The medical letter on drugs and therapeutics september 12 2016

The Medical Letter

®

on Drugs and Therapeutics

Volume 58

ISSUE
ISSUE
No.

1433
1503
Volume 56

September 12, 2016

IN THIS ISSUE

Byvalson – A Beta Blocker/ARB Combination for Hypertension ..................................... p 115
Daclizumab (Zinbryta) for Multiple Sclerosis .................................................................... p 117
In Brief: Defibrotide (Defitelio) 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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The Medical Letter

®

on Drugs and Therapeutics

Volume 58

September 12, 2016
Take CME Exams

ISSUE

ISSUE No.

1433
1503
Volume 56

▶

ALSO IN THIS ISSUE

Daclizumab (Zinbryta) for Multiple Sclerosis .................................................................... p 117
In Brief: Defibrotide (Defitelio) 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

Byvalson – A Beta Blocker/ARB
Combination for Hypertension

The FDA has approved Byvalson (Allergan), a fixeddose 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 first 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 nonblack 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

Table 1. Initial Treatment of Hypertension1,2
General Population
Non-black

Thiazide-type diuretic,3 CCB,
ACE inhibitor, or ARB
Thiazide-type diuretic3 or CCB

Black
Chronic Kidney Disease
Non-black
Black

ACE inhibitor or ARB
ACE inhibitor or ARB

Diabetes
Non-black
Black

ACE inhibitor or ARB
Thiazide-type diuretic3 or CCB4

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.

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 first drug and often allows for use of lower, bettertolerated 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 2. Byvalson and Components
Drug

Formulations

Usual Adult Dosage

Cost1

Nebivolol/valsartan – Byvalson (Allergan)

5/80 mg tabs

5/80 mg once/d2

$1315.20

Nebivolol – Bystolic (Allergan)

2.5, 5, 10, 20 mg tabs

5-40 mg once/d

1315.20

Valsartan – generic
Diovan (Novartis)

40, 80, 160, 320 mg tabs

80-320 mg once/d

309.60
2041.20

1. Approximate WAC for 1 year's treatment at the lowest usual adult dosage. WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price. Source: AnalySource® Monthly. 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 benefit.

115

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The Medical Letter

Vol. 58 (1503)

®

Table 3. Some Other Combinations for Hypertension
Drug

Formulations

Cost1

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
Atacand HCT (AstraZeneca)

1269.90
1575.10

Irbesartan/HCTZ
generic
Avalide (Sanofi)

150/12.5, 300/12.5 mg
tabs

272.00
2477.70

Losartan/HCTZ
generic
Hyzaar (Merck)

50/12.5, 100/12.5,
100/25 mg tabs

Olmesartan/HCTZ
Benicar HCT
(Daiichi Sankyo)

20/12.5, 40/12.5,
40/25 mg tabs

Telmisartan/HCTZ
generic
Micardis HCT
(Boehringer Ingelheim)

40/12.5, 80/12.5,
80/25 mg tabs

Valsartan/HCTZ
generic
Diovan HCT (Novartis)

80/12.5, 160/12.5,
160/25, 320/12.5,
320/25 mg tabs

79.10
1393.20
2095.20

1542.90
2133.70

408.40
2522.40

ARBs and CCBs

Amlodipine/telmisartan
5/40, 5/80, 10/40,
10/80 mg tabs
generic
Twynsta (Boehringer Ingelheim)

1515.80
2295.80

Amlodipine/valsartan
generic
Exforge (Novartis)

5/160, 5/320, 10/160,
10/320 mg tabs

572.90
2630.40

Amlodipine/olmesartan
Azor (Daiichi Sankyo)

5/20, 5/40, 10/20,
10/40 mg tabs

2613.60

ARBs, CCBs, and Diuretics
Valsartan/amlodipine/HCTZ 160/5/12.5, 160/5/25,
160/10/12.5,

generic
Exforge HCT (Novartis)
160/10/25,
320/10/25 mg tabs

1340.40
2630.40

Olmesartan/amlodipine/HCTZ 20/5/12.5, 40/5/12.5,
Tribenzor (Daiichi Sankyo)
40/5/25, 40/10/12.5,
40/10/25 mg tabs

2613.60

Beta-Adrenergic Blockers and Diuretics
Atenolol/chlorthalidone
generic
Tenoretic (Almatica)

50/25, 100/25 mg tabs

Bisoprolol/HCTZ
generic
Ziac (Duramed/Barr)

2.5/6.25, 5/6.25,
10/6.25 mg tabs

Metoprolol/HCTZ

generic
Lopressor HCT (Validus)

50/25, 100/25,
100/50 mg tabs
50/25 mg tabs

Nadolol/bendroflumethiazide
generic
Corzide (Pfizer)

40/5, 80/5 mg tabs

197.20
4320.00
96.70
1869.40
331.00
745.40
1341.40
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
reserved. ©2016. www.fdbhealth.com/policies/drug-pricing-policy.

116

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: fixed-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
significantly 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 significantly 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 hyperkalemia 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-angiotensinaldosterone system (RAAS). Use of valsartan with
potassium-sparing diuretics or other drugs that


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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 benefit. Patients already taking nebivolol
5 mg and valsartan 80 mg separately can switch to
the fixed-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 (ChildPugh 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 fixed-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 first
choice for add-on therapy in patients inadequately
controlled on an ARB. ■
1. Drugs for hypertension. Treat Guidel Med Lett 2014; 12:31.
2. TD Giles et al. Efficacy and safety of nebivolol and valsartan as
fixed-dose combination in hypertension: a randomised, multicentre study. Lancet 2014; 383:1889.
3. J Fongemie and E Felix-Getzik. A review of nebivolol pharmacology and clinical evidence. Drugs 2015; 75:1349.
4. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2016. Available at: ical
letter.org/downloads/CYP_PGP_Tables.pdf. Accessed September 1, 2016.

Vol. 58 (1503)

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September 12, 2016

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
first subcutaneously injected monoclonal antibody to

be approved for treatment of MS.
Pronunciation Key
Daclizumab: da kliz’ ue mab
Zinbryta: zin brye’ tuh

Because of safety concerns, the label recommends 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 first-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, fingolimod (Gilenya) and dimethyl
fumarate (Tecfidera) appear to be more effective than
teriflunomide (Aubagio).2
Table 1. Pharmacology
Class

Interleukin-2 antagonist monoclonal antibody

Formulation

150 mg/mL single-dose prefilled syringe

Route

Subcutaneous injection

Tmax

5-7 days

Metabolism

Catabolism to peptides and amino acids

Half-life

21 days

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-affinity 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
117


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September 12, 2016

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

Drug

Reduction
in Clinical
Relapse Rate

Usual
Maintenance Dosage

Frequent or Serious
Adverse Effects

Cost1

Injectable
Interferon beta-1a –

Avonex (Biogen-Idec)
Rebif (EMD Serono)
Peginterferon beta-1a –
Plegridy (Biogen-Idec)
Interferon beta-1b –
Betaseron (Bayer)
Extavia (Novartis)

30-35%2

Glatiramer acetate –
Copaxone (Teva)

~30%2

250 mcg SC every
other day

Injection-site reactions, flu-like
symptoms, depression, transaminase elevations, possible
cardiac toxicity, autoimmune
disorders, allergic reactions,
hepatotoxicity, seizures, suicidal
ideation, lymphopenia with
interferon beta-1b

20 mg SC once/d
or 40 mg 3x/wk
20 mg SC once/d

Injection-site reactions, transient
post-injection systemic reactions
(flushing, chest pain, palpitations,
dyspnea)

30 mcg IM once/wk
44 mcg SC 3x/wk
125 mcg SC q2 wks

Glatopa (Sandoz)

$75,673.00
81,686.30
75,673.00
81,286.80
67,810.70
80,216.10
70,251.50
63,192.50

Natalizumab – Tysabri
(Biogen-Idec)

68%3

300 mg IV q4 wks

Headache, fatigue, arthralgia,
depression, infections, hypersensitivity reactions, hepatotoxicity,
PML

75,361.00

Alemtuzumab – Lemtrada
(Genzyme)

50-55%4

12 mg IV once/d x 5d
followed 1 year later by
12 mg IV once/d x 3d

Infusion reactions (rash, headache,
pyrexia, nausea, urticaria), nasopharyngitis, autoimmune disorders
(immune cytopenias [especially
thrombocytopenia], glomerular
nephropathies, thyroid disorders),
infections, pneumonitis, malignancies

60,731.305

Daclizumab – Zinbryta
(Biogen/Abbvie)

456-54%7

150 mg SC once/mo

Autoimmune disorders (skin reactions,
lymphadenopathy, autoimmune

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

82,000.00

Mitoxantrone – generic

~60%8

12 mg/m2 IV q3 mos

Nausea, alopecia, amenorrhea,
cardiotoxicity at cumulative doses
>100 mg/m2, myelosuppression,
acute and chronic myeloid leukemia

Fingolimod – Gilenya
(Novartis)

~55%10

0.5 mg PO once/d

Transaminase elevations, bradycardia,
AV block, macular edema, mild
hypertension, lymphopenia, decreased
pulmonary function, hypersensitivity
reactions, malignancies, serious
viral and fungal infections, PML

82,044.70

Teriflunomide – Aubagio
(Sanofi-Aventis)

~30%11

7 or 14 mg PO once/d

Diarrhea, nausea, alopecia, transaminase elevations, neutropenia,
leukopenia, peripheral neuropathy,
hyperkalemia, hypophosphatemia,
hypertension, hepatic failure, acute
renal failure, Stevens-Johnson
syndrome, toxic epidermal necrolysis

74,379.70

Dimethyl fumarate –
Tecfidera (Biogen-Idec)

~50%12

240 mg PO bid

Flushing, abdominal pain, nausea,
vomiting, diarrhea, lymphopenia,
anaphylaxis, angioedema, PML

76,832.50

1330.409

Oral

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 first 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 m2 using 12.5-mL multi-dose vials containing 25 mg (2 mg/mL).
10. Oral fingolimod (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 (Tecfidera) for multiple sclerosis. Med Lett Drugs Ther 2013; 55:45.

118


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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 significantly lower in
patients treated with daclizumab (0.21 vs 0.46 with
placebo). Patients treated with daclizumab also had
significantly fewer new or newly-enlarging brain lesions
seen on MRI scans. The percentage of patients with
confirmed disability progression at week 52 (KaplanMeier estimate) was 6% with daclizumab versus 13%
with placebo.4 Extensions of this trial found that clinical
efficacy 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 significantly 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 significantly lower with

daclizumab. The estimated percentage of patients
with confirmed disability progression at week 144 was
16% with daclizumab compared to 20% with interferon
beta-1a, a nonsignificant 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

Vol. 58 (1503)

September 12, 2016

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 prefilled syringes.
The recommended dosage is 150 mg injected subcutaneously 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 subcutaneously injected interleukin-2 blocking monoclonal
antibody, appears to be more effective than intramuscular 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 diseasemodifying drug used to treat MS. ■
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 efficacy and safety of daclizumab and its potential
role in the treatment of multiple sclerosis. Ther Adv Neurol Disord 2014; 7:7.
4. 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.
5. G Giovannoni et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECTION): a multicentre,

randomised, double-blind extension trial. Lancet Neurol 2014;
13:472.
6. R Gold et al. Safety and efficacy of daclizumab in relapsingremitting 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).

119


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September 12, 2016

Vol. 58 (1503)

IN BRIEF

IN BRIEF

Defibrotide (Defitelio) for Hepatic
Veno-Occlusive Disease

Repatha Pushtronex – A New
Evolocumab Injection Device

The FDA has approved defibrotide sodium (Defitelio –
Jazz), a mixture of mostly single-stranded polydeoxyribonucleotide 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 first drug to be approved
by the FDA for treatment of severe hepatic veno-occlusive
disease. Defibrotide was approved earlier by the European
Medicines Agency for the same indication.

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
(LDL-C), and as an adjunct to diet and other LDLlowering therapies for patients with homozygous familial
hypercholesterolemia (HoFH).

Hepatic veno-occlusive disease is an uncommon (<2%)
complication of HSCT, but it has been associated with
a 70-80% mortality rate. Defibrotide has antithrombotic,
anti-inflammatory, and antioxidant properties that protect
hepatic endothelial cells from the damage associated
with HSCT.1
Approval of defibrotide 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
defibrotide 6.25 mg/kg every 6 hours for a median of 21.5
days was associated with a 38.2% survival rate (defined
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 defibrotide 25 mg/kg/day.3 In an unpublished study
(summarized in the package insert), the survival rate was
45% among 351 patients treated with defibrotide as part of
an expanded access program.
Compared with historical controls, the overall incidence
of adverse effects was similar with defibrotide. The
most common serious adverse effects have been
hypotension and hemorrhage, particularly pulmonary
alveolar hemorrhage (7%). Concurrent use of defibrotide
and a systemic anticoagulant or fibrinolytic drug
is contraindicated. The recommended dosage of
defibrotide 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 defibrotide for a patient weighing
70 kg is $155,925.4
1. M Palomo et al. What is going on between defibrotide and endothelial cells? Snapshots reveal the hot spots of their romance. Blood
2016; 127:1719.
2. PG Richardson et al. Phase 3 trial of defibrotide for the treatment
of severe veno-occlusive disease and multi-organ failure. Blood
2016; 127:1656.
3. PG Richardson et al. Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell
transplantation: a multicenter, randomized, dose-finding trial. Biol
Blood Marrow Transplant 2010; 16:1005.

4. 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. August 5, 2016. Reprinted with permission by First Databank, Inc. All rights reserved.
©2016. www.fdbhealth.com/policies/drug-pricing-policy.

120

Evolocumab is also available in 140-mg single-use prefilled
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 singledose prefilled syringes and pens.
Table 1. Evolocumab Products
Drug

Formulations

Usual Adult Dosage

Repatha (Amgen)

140 mg/mL single-use
prefilled syringe

140 mg SC q2 wks
or 420 mg SC
once/month1,2

Repatha Sureclick

140 mg/mL single-use
prefilled autoinjector

140 mg SC q2 wks
or 420 mg SC
once/month1,2

Repatha Pushtronex

420 mg/3.5 mL singleuse infusor with
prefilled cartridge

420 mg SC
once/month

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.

The Repatha Pushtronex system consists of a singleuse, battery-powered infusor and a prefilled 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 prefilled syringes cost $1627.2
1. Evolocumab (Repatha) – a second PCSK9 inhibitor to lower LDLcholesterol. Med Lett Drugs Ther 2015; 57:140.
2. Approximate WAC for one 420-mg dose. 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.

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

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The Medical Letter

®

on Drugs and Therapeutics

Volume 58 (Issue 1503)

September 12, 2016

IN BRIEF

Epinephrine Auto-Injectors for
Anaphylaxis

Related article(s) since publication

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
First Databank, Inc. All rights reserved. ©2016. www.fdbhealth.
com/policies/drug-pricing-policy.

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Review the efficacy and safety of nebivolol/valsartan (Byvalson) for treatment of hypertension.
Review the efficacy and safety of daclizumab (Zinbryta) for treatment of multiple sclerosis.
Review the efficacy and safety of defibrotide (Defitelio) for treatment of hepatic veno-occlusive disease.
Discuss how the Repatha Pushtronex device compares to other available formulations of evolocumab.

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Issue 1503 Questions
(Correspond to questions #51-60 in Comprehensive Exam #75, available January 2017)
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 nonblack 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. beta1-adrenergic receptors
b. beta2-adrenergic receptors
c. beta3-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 significantly 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%

6. Daclizumab was more effective in reducing annualized relapse
rates than:
a. interferon beta-1a
b. glatiramer acetate
c. natalizumab
d. fingolimod

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
Defibrotide (Defitelio) for Hepatic Veno-Occlusive Disease
9. In open-label studies, treatment with defibrotide 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

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
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