The medical letter on drugs and therapeutics september 12 2016

1503 on Drugs and Therapeutics Daclizumab Zinbryta for Multiple Sclerosis ...p 117 In Brief: Defi brotide Defi telio for Hepatic Veno-Occlusive Disease ...p 120 In Brief: Repatha Pushtro

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IN THIS ISSUE

ISSUE

1433

Volume 56

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

ISSUE No

1503

on Drugs and Therapeutics

Daclizumab (Zinbryta) for Multiple Sclerosis p 117

In Brief: Defi brotide (Defi telio) for Hepatic Veno-Occlusive Disease p 120

In Brief: Repatha Pushtronex – A New Evolocumab Injection Device p 120

In Brief: Epinephrine Auto-Injectors for Anaphylaxis online only

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115

Take CME Exams

ISSUE

1433

Volume 56

ISSUE No

1503 Daclizumab (Zinbryta) for Multiple Sclerosis In Brief: Defi brotide (Defi telio) for Hepatic Veno-Occlusive Disease p 117p 120

In Brief: Repatha Pushtronex – A New Evolocumab Injection Device p 120

In Brief: Epinephrine Auto-Injectors for Anaphylaxis online only

ALSO IN THIS ISSUE

Byvalson – A Beta Blocker/ARB

Combination for Hypertension

▶

The FDA has approved Byvalson (Allergan), a fi

xed-dose combination of the beta blocker nebivolol

(Bystolic) and the angiotensin receptor blocker (ARB)

valsartan (Diovan, and generics), for treatment of

hypertension It is the only combination product that

contains nebivolol, and the fi rst to combine a beta

blocker with an ARB

Pronunciation Key Nebivolol: ne biv’ oh lol Byvalson: bye val' son

Valsartan: val sar’ tan

STANDARD TREATMENT — Most recent guidelines

recommend a thiazide-type diuretic (chlorthalidone

is preferred), a calcium channel blocker, an

angiotensin-converting enzyme (ACE) inhibitor, or

an ARB as initial therapy for hypertension in

non-black patients A thiazide-type diuretic or a calcium

channel blocker is preferred for initial treatment of

black patients, except those with chronic kidney

disease or heart failure, who should receive an ACE

inhibitor or an ARB Beta blockers generally are no

longer recommended as initial therapy, except in

patients with a comorbidity such as coronary heart

disease or left ventricular dysfunction.1

Many patients with hypertension need more than one drug to control their blood pressure If monotherapy does not achieve blood pressure goals, adding a second drug with a different mechanism of action is generally more effective than increasing the dose of the fi rst drug and often allows for use of lower, better-tolerated doses of both drugs If an ACE inhibitor or an ARB was used initially, it would be reasonable to add

a thiazide-type diuretic or a calcium channel blocker When baseline blood pressure is >20/10 mm Hg above goal, many experts would begin treatment with two drugs

Table 1 Initial Treatment of Hypertension 1,2

General Population

Non-black Thiazide-type diuretic, 3 CCB,

ACE inhibitor, or ARB Black Thiazide-type diuretic 3 or CCB

Chronic Kidney Disease

Non-black ACE inhibitor or ARB Black ACE inhibitor or ARB

Diabetes

Non-black ACE inhibitor or ARB Black Thiazide-type diuretic 3 or CCB 4 ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; CCB = calcium channel blocker

1 PA James et al JAMA 2014; 311:507.

2 When baseline blood pressure is >20/10 mm Hg above goal, many experts would begin this treatment with two drugs.

3 Chlorthalidone is preferred.

4 Black patients with both diabetes and chronic kidney disease should receive an ACE inhibitor or an ARB.

Table 2 Byvalson and Components

Drug Formulations Usual Adult Dosage Cost 1

Nebivolol/valsartan – Byvalson (Allergan) 5/80 mg tabs 5/80 mg once/d 2 $1315.20

Nebivolol – Bystolic (Allergan) 2.5, 5, 10, 20 mg tabs 5-40 mg once/d 1315.20 Valsartan – generic 40, 80, 160, 320 mg tabs 80-320 mg once/d 309.60

1 Approximate WAC for 1 year's treatment at the lowest usual adult dosage WAC = wholesaler acquisition cost or manufacturer’s published price to wholesal-ers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly August 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy.

2 Higher doses do not appear to offer additional benefi t.

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The Medical Letter ® Vol 58 (1503) September 12, 2016

MECHANISM OF ACTION — At doses ≤10 mg/

day, nebivolol selectively inhibits beta1-adrenergic receptors and acts as an agonist at beta3-adrenergic receptors Beta1 inhibition decreases heart rate, myocardial contractility, and renin activity Beta3 activation induces vasodilation through endothelial release of nitric oxide Valsartan blocks the vasoconstricting and aldosterone-secreting effects

of angiotensin II by preventing it from binding to the AT1 receptor

CLINICAL STUDIES — Approval of the new combination

was based on the results of an 8-week, double-blind trial in 4161 adults with hypertension (BP <180/110

mm Hg) who were randomized into 8 treatment groups: fi xed-dose nebivolol/valsartan 5/80 mg, 5/160 mg, or 10/160 mg, nebivolol 5 mg or 20 mg, valsartan 80 mg or 160 mg, or placebo, each taken once daily for 4 weeks The dosages were doubled after week 4.2 At 4 weeks, the placebo-adjusted mean reduction in blood pressure from baseline was signifi cantly greater with nebivolol/valsartan 5/80 mg (8.3/7.2 mm Hg) than with nebivolol 5 mg alone (4.7/4.4 mm Hg) or valsartan 80 mg alone (5.4/3.9

mm Hg) Higher doses of the combination (5/160 mg and 10/160 mg) did not have a signifi cantly greater antihypertensive effect than the FDA-approved 5/80-mg dose

ADVERSE EFFECTS — In the clinical trial, adverse

effects with nebivolol/valsartan 5/80 mg were similar

to those with the individual components and placebo Like other beta blockers, nebivolol can cause fatigue, dizziness and bradycardia, increase serum triglyceride levels, and decrease high-density lipoprotein (HDL) cholesterol levels Unlike other beta blockers, it does not diminish, and may even improve, erectile function because it stimulates nitric oxide release.3

ARBs are generally well tolerated; they can cause hy-perkalemia and acute renal failure, but are less likely than ACE inhibitors to cause cough or angioedema

DRUG INTERACTIONS — CYP2D6 inhibitors such as

fluoxetine (Prozac, and generics)4 can increase serum concentrations of nebivolol; concurrent use is not recommended Coadministration of nebivolol with digoxin or calcium channel blockers could result in additive cardiac effects

Valsartan should not be used with ACE inhibitors

or other drugs that block the renin-angiotensin-aldosterone system (RAAS) Use of valsartan with potassium-sparing diuretics or other drugs that

Table 3 Some Other Combinations for Hypertension

Drug Formulations Cost 1

ARBs and Diuretics

Azilsartan/chlorthalidone 40/12.5, 40/25 mg tabs

Edarbyclor (Arbor) $1934.20

Candesartan/HCTZ 16/12.5, 32/12.5,

generic 32/25 mg tabs 1269.90

Atacand HCT (AstraZeneca) 1575.10

Irbesartan/HCTZ 150/12.5, 300/12.5 mg

generic tabs 272.00

Avalide (Sanofi ) 2477.70

Losartan/HCTZ 50/12.5, 100/12.5,

Hyzaar (Merck) 1393.20

Olmesartan/HCTZ 20/12.5, 40/12.5,

Benicar HCT 40/25 mg tabs 2095.20

(Daiichi Sankyo)

Telmisartan/HCTZ 40/12.5, 80/12.5,

Micardis HCT 2133.70

(Boehringer Ingelheim)

Valsartan/HCTZ 80/12.5, 160/12.5,

generic 160/25, 320/12.5, 408.40

Diovan HCT (Novartis) 320/25 mg tabs 2522.40

ARBs and CCBs

Amlodipine/telmisartan 5/40, 5/80, 10/40,

Twynsta (Boehringer Ingelheim) 2295.80

Amlodipine/valsartan 5/160, 5/320, 10/160,

Exforge (Novartis) 2630.40

Amlodipine/olmesartan 5/20, 5/40, 10/20,

Azor (Daiichi Sankyo) 10/40 mg tabs 2613.60

ARBs, CCBs, and Diuretics

Valsartan/amlodipine/HCTZ 160/5/12.5, 160/5/25,

generic 160/10/12.5, 1340.40

Exforge HCT (Novartis) 160/10/25, 2630.40

320/10/25 mg tabs Olmesartan/amlodipine/HCTZ 20/5/12.5, 40/5/12.5,

Tribenzor (Daiichi Sankyo) 40/5/25, 40/10/12.5, 2613.60

40/10/25 mg tabs

Beta-Adrenergic Blockers and Diuretics

Atenolol/chlorthalidone 50/25, 100/25 mg tabs

generic 197.20

Tenoretic (Almatica) 4320.00

Bisoprolol/HCTZ 2.5/6.25, 5/6.25,

generic 10/6.25 mg tabs 96.70

Ziac (Duramed/Barr) 1869.40

Metoprolol/HCTZ 50/25, 100/25,

Lopressor HCT (Validus) 50/25 mg tabs 745.40

Nadolol/bendroflumethiazide 40/5, 80/5 mg tabs

generic 1341.40

Corzide (Pfi zer) 2185.80

ARB = angiotensin receptor blocker; CCB = calcium channel blocker;

HCTZ = hydrochlorothiazide

1 Approximate WAC for 1 year’s treatment at the lowest available 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

August 5, 2016 Reprinted with permission by First Databank, Inc All rights

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Pronunciation Key Daclizumab: da kliz’ ue mab Zinbryta: zin brye’ tuh

1 Drugs for hypertension Treat Guidel Med Lett 2014; 12:31.

2 TD Giles et al Effi cacy and safety of nebivolol and valsartan as

fi xed-dose combination in hypertension: a randomised,

multi-centre study Lancet 2014; 383:1889

3 J Fongemie and E Felix-Getzik A review of nebivolol

pharma-cology and clinical evidence Drugs 2015; 75:1349.

4 Inhibitors and inducers of CYP enzymes and P-glycoprotein

Med Lett Drugs Ther 2016 Available at: http://secure.medical

letter.org/downloads/CYP_PGP_Tables.pdf Accessed

Septem-ber 1, 2016.

Table 1 Pharmacology

Class Interleukin-2 antagonist monoclonal antibody Formulation 150 mg/mL single-dose prefi lled syringe Route Subcutaneous injection

Tmax 5-7 days Metabolism Catabolism to peptides and amino acids Half-life 21 days

increase potassium levels could increase the risk of

hyperkalemia NSAIDs can reduce the antihypertensive

effect of valsartan and can increase the risk of renal

impairment Taking lithium with an ARB can result in

increased lithium serum concentrations

PREGNANCY AND LACTATION — Nebivolol/valsartan

should not be taken during pregnancy Drugs that

act on the RAAS can cause fetal injury and death

Embryofetal and perinatal death has occurred

when nebivolol was given to pregnant rats at doses

equivalent to maximum recommended human

doses Women taking nebivolol/valsartan should

not breastfeed; nebivolol can cause bradycardia and

other serious adverse effects in breastfed infants, and

valsartan can affect postnatal renal development

DOSAGE AND ADMINISTRATION — Byvalson is

available in tablets containing 5 mg of nebivolol and

80 mg of valsartan The recommended dosage is one

tablet once daily; higher doses do not appear to offer

additional benefi t Patients already taking nebivolol

5 mg and valsartan 80 mg separately can switch to

the fi xed-dose tablet The combination can also be

used as initial therapy and in patients whose blood

pressure is not adequately controlled with either

drug alone (80 mg/day of valsartan or ≤10 mg/day

of nebivolol)

Hepatic impairment can increase nebivolol exposure;

Byvalson is not recommended for initial treatment of

patients with moderate hepatic impairment

(Child-Pugh B) and is contraindicated for use in patients

with severe hepatic impairment (Child-Pugh C) The

combination should not be used in patients with left

ventricular dysfunction

CONCLUSION — Taking the fi xed-dose combination

of the beta blocker nebivolol and the angiotensin

receptor blocker (ARB) valsartan (Byvalson) is more

convenient than taking the two drugs separately,

but beta blockers are generally not recommended

for initial treatment of hypertension or as the fi rst

choice for add-on therapy in patients inadequately

controlled on an ARB ■

Daclizumab (Zinbryta) for Multiple

Sclerosis

▶

The FDA has approved daclizumab (Zinbryta – Biogen/

Abbvie), an interleukin-2 (IL-2) receptor blocking monoclonal antibody, for treatment of adults with relapsing forms of multiple sclerosis (MS) It is the

fi rst subcutaneously injected monoclonal antibody to

be approved for treatment of MS

Because of safety concerns, the label recom-mends that daclizumab generally be used only for patients who have had an inadequate response to

≥2 other MS drugs, and its availability is restricted

by a Risk Evaluation and Mitigation Strategy (REMS)

program Zenapax, an earlier IV formulation of

daclizumab, was approved by the FDA in 1997 for prevention of acute renal transplant rejection,1 but it

is no longer marketed

TREATMENT OF MS — Interferons have been used

for fi rst-line treatment of MS, but they appear to

be less effective than some of the newer drugs and they frequently cause injection-site reactions and a flu-like syndrome Use of oral agents or

IV natalizumab (Tysabri) for initial treatment is

increasing Natalizumab is highly effective and needs

to be infused only every 4 weeks, but progressive multifocal leukoencephalopathy (PML), a potentially fatal infection caused by the JC virus, is a concern; patients who have anti-JC virus antibodies or are immunosuppressed have the highest risk Among

the oral drugs, fi ngolimod (Gilenya) and dimethyl fumarate (Tecfi dera) appear to be more effective than teriflunomide (Aubagio).2

MECHANISM OF ACTION — Activated T cells are

thought to be involved in the pathogenesis of MS Daclizumab binds to the alpha subunit (CD25) of the high-affi nity IL-2 receptor expressed on activated

T cells, blocking IL-2 dependent T-cell functions It increases the number of immunoregulatory CD56bright

natural killer (NK) cells, which kill autologous activated

T cells in the central nervous system The increase

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Table 2 FDA-Approved Drugs for Relapsing-Remitting Multiple Sclerosis

Reduction

in Clinical Usual Frequent or Serious Drug Relapse Rate Maintenance Dosage Adverse Effects Cost 1

Injectable

Interferon beta-1a – 30-35% 2 Injection-site reactions, flu-like

Avonex (Biogen-Idec) 30 mcg IM once/wk symptoms, depression, trans- $75,673.00

Rebif (EMD Serono) 44 mcg SC 3x/wk aminase elevations, possible 81,686.30 Peginterferon beta-1a – cardiac toxicity, autoimmune

Plegridy (Biogen-Idec) 125 mcg SC q2 wks disorders, allergic reactions, 75,673.00 Interferon beta-1b – hepatotoxicity, seizures, suicidal

Betaseron (Bayer) 250 mcg SC every ideation, lymphopenia with 81,286.80

Extavia (Novartis) other day interferon beta-1b 67,810.70 Glatiramer acetate – ~30% 2 Injection-site reactions, transient

or 40 mg 3x/wk (flushing, chest pain, palpitations, 70,251.50

Glatopa (Sandoz) 20 mg SC once/d dyspnea) 63,192.50

Natalizumab – Tysabri 68%3 300 mg IV q4 wks Headache, fatigue, arthralgia, 75,361.00 (Biogen-Idec) depression, infections,

sensitivity reactions, hepatotoxicity, PML

Alemtuzumab – Lemtrada 50-55%4 12 mg IV once/d x 5d Infusion reactions (rash, headache, 60,731.30 5

(Genzyme) followed 1 year later by pyrexia, nausea, urticaria), naso-

12 mg IV once/d x 3d pharyngitis, autoimmune disorders

(immune cytopenias [especially thrombocytopenia], glomerular nephropathies, thyroid disorders), infections, pneumonitis, malignancies

Daclizumab – Zinbryta 456 -54% 7 150 mg SC once/mo Autoimmune disorders (skin reactions, 82,000.00 (Biogen/Abbvie) lymphadenopathy, autoimmune

hepatitis, noninfectious colitis), infections, depression, hepatotoxicity, hypersensitivity reactions

Mitoxantrone – generic ~60% 8 12 mg/m 2 IV q3 mos Nausea, alopecia, amenorrhea, 1330.40 9

cardiotoxicity at cumulative doses >100 mg/m 2 , myelosuppression, acute and chronic myeloid leukemia

Oral

Fingolimod – Gilenya ~55%10 0.5 mg PO once/d Transaminase elevations, bradycardia, 82,044.70 (Novartis) AV block, macular edema, mild

hypertension, lymphopenia, decreased pulmonary function, hypersensitivity reactions, malignancies, serious viral and fungal infections, PML

Teriflunomide – Aubagio ~30%11 7 or 14 mg PO once/d Diarrhea, nausea, alopecia, trans- 74,379.70 (Sanofi -Aventis) aminase elevations, neutropenia,

leukopenia, peripheral neuropathy, hyperkalemia, hypophosphatemia, hypertension, hepatic failure, acute renal failure, Stevens-Johnson syndrome, toxic epidermal necrolysis Dimethyl fumarate – ~50% 12 240 mg PO bid Flushing, abdominal pain, nausea, 76,832.50

Tecfi dera (Biogen-Idec) vomiting, diarrhea, lymphopenia,

anaphylaxis, angioedema, PML

PML = progressive multifocal leukoencephalopathy

1 Approximate WAC for 1 year’s treatment at the usual maintenance 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 August 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy

2 Peginterferon beta-1a (Plegridy) for multiple sclerosis Med Lett Drugs Ther 2015; 57:67.

3 CH Polman et al A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis N Engl J Med 2006; 354:899.

4 Compared to interferon beta-1a (JA Cohen et al Lancet 2012; 380:1819; AJ Coles et al Lancet 2012; 380:1829).

5 Cost for second year of treatment; cost for fi rst year’s treatment is $101,218.80.

6 Compared to interferon beta-1a (L Kappos et al N Engl J Med 2015; 373:1418).

7 R Gold et al Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial

Lancet 2013; 381:2167.

8 HP Hartung et al Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial Lancet 2002; 360:2018.

9 Cost for treatment of a patient with a body surface area of 1.7 m 2 using 12.5-mL multi-dose vials containing 25 mg (2 mg/mL).

10 Oral fi ngolimod (Gilenya) for multiple sclerosis Med Lett Drugs Ther 2010; 52:98.

11 New drugs for multiple sclerosis Med Lett Drugs Ther 2012; 54:89.

12 Dimethyl fumarate (Tecfi dera) for multiple sclerosis Med Lett Drugs Ther 2013; 55:45.

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in NK cells appears to be a biomarker for reductions

in brain inflammatory activity in MS patients treated

with daclizumab.3

CLINICAL STUDIES — Approval of daclizumab was

based on the results of two randomized, double-blind

trials in patients with relapsing-remitting MS

The SELECT trial compared daclizumab 150 mg SC

every 4 weeks with placebo in 412 adults who had

had at least one relapse in the previous 12 months

or one new brain lesion in the previous 6 weeks The

annualized relapse rate was signifi cantly lower in

patients treated with daclizumab (0.21 vs 0.46 with

placebo) Patients treated with daclizumab also had

signifi cantly fewer new or newly-enlarging brain lesions

seen on MRI scans The percentage of patients with

confi rmed disability progression at week 52

(Kaplan-Meier estimate) was 6% with daclizumab versus 13%

with placebo.4 Extensions of this trial found that clinical

effi cacy was maintained for three years among patients

receiving continuous treatment with daclizumab.5,6

The DECIDE trial compared daclizumab 150 mg SC

every 4 weeks with interferon beta-1a (Avonex) 30 mcg

IM once a week for up to 144 weeks in 1841 adults who

had had 2 or more relapses during the previous 3 years

or at least one relapse and one new brain lesion during

the previous 2 years (one of these events had to have

occurred within 12 months before randomization) The

annualized relapse rate was signifi cantly lower with

daclizumab (0.22 vs 0.39 with interferon beta-1a) The

number of new or newly-enlarged T2 brain lesions

seen on MRI scans was also signifi cantly lower with

daclizumab The estimated percentage of patients

with confi rmed disability progression at week 144 was

16% with daclizumab compared to 20% with interferon

beta-1a, a nonsignifi cant difference.7

ADVERSE EFFECTS — The daclizumab package insert

includes a boxed warning about the risk of severe

hepatic injury, including liver failure and autoimmune

hepatitis, and other immune-mediated disorders such

as skin reactions, lymphadenopathy, and noninfectious

colitis In the SELECT trial, hepatic transaminase

elevations >5 times the upper limit of normal occurred

in 4% of patients treated with daclizumab compared to

1% of those treated with placebo

Cutaneous adverse effects, including rashes, dermatitis,

and eczema, were more common with daclizumab than

with interferon beta-1a or placebo in clinical trials;

patients with a history of skin conditions had the

highest risk Use of daclizumab also increased the risk

1 New monoclonal antibodies to prevent transplant rejection Med Lett Drugs Ther 1998; 40:93.

2 Drugs for multiple sclerosis Med Lett Drugs Ther 2016; 58:71.

3 R Milo The effi cacy and safety of daclizumab and its potential role in the treatment of multiple sclerosis Ther Adv Neurol Dis-ord 2014; 7:7.

4 R Gold et al Daclizumab high-yield process in relapsing-remit-ting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial Lancet 2013; 381:2167.

5 G Giovannoni et al Daclizumab high-yield process in relaps-ing-remitting multiple sclerosis (SELECTION): a multicentre, randomised, double-blind extension trial Lancet Neurol 2014; 13:472.

6 R Gold et al Safety and effi cacy of daclizumab in relapsing-remitting multiple sclerosis: 3-year results from the SELECTED open-label extension study BMC Neurol 2016; 16:117.

7 L Kappos et al Daclizumab HYP versus interferon beta-1a in relapsing multiple sclerosis N Engl J Med 2015; 373:1418.

8 R Gold et al Pregnancy experience: nonclinical studies and pregnancy outcomes in the daclizumab clinical study program Neurol Ther 2016 July 13 (epub).

of infections and depression-related events compared

to interferon beta-1a and placebo

PREGNANCY AND LACTATION – There are no formal

studies of daclizumab use in pregnant women Administration of daclizumab to pregnant monkeys resulted in embryofetal death and reduced fetal growth at exposures >30 times the expected exposure

in humans at the recommended dose A review of data on 38 pregnancies exposed to daclizumab during clinical trials found no evidence of an increased risk for adverse fetal or maternal outcomes.8 Daclizumab has been detected in the milk of lactating monkeys

DOSAGE AND ADMINISTRATION — Zinbryta is

available in 150-mg single-dose prefi lled syringes The recommended dosage is 150 mg injected sub-cutaneously once a month into the thigh, abdomen, or the back of the upper arm Patients must be trained

to self-administer the drug at home Zinbryta is

contraindicated in patients with pre-existing hepatic disease or impairment, or a history of autoimmune conditions involving the liver; transaminase and bilirubin levels should be monitored monthly during treatment and for up to 6 months after the last dose

of the drug

CONCLUSION — Daclizumab (Zinbryta), a

subcutane-ously injected interleukin-2 blocking monoclonal antibody, appears to be more effective than intra-muscular interferon beta-1a at reducing relapse rates

in patients with relapsing-remitting multiple sclerosis (MS), but it can cause severe adverse effects including hepatotoxicity and immune-mediated disorders It has not been compared directly with any other disease-modifying drug used to treat MS ■

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IN BRIEF

Repatha Pushtronex – A New

Evolocumab Injection Device

The PCSK9 inhibitor evolocumab (Repatha – Amgen)

is now available in a single-dose, hands-free device

(Repatha Pushtronex) for once-monthly subcutaneous

infusion Evolocumab is FDA-approved as an adjunct to diet and maximally tolerated statin therapy for patients with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease who require additional lowering of low-density lipoprotein cholesterol (C), and as an adjunct to diet and other LDL-lowering therapies for patients with homozygous familial hypercholesterolemia (HoFH).

Evolocumab is also available in 140-mg single-use prefi lled

syringes and autoinjectors (Repatha Sureclick).1 Use of these formulations to administer the once-monthly dose (420 mg) requires patients to inject themselves three consecutive times within 30 minutes Another PCSK9 inhibitor, alirocumab

(Praluent), is injected every 2 weeks; it is available in

single-dose prefi lled syringes and pens.

Table 1 Evolocumab Products

Drug Formulations Usual Adult Dosage

Repatha (Amgen) 140 mg/mL single-use 140 mg SC q2 wks

prefilled syringe or 420 mg SC

once/month1,2

Repatha Sureclick 140 mg/mL single-use 140 mg SC q2 wks

Repatha Pushtronex 420 mg/3.5 mL single- 420 mg SC

1 Dosage for patients with HeFH or atherosclerotic cardiovascular disease Dosage for patients with HoFH is 420 mg SC once monthly.

2 The 420-mg dose is given as three consecutive 140-mg injections within 30 minutes.

IN BRIEF

Defi brotide (Defi telio) for Hepatic

Veno-Occlusive Disease

The FDA has approved defi brotide sodium (Defi telio –

Jazz), a mixture of mostly single-stranded

polydeoxy-ribonucleotide sodium salts, for treatment of adults

and children with hepatic veno-occlusive disease (also

known as sinusoidal obstruction syndrome) and renal or

pulmonary dysfunction following hematopoietic stem cell

transplantation (HSCT) It is the fi rst drug to be approved

by the FDA for treatment of severe hepatic veno-occlusive

disease Defi brotide was approved earlier by the European

Medicines Agency for the same indication.

Hepatic veno-occlusive disease is an uncommon (<2%)

complication of HSCT, but it has been associated with

a 70-80% mortality rate Defi brotide has antithrombotic,

anti-inflammatory, and antioxidant properties that protect

hepatic endothelial cells from the damage associated

with HSCT 1

Approval of defi brotide was based on the results of three

open-label studies in patients with hepatic veno-occlusive

disease and multi-organ dysfunction following HSCT

In one trial in 102 adults and children, treatment with

defi brotide 6.25 mg/kg every 6 hours for a median of 21.5

days was associated with a 38.2% survival rate (defi ned

as survival at day +100 post-HSCT), compared to a 25.0%

survival rate in 32 matched historical controls 2 In another

trial, the survival rate was 44% among 75 patients treated

with defi brotide 25 mg/kg/day 3 In an unpublished study

(summarized in the package insert), the survival rate was

45% among 351 patients treated with defi brotide as part of

an expanded access program.

Compared with historical controls, the overall incidence

of adverse effects was similar with defi brotide The

most common serious adverse effects have been

hypotension and hemorrhage, particularly pulmonary

alveolar hemorrhage (7%) Concurrent use of defi brotide

and a systemic anticoagulant or fi brinolytic drug

is contraindicated The recommended dosage of

defi brotide is 6.25 mg/kg given as a 2-hour IV infusion

every 6 hours for a minimum of 21 days The cost of 21

days of treatment with defi brotide for a patient weighing

70 kg is $155,925 4

1 M Palomo et al What is going on between defi brotide and

endothe-lial cells? Snapshots reveal the hot spots of their romance Blood

2016; 127:1719.

2 PG Richardson et al Phase 3 trial of defi brotide for the treatment

of severe veno-occlusive disease and multi-organ failure Blood

2016; 127:1656.

3 PG Richardson et al Defi brotide for the treatment of severe

he-patic veno-occlusive disease and multiorgan failure after stem cell

transplantation: a multicenter, randomized, dose-fi nding trial Biol

Blood Marrow Transplant 2010; 16:1005.

4 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

transac-tional price Source: AnalySource® Monthly August 5, 2016

The Repatha Pushtronex system consists of a

single-use, battery-powered infusor and a prefi lled cartridge containing a 420-mg dose of evolocumab Once assembled, the patient adheres the device to the skin of the abdomen, thigh, or upper arm and presses a button

to begin the subcutaneous injection; infusion of the

dose takes about 9 minutes One Repatha Pushtronex device costs $1175 Three 140-mg Repatha Sureclick autoinjectors or Repatha prefi lled syringes cost $1627.2

1 Evolocumab (Repatha) – a second PCSK9 inhibitor to lower LDL-cholesterol Med Lett Drugs Ther 2015; 57:140.

2 Approximate WAC for one 420-mg dose WAC = wholesaler acquisi-tion cost or manufacturer’s published price to wholesalers; WAC rep-resents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly August 5,

Online Only Article

In Brief: Epinephrine Auto-Injectors for Anaphylaxis www.medicalletter.org/TML-article-1503e

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e120

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IN BRIEF

Epinephrine Auto-Injectors for

Anaphylaxis

News about recent price increases for EpiPen

and EpiPen Jr (Mylan) may have patients asking

about other options for emergency treatment of

anaphylaxis Adrenaclick and its generic equivalent

(epinephrine injection auto-injector) are the only

other epinephrine auto-injectors currently available

in the US According to Impax (the manufacturer of

both the brand and generic products), Adrenaclick

is no longer being manufactured; the generic

product will continue to be marketed after supplies

of Adrenaclick are depleted Auvi-Q (Sanofi ), an

epinephrine auto-injector that was approved by the

FDA in 2013, was removed from the market in 2015

due to inconsistencies in delivery of epinephrine

doses, including failure to deliver the drug.1

Adrenaclick and its generic equivalent are similar to

EpiPen and EpiPen Jr in size and functionality, but they

are not considered interchangeable with the EpiPen

products due to differences in device design and

instructions for use One pack (two auto-injectors)

of EpiPen or EpiPen Jr costs $608.60 One pack of

Impax's generic auto-injectors costs $395.20.2

According to Mylan, generic versions of EpiPen and

EpiPen Jr will soon become available at about half the

cost of the brand-name products

1 FDA Updated: Sanofi US issues voluntary nationwide recall

of all Auvi-Q due to potential inaccurate dosage delivery

Available at www.fda.gov/Safety/Recalls/ucm469980.htm

Accessed September 1, 2016.

2 Approximate WAC WAC = wholesaler acquisition cost

or manufacturer’s published price to wholesalers; WAC

represents a published catalogue or list price and may not

represent an actual transactional price Source: AnalySource®

Monthly September 5, 2016 Reprinted with permission by

com/policies/drug-pricing-policy.

Related article(s) since publication

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Questions start on next page

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

1 Review the effi cacy and safety of nebivolol/valsartan (Byvalson) for treatment of hypertension.

2 Review the effi cacy and safety of daclizumab (Zinbryta) for treatment of multiple sclerosis.

3 Review the effi cacy and safety of defi brotide (Defi telio) for treatment of hepatic veno-occlusive disease.

4 Discuss how the Repatha Pushtronex device compares to other available formulations of evolocumab.

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DO NOT FAX OR MAIL THIS EXAM

To take CME exams and earn credit, go to:

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Issue 1503 Questions

(Correspond to questions #51-60 in Comprehensive Exam #75, available January 2017)

6 Daclizumab was more effective in reducing annualized relapse rates than:

a interferon beta-1a

b glatiramer acetate

c natalizumab

d fi ngolimod

7 A 30-year-old woman with MS relapses while being treated with glatiramer acetate She has not been treated previously with any other MS drugs You are considering switching her to daclizumab Which of the following statements about the use of daclizumab is true?

a She would not be a candidate for daclizumab treatment because it should generally be used only in patients who have had an inadequate response to ≥2 MS drugs

b Depression occurred more frequently with daclizumab than with interferon beta-1a in clinical trials

c Monthly monitoring of liver function is recommended during treatment with daclizumab

d all of the above

8 Daclizumab should be administered:

a orally

b subcutaneously

c intramuscularly

d intravenously

Defi brotide (Defi telio) for Hepatic Veno-Occlusive Disease

9 In open-label studies, treatment with defi brotide was associated with a survival rate of about:

a 20-25%

b 40-45%

c 60-65%

d 80-85%

Repatha Pushtronex – A New Evolocumab Injection Device

10 How many injections are needed to deliver a 420-mg dose of

evolocumab using Repatha Sureclick?

a 1

b 2

c 3

d 4

Byvalson – A Beta Blocker/ARB Combination for Hypertension

1 Use of nebivolol/valsartan can increase serum concentrations of:

a lithium

b potassium

c triglycerides

d all of the above

2 Which of the following drug classes is NOT generally

recommended for initial treatment of hypertension in a

non-black patient without comorbidities?

a thiazide-type diuretics

b ACE inhibitors

c beta blockers

d calcium channel blockers

3 At doses ≤10 mg/day, nebivolol acts as an antagonist at:

a beta 1 -adrenergic receptors

b beta 2 -adrenergic receptors

c beta 3 -adrenergic receptors

d both a and c

4 You prescribed nebivolol/valsartan 5/80 mg once daily for

a 53-year-old man with hypertension Despite adherence to

therapy for the past 2 months, his blood pressure goal has not

been reached You should:

a double the daily dose of nebivolol/valsartan to achieve a

greater antihypertensive effect

b consider switching to a different antihypertensive regimen

because higher dosages of nebivolol/valsartan do not

have a signifi cantly greater antihypertensive effect

c instruct the patient to cut the nebivolol/valsartan tablets,

taking a half tablet each morning and evening to achieve a

more consistent antihypertensive effect throughout the day

d add an ACE inhibitor to the patient’s antihypertensive

regimen because it will act synergistically with the ARB

valsartan

Daclizumab (Zinbryta) for Multiple Sclerosis

5 In clinical trials, daclizumab reduced annualized relapse rates

compared to placebo by about:

a 30%

b 50%

c 60%

d 75%

ACPE UPN: Per Issue Exam: 0379-0000-16-503-H01-P; Release: September 12, 2016, Expire: September 12, 2017 Comprehensive Exam 75: 0379-0000-17-075-H01-P; Release: January 2017, Expire: January 2018

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,

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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;

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