The medical letter on drugs and therapeutics may 11 2015

The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959

Volume 57

ISSUE
ISSUE
No.

1433
1468
Volume 56

May 11, 2015

IN THIS ISSUE

Peginterferon Beta-1a (Plegridy) for Multiple Sclerosis ....................................................p 67
Concentrated Insulin Glargine (Toujeo) for Diabetes ..........................................................p 69
Extended-Release Hydrocodone (Hysingla ER) for Pain ....................................................p 71
Testosterone Nasal Gel (Natesto) for Hypogonadism .........................................................p 73
Blinatumomab (Blincyto) for Acute Lymphoblastic Leukemia ..................................online only

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The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959

Volume 57

ISSUE

ISSUE No.

1433

1468
Volume 56

▶

May 11, 2015
Take CME Exams
ALSO IN THIS ISSUE

Concentrated Insulin Glargine (Toujeo) for Diabetes ..........................................................p 69
Extended-Release Hydrocodone (Hysingla ER) for Pain ....................................................p 71
Testosterone Nasal Gel (Natesto) for Hypogonadism .........................................................p 73
Blinatumomab (Blincyto) for Acute Lymphoblastic Leukemia ..................................online only

Peginterferon Beta-1a (Plegridy)
for Multiple Sclerosis

The FDA has approved a pegylated form of interferon
beta-1a (Plegridy – Biogen) for biweekly treatment of
patients with relapsing multiple sclerosis (MS).
Pronunciation Key
Peginterferon: peg" in ter feer' on
Plegridy: pleh' gri dee

STANDARD TREATMENT — FDA-approved drugs for
treatment of relapsing-remitting MS are listed in
Table 2 (see p. 68). Interferon beta (Avonex, and others)
and glatiramer acetate (Copaxone, Glatopa), both
of which must be injected, are generally used first.
They reduce clinical relapse rates by about 30% and

decrease the number of brain lesions seen on MRI.1
Second-line drugs are usually reserved for patients
with severe disease and for those who cannot
take first-line drugs. Natalizumab (Tysabri), an IV
recombinant humanized monoclonal antibody, can
decrease relapse frequency and slow progression
of the disease. Alemtuzumab, an IV anti-CD52
monoclonal antibody, is now approved as Lemtrada
for treatment of MS; it has been more effective than
interferon beta in preventing relapses in treatmentnaive patients, but because of its safety profile, the
package insert recommends reserving Lemtrada for
patients who have had an inadequate response to two
or more anti-MS drugs.
Oral drugs have only been available since 2010 and
have generally been used as second-line agents.
Fingolimod (Gilenya), the first oral drug approved for
treatment of MS, has reduced relapse rates by >50%
and delayed progression of disability. Teriflunomide

Table 1. Pharmacology
Class
Route

Interferon beta
Subcutaneous injection

Formulation

63 mcg/0.5 mL, 94 mcg/0.5 mL,1
125 mcg/0.5 mL preservative-free solution

in single-use pen or prefilled syringe
1-1.5 days
~78 hrs
Catabolic
Primarily renal

Tmax
Half-life (terminal)
Metabolism
Excretion

1. The 63 mcg/0.5 mL and 94 mcg/0.5 mL pens and syringes are only available in a 4-week starter pack.

(Aubagio), a pyrimidine synthesis inhibitor, appears
to cause smaller reductions in relapse rates than
fingolimod, but is better tolerated.2 Dimethyl fumarate
(Tecfidera) is an antioxidant that appears to be more
effective than teriflunomide and is also better tolerated
than fingolimod.3
THE NEW FORMULATION — Interferon beta was the
first drug to alter the course of MS, but its adverse
effects and the need for every-other-day subcutaneous or weekly intramuscular injections have made
it difficult to use.4 Plegridy is pegylated (attached to
polyethylene glycol) to increase its duration of action.
A CLINICAL STUDY — FDA approval of peginterferon
beta-1a was based on a 96-week, randomized,
double-blind clinical trial (ADVANCE) comparing the
new formulation given once every 2 or 4 weeks with
placebo in 1512 patients with relapsing-remitting
MS. Annualized relapse rates after 48 weeks were

significantly lower with peginterferon beta-1a every
2 weeks (0.256) and every 4 weeks (0.288) than with
placebo (0.397).5 After 48 weeks, patients receiving
placebo were re-randomized into one of the two active
drug groups. The annualized relapse rate during the
second half of the trial was 0.178 among patients
67

Published by The Medical Letter, Inc. • A Nonprofit Organization


The Medical Letter

May 11, 2015

Vol. 57 (1468)

®

Table 2. FDA-Approved Drugs for Relapsing Multiple Sclerosis
Frequent or Serious
Adverse Effects

Drug

Reduction in Clinical Usual Maintenance
Relapse Rate
Dosage

Cost1

$59,250.003

Parenteral
Alemtuzumab – Lemtrada
(Genzyme)

Rash, headache, pyrexia, nasopharyngitis,
nausea, autoimmune disorders, infusion
reactions, malignancies, immune cytopenias
(especially thrombocytopenia), glomerular
nephropathies, thyroid disorder, infections,
pneumonitis

50%-55%2

Glatiramer acetate –
Copaxone (Teva)

Injection-site reactions, transient
post-injection systemic reactions,
chest pain

~30%4

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

30%-35%4

Glatopa (Sandoz)

5

Interferon beta-1a –
Avonex (Biogen)
Rebif (EMD SeronoIdec)
pegylated – Plegridy
(Biogen)
Interferon beta-1b –
Betaseron (Bayer)
Extavia (Novartis)

Year 1: 12 mg IV once/d x 5d
Year 2: 12 mg IV once/d x 3d

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

73,326.00
65,104.00
N.A.

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

65,442.00
70,638.10
65,442.00

250 mcg SC
every other day

69,397.00
57,693.60

Mitoxantrone – generic

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

~60%6

12 mg/m2 IV q3 mos

Natalizumab – Tysabri
(Biogen)

Headache, fatigue, arthralgia, depression,
infections, hypersensitivity reactions,
hepatotoxicity, progressive multifocal
leukoencephalopathy (PML)

~65%

300 mg IV q4 wks

64,480.00

Fingolimod – Gilenya
(Novartis)

Transaminase elevations, bradycardia,
AV block, macular edema, mild
hypertension, decreased pulmonary
function, serious viral infections

~55%8

0.5 mg PO once/d

70,752.10

Teriflunomide – Aubagio
(Genzyme)

Diarrhea, nausea, alopecia, transaminase
elevations, neutropenia, leukopenia,
peripheral neuropathy, hyperkalemia,
hypophosphatemia, hypertension,
hepatic failure, acute renal failure

~30%4

7 or 14 mg PO once/d

66,017.00

Dimethyl fumarate –
Tecfidera (Biogen)

Flushing, abdominal pain, nausea,
lymphopenia, progressive multifocal
leukoencephalopathy (PML)

~50%9

240 mg PO bid

65,520.00

3167.407

Oral

N.A. = cost not yet available
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. April 5, 2015. Reprinted
with permission by First Databank, Inc. All rights reserved. ©2015. www.fdbhealth.com/policies/drug-pricing-policy.
2. Compared to interferon beta-1a (JA Cohen et al. Lancet 2012; 380:1819; AJ Coles et al. Lancet 2012: 380:1829).
3. Cost for first year’s treatment is $98,750.
4. Med Lett Drugs Ther 2012; 54:89.
5. Branded generic 20 mg/mL formulation approved April 16, 2015. Not commercially available at press time.

6. HP Hartung et al. Lancet 2002; 360:9018.
7. Cost for treatment of a patient with a body surface area of 1.7 m2 using 10-mL multi-dose vials containing 2 mg/mL.
8. Med Lett Drugs Ther 2010; 52:98.
9. Med Lett Drugs Ther 2013; 55:45.

receiving peginterferon beta-1a every 2 weeks and
0.291 among those receiving the drug every 4 weeks.6
No studies directly comparing peginterferon beta-1a
with other beta interferon formulations are available,
but reductions in relapse rates have been similar.
ADVERSE EFFECTS — Injection-site reactions,
influenza-like symptoms, fever, and headache were
the most common adverse effects of peginterferon
beta-1a in the ADVANCE trial.
68

DOSAGE AND ADMINISTRATION — The recommended
dosage of peginterferon beta-1a is 63 mcg by
subcutaneous injection on day 1, followed by 94 mcg
on day 15 and 125 mcg on day 29 and every 14 days
thereafter. Plegridy is supplied in cartons containing
two single-use prefilled pens or syringes. A starter
pack contains the initial 63-mcg (orange) and 94mcg (blue) doses. Most patients can self-inject after
receiving proper training.


The Medical Letter

®

CONCLUSION — Pegylated interferon beta-1a
(Plegridy) injected subcutaneously every 2 weeks
appears to be similar in its efficacy and adverse effects
to older interferon formulations that must be injected
more frequently. ■
1. Canadian Agency for Drugs and Technologies in Health. CADTH
therapeutic review. Comparative clinical and cost-effectiveness
of drug therapies for relapsing-remitting multiple sclerosis
[Internet]. Ottawa: The Agency; 2013 Oct. (CADTH Therapeutic
Review vol. 1, no. 26). [cited 2015 April 30]. Available at: https://
www.cadth.ca/media/pdf/TR0004_RRMS_ScienceReport_e.pdf.
2. New drugs for multiple sclerosis. Med Lett Drugs Ther 2012;
54:89.
3. Dimethyl fumarate (Tecfidera) for multiple sclerosis. Med Lett
Drugs Ther 2013; 55:45.
4. V Annibali et al. IFN-β and multiple sclerosis: from etiology to
therapy and back. Cytokine Growth Factor Rev 2015; 26:221.
5. PA Calabresi et al. Pegylated interferon -1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3,
double-blind study. Lancet Neurol 2014; 13:657.
6. BC Kieseier et al. Peginterferon beta-1a in multiple sclerosis: 2-year
results from ADVANCE. Mult Scler 2014 November 28 (epub).

▶

Concentrated Insulin Glargine
(Toujeo) for Diabetes

The FDA has approved Toujeo (Sanofi), a more
concentrated form of insulin glargine containing 300
IU/mL compared to the 100 IU/mL in Lantus (Sanofi).

Lantus is nearing the end of its patent protection in the
US, and biosimilars are expected to become available.
Pronunciation Key
Insulin glargine: in’ su lin glar’ jeen Toujeo: too jay’ oh

INSULIN GLARGINE — A long-acting analog of
human insulin synthesized by recombinant DNA
technology, insulin glargine forms microprecipitates
in subcutaneous tissue that prolong its duration
of action, permitting once-daily injection in most
patients. Toujeo has a more gradual and prolonged
release of insulin from the subcutaneous depot than
Lantus, resulting in more even activity throughout the
dosing period and a longer duration of action. The
prolonged time in subcutaneous tissue may reduce
the bioavailability of Toujeo.1,2
CLINICAL STUDIES — FDA approval of Toujeo was
based on one open-label trial in patients with type 1
diabetes (available only as an abstract) and 3 openlabel studies in patients with type 2 diabetes.3-6 All of
the studies compared Toujeo with Lantus; the primary
endpoint was the change in HbA1c from baseline at
26 weeks, and the main secondary endpoint was the
percentage of patients with at least one confirmed
(≤70 mg/dL) or severe nocturnal hypoglycemic

Vol. 57 (1468)

May 11, 2015

Table 1. Some Toujeo Clinical Trials

Study
Design

Regimen

Type 2 Diabetes
EDITION 13 Mealtime insulin
26 weeks
+/- metformin4
(n=807)
+ Glargine 300 IU/mL
+ Glargine 100 IU/mL

HbA1c
Nocturnal
Change (%)1 Hypoglycemia2

-0.83
-0.83

36%†
46%

EDITION 25
26 weeks
(n=811)

Oral antidiabetic drugs6
+ Glargine 300 IU/mL
+ Glargine 100 IU/mL

-0.57
-0.56

21.6%†
27.9%

EDITION 37
26 weeks
(n=878)

Oral antidiabetic drugs8
+ Glargine 300 IU/mL
+ Glargine 100 IU/mL

-1.42
-1.46

16%
17%

-0.40
-0.44

8.110
7.910

Type 1 Diabetes
EDITION 49 Mealtime insulin
26 weeks

+ Glargine 300 IU/mL
(n=549)
+ Glargine 100 IU/mL

†Statistically significant compared to insulin glargine 100 IU/mL
1. Mean change from baseline.
2. Percent of patients with at least one confirmed (≤70 mg/dL) or severe
nocturnal hypoglycemic event between week 9 and month 6.
3. MC Riddle et al. Diabetes Care 2014; 37:2755.
4. In patients previously uncontrolled on ≥42 units/day of basal insulin and
mealtime insulin with or without metformin.
5. H Yki-Järvinen et al. Diabetes Care 2014; 37:3235.
6. In patients previously taking ≥42 units/day of basal insulin and oral antidiabetic drugs (except sulfonylureas).
7. GB Bolli et al. Diabetes Obes Metab 2015; 17:386.
8. In insulin-naive patients who were taking oral antidiabetic drugs. Glinides,
sulfonylureas, and oral antidiabetic drugs not approved for use with insulin were discontinued at baseline.
9. PD Home et al. Diabetologia 2014; 57 (Suppl 1):S69. Abstract 148.
10. Events per participant-year of confirmed (≤70 mg/dL) or severe nocturnal
hypoglycemia between week 9 and month 6.

event reported between week 9 and month 6. In
all 4 studies, the reduction in HbA1c with glargine
300 IU/mL was similar to that with the 100 IU/mL
formulation. In 2 of the trials in patients with type
2 diabetes, rates of nocturnal hypoglycemia were
significantly lower in the glargine 300 IU/mL group
compared to the glargine 100 IU/mL group. Patients
treated with glargine 300 IU/mL required about 1015% more basal insulin per day than those treated
with glargine 100 IU/mL.
In a 6-month, open-label extension of one of the type

2 diabetes trials, glycemic control at the end of 12
months was maintained in both the glargine 300 IU/
mL group and the glargine 100 IU/mL group. Fewer
patients treated with glargine 300 IU/mL experienced
at least one confirmed or severe hypoglycemic event
at night or at any time of the day compared to those
treated with glargine 100 IU/mL. Annualized rates of
hypoglycemia were similar in both groups.8
A meta-analysis of the 3 clinical trials in patients with
type 2 diabetes (available only as an abstract) found
that the risk of a nocturnal hypoglycemic event or a
hypoglycemic event at any time of day was lower in
patients treated with glargine 300 IU/mL than in those
treated with glargine 100 IU/mL (31.7% vs 41.3% and
67.8% vs 73.8%, respectively).7
69


The Medical Letter

May 11, 2015

Vol. 57 (1468)

®

Table 2. Intermediate- and Long-Acting Insulins
Drug

Concentration

Some Formulations

Intermediate-Acting Insulins
NPH –
Humulin N 2 (Lilly)
Novolin N 2 (Novo Nordisk)
ReliOn/Novolin N 2 (Novo Nordisk)

Onset

Duration

1-2 hrs

16-24+ hrs

Cost1

100 IU/mL
100 IU/mL
100 IU/mL

3, 10 mL vials; 3 mL KwikPen
10 mL vial
10 mL vial

100 IU/mL

10 mL vial; 3 mL FlexTouch pen

1-4 hrs

12-20 hrs

298.20

100 IU/mL
300 IU/mL

10 mL vial; 3 mL SoloStar pen
1.5 mL SoloStar pen

1-4 hrs
1-6 hrs

22-24 hrs
24-36 hrs

298.20
335.50

$278.303
219.103
49.803,4

Long-Acting Insulins
Insulin detemir –
Levemir (Novo Nordisk)
Insulin glargine –

Lantus (Sanofi)
Toujeo (Sanofi)

1. Approximate WAC for 30 days' treatment with 40 IU/day in prefilled pens (or vials if pen formulation not available). 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. April 5, 2015. Reprinted with permission by First Databank, Inc. All rights reserved. ©2015. www.fdbhealth.com/policies/drug-pricing-policy.
2. Available over the counter.
3. Cost of 2 vials.
4. Cost from manufacturer. Available at www.relion.com/products/relionnovolin-human-insulin-n-inj. Accessed April 27, 2015. Available only at Walmart.

ADVERSE EFFECTS — In the 3 published studies in
patients with type 2 diabetes, there were no differences
in adverse effects other than nocturnal hypoglycemia
between glargine 300 IU/mL and 100 IU/mL, except
that in one study (EDITION 2), weight gain was less
with glargine 300 IU/mL (0.08 kg vs 0.66 kg).
PREGNANCY — There are no clinical studies of Toujeo
in pregnant women. According to the manufacturer, it
should only be used if the potential benefit outweighs
the potential risk. Lantus is classified as category C
(risk cannot be ruled out) for use during pregnancy.
DOSAGE AND ADMINISTRATION — Toujeo is injected
subcutaneously once daily, at the same time each
day. The recommended starting dose for insulinnaive patients with type 1 diabetes is about one-third
to one-half of the total daily insulin dose (the usual
total daily starting dose of insulin for patients with
type 1 diabetes is about 0.2-0.4 IU/kg); the remainder
of the total daily insulin dose should be given as
rapid-acting insulin. In insulin-naive patients with
type 2 diabetes, the recommended starting dose is
0.2 IU/kg once daily.

In patients switching from a once-daily long-acting
insulin, the starting dose of Toujeo should be the same
as the once-daily long-acting insulin dose. Patients
previously controlled on Lantus may need a 10-15%
higher daily dose of Toujeo to maintain glycemic
control. Patients switching from twice-daily NPH
insulin should start Toujeo at a dose that is 80% of the
total daily NPH dose. The dose of Toujeo should not be
titrated more frequently than every 3 to 4 days.
Toujeo is available in 1.5-mL disposable prefilled pens.
Unused pens should be refrigerated; pens that have
70

been opened should be stored at room temperature
and discarded after 28 days.
CONCLUSION — Toujeo, the new 300 IU/mL formulation
of insulin glargine, is as effective as insulin glargine
100 IU/mL (Lantus) in lowering HbA1c, and might
cause less hypoglycemia. ■
1. RH Becker et al. New insulin glargine 300 units·mL-1 provides
a more even activity profile and prolonged glycemic control at
steady state compared with insulin glargine 100 units·mL-1.
Diabetes Care 2015; 38:637.
2. M Shiramoto et al. Single-dose new insulin glargine 300 U/ml
provides prolonged, stable glycaemic control in Japanese and
European people with type 1 diabetes. Diabetes Obes Metab
2015; 17:254.
3. PD Home et al. Glycaemic control and hypoglycaemia with new
insulin glargine 300 U/mL in people with type 1 diabetes (EDITION 4). Diabetologia 2014; 57 (Suppl 1):S69. Abstract 148.
4. MC Riddle et al. New insulin glargine 300 units/mL versus

glargine 100 units/mL in people with type 2 diabetes using
basal and mealtime insulin: glucose control and hypoglycemia
in a 6-month randomized controlled trial (EDITION 1). Diabetes
Care 2014; 37:2755.
5. H Yki-Järvinen et al. New insulin glargine 300 units/mL versus
glargine 100 units/mL in people with type 2 diabetes using oral
agents and basal insulin: glucose control and hypoglycemia in
a 6-month randomized controlled trial (EDITION 2). Diabetes
Care 2014; 37:3235.
6. GB Bolli et al. New insulin glargine 300 U/ml compared with
glargine 100 U/ml in insulin-naïve people with type 2 diabetes
on oral glucose-lowering drugs: a randomized controlled trial
(EDITION 3). Diabetes Obes Metab 2015; 17:386.
7. I Hramiak et al. New insulin glargine 300 U/mL: glycemic control and hypoglycemia in a meta-analysis of phase 3a EDITION
clinical trials in people with T2DM. Can J Diabetes 2014; 38:s8.
Abstract 16.
8. MC Riddle et al. One year sustained glycaemic control and less
hypoglycaemia with new insulin glargine 300 U/mL compared
with 100 U/mL in people with type 2 diabetes using basal +
meal-time insulin (EDITION 1 12-month randomized trial including 6-month extension). Diabetes Obes Metab 2015 April 2
(epub).


The Medical Letter

▶

®

Extended-Release Hydrocodone

(Hysingla ER) for Pain

The FDA has approved a second extended-release (ER)
formulation of the oral opioid agonist hydrocodone
(Hysingla ER – Purdue) for management of pain severe
enough to require continuous long-term therapy and
for which alternative treatment options are inadequate.
Hysingla ER tablets have abuse-deterrent properties
to discourage their misuse.
Pronunciation Key
Hydrocodone: hye droe koe' done
Hysingla: hye sing' luh

HYDROCODONE — Hydrocodone has been available for
years in combination with acetaminophen (Vicodin, and
others) or ibuprofen (Vicoprofen, and others). The first
single-ingredient hydrocodone product to be marketed
in the US was Zohydro ER,1 which is formulated
as a capsule. It was originally approved without
abuse-deterrent properties, but a new formulation
incorporating excipients that form a viscous gel when
the capsules are crushed and dissolved has been
approved and will be available soon.
Hydrocodone is a schedule II controlled substance.
Combination pain medications containing hydrocodone
were previously classified as schedule III, but were reclassified as schedule II in October 2014. As part of a Risk
Evaluation and Mitigation Strategy (REMS) program, the
FDA has required that training in the use of extendedrelease or long-acting opioids such as Hysingla ER be
made available to prescribers from the manufacturers.

Vol. 57 (1468)

May 11, 2015

POTENTIAL FOR ABUSE — The clinical abuse potential
of Hysingla ER tablets by the intranasal or oral route
was evaluated in 2 double-blind, randomized trials
(summarized in the package insert), each in about 30
nondependent opioid abusers.
In the intranasal administration trial, coarsely and
finely ground Hysingla ER 60-mg tablets were
compared to the same dose of powdered immediaterelease (IR) hydrocodone. Incomplete dosing (due
to the drug falling from the nostril) occurred in 23
patients (82%) taking Hysingla ER and in none of
those taking hydrocodone powder. Patients taking
Hysingla ER had significantly lower scores for “drug
liking” and desire to “take drug again”.
In the oral administration trial, scores for “drug liking”
and desire to “take drug again” were also significantly
lower with intact and chewed Hysingla ER 60-mg
tablets compared to the same dose of an oral solution
of IR hydrocodone.
If a Hysingla ER tablet is dissolved, it will form a viscous
gel that is difficult to inject through a hypodermic
needle.
PHARMACOLOGY — Plasma hydrocodone concentrations increase gradually with Hysingla ER and reach
a peak (Tmax) after a median of 14-16 hours. The
area under the concentration time curve (AUC) and
maximum concentration (Cmax) increase linearly with
doses of 20-120 mg. The mean terminal half-life for all

doses ranges from 7-9 hours.

Table 1. Some Extended-Release Oral Opioids
Drug
Hydrocodone –
Hysingla ER (Purdue)
Zohydro ER (Pernix)
Hydromorphone – Exalgo (Mallinckrodt)
generic
Morphine –
Kadian (Actavis)
generic
MS Contin (Purdue)
generic
Morphine/naltrexone – Embeda (Pfizer)
Oxycodone – OxyContin (Purdue)
generic
Oxymorphone – Opana ER (Endo)
generic

Formulations

Starting Dosage1

Duration
of Action

20, 30, 40, 60, 80, 100, 120 mg ER tabs
10, 15, 20, 30, 40, 50 mg ER caps
8, 12, 16, 32 mg ER tabs

8, 12, 16 mg ER tabs

20 mg q24h
10 mg q12h
Footnote 3

24 hrs
12 hrs
24 hrs

10, 20, 30, 40, 50, 60, 70, 80,
100, 130, 150, 200 mg ER caps
20, 30, 50, 60, 80, 100 mg ER caps
15, 30, 60, 100, 200 mg ER tabs

30 mg q24h

12-24 hrs

15 mg q12h

8-12 hrs

20/0.8 mg q24h

24 hrs

10 mg q12h

12 hrs

5 mg q12h

12 hrs

20/0.8, 30/1.2, 50/2, 60/2.4, 80/3.2,
100/4 mg ER caps
10, 15, 20, 30, 40, 60, 80 mg ER tabs
10, 20, 40, 80 mg ER tabs
5, 7.5, 10, 15, 20, 30, 40 mg ER tabs

Cost2
$197.10
368.40
380.304
333.504
242.20
136.50
156.30
41.60
166.80
161.50
129.80
139.50
87.00

ER = extended-release
1. For patients who are not opioid tolerant. For patients switching from another opioid, starting dosage is based on previous opioid dosage.
2. Approximate WAC for 30 days’ treatment at the starting dosage. WAC = wholesaler acquisition cost, or manufacturer’s published price to wholesalers; WAC
represents a published catalogue or list price and may not represent actual transactional prices. Source: AnalySource® Monthly. April 5, 2015. Reprinted with

permission by First Databank, Inc. All rights reserved. ©2015. www.fdbhealth.com/policies/drug-pricing-policy.
3. Only recommended for patients who are opioid tolerant. Starting dosage determined by previous opioid dosage.
4. Cost for 30 8-mg ER tablets.

71


The Medical Letter

®

CLINICAL STUDIES — FDA approval of Hysingla ER
was based on one unpublished trial (summarized
in the package insert) in patients with moderate to
severe chronic lower back pain inadequately controlled
by previous analgesic therapy. Patients (n=905)
discontinued their analgesic medications and took
Hysingla ER once daily titrated every 3-5 days until an
effective and tolerable dose was reached (maximum
120 mg). A total of 588 patients entered the doubleblind phase of the trial and were randomized to continue
treatment with Hysingla ER or begin a gradual tapering
of their dose to placebo. At week 12, the hydrocodone
group had significantly lower pain scores than the
placebo group, and more patients treated with Hysingla
ER experienced a  ≥30% or a  ≥50% improvement in their
weekly average pain scores.
ADVERSE EFFECTS — Adverse effects that occurred
in ≥5% of patients who took the active drug during
clinical trials were constipation, nausea, vomiting,
fatigue, upper respiratory tract infection, dizziness,

headache, and somnolence.
Serious, sometimes fatal, respiratory depression can
occur with modified-release opioids even when used
as directed. The risk of respiratory depression is
greatest following initiation of therapy or after a dose
increase. Patients who are elderly or debilitated, have
chronic obstructive pulmonary disease, have suffered
a head injury or increased intracranial pressure, or
are taking other CNS depressants concomitantly are
at increased risk. QTc prolongation has occurred in
patients taking 160-mg doses of Hysingla ER.
Use of hydrocodone/acetaminophen, particularly
with high doses of hydrocodone, has rarely been
associated with sensorineural hearing loss2; audiologic assessments in 1207 patients treated with
Hysingla ER for up to 1 year found no evidence of
drug-induced ototoxicity.3
PREGNANCY — Hysingla ER is classified as category
C (teratogenic effects in animals; no adequate studies
in women) for use during pregnancy. Infants born to
mothers who received opioid therapy while pregnant
may need treatment for neonatal opioid withdrawal
syndrome.
DRUG INTERACTIONS — Hydrocodone is metabolized
primarily by CYP3A4 to norhydrocodone and partly
by CYP2D6 to hydromorphone. Coadministration
of Hysingla ER with ketoconazole, a strong
CYP3A4 inhibitor, significantly increased plasma
concentrations of hydrocodone and hydromorphone.

72

Vol. 57 (1468)

May 11, 2015

Taking the drug with a CYP3A4 inducer may lower
plasma concentrations of hydrocodone, leading
to decreased efficacy and possibly to withdrawal
symptoms.4 Administration of Hysingla ER with the
strong CYP2D6 inhibitor paroxetine (Paxil, Brisdelle,
and others) did not result in significant changes in
the AUC and Cmax of hydrocodone, but it did reduce
the formation of hydromorphone, which might lead to
reduced analgesia.
Taking hydrocodone with CNS depressants such as
alcohol, sedatives, or other opioids can increase the
risk of profound sedation, respiratory depression,
coma, and death. Mixed agonist/antagonist opioid
analgesics such as pentazocine (Talwin) or butorphanol (Stadol, and generics) could decrease the
analgesic effect of hydrocodone and cause withdrawal
symptoms. Urinary retention and severe constipation,
possibly leading to paralytic ileus, could occur with
concurrent use of an opioid and an anticholinergic drug.
Use of Hysingla ER within 14 days of a monoamine
oxidase inhibitor is not recommended. Taking a
strong laxative such as lactulose concomitantly could
decrease absorption of Hysingla ER.
DOSAGE AND ADMINISTRATION — Patients switching
from another oral hydrocodone product can take
the same amount of Hysingla ER as the total daily

hydrocodone dose of their previous drug. For patients
switching from another opioid, the dosage depends
on the previous drug and its dose; conversion factors
for different opioids are listed in the package insert.
The recommended starting dosage of Hysingla ER in
opioid-naive patients is 20 mg once daily.
CONCLUSION — Hysingla ER, the second singleingredient extended-release hydrocodone product to
become available in the US, is formulated for oncedaily use. Zohydro ER is dosed twice daily and costs
more. Both Hysingla ER and the new formulation of
Zohydro ER have abuse-deterrent properties, but they
will still be subject to misuse. ■
1. Extended-release hydrocodone (Zohydro ER) for pain. Med Lett
Drugs Ther 2014; 56:45.
2. D Krashin et al. Extended-release hydrocodone – gift or curse?
J Pain Res 2013; 6:53.
3. JW Kutz, Jr et al. No hearing impairment from once-daily,
single-entity hydrocodone treatment (Hysingla ER): results
of 2 phase-3 studies. Presented at PAINWeek National
Conference, Sept 2-6, 2014, Las Vegas, NV. Abstract 149.
Available at />attachments/04/724-painweek2014acceptedabstracts.pdf.
Accessed April 28, 2015.
4. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2013; 55:e44.


The Medical Letter

▶

®

Testosterone Nasal Gel (Natesto)
for Hypogonadism

The FDA has approved an intranasal gel formulation of
testosterone (Natesto – Trimel/Endo) for replacement
therapy in men with hypogonadism. Packaged in a
metered-dose pump, Natesto is the first intranasal
testosterone to become available in the US. Like other
testosterone products, it is classified as a schedule
III controlled substance. The FDA recently cautioned
against using testosterone to treat low testosterone
levels solely due to aging because the benefits and
safety of such use have not been established, and there
is a possible increased risk of myocardial infarction (MI)
and stroke.1
Pronunciation Key
Testosterone: tes tos' ter one
Natesto: na tes' toe

HYPOGONADISM — Failure of the testes to produce
adequate amounts of testosterone can lead to loss
of energy, irritability, depression, decreased libido,
erectile dysfunction, decreased axillary and pubic
hair, loss of muscle mass, anemia, and osteoporosis.
Testosterone serum concentrations decrease by about

Vol. 57 (1468)

May 11, 2015

1-2% per year after age 40. The normal range (usually
300-1000 ng/dL) is based on serum concentrations in
younger men. Older men with signs and symptoms of
hypogonadism may have levels ≤200 ng/dL.
TESTOSTERONE REPLACEMENT — Testosterone is
not effective when taken orally because of gut wall
and first-pass hepatic metabolism, but injectable,
transdermal, and buccal formulations can achieve
normal serum concentrations. The intranasal route
offers a large surface area and avoidance of firstpass hepatic metabolism.2 Pharmacokinetic studies
have shown that administration of testosterone
intranasally 2 or 3 times daily in severely hypogonadal
men can achieve serum concentrations in the normal
physiological range.3
CLINICAL STUDIES — FDA approval of testosterone
nasal gel was based on a single unpublished,
90-day, open-label trial (summarized in the package
insert) in 306 hypogonadal men with a mean age of
54 years. Patients self-administered 11 mg of the
drug either 2 or 3 times daily. At day 90, 69 of 73 men
(90%) who used the drug three times daily had an
average serum testosterone concentration within

Table 1. Some Testosterone Replacement Products
Drugs

Some Formulations

Usual Adult Dosage

Cost1

Testosterone enanthate – generic
Delatestryl (Endo)

5 mL vial (200 mg/mL)

50-400 mg IM every 2-4 wks

$68.00
82.80

Testosterone cypionate – generic
Depo-Testosterone (Pfizer)

1, 10 mL vial (100 mg/mL, 200 mg/mL)2
1, 10 mL vial (100 mg/mL, 200 mg/mL)2

50-400 mg IM every 2-4 wks

45.30
73.50

Testosterone undecanoate –
Aveed (Endo)

3 mL vial (250 mg/mL)

Injectable

750 mg IM at 0 and 4 wks, then
q10 wks

837.40

Transdermal
Androderm (Actavis)

2, 4 mg/d patch

4 mg once nightly

404.00

Androgel 1% (Abbvie)

2.5 g gel packet (25 mg test.); 5 g gel packet
(50 mg test.); 75 g MDP (12.5 mg test. in
1.25 g gel/act)

50 mg once/d

444.90

Androgel 1.62% (Abbvie)

1.25 g gel packet (20.25 mg test.); 2.5 g gel
packet (40.5 mg test.); 75 g MDP (20.25 mg
test. in 1.25 g gel/act)

40.5 mg once/d

432.90

Axiron (Lilly)

90 mL MDP (30 mg test. in 1.5 mL soln/act)

60 mg once/d3

432.00

Fortesta (Endo)

60 g MDP (10 mg test. in 0.5 g gel/act)

40 mg once/d

383.50

Testim (Auxilium/Endo)

5 g tube of gel (50 mg test.)

50 mg once/d

445.50

11 g MDP (5.5 mg test. in 0.122 g gel/act)

11 mg tid4

597.00

30 mg buccal tablet

30 mg bid

496.00

Intranasal
Natesto (Trimel/Endo)
Buccal
Striant (Auxilium/Endo)

act = actuation; MDP = metered-dose pump; test. = testosterone
1. Approximate wholesale acquisition cost (WAC) for one 5-mL vial of testosterone enanthate, one 10-mL vial (100 mg/mL) of testosterone cypionate, one 3-mL
vial of Aveed, or a 30-day supply of transdermal or buccal formulations at the 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.
April 5, 2015. Reprinted with permission by First Databank, Inc. All rights reserved. ©2015. www.fdbhealth.com/policies/drug-pricing-policy. Cost of administration is not included.
2. The 100-mg/mL formulation is only available in a 10-mL vial.
3. Should be administered as 1 pump actuation (30 mg) to each axilla.
4. Should be administered as 1 pump actuation (5.5 mg) in each nostril.

73


The Medical Letter

®

Table 2. Pharmacology
Class

Androgen

Formulation

11 g metered-dose pump
(5.5 mg testosterone/actuation)

Route

Intranasal

Tmax

~40 min

Half-life (terminal)

10-100 min

Metabolism

Metabolized by 5α-reductase and aromatase to various 17-ketosteroids

Excretion

Not characterized

the normal range (300-1050 ng/dL). No information is
provided on the results with twice-daily dosing.
An NIH-sponsored trial of testosterone efficacy in
elderly men is in progress.4
ADVERSE EFFECTS — The most common adverse
effects in the clinical trial of intranasal testosterone
were an increased prostate specific antigen (PSA)
level, headache, rhinorrhea, epistaxis, nasal discomfort, nasopharyngitis, bronchitis, upper respiratory
tract infection, sinusitis, and nasal scab. Venous
thromboembolism has been reported.
The concern about an increased risk of MI and stroke
with testosterone is based on 2 studies.5 The first
examined the records of 8709 men who had undergone
coronary angiography and incidentally were found to
have low testosterone levels (<300 ng/dL); 3 years after
coronary angiography, the Kaplan-Meier estimated
cumulative percentages of men who had died or had
an MI or ischemic stroke were 26% of those who had
been treated with testosterone by their physicians and
20% of those who were not treated with the hormone.6
The second study compared the rates of nonfatal MI in
55,593 men given a prescription for testosterone and
in 167,279 given a prescription for sildenafil (Viagra)
or tadalafil (Cialis) during the 90 days after filling the
prescription with the rates in each group the prior
year. In the testosterone group as a whole, the post/
pre-prescription nonfatal MI rate ratio was 1.36, but
in men ≥65 years old it was 2.19 and in men <65 years

old with a history of heart disease it was 2.90. In men
who received a prescription for sildenafil or tadalafil,
the rate ratio was 1.08 for all ages, 1.15 for those ≥65
years old, and 1.40 for men <65 years old with a history
of heart disease.7
An earlier study comparing testosterone gel and
placebo gel applied once daily to the skin of 209 men
≥65 years old with a total serum testosterone level of
100-350 ng/dL (or a free serum testosterone level of
<50 pg/mL) found that cardiovascular adverse effects
74

Vol. 57 (1468)

May 11, 2015

occurred in 23 men treated with testosterone and in 5
treated with placebo.8
DOSAGE AND ADMINISTRATION – One pump actuation of Natesto delivers 5.5 mg of testosterone. The
recommended dosage of Natesto is 11 mg, 1 pump
actuation in each nostril, 3 times daily. The metereddose pump should be primed by inverting it and
depressing the pump 10 times before it is used for the
first time. Intranasal testosterone should be stopped
if severe rhinitis occurs. Natesto should not be used
concurrently with sympathomimetic decongestants
that are also administered intranasally.
CONCLUSION — In one study, Natesto nasal gel
administered intranasally 3 times daily was effective
in raising low serum testosterone levels into the
normal range in patients with hypogonadism. Whether

patients will find this method of administration more
acceptable than an intramuscular injection every 2-4
weeks or once-daily application to the skin remains
to be determined. Based on the lack of convincing
evidence of benefit in older men and concerns about its
safety, the FDA has warned against using testosterone
to treat hypogonadism due solely to aging. ■
1. FDA drug safety communication: FDA cautions about using
testosterone products for low testosterone due to aging;
requires labeling change to inform of possible increased risk of
heart attack and stroke with use. Available at: .
gov/Drugs/DrugSafety/ucm436259.htm. Accessed April 30,
2015.
2. S Türker et al. Nasal route and drug delivery systems. Pharm
World Sci 2004; 26:137.
3. C Mattern et al. Testosterone supplementation for hypogonadal
men by the nasal route. Aging Male 2008; 11:171.
4. PJ Snyder et al. The testosterone trials: seven coordinated
trials of testosterone treatment in elderly men. Clin Trials 2014;
11:362.
5. In brief: testosterone and cardiovascular risk. Med Lett Drugs
Ther 2014; 56:17.
6. R Vigen et al. Association of testosterone therapy with mortality,
myocardial infarction, and stroke in men with low testosterone
levels. JAMA 2013; 310:1829.
7. WD Finkle et al. Increased risk of non-fatal myocardial infarction
following testosterone therapy prescription in men. PLoS One
2014; 9:e85805.
8. S Basaria et al. Adverse events associated with testosterone
administration. N Engl J Med 2010; 363:109.

Coming Soon in The Medical Letter:
Ceftazidime/Avibactam (Avycaz) – A New Intravenous
Antibiotic
Fluticasone Furoate Inhaler (Arnuity) for Asthma
Ivabradine (Corlanor) for Heart Failure
Drugs for Psoriasis and Psoriatic Arthritis


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The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959

Volume 57

ISSUE

ISSUE No.

1433
1468

May 11, 2015

IN THIS ISSUE

Blinatumomab (Blincyto) for Acute Lymphoblastic Leukemia ................................online only

Volume 56

▶

Blinatumomab (Blincyto) for Acute
Lymphoblastic Leukemia

The FDA has approved blinatumomab (Blincyto –
Onyx/Amgen) for treatment of relapsed or refractory
Philadelphia chromosome-negative (Ph-) B-cell precursor acute lymphoblastic leukemia (ALL).
Pronunciation Key
Blinatumomab: blin” a toom’ oh mab
Blincyto: blin sye’ toe

TREATMENT OF ALL – Induction therapy usually
includes vincristine, a glucocorticoid, and an anthracycline, with or without asparaginase. Patients with Ph+
ALL may also receive a targeted agent such as imatinib
(Gleevec). For non-responders or patients who respond
initially and then relapse, allogeneic hematopoietic
stem cell transplantation is potentially curative.
MECHANISM OF ACTION – Blinatumomab is a bispecific CD19-directed CD3 T-cell engager. It binds
to CD19, a protein found on the surface of most
B-precursor lymphoblasts, and CD3, a protein on
T-cell lymphocytes. It activates endogenous T-cells
by connecting CD3 in the T-cell receptor complex with

CD19 on benign and malignant B-cells, and mediates
upregulation of cell adhesion molecules, production of
cytolytic proteins, release of inflammatory cytokines,
Table 1. Pharmacology
Class

Immunotherapeutic agent

Formulation

35 mcg single-use vial

Route

Intravenous

Metabolism

Not characterized

Half-life

2.11 hrs

and proliferation of T-cells, resulting in lysis of normal
and malignant B-cells.
A CLINICAL STUDY – Accelerated approval of
blinatumomab was based on a single-arm, open-label
trial in 189 adults with Ph- B-cell precursor ALL who
were refractory after induction therapy or who had

relapsed within 12 months of first remission, relapsed
within 12 months after allogeneic hematopoietic stem
cell transplantation, or did not respond to or relapsed
after first salvage therapy or beyond. Patients received
blinatumomab 9 mcg/day IV for 7 days, followed by 28
mcg/day for 21 days every 6 weeks for up to 5 cycles.
After 2 cycles of blinatumomab, 33% of patients achieved complete remission with a median duration of about
6.7 months, and 10% achieved complete remission with
only partial hematological recovery of peripheral blood
counts with a median duration of 5.0 months.1
ADVERSE EFFECTS – A boxed warning in the labeling
of blinatumomab states that life-threatening or
fatal cytokine release syndrome and severe or lifethreatening neurological toxicity have been reported in
patients taking the drug.
Grade 3 or 4 adverse effects, which have occurred
in 80% of patients treated with blinatumomab, have
included febrile neutropenia, neutropenia, anemia,
neurologic toxicity including seizures, tumor lysis
syndrome, and cytokine release syndrome. Less severe
adverse effects included headache, peripheral edema,
nausea, hypokalemia, tremor, rash, and constipation.
DRUG INTERACTIONS – No drug interaction studies
have been conducted with blinatumomab. Transient
elevation of cytokines may suppress CYP450 enzymes
and increase serum concentrations of drugs that are
CYP450 substrates.2
e74

Published by The Medical Letter, Inc. • A Nonprofit Organization

The Medical Letter

Vol. 57 (1468)

®

DOSAGE,
ADMINISTRATION,
AND
COST
–
Blinatumomab is available in a 35-mcg single-use
vial. The recommended starting dosage for adults
≥45 kg is 9 mcg/day IV as a continuous 24-hour
infusion on days 1-7, followed by 28 mcg/day on
days 8-28 for the first cycle and 28 mcg/day on days
1-28 for subsequent cycles, followed by a 2-week
treatment-free interval. Treatment should be continued
for up to a total of 5 cycles. Patients should receive
dexamethasone 20 mg IV one hour before the first dose
of each treatment cycle, before each increase in dose
of blinatumomab, or if the infusion has been withheld
for 4 hours. The patient should be hospitalized for the
first 9 days of the first cycle and for the first 2 days of
the second cycle. The labeling specifies a number of
dosage adjustments that should be made when adverse
effects occur. The cost for one 6-week treatment cycle
with blinatumomab is $60,390.3

May 11, 2015

CONCLUSION – Blinatumomab (Blincyto) was
effective in inducing a complete remission in 33%
of patients with relapsed or refractory Philadelphia
chromosome-negative (Ph-) B-cell precursor acute
lymphoblastic leukemia (ALL). Grade 3 or 4 adverse
effects occur frequently. ■
1. MS Topp et al. Safety and activity of blinatumomab for adult
patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study.
Lancet Oncol 2015; 16:57.
2. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2013; 55:e44.
3. 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. April 5, 2015.
Reprinted with permission by First Databank, Inc. All rights reserved. ©2015. www.fdbhealth.com/policies/drug-pricing-policy.

EDITOR IN CHIEF: Mark Abramowicz, M.D.; EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR: Jean-Marie Pflomm, Pharm.D.;
ASSISTANT EDITORS, DRUG INFORMATION: Susan M. Daron, Pharm.D., Corinne Z. Morrison, Pharm.D., Michael P. Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M. Shah, Pharm.D.,
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; Jules Hirsch, M.D., Rockefeller
University; David N. Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre; Richard B. Kim, M.D., University of Western Ontario; Hans Meinertz, M.D., University Hospital,
Copenhagen; 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.
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Issue 1468 Questions

(Correspond to questions #91-100 in Comprehensive Exam #72, available July 2015)
Peginterferon Beta-1a (Plegridy) for Multiple Sclerosis
1. Peginterferon beta-1a is administered:
a. subcutaneously twice weekly
b. intramuscularly once weekly
c. subcutaneously biweekly
d. intramuscularly once monthly
2. Treatment of MS with interferon beta:
a. reduces clinical relapse rates
b. decreases the number of brain lesions seen on MRI
c. can cause influenza-like symptoms
d. all of the above
3. Compared to older interferon formulations, peginterferon beta-1a
appears to be:
a. similar in efficacy
b. similar in safety
c. similar in cost
d. all of the above
Concentrated Insulin Glargine (Toujeo) for Diabetes
4. Compared to Lantus, Toujeo:
a. is more concentrated
b. releases insulin more gradually
c. has a longer duration of action
d. all of the above
5. A 56-year-old woman with type 2 diabetes taking Lantus tells you
that she’s heard about a new form of insulin glargine and wants
to try it. What can you tell her about Toujeo?
a. Toujeo is more effective than Lantus in lowering HbA1c

b. Toujeo is more likely than Lantus to cause nocturnal
hypoglycemia
c. She may need a higher daily basal insulin dose if she
switches to Toujeo.
d. She would only need to inject Toujeo once per week.
6. Which of the following adverse effects is more common with
Toujeo than with Lantus?
a. nocturnal hypoglycemia
b. weight gain
c. injection-site reactions
d. none of the above

Extended-Release Hydrocodone (Hysingla ER) for Pain
7. A 79-year-old woman with diabetes, constipation, and COPD
takes immediate-release hydrocodone 10 mg every 6 hours for
severe chronic back pain. You are considering switching her to a
long-acting formulation of hydrocodone. Which of the following
statements about the available extended-release hydrocodone
products is true?
a. Hysingla ER and Zohydro ER are both dosed once/day
b. only Hysingla ER has been approved in an abuse-deterrent
formulation
c. Hysingla ER was shown to provide more rapid pain relief
than Zohydro ER in a head-to-head trial.
d. none of the above
8. You decide to prescribe Hysingla ER for the patient in question 7.
Which of the following is true regarding the use of the drug in this
patient?
a. She may be at increased risk for respiratory depression
because of her age and comorbid conditions.

b. Her dose of Hysingla ER should be 40 mg once daily.
c. Strong laxatives could decrease absorption of Hysingla ER.
d. all of the above
Testosterone Nasal Gel (Natesto) for Hypogonadism
9. Intranasal administration of testosterone gel has been shown to:
a. increase serum testosterone concentrations in hypogonadal
men
b. reduce symptoms of hypogonadism in elderly men
c. be safe for use in elderly hypogonadal men
d. all of the above
10. An otherwise healthy 66-year-old man comes to your office
complaining of loss of energy, irritability, and decreased libido,
which he believes could be due to a low testosterone level. He
would like to try a testosterone replacement product. You could
tell him that:
a. the FDA has warned against use of testosterone products to
treat low testosterone levels due to aging
b. there is convincing evidence that such treatment would be
effective
c. there is no reason to believe that testosterone could cause
serious side effects
d. all of the above

ACPE UPN: Per Issue Exam: 0379-0000-15-468-H01-P; Release: May 11, 2015, Expire: May 11, 2016
Comprehensive Exam 72: 0379-0000-15-072-H01-P; Release: July 2015, Expire: July 2016

EDITOR IN CHIEF: Mark Abramowicz, M.D.; EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR: Jean-Marie Pflomm, Pharm.D.;
ASSISTANT EDITORS, DRUG INFORMATION: Susan M. Daron, Pharm.D., Corinne Z. Morrison, Pharm.D., Michael P. Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M. Shah, Pharm.D.,
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; Jules Hirsch, M.D., Rockefeller
University; David N. Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre; Richard B. Kim, M.D., University of Western Ontario; Hans Meinertz, M.D., University Hospital,
Copenhagen; 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 nonprofit 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
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resulting from any error, inaccuracy, or omission.

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