The medical letter on drugs and therapeutics january 4 2016

1485 on Drugs and Therapeutics Naloxone Narcan Nasal Spray for Opioid Overdose ...p 1 Ambrisentan Letairis and Tadalafi l Adcirca for Pulmonary Arterial Hypertension ...p 2 Eluxadoline

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IN THIS ISSUE

ISSUE

1433

Volume 56

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

ISSUE No

1485

on Drugs and Therapeutics

Naloxone (Narcan) Nasal Spray for Opioid Overdose p 1

Ambrisentan (Letairis) and Tadalafi l (Adcirca) for Pulmonary Arterial Hypertension p 2

Eluxadoline (Viberzi) for Irritable Bowel Syndrome with Diarrhea p 4

ColciGel – A Homeopathic Colchicine Gel for Gout p 5

In Brief: New Indications for Harvoni p 6

1

on Drugs and Therapeutics

ISSUE

1433

Volume 56

ISSUE No

1485 Ambrisentan (Letairis) and Tadalafi l (Adcirca) for Pulmonary Arterial Hypertension Eluxadoline (Viberzi) for Irritable Bowel Syndrome with Diarrhea p 2p 4

ColciGel – A Homeopathic Colchicine Gel for Gout p 5

In Brief: New Indications for Harvoni p 6

ALSO IN THIS ISSUE

Naloxone (Narcan) Nasal Spray for

Opioid Overdose

▶

The recent increase in deaths due to overdose of

heroin and prescription opioids in the US has renewed

interest in the opioid antagonist naloxone, particularly

in making it available to fi rst responders and to

relatives and close friends of persons using heroin or

taking prescription opioids IV or IM administration

by healthcare professionals is preferred, but

peripheral venous access may be diffi cult to obtain

in IV drug abusers, and exposure to their blood may

be hazardous

Pronunciation Key Naloxone: nal ox’ one Narcan: nar' kan

The FDA has now approved an intranasal formulation

of naloxone (Narcan nasal spray – Adapt) for

emergency treatment of opioid overdose It is the fi rst

nasal spray to be approved for this indication, but

naloxone solution has been administered intranasally

off-label, using a mucosal atomizer device.1 The drug

also recently became available in an auto-injector

formulation (Evzio) for IM or SC administration.2

PHARMACOLOGY — Naloxone is a competitive

mu-opioid receptor antagonist in the brain and has no

opioid agonist effects In opioid overdose, naloxone

begins to reverse sedation, respiratory depression, and

hypotension within 1-2 minutes after IV

administra-tion, 2-5 minutes after IM or SC administraadministra-tion, and

8-13 minutes after intranasal administration

The half-life of naloxone is much shorter than that

of most opioids and repeated administration may be necessary, especially for overdose with a long-acting opioid agonist such as methadone or a sustained-release formulation of a short-acting agonist such as oxycodone.3 Pure heroin is an exception, with a half-life of only 2-6 minutes, but other drugs used to "cut" heroin may have longer half-lives

CLINICAL STUDIES — No new clinical trials were

required for FDA approval of Narcan nasal spray An

unpublished pharmacokinetic study (summarized

in the package insert) in 30 healthy adults compared intranasal naloxone 4 mg (one dose) and

8 mg (two doses) with 0.4 mg of naloxone given

Table 1 Pharmacology

Class Opioid antagonist

Formulation 4 mg in 0.1 mL nasal spray

Route Intranasal

Tmax 20-30 minutes

Half-life ~2 hours

Table 2 Some Naloxone Formulations Drug Formulation Usual Dosage Cost 1

Parenteral

generic 0.4 mg/mL vials 0.4-2 mg IV, $17.40 3

and syringes; IM, or SC 2

1 mg/mL syringes

Evzio (Kaleo) 0.4 mg/0.4 mL 0.4 mg IM or SC 4 375.00 5

prefi lled auto- injector

Intranasal

Narcan nasal 4 mg/0.1 mL 4 mg intranasally 4 62.50 6,7

spray (Adapt) nasal spray

1 Approximate WAC for a single dose at the lowest usual dosage WAC = wholesaler acquisition cost or manufacturer’s published price to whole-salers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly December 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/ policies/drug-pricing-policy

2 Dose can be repeated every 2-3 minutes up to a total of 10 mg.

3 Cost for a 1-mL vial.

4 Dose can be repeated every 2-3 minutes until the patient responds or emergency medical personnel arrive

5 Cost for one injector, but supplied in packages containing 2 auto-injectors.

6 Cost for one nasal spray device, but supplied in cartons containing 2 nasal spray devices.

7 Available from the manufacturer at a discounted price of $37.50 per 4 mg nasal spray device to law enforcement, fi refi ghters, fi rst responders, departments of health, local school districts, colleges and universities, and community-based organizations

Note: A clarifi cation to this article has been published

The Medical Letter ® Vol 58 (1485) January 4, 2016

intramuscularly Intranasal administration of either

1 or 2 doses resulted in serum concentrations

higher than those achieved with a single dose

of the IM formulation The time to reach peak

serum concentrations was similar with intranasal

administration and IM injection (20 minutes with

2 doses of the intranasal formulation, 23 minutes

with IM administration, and 30 minutes with a single

intranasal dose)

ADVERSE EFFECTS — Whether naloxone itself has

any toxicity is unclear, but it can precipitate acute

withdrawal symptoms in opioid-dependent patients

Acute opioid withdrawal is associated with anxiety,

piloerection, yawning, sneezing, rhinorrhea, nausea,

vomiting, diarrhea, and abdominal or muscle cramps,

which are uncomfortable but generally not

life-threatening, except in neonates

In the pharmacokinetic study, the most common

adverse effects of intranasal naloxone were increased

blood pressure, musculoskeletal pain, headache,

and intranasal effects including dryness, edema,

congestion, and inflammation

PREGNANCY — No embryotoxic or teratogenic effects

were observed in mice and rats treated with large

doses of naloxone Naloxone does cross the placenta,

however, and may cause fetal opioid withdrawal

DOSAGE AND ADMINISTRATION — Narcan nasal

spray is supplied in cartons containing two

4 mg/0.1 mL single-use nasal spray devices The

recommended dosage for adults and children is

4 mg administered as a single spray into one nostril

Additional doses can be given every 2 to 3 minutes in

alternating nostrils using a new nasal spray device

for each dose

No assembly or priming of the device is required

Caregivers should be instructed to call emergency

medical personnel immediately after the fi rst dose of

Narcan nasal spray is given

CONCLUSION — Naloxone (Narcan) nasal spray is a

needle-free alternative to injectable formulations of

the drug that can be administered by fi rst responders

or family members for emergency treatment of

life-threatening opioid overdose ■

1 Intranasal naloxone for treatment of opioid overdose Med Lett

Drugs Ther 2014; 56:21.

2 In brief: a naloxone auto-injector (Evzio) Med Lett Drugs Ther

2014; 56:45.

3 EW Boyer Management of opioid analgesic overdose N Engl J

Med 2012; 367:146.

Ambrisentan (Letairis) and Tadalafi l

(Adcirca) for Pulmonary Arterial

Hypertension

▶

The FDA has approved the use of ambrisentan

(Letairis) and tadalafi l (Adcirca) together for treatment

of pulmonary arterial hypertension (PAH) It is the fi rst 2-drug regimen to be approved for this indication

Pronunciation Key Ambrisentan: am" bri sen' tan Letairis: le tair' is

Tadalafi l: ta da' la fi l Adcirca: ad sur' kuh

TREATMENT OF PAH — Monotherapy with an oral drug

is usually recommended for initial treatment of PAH Drugs approved by the FDA for this indication include phosphodiesterase-5 (PDE5) inhibitors, endothelin receptor antagonists, and a guanylate cyclase

stimulator.1 Patients with more advanced disease may

be treated with a prostacyclin (see Table 2) The FDA recently approved the oral selective IP prostacyclin

receptor agonist selexipag (Uptravi) for treatment of

PAH; it will be reviewed in a future issue

Combination Therapy – Limited data are available on

the effectiveness of combination therapy for initial treatment of PAH.2 Current US guidelines recommend treatment with two or more classes of PAH drugs only when the response is inadequate or the patient deteriorates on monotherapy, but recently published European guidelines include recommendations for initial combination therapy.3,4

CLINICAL STUDY — In a randomized, double-blind trial (AMBITION), treatment-naive patients with WHO functional class II or III symptoms of PAH were treated with ambrisentan plus tadalafi l (n=253), ambrisentan alone (n=126), or tadalafi l alone (n=121) Doses were titrated to a target of 10 mg once daily for ambrisentan and 40 mg once daily for tadalafi l The mean duration

of study medication use was 517 days

Table 1 AMBITION Trial Results 1

Ambrisentan/

Effi cacy Endpoint Tadalafi l Ambrisentan Tadalafi l

Clinical failure 2 18% 34% 28%

Change in 6-minute +49 meters +27 meters +23 meters walk distance 3

Satisfactory clinical 39% 31% (NS) 27%

response 4

NS = Difference not signifi cant vs combination therapy

1 N Galiè et al N Engl J Med 2015; 373:834.

2 First occurrence of death, hospitalization for worsening PAH, disease progression, or unsatisfactory long-term clinical response (the composite primary endpoint).

3 Median change from baseline to week 24 in 6-minute walk distance (a secondary endpoint).

4 Increase of 10% from baseline in 6-minute walk distance, reduction of symptoms to, or maintenance of, WHO functional class I or II, and no wors-ening of clinical condition at week 24 (a secondary endpoint).

Dual therapy signifi cantly reduced the risk of a

fi rst event of clinical failure, the primary endpoint,

compared to either drug alone (see Table 1) The

reduced risk was primarily due to a lower rate of

hospitalization for worsening PAH in patients treated

with both ambrisentan and tadalafi l (4% vs 14% with

ambrisentan alone and 10% with tadalafi l alone)

Decreases in levels of N-terminal pro-brain

natriuretic peptide (NT-proBNP), a biomarker of

right-sided heart failure and death, were

signifi-cantly greater with dual therapy than with the

monotherapies from baseline to week 24 There were

no significant differences between groups in change

in WHO functional class.5

ADVERSE EFFECTS — Adverse effects reported with

the two drugs together were similar to those with

the individual drugs Peripheral edema, headache,

nasal congestion, cough, anemia, dyspepsia, and

bronchitis occurred more often with the two drugs

together than with either drug alone

PREGNANCY — Ambrisentan can cause fetal harm

and is contraindicated for use during pregnancy It is only available for women through a Risk Evaluation and Mitigation Strategy (REMS) program Tadalafi l is classifi ed as category B (no evidence of fetal harm) for use during pregnancy

DOSAGE — The starting dosages of the two drugs when they are used together are ambrisentan 5 mg and tadalafi l 20 mg once daily The doses can be in-creased at 4-week intervals as needed and tolerated

to 10 mg for ambrisentan and 40 mg for tadalafi l

CONCLUSION — Use of the endothelin receptor

antagonist ambrisentan (Letairis) and the phospho-diesterase-5 (PDE5) inhibitor tadalafi l (Adcirca)

together in treatment-naive patients with symptomatic pulmonary arterial hypertension (PAH) improved clinical outcomes and exercise capacity compared

to monotherapy with either drug Data are limited on the effectiveness of using other drug combinations for initial treatment of PAH ■

Table 2 Some Drugs for Treatment of Pulmonary Arterial Hypertension

Soluble Guanylate Cyclase (sGC) Stimulator

Riociguat – Adempas (Bayer) Oral 0.5, 1, 1.5, 2, 2.5 mg tabs 1-2.5 mg tid $8188.50

Endothelin Receptor Antagonists

Ambrisentan – Letairis (Gilead) Oral 5, 10 mg tabs 5-10 mg once/d 7368.90

Bosentan – Tracleer (Actelion) Oral 62.5, 125 mg tabs 62.5 mg bid for 4 wks, then 125 mg bid 2 8220.00

Macitentan – Opsumit (Actelion) Oral 10 mg tabs 10 mg once/d 7185.00

Phosphodiesterase-5 (PDE5) Inhibitors

Sildenafi l – generic Oral 20 mg tabs 20 mg tid 117.80

Tadalafi l – Adcirca (Lilly) Oral 20 mg tabs 40 mg once/d 2749.80

Prostacyclins

Epoprostenol – generic IV 0.5, 1.5 mg in 10 mL 20-40 ng/kg/min continuous 1603.90 5

Flolan (GSK) 0.5, 1.5 mg in 17 mL 1850.70 5

single-dose vials

Iloprost – Ventavis (Actelion) Inhalation 10, 20 mcg/mL ampules 2.5-5 mcg/inhalation 6-9 times/d 19,260.00 6

Treprostinil – Orenitram Oral 0.125, 0.25, 1, 2.5 mg 0.25-21 mg bid 7 11,700.00 8

(United Therapeutics) ER tabs

Remodulin SC or IV 1, 2.5, 5, 10 mg/mL 40-160 ng/kg/min continuous 7130.60 5

(United Therapeutics) multidose vials infusion 9

Tyvaso (United Therapeutics) Inhalation 1.74 mg/2.9 mL ampules 9 breaths (54 mcg) qid 10 13,650.00 11

1 Approximate WAC for 30 days’ treatment at the lowest usual 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 December 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy.

2 Initial and maintenance dosage for patients <40 kg and >12 years old is 62.5 mg bid.

3 Also available in an IV formulation for patients on oral sildenafi l who are temporarily unable to take oral medication, and in a powder for oral suspension.

4 Initial dosage is 2 ng/kg/min with subsequent increases of 1-2 ng/kg/min every 15 minutes or longer as tolerated Average dosage after 6 months is about 20-40 ng/kg/min

5 Approximate WAC for a 70-kg patient

6 Approximate WAC for 180 ampules of either strength.

7 The initial dosage is 0.25 mg bid or 0.125 tid with food, with subsequent increases of 0.25 or 0.5 mg bid or 0.125 mg tid every 3-4 days if tolerated Average dose after 12 weeks in a clinical trial was 3.4 mg bid Maximum doses studied have been 12 mg bid (in a 12-week blinded study) and 21 mg bid (in a long-term open-label study).

8 Approximate WAC for a dose of 5 mg bid for 30 days.

9 Initial dosage is 1.25 ng/kg/min, or half if poorly tolerated, with subsequent increases of 1.25 ng/kg/min weekly for the fi rst 4 weeks, then 2.5 ng/kg/min weekly thereafter Average dosage after 9 months is about 60 ng/kg/min

10 Initial dosage is 3 breaths (18 mcg) 4 times daily, or 1-2 breaths if poorly tolerated then increasing to 3 breaths The dosage should be increased by an additional 3 breaths at 1-2 week intervals as tolerated The target and maximum dosage is 9 breaths (54 mcg) 4 times daily.

11 Approximate WAC for 7 foil pouches containing 4 ampules each.

The Medical Letter ® Vol 58 (1485) January 4, 2016

Eluxadoline (Viberzi) for Irritable

Bowel Syndrome with Diarrhea

▶

The FDA has approved eluxadoline (Viberzi – Actavis),

a mu-opioid receptor agonist and delta-opioid

receptor antagonist, for oral treatment of adults with

irritable bowel syndrome with diarrhea (IBS-D)

Pronunciation Key Eluxadoline: el ux ad' oh leen Viberzi: vye ber' zee

IBS — Symptoms of IBS can include abdominal pain,

bloating, flatulence, diarrhea, and constipation IBS

is subtyped, according to the predominant bowel

symptom, as IBS-D, IBS with constipation (IBS-C),

mixed-type (IBS-M), or unclassifi ed (IBS-U)

SOME DRUGS FOR IBS-D — The goal of IBS treatment

is symptom control; dietary modifi cations may help

improve symptoms of all subtypes of the disorder

For patients with IBS-D, antidiarrheals such as

loperamide (Imodium A-D, and others) taken as

needed may reduce stool urgency and frequency

In short-term clinical trials, the minimally absorbed

antibiotic rifaximin (Xifaxan) was modestly more

effective than placebo in relieving symptoms of IBS-D,

but relapse was common Alosetron (Lotronex, and

generics), a serotonin (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 serious GI

adverse effects such as ischemic colitis.1

MECHANISM OF ACTION — Eluxadoline stimulates

mu-opioid receptors in the GI tract, leading to

decreased muscle contractility, inhibition of water and

electrolyte secretion, and increased rectal sphincter

Table 1 Pharmacology

Class Mu-opioid agonist, delta-opioid antagonist Route Oral

Formulation 75, 100 mg tablets Metabolism Not established Excretion Feces (82.2%); urine (<1%) Half-life (terminal) 3.7-6 hours

1 Riociguat (Adempas) for pulmonary hypertension Med Lett

Drugs Ther 2014; 56:17.

2 G Ruiz et al Combination therapy in pulmonary arterial

hyper-tension: is this the new standard of care? Am J Manag Care

2015; 21:s151.

3 DB Taichman et al Pharmacologic therapy for pulmonary

arte-rial hypertension in adults: CHEST guideline and expert panel

report Chest 2014; 146:449.

4 N Galiè et al 2015 ESC/ERS Guidelines for the diagnosis and

treatment of pulmonary hypertension: The Joint Task Force for

the Diagnosis and Treatment of Pulmonary Hypertension of the

European Society of Cardiology (ESC) and the European

Re-spiratory Society (ERS) endorsed by: Assoication for European

Paediatric and Congenital Cardiology (AEPC), International

So-ciety for Heart and Lung Transplantation (ISHLT) Eur Heart J

2015 Aug 29 (epub).

5 N Galiè et al Initial use of ambrisentan plus tadalafi l in

pulmo-nary arterial hypertension N Engl J Med 2015; 373:834.

tone It also acts as an antagonist at delta-opioid receptors in the gut, which may reduce the risk of iatrogenic constipation and abdominal pain.2   Systemic absorption of the drug is minimal at therapeutic doses

CLINICAL STUDIES — FDA approval of eluxadoline

was based on two unpublished, double-blind trials (summarized in the package insert) in a total of 2428 patients with IBS-D Patients were randomized to receive eluxadoline 75 or 100 mg or placebo twice daily

In both trials, the composite response rate at week 12 (defi ned as a ≥30% improvement in abdominal pain score and an improvement in stool consistency from baseline on ≥50% of treatment days) was signifi cantly higher with eluxadoline 75 mg (24% and 29%) and

100 mg (25% and 30%) than with placebo (17% and 16%) Statistically signifi cant improvements in composite response rates persisted through 26 weeks

of treatment with the 100-mg dose in both trials and with the 75-mg dose in one trial

ADVERSE EFFECTS — In clinical trials, adverse effects

occurring in ≥5% of patients taking eluxadoline

100 mg twice daily and more frequently than with placebo included constipation, nausea, abdominal pain, and upper respiratory tract infection Sphincter

of Oddi spasm and pancreatitis each occurred in

<1% of patients, but those considered at risk for pancreatitis were excluded from the clinical trials Eluxadoline is contraindicated in patients with known or suspected biliary duct, pancreatic duct,

or GI tract obstruction, sphincter of Oddi disease

or dysfunction, severe hepatic impairment (Child-Pugh C), alcohol abuse (including patients who consume >3 servings of alcohol per day), or a history

of pancreatitis, structural pancreatic disease, or chronic or severe constipation

ABUSE POTENTIAL — Eluxadoline is classifi ed as a

schedule IV controlled substance.3 In two unpublished abuse potential studies in recreational drug users (summarized in the package insert), supratherapeutic oral and intranasal doses of eluxadoline were more likely than placebo, but less likely than oxycodone, to induce euphoria

STANDARD TREATMENT — An oral nonsteroidal

anti-inflammatory drug (NSAID) can successfully treat acute gout flares in most patients Those with contraindications to NSAIDs, such as renal disease or peptic ulcer disease, can be treated with colchicine Short courses of an oral or parenteral corticosteroid such as prednisone or methylprednisolone are also effective for treatment of acute flares Intra-articular injection of methylprednisolone or triamcinolone is also considered effective, but randomized controlled trials are lacking Prophylaxis with oral colchicine or an NSAID can prevent acute gout flares associated with initiation of urate-lowering therapy.2

HOMEOPATHIC DRUGS — There is no convincing

evidence that any homeopathic drug is more effective than placebo for the treatment of any disease The FDA regulates the manufacturing, marketing, and sales of homeopathic drugs and requires that those indicated for treatment of “conditions not amenable

to over-the-counter use” be made available only

by prescription; it does not, however, evaluate their effi cacy or safety.3

Table 2 Some Drugs for IBS with Diarrhea

Alosetron 2 – generic 0.5-1 mg bid $1264.20

Lotronex (Prometheus) 1635.30

Eluxadoline – Viberzi (Actavis) 100 mg bid3 960.00

Rifaximin – Xifaxan (Salix) 550 mg tid x 14 d 4 1176.80 5

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 a published catalogue or list price and

may not represent an actual transactional price Source: AnalySource®

Monthly December 5, 2015 Reprinted with permission by First Databank,

Inc All rights reserved ©2015

www.fdbhealth.com/policies/drug-pric-ing-policy

2 Only FDA-approved for use in women with severe IBS-D that has not

responded to conventional therapy

3 The recommended dosage is 75 mg bid for patients who cannot tolerate

the usual dosage, do not have a gallbladder, are receiving concomitant

treatment with an OATP1B1 inhibitor, or have mild to moderate hepatic

impairment (Child-Pugh A/B).

4 Can be repeated up to 2 times if symptoms recur.

5 Cost for one 14-day treatment course.

PREGNANCY — Eluxadoline has not been studied in

pregnant women Supratherapeutic doses of the drug

did not affect prenatal or postnatal development in rats

DRUG INTERACTIONS — Coadministration of

elux-adoline and other drugs that reduce GI motility, such

as anticholinergics or systemically active opioids,

could result in additive effects and should be avoided

Loperamide can be administered with eluxadoline for

acute treatment of severe diarrhea, but it should be

discontinued if constipation occurs

Eluxadoline is a substrate of organic anion

trans-porting polypeptide (OATP) 1B1 and an inhibitor

of OATP1B1 and breast cancer resistance protein

(BCRP).4 Drugs that are substrates of both transporters

such as rosuvastatin (Crestor) should be administered

at the lowest effective dose if taken with eluxadoline

Whether eluxadoline is a substrate or inhibitor of

CYP or P-glycoprotein in the gut is not established

The package insert states that strong CYP inhibitors

eluxadoline might increase serum concentrations of

CYP3A substrates.5

DOSAGE AND ADMINISTRATION — The recommended

dosage of eluxadoline is 100 mg taken twice daily

with food The dosage should be reduced to 75 mg

twice daily in patients who cannot tolerate the

100-mg dose, do not have a gallbladder, have mild or

moderate hepatic impairment (Child-Pugh A/B), or are

concomitantly taking an OATP1B1 inhibitor, such as

cyclosporine If a dose is missed, it should be skipped

If severe constipation occurs for >4 days, eluxadoline

should be discontinued Patients should be cautioned

to avoid chronic or acute excessive alcohol use (>3

servings per day) while taking the drug

CONCLUSION — The oral mu-opioid receptor agonist/

delta-opioid receptor antagonist eluxadoline (Viberzi)

does not appear to be much more effective than placebo

in improving symptoms of irritable bowel syndrome with diarrhea Eluxadoline can cause pancreatitis, and

it is expensive ■

1 Rifaximin (Xifaxan) for irritable bowel syndrome with diarrhea Med Lett Drugs Ther 2015; 57:109.

2 J Nee et al Novel therapies in IBS-D treatment Curr Treat Op-tions Gastro 2015; 13:432.

3 Drug Enforcement Administration, DOJ Schedules of con-trolled substances: placement of eluxadoline into schedule IV Final rule Fed Regist 2015; 80:69861.

4 JM Davenport et al Effect of uptake transporters OAT3 and OATP1B1 and efflux transporter MRP2 on the pharmacokinet-ics of eluxadoline J Clin Pharmacol 2015; 55:534.

5 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2013; 55:e44.

ColciGel – A Homeopathic

Colchicine Gel for Gout

▶

Pronunciation Key

ColciGel: kul' see jel

Homeopathic drugs characteristically consist of very large dilutions of "proven" substances Serial dilutions

ColciGel (Gensco), a prescription homeopathic

gel containing a 10,000-fold dilution of colchicine (colchicinum 4X), is now being marketed for topical treatment and prophylaxis of gout

The Medical Letter ® Vol 58 (1485) January 4, 2016

IN BRIEF

New Indications for Harvoni

Harvoni, a once-daily fi xed-dose combination of the

direct-acting antiviral agents ledipasvir and sofosbuvir approved by the FDA in 2014 for treatment of hepatitis

C virus (HCV) genotype 1 infection,1 has now been approved for use in patients infected with HCV genotype

4, 5, or 6, and in patients co-infected with HCV and HIV-1

A 12-week course of treatment with Harvoni plus ribavirin

has also been approved as an alternative to 24 weeks

of Harvoni alone for treatment-experienced, cirrhotic

patients with HCV genotype 1 infection

HCV genotypes 4, 5, and 6 are responsible for <2% of HCV

cases in the US and Canada They are more prevalent in the Middle East, North Africa, and Central sub-Saharan Africa (genotype 4), Southern sub-Saharan Africa (genotype 5), and Southeast Asia (genotype 6).2

In two open-label trials (both summarized in the package insert), 44 patients infected with HCV genotype 4, 41 patients with genotype 5, and 25 patients with genotype

6 received 12 weeks of treatment with ledipasvir/ sofosbuvir.3 The rates of sustained virologic response 12 weeks after stopping treatment (SVR12) were 93%, 93%, and 96% in patients infected with HCV genotypes 4, 5, and

6, respectively

In a single-arm trial (ION-4), 335 patients co-infected

with HIV-1 and HCV genotype 1 (98%) or 4 (2%) received

12 weeks of treatment with ledipasvir/sofosbuvir An SVR12 was achieved in 322 patients (96%), including 94% of 67 cirrhotic patients and 97% of 185 treatment-experienced patients.4

In a randomized, double-blind trial (SIRIUS), 154

treatment-experienced patients with HCV genotype 1 infection and cirrhosis who had not responded to

peg-interferon plus ribavirin with and without a protease inhibitor received either ledipasvir/sofosbuvir plus ribavirin 1000-1200 mg daily for 12 weeks or ledipasvir/ sofosbuvir without ribavirin for 24 weeks An SVR12 was achieved in 74 of 77 patients (96%) in the 12-week arm and in 75 of 77 patients (97%) in the 24-week arm.5

1 A combination of ledipasvir and sofosbuvir (Harvoni) for hepatitis

C Med Lett Drugs Ther 2014; 56:111.

2 JP Messina et al Global distribution and prevalence of hepatitis C virus genotypes Hepatology 2015; 61:77.

3 EJ Gane et al Effi cacy of ledipasvir and sofosbuvir, with or without ribavirin, for 12 weeks in patients with HCV genotype 3 or 6 infec-tion Gastroenterology 2015; 149:1454.

4 S Naggie et al Ledipasvir and sofosbuvir for HCV in patients coin-fected with HIV-1 N Engl J Med 2015; 373:705.

5 M Bourlière et al Ledipasvir-sofosbuvir with or without ribavirin

to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to previous protease-inhibitor therapy: a randomised, double-blind, phase 2 trial (SIRIUS) Lancet Infect Dis 2015; 15:397.

THE NEW FORMULATION — A single 0.25-mL dose

of ColciGel contains 5 mcg of colchicine In an

unpublished pharmacokinetic study in 6 healthy

volunteers (summarized in the package insert),

systemic absorption of colchicine after topical

application of the gel was minimal No clinical trials

evaluating the effi cacy of ColciGel are available.

ADVERSE EFFECTS — The most commonly reported

adverse effect of ColciGel has been skin irritation at

the application site

DOSAGE, ADMINISTRATION, AND COST — Each

actuation of ColciGel delivers 0.25 mL of gel, enough

to cover 4 square inches of skin The dosage

recommended in the labeling for treatment of gout is

2 to 4 actuations applied to the affected area at the

fi rst sign of a flare, and then every hour as needed

(maximum 16 actuations/24 hours) For prophylaxis

of gout flares, the recommended dosage is 1 to 3

actuations applied twice daily ColciGel is supplied by

specialty pharmacies listed on the product website

The cost for a package containing two 15-mL bottles

(120 actuations) is $631.20.4

CONCLUSION — Homeopathic drugs, even if they

require a prescription and are accompanied by a

package insert, are not reviewed or approved by the

FDA, and none has been shown unequivocally to be

more effective than placebo for the treatment of any

disease There is no evidence that ColciGel is effective

for treatment or prophylaxis of gout ■

1 Homeopathic products Med Lett Drugs Ther 1999; 41:20.

2 Drugs for gout Med Lett Drugs Ther 2014; 56:22.

3 FDA CPG Sec 400.400 Conditions under which homeopathic

drugs may be marketed Available at: www.fda.gov/ICECI/

ComplianceManuals/CompliancePolicyGuidanceManual/

ucm074360.htm Accessed December 21, 2015.

4 Approximate wholesale acquisition cost (WAC) WAC =

whole-saler 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 December 5, 2015 Reprinted

with permission by First Databank, Inc All rights reserved

©2015 www.fdbhealth.com/policies/drug-pricing-policy.

2015 Year-End Index

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32

on Drugs and Therapeutics

Clarifi cation: Half-Life of Heroin

A reader expressed concern that a statement in our article

Naloxone (Narcan) Nasal Spray for Opioid Overdose (Med

Lett Drugs Ther 2016; 58:1) might be misleading We

stated that heroin has a half-life of 2-6 minutes, which is

correct, but heroin is a prodrug that is rapidly metabolized

to 6-acetylmorphine and morphine The risk of respiratory

depression is related to those active metabolites, and it may

persist well beyond the clearance of heroin from the blood.

PRESIDENT: Mark Abramowicz, M.D.; VICE PRESIDENT AND EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR IN CHIEF: Jean-Marie Pflomm,

Pharm.D.; ASSOCIATE EDITORS: Susan M Daron, Pharm.D., Amy Faucard, MLS, Corinne Z Morrison, Pharm.D., Michael P Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M Shah,

Pharm.D., F Peter Swanson, M.D

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; David N Juurlink, BPhm, M.D., Ph.D.,

Sunnybrook Health Sciences Centre; Richard B Kim, M.D., University of Western Ontario; 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

EXECUTIVE DIRECTOR OF SALES: Gene Carbona; FULFILLMENT AND SYSTEMS MANAGER: Cristine Romatowski; EXECUTIVE DIRECTOR OF MARKETING AND 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 prior permission in writing The editors do not warrant that all the material in this publication is accurate and complete in every respect The editors shall not be held responsible for any damage resulting from any error, inaccuracy, or omission.

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

1 Discuss the potential advantages and disadvantages of naloxone (Narcan) nasal spray compared to other naloxone formulations for treatment of opioid overdose.

2 Review the effi cacy and safety of combined use of ambrisentan (Letairis) and tadalafi l (Adcirca) for treatment of pulmonary arterial hypertension.

3 Review the effi cacy and safety of eluxadoline (Viberzi) for treatment of irritable bowel syndrome with diarrhea.

4 Review the effi cacy and safety of homeopathic colchicine gel (ColciGel) for treatment and prophylaxis of gout flares.

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Issue 1485 Questions

(Correspond to questions #1-10 in Comprehensive Exam #74, available July 2016)

Eluxadoline (Viberzi) for Irritable Bowel Syndrome with Diarrhea

6 In double-blind trials, the placebo-corrected composite response rate at week 12 with eluxadoline 100 mg in patients with IBS-D was about:

a 8-14%

b 14-20%

c 20-26%

d 26-32%

7 Which of the following statements about the abuse potential of eluxadoline is true?

a It is classifi ed as a schedule V controlled substance.

b Supratherapeutic oral doses of eluxadoline were more likely than placebo to induce euphoria.

c Its antagonistic effects at delta-opioid receptors prevent induction of euphoria with intranasal administration.

d All of the above are true.

8 Which of the following is a contraindication for use of eluxadoline?

a severe hepatic impairment

b history of pancreatitis

c sphincter of Oddi disease or dysfunction

d all of the above

ColciGel – A Homeopathic Colchicine Gel for Gout

9 Which of the following statements about regulation of homeopathic products in the US is true?

a They are considered dietary supplements.

b Some are available only by prescription.

c Their effi cacy is evaluated by the FDA.

d They cannot be marketed for treatment of specifi c diseases.

10 A 38-year-old man with peptic ulcer disease develops an acute gout flare in his right great toe It would be reasonable to treat him with oral:

a meloxicam

b allopurinol

c colchicine

d acetaminophen

Naloxone (Narcan) Nasal Spray for Opioid Overdose

1 In opioid overdose, how soon after intranasal administration of

naloxone does reversal of sedation, respiratory depression, and

hypotension begin?

a 1-2 minutes

b 2-5 minutes

c 6-8 minutes

d 8-13 minutes

2 Use of intranasal naloxone may cause:

a acute opioid withdrawal

b intranasal dryness

c intranasal edema

d all of the above

3 A 19-year-old college student calls you because his roommate

had taken several tablets of oxycodone and was unarousable,

but he administered intranasal naloxone, and the roommate

woke up He asks whether there is anything else he should do

You should tell him that:

a it is now safe for his roommate to go to sleep

b naloxone is longer-acting than oxycodone, so as long as

the roommate does not take any more oxycodone, nothing

else needs to be done

c oxycodone may last longer than naloxone in the

roommate’s blood, so more treatment could be necessary,

and he should call emergency medical personnel

d naloxone itself can depress respiration, so he should sit up

with his roommate and monitor his breathing

Ambrisentan (Letairis) and Tadalafi l (Adcirca) for Pulmonary

Arterial Hypertension

4 In patients with PAH, compared to monotherapy with either

drug, ambrisentan and tadalafi l together:

a decreased the rate of clinical failure

b decreased the rate of hospitalization for worsening PAH

c increased the 6-minute walk distance

d all of the above

5 Ambrisentan and tadalafi l together have been shown to be

more effective for initial treatment of PAH than:

a bosentan plus sildenafi l

b ambrisentan plus sildenafi l

c ambrisentan alone

d all of the above

ACPE UPN: Per Issue Exam: 0379-0000-16-485-H01-P; Release: January 4, 2016, Expire: January 4, 2017 Comprehensive Exam 74: 0379-0000-16-074-H01-P; Release: July 2016, Expire: July 2017

PRESIDENT: Mark Abramowicz, M.D.; VICE PRESIDENT/EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR-IN-CHIEF: 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; David N Juurlink, BPhm, M.D., Ph.D.,

Sunnybrook Health Sciences Centre; Richard B Kim, M.D., University of Western Ontario; 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

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 prior permission in writing The editors do not warrant that all the material in this publication is accurate and complete in every respect The editors shall not be held responsible for any damage resulting from any error, inaccuracy, or omission.

Subscription Services

Address: Customer Service: Permissions: Subscriptions (US): Site License Inquiries:

The Medical Letter, Inc Call: 800-211-2769 or 914-235-0500 To reproduce any portion of this issue, 1 year - $129; 2 years - $232; E-mail: info@medicalletter.org

145 Huguenot St Ste 312 Fax: 914-632-1733 please e-mail your request to: 3 years - $345 $65 per year Call: 800-211-2769 ext 315 New Rochelle, NY 10801-7537 E-mail: custserv@medicalletter.org permissions@medicalletter.org for students, interns, residents, and Special rates available for bulk www.medicalletter.org fellows in the US and Canada subscriptions.

Reprints - $12 each