Transcript drug therapy update

BENJAMIN GROSS, PHARM D, BCPS, BCACP,CDE,BC-ADM
UNIVERSITY OF TENNESSEE COLLEGE OF PHARMACY
DEPARTMENT OF CLINICAL PHARMACY
CLINICAL PHARMACY DIRECTOR HOLSTON MEDICAL GROUP
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Understand recent updates in drug therapy
management
Review new medications that have recently
come to market
Understand recent dosing changes and
contraindications of common medication
therapies
Discuss recent reported medication adverse
reactions
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Advisory Board for
Sanofi Aventis
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OFFICE
◦ 423-578-1537
◦ 105 WEST STONE DRIVE
◦ KINGSPORT, TN 37660
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EMAIL
◦ [email protected]
◦ [email protected]
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↓LDL (18-63%)
↑HDL (5-15%)
↓TG (7-30%)
Adverse effects
◦ Myopathy
 Myalgia
 Rhabdomyolysis
◦ Rash, headache
◦ GI complaints
◦ Vivid Dreams
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DOSE LIMITIATION
◦ FDA ISSUES SAFETY COMMUNICATION
 80 MG DOSE
 INCREASED RISK OF MUSCLE DAMAGE
 ONLY USED IN THOSE WHO HAVE BEEN TAKING THE
MEDICATION 12 MONTHS OR LONGER WITHOUT EVIDENCE
OF MUSCLE INJURY
 DO NOT USE IN NEW PATIENTS
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Study of the Effectiveness of Additional
Reduction in Cholesterol and Homocysteine
(SEARCH) trial
◦ 80mg vs 20 mg
 With or without Vitamin B12 (1 mg) and folate (2mg)
daily
 Survivors of myocardial infarctions: 12, 064 patients
 Mean duration: 6.7 years
 Incidence of major vascular events
 25.75% in the 20 mg group
 24.5% in the 80 mg group
 Am Heart J. 2007 Nov;154(5):815-23
SEARCH: Effects of more vs less STATIN on MORTALITY
Cause of death
Simvastatin allocation
80mg
20mg
(n=6031) (n=6033)
CHD
447 (7.4%)
Stroke
Other vascular
57
53
(0.9%)
(0.9%)
438 (7.3%)
67
56
(1.1%)
(0.9%)
All vascular
557 (9.2%)
561 (9.3%)
Neoplastic
Respiratory
Other medical
Non-medical
245
74
75
13
266
58
70
14
All non-vascular
407 (6.7%)
408 (6.8%)
All causes
964 (16.0%)
969 (16.1%)
(4.1%)
(1.2%)
(1.2%)
(0.2%)
Risk ratio & 95% CI
80mg better 20mg better
0.7% SE 5.9
reduction
(4.4%)
(1.0%)
(1.2%)
(0.2%)
0.2% SE 7.0
reduction
0.5% SE 4.6
reduction
0.6
0.8
1.0
1.2
1.4
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Myopathy
◦ 55 patients (0.9%) in the 80 mg group
◦ 1 patient (0.02%) in the 20 mg group
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Rhabdomyolysis
◦ 22 patients (0.4%) in the 80 mg group
◦ 0 patients in the 20 mg group
◦ Highest in the first 12 months of treatment
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Increased risk
◦ Older and female sex
◦ Calcium channel blockers
 Diltiazem
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Analysis of FDA’s Adverse Event Reporting
System (AERS) database and this trial was the
basis of their safety communication
Previous Simvastatin Label
New Simvastatin Label
Avoid Simvastatin with:
Avoid Simvastatin with:
Itraconazole
Itraconazole
Ketoconazole
Ketoconazole
Erythromycin
Erythromycin
Clarithromycin
Clarithromycin
Telithromycin
Telithromycin
HIV Protease Inhibitors
HIV Protease Inhibitors
Nefazodone
Nefazodone
Gemfibrozil
Cyclosporine
Danazol
Previous Simvastatin Label
New Simvastatin Label
Do not exceed 10 mg
Do not exceed 10 mg
Gemfibrozil
Amiodarone
Cyclosporine
Verapamil
Danazol
Diltiazem
Do not exceed 20 mg
Do not exceed 20 mg
Amiodarone
Amlodipine
Verapamil
Ranolazine
Do not exceed 40 mg
Diltiazem
Previous Lovastatin Label
New Lovastatin Label
Avoid Lovastatin with:
Contraindicated with Lovastatin :
Itraconazole
Itraconazole
Ketoconazole
Ketoconazole
Erythromycin
Erythromycin
Clarithromycin
Clarithromycin
Telithromycin
Telithromycin
HIV Protease Inhibitors
HIV Protease Inhibitors
Nefazodone
Nefazodone
Posaconazole
Boceprevir
Telaprevir
Avoid Lovastatin with:
Cyclosporine
Gemfibrozil
Previous Lovastatin Label
New LovastatinLabel
Do not exceed 20 mg
Do not exceed 20 mg
Gemfibrozil
Danazol
Cyclosporine
Verapamil
Danazol
Diltiazem
Niacin (>1g/day)
Other fibrates
Do not exceed 40 mg
Do not exceed 40 mg
Amiodarone
Amiodarone
Verapamil
Avoid Large Quantities of
grapefruit juice (>1 quart daily)
Avoid Large Quantities of
grapefruit juice (>1 quart daily)
Dosing
Range
30-40%
Reduction
FLUVASTATIN
LESCOL
20-80
80
LOVASTATIN
MEVACOR
20-40
40
PRAVASTATIN
PRAVACHOL
20-80
40
SIMVASTATIN
ZOCOR
20-80
20
ATORVASTATIN
LIPITOR
10-80
10
ROSUVASTATIN
CRESTOR
5-40
5
PITAVASTATIN
LIVALO
1-4
2
Ator
10
20
Fluva
Pita
Lova
Prava
Rosu
Vytorin Simva
%LDL
Red.
40
1
20
20
10
30
80
2
40 or
80
40
20
38
4
80
80
5
10/10
40
41
40
10
10/20
80
47
80
20
10/40
55
40
10/80
63
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NEWEST STATIN
DOSAGE: 2-4 MG
LDL: 38-45% REDUCTION
GFR: 30 to <60
mL/min/1.73m2, or
hemodialysis
◦ Initial dose: 1 mg
◦ Max dose 2 mg initial daily
dose is 1 mg, max daily dose
is
2 mg.
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Do not use if GFR <30
mL/min/1.73m2
Very few drug interactions
◦ Avoid with cyclosporine
◦ 1 mg with erythromycin
◦ 2 mg with rifampin
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Meta-analysis
◦ Five studies
◦ 40,000 patients
◦ No evidence that the use of a statin increased risk
of developing type 2 diabetes
 Tendency toward reducing the risk with pravastatin
 Small, significant increased risk with other statins
 Coleman et al. Curr Med Res Opin 2008: 1359-62
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Jupiter Trial
◦ 18, 000 patients: healthy, normal LDL levels
◦ Rosuvastatin 20 mg for two years
◦ Reduced primary end point of heart attack, stroke,
arterial revascularization or CV death was reduced
◦ For every 167 patients treated one more case of
diabetes
 Six more cases per 1000 patients
 Were physician reported
 Protocol-specified fasting blood glucose did not differ
 Ridker et al. NEJM 2008: 2195-2207.
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Meta-analysis
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Six studies
60,000 patients
Statins not found to increase risk
One of the studies excluded (WOSCOPS)
 Small increase risk of diabetes
 Rajpathak et al. Diabetes Care 2009: 735-42.
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Meta-analysis
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Five studies
32,752 patients
Moderate dose versus intensive dose
High dose significantly more developed diabetes
 2 additional cases for every 1000 patient-years
 6.5 fewer cases of cardiovascular events
 Priess et al. JAMA 2011: 2556-64.
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2010 Lancet meta-analysis, which found a small but measurable risk
for new-onset diabetes after all statin use.
Predictors of New-Onset Diabetes in Patients Treated with
Atorvastatin
◦ Analysis of three large randomized control trials
 TNT
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Randomized to atorvastatin 80 mg vs. 10 mg
9.24% vs. 8.11%, p=0.226
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Randomized to atorvastatin 80 mg vs. 20 mg simvastatin
6.4% vs. 5.59%, p=0.072
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Randomized to atorvastatin 80 mg vs. placebo
8.71% vs. 6.06%, p=0.011
 IDEAL
 SPARCL
◦ Major cardiovascular events
 11.3% with new-onset diabetes vs. 10.8% without new-onset diabetes,
(p=0.69)
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JAAC 2011; 57:1535-1545
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Routine periodic monitoring of liver enzymes
no longer necessary
◦ Before starting therapy and as clinically indicated
◦ FDA has concluded that serious liver injury with
statins is rare and unpredictable and that routine
periodic monitoring of liver enzymes does not
appear to be effective in detecting or preventing
serious liver injury.
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Information about the potential for generally nonserious and reversible cognitive side effects (memory
loss, confusion, etc.)
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Memory loss and confusion have been reported with
statin use. These reported events were generally not
serious and went away once the drug was no longer
being taken.
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Crestor causing heart attacks
◦ Commercial from law firm
◦ Where does this come from?
 Based on crestor causing rhabdomyolysis and thus
weakening heart muscles
 Public Citizen, independent watchdog group claims
that crestor causes rhabdomyolysis 22 times more
than its lowest dose competitor and 3 times more
than its highest dose competitor
 www.citizen.org/hrg1729
 FDA findings
 Risk of serious muscle damage is similar with Crestor
compared to other statins
 Literature review
 The safety of rosuvastatin in comparison with other
statins in over 100,000 statin users in UK primary care
 10, 289 patients on rosuvastatin
 No cases of myopathy, rhabdomyolysis or acute liver
injury
 Use of multiple international healthcare databases for
the detection of rare drug-associated outcomes: a
pharmacoepidemiological programme comparing
rosuvastatin with other marketed statins
 Associated with no significant difference in the incidence of
hospitalized myopathy, rhabdomyolysis, or acute renal
failure
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Journal of the American College of
Cardiology
◦ Expert review panel
 The dose of the statin is a greater predictor of
myopathy, etc and not the potency of the statin
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More emphasis on diet and exercise
Less emphasis on meds for most people
For fasting triglyceride levels of 150 to
199 mg/dL, focus on diet and exercise first.
For fasting triglyceride levels of 200 to 499
mg/dL, diet and exercise should still be
considered first. However, this is the point at
which non-HDL cholesterol levels should be
considered as a secondary target to LDL
cholesterol
 Circulation May 24, 2011 123(20): 2292-2333
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For high non-HDL cholesterol, consider a statin
or a dose increase for patients already taking a
statin. Adding omega-3 fatty acids to the statin
is also an option.
◦ There is some evidence that a statin plus niacin can
reduce surrogate markers of cardiovascular disease,
such as carotid artery intima-media thickness.
◦ If LDL cholesterol is controlled and non-HDL
cholesterol is still high, a drug therapy for lowering
triglycerides such as niacin, fibrates, etc. can be
considered.
 Circulation May 24, 2011 123(20): 2292-2333
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AIM-HIGH Study
◦ Niacin (1500-2000 mg) and 40 mg Simvastatin
 Primary outcome was time to first CHD death, nonfatal
MI, ischemic stroke, acute coronary syndrome
hospitalization, or symptoms requiring coronary or
cerebral revascularization
 3500 patients
 Stopped early due to lack of benefit of
Niacin/Simvastatin vs simvastatin alone
 Most patients had well-controlled LDL on a statin at
baseline
 LDL vs HDL
 Am Heart J 2011; 161:471-77
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JUVISYNC
◦ JANUVIA AND SIMVASTATIN
 100/10, 100/20, 100/40
 Same price as Januvia
 Same cautions, contraindications, adverse effects as
each component alone
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Celexa (citalopram)
Should no longer be used at doses greater
than 40 mg/day
Prolongation of the QT interval
No benefit in doses higher than 40 mg/day
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Increased risk
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Max dose: 20 mg
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◦ CHF
◦ Bradyarrhythmias
◦ Predisposition to hypokalemia or hypomagnesemia
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Hepatic impairment
>60 years old
CYP2C19 poor metabolizers
CYP2C19 inhibitors
 Omeprazole, Cimetidine
Not to exceed 20 mg escitalopram (Lexapro)
Sertraline, paroxetine, and fluoxetine lower risk
and alternative agents
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chloramphenicol
cimetidine
citalopram
delavirdine
efavirenz
esomeprazole
ethinyl estradiol
etravirine
felbamate
fluconazole
fluoxetine
fluvoxamine
indomethacin
isoniazid
kava
ketoconazole
lansoprazole
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letrozole
moclobemide
modafinil
nicardipine
omeprazole
oxcarbazepine
pantoprazole
rabeprazole
telmisartan
ticlopidine
topiramate
vilazodone
voricon
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Switching between SSRIs
◦ Usually overlap in their mechanism of action, and
the new SSRI will usually prevent discontinuation
symptoms that may occur when the first SSRI is
stopped.
◦ Substituting a new SSRI at the relatively equivalent
dose of the former SSRI is typically well-tolerated
AGENT
DOSE
Fluoxetine
20 mg
Paroxetine
40 mg
Sertraline
50-75 mg
Citalopram
20 mg
Escitalopram
10 mg
Fluvoxamine
100 mg
Venlafaxine
75 mg
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Switching from SSRI to TCA
◦ Cross-taper
◦ Fluoxetine and Paroxetine
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Strong inhibitors of the p450 enzyme 2D6
Sertraline, citalopram, and escitalopram are milder inhibitors
Enzyme involved in metabolism of many TCAs
Inhibition increase levels and increased risk of toxicity
◦ TCAs should be started at low doses when crosstapering with an SSRI, particularly with fluoxetine and
paroxetine
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Inhibition of p450 2D6 will be present to some
degree until the SSRI is completely cleared
◦ Most in 5 days; fluoxetine up to 5 weeks
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SSRI to venlafaxine or duloxetine
◦ Both have strong serotonergic properties
◦ Switching immediately from most SSRIs to the
equivalent dose
 Well tolerated
 If higher dose of an SSRI, consider cross-taper
 Caution when switching from fluoxetine or paroxetine,
because venlafaxine and duloxetine are metabolized
by p450 2D6
 Start at lower dose
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Venlafaxine or duloxetine to antidepressants
◦ Venlafaxine is associated with uncomfortable
discontinuation symptoms upon cessation.
◦ Recommend cross taper as well as duloxetine
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Cross-taper also when switching to or from
Mirtazapine (Remeron)
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Bupropion to or from antidepressants
◦ Does not have significant serotonergic properties
◦ Switching from an SSRI, a TCA, venlafaxine, duloxetine,
mirtazapine to bupropion
 Cross-tapering off the former medication over a one to two
week period
 Two to three weeks for venlafaxine and duloxetine
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Bupropion itself is not frequently associated with
discontinuation symptoms
◦ Tapered off over one week while initiating new
antidepressant
◦ Avoid prescribing high-dose bupropion concomitantly
with paroxetine, fluoxetine, or fluvoxamine due to
metabolism of Bupropion
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Avandia – CV events including MI
TZD’s - ↑ fractures
Byetta and Januvia – pancreatitis
Byetta- kidney problems
Lantus-cancer?
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Epidemiological study conducted in France
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French National Health Insurance Plan data
1.5 million patients with diabetes
Followed for 4 years
Statically significant increase risk of bladder cancer
in patients
 Increased risk with cumulative dose >28,000 mg and
exposure for longer than one year
 Increased risk in males
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FDA reviewed data from an 5-year interim
analysis of an ongoing 10-year
epidemiological study
◦ Kaiser Permanente Northern California health plan
data
◦ 193,099 patients
◦ New diagnosis of bladder cancer
 No overall increased risk
 Noted increased risk
 Longest exposure (greater than 1 year)
 Highest cumulative dose
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Not to use pioglitazone in patients with active
bladder cancer
Use with caution in patients with a prior
history of bladder cancer
FYI: Bladder cancer is estimated to occur in
20 per 100,000 persons per year in the U.S.
◦ Higher in diabetics????
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BROMOCRIPTINE (Cycloset)
◦ Dopamine agonist
 Parlodel: Parkinson’s disease, acromegaly,
hyperprolactinemia
◦ FDA-approved for Type 2 diabetics
 Mechanism unclear
 May reverse metabolic changes associated with insulin
resistance and obesity
 Improve blood glucose control
 Without increasing insulin levels
 A1C reduction: 0.1-0.6% (average of 0.4-0.5%)
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Starting dose 0.8 mg once daily
◦ Increased 0.8 mg/day each week
◦ Max dose 4.8 mg/day
◦ First thing in the morning within 2 hours of rising
 Circadian rhythm
 If dosed missed, take it the next day
◦ Taken with food
 Nausea
 Also cause somnolence, hypotension, and syncope
 Aggravate psychotic disorders
◦ No increase risk of CV events
◦ Drug-drug interactions
◦ $$$$; will be generic within 5 years
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Tradjenta (Linagliptin)
◦ DPP-IV inhibitor
◦ Dosing
 5 mg once daily
 No adjustment for renal or hepatic insufficiency
◦ Efficacy
 0.5-0.8%
◦ Adverse effect
 Nasopharyngitis
 Pancreatitis has been reported
◦ No contraindications
◦ Drug interaction: P-glycoprotein/ CYP3A4 inducer
 Example: Rifampin
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Bydureon
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Once a week exenatide
2 mg daily
With or without meals
Administered immediately after the powder is
suspended
Qnexa
◦ phentermine and topiramate
◦ Once daily
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Levaquin went generic in June 2011
◦ FDA approved application for 12 companies
to manufacture generic versions of
levofloxacin
◦ Infectious Disease Society of America/American
Thoracic Society Consensus Guideline on the
Management of Community Acquired Pneumonia
No recent antibiotic therapy within the previous 3 months
and no risk for drug resistant S. Pneumoniae
Macrolide or doxycycline
Comorbidities:
COPD, diabetes, chronic heart, liver, lung or renal disease,
malignancy, alcoholism, asplenia, immunosuppressing
conditions or use of immunosuppressive drugs or use of
antimicrobials within last three months
Respiratory fluoroquinolones or B-lactams
plus a macrolide
In regions with a 25% or higher rate of infection with high
level (MIC ≥16 µg/ml) macrolide resistant S. Pneumoniae
(regardless of comorbidities)
Respiratory Fluoroquinolones or B-lactams
plus a macrolide
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Recommendation 1: ACP, ACCP, ATS, and ERS recommend that
spirometry should be obtained to diagnose airflow obstruction in
patients with respiratory symptoms (Grade: strong
recommendation, moderate-quality evidence). Spirometry should
not be used to screen for airflow obstruction in individuals
without respiratory symptoms (Grade: strong recommendation,
moderate-quality evidence).
Recommendation 2: For stable COPD patients with respiratory
symptoms and FEV1 between 60% and 80% predicted, ACP, ACCP,
ATS, and ERS suggest that treatment with inhaled
bronchodilators may be used (Grade: weak recommendation,
low-quality evidence).
Recommendation 3: For stable COPD patients with respiratory
symptoms and FEV1 <60% predicted, ACP, ACCP, ATS, and ERS
recommend treatment with inhaled bronchodilators (Grade:
strong recommendation, moderate-quality evidence).
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Recommendation 4: ACP, ACCP, ATS, and ERS recommend
that clinicians prescribe monotherapy using either longacting inhaled anticholinergics or long-acting inhaled βagonists for symptomatic patients with COPD and FEV1
<60% predicted. (Grade: strong recommendation,
moderate-quality evidence). Clinicians should base the
choice of specific monotherapy on patient preference,
cost, and adverse effect profile.
Recommendation 5: ACP, ACCP, ATS, and ERS suggest that
clinicians may administer combination inhaled therapies
(long-acting inhaled anticholinergics, long-acting inhaled
β-agonists, or inhaled corticosteroids) for symptomatic
patients with stable COPD and FEV1<60% predicted (Grade:
weak recommendation, moderate-quality evidence).
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Recommendation 6: ACP, ACCP, ATS, and ERS
recommend that clinicians should prescribe
pulmonary rehabilitation for symptomatic patients
with an FEV1 <50% predicted (Grade: strong
recommendation, moderate-quality evidence).
Clinicians may consider pulmonary rehabilitation for
symptomatic or exercise-limited patients with an
FEV1 >50% predicted. (Grade: weak recommendation,
moderate-quality evidence).
Recommendation 7: ACP, ACCP, ATS, and ERS
recommend that clinicians should prescribe
continuous oxygen therapy in patients with COPD
who have severe resting hypoxemia (Pao2 ≤55 mm
Hg or Spo2 ≤88%) (Grade: strong recommendation,
moderate-quality evidence).
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Chronic Azithromycin to prevent recurrent
COPD exacerbations
◦ 250 mg/day to standard COPD therapy reduces
the risk of acute exacerbations
◦ 1 less exacerbation for every 3 COPD patients on
oxygen or with prior exacerbations that take
azithromycin for one year
◦ Anti-inflammatory and immunomodulatory
effects
◦ Place in therapy
 Severe COPD and frequent hospitalizations for acute
exacerbations
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Phosphodiesterase 4 (PDE 4) inhibitor
Place in therapy
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Dosage
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◦ Add-on therapy to maximized bronchodilators to decrease risk
of COPD exacerbations in patients with severe COPD
associated with chronic bronchitis and a history of
exacerbations.
◦ Experts: More symptomatic and severe to very severe disease
with frequent exacerbations showed greatest improvement
◦ 500 mcg daily
 May require several weeks to reach effect
◦ Not recommended in those with moderate to severe renal
impairment
◦ Not studied in those with hepatic impairment
 Contraindicated in severe hepatic impairment (Child-Pugh
Class B or C)
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Adverse effects
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Diarrhea (9.5%)
Back pain Abdominal pain
Weight decrease (7.5%)
Influenza
Nausea (4.7%)
Dizziness
Headache (4.4%)
Decreased appetite
Some reports
 Anxiety, depression and sleep disorders
 Rare: suicidal ideation and completed suicides
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Drug interactions
◦ Not recommended with strong inducers:
(decreased effectiveness)
 Rifampin, carbamazepine, phenytoin,
phenobarbital
◦ Caution use with: (increased systemic exposure
and increase adverse effects)
 Erythromycin, ketoconazole, fluvoxamine,
cimetidine
Pregnancy Category C; not to be used
during breastfeeding
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Overall Evidence
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FYI
◦ 9349 patients studied in 8 RCT trials
 Two trials showed rate of moderate or severe
exacerbations reduced by 15-18%
 Number of patient exacerbations per patient-year was 1.1
vs. 1.3 (placebo) and 1.2 vs. 1.5 (placebo); Absolute
reduction was 0.2 and 0.3 exacerbations per patient year.
◦ Originally the FDA advisory committee voted against
approving the medication in 2010
 Only moderately improved FEV1 over baseline, concern
about d/c due to GI effects and psychiatric events
 Cancer events
 218 patients
 60% in roflumilast vs. 40% placebo
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Long acting Beta-2 adrenergic agonists
 Indication
 Treatment for COPD
 Inhalation powder hard capsule: 75 mg
 Inhaled once daily
 Contraindications
 Asthma without use of a long term asthma control
medications
 Adverse effects
 Cough, oropharyngeal nasopharyngitis, headache, nausea
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Angiotensin Receptor Blockers and Cancer
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Vitamins Associated With Increased Risk Of Death
In Older Women
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Caffeine, Coffee, and Depression
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Vitamin E Associated with Increased Prostate
Cancer Risk
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Aspirin reduces risk of cancer and prevent
tumors from spreading
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Chantix and Cardiovascular events
◦ Risk of serious adverse cardiovascular events
associated with varenicline: a systematic review
and meta-analysis
 Results
 Increase risk of serious adverse cardiovascular events
compared to placebo
 Absolute risk 1.06%(52/4908) vs 0.82% (27/3308) placebo
 ODDs ratio 1.72
 72% increase risk of any ischemic or arrhythmic adverse
cardiovascular event
 Singh, et al. CMAJ July 2011
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PALLAS Study
◦ 65 year old with permanent A fib
◦ Outcome : Major CV risk and death
◦ Results
 2 fold increase in death
 2 fold increase in stroke and hospitalization for
heart failure
◦ FDA advisory
 Do not use in permanent A fib patients
◦ Package insert has been changed 3 times recently
 Concerns about safety
 Can increase INR