Rifaximin Xifaxan for Irritable Bowel Syndrome with Diarrhea ...p 107p 109 Polidocanol Varithena for Varicose Veins ...p 111 In Brief: Duopa – A Carbidopa/Levodopa Enteral Suspension for
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IN THIS ISSUE
ISSUE
1433
Volume 56
Published by The Medical Letter, Inc • A Nonprofi t Organization
ISSUE No
1474 Sacubitril/Valsartan (Entresto) for Heart Failure . Rifaximin (Xifaxan) for Irritable Bowel Syndrome with Diarrhea p 107p 109
Polidocanol (Varithena) for Varicose Veins p 111
In Brief: Duopa – A Carbidopa/Levodopa Enteral Suspension for Parkinson’s Disease p 112
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Trang 2107
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ISSUE
1433
Volume 56
ISSUE No
1474 Rifaximin (Xifaxan) for Irritable Bowel Syndrome with Diarrhea Polidocanol (Varithena) for Varicose Veins p 109p 111
In Brief: Duopa – A Carbidopa/Levodopa Enteral Suspension for Parkinson’s Disease p 112
ALSO IN THIS ISSUE
The FDA has approved Entresto (Novartis), an oral
fi xed-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 fi rst neprilysin inhibitor to become available in
the US
(Vasotec, and generics) 10 mg twice daily, both in
addition to other drugs The study was stopped early because a prespecifi ed 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
fi rst hospitalization for worsening heart failure or cardiovascular death, occurred in signifi cantly fewer patients taking the combination compared to those taking enalapril (21.8% vs 26.5%) The combination signifi cantly reduced the risk of fi rst 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
Sacubitril/Valsartan (Entresto) for
Heart Failure
▶
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
pep-tides, including natriuretic peppep-tides, 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 Angiotensin-receptor neprilysin inhibitor Formulation Sacubitril/valsartan - 24/26 mg, 49/51 mg,
97/103 mg tablets Route Oral Tmax 0.5 hrs (sacubitril); 2 hrs (LBQ657) 1 ;
1.5 hrs (valsartan) Elimination Sacubitril (52-68% urine; 37-48% feces);
Valsartan (~13% urine; 86% feces) Half-life 1.4 hrs (sacubitril); 11.5 hrs (LBQ657) 1 ;
9.9 hrs (valsartan)
1 Active metabolite of sacubitril.
Trang 3The Medical Letter ® Vol 57 (1474) August 3, 2015
Table 2 Some Drugs for Heart Failure with Reduced Ejection Fraction
Angiotensin-Converting Enzyme (ACE) Inhibitors
Captopril – generic 12.5, 25, 50, 100 mg tabs 3 6.25 mg tid 50 mg tid $151.50 Enalapril – generic 2.5, 5, 10, 20 mg tabs 2.5 mg bid 20 mg bid 39.90
Fosinopril – generic 10, 20, 40 mg tabs 3 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 2.70
Prinivil (Merck) 5, 10, 20 mg tabs 94.10
Zestril (Almatica) 2.5, 5, 10, 20, 30, 40 mg tabs 48.00 Perindopril erbumine 4 – generic 2, 4, 8 mg tabs 2 mg once/d 16 mg once/d 37.30
Quinapril – generic 5, 10, 20, 40 mg tabs 5 mg bid 20 mg bid 23.60
Ramipril – generic 1.25, 2.5, 5, 10 mg caps 1.25-2.5 mg once/d 10 mg once/d 15.80
Trandolapril – generic 1, 2, 4 mg tabs 1 mg once/d 4 mg once/d 16.20
Angiotensin Receptor Blockers (ARBs)
Azilsartan medoxomil 4 – Edarbi (Arbor) 40, 80 mg tabs 40-80 mg once/d 80 mg once/d 162.60 Candesartan cilexetil – generic 4, 8, 16, 32 mg tabs 4-8 mg once/d 32 mg once/d 103.30
Losartan 4 – generic 25, 50, 100 mg tabs 25-50 mg once/d 150 mg once/d 16.20
Valsartan – generic 40, 80, 160, 320 mg tabs 3 20-40 mg bid 160 mg bid 52.40
Beta-Adrenergic Blockers
Bisoprolol 4 – generic 5, 10 mg tabs 3 1.25 mg once/d 10 mg once/d 24.60
Carvedilol – generic 3.125, 6.25, 12.5, 25 mg tabs 3.125 mg bid 25 mg bid 14.70
Coreg (GSK) (50 mg bid for pts >85kg) 218.70
extended-release – Coreg CR 10, 20, 40, 80 mg ER caps 10 mg once/d 80 mg once/d 219.60 Metoprolol succinate ER – generic 25, 50, 100, 200 mg ER tabs 3 12.5-25 mg once/d 200 mg once/d 45.00
Aldosterone Antagonists
Eplerenone – generic 25, 50 mg tabs 25 mg once/d 5 50 mg once/d 5 104.10
Spironolactone – generic 25, 50, 100 mg tabs 3 12.5-25 mg once/d 5 25 mg once/d or bid 5 6.30
Vasodilators
Isosorbide dinitrate/hydralazine 6 –
BiDil (Arbor)7 20/37.5 mg tabs 20 mg/37.5 mg tid 40 mg/75 mg tid 528.70
Loop Diuretics
Bumetanide – generic 0.5, 1, 2 mg tabs 0.5-1 mg once/d or bid 10 mg once/d or 166.10
in divided doses Furosemide – generic 20, 40, 80 mg tabs 20-40 mg once/d or bid 600 mg once/d or 31.10
Lasix (Sanofi ) in divided doses 274.50 Torsemide – generic 5, 10, 20, 100 mg tabs 10-20 mg once/d 200 mg once/d or 54.20
Demadex (Meda) in divided doses 585.00
Digitalis Glycoside
Digoxin – generic 0.125, 0.25 mg tabs 0.125 mg once/d 0.125-0.25 mg once/d 16.70
Lanoxin (Covis) 0.0625, 0.125, 0.1875, 0.25 mg tabs or once every other day 34.80
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Blocker
Ivabradine – Corlanor (Amgen) 5, 7.5 mg tabs 2.5-5 mg bid 7.5 mg bid 375.00
Angiotensin-Receptor Neprilysin Inhibitor
Sacubitril/valsartan – Entresto (Novartis) 24/26, 49/51, 97/103 mg tabs 49/51 mg bid 8 97/103 mg bid 375.00 9
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 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
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 m 2 or for those with moderate hepatic impairment, the dose is 24/26 mg bid.
9 WAC according to the manufacturer.
Trang 4PREGNANCY — 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 fi nal 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 signifi cantly 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 fi rst-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
com-pared with enalapril on the risk of clinical progression in
surviv-ing patients with heart failure Circulation 2015; 131:54.
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
Pronunciation Key Rifaximin: rif ax' i min 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 unclassifi ed (IBS-U) The goal of treatment
is symptom control; dietary modifi cations 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 fi ber 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
Trang 5The Medical Letter ® Vol 57 (1474) August 3, 2015
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 Signifi cantly more patients taking rifaximin
(40.7% vs 31.7% with placebo) had adequate relief
from IBS symptoms for at least 2 of the fi rst 4 weeks
after treatment, the primary endpoint Adequate relief
of bloating, a secondary endpoint, was reported in
signifi cantly 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 fi rst 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 signifi cantly
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 Signifi cantly 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 fi rst repeat treatment course (38%
vs 31% with placebo) Among patients who responded
to the fi rst repeat treatment course, 17.1% of
rifaximin-treated patients and 11.7% of placebo-rifaximin-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
with placebo.6 The most common adverse effects reported in ≥2% of patients treated with the drug were
headache, nausea, and ALT increases Clostridium diffi cile-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
Alosetron 2 – generic 0.5-1 mg bid $1264.20
Lotronex (Prometheus) 1635.00 Loperamide 3 – generic 2 mg as needed 3.90 4
(max 16 mg/d)
Rifaximin – Xifaxan (Salix) 550 mg tid x 14 d 5 1176.80 6
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-pricing-policy
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 Mit-igation 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.
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
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 effi cacy and safety for treatment of IBS-D have not been established, and
it is expensive ■
Trang 61 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
id-iopathic constipation Am J Gastroenterol 2014; 109:S2.
3 L Laterza et al Rifaximin for the treatment of
diarrhoea-pre-dominant irritable bowel syndrome Expert Opin Pharmacother
2015; 16:607.
4 N Iorio et al Profi le 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
bow-el 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
constipa-tion: a pooled analysis of randomised, double-blind, placebo-
controlled 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 fi rst 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
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 signifi cantly 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%), superfi cial 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
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 fi brous 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
ultrasound-guided 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
Trang 7The Medical Letter ® Vol 57 (1474) August 3, 2015
Varithena than with manually compounded foams,
which are typically nitrogen/oxygen gas mixtures
with large bubbles and wide bubble size distribution
No clinically signifi cant 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 effi cacy 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
guide-lines of the Society for Vascular Surgery and the American
Ve-nous 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
en-dovenous laser ablation, radiofrequency ablation, foam
sclero-therapy 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 effi cacy and safety of
poli-docanol endovenous microfoam 0.5% and 1.0% compared with
placebo for the treatment of saphenofemoral junction
incom-petence Phlebology 2014; 29:608.
6 D Carugo et al Benefi ts of polidocanol endovenous microfoam
(Varithena) compared with physician-compounded foams
Phlebology 2015 Jun 1 (epub).
7 Approximate WAC WAC = wholesaler acquisition cost or
manufac-turer’s published price to wholesalers; WAC represents a published
catalogue or list price and may not represent an actual
transaction-al price Source: Antransaction-alySource® Monthly July 5, 2015 Reprinted
with permission by First Databank, Inc All rights reserved ©2015
www.fdbhealth.com/policies/drug-pricing-policy.
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 effi cacy To bypass the stomach, the new form-ulation 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 signifi cantly 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 immediate-release 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 signifi cantly increase the cost of treatment.3
1 CW Olanow et al Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease: a randomised, controlled, double-blind,
double-dum-my study Lancet Neurol 2014; 13:141
2 Approximate WAC WAC = wholesaler acquisition cost or man-ufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an ac-tual 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 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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1 Review the effi cacy and safety of sacubitril/valsartan (Entresto) for treatment of heart failure with reduced ejection fraction.
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3 Review the effi cacy and safety of polidocanol injectable foam (Varithena) for treatment of varicose veins.
4 Review the effi cacy 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 modifi cation
b linaclotide
c alosetron
d all of the above
7 In the two double-blind trials (TARGET 1 and 2), signifi cantly 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
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 immediate-release carbidopa/levodopa by about:
a 30 minutes
b 45 minutes
c 1 hour
d 2 hours
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 (fi rst
hospital-ization for worsening heart failure or cardiovascular death)
oc-curred 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%
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
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.,
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