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On Drugs and Therapeutics Published by The Medical Letter, Inc • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofi t Publication

Simeprevir (Olysio) for Chronic Hepatitis C p 1

New Oral Anticoagulants for Acute Venous Thromboembolism p 3

In Brief: Khedezla — A New Brand of Desvenlafaxine p 4

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On Drugs and Therapeutics Published by The Medical Letter, Inc • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofi t Publication

January 6, 2014

Take CME exams

ALSO IN THIS ISSUE

2013 Year-End Index

For an electronic copy of the 2013 index, go to:

www.medicalletter.org/downloads/tmlindex2013.pdf

New Oral Anticoagulants for Acute Venous

Thromboembolism p 3

In Brief: Khedezla — A New Brand of

Desvenlafaxine p 4

The FDA has recently approved 2 new drugs for

treat-ment of chronic hepatitis C virus (HCV) infection

Simeprevir (Olysio – Janssen) is the third oral

pro-tease inhibitor to be approved for use in combination

with peginterferon and ribavirin for treatment of chronic

HCV genotype 1 infection in adults with compensated

liver disease Telaprevir (Incivek) and boceprevir

(Vic-trelis) were approved in 2011 for the same indication

Sofosbuvir (Sovaldi – Gilead), a nucleotide analog

polymerase inhibitor that has been approved for use

with and without interferon for treatment of multiple

HCV genotypes, will be reviewed in the next issue of

The Medical Letter

Simeprevir (Olysio) for Chronic

Hepatitis C

Table 1 Pharmacology

Class NS3/4A protease inhibitor

Route Oral

Formulation 150 mg capsules

Distribution >99.9% protein bound

Metabolism Hepatic, primarily CYP3A

STANDARD THERAPY — For many years, the

stan-dard therapy for chronic HCV genotype 1 infection (the

most common genotype in the US and Europe) was

48 weeks of subcutaneously-injected pegylated

inter-feron alfa and oral ribavirin This combination usually

Table 2 Protease Inhibitors for Chronic Hepatitis C Genotype 1 Infection

Telaprevir – 750 mg tid $66,155.10

Incivek (Vertex)2 PO x 12 wks 3 Boceprevir – 800 mg tid 36,506.20 5

Victrelis (Merck)4 PO x 24-44 wks 3 Simeprevir – 150 mg once/day 66,360.00

Olysio (Janssen)6 PO x 12 wks 3

1 Approximate wholesale acquisition cost (WAC) for 12 weeks’ treatment Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) December 5, 2013 Reprinted with permission by FDB, Inc All rights reserved

©2013 www.fdbhealth.com/policies/drug-pricing-policy Actual retail prices may be higher Cost of peginterferon and ribavirin is not included.

2 Available as a 375-mg tablet Must be taken with food (not low fat).

3 Given in combination with peginterferon and ribavirin (PR) PR treatment duration should be based on patient response with boceprevir (28, 36, or 48 weeks [includes 4 weeks of peginterferon and ribavirin before starting bo-ceprevir]) and telaprevir (24 or 48 weeks); treatment duration with simeprevir

is 24 or 48 weeks depending on baseline characteristics of patients.

4 Available as a 200-mg capsule Must be taken with a light meal or snack.

5 Cost for 24 weeks of treatment.

6 Available as a 150-mg capsule Must be taken with food.

produces a sustained virologic response (SVR; unde-tectable HCV RNA 24 weeks after stopping treatment)

in 40-50% of patients with HCV genotype 1 infection Addition of telaprevir or boceprevir to peginterferon and ribavirin increases SVR rates to 60-75% and has be-come the standard of care for patients with HCV geno-type 1 infection.1-3

CLINICAL STUDIES — The effi cacy of simeprevir was

evaluated in three phase 3 (QUEST 1 and 2, PROM-ISE) and two phase 2b (PILLAR, ASPIRE) randomized, double-blind, placebo-controlled trials in more than

2000 treatment-nạve and treatment-experienced pa-tients with chronic HCV genotype 1 infection Papa-tients taking simeprevir with peginterferon/ribavirin had sig-nifi cantly higher SVR rates compared to placebo in all

of the trials (Table 3)

The effi cacy of simeprevir was substantially reduced

in patients with HCV genotype 1a infection who had the NS3 Q80K polymorphism at baseline (35% of US patients in the clinical studies) Genotype 1a patients should be screened for this polymorphism and

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ADVERSE EFFECTS — Adverse effects occurring

with at least 3% higher frequency with simeprevir than

placebo in the phase 3 clinical trials were rash,

pruri-tus, nausea, myalgia, and dyspnea Grade 3 rash

oc-curred in 1% of patients treated with simeprevir; there

were no reports of Stevens-Johnson syndrome or

toxic epidermal necrolysis In vitro studies found that

simeprevir is phototoxic after UVA exposure and

pa-tients in the phase 3 clinical studies were advised to

use sun protection; 5% of those treated with simeprevir

Table 3 Simeprevir Clinical Studies

Clinical Trial (simeprevir vs placebo)

Treatment-Nạve Patients

QUEST 1 and QUEST 2 (n=785)1,2

Simeprevir 150 mg x 12 wks SVR12: 80% vs 50%

+ PR x 24 or 48 wks 3

Placebo + PR 48 wks

PILLAR (n=386)4

Simeprevir 75 or 150 mg x 12 or 24 wks SVR24: 75-86% vs 65%

+ PR x 24 or 48 wks 3

Placebo x 24 wks + PR x 48 wks

Treatment-Experienced Patients

PROMISE (n=393)5

Simeprevir 150 mg x 12 wks SVR12: 80% vs 37%

+ PR x 24 or 48 wks 3

Placebo + PR x 48 wks

ASPIRE (n=462)6

Simeprevir 100 or 150 mg x 12, 24, SVR24: 61-80% vs 23%

or 48 wks + PR x 48 wks

Placebo + PR x 48 wks

PR = peginterferon plus ribavirin; SVR12 = HCV RNA <25 IU/mL detectable or

undetectable 12 weeks after end of treatment; SVR24 = HCV RNA undetectable

24 weeks after end of treatment.

1 I Jacobson et al Simeprevir (TMC435) with peginterferon/ribavirin for chronic

HCV genotype-1 infection in treatment-nạve patients; results from QUEST-1, a

phase III trial Gastroenterology 2013; 144(5) suppl1:S-374 Abs Sa2072.

2 F Poordad et al Simeprevir (TMC435) with peginterferon/ribavirin for treatment

of chronic HCV genotype-1 infection in treatment-nạve patients: results from

QUEST-2, a phase III trial Gastroenterology 2013; 144(5) suppl1:S-151 Abs

869a.

3 Overall duration of treatment with PR was response-guided PR treatment

was stopped at 24 weeks if HCV RNA levels were <25 IU/mL at week 4 and

undetectable at week 12.

4 MW Fried et al Once-daily simeprevir (TMC435) with pegylated interferon and

ribavirin in treatment-nạve genotype 1 hepatitis C: The randomized PILLAR

study Hepatology 2013; 58:1918.

5 E Lawitz et al Simeprevir (TMC435) with peginterferon/ribavirin for treatment

of chronic HCV genotype 1 infection in patients who relapsed after previous

interferon-based therapy: results from PROMISE, a phase III trial

Gastroenter-ology 2013; 144(5) suppl1:S-151 Abs 869b.

6 Included patients who did not respond, had a partial response or relapsed

following treatment with PR [S Zeuzem et al Simeprevir increases rate of

sustained virologic response among treatment-experienced patients with HCV

genotype-1 infection: a phase IIb trial Gastroenterology 2013 November 1

(epub)].

reported photosensitivity compared with 1% of those

in the control group Transient elevations in both direct and indirect bilirubin, mostly mild to moderate, were reported in 49% of patients receiving simeprevir, but were not associated with hepatic toxicity Unlike bo-ceprevir and telaprevir, simeprevir did not exacerbate anemia caused by peginterferon/ribavirin Patients of East Asian ancestry and those with moderate or se-vere hepatic impairment have higher plasma concen-trations of simeprevir and may have a higher risk of adverse effects

Simeprevir has not been studied in pregnant women, but combination therapy with simeprevir, ribavirin (which

is teratogenic and embryotoxic), and peginterferon is contraindicated for use during pregnancy (category X) and in men whose female partners are pregnant

DRUG INTERACTIONS — In vitro studies show that

simeprevir is a substrate and mild inhibitor of intestinal CYP3A and a substrate and inhibitor of the drug transporters P-glycoprotein (P-gp) and OATP1B1/3 Simeprevir should not be administered with moderate

or strong inhibitors or inducers of CYP3A.4 Simeprevir can increase plasma concentrations of some statins

by inhibiting OATP1B1 and/or CYP3A4 If used concomitantly with simeprevir, maximum daily doses

of 10 mg of rosuvastatin (Crestor) and 40 mg of atorvastatin (Lipitor, and generics) are recommended.

DOSAGE — The recommended dosage of simeprevir

is 150 mg taken once daily with food for 12 weeks

in combination with peginterferon alfa and ribavirin Peginterferon and ribavirin should be given for an additional 12 weeks in treatment-nạve and prior-relapse patients and for an additional 36 weeks in prior non-responders Patients with an inadequate virologic response after 4, 12, or 24 weeks (HCV RNA >25 IU/ mL) should discontinue all drugs

CONCLUSION — Addition of simeprevir (Olysio) to

peginterferon and ribavirin can increase sustained virologic response rates in patients with HCV genotype

1 infection Simeprevir appears to be at least as effective

as telaprevir (Incivek) or boceprevir (Victrelis), except

in genotype 1a patients with the NS3 Q80K mutation

It has the advantage of once-daily dosing and does not exacerbate anemia caused by peginterferon/ribavirin, but it can cause rash and photosen sitivity reactions □

1 TJ Liang and MG Ghany Current and future therapies for hepatitis

C virus infection N Engl J Med 2013; 368:1907.

2 Antiviral drugs Treat Guidel Med Lett 2013; 11:19.

3 Drugs for hepatitis C Med Lett Drugs Ther 2012; 54:81.

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

tive therapy should be considered for those who have

it Effi cacy was not reduced in patients with the Q80K

polymorphism who received telaprevir or

bocepre-vir in clinical trials In general, however, patients who

fail treatment with simeprevir may also be resistant to

treatment with the other approved protease inhibitors

No controlled clinical trials are available comparing

simeprevir with either telaprevir or boceprevir

New Oral Anticoagulants for Acute

Venous Thromboembolism

Anticoagulants are the drugs of choice for

treat-ment of deep vein thrombosis (DVT) and pulmonary

embolism (PE), collectively referred to as venous

thromboembolism (VTE)

STANDARD TREATMENT — Patients with acute

VTE are often treated initially with a parenteral

anticoagulant such as unfractionated heparin, low

molecular weight heparin (LMWH), or fondaparinux

(Arixtra, and generics); all are associated with similar

rates of mortality, recurrent VTE, and major bleeding

For most patients, the oral vitamin K antagonist

warfarin (Coumadin, and others) is started on the same

day as parenteral therapy and titrated to maintain an

INR between 2 and 3 After >5 days, the parenteral

anticoagulant is stopped and warfarin is continued as

monotherapy, usually for at least 3 months.1

NEW ORAL ANTICOAGULANTS — Rivaroxaban

(Xarelto), dabigatran etexilate (Pradaxa), apixaban

(Eliquis), and edoxaban (not FDA-approved) have

all been studied for treatment of acute VTE, but only

rivaroxaban is FDA-approved for this indication

Unlike warfarin, the newer drugs do not require INR

monitoring and have no dietary restrictions, but they

have shorter half-lives (increasing the risks associated

with missed doses) and no specifi c antidote to reverse

their anticoagulant effect

CLINICAL STUDIES — Only a small minority of

patients in any clinical trial of a new oral anticoagulant for treatment of acute VTE were >75 years old, had a creatinine clearance (CrCl) <50 mL/min, or had cancer

Rivaroxaban (Xarelto) – A randomized

open-label study (EINSTEIN) in 3449 patients compared rivaroxaban alone to standard therapy with the

LMWH enoxaparin (Lovenox, and generics) plus

a vitamin K antagonist for treatment of acute VTE Rivaroxaban was non-inferior to standard therapy in reducing the rate of recurrent VTE The rate of major

or clinically relevant non-major bleeding, the primary safety endpoint, was the same in both groups.2 A second randomized open-label study (EINSTEIN-PE) in 4832 patients with PE found that rivaroxaban was non-inferior to enoxaparin plus a vitamin K antagonist in reducing the rate of recurrent VTE with a similar rate of major or clinically relevant non-major bleeding.3

Dabigatran etexilate (Pradaxa) – A 6-month,

randomized, double-blind trial (RE-COVER) in 2539 patients compared dabigatran to warfarin for treatment

of acute VTE after initial treatment with a parenteral anticoagulant Twice-daily dabigatran was non-inferior

to warfarin in preventing recurrent VTE or VTE-related death, the primary effi cacy endpoint Rates of major bleeding were similar in the two groups.4

Apixaban (Eliquis) – A 6-month, randomized,

double-blind trial (AMPLIFY) in 5395 patients compared apixaban alone to enoxaparin plus warfarin for treatment

of acute VTE Twice-daily apixaban was non-inferior

in preventing recurrent VTE or VTE-related death (the primary effi cacy endpoint) Major bleeding, the primary safety outcome, occurred less frequently with apixaban (0.6% vs 1.8%).5

Edoxaban – In a randomized, double-blind trial

of 8240 patients with acute VTE fi rst treated with unfractionated heparin or LMWH, once-daily edoxaban (not FDA-approved) was non-inferior to warfarin in preventing recurrent VTE or VTE-related death (the primary endpoint) Patients taking edoxaban had a signifi cantly lower rate of major or clinically relevant non-major bleeding (8.5% vs 10.3%).6

CONCLUSION — The new oral anticoagulants

rivaroxaban (Xarelto), dabigatran etexilate (Pradaxa), and apixaban (Eliquis), and the investigational oral

anticoagulant edoxaban all appear to be effective and safe for treatment of acute venous thromboembolism, but data in older and sicker patients are limited They

Table 1 Oral Anticoagulants for Treatment of Venous

Thromboembolism

Warfarin – generic Vitamin K 2-10 mg 2 $6.00

(Coumadin) antagonist once/d 43.00

Rivaroxaban – Direct factor Xa 15 mg bid

(Xarelto) inhibitor for 3 wks, 265.00

then 20 mg once/d 3 Apixaban – Direct factor Xa 10 mg bid

(Eliquis)4 inhibitor for 7 days, 265.00

then 5 mg bid 5 Dabigatran etexilate – Direct thrombin 150 mg bid 6

(Pradaxa)4 inhibitor 265.00

1 Approximate wholesale acquisition cost of 30 days’ treatment at the lowest

daily dose Source: Analy$ource® Monthly (Selected from FDB

Medknowl-edge™) December 5, 2013 Reprinted with permission by FDB, Inc All rights

reserved ©2013 www.fdbhealth.com/policies/drug-pricing-policy Actual retail

prices may be higher.

2 Monitor INR daily and adjust dose until in therapeutic range (2-3) for >24 hours.

3 With food; avoid use with combined P-glycoprotein and strong CYP3A4

inhibi-tors or inducers, or in patients with CrCl <30 mL/min.

4 Not FDA-approved for treatment of VTE.

5 Not studied in patients with acute VTE who are taking strong CYP3A4

inhibi-tors or who have CrCl <25 mL/min or serum creatinine >2.5 mg/dL.

6 Avoid use with P-glycoprotein inducers; not studied for acute VTE in patients

who have CrCl <30 mL/min.

Related article(s) since publication

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On Drugs and Therapeutics

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Copyright 2014 ISSN 1523-2859

The Medical Letter • Volume 56 • Issue 1433 • January 6, 2014

Omacetaxine Mepesuccinate (Synribo) for CML Sofosbuvir (Sovaldi) for Chronic Hepatitis C Tobramycin Inhalation Solution (Bethkis) for Cystic Fibrosis

Coming Soon in Treatment Guidelines:

Drugs for HIV Infection Treatment of Atrial Fibrillation

Khedezla – A New Brand of Desvenlafaxine

The FDA has approved the marketing of another

extended-release brand-name formulation of the serotonin and

norepinephrine reuptake inhibitor (SNRI) desvenlafaxine

(Khedezla – Par/Osmotica) for treatment of depression

It is the third extended-release formulation of

desven-lafaxine to become available in the US Khedezla was

approved using a 505(b)(2) application, a new drug

appli-cation (NDA) that relies upon the FDA’s fi ndings of safety

and/or effectiveness for a previously approved drug

Table 1 Desvenlafaxine Products

Usual Adult

Drug Dosage Cost 1

Desvenlafaxine succinate 2 – 50 mg once/d

Desvenlafaxine base 2 – 50 mg once/d

Khedezla (Par/Osmotica) 134.00

1 Approximate wholesale acquisition cost (WAC) for 30 days’ treatment at the

usual daily dosage Source: Analy$ource® Monthly (Selected from FDB

Med-Knowledge™) December 5, 2013 Reprinted with permission by FDB, Inc

All rights reserved ©2013 www.fdbhealth.com/policies/drug-pricing-policy

Actual retail prices may be higher.

2 Extended- or delayed-release.

Khedezla does not appear to offer any advantage

over the other extended-release formulations of

desvenlafaxine There is no evidence that any formulation

of desvenlafaxine is more effective for treatment of

depression than other SNRIs or any SSRI, which are

available in less expensive generic formulations.1

1 Drugs for psychiatric disorders Treat Guidel Med Lett 2013; 11:53.

do not require INR monitoring and do not have dietary

restrictions, but they have short half-lives that increase

the risk of thrombosis with missed doses and no specifi c

antidote to reverse their anticoagulant effect □

1 C Kearon et al Antithrombotic therapy for VTE disease:

antithrom-botic therapy and prevention of thrombosis, 9 th ed: American

Col-lege of Chest Physicians evidence-based clinical practice

guide-lines Chest 2012; 141 (2 suppl): e419S.

2 EINSTEIN Investigators Oral rivaroxaban for symptomatic venous

thromboembolism N Engl J Med 2010; 363:2499.

3 EINSTEIN-PE Investigators Oral rivaroxaban for the treatment of

symptomatic pulmonary embolism N Engl J Med 2012; 366:1287.

4 S Schulman et al Dabigatran versus warfarin in the treatment of

acute venous thromboembolism N Engl J Med 2009; 361:2342.

5 G Agnelli et al Oral apixaban for the treatment of acute venous

thromboembolism N Engl J Med 2013; 369:799.

6 Hokusai-VTE Investigators Edoxaban versus warfarin for the

treatment of symptomatic venous thromboembolism N Engl J Med

2013; 369:1406

The Medical Letter®

Online Continuing Medical Education

To take CME exams and earn credit, go to:

medicalletter.org/CMEstatus

Issue 1433 Questions

(Correspond to questions #1-6 in Comprehensive Exam #70, available July 2014)

Simeprevir (Olysio) for Chronic Hepatitis C

1 In clinical trials in treatment-nạve patients, simeprevir

produced a sustained virologic response in about what

percentage of patients?

2 Simeprevir is less effective in patients:

a with renal dysfunction

b with genotype 1a infection and the NS3 Q80K mutation

c who are also taking a strong CYP3A4 inhibitor

d who are pregnant

3 Adverse effects of simeprevir include:

a photosensitivity

c an increase in bilirubin levels

d all of the above

New Oral Anticoagulants for Acute Venous Thromboembolism

4 The only new oral anticoagulant that is currently FDA-approved

for treatment of venous thromboembolism is:

a dabigatran

b apixaban

c rivaroxaban

d all of the above

5 The new oral anticoagulants:

a have shorter half-lives than warfarin

b do not require INR monitoring

c have no dietary restrictions

d all of the above

6 In clinical studies for treatment of acute venous thromboembolism,

the new oral anticoagulants:

a appear to be less effective than warfarin

b caused more major bleeding than warfarin

c were more effective than warfarin in older

patients with renal dysfunction

d none of the above

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1 Review the effi cacy and safety of simeprevir (Olysio) for treatment of chronic hepatitis C.

2 Discuss the evidence supporting the effi cacy and safety of the new oral anticoagulants for treatment of venous thromboembolism.

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