The medical letter on drugs and therapeutics january 19 2015

According to recent guidelines, patients with a left ventricular ejection fraction LVEF ≤40% are considered to have heart failure with reduced ejection with a LVEF ≥50% and symptoms of h

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IN THIS ISSUE

ISSUE

1433

Volume 56

Published by The Medical Letter, Inc • A Nonprofi t Organization

ISSUE No

1460 Drugs for Chronic Heart Failure p 9

Metreleptin (Myalept) – A Leptin Analog for Generalized Lipodystrophy .p 13

In Brief: Concerns About Oseltamivir (Tamiflu) .p 14

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ISSUE

1433

Volume 56

ISSUE No

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ALSO IN THIS ISSUE

Metreleptin (Myalept) – A Leptin Analog for Generalized Lipodystrophy .p 13

In Brief: Concerns About Oseltamivir (Tamiflu) .p 14

II (hypotension and renal insuffi ciency), and reduction

of aldosterone production (hyperkalemia) Cough and angioedema can usually be relieved by replacing the ACE inhibitor with an angiotensin receptor blocker (ARB); ARBs do not increase concentrations of kinins

to the same degree Rash, taste disturbances, and neutropenia can occur with captopril, but appear to be uncommon at the currently recommended dosage

Choice of an ACE Inhibitor – No data are available

showing that any one ACE inhibitor is more effective than any other for treatment of heart failure Some ACE inhibitors (perindopril and benazepril) have not been approved by the FDA for treatment of heart failure

ARBs — Long-term therapy with an angiotensin

receptor blocker (ARB) reduces the risk of death

Heart failure is usually associated with left ventricular

dysfunction According to recent guidelines, patients

with a left ventricular ejection fraction (LVEF) ≤40% are

considered to have heart failure with reduced ejection

with a LVEF ≥50% and symptoms of heart failure

are considered to have heart failure with preserved

ejection fraction (HFpEF) or diastolic heart failure;

there is little evidence that drug treatment improves

acute heart failure is not included here

ACE INHIBITORS — All patients with heart failure

with reduced ejection fraction should receive an

angiotensin-converting enzyme (ACE) inhibitor These

drugs improve symptoms (generally over 4-12 weeks),

decrease the incidence of hospitalization, and prolong

survival in patients with heart failure

Dosage – ACE inhibitors should be started at low doses

and titrated to the highest tolerated dose, targeting the

maximum daily dosages listed in Table 1 on page 11

Cautions – ACE inhibitors should be used cautiously

in patients with systolic blood pressure <80 mm Hg,

serum creatinine >3 mg/dL, serum potassium >5.0

mEq/L, or bilateral renal artery stenosis They should

not be used in patients with a history of angioedema

Blood pressure, renal function, and serum potassium

levels should be monitored in patients taking an ACE

inhibitor ACE inhibitors can increase fetal mortality

and should not be used during pregnancy

Adverse Effects – The most common adverse

effects of ACE inhibitors are related to inhibiting

breakdown of endogenous kinins (cough and, less

commonly, angioedema), suppression of angiotensin

Drugs for Chronic Heart Failure

Chronic Heart Failure 1,2

▶ Unless there is a specifi c contraindication, all patients with heart failure with reduced ejection fraction (LVEF ≤40%) should take both an ACE inhibitor and a beta blocker, and if volume overloaded, a diuretic as well

▶ An angiotensin receptor blocker (ARB) is recommended for patients who cannot tolerate an ACE inhibitor

▶ Addition of an aldosterone antagonist can reduce mortality and hospitalization in patients with symptomatic heart failure or with left ventricular dysfunction after a myocardial infarction

▶ Addition of a combination of hydralazine and isosorbide dinitrate to standard therapy has been shown to reduce mortality and symptoms in black patients with NYHA class III-IV heart failure with reduced ejection fraction

▶ Digoxin can decrease symptoms and lower the rate of hospitalization for heart failure, but it does not reduce mortality

▶ There is little evidence that drug treatment improves clinical outcomes in patients with heart failure with preserved ejection fraction (HFpEF).

1 CW Yancy et al Circulation 2013; 118:e240.

2 J Lindenfeld et al J Card Fail 2010; 16:e1.

Related article(s) since publication

in patients with heart failure with reduced ejection

fraction; results appear to be similar to those obtained

with ACE inhibitors ARBs can be used in patients

who cannot tolerate (primarily due to cough) an ACE

inhibitor Routine use of an ACE inhibitor and an ARB

together is generally not recommended

Dosage – ARBs should be started at low doses and

titrated to the highest tolerated dose, which is usually

achieved by doubling the dose until the maximum

daily dose (listed in Table 1) is reached

Cautions – As with ACE inhibitors, blood pressure,

renal function, and serum potassium concentrations

should be monitored in patients taking an ARB

Angioedema could occur in patients taking an ARB

who had previously developed it while taking an ACE

inhibitor Like ACE inhibitors, ARBs can increase fetal

mortality and should not be used during pregnancy

Adverse Effects – ARBs, like ACE inhibitors, block the

effects of angiotensin II and may cause hypotension,

renal insuffi ciency, and hyperkalemia, but they do not

cause cough Angioedema occurs less frequently with

ARBs than with ACE inhibitors

Choice of an ARB – Candesartan and valsartan are the

only ARBs approved by the FDA for treatment of heart

failure; losartan, which is available generically, has

BETA BLOCKERS — Unless there is a specifi c

contraindication, all patients with stable heart failure

with reduced ejection fraction should receive a

beta blocker in addition to an ACE inhibitor Use of

bisoprolol, carvedilol, or extended-release metoprolol

succinate in addition to an ACE inhibitor consistently

leads to a 30-40% reduction in hospitalization and

mortality in adults with New York Heart Association

(NYHA) class II–IV heart failure The effi cacy of

adding a beta blocker to standard therapy for heart

failure is less certain in children and adolescents and

in patients with a reduced ejection fraction who are

rate of all-cause mortality.6

Dosage – Beta blockers should be started at low

doses and increased gradually, usually at 2-week

intervals, to the highest tolerated dose Full clinical

benefi ts may not occur for 3-6 months or more

Cautions – Beta blockers should be used cautiously, if at

all, in patients with asthma or severe bradycardia

Adverse Effects – Fatigue, hypotension,

brady-cardia, asymptomatic fluid retention, and worsening heart failure may occur during the fi rst 2-4 weeks of treatment Increasing the dose of a concurrent diuretic may be helpful for fluid retention

Choice of a Beta Blocker – Carvedilol, extended-release

metoprolol succinate, and bisoprolol have been shown

to reduce mortality and hospitalization in patients with heart failure with reduced ejection fraction Bisoprolol

is not approved by the FDA for treatment of heart failure There is no defi nitive clinical trial comparing extended-release metoprolol succinate with carvedilol Carvedilol has been shown to reduce the incidence of

extended-release metoprolol succinate are once-daily dosing, less hypotension, and more selective beta-1 blockade that may reduce the risk of bronchospasm

ALDOSTERONE ANTAGONISTS — The addition of an

aldosterone antagonist is recommended for patients with NYHA Class II-IV heart failure with a LVEF

≤35% When added to standard therapy in patients with heart failure, aldosterone antagonists have been shown to reduce the risk of hospitalization and

in patients with heart failure after myocardial infarction, one study found that eplerenone signifi cantly reduced the primary endpoints of all-cause mortality and mortality or hospitalization for

adding an aldosterone antagonist after an acute myocardial infarction in patients with heart failure symptoms and an LVEF ≤40%

In a study in patients with heart failure with preserved ejection fraction, spironolactone improved non-invasive measures of diastolic function, but it did not

trial, use of spironolactone did not signifi cantly reduce the incidence of the primary composite endpoint of cardiovascular death, cardiac arrest, or heart failure

Cautions – Aldosterone antagonists should be avoided

in patients with serum potassium >5.0 mEq/L and in those with reduced renal function (baseline serum creatinine >2.0 mg/dL for women or >2.5 mg/dL for

function and serum creatinine concentrations should

be monitored during treatment

Adverse Effects – Hyperkalemia occurs frequently with

Table 1 Some Drugs for Chronic Heart Failure with Reduced Ejection Fraction 1

Angiotensin-Converting Enzyme (ACE) Inhibitors

Captopril 5 – generic 12.5, 25, 50, 100 mg tabs 6.25 mg tid 50 mg tid $130.00 4

Enalapril – generic 2.5, 5, 10, 20 mg tabs 2.5 mg bid 20 mg bid 12.00 4

Fosinopril 5 – generic 10, 20, 40 mg tabs 5-10 mg once/d 40 mg once/d 10.40 Lisinopril – generic 2.5, 5, 10, 20, 40 mg tabs 2.5-5 mg once/d 40 mg once/d 1.80

Perindopril* – generic 2, 4, 8 mg tabs 2 mg once/d 16 mg once/d 20.20

Quinapril – generic 5, 10, 20, 40 mg tabs 5 mg bid 20 mg bid 24.10

Ramipril – generic 1.25, 2.5, 5, 10 mg caps 1.25-2.5 mg once/d 10 mg once/d 9.70

Trandolapril – generic 1, 2, 4 mg tabs 1 mg once/d 4 mg once/d 17.20

Angiotensin Receptor Blockers (ARBs)

Azilsartan medoxomil* –

Edarbi (Arbor) 40, 80 mg tabs 40-80 mg once/d 80 mg once/d 135.60 Candesartan cilexetil – generic 4, 8, 16, 32 mg tabs 4-8 mg once/d 32 mg once/d 103.10

Losartan* – generic 25, 50, 100 mg tabs 25-50 mg once/d 150 mg once/d 6.00

Valsartan 5 – generic 40, 80, 160, 320 mg tabs 20-40 mg bid 160 mg bid 264.40

Beta-Adrenergic Blockers

Bisoprolol* – generic 5, 10 mg tabs 5 1.25 mg once/d 10 mg once/d 24.50

Carvedilol – generic 3.125, 6.25, 12.5, 25 mg tabs 3.125 mg bid 25 mg bid 5.40 4

extended-release – Coreg CR 10, 20, 40, 80 mg ER caps 10 mg once/d 80 mg once/d 173.60 Metoprolol succinate ER –

generic 25, 50, 100, 200 mg ER tabs 5 12.5-25 mg once/d 200 mg once/d 50.20

Aldosterone Antagonists

Eplerenone – generic 25, 50 mg tabs 25 mg once/d 6 50 mg once/d 6 104.10

Spironolactone 5 – generic 25, 50, 100 mg tabs 12.5-25 mg once/d 6 25 mg once/d or bid 6 5.80 4

Vasodilators

Isosorbide dinitrate/hydralazine 7 –

BiDil (Arbor)8 20/37.5 mg tabs 20 mg/37.5 mg tid 40 mg/75 mg tid 228.60

Loop Diuretics

Bumetanide – generic 0.5, 1, 2 mg tabs 0.5-1 mg once/d or bid 10 mg once/d or 117.80 4

in divided doses Furosemide – generic 20, 40, 80 mg tabs 20-40 mg once/d or bid 600 mg once/d or 192.00 4

Torsemide – generic 5, 10, 20, 100 mg tabs 10-20 mg once/d 200 mg once/d or 73.60

Digitalis Glycoside

Digoxin – generic 0.125, 0.25 mg tabs 0.125 mg once/d 0.125-0.25 mg once/d 36.10 4

Lanoxin (Covis) 0.0625, 0.125, 0.1875, 0.25 mg tabs or once every other day 67.80

ER = extended-release

* Not approved by the FDA for treatment of heart failure.

1 For treatment of heart failure with reduced ejection fraction (HFrEF).

2 Dosage adjustment may be needed for hepatic or renal impairment.

3 Approximate WAC for 30 days’ treatment at the lowest maximum dosage WAC = wholesaler acquisition cost or manufacturer’s published price to

wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly January

5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy.

4 A 30-day supply costs $4.00 at some large discount pharmacies.

5 Available as scored tablets.

6 For patients with an eGFR ≥50 mL/min/1.73 m 2 For patients with an eGFR 30-49 mL/min/1.73 m 2 , the initial dose is 25 mg every other day for eplerenone and 12.5 mg once daily or every other day for spironolactone and the maintenance dose is 25 mg once daily for eplerenone and 12.5-25 mg once daily for spironolactone

7 Both of these drugs are available generically as single agents Isosorbide dinitrate is available in 5, 10, 20, and 30-mg tablets and hydralazine in 10, 25, 50, and 100-mg tablets.

8 FDA-approved as adjunctive therapy for treatment of heart failure in black patients.

addition of an aldosterone antagonist can sometimes overcome diuretic resistance

Adverse Effects – The most common adverse effect

of diuretic therapy is hypokalemia Diuretics can also cause worsening of renal function

Choice of a Diuretic – Torsemide is better absorbed

than furosemide and has a longer duration of action, but there is no clinical evidence that torsemide or bumetanide is more effective than furosemide, which has been in use much longer

DIGOXIN — Digoxin can decrease the symptoms of

heart failure, increase exercise tolerance, and decrease the rate of hospitalization, but it does not prolong survival

Dosage – A low dose of digoxin (0.125 mg/d) is

generally recommended for patients with heart failure with reduced ejection fraction Dose adjustments based

on renal function, age, and concomitant medications may be required Digoxin levels of 0.5-0.9 ng/mL are recommended

Adverse Effects – The most common adverse effects

of digoxin are conduction disturbances, cardiac arrhythmias, nausea, vomiting, confusion, and visual disturbances

OTHER DRUGS — A large trial in patients with NYHA

class II-IV systolic heart failure (GISSI-HF) found

that the addition of n-3 polyunsaturated fatty acids

1 gram daily to standard therapy for a median of 3.9 years modestly reduced all-cause mortality and

Aliskiren (Tekturna) is a direct renin inhibitor approved

for treatment of hypertension Although it offers the theoretical benefi t of upstream renin-angiotensin system inhibition, one study in patients hospitalized for heart failure found that addition of aliskiren to standard therapy did not reduce cardiovascular death

or rehospitalization for heart failure at 6 months or 12

Sacubitril plus Valsartan – A recent trial

(PARADIGM-HF) found that the combination of the investigational neprilysin inhibitor sacubitril and the ARB valsartan was superior to the ACE inhibitor enalapril alone

in reducing the rate of death from cardiovascular causes or hospitalization for heart failure, the primary composite endpoint, in patients with heart failure with reduced ejection fraction.19,20 ■

also taking an ACE inhibitor or an ARB, and in those with

renal impairment Spironolactone has anti-androgenic

activity and can cause erectile dysfunction and painful

gynecomastia in men and menstrual irregularities

in women; the incidence of these effects has been

reported to be lower with eplerenone

Choice of an Aldosterone Antagonist – Eplerenone

may be similar in effectiveness to spironolactone and

may have less anti-androgenic activity, but it costs

much more Comparative studies of their use in heart

failure are lacking

VASODILATORS — Use of hydralazine plus isosorbide

dinitrate may be benefi cial for some patients The

addition of a fi xed-dose combination of

hydrala-zine and isosorbide dinitrate (BiDil) to standard

therapy in African-American patients who remained

symptomatic despite standard therapy signifi cantly

non-African-American patients is less well established, but

the combination can be considered in those intolerant

to an ACE inhibitor or an ARB or in those who need

additional blood pressure control despite maximal

doses of standard therapy

Adverse Effects – Hydralazine/isosorbide dinitrate

frequently causes headache and dizziness

Hydrala-zine alone can cause tachycardia, peripheral neuritis,

and a lupus-like syndrome Phosphodiesterase

inhibitors, such as sildenafi l (Viagra, Revatio, and

generics), should not be taken concurrently with

hydralazine/isosorbide dinitrate because of the risk of

additive hypotension

DIURETICS — Most patients with heart failure have

fluid retention In such patients, diuretics relieve

symptoms, but their effect on survival is unknown

Diuretics provide symptomatic relief of pulmonary and

peripheral edema more rapidly than other drugs used

for the treatment of heart failure Diuretics that act on

the loop of Henle, such as furosemide, bumetanide,

or torsemide, are more effective for treatment of

heart failure than thiazide-type diuretics, such as

hydrochlorothiazide or chlorthalidone, which act on

the distal tubule

Dosage – Diuretics should be started at a low dose,

which can be titrated upward until urine output

increases and weight decreases Patients with renal

dysfunction or prior refractoriness to loop diuretics can

be started at higher doses Intravenous administration,

concurrent use of 2 diuretics (1 loop, 1 thiazide-like), or

1 CW Yancy et al 2013 ACCF/AHA guideline for the management

of heart failure: a report of the American College of Cardiology

Foundation/American Heart Association Task Force on practice

guidelines Circulation 2013; 128:e240.

2 J Lindenfeld et al HFSA 2010 comprehensive heart failure

practice guideline J Card Fail 2010; 16:e1.

3 H Svanström et al Association of treatment with losartan vs

candesartan and mortality among patients with heart failure

JAMA 2012; 307:1506.

4 MA Konstam et al Effects of high-dose versus low-dose

losartan on clinical outcomes in patients with heart failure

(HEAAL study): a randomised, double-blind trial Lancet 2009;

374:1840.

5 RE Shaddy et al Carvedilol for children and adolescents

with heart failure: a randomized controlled trial JAMA 2007;

298:1171.

6 LH Lund et al Association between use of β-blockers and

outcomes in patients with heart failure and preserved ejection

fraction JAMA 2014; 312:2008.

7 C Torp-Pederson et al Effects of metoprolol and carvedilol on

pre-existing and new onset diabetes in patients with chronic

heart failure: data from the Carvedilol Or Metoprolol European

Trial (COMET) Heart 2007; 93:968.

8 MH Ruwald Impact of carvedilol and metoprolol on

inappropriate implantable cardioverter-defi brillator therapy:

the MADIT-CRT trial (Multicenter Automatic Defi brillator

Implantation with Cardiac Resynchronization Therapy) J Am

Coll Cardiol 2013; 62:1343.

9 G Sayer and G Bhat The renin-angiotensin-aldosterone system

and heart failure Cardiol Clin 2014; 32:21.

10 F Zannad et al Eplerenone in patients with systolic heart failure

and mild symptoms N Engl J Med 2011; 364:11.

11 B Pitt et al The effect of spironolactone on morbidity and

mortality in patients with severe heart failure Randomized

Aldactone Evaluation Study Investigators N Engl J Med 1999;

341:709.

12 B Pitt et al Eplerenone, a selective aldosterone blocker, in

patients with left ventricular dysfunction after myocardial

infarction N Engl J Med 2003; 348:1309.

13 F Edelmann et al Effect of spironolactone on diastolic

function and exercise capacity in patients with heart failure

with preserved ejection fraction: the Aldo-DHF randomized

controlled trial JAMA 2013; 309: 781.

14 B Pitt et al Spironolactone for heart failure with preserved

ejection fraction N Engl J Med 2014; 370:1383.

15 KB Shah et al The adequacy of laboratory monitoring in patients

treated with spironolactone for congestive heart failure J Am

Coll Cardiol 2005; 46:845.

16 AL Taylor et al Early and sustained benefi t on event-free

survival and heart failure hospitalization from fi xed-dose

combination of isosorbide dinitrate/hydralazine: consistency

across subgroups in the African-American Heart Failure Trial

Circulation 2007; 115:1747.

17 GISSI-HF Investigators et al Effect of n-3 polyunsaturated fatty

acids in patients with chronic heart failure (the GISSI-HF trial):

a randomised, double-blind, placebo-controlled trial Lancet

2008; 372:1223.

18 M Gheorghiade et al Effect of aliskiren on postdischarge

mortality and heart failure readmissions among patients

hospitalized for heart failure: the ASTRONAUT randomized trial

JAMA 2013; 309:1125.

19 JJ McMurray et al Angiotensin-neprilysin versus enalapril in

heart failure N Engl J Med 2014; 371:993.

20 O Vardeny et al Combined neprilysin and renin-angiotensin

system inhibition for the treatment of heart failure JACC Heart

Fail 2014; 2:663.

Metreleptin (Myalept – Amylin), a recombinant leptin analog produced in E coli, has been approved by the

FDA to treat the complications of leptin defi ciency

in patients with congenital or acquired generalized lipodystrophy It has not been approved to date for the treatment of partial lipodystrophies, including those associated with the use of protease inhibitors in patients with HIV Metreleptin is approved in Japan for the treatment of any lipodystrophy disorder

Metreleptin (Myalept) – A Leptin

Analog for Generalized Lipodystrophy

▶

LEPTIN — Leptin is a protein hormone secreted by

adipose tissue that acts on the hypothalamus to induce satiety In patients with leptin defi ciency, exogenous leptin administration results in weight loss and reductions in blood insulin, glucose, and triglyceride levels It has not been effective in treating ordinary obesity

CLINICAL STUDIES — FDA approval of metreleptin was

based on an unpublished, open-label, single-arm clinical trial (summarized in the package insert) in 48 patients with congenital or acquired generalized lipodystrophy and diabetes mellitus, hypertriglyceridemia, and/or

Table 1 Pharmacology

Drug class Leptin analog Route Subcutaneous Formulation 11.3 mg lyophilized powder

(5 mg/mL after reconstitution)

Half-life 3.8-4.7 hours in healthy subjects Elimination Primarily renal

Pronunciation Key Metreleptin: met' re lep' tin Myalept: mye' a lept'

THE DISORDER — Generalized lipodystrophy is a rare

Congenital and acquired generalized lipodystrophy are characterized by a near total lack of adipose tissue Fat is deposited ectopically in muscle and liver tissue and can cause metabolic complications including insulin resistance, hyperinsulinemia, diabetes mellitus, and non-alcoholic fatty liver disease Severe hypertri-glyceridemia is common in patients with generalized lipodystrophy and can lead to acute pancreatitis The metabolic abnormalities associated with generalized li-podystrophy are often aggravated by overconsumption

HIV-associated lipodystrophy, the most common form

of lipodystrophy, is also associated with reduced leptin levels, dyslipidemia, hypertriglyceridemia, and insulin resistance

hyperinsulinemia Compared to baseline, mean HbA1c

and fasting glucose levels and median fasting triglyceride

levels were all signifi cantly reduced after 12 months

of therapy with metreleptin Earlier small uncontrolled

clinical trials in patients with generalized lipodystrophy

produced similar results Some other small studies

have found that metreleptin can correct metabolic

abnormalities and decrease truncal fat mass in patients

ADVERSE EFFECTS — The most common adverse effects

reported in patients taking metreleptin have been

head-ache, hypoglycemia, weight loss, and abdominal pain A

boxed warning states that anti-metreleptin antibodies,

serious infections, and worsening metabolic control have

been reported in patients taking the drug, and that some

patients with acquired generalized lipodystrophy taking

metreleptin (as well as some not taking the drug) have

developed T-cell lymphoma As part of a Risk Evaluation

and Mitigation Strategy (REMS), the FDA has required

healthcare providers to be trained in the use of metreleptin

before prescribing it and to attest that patients for whom

they prescribe metreleptin have a labeled indication for

the drug Metreleptin is classifi ed as category C (no

ad-equate studies in women) for use during pregnancy

DOSAGE, ADMINISTRATION, AND COST — Metreleptin

is administered subcutaneously once daily at starting

doses of 0.06 mg/kg, 2.5 mg, and 5 mg for patients ≤40 kg,

males >40 kg, and females >40 kg, respectively, and

may be titrated to a maximum daily dose of 0.13 mg/kg

in patients ≤40 kg or 10 mg in those >40 kg The drug is

available in vials containing 11.3 mg of metreleptin as a

lyophilized powder, which should be refrigerated during

storage Each vial is reconstituted with 2.2 mL of sterile

water for injection (WFI) or sterile bacteriostatic water

for injection (BWFI) to a fi nal concentration of 5 mg/mL

If reconstituted with BWFI, metreleptin solution can

be refrigerated and used within 3 days of preparation;

solution prepared with WFI must be used immediately

or discarded Neonates and infants should not receive

metreleptin solution prepared with BWFI because of its

benzyl alcohol content A 30-day supply of Myalept at a

CONCLUSION — The results of an unpublished,

single-arm, open-label trial indicate that the leptin analog

metreleptin (Myalept) can ameliorate the metabolic

abnormalities found in patients with generalized

lipodystrophy, but controlled trials are lacking and

the drug’s long-term safety is unknown Metreleptin

may also be effective in treating HIV-associated

lipodystrophy, but more data are needed, and it has not

1 A Garg Acquired and inherited lipodystrophies N Engl J Med 2004; 350:1220.

2 MA Tsoukas et al Leptin in congenital and HIV-associated lipo-dystrophy Metabolism 2015; 64:47.

3 Approximate WAC for 30 days’ treatment WAC = wholesaler acquisition cost, or manufacturer’s published price to whole-salers; WAC represents published catalogue or list prices and may not represent actual transactional prices Source: Analy-Source® Monthly January 5, 2015 Reprinted with permission

by First Databank, Inc All rights reserved ©2015 www.fdb-health.com/policies/drug-pricing-policy.

IN BRIEF

Concerns about Oseltamivir (Tamiflu)

Some readers of our article on Antiviral Drugs for Seasonal Influenza1 have expressed concerns regarding our recommendation for use of the oral neuraminidase

inhibitor oseltamivir (Tamiflu) to treat high-risk patients

with confi rmed or suspected influenza illness, citing the

British Medical Journal and The Cochrane Collaboration,

which have contended that there is no acceptable evidence that the drug prevents complications or hospitalizations and have questioned the completeness

of the results of controlled trials conducted by the manufacturer (Roche).2

Randomized controlled trials, mainly in patients with mild influenza illness, have shown that treatment

with oseltamivir or zanamivir (Relenza), an inhaled

neuraminidase inhibitor, started within 48 hours of the onset of illness can shorten the duration of symptoms

by about one day Most controlled trials of the effectiveness of these drugs in preventing pneumonia or other serious complications of influenza have not been powered adequately to provide convincing evidence of effi cacy, but a broad consensus of expert clinicians has interpreted the combined results of controlled trials, observational studies, and meta-analyses as showing that early antiviral treatment of high-risk patients with influenza can reduce the risk of complications such as pneumonia, respiratory failure, and death.3,4

Influenza kills about 50,000 patients annually in the US Oseltamivir and zanamivir are generally well tolerated, and there is no alternative treatment (Since this article

was fi rst posted online, peramivir (Rapivab), an IV

neur-aminidase inhibitor, has been approved by the FDA It will be reviewed in our February 2, 2015 issue.)

1 Antiviral drugs for seasonal influenza 2014-2015 Med Lett Drugs Ther 2014; 56:121.

2 T Jefferson et al Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children Cochrane Data-base Syst Rev 2014; 4:CD008965.

3 CDC Influenza antiviral medications: summary for clinicians Available at http://www.cdc.gov/flu/professionals/antivirals/ summary-clinicians.htm Accessed December 23, 2014

4 IDSA Statement by the Infectious Disease Society of America (IDSA)

on the recent publication on "Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children." April 2014 Available at: http://www.idsociety.org/Influenza_Statement.aspx Accessed December 23, 2014.

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The expected outcome of the CME program is to increase the participant’s ability to know, or apply knowledge into practice after assimilating, information presented in

materials contained in The Medical Letter.

The Medical Letter will strive to continually improve the CME program through periodic assessment of the program and activities The Medical Letter aims to be a leader in supporting the professional development of healthcare providers through Core Competencies by providing continuing medical education that is unbiased and free of industry influence The Medical Letter is supported solely by subscription fees and accepts no advertising, grants, or donations.

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Activity participants will read and assimilate unbiased reviews of FDA-approved and off-label uses of drugs and other treatment modalities Activity participants will be

able to select and prescribe, or confi rm the appropriateness of the prescribed usage of, the drugs and other therapeutic modalities discussed in The Medical Letter with

specifi c attention to clinical trials, pathophysiology, dosage and administration, drug metabolism and interactions, and patient management Activity participants will make independent and informed therapeutic choices in their practice.

Upon completion of this program, the participant will be able to:

1 Explain the current approach to the management of chronic heart failure.

2 Discuss the pharmacologic options available for treatment of chronic heart failure and compare them based on their effi cacy, dosage and administration, and potential adverse effects.

3 Determine the most appropriate therapy given the clinical presentation of an individual patient with chronic heart failure.

4 Review the effi cacy and safety of metreleptin (Myalept) for treatment of leptin defi ciency in patients with congenital or acquired generalized lipodystrophy.

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Online Continuing Medical Education

DO NOT FAX OR MAIL THIS EXAM

To take CME exams and earn credit, go to:

medicalletter.org/CMEstatus Issue 1460 Questions

(Correspond to questions #11-20 in Comprehensive Exam #72, available July 2015)

7 A 59-year-old white man presents post-MI with heart failure symptoms and a LVEF of 29% He is currently being treated with

an ACE inhibitor and extended-release metoprolol succinate Addition of which of the following drugs has been shown to prolong survival in such a patient?

a digoxin

b hydrochlorothiazide

c eplerenone

d hydralazine and isosorbide dinitrate

8 A 68-year-old white man with heart failure with reduced ejection fraction being treated with enalapril and carvedilol comes to your offi ce complaining of shortness of breath On physical examination, he has bilateral rales and edema in both lower extremities Which of the following would you recommend for acute relief of symptoms in this patient?

a a combination of hydralazine and isosorbide dinitrate

b valsartan

c a loop diuretic

d digoxin

Metreleptin (Myalept) – A Leptin Analog for Generalized

Lipodystrophy

9 Metreleptin (Myalept) has been approved by the FDA for treatment of:

a any partial lipodystrophy

b lipodystrophy associated with use of protease inhibitors in patients with HIV

c congenital or acquired generalized lipodystrophy

d all of the above

10 Adverse effects of metreleptin have included:

a hypoglycemia

b weight loss

c abdominal pain

d all of the above

Drugs for Chronic Heart Failure

1 In patients with heart failure with reduced ejection fraction, ACE

inhibitors have been shown to:

a improve symptoms

b decrease hospitalizations

c prolong survival

d all of the above

2 The most common adverse effect of ACE inhibitors is:

a cough

b angioedema

c hypokalemia

d dizziness

3 ARBs:

a are less effective than ACE inhibitors for treatment of

chronic heart failure

b are more likely than ACE inhibitors to cause angioedema

c do not cause cough

d all of the above

4 Potential advantages of extended-release metoprolol succinate

over carvedilol include:

a less hypotension

b a lower risk of bronchospasm

c once-daily dosing

d all of the above

5 Hyperkalemia can occur with:

a ACE inhibitors

b ARBs

c aldosterone antagonists

d all of the above

6 In patients with heart failure, digoxin has not been shown to:

a improve symptoms

b decrease hospitalizations

c prolong survival

d all of the above

ACPE UPN: Per Issue Exam: 0379-0000-15-460-H01-P; Release: January 19, 2015, Expire: January 19, 2016 Comprehensive Exam 72: 0379-0000-15-072-H01-P; Release: July 2015, Expire: July 2016

EDITOR IN CHIEF: Mark Abramowicz, M.D.; EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR: Jean-Marie Pflomm, Pharm.D.; ASSISTANT EDITORS, DRUG INFORMATION: Susan M Daron, Pharm.D., Corinne Z Morrison, Pharm.D., Michael P Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M Shah, Pharm.D.,

F Peter Swanson, M.D; SENIOR ASSOCIATE EDITOR: Amy Faucard

CONTRIBUTING EDITORS: Carl W Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons; Vanessa K Dalton, M.D., M.P.H., University of Michigan Medical

School; Eric J Epstein, M.D., Albert Einstein College of Medicine; Jane P Gagliardi, M.D., M.H.S., F.A.C.P., Duke University School of Medicine; Jules Hirsch, M.D., Rockefeller University; David N Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre; Richard B Kim, M.D., University of Western Ontario; Hans Meinertz, M.D., University Hospital, Copenhagen; Sandip K Mukherjee, M.D., F.A.C.C., Yale School of Medicine; Dan M Roden, M.D., Vanderbilt University School of Medicine; Esperance A.K Schaefer, M.D., M.P.H., Harvard Medical School; F Estelle R Simons, M.D., University of Manitoba; Neal H Steigbigel, M.D., New York University School of Medicine; Arthur M F Yee, M.D., Ph.D., F.A.C.R.,

Weill Medical College of Cornell University

MANAGING EDITOR: Susie Wong; ASSISTANT MANAGING EDITOR: Liz Donohue; EDITORIAL ASSISTANT: Cheryl Brown

EXECUTIVE DIRECTOR OF SALES: Gene Carbona; FULFILLMENT & SYSTEMS MANAGER: Cristine Romatowski; DIRECTOR OF MARKETING COMMUNICATIONS: Joanne F Valentino; VICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy

Founded in 1959 by Arthur Kallet and Harold Aaron, M.D.

Copyright and Disclaimer: The Medical Letter, Inc is an independent nonprofi t organization that provides healthcare professionals with unbiased drug prescribing recommendations The editorial

process used for its publications relies on a review of published and unpublished literature, with an emphasis on controlled clinical trials, and on the opinions of its consultants The Medical Letter, Inc is supported solely by subscription fees and accepts no advertising, grants, or donations No part of the material may be reproduced or transmitted by any process in whole or in part without resulting from any error, inaccuracy, or omission.

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