The medical letter on drugs and therapeutics august 3 2015

The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959
Volume 57

ISSUE
ISSUE
No.

1433
1474
Volume 56

August 3, 2015

IN THIS ISSUE

Sacubitril/Valsartan (Entresto) for Heart Failure ............................................................. p
Rifaximin (Xifaxan) for Irritable Bowel Syndrome with Diarrhea ..................................... p
Polidocanol (Varithena) for Varicose Veins ....................................................................... p
In Brief: Duopa – A Carbidopa/Levodopa Enteral Suspension for Parkinson’s Disease ...... p

107
109
111
112

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The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959
Volume 57

ISSUE

ISSUE No.

1433
1474
Volume 56

▶

August 3, 2015
Take CME Exams
ALSO IN THIS ISSUE

Rifaximin (Xifaxan) for Irritable Bowel Syndrome with Diarrhea ......................................p 109
Polidocanol (Varithena) for Varicose Veins ........................................................................p 111
In Brief: Duopa – A Carbidopa/Levodopa Enteral Suspension for Parkinson’s Disease ....... p 112

Sacubitril/Valsartan (Entresto) for
Heart Failure

The FDA has approved Entresto (Novartis), an oral
fixed-dose combination of the neprilysin inhibitor
sacubitril and the angiotensin receptor blocker (ARB)
valsartan, to reduce the risk of cardiovascular death
and heart failure hospitalization in patients with
heart failure with reduced ejection fraction. Sacubitril
is the first neprilysin inhibitor to become available in
the US.
Pronunciation Key
Sacubitril: sak ue’ bi tril
Entresto: en tress’ toh
Valsartan: val sar’ tan

Neprilysin: nep" ri lye' sin

STANDARD TREATMENT — Patients with symptomatic
heart failure with reduced ejection fraction generally
take an angiotensin-converting enzyme (ACE) inhibitor,
a beta blocker, and an aldosterone antagonist. If
volume overloaded, they may take a diuretic as well.
An ARB is recommended for patients who cannot
tolerate an ACE inhibitor.1
MECHANISM OF ACTION — Neprilysin is a neutral
endopeptidase that degrades some vasoactive peptides, including natriuretic peptides, bradykinin, and
adrenomedullin. Inhibition of neprilysin by LBQ657, the
active metabolite of sacubitril, increases the levels of
these peptides, decreasing vasoconstriction, sodium
retention, and maladaptive remodeling. Valsartan
blocks the angiotensin II type-1 (AT1) receptor, inhibiting
angiotensin II and the release of aldosterone.2
CLINICAL STUDIES — Approval of Entresto was
based on a double-blind trial (PARADIGM-HF) in
8442 patients with class II-IV heart failure and a
reduced ejection fraction who were randomized
to Entresto 200 mg (sacubitril 97 mg/valsartan
103 mg) twice daily or the ACE inhibitor enalapril

Table 1. Pharmacology
Class
Formulation
Route
Tmax
Elimination

Half-life

Angiotensin-receptor neprilysin inhibitor
Sacubitril/valsartan - 24/26 mg, 49/51 mg,
97/103 mg tablets
Oral
0.5 hrs (sacubitril); 2 hrs (LBQ657)1;
1.5 hrs (valsartan)
Sacubitril (52-68% urine; 37-48% feces);
Valsartan (~13% urine; 86% feces)
1.4 hrs (sacubitril); 11.5 hrs (LBQ657)1;
9.9 hrs (valsartan)

1. Active metabolite of sacubitril.

(Vasotec, and generics) 10 mg twice daily, both in
addition to other drugs. The study was stopped
early because a prespecified interim analysis
showed lower cardiovascular mortality in patients
randomized to Entresto. After a median follow-up
of 27 months, the primary endpoint, a composite of
first hospitalization for worsening heart failure or
cardiovascular death, occurred in significantly fewer
patients taking the combination compared to those
taking enalapril (21.8% vs 26.5%). The combination
significantly reduced the risk of first hospitalization
for worsening heart failure (12.8% vs 15.6%), death
from cardiovascular causes (13.3% vs 16.5%), and
all-cause mortality (17.0% vs 19.8%).3 It also slowed
the progression of heart failure.4

ADVERSE EFFECTS — Hypotension and hyperkalemia
were the most common adverse effects in the
clinical trial; symptomatic hypotension occurred
in 14% of patients taking Entresto, even though the
study excluded those with baseline hypotension.
Cough (11.3%) and elevated serum creatinine (3.3%)
occurred in patients treated with the combination,
but less frequently than with enalapril. Neprilysin
inhibition can cause angioedema, which occurred
in 0.5% of patients treated with the combination
compared to 0.2% of those treated with enalapril.
107

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The Medical Letter

®

August 3, 2015

Vol. 57 (1474)

Table 2. Some Drugs for Heart Failure with Reduced Ejection Fraction
Drug

Some Oral
Formulations

Angiotensin-Converting Enzyme (ACE) Inhibitors
Captopril – generic
12.5, 25, 50, 100 mg tabs3
Enalapril – generic
2.5, 5, 10, 20 mg tabs
Vasotec (Valeant)
Fosinopril – generic
10, 20, 40 mg tabs3
Lisinopril – generic
2.5, 5, 10, 20, 40 mg tabs
Prinivil (Merck)
5, 10, 20 mg tabs
Zestril (Almatica)
2.5, 5, 10, 20, 30, 40 mg tabs
Perindopril erbumine4 – generic
2, 4, 8 mg tabs
Aceon (Symplmed)
Quinapril – generic
5, 10, 20, 40 mg tabs
Accupril (Pfizer)
Ramipril – generic
1.25, 2.5, 5, 10 mg caps
Altace (Merck)
Trandolapril – generic
1, 2, 4 mg tabs
Mavik (Abbvie)
Angiotensin Receptor Blockers (ARBs)
Azilsartan medoxomil4 – Edarbi (Arbor)
40, 80 mg tabs
Candesartan cilexetil – generic

4, 8, 16, 32 mg tabs
Atacand (AstraZeneca)
Losartan4 – generic
25, 50, 100 mg tabs
Cozaar (Merck)
Valsartan – generic
40, 80, 160, 320 mg tabs3
Diovan (Novartis)
Beta-Adrenergic Blockers
Bisoprolol4 – generic
5, 10 mg tabs3
Zebeta (Duramed/Barr)
Carvedilol – generic
3.125, 6.25, 12.5, 25 mg tabs
Coreg (GSK)
extended-release – Coreg CR
10, 20, 40, 80 mg ER caps
Metoprolol succinate ER – generic
25, 50, 100, 200 mg ER tabs3
Toprol-XL (AstraZeneca)
Aldosterone Antagonists
Eplerenone – generic
25, 50 mg tabs
Inspra (Pfizer)
Spironolactone – generic
25, 50, 100 mg tabs3
Aldactone (Pfizer)
Vasodilators
Isosorbide dinitrate/hydralazine6 –
BiDil (Arbor)7

20/37.5 mg tabs
Loop Diuretics
Bumetanide – generic
0.5, 1, 2 mg tabs
Furosemide – generic
Lasix (Sanofi)
Torsemide – generic
Demadex (Meda)
Digitalis Glycoside
Digoxin – generic
Lanoxin (Covis)

20, 40, 80 mg tabs
5, 10, 20, 100 mg tabs

Usual Initial
Adult Dosage1

Usual Maximum
Adult Dosage1

6.25 mg tid
2.5 mg bid

50 mg tid
20 mg bid

5-10 mg once/d
2.5-5 mg once/d

40 mg once/d
40 mg once/d

2 mg once/d

16 mg once/d

5 mg bid

20 mg bid

1.25-2.5 mg once/d

10 mg once/d

1 mg once/d

4 mg once/d

40-80 mg once/d
4-8 mg once/d

80 mg once/d
32 mg once/d

25-50 mg once/d

150 mg once/d

20-40 mg bid

160 mg bid

1.25 mg once/d

10 mg once/d

3.125 mg bid
10 mg once/d
12.5-25 mg once/d

Cost2
$151.50
39.90
1311.60
10.40
2.70
94.10
48.00
37.30
196.20
23.60
185.10
15.80
139.90
16.20
59.10

24.60
149.70

25 mg bid
14.70
(50 mg bid for pts >85kg) 218.70
80 mg once/d
219.60
200 mg once/d
45.00
85.50

25 mg once/d5

50 mg once/d5

12.5-25 mg once/d5

25 mg once/d or bid5

20 mg/37.5 mg tid

40 mg/75 mg tid

0.5-1 mg once/d or bid

10 mg once/d or
in divided doses
20-40 mg once/d or bid 600 mg once/d or
in divided doses
10-20 mg once/d
200 mg once/d or
in divided doses

0.125, 0.25 mg tabs
0.125 mg once/d
0.0625, 0.125, 0.1875, 0.25 mg tabs

162.60
103.30
131.10
16.20
297.40
52.40
319.20

0.125-0.25 mg once/d
or once every other day

104.10
217.80
6.30
48.30

528.70
166.10
31.10
274.50
54.20
585.00
16.70
34.80

Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Blocker
Ivabradine – Corlanor (Amgen)

5, 7.5 mg tabs

Angiotensin-Receptor Neprilysin Inhibitor
Sacubitril/valsartan – Entresto (Novartis) 24/26, 49/51, 97/103 mg tabs

2.5-5 mg bid

7.5 mg bid

375.00

49/51 mg bid8

97/103 mg bid

375.009

ER = extended-release
1. Dosage adjustment may be needed for hepatic or renal impairment.
2. Approximate WAC for 30 days’ treatment at the lowest usual maximum adult 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. July 5,
2015. Reprinted with permission by First Databank, Inc. All rights reserved. ©2015. www.fdbhealth.com/policies/drug-pricing-policy.
3. Available as scored tablets.
4. Not approved by the FDA for treatment of heart failure.
5. For patients with an eGFR ≥50 mL/min/1.73 m2. For patients with an eGFR 30-49 mL/min/1.73 m2, 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.

6. 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.
7. FDA-approved as adjunctive therapy for treatment of heart failure in black patients.
8. For patients with an eGFR <30 mL/min/1.73 m2 or for those with moderate hepatic impairment, the dose is 24/26 mg bid.
9. WAC according to the manufacturer.

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PREGNANCY — ARBs should not be used during
pregnancy because they can reduce fetal renal function
and increase fetal and neonatal morbidity and death.
DRUG INTERACTIONS — Concurrent use of Entresto
with an ACE inhibitor is contraindicated because
of the risk of serious angioedema, which occurs
more often in black patients. Concurrent use of the
combination with potassium-sparing diuretics or
potassium supplements could lead to hyperkalemia,
especially in patients with renal impairment, diabetes,
or hypoaldosteronism. Worsening of renal function
and acute renal failure could occur in patients taking
Entresto and NSAIDs concurrently. Lithium toxicity
has occurred in patients taking lithium and an ARB.
DOSAGE AND ADMINISTRATION — The valsartan salt
in Entresto is different from the one in Diovan; 103 mg
of valsartan in Entresto is equivalent to 160 mg of

valsartan in Diovan. The recommended starting
dosage of Entresto is 49/51 mg twice daily. The dose
should be doubled after 2-4 weeks as tolerated to
reach the target maintenance dosage of 97/103 mg
twice daily. ACE inhibitor treatment should be stopped
for 36 hours before starting treatment with Entresto.
For patients not currently taking an ACE inhibitor or
an ARB, or for those with severe renal impairment
(eGFR <30 mL/min/1.73 m2) or moderate hepatic
impairment, the starting dosage of Entresto is 24/26
mg twice daily. The dose should be doubled every 2-4
weeks as tolerated to reach a final dose of 97/103
mg. Entresto is not recommended for patients with
severe hepatic impairment.
CONCLUSION — Entresto, a combination of the
neprilysin inhibitor sacubitril and the ARB valsartan,
was significantly more effective than the ACE
inhibitor enalapril in reducing the rate of death from
cardiovascular causes or hospitalization for heart
failure in patients with heart failure with reduced
ejection fraction. It should be considered for use
instead of an ACE inhibitor or an ARB for first-line
treatment of heart failure with reduced ejection
fraction. Hypotension and angioedema could be
problematic. ■
1. Drugs for chronic heart failure. Med Lett Drugs Ther 2015; 57:9.
2. O Vardeny et al. Combined neprilysin and renin-angiotensin
system inhibition for the treatment of heart failure. JACC Heart
Fail 2014; 2:663.
3. JJ McMurray et al. Angiotensin-neprilysin inhibition versus

enalapril in heart failure. N Engl J Med 2014; 371:993.
4. M Packer et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation 2015; 131:54.

Vol. 57 (1474)

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August 3, 2015

Rifaximin (Xifaxan) for Irritable
Bowel Syndrome with Diarrhea

Rifaximin (Xifaxan – Salix), a minimally absorbed
oral antibiotic approved previously to treat travelers’
diarrhea and to reduce the risk of recurrent hepatic
encephalopathy, has now been approved by the FDA
for treatment of irritable bowel syndrome with diarrhea
(IBS-D). Eluxadoline (Viberzi – Actavis), a mu-opioid
receptor agonist, was also recently approved for IBS-D
and will be reviewed in a future issue.
Rifaximin: rif ax' i min

Pronunciation Key
Xifaxan: zye' fax in

SOME TREATMENTS FOR IBS — Symptoms of IBS
can include abdominal pain, bloating, flatulence,
diarrhea, and constipation. Extra-intestinal complaints
are also common. IBS is subtyped, according to the
predominant bowel symptom, as IBS with diarrhea

(IBS-D), IBS with constipation (IBS-C), mixed-type
(IBS-M), or unclassified (IBS-U). The goal of treatment
is symptom control; dietary modifications may help
improve symptoms of all subtypes of IBS.
For patients with IBS-D, antidiarrheals such as
loperamide (Imodium A-D, and others), taken as
needed, may reduce stool urgency and frequency, but
they have not been shown to improve other symptoms.
Alosetron (Lotronex, and generics), a 5-HT3 receptor
antagonist that decreases intestinal motility and pain
signals, is FDA-approved for treatment of women with
severe IBS-D that has not responded to conventional
therapy, but its use has been limited by a risk of
serious GI adverse effects including ischemic colitis.
Fiber is often effective in reducing overall symptoms of
IBS-C. Laxatives such as polyethylene glycol (Miralax,
and others) can increase the frequency of bowel
movements in patients with IBS-C, but may not improve
overall symptoms. Linaclotide (Linzess), a guanylate
cyclase-C receptor agonist that increases intraluminal
fluid and accelerates intestinal transit, and lubiprostone
(Amitiza), a prostaglandin derivative that stimulates
intestinal fluid secretion, can be used to treat IBS-C that
has not responded to fiber and laxatives.1,2
MECHANISM OF ACTION — Rifaximin is a minimally
absorbed, broad-spectrum antibiotic. Some studies
suggest that changes in gut microbiota, sometimes
following a GI infection, may play a role in the
development of IBS.3 The exact mechanism of action
of rifaximin for treatment of IBS-D is unclear; it alters

gut microbiota and may reduce mucosal inflammation
and visceral hypersensitivity.4
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The Medical Letter

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Table 1. Pharmacology
Class

Rifamycin antimicrobial

Route

Oral

Formulation

200, 550 mg tabs

Bioavailability

<0.4% absorbed from GI tract

Half-life

6.1 hours in IBS-D patients (after 14 days)

Metabolism

Primarily by CYP3A4

Excretion

Feces (unchanged, 97% ); urine (unchanged,
<1%); possible biliary excretion

CLINICAL STUDIES — In two identical double-blind
trials (TARGET 1 and 2), a total of 1260 adults with
IBS without constipation were randomized to receive
either rifaximin 550 mg three times daily or placebo
for 14 days, and were then followed for an additional
10 weeks.5 Significantly more patients taking rifaximin
(40.7% vs 31.7% with placebo) had adequate relief
from IBS symptoms for at least 2 of the first 4 weeks
after treatment, the primary endpoint. Adequate relief
of bloating, a secondary endpoint, was reported in
significantly more patients taking rifaximin (40.2% vs
30.3% with placebo). More rifaximin-treated patients
also achieved an exploratory endpoint, a composite
of a reduction in daily abdominal pain and discomfort
(≥30% decrease from baseline) and improvement in
stool consistency for ≥2 weeks during the first 4 weeks
after treatment (46.6% vs 37.4% with placebo). Over
the 10 weeks of follow-up, the percentage of patients
reporting adequate symptom relief decreased in both
groups, but the rifaximin group had a significantly
higher percentage of patients with adequate symptom

relief at all time points.
A third trial (TARGET 3), summarized in the package
insert, evaluated retreatment with rifaximin among
adults with IBS-D whose symptoms recurred after
initially responding to a single open-label course of
the drug. Among the 1074 initial responders (44% of
2438), 636 had recurrent symptoms; these patients
were randomized to 2 additional 14-day courses of
rifaximin separated by a 10-week treatment-free
period, or to placebo. Significantly more patients in the
rifaximin group met the primary endpoint of achieving
both a reduction in abdominal pain scores and an
improvement in stool consistency for at least 2 of the 4
weeks following the first repeat treatment course (38%
vs 31% with placebo). Among patients who responded
to the first repeat treatment course, 17.1% of rifaximintreated patients and 11.7% of placebo-treated patients
did not experience a recurrence of symptoms during
the 10-week treatment-free period.
ADVERSE EFFECTS — In clinical trials of rifaximin for
IBS-D, adverse events were generally similar to those
110

Vol. 57 (1474)

August 3, 2015

with placebo.6 The most common adverse effects
reported in ≥2% of patients treated with the drug were
headache, nausea, and ALT increases. Clostridium
difficile-associated colitis, increased blood creatinine

phosphokinase, and myalgia have occurred rarely.
Hypersensitivity reactions have been reported.
Whether long-term use of rifaximin for IBS-D could
lead to bacterial resistance remains to be established.
PREGNANCY — Teratogenic effects occurred when
pregnant rats and rabbits were given rifaximin at doses
higher than those recommended for humans.
DRUG INTERACTIONS — Rifaximin is a substrate of
P-glycoprotein (P-gp). Concomitant administration of
cyclosporine, a P-gp inhibitor, resulted in an 83-fold
increase in the Cmax and a 124-fold increase in the
AUC of rifaximin. Other P-gp inhibitors may have a
similar effect.7 Whether such large increases in serum
concentrations of the drug could have adverse effects
is unclear.
Table 2. Some Drugs for IBS with Diarrhea
Drug

Usual
Adult Dosage

Alosetron2 – generic
Lotronex (Prometheus)

0.5-1 mg bid

Loperamide3 – generic

2 mg as needed
(max 16 mg/d)

Rifaximin – Xifaxan (Salix)

550 mg tid x 14 d5

Cost1
$1264.20
1635.00
3.904
1176.806

1. Approximate WAC for 30 days’ treatment with the lowest usual dosage.
WAC = wholesaler acquisition cost, or manufacturer's published price
to wholesalers; WAC represents published catalogue or list prices and
may not represent actual transactional prices. Source: AnalySource®
Monthly. July 5, 2015. Reprinted with permission by First Databank, Inc.
All rights reserved. ©2015. www.fdbhealth.com/policies/drug-pricingpolicy.
2. Only FDA-approved for use in women with severe IBS-D that has not
responded to conventional therapy. As part of a Risk Evaluation and Mitigation Strategy (REMS), the FDA has required that healthcare providers
receive special training in the use of alosetron before prescribing the
drug.
3. Available over the counter.
4. Cost for 30 2-mg tablets or capsules.
5. Can be repeated up to 2 times if symptoms recur.
6. Cost for one 14-day treatment course.

DOSAGE AND ADMINISTRATION — The recommended
dosage of rifaximin for treatment of IBS-D is 550 mg
three times daily for 14 days, which can be repeated
up to 2 times if symptoms recur. Rifaximin should

be used with caution in patients with severe hepatic
impairment.
CONCLUSION — The minimally absorbed oral
antibiotic rifaximin (Xifaxan) has been modestly
more effective than placebo in relieving symptoms of
irritable bowel syndrome with diarrhea (IBS-D), but
relapse is common, its long-term efficacy and safety
for treatment of IBS-D have not been established, and
it is expensive. ■


The Medical Letter

®

1. Drugs for irritable bowel syndrome. Treat Guidel Med Lett 2011;
9:41.
2. AC Ford et al. American College of Gastroenterology monograph
on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol 2014; 109:S2.
3. L Laterza et al. Rifaximin for the treatment of diarrhoea-predominant irritable bowel syndrome. Expert Opin Pharmacother
2015; 16:607.
4. N Iorio et al. Profile of rifaximin and its potential in the treatment
of irritable bowel syndrome. Clin Exp Gastroenterol 2015; 8:159.
5. M Pimentel et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med 2011; 364:22.
6. P Schoenfeld et al. Safety and tolerability of rifaximin for
the treatment of irritable bowel syndrome without constipation: a pooled analysis of randomised, double-blind, placebocontrolled trials. Aliment Pharmacol Ther 2014; 39:1161.
7. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2013; 55:e44.

▶

Polidocanol (Varithena) for
Varicose Veins

An injectable foam formulation of the sclerosing
agent polidocanol (Varithena – Provensis/BTG)
has been approved by the FDA for treatment of
incompetent veins and visible varicosities of the great
saphenous vein system. It is the first foam therapy to
be approved for this indication, but polidocanol and
other sclerosants have been used for years as foam
formulations compounded by physicians. Polidocanol
is also available in a liquid formulation (Asclera)
to treat smaller veins. Sodium tetradecyl sulfate
(Sotradecol) is FDA-approved in a liquid formulation
for use in sclerotherapy.
Pronunciation Key
Polidocanol: pol" i doe kay' nol
Varithena: var i thee' nuh

MECHANISM OF ACTION — Intravenous injection of
polidocanol displaces blood from the vein. The foam
attaches to the lipid cell membrane of the venous
endothelium, which leads to endothelial damage,
thrombus formation, and venous occlusion. The
occluded vein is eventually replaced by fibrous tissue.
Delivering the solution as a foam rather than a liquid
increases the surface area of the sclerosant, allowing
use of lower doses.
TREATMENT OF VARICOSE VEINS — Minimally

invasive techniques, such as ultrasound-guided foam
sclerotherapy and endovenous thermal ablation using
laser or radiofrequency energy, are now being used
more frequently. A procedure that uses an ultrasoundguided catheter to deliver an injection of cyanoacrylate
adhesive into the vein to seal it off (VenaSeal) has
recently become available. These techniques are
generally associated with faster recovery and fewer

Vol. 57 (1474)

August 3, 2015

complications than conventional surgery involving
vein ligation and stripping.1
A meta-analysis of 13 randomized controlled trials in
˃3000 patients with great saphenous varicose veins
found that ultrasound-guided foam sclerotherapy,
endovenous laser therapy, and radiofrequency
ablation were at least as effective as surgical ligation
and stripping.2 Randomized trials comparing foam
sclerotherapy, laser ablation, and radiofrequency
ablation with each other for treatment of great
saphenous varicose veins found that one-year success
rates were lowest with foam sclerotherapy.3,4
CLINICAL STUDIES — Approval of polidocanol
injectable foam 1% was based on the results of two
trials (VANISH-1 and VANISH-2), only the second
of which has been published, in 511 patients with
varicose veins who were randomized to polidocanol
0.5%, 1%, or 2% (VANISH-1), 0.5% or 1% (VANISH-2), or

0.125% (as a subtherapeutic control in both studies),
or to placebo.5 Most patients received one treatment,
but patients in VANISH-2 could receive a second
treatment 1 week later.
Improvement in patient-reported varicose vein
symptoms (heaviness, achiness, swelling, throbbing,
and itching) from baseline to week 8, the primary
endpoint, was significantly greater with polidocanol
than with placebo in both studies. A clinically
meaningful improvement in symptoms was reported by
64.7% and 75.9% of patients treated with polidocanol
1% in the 2 studies compared to 5.4% and 19.6% of
those treated with placebo. More patients treated
with polidocanol 1% also reported improvement in the
appearance of visible varicosities (54.9% and 69.0% vs
3.6% and 7.1% with placebo).
ADVERSE EFFECTS — In clinical trials, adverse effects
that occurred in more patients treated with polidocanol
foam than with placebo included thrombosis (16%),
hematoma (15%), and pain (11%) at the injection site,
leg pain (17%), venous thrombosis (8%), superficial
thrombophlebitis (5%), and deep vein thrombosis (5%).
Skin discoloration occurred rarely. Severe allergic
reactions, including fatal anaphylaxis, can occur.
Extravasation of the foam could cause necrosis,
ischemia, or gangrene. Polidocanol should not be used
during pregnancy.
Use of foam sclerosants has been associated with a
risk of intracerebral gas emboli, which can result in
neurologic adverse events, including stroke, migraine,

and visual disturbances. The risk may be lower with
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Varithena than with manually compounded foams,
which are typically nitrogen/oxygen gas mixtures
with large bubbles and wide bubble size distribution.
No clinically significant neurologic adverse events
occurred during clinical trials with Varithena, which
is a low-nitrogen oxygen/carbon dioxide mixture with
smaller bubbles and a narrow bubble size distribution.6
DOSAGE, ADMINISTRATION, AND COST — Varithena
is supplied in a pouch containing 2 canisters. One
contains a 1% polidocanol solution under a carbon
dioxide atmosphere and the other pressurized oxygen;
joining the 2 canisters activates the product, which then
has a shelf-life of 7 days. The freshly generated foam
is transferred to a syringe and injected intravenously
within 75 seconds under ultrasound guidance. Up
to 5 mL of foam can be given in one injection, with a
maximum of 15 mL per treatment session. Additional
treatments may be needed; sessions should be
separated by at least 5 days. Compression bandages
are applied after treatment and should be kept in place
for 48 hours; compression stockings should be worn
for 2 weeks. The cost for 1 pouch of Varithena that

supplies 45 mL of usable foam is $3195.7
CONCLUSION — Polidocanol injectable foam 1%
(Varithena) improves the symptoms and appearance of
varicose veins. How it compares in efficacy and safety
to physician-compounded foam or to other treatments
for varicose veins remains to be established. ■
1. P Gloviczki et al. The care of patients with varicose veins and
associated chronic venous diseases: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum. J Vasc Surg 2011; 53(5 suppl):2S.
2. C Nesbitt et al. Endovenous ablation (radiofrequency and laser)
and foam sclerotherapy versus open surgery for great saphenous
vein varices. Cochrane Database Syst Rev 2014; 7:CD005624.
3. LH Rasmussen et al. Randomized clinical trial comparing endovenous laser ablation, radiofrequency ablation, foam sclerotherapy and surgical stripping for great saphenous varicose
veins. Br J Surg 2011; 98:1079.
4. AA Biemans et al. Comparing endovenous laser ablation, foam
sclerotherapy, and conventional surgery for great saphenous
varicose veins. J Vasc Surg 2013; 58:727.
5. KL Todd 3rd et al. The VANISH-2 study: a randomized, blinded,
multicenter study to evaluate the efficacy and safety of polidocanol endovenous microfoam 0.5% and 1.0% compared with
placebo for the treatment of saphenofemoral junction incompetence. Phlebology 2014; 29:608.
6. D Carugo et al. Benefits of polidocanol endovenous microfoam
(Varithena) compared with physician-compounded foams.
Phlebology 2015 Jun 1 (epub).
7. Approximate WAC. 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. July 5, 2015. Reprinted
with permission by First Databank, Inc. All rights reserved. ©2015.
www.fdbhealth.com/policies/drug-pricing-policy.

112

Vol. 57 (1474)

August 3, 2015

IN BRIEF

Duopa – A Carbidopa/Levodopa
Enteral Suspension for Parkinson’s
Disease
The FDA has approved Duopa (Abbvie), a carbidopa/
levodopa enteral suspension, for treatment of motor
fluctuations in patients with advanced Parkinson’s
disease (PD). It has been available in Europe since 2001.
In patients with advanced PD, emptying of the stomach
may be delayed and unpredictable, which can affect the
rate and amount of absorption of carbidopa/levodopa
and its efficacy. To bypass the stomach, the new formulation is delivered through a nasojejunal (NJ) tube or
percutaneous endoscopic gastrostomy with jejunal
(PEG-J) tube.
A randomized, double-blind, active-controlled, 12-week
trial in 66 levodopa-responsive patients with advanced
PD and motor complications found that Duopa reduced
daily mean “off” time from baseline significantly more
than oral immediate-release carbidopa/levodopa (by
4.04 hours vs 2.14 hours). Mean “on” time without
troublesome dyskinesia increased by 4.11 hours with
the new formulation and by 2.24 hours with immediaterelease tablets.1
Duopa is available in a 100-mL single-use cassette
containing 4.63 mg of carbidopa and 20 mg of levodopa
per mL. It should be administered over 16 hours through
a NJ or PEG-J tube with the CADD-Legacy 1400

portable infusion pump. Patients should be switched
to oral immediate-release carbidopa/levodopa before
starting Duopa; the labeling has instructions for
conversion from immediate-release tablets to Duopa.
The maximum recommended daily dose of levodopa is
2000 mg (1 cassette/day). Patients must also take oral
immediate-release carbidopa/levodopa in the evening
after disconnecting the pump. The medication cassette
should be stored in the refrigerator and removed 20
minutes before administration.
One month's supply of Duopa costs $60542; PEG-J
tube insertion and administration-related expenses will
significantly increase the cost of treatment.3
1. CW Olanow et al. Continuous intrajejunal infusion of levodopacarbidopa intestinal gel for patients with advanced Parkinson's
disease: a randomised, controlled, double-blind, double-dummy study. Lancet Neurol 2014; 13:141.
2. Approximate WAC. 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. July
5, 2015. Reprinted with permission by First Databank, Inc. All
rights reserved. ©2015. www.fdbhealth.com/policies/drugpricing-policy.
3. F Valldeoriola et al. Cost analysis of the treatments for patients
with advanced Parkinson's disease: SCOPE study. J Med Econ
2013; 16:191.

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Review the efficacy and safety of polidocanol injectable foam (Varithena) for treatment of varicose veins.
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Review the efficacy and safety of carbidopa/levodopa enteral suspension (Duopa) for treatment of Parkinson’s disease.

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Issue 1474 Questions

(Correspond to questions #21-30 in Comprehensive Exam #73, available January 2016)
6. Initial treatment of IBS with diarrhea includes:
a. dietary modification
b. linaclotide
c. alosetron
d. all of the above

Sacubitril/Valsartan (Entresto) for Heart Failure
1. Inhibition of neprilysin:
a. decreases vasoconstriction
b. decreases sodium retention

c. decreases maladaptive remodeling
d. all of the above
2. In the PARADIGM-HF trial, the composite endpoint (first hospitalization for worsening heart failure or cardiovascular death) occurred in fewer patients treated with Entresto than with enalapril.
The absolute difference between the 2 groups was about:
a. 5%
b. 10%
c. 15%
d. 20%

7. In the two double-blind trials (TARGET 1 and 2), significantly more
patients treated with rifaximin than with placebo achieved relief
from IBS symptoms for at least 2 of the 4 weeks after treatment,
the primary endpoint. The absolute difference between the 2
groups was:
a. 5%
b. 9%
c. 16%
d. 25%
Polidocanol (Varithena) for Varicose Veins

3. Entresto can cause:
a. hypokalemia
b. hypertension
c. angioedema
d. all of the above
4. A 66-year-old man with asymptomatic (NYHA class I) heart
failure with preserved ejection fraction and cirrhosis asks if he
should take Entresto for his heart failure. You could tell him that
he cannot because:
a. his heart failure is asymptomatic

b. his ejection fraction is not reduced
c. Entresto is not recommended for patients with severe liver
impairment
d. all of the above
Rifaximin (Xifaxan) for Irritable Bowel Syndrome with Diarrhea
5. A 44-year-old woman with IBS with diarrhea complains of
diarrhea, bloating, and abdominal cramps. She asks if she should
take an antidiarrheal such as loperamide. You could tell her that:
a. she should only take loperamide as needed to reduce stool
urgency and frequency
b. she should take loperamide 4 mg every 4 hours to prevent
diarrhea
c. loperamide has been shown to improve symptoms of IBS other
than diarrhea
d. she should take alosetron instead

8. For treatment of great saphenous varicose veins, success rates
with foam sclerosants appear to be:
a. lower than those with laser ablation
b. lower than those with radiofrequency ablation
c. similar to those with surgical ligation and stripping
d. all of the above
9. In the 2 clinical trials supporting approval of Varithena (VANISH 1
and 2), about what percentage of patients reported improvement
in varicose vein symptoms at week 8?
a. 15-25%
b. 30-40%
c. 50-60%
d. 65-75%
In Brief: Duopa – A Carbidopa/Levodopa Enteral Suspension for

Parkinson’s Disease
10. In patients with advanced Parkinson’s disease, Duopa reduced
“off” time and increased “on” time compared to oral immediaterelease carbidopa/levodopa by about:
a. 30 minutes
b. 45 minutes
c. 1 hour
d. 2 hours

ACPE UPN: Per Issue Exam: 0379-0000-15-474-H01-P; Release: August 3, 2015, Expire: August 3, 2016
Comprehensive Exam 73: 0379-0000-16-073-H01-P; Release: January 2016, Expire: January 2017

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; Franco M. Muggia, M.D., New York University Medical Center; 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
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Arthur Kallet and Harold Aaron, M.D.
Copyright and Disclaimer: The Medical Letter, Inc. is an independent nonprofit organization that provides healthcare professionals with unbiased drug prescribing recommendations. The editorial
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