir: Increases paritaprevir
levels thru CYP3A4 inhibition
SVR 12 (% of patients)
92
96
80
89
94
100
99
94 95
99
90
70
60
With
ribavirn
Without
ribavirin
50
40
30
10
0
Genotype 1a
Genotype 1b
Ferenci et al. NEJM 2014;370:1983-92.
Paritaprevir/ritonovir, ombitasvir,
dasabuvir +/= ribavirin (Viekira®)
Clinical Results—Cirrhosis
90
99
97
20
Viekira Pak [PI] 2014.
100
80
100
97
 Drug interactions
100
94
95
 Many, many, many
87
 Need to utilize databases
70
 Ritonavir inhibits CYP3A4
60
50
12 week
40
24 week
30
20
10
0
Overall
1a
1b
Genotype
Poordad NEJM 2014;370:1973-82.
 Ombitasvir, pariaprevir, dasabuvir and
ritonavir are metabolized by pglycoprotein
 Detailed tables in packaging
No Prior Relapse Partial
No
tx
response response
Previously treated
Viekira Pak [PI] 2014.
11
8/27/2015
Paritaprevir/ritonovir, ombitasvir,
dasabuvir (Viekira®)
 Dosing
 AM: 2 tablets of ombitasvir/
paritaprevir/ritonavir and 1 tablet of
dasabuvir
 PM 1 tablet of dasabuvir
 Ribavirin (not included in the dose
pack)
 < 75kg: 400mg in the AM, 600mg
in the PM
 > 75 kg: 600mg BID
Viekira Pak [PI] 2014.
Hepatitis C Dosage and Cost Summary
HCV Infection
Treatment
Genotype 1
Harvoni®
Genotype
1*
Viekira Pak™ +
ribavirin
Duration
Cost
12
weeks‡
$94,500
12
weeks†
$83,300
Genotype 2
Sofosbuvir +
ribavirin
12 weeks
~ $84,000
Genotype 3
Sofosbuvir +
ribavirin
24 weeks
~ $168,000
Genotype 3
Sofosbuvir +
daclatasvir
12 weeks
~ $150,000
Genotype 4
Technivie™+
ribavirin
12 weeks
~ $77,000
•
‡ For
patients receiving prior treatment and having cirrhosis 24
weeks is recommended
• *For genotype 1b without cirrhosis ribavirin not needed
• † For 1a with cirrhosis 24 weeks recommended
Alirocumab has been shown to reduce:
Alirocumab (Praluent®)
1. LDL-C
 Indication
Sovaldi [PI]. 2013.
Viekira Pak [PI] 2014.
Harvoni [PI] 2014.
Daklinza [PI] 2015
Technivie [PI] 2015
 Adjunct to diet and max tolerated statin
2. Mortality
for adults with heterozygous familial
hypercholesterolemia OR clinical
atherosclerotic cardiovascular disease
who require additional lowering of LDL-C
3. Bank accounts
4. 1 & 2
5. 1 & 3
 Pharmacology
 Proprotein Convertase Subtilisin Kexin
6. All of the above
Type 9 (PCSK9) inhibitor
Praluent PI 2015
Alirocumab (Praluent®)
Alirocumab (Praluent®)
 Pharmacokinetics
 Contraindication/warnings/precautions
 Tmax 3-7 days
 Hypersensitivity reactions
 Max PCSK9 inhibition in 4-9 hours
 LDL nadir in ~ 15 days
 No data in severe renal or hepatic
impairment
Praluent PI 2015
 Some have required hospitalization
 Drug interactions
 None identified
Praluent PI 2015
12
8/27/2015
Adverse Reactions
Reaction
Alirocumab
N = 2476
Long Term Odyssey Study
Placebo
N = 1276
% reduction in LDL-C at 24 weeks
70
60
Injection site reactions
7.2%
5.1%
50
40
Allergic reactions
8.6%
7.8%
30
20
10
Anti-drug antibodies
4.8%*
0.6%
0
Alirocumab N = 1530
Placebo N = 780
* Patients had higher rate of injection site reactions (10.2% vs. 5.9%)
Praluent PI 2015
N Engl J Med 2015;372:1489-99.
Alirocumab (Praluent®)
Alirocumab (Praluent®)
 Dosing
 Administration
 75mg SQ every 2 weeks
 If inadequate response after 4-8
weeks may increase to 150 mg SQ
every 2 weeks
P < 0.001
 Warm to room temp for 30-40 min
prior to administering
 Do not use if at room temp for ≥ 24h
 Inject SQ into thigh, abdomen or
upper arm
 Cost
 ~ $14,600 per year
 Prefilled pens or syringes
Praluent PI 2015
Praluent PI 2015
Alirocumab (Praluent®)
Evolocumab (Repatha™)
 Bottom line
 Dosing
 Highly effective at lowering LDL-C
 Expensive!!!
 Need to maximize statin therapy
 No data on CV morbidity & mortality
 Awaiting Odyssey Outcomes trial (late
2017?)
 Additional review
 Giugliano RP et al. J Am Coll Cardiol
 140 mg SQ every 2 weeks
 420 mg SQ once monthly
 Cost
 Estimated at ~ $7,000-12,000 per year
 Fourier Trial is evaluating mortality
 Expected results in 2018
2015;65:2638-51.
Repatha PI 2015
https://www.clinicaltrials.gov/ct2/show/NCT01764633?term=evolocumab&rank=18
13
8/27/2015
Flibanserin should not be used:
Flibanserin (Addyi™)
1. In renal impairment
 Indication
2. In pre-menopausal
women
3. With alcohol
 Hypoactive sexual desire disorder
(HSDD) in premenopausal women
 Pharmacology
 Unknown mechanism for HSDD
4. With cigarettes
 5-HT1A agonist, 5-HT2A, 5HT2B, 5-
HT2C, D4 antagonist
Addyi PI 2015
Adverse Reactions from Placebo Controlled Trials
Flibanserin (Addyi™)
 Contraindications
 Alcohol
 Moderate to strong CYP3A4 inhibitors
 Hepatic impairment
 Warnings & precautions
 Hypotension & syncope
 Somnolence & sedation
Reaction
Filbanserin
N = 1543
Placebo
N = 1556
Dizziness
11.4%
2.2%
Somnolence
11.2%
2.9%
Nausea
10.4%
3.9%
Fatigue
9.2%
5.5%
Insomnia
4.9%
2.8%
Dry mouth
2.4%
1%
Addyi PI 2015
Addyi PI 2015
Flibanserin (Addyi™)
Flibanserin (Addyi™)
 Clinical efficacy
 Dosing
 Three phase 3 trials; 2375 women
 Increased the number of “satisfying
sexual events” per 28 days by 0.5-1
over placebo
 In two studies the co-primary
endpoint (sexual desire) was not
significantly better than placebo
Addyi PI 2015
 100 mg at night
 May cause drowsiness
 Stop after 8 weeks if no improvement
 Prescribers and pharmacies must
be certified through the Addyi
REMS program
 www.addyirems.com
 Available October 17th, 2015???
Addyi PI 2015
14
8/27/2015
Flibanserin (Addyi™)
 Bottom line
 First drug approved for HSDD
 Controversial approval
 Watch for drug interactions and
remind patients to avoid alcohol
 Additional review
 Gellad WF, et al. JAMA; published on-
When starting naloxegol other
laxatives should be:
1. Stopped for a least
3 days
2. Permanently
discontinued
3. Tapered over 3 days
4. Continued
line July 6, 2015.
Naloxegol (Movantik™)
Naloxegol (Movantik™)
 Indication
 Pharmacokinetics
 Treatment of opioid-induced
 Peaks within 2 hours
constipation in adults with chronic noncancer pain
 Pharmacology
 Pegylated naloxone
 Minimal CNS penetration
 Displaces opioids from mu receptors
in the GI tract
 T ½ 6-11 hours
 CYP3A4 metabolism
 Renal excretion ~ 16%
 Contraindications
 GI obstruction
 Strong CYP3A4 inhibitors (i.e.
ketoconazole or clarithromycin)
Movantik PI 2015
Movantik PI 2015
Common Adverse Reactions
Naloxegol (Movantik™)
 Warnings and precautions
 GI perforation
 Opioid withdrawal
 No data in severe hepatic impairment
 Drug interactions
Adverse
Reaction
Naloxegol 25 mg Naloxegol 12.5 mg
n = 446
n = 441
Placebo
n = 444
Abdominal
pain
21%
12%
7%
Diarrhea
9%
6%
5%
Nausea
8%
7%
5%
Flatulence
6%
3%
3%
 Avoid moderate CYP3A4 inhibitors or
reduce the dose (avoid grapefruit juice)
 Avoid strong inducers of CYP3A4
Movantik PI 2015
Movantik PI 2015
15
8/27/2015
Efficacy for Opioid Induced Constipation
KODIAC-4 Trial
Naloxegol 12.5 mg Naloxegol 25 mg
N = 213
N = 214
*Response rate
p-value vs.
placebo
Placebo
N = 214
40.8%
44.4%
29.4%
0.02
0.001
--
Naloxegol 12.5 mg Naloxegol 25 mg
N = 232
N = 232
KODIAC-5 Trial
Placebo
N = 232
*Response rate
35%
39.7%
29.3%
p-value vs.
placebo
0.202
0.02
--
*at least 3 SBMs/wk, and increase of at least 1 SBM/wk in
9 of the 12 weeks & 3 out of the last 4 weeks
Naloxegol (Movantik™)
 Dosing
 Normal renal function
 25 mg daily in the AM on an empty
stomach
 CrCl < 60ml/min
 Start at 12.5 mg daily in the AM on an
empty stomach
 Moderate CYP3A4 inhibitors
 12.5 mg daily in the AM on an empty
stomach
 Discontinue maintenance laxatives; may
resume in 3 days
Movantik PI 2015
N Engl J Med. 2014 Jun 19;370(25):2387-96
Naloxegol (Movantik™)
Naloxegol (Movantik™)
 Cost
 Bottom line
 #30 = ~$300
 Same price for 12.5 mg or 25 mg
 Advised not to split or crush
 Likely used when osmotic laxatives
and stimulants not effective
 No direct comparison vs. other agents
 Stop laxatives when initiating therapy
 Additional review
 Poulsen JL, et al. Clin Exp
Gastroenterol 2014;7:345-58.
Pharmacists Letter June 2015;31.
Eluxadoline should be dose adjusted for:
Eluxadoline (Viberzi™)
1. CrCl < 30ml/min
 Indication
2. Age > 65 years
3. Cholecystectomy
4. Diarrhea
 Treatment of irritable bowel syndrome
with diarrhea (IBS-D)
 Pharmacology
 Mu-opioid receptor agonist
 Delta-opioid receptor antagonist
Viberzi PI 2015
16
8/27/2015
Eluxadoline (Viberzi™)
Eluxadoline (Viberzi™)
 Cmax 2-4 hours
 Contraindications
 Biliary obstruction, sphincter of Oddi
 T ½ 4-6 hours
dysfunction, EtOH use, pancreatitis,
severe liver impairment, history of
chronic or severe constipation, GI
obstruction
 Metabolism
 Unclear; possible glucuronidation
 Elevated levels in hepatic impairment
 Warnings
 Minimal renal excretion
 Risk of pancreatitis & sphincter of
Oddi spasm
Viberzi PI 2015
Viberzi PI 2015
Common Adverse Reaction in Placebo-Controlled
Trials
Eluxadoline (Viberzi™)
 Drug interactions
Eluxadoline
100 mg BID
N = 1032
Eluxadoline 75
mg BID
N = 807
Placebo
N = 975
Constipation
8%
7%
3%
Nausea
7%
8%
5%
Abdominal
pain
7%
6%
4%
Vomiting
4%
4%
1%
Adverse
Reaction
 OATP1B1 Inhibitors
 Increase levels of eluxadoline
 Cyclosporine, gemfibrozil, antiretrovirals
 OATP1B1 & BCRP substrates
 Rosuvastatin levels may increase
 Drugs causing constipation
 Anticholinergics, opioids
Viberzi PI 2015
Viberzi PI 2015
Efficacy for IBS-D
Study 1
*Response rate
p-value vs. placebo
Study 2
*Response rate
p-value vs. placebo
Eluxadoline
75 mg BID
N = 427
Eluxadoline
100 mg BID
N = 426
Placebo
N = 427
24%
25%
17%
< 0.01
< 0.05
--
Eluxadoline
75 mg BID
N = 381
Eluxadoline
100 mg BID
N = 382
Placebo
N = 382
29%
30%
16%
< 0.001
< 0.001
--
Eluxadoline (Viberzi™)
 Dosing
 100mg BID with food
 75 mg BID if:
 No gallbladder
*Simultaneous improvement in the daily worst abdominal pain score by ≥ 30%
vs. baseline weekly average AND reduction in the Bristol Stool Scale to < 5 on
Viberzi PI 2015
at least 50% of the days within a 12-week time interval
 Mild-moderate hepatic impairment
 Does not tolerate 100mg BID
 Taking a OATP1B1 inhibitor
 Discontinue if constipation develops
and lasts for > 4 days
Viberzi PI 2015
17
8/27/2015
Eluxadoline (Viberzi™)
Dantrolene (Ryanodex®)
 Bottom line
 Indication
 Another option for IBS-D patients
 No active comparator trials
 Treatment of malignant hyperthermia
 Pharmacology
 Direct skeletal muscle relaxant
 Produces relaxation by affecting
 Opioid-agonist; will be a controlled
substance; awaiting scheduling
contractile response of muscle at a site
beyond myoneuronal junction
 Dissociates the excitation-contraction
coupling, probably interfering with
release of Ca++ from sarcoplasmic
reticulum
 Expected first quarter 2016?
 Additional review
 Garnock-Jones. Drugs;75:1305-10.
Viberzi PI 2015
Ryanodex [PI] 2014.
Dosage and Reconstitution
Available IV Products
 Revonto®
 20 mg lyophilized dantrolene sodium
powder for solution
 Ryanodex®
 250 mg lyophilized dantrolene powder
for suspension
Revonto®
Ryanodex®
Initial
1 mg/kg
1 mg/kg
Maximum
10 mg/kg
10 mg/kg
Malignant
2.5 mg/kg
Hyperthermia Crisis
2.5 mg/kg
Vial
20 mg
250 mg
Reconstitution
60 mL SWFI
5 mL SWFI without
without
bacteriostatic agent
bacteriostatic agent
Revonto [PI] 2011.
Ryanodex [PI] 2014.
Revonto [PI] 2011.
Ryanodex [PI] 2014.
Patient Case
Patient Case
 TD is a 78 kg female patient. She
quickly deteriorates after scheduled
procedure ends and anesthetic is
stopped. She shows signs of
increased temperature, rigid
muscles, hyperkalemia, and
tachycardia. Physician diagnoses
TD with malignant hyperthermia.
Patient requires 500 mg of
dantrolene treatment to abate
symptoms.
 What is the initial dose?
 What is the maximum dose?
 How many vials of Revonto are
required?
 How many vials of Ryanodex are
required?
18
8/27/2015
RCRH Dantrolene Expenditure
RCRH Dantrolene Expenditure
Drug
Cost per Vial
Vials/OR or
Crash Cart
Cost per OR or
Crash Cart
Revonto
$65.00
12
$780.00
Ryanodex
$2,070.00
1
$2070.00
Drug
Times
Total
Cycled
Total Vials Shelf
Inventory Cost every
in Stock Drug Cost Shelf Life in 10yrs 10 years
Dantrolene
60
$3,900.00
3 years
3
$11,700.00
Ryanodex
5
$10,350.00
2 years
5
$51,750.00
West 2014
RCRH Dantrolene Expenditure
Cost Increase Over 10 yrs
Percent of Cost Increase
West 2014
Bottom line
 Ryanodex requires less intensive
means to prepare for patients in a
malignant hyperthermia crisis
$40,050.00
 Cost of Ryanodex may be
considered prohibitive
342%
 Additional review
 Malignant Hyperthermia Association of
the United States. MHAUS.
http://www.mhaus.org
West 2014
Edoxaban should NOT be used in A. fib if:
1. CrCl is < 30ml/min
2. CrCl is < 50 ml/min
3. CrCl is > 95 ml/min
Response
Counter
30
19
8/27/2015
Ivabradine works for heart failure by:
Sacubitril should NOT be used with:
1. Increasing
contractility
1. HCTZ
2. Increasing urine
output
3. Spironolactone
2. Lisinopril
4. Metoprolol
3. Slowing the heart
rate
4. Reducing afterload
Response
Counter
30
Response
Counter
Avycaz will be used for ____ infections
Zerbaxa will be used for ____ infections
1. MRSA
1. MRSA
2. VRE
2. VRE
3. Gram negative
3. Gram negative
4. Anaerobic
4. Anaerobic
Response
Counter
30
Response
Counter
Compared to the older agents the new
hepatitis C medications:
Alirocumab has been shown to reduce:
1. Are less expensive
1. LDL-C
2. Have more side
effects
2. Mortality
3. Have more drug
interactions
4. 1 & 2
4. Require longer
treatment duration
6. All of the above
Response
Counter
30
30
3. Bank accounts
5. 1 & 3
30
Response
Counter
30
20
8/27/2015
When starting naloxegol other
laxatives should be:
Flibanserin should not be used:
1. In renal impairment
1. Stopped for a least
3 days
2. In pre-menopausal
women
3. With alcohol
2. Permanently
discontinued
4. With cigarettes
3. Tapered over 3 days
4. Continued
Response
Counter
30
Response
Counter
30
Eluxadoline should be dose adjusted for:
1. CrCl < 30ml/min
2. Age > 65 years
3. Cholecystectomy
4. Diarrhea
Response
Counter
30
21