The medical letter on drugs and therapeutics janurary 30 2017

The Medical Letter

®

on Drugs and Therapeutics

Volume 59

ISSUE
ISSUE
No.

1433
1513
Volume 56

January 30, 2017

IN THIS ISSUE

Lixisenatide for Type 2 Diabetes .......................................................................................... p 19
Pembrolizumab (Keytruda) for First-Line Treatment of Metastatic NSCLC ...................... p 22
Inflectra — An Infliximab Biosimilar..................................................................................... p 23
Yosprala — A Combination of Aspirin and Omeprazole ...................................................... p 25
Drug Interaction: Dabigatran (Pradaxa) and Statins........................................................... p 26
Corrections ............................................................................................................................ p 26
Comparison Chart of SGLT2 Inhibitors ........................................................................online only

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The Medical Letter

®

on Drugs and Therapeutics
Volume 59

January 30, 2017
Take CME Exams

ISSUE

ISSUE No.

1433
1513
Volume 56

▶

IN THIS ISSUE

Pembrolizumab (Keytruda) for First-Line Treatment of Metastatic NSCLC ...................... p 22
Inflectra — An Infliximab Biosimilar..................................................................................... p 23
Yosprala — A Combination of Aspirin and Omeprazole ...................................................... p 25
Drug Interaction: Dabigatran (Pradaxa) and Statins........................................................... p 26
Corrections ............................................................................................................................ p 26
Comparison Chart of SGLT2 Inhibitors ........................................................................online only

Lixisenatide for Type 2 Diabetes

The FDA has approved lixisenatide (Sanofi), a shortacting injectable GLP-1 (glucagon-like peptide-1)
receptor agonist, for once-daily treatment of adults
with type 2 diabetes, both alone (Adlyxin) and in a
fixed-ratio combination with insulin glargine (Soliqua
100/33). Lixisenatide has been available since 2013 in
many other countries as Lyxumia. It is the fifth GLP-1
receptor agonist to be approved in the US.
Pronunciation Key
Lixisenatide: lix" i sen' a tide
Adlyxin: ad lix' in
Soliqua: so lee' kwa

GLP-1 RECEPTOR AGONISTS — GLP-1 receptor
agonists lower glucose levels by potentiating glucosedependent secretion of insulin, suppressing postprandial glucagon secretion, slowing gastric emptying, and
promoting satiety. They lower glycated hemoglobin
(A1C) by about 1-1.5%, have been associated with
average weight loss of 1.5-2.8 kg, and rarely cause
hypoglycemia.1 The GLP-1 receptor agonist liraglutide
(Victoza) has been shown to reduce the overall risk of
a major cardiovascular event and the risk of death from
cardiovascular causes in patients with type 2 diabetes
and high cardiovascular risk.2 Patients who are using a
basal insulin such as insulin glargine, which primarily
targets fasting plasma glucose, may benefit from addition of a short-acting GLP-1 receptor agonist such as
lixisenatide, liraglutide, or exenatide (Byetta) to control
postprandial plasma glucose concentrations.3
CLINICAL STUDIES — Lixisenatide – In randomized
trials in patients with type 2 diabetes, use of
lixisenatide alone and in combination with metformin,
a sulfonylurea, pioglitazone, or insulin lowered
A1C and reduced weight (see Table 2). In one study
in patients inadequately controlled on metformin
(GetGoal-X), sponsored by Sanofi, addition of oncedaily lixisenatide was noninferior to addition of twice-

Table 1. Pharmacology of Lixisenatide
Class
Route
Tmax (median)
Elimination
Half-life (terminal)

GLP-1 receptor agonist

SC injection
1-3.5 hours
Renal; glomerular filtration and proteolytic
degradation
~3 hours

daily exenatide in reducing A1C, but exenatide caused
more weight loss than lixisenatide.4
In a randomized, 26-week trial comparing once-daily
lixisenatide 20 mcg with once-daily liraglutide 1.8 mg
as add-ons to metformin, sponsored by Novo Nordisk,
lixisenatide was significantly less effective than
liraglutide in reducing A1C (-1.2% vs -1.8%); weight
loss was similar with both drugs.5
In a randomized, double-blind trial in 6068 patients
with type 2 diabetes who had had either a myocardial
infarction or an unstable angina event within the last
6 months, rates of major cardiovascular events over
a median follow-up of 25 months were similar with
addition of lixisenatide or placebo to conventional
therapy (13.4% vs 13.2%).6
Insulin Glargine/Lixisenatide – Approval of insulin
glargine/lixisenatide was based on the results of an
open-label trial in 736 patients with type 2 diabetes
inadequately controlled on basal insulin and one or two
oral antihyperglycemic drugs. After a 6-week run-in
period, patients stabilized on a daily dose of 20-50 units
of insulin glargine, with an A1C of 7-10% and fasting
blood glucose ≤140 mg/dL, were randomized to receive
insulin glargine/lixisenatide or continue on insulin

glargine alone for 30 weeks; oral antihyperglycemic
drugs other then metformin were discontinued. The
daily dose ranged from 10 to 60 units of insulin glargine
and from 5 to 20 mcg of lixisenatide. At week 30, there
was a significantly greater reduction in A1C with the
combination than with insulin glargine alone (-1.1%
vs -0.6%). Mean body weight decreased by 0.7 kg with
19

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


The Medical Letter

Vol. 59 (1513)

®

Table 2. Some Lixisenatide Clinical Trials

Drug Regimen

A1C
Weight
Change Change
(%)1
(kg)1

Lixisenatide 20 mcg/d3
Lixisenatide 20 mcg/d4

Placebo

-0.7
-0.9
-0.2

-2.0
-2.0
-2.0

Get Goal-X5
24 wks
(n=634)

Metformin
+ Lixisenatide 20 mcg/d3
+ Exenatide 10 mcg bid

-0.8
-1.0

-3.0
-4.0

Get Goal-F16
24 wks
(n=484)

Metformin
+ Lixisenatide 20 mcg/d3

+ Lixisenatide 20 mcg/d4
+ Placebo

-0.8
-0.9
-0.4

-2.7
-2.6
-1.6

Get Goal-M-Asia7
24 wks5
(n=391)

Metformin ± sulfonylurea
+ Lixisenatide 20 mcg/d4
+ Placebo

-0.8
-0.5

-1.5
-1.2

Get Goal-S8
24 wks
(n=859)

Sulfonylurea ± metformin

+ Lixisenatide 20 mcg/d3
+ Placebo

-0.9
-0.1

-1.8
-0.9

Get Goal-P9
24 wks
(n=484)

Pioglitazone ± metformin
+ Lixisenatide 20 mcg/d3
+ Placebo

-0.9
-0.3

-0.2
+0.2

Get Goal-L10
24 wks
(n=495)

Basal insulin ± metformin
+ Lixisenatide 20 mcg/d3
+ Placebo

-0.7
-0.4

-1.8
-0.5

Get Goal-Duo 111
24 wks
(n=446)

Insulin glargine ± metformin ± thiazolidinedione
+ Lixisenatide 20 mcg/d3
-0.7
+0.3
+ Placebo
-0.4
+1.2

Get Goal Duo-212
26 wks
(n=894)

Insulin glargine ± metformin
+ Lixisenatide 20 mcg/d4
-0.6
+ Insulin glulisine once/d
-0.6
+ Insulin glulisine tid
-0.8

-0.6
+1.0
+1.4

Get Goal-L Asia13
24 wks
(n=311)

Basal insulin ± sulfonylurea
+ Lixisenatide 20 mcg/d3
-0.8
+ Placebo
+0.11

-0.4
+0.1

Study
Monotherapy
Get Goal-Mono2
12 wks
(n=361)
Add-on Therapy

1. Least squares (LS) mean change from baseline.
2. VA Fonseca et al. Diabetes Care 2012; 35:1225.
3. Lixisenatide 10 mcg once daily for 1 week, 15 mcg once daily for 1 week, and
then 20 mcg once daily.
4. Lixisenatide 10 mcg once daily for 2 weeks, and then 20 mcg once daily.

5. J Rosenstock et al. Diabetes Care 2013; 36:2945.
6. GB Bolli et al. Diabet Med 2014; 31:176.
7. Study in Asian patients. C Yu Pan et al. Diabetes Metab Res Rev 2014; 30:726.
8. J Rosenstock et al. J Diabetes Complications 2014; 28:386.
9. M Pinget et al. Diabetes Obes Metab 2013; 15:1000.
10. MC Riddle et al. Diabetes Care 2013; 36:2489.
11. MC Riddle et al. Diabetes Care 2013; 36:2497.
12. J Rosenstock et al. Diabetes Care 2016; 39:1318.
13. Study in Asian patients. Y Seino et al. Diabetes Obes Metab 2012; 14:90.

the combination and increased by 0.7 kg with insulin
glargine alone.7
An open-label, 30-week trial in 1170 patients with
type 2 diabetes inadequately controlled on metformin
compared insulin glargine 10-60 units/lixisenatide
5-20 mcg daily to insulin glargine 10-60 units/day
alone and to lixisenatide 10-20 mcg/day alone.
Reductions in A1C were greater with the combination
than with either component alone (-1.6% vs -1.3% with
insulin glargine and -0.9% with lixisenatide). Mean
body weight decreased by 2.3 kg with lixisenatide alone
and by 0.3 kg with the combination, and increased by
1.1 kg with insulin glargine alone.8
20

January 30, 2017

ADVERSE EFFECTS — Nausea, vomiting, and other GI
adverse effects occurred in 39.7% of patients treated
with lixisenatide in clinical trials, which is similar to the

rate with other GLP-1 receptor agonists; 4.3% of patients discontinued the drug because of GI symptoms.
GLP-1 receptor agonists slow gastric emptying and
should not be used in patients with severe gastroparesis.
Other common adverse effects of lixisenatide were
headache (9%) and dizziness (7%).
Anaphylaxis occurred in 0.1% of lixisenatide-treated
patients. Other serious hypersensitivity reactions such
as angioedema have also been reported. Antibodies to
lixisenatide developed in 70% of patients; these patients
were more likely to experience allergic or injectionsite reactions and those with the highest antibody
concentrations had a reduced glycemic response.
Use of GLP-1 receptor agonists has been associated
with renal insufficiency and worsening of chronic renal
failure. Their use may also be associated with a risk
of acute pancreatitis, but a causal relationship has not
been established.1
The most common adverse effect of the insulin
glargine/lixisenatide combination is hypoglycemia.
Allergic and injection-site reactions, lipodystrophy,
weight gain, and peripheral edema can occur. The
incidence of GI adverse effects with the combination
was lower than with lixisenatide alone (possibly as a
result of more gradual dose titration), but higher than
with insulin glargine alone.
DRUG INTERACTIONS — Since lixisenatide slows
gastric emptying, it may decrease the rate and extent
of absorption of oral medications taken concomitantly.
Oral contraceptives should be taken 1 hour before
or 11 hours after lixisenatide. Lixisenatide does not
significantly inhibit or induce any CYP isozymes.

PREGNANCY AND LACTATION — Lixisenatide has
not been studied in pregnant women. Administration
of lixisenatide to pregnant animals during
organogenesis was associated with visceral closure
and skeletal defects at systemic exposures 1-6
times higher than those achieved in humans at the
recommended dose. Low levels of lixisenatide have
been detected in rat milk.
DOSAGE AND ADMINISTRATION — Adlyxin is available
in prefilled pens containing 14 preset 10-mcg or
20-mcg doses. The recommended starting dosage is
10 mcg SC once daily for 14 days; on day 15, the daily
dosage should be increased to 20 mcg.


The Medical Letter

Vol. 59 (1513)

®

January 30, 2017

Table 3. GLP-1 Receptor Agonists
Drug

Formulations

Albiglutide – Tanzeum (GSK)

30, 50 mg single-dose pen

Dulaglutide – Trulicity (Lilly)

0.75 mg/0.5 mL, 1.5 mg/0.5 mL
single-dose pen or syringe

0.75 or 1.5 mg SC once/wk3

626.00

250 mcg/mL
(1.2, 2.4 mL prefilled pen)

5 or 10 mcg SC bid4,5

668.30

2 mg single-dose pen or powder
for injectable suspension2
6 mg/mL (3 mL prefilled pen)
50 mcg/mL, 100 mcg/mL
(3 mL prefilled pen)

2 mg SC once/wk3,5

622.80

1.2 or 1.8 mg SC once/d3,6
20 mcg SC once/d7,8

498.40
557.20

Exenatide –
immediate-release
Byetta (AstraZeneca)
extended-release
Bydureon (AstraZeneca)
Liraglutide – Victoza (Novo Nordisk)
Lixisenatide – Adlyxin (Sanofi)

Usual Adult Dosage

Cost1

30 or 50 mg SC once/wk

2

3

$478.90

Combinations with Long-Acting Insulin Analogs
Insulin glargine/lixisenatide –
Soliqua 100/33 (Sanofi)

100 units/33 mcg/mL
(3 mL prefilled pen)

15 units/5 mcg-60 units/ 20 mcg
SC once/d7,9

508.0010

Insulin degludec/liraglutide –
Xultophy 100/3.6 (Novo Nordisk)

100 units/3.6 mg/mL
(3 mL prefilled pen)

16 units/0.58 mg-50 units/1.8 mg
SC once/d11

762.4010

1.

Approximate WAC for 4 weeks’ or 30 days’ 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 January 5,
2017. Reprinted with permission by First Databank, Inc. All rights reserved. ©2017. www.fdbhealth.com/policies/drug-pricing-policy.
2. Requires reconstitution before injection.
3. Can be given at any time of day, with or without food.
4. Starting dosage is 5 mcg twice daily. After one month, the dose can be increased to 10 mcg twice daily. Should be given within 60 minutes before morning and
evening meals (or before the two main meals of the day, approximately 6 hours or more apart).
5. Not recommended for patients with a CrCl <30 mL/min.
6. Starting dosage is 0.6 mg once daily for 7 days.
7. Should be given within 60 minutes before the first meal of the day.
8. Starting dosage is 10 mcg once daily for 14 days.

9. Starting dosage is 15 units/5 mcg in patients inadequately controlled on <30 units of basal insulin or on lixisenatide and is 30 units/10 mcg in those inadequately controlled on 30-60 units of basal insulin; titrate up or down by 2-4 units/week to achieve desired fasting plasma glucose.
10. Cost of 30 days’ treatment for a patient using Soliqua 40 units/13.3 mcg daily or Xultophy 40 units/1.44 mg daily.
11. Starting dosage is 16 units/0.58 mg; titrate up or down by 2 units every 3-4 days to achieve desired fasting plasma glucose. Should be given at the same time
each day with or without food.

Soliqua 100/33 is available in packages of five 3-mL
prefilled pens, each containing 100 units/mL of insulin
glargine and 33 mcg/mL of lixisenatide. The recommended starting dosage is insulin glargine 15 units/
lixisenatide 5 mcg SC once daily in patients inadequately
controlled on <30 units of basal insulin or on lixisenatide,
and 30 units/10 mcg in those inadequately controlled on
30-60 units of basal insulin. The dose can then be titrated
up or down by 2-4 units per week to achieve the desired
fasting plasma glucose concentrations; the maximum
daily dosage is 60 units/20 mcg.
For both products, unused pens should be stored in the
refrigerator; after first use, the pen can be kept at room
temperature for up to 14 days, but must be protected
from light. A new needle (purchased separately)
should be attached for each injection. Adlyxin and
Soliqua 100/33 are injected subcutaneously in the
abdomen, thigh, or upper arm within one hour before
the first meal of the day.
CONCLUSION — Lixisenatide (Adlyxin), a new oncedaily injectable GLP-1 receptor agonist, reduces A1C
and weight in patients with type 2 diabetes. As addon treatment to metformin, its efficacy appears to be
similar to that of twice-daily exenatide (Byetta), but
less than that of once-daily liraglutide (Victoza).

The fixed-ratio combination of insulin glargine and
lixisenatide (Soliqua 100/33) reduces A1C more than

either of its components alone, but it carries a greater
risk of hypoglycemia and weight gain than lixisenatide
alone and a greater risk of nausea and vomiting than
insulin glargine alone. ■
1. Drugs for type 2 diabetes. Med Lett Drugs Ther 2017; 59:9.
2. SP Marso et al. Liraglutide and cardiovascular outcomes in
type 2 diabetes. N Engl J Med 2016; 375:311.
3. T Forst. Lixisenatide as add-on to insulin glargine for the treatment of type 2 diabetes mellitus. Expert Opin Pharmacother
2016; 17:1703.
4. J Rosenstock et al. Efficacy and safety of lixisenatide once daily
versus exenatide twice daily in type 2 diabetes inadequately controlled on metformin: a 24-week, randomized, open-label, activecontrolled study (GetGoal-X). Diabetes Care 2013; 36:2945.
5. M Nauck et al. Once-daily liraglutide versus lixisenatide as addon to metformin in type 2 diabetes: a 26-week randomized controlled clinical trial. Diabetes Care 2016; 39:1501.
6. MA Pfeffer et al. Lixisenatide in patients with type 2 diabetes
and acute coronary syndrome. N Engl J Med 2015; 373:2247.
7. VR Aroda et al. Efficacy and safety of LixiLan, a titratable fixedratio combination of insulin glargine plus lixisenatide in type 2
diabetes inadequately controlled on basal insulin and metformin:
the LixiLan-L randomized trial. Diabetes Care 2016; 39:1972.
8. J Rosenstock et al. Benefits of LixiLan, a titratable fixed-ratio
combination of insulin glargine plus lixisenatide, versus insulin
glargine and lixisenatide monocomponents in type 2 diabetes
inadequately controlled on oral agents: the LixiLan-O randomized trial. Diabetes Care 2016; 39:2026.

21


The Medical Letter

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®

Pembrolizumab (Keytruda) for FirstLine Treatment of Metastatic NSCLC

The FDA has approved the immune checkpoint inhibitor pembrolizumab (Keytruda – Merck), a programmed
death receptor-1 (PD-1) inhibitor, for first-line treatment
of patients with metastatic non-small cell lung cancer
(NSCLC) that highly expresses programmed deathligand 1 (PD-L1) and has no epidermal growth factor
receptor (EGFR) mutations or anaplastic lymphoma
kinase (ALK) translocations. About 25% of patients with
advanced NSCLC have tumors with high levels of PD-L1
expression (PD-L1 expressed on ≥50% of tumor cells).
Pembrolizumab was approved earlier for treatment of
metastatic NSCLC with PD-L1 expression ≥1% that
progressed on or after platinum-based chemotherapy.1

January 30, 2017

Vol. 59 (1513)

Pronunciation Key
Pembrolizumab: pem” broe liz’ ue mab Keytruda: key true' duh

MECHANISM OF ACTION — PD-1 is an inhibitory
receptor expressed by T-cells during long-term antigen
exposure. Activation of PD-1 by its ligands (PD-L1
and PD-L2) inhibits T-cell proliferation and cytokine
production. Upregulation of these ligands occurs
in some tumors. Pembrolizumab is a humanized
monoclonal antibody that binds to the PD-1 receptor,
blocking the interaction of PD-1 with its ligands and

promoting antitumor immune responses.
OTHER IMMUNE CHECKPOINT INHIBITORS —
Nivolumab (Opdivo), the only other FDA-approved
PD-1 inhibitor, is approved for second-line treatment of
metastatic NSCLC. In previously untreated patients, it

Table 1. Some Drugs for Metastatic NSCLC
Drug

FDA-Approved Indication

Usual Adult Dosage1

Cost2

ALK-positive metastatic NSCLC
ROS1-positive metastatic NSCLC

250 mg PO bid

$14,845.90

ALK-positive metastatic NSCLC in patients with disease
progression on or who are intolerant to crizotinib
ALK-positive metastatic NSCLC in patients with disease
progression on or who are intolerant to crizotinib

600 mg PO bid3

13,313.60

750 mg PO once/d4

15,079.50

First-line treatment of metastatic NSCLC with EGFR
exon 19 deletions or exon 21 (L858R) substitutions
Metastatic squamous NSCLC with disease progression
after platinum-based chemotherapy

40 mg PO once/d5

7550.70

Erlotinib – Tarceva
(Genentech)

Metastatic NSCLC with EGFR exon 19 deletions or exon 21
(L858R) substitutions with disease progression after
at least one chemotherapy regimen

150 mg PO once/d6

7825.40

Gefitinib – Iressa
(AstraZeneca)

First-line treatment of metastatic NSCLC with EGFR exon
19 deletions or exon 21 (L858R) substitutions

250 mg PO once/d

7597.80

Necitumumab – Portrazza
(Lilly)

First-line treatment of metastatic squamous NSCLC in
combination with gemcitabine and cisplatin

800 mg IV on days 1
and 8 of a 3-week cycle

8160.007

Osimertinib – Tagrisso
(AstraZeneca)

EGFR T790M mutation-positive metastatic NSCLC with
disease progression on or after EGFR tyrosine kinase
inhibitor therapy

80 mg PO once/d

14,190.80

Metastatic NSCLC with disease progression on or after
platinum-based chemotherapy8

240 mg IV q2 wks

12,036.20

First-line treatment of metastatic NSCLC with high PD-L1
expression (on ≥50% of tumor cells)
Metastatic NSCLC with PD-L1 expression (≥1%) and disease
progression on or after platinum-based chemotherapy8

200 mg IV q3 wks

8893.00

Metastatic NSCLC with disease progression on or after
platinum-based chemotherapy8

1200 mg IV q3 wks

8620.00

ALK/ROS1 Tyrosine Kinase Inhibitor
Crizotinib – Xalkori
(Pfizer)
ALK Tyrosine Kinase Inhibitors
Alectinib – Alecensa
(Genentech)
Ceritinib – Zykadia
(Novartis)
EGFR Tyrosine Kinase Inhibitors
Afatinib – Gilotrif

(Boehringer Ingelheim)

PD-1 Inhibitors
Nivolumab – Opdivo
(BMS)
Pembrolizumab – Keytruda
(Merck)

PD-L1 Inhibitor
Atezolizumab – Tecentriq
(Genentech)

ALK = anaplastic lymphoma kinase; EGFR = epidermal growth factor receptor; PD-1 = programmed death receptor-1; PD-L1 = programmed death-ligand 1;
ROS1 = c-ros oncogene 1
1. Dosage adjustment may be needed for hepatic or renal impairment.
2. Approximate WAC for 30 days’ treatment. 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. January 5, 2017. Reprinted with permission by First
Databank, Inc. All rights reserved. ©2017. www.fdbhealth.com/policies/drug-pricing-policy.
3. Taken with food.
4. Should not be taken within 2 hours of a meal.
5. Taken at least 1 hour before or 2 hours after a meal.
6. Taken on an empty stomach.
7. Cost of gemcitabine and cisplatin not included.
8. Patients with EGFR or ALK genomic tumor aberrations should receive treatment with drugs specific for these aberrations before receiving a PD-1 or PD-L1 inhibitor.

22


The Medical Letter

®

failed to improve progression-free survival in a clinical
trial that was not limited to patients with NSCLC that
highly expressed PD-L1.2
Atezolizumab (Tecentriq), a PD-L1 inhibitor, is also
approved for second-line treatment of metastatic NSCLC.
In one clinical trial, increased PD-L1 expression was associated with improvement in overall survival in patients
treated with atezolizumab.3 Clinical trials evaluating its
efficacy in previously untreated patients are in progress.
CLINICAL STUDIES — FDA approval of pembrolizumab
for first-line treatment of metastatic NSCLC was based
on the results of an open-label trial in 305 patients with
previously untreated metastatic NSCLC with high levels
of PD-L1 expression who were randomized to receive
either pembrolizumab 200 mg every 3 weeks or platinumbased chemotherapy. Patients with EGFR mutations
or ALK translocations were excluded from the trial.
Median progression-free survival, the primary endpoint,
was significantly longer with pembrolizumab than with
chemotherapy (10.3 vs 6.0 months). The estimated rate
of overall survival at 6 months, a secondary endpoint,
was significantly higher with pembrolizumab than with
chemotherapy (80.2% vs 72.4%).4
ADVERSE EFFECTS — Diarrhea, fatigue, and fever were
the most common adverse effects of pembrolizumab
in the clinical trial. Severe (grade 3 or higher)
treatment-related adverse effects occurred in 26.6%
of patients who received pembrolizumab and in
53.3% of those who received chemotherapy. Immunemediated adverse effects including pneumonitis,
colitis, nephritis, hepatitis, and hypothyroidism have

occurred rarely with pembrolizumab in other studies.
Type 1 diabetes has been reported.
CONCLUSION — Pembrolizumab (Keytruda) is more
effective and better tolerated than platinum-based
chemotherapy for first-line treatment of patients with
metastatic NSCLC that highly expresses PD-L1. ■
1. RS Herbst et al. Pembrolizumab versus docetaxel for previously
treated, PD-L1-positive, advanced non-small-cell lung cancer
(KEYNOTE-010): a randomised controlled trial. Lancet 2016;
387:1540.
2. M Socinski et al. NSCLC, metastatic CheckMate 026: a phase
3 trial of nivolumab vs investigator's choice (IC) of platinumbased doublet chemotherapy (PT-DC) as first-line therapy for
stage IV/recurrent programmed death ligand 1 (PD-L1)−positive NSCLC. Ann Oncol 2016; 27(Suppl 6):LBA7_PR.
3. L Fehrenbacher et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled
trial. Lancet 2016; 387:1837.
4. M Reck et al. Pembrolizumab versus chemotherapy for PD-L1positive non-small-cell lung cancer. N Engl J Med 2016;
375:1823.

Vol. 59 (1513)

▶

January 30, 2017

Inflectra – An Infliximab
Biosimilar

The FDA has approved infliximab-dyyb (Inflectra –
Pfizer; marketed as Remsima in some countries), as a
biosimilar of the TNF inhibitor infliximab (Remicade).

Infliximab-dyyb was approved in the European Union
(EU) in 2013 and in Canada in 2014. It is the second
biosimilar to be approved by the FDA. Filgastrim-sndz
(Zarxio), a recombinant human granulocyte colonystimulating factor, was the first.1
Pronunciation Key
Infliximab: in flix' i mab
Inflectra: in flek' tra

Table 1. Remicade and Inflectra
Drug

Available Formulations

Cost1

Infliximab –
Remicade (Janssen)

100 mg/20 mL vials

$20,038.90

Infliximab-dyyb –
Inflectra (Pfizer)

100 mg/20 mL vials

17,033.00

1. Approximate WAC for 54 weeks’ treatment of rheumatoid arthritis in a patient weighing 65 kg (3 mg/kg IV at 0, 2, and 6 weeks, then every 8 weeks).

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.
January 5, 2017. Reprinted with permission by First Databank, Inc. All
rights reserved. ©2017. www.fdbhealth.com/policies/drug-pricing-policy.

BIOSIMILARS — US law defines a biosimilar as a
biologic product that is highly similar to an approved
biologic product (reference product) with no clinically
meaningful differences in safety, purity, or potency;
minor differences in clinically inactive components are
allowed. An approved biosimilar product must have the
same mechanism of action, route of administration,
dosage form, and strength as the reference product.
Bioanalytical and functional assays have found
that the structural and functional characteristics of
infliximab-dyyb are highly similar to those of USlicensed Remicade. Inflectra is approved for most of
the same indications as US-licensed Remicade (see
Table 2), but was not reviewed for “interchangeability”
with Remicade. A biosimilar that is approved as an
interchangeable product may be substituted by a
pharmacist for the reference product in states that
permit such substitutions.2
The FDA recently issued a draft of new guidance on
the criteria for biosimilars to meet the standard for
interchangeability. To demonstrate interchangeability,
the data and information submitted to the FDA must
show that a proposed interchangeable product is
biosimilar to the reference product and that it can
be expected to produce the same clinical results as

the reference product in any given patient. Also, for
23


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®

Table 2. Summary of FDA-Approved Indications for
Remicade and Inflectra1

▶
▶
▶
▶
▶

Induction and maintenance treatment of moderately to severely
active Crohn’s disease or ulcerative colitis in adults who have
had an inadequate response to conventional therapy
Induction and maintenance treatment of moderately to severely
active Crohn’s disease in children ≥6 years old who have had an
inadequate response to conventional therapy
Treatment of moderately to severely active rheumatoid arthritis
(in combination with methotrexate)
Treatment of active ankylosing spondylitis and psoriatic arthritis
Treatment of adults with chronic severe plaque psoriasis

1. Remicade is also approved for induction and maintenance treatment of
moderately to severely active ulcerative colitis in children ≥6 years old

who have had an inadequate response to conventional therapy. This indication is protected by orphan drug exclusivity until September 23, 2018.

products that will be administered more than once,
the data and information must show that switching a
patient back and forth between the reference product
and the proposed interchangeable product is not less
safe or effective than treating them with the reference
product continuously.2
PHARMACOKINETICS — In a randomized, doubleblind, single-dose, pharmacokinetic study in 213
healthy volunteers, Inflectra was compared with
both US-licensed and EU-approved Remicade.
The pharmacokinetic profiles of all three products
were highly similar; all comparisons fell within the
predefined equivalence limits of 80-125%.3
CLINICAL STUDIES — The clinical development
program for infliximab-dyyb was conducted outside
the US using EU-approved Remicade as a comparator.
In a randomized, double-blind trial (PLANETRA) in 606
adults with moderately to severely active rheumatoid
arthritis and an inadequate response to methotrexate,
Inflectra 3 mg/kg IV at weeks 0, 2, and 6, and then
every 8 weeks was compared to the same dosage of
Remicade, both given in combination with methotrexate
12.5-25 mg/week. The ACR20 response rates (≥20%
improvement on the American College of Rheumatology
scale) in the per-protocol population at weeks 30 and
54 were 73.4% and 74.7% with Inflectra, compared to
69.7% and 71.3% with Remicade; these differences were
not statistically significant. At 54 weeks, radiographic
progression was also similar in both groups.4,5 In an

open-label extension, patients who were receiving
Inflectra remained on the drug and those receiving
Remicade switched to Inflectra. At week 102, ACR
response rates remained similar between the groups.6
A randomized, double-blind trial in 250 adults with
active ankylosing spondylitis (PLANETAS) compared
Inflectra with Remicade, both given as 5 mg/kg IV at
weeks 0, 2, and 6, and then every 8 weeks. ASAS20 and
ASAS40 response rates (clinical response according to
24

Vol. 59 (1513)

January 30, 2017

Assessment of Spondyloarthritis International Society
[ASAS] 20 and ASAS40 criteria) at week 30 were 70.5%
and 51.8%, respectively, with Inflectra compared to
72.4% and 47.4% with Remicade.7 At week 54, these
response rates were 67.0% and 54.7% with Inflectra
versus 69.4% and 49.1% with Remicade.8 There were
no statistically significant differences between the
groups. In an open-label extension, patients receiving
Inflectra remained on it and those receiving Remicade
switched to Inflectra. At week 102, ASAS response
rates remained similar between the groups.9
A randomized, double-blind trial comparing Inflectra
with Remicade in patients with active Crohn’s disease
is ongoing.10 The results of uncontrolled studies in
patients with Crohn’s disease or ulcerative colitis

suggest that Inflectra is effective in these patients.11
In an unpublished, double-blind, 52-week trial (NORSWITCH), available only as an abstract, 481 Norwegian
adults with rheumatoid arthritis, ankylosing spondylitis,
psoriatic arthritis, ulcerative colitis, Crohn’s disease,
or chronic plaque psoriasis who had been on stable
infliximab treatment for at least 6 months were
randomized to either switch to infliximab-dyyb or
continue their current treatment. Overall, the biosimilar
product was found to be noninferior to infliximab; disease
worsening (the primary endpoint) occurred in 61 (29.6%)
patients who switched to the biosimilar compared to 53
(26.2%) of those who continued to take infliximab. In the
subgroup of patients with Crohn’s disease, however, the
rate of disease worsening was higher among patients
who switched treatments (36.5% vs 21.2%).12
ADVERSE EFFECTS — In patients treated for up to 54
weeks in the clinical trials, there were no significant
differences in adverse effects between Inflectra and
Remicade. Serious infections, including bacterial
infections, invasive or disseminated fungal infections,
and reactivation of tuberculosis and hepatitis B virus,
have occurred with infliximab. Transaminase elevations
and hepatotoxicity, including autoimmune hepatitis,
and cases of new-onset or worsening heart failure
have been reported. Hypersensitivity reactions, mainly
related to the infusion, can occur. Malignancies have
been reported in patients receiving infliximab, but a
cause-and-effect relationship has not been established.
Inflectra should not be offered to patients with a
previous anaphylactic or infusion-related reaction to

infliximab, or to those with antibodies to infliximab.
IMMUNOGENICITY — Use of infliximab has been
associated with the development of antibodies that
reduced the efficacy of the drug. In clinical trials


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®

in patients with rheumatoid arthritis or ankylosing
spondylitis, the percentage of patients who developed
antidrug antibodies was similar with Inflectra and
Remicade after up to 102 weeks of treatment.
Preliminary results from the ongoing trial in patients
with Crohn’s disease found that the incidence of
antidrug antibodies was similar with Inflectra and
Remicade after 14 weeks of treatment.10
CONCLUSION — Infliximab-dyyb (Inflectra) has been
approved by the FDA as a biosimilar of infliximab
(Remicade). In clinical trials in patients with
rheumatoid arthritis or ankylosing spondylitis, it was
similar to Remicade in efficacy and safety. Inflectra
could be a less expensive alternative to Remicade
in such patients. The efficacy and adverse effects of
Inflectra are also expected to be generally similar to
those of Remicade in patients with other conditions for
which infliximab is approved, but in one unpublished
study, the rate of disease worsening in patients with
Crohn’s disease was higher in those who switched

from Remicade to Inflectra than in those who remained
on Remicade. ■
1. Zarxio – a filgrastim biosimilar. Med Lett Drugs Ther 2016;
58:34.
2. FDA. Biosimilars Guidances. Available at: www.fda.gov/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/
ucm290967.htm. Accessed January 19, 2016.
3. W Park et al. Comparison of the pharmacokinetics and safety
of three formulations of infliximab (CT-P13, EU-approved reference infliximab and the US-licensed reference infliximab) in
healthy subjects: a randomized, double-blind, three-arm, parallel-group, single-dose, phase I study. Expert Rev Clin Immunol
2015; 11 Suppl 1:S25.
4. DH Yoo et al. A randomised, double-blind, parallel-group study
to demonstrate equivalence in efficacy and safety of CT-P13
compared with innovator infliximab when coadministered with
methotrexate in patients with active rheumatoid arthritis: the
PLANETRA study. Ann Rheum Dis 2013; 72:1613.
5. DH Yoo et al. A phase III randomized study to evaluate the efficacy and safety of CT-P13 compared with reference infliximab
in patients with active rheumatoid arthritis: 54-week results
from the PLANETRA study. Arthritis Res Ther 2016; 18:82.
6. DH Yoo et al. Efficacy and safety of CT-P13 (biosimilar infliximab) in patients with rheumatoid arthritis: comparison between switching from reference infliximab to CT-P13 and continuing CT-P13 in the PLANETRA extension study. Ann Rheum
Dis 2017; 76:355.
7. W Park et al. A randomised, double-blind, multicenter, parallelgroup, prospective study comparing the pharmacokinetics,
safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study. Ann
Rheum Dis 2013; 72:1605.
8. W Park et al. Comparable long-term efficacy, as assessed by
patient-reported outcomes, safety and pharmacokinetics, of
CT-P13 and reference infliximab in patients with ankylosing
spondylitis: 54-week results from the randomized, parallelgroup PLANETAS study. Arthritis Res Ther 2016; 18:25.
9. W Park et al. Efficacy and safety of switching from reference
infliximab to CT-P13 compared with maintenance of CT-P13 in

ankylosing spondylitis: 102-week data from the PLANETAS extension study. Ann Rheum Dis 2016; Apr 26 (epub).

Vol. 59 (1513)

January 30, 2017

10. FDA Medical Review. Inflectra (infliximab-dyyb) for injection. Available at: www.accessdata.fda.gov/drugsatfda_docs/
nda/2016/125544Orig1s000TOC.cfm. Accessed January 19, 2017.
11. J Jahnsen. Clinical experience with infliximab biosimilar Remsima (CT-P13) in inflammatory bowel disease patients. Therap
Adv Gastroenterol 2016; 9:322.
12. KK Jorgensen et al. Biosimilar infliximab (CT-P13) is not inferior to originator infliximab: results from the 52-week randomized NOR-SWITCH trial. UEG Journal 2016; 4(6):805. Abstract LB15. Available at: />pdf/10.1177/2050640616678364. Accessed January 19, 2017.

▶

Yosprala – A Combination of
Aspirin and Omeprazole

The FDA has approved Yosprala (Aralez), a fixeddose combination of delayed-release aspirin and
immediate-release omeprazole, for secondary
prevention of cardiovascular and cerebrovascular
events in patients who are at risk of developing aspirinassociated gastric ulcers (≥55 years old or history of
gastric ulcers). Yosprala is the first product to become
available in the US that combines aspirin and a proton
pump inhibitor (PPI).
Pronunciation Key
Yosprala: yo spra' lah

SECONDARY PREVENTION — Aspirin irreversibly
acetylates cyclooxygenase-1, blocking thromboxane
synthesis and inhibiting platelet activation and

aggregation for the life of the platelet (up to 10 days). It
reduces the incidence of myocardial infarction by 30%,
stroke by 20%, and all-cause mortality by 18% when used
for secondary prevention of thromboembolic events.
The annual risk of serious GI bleeding with aspirin
doses ≤325 mg/day is about 0.4%, which is 2.5 times
the risk without aspirin.1 Use of a PPI has been shown to
reduce the risk of recurrent gastric ulcers and bleeding
in patients who continue to take aspirin for secondary
prevention of thromboembolic events despite a history
of aspirin-induced GI toxicity.2
CLINICAL STUDIES — Approval of Yosprala was based
on the results of two 6-month trials in a total of 1049
patients at risk for developing aspirin-associated
gastric ulcers (≥55 years old or 18 to 54 years old with
a history of gastric or duodenal ulceration within 5
years) who had been taking aspirin 325 mg/day for ≥3
months for secondary prevention of cardiovascular or
cerebrovascular events and were expected to continue
taking it for ≥6 months. In both trials, patients were
randomized to receive either Yosprala 325/40 mg or
enteric-coated aspirin 325 mg once daily for 6 months.
Significantly fewer patients taking the combination
25


The Medical Letter

®

developed endoscopic gastric ulcers compared to those
taking enteric-coated aspirin alone (3.8% vs 8.7% in trial
1 and 2.7% vs 8.5% in trial 2). Treatment discontinuation
due to upper GI adverse effects was significantly lower
with the combination than with enteric-coated aspirin
alone (1.5% vs 8.2%).3
DOSAGE AND COST — Yosprala tablets consist of a
core of either 81 or 325 mg of enteric-coated aspirin
surrounded by an outer layer of 40 mg of immediaterelease omeprazole. The combination should be taken
once daily at least 60 minutes before a meal. The
tablets must be swallowed whole; they should not be
split, crushed, dissolved, or chewed. A 30-day supply
of either strength of Yosprala costs $150.4 A 30-day
supply of enteric-coated aspirin (30 81-mg or 325-mg
tablets) and delayed-release omeprazole (60 20-mg
tablets), which are both available generically over the
counter, costs about $35.80.5
CONCLUSION — Use of the fixed-dose combination
of delayed-release aspirin and immediate-release
omeprazole (Yosprala) can decrease the incidence
of endoscopically-detected gastric ulcers in
patients taking aspirin for secondary prevention of
thromboembolic events who are at increased risk of
aspirin-associated gastric ulcers. How it compares
with taking a delayed-release proton pump inhibitor
and enteric-coated aspirin separately, which costs
much less, remains to be established. ■
1. SM Weisman and DY Graham. Evaluation of the benefits and risks
of low-dose aspirin in the secondary prevention of cardiovascular
and cerebrovascular events. Arch Intern Med 2002; 162:2197.

2. Primary prevention of ulcers in patients taking aspirin or
NSAIDs. Med Lett Drugs Ther 2010; 52:17.
3. DJ Whellan et al. PA32540 (a coordinated-delivery tablet of
enteric-coated aspirin 325 mg and immediate-release omeprazole 40 mg) versus enteric-coated aspirin 325 mg alone in subjects at risk for aspirin-associated gastric ulcers: results of two
6-month, phase 3 studies. Am Heart J 2014; 168:495.
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. January 5, 2017. Reprinted with permission by First Databank, Inc. All rights reserved.
©2017. www.fdbhealth.com/policies/drug-pricing-policy.
5. Cost at CVS.com. Accessed January 19, 2017.

Corrections
Drugs for Diabetes (Med Lett Drugs Ther 2017; 59:9)
In the 4th paragraph of the GLP-1 receptor agonists section,
we mistakenly stated that Xultophy 100/3.6 is a combination
of insulin degludec and albiglutide; Xultophy 100/3.6 is a
combination of insulin degludec and liraglutide.
Another Insulin Glargine (Basaglar) for Diabetes (Med Lett Drugs
Ther 2017; 59:3)
In the Dosage and Administration section, we removed the word
“syringe” to describe Basaglar’s KwikPen device. Basaglar is not
available as a prefilled syringe; it is only available as a KwikPen.
26

Vol. 59 (1513)

January 30, 2017

Drug Interaction: Dabigatran (Pradaxa) and Statins
The results of a recently published study suggest that
taking the oral direct thrombin inhibitor dabigatran

etexilate (Pradaxa) with either simvastatin (Zocor, and
others) or lovastatin (Altoprev, and others) increases the
risk of major hemorrhage.1
POSSIBLE MECHANISMS — The mechanism for this
potential interaction has not been established. Dabigatran
etexilate is a substrate of the transporter P-glycoprotein
(P-gp); drugs that inhibit P-gp could increase dabigatran
serum concentrations and the risk of bleeding.2 In in vitro
studies, simvastatin and lovastatin have been shown to
inhibit P-gp3; however, limited data from in vivo studies
suggest simvastatin and lovastatin have little to no
effect on serum concentrations of P-gp substrates such
as digoxin.4-6 Some studies have suggested that statins
may have antiplatelet effects.7
THE STUDY — The risk of major hemorrhage was
evaluated in a population-based, case-control study in
patients ≥66 years old with nonvalvular atrial fibrillation
who were taking dabigatran etexilate and had received a
prescription for a statin. Patients prescribed simvastatin
or lovastatin were more likely to have a major hemorrhage
than those prescribed other statins (adjusted OR 1.46;
95% CI 1.17-1.82). The number of patients prescribed
simvastatin or lovastatin in this study was small
compared to the number prescribed other statins such
as atorvastatin (Lipitor, and others).
CONCLUSION — The results of one case-control study
suggest that older patients taking dabigatran etexilate
(Pradaxa) with either simvastatin (Zocor, and others) or
lovastatin (Altoprev, and others) are at increased risk of
major hemorrhage, compared to those taking the drug

with another statin. Although the study had several
limitations and a mechanism has not been firmly established, it may be reasonable to use another statin such as
atorvastatin (Lipitor, and others) in older patients taking
dabigatran until more data become available. ■
1. T Antoniou et al. Association between statin use and ischemic
stroke or major hemorrhage in patients taking dabigatran for atrial
fibrillation. CMAJ 2016 Nov 21 (epub).
2. Which oral anticoagulant for atrial fibrillation? Med Lett Drugs Ther
2016; 58:45.
3. C Chen et al. Differential interaction of 3-hydroxy-3-methylglutarylcoa reductase inhibitors with ABCB1, ABCC2, and OATP1B1. Drug
Metab Dispos 2005; 33:537.
4. FDA. Center for Drug Evaluation and Research. Juvisync (sitagliptin +
simvastatin tablets). Clinical Pharmacology and Biopharmaceutics
Review(s). Available at: www.accessdata.fda.gov/drugsatfda_docs/
nda/2011/202343orig1s000ClinPharmR.pdf. Accessed January 19,
2017.
5. A Bernsdorf et al. Simvastatin does not influence the intestinal Pglycoprotein and MPR2, and the disposition of talinolol after chronic
medication in healthy subjects genotyped for the ABCB1, ABCC2
and SLCO1B1 polymorphisms. Br J Clin Pharmacol 2006; 61:440.
6. W Dieterle et al. Pharmacokinetic interactions of the oral renin inhibitor aliskiren with lovastatin, atenolol, celecoxib and cimetidine.
Int J Clin Pharmacol Ther 2005; 43:527.
7. F Violi et al. Statins as antithrombotic drugs. Circulation 2013;
127:251.

Comparison Chart of SGLT2 Inhibitors (online only)
www.medicalletter.org/downloads/SGLT-2_inhibitors_LS.pdf


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Review the efficacy and safety of lixisenatide (Adlyxin) and insulin glargine/lixisenatide (Soliqua 100/33) for treatment of type 2 diabetes.
Review the efficacy and safety of pembrolizumab (Keytruda) for first-line treatment of metastatic non-small cell lung cancer that highly expresses programmed deathligand 1 (PD-L1).
Review the efficacy and safety of the infliximab biosimilar Inflectra, and discuss how it compares to Remicade.
Review the efficacy and safety of the fixed-dose combination of aspirin and omeprazole (Yosprala) for secondary prevention of thromboembolic events in patients who
are at risk of developing aspirin-associated gastric ulcers.
Discuss the possible mechanism for the interaction between dabigatran etexilate (Pradaxa) and simvastatin (Zocor, and others) or lovastatin (Altoprev, and others), and
the risks of taking these drugs concurrently.

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Issue 1513 Questions
(Correspond to questions #21-30 in Comprehensive Exam #76, available July 2017)
Lixisenatide for Type 2 Diabetes

Inflectra – An Infliximab Biosimilar

1. Lixisenatide commonly causes:
a. nausea
b. hypoglycemia
c. weight gain
d. malignancy

7. In a randomized, double-blind trial in patients with rheumatoid
arthritis who had not responded adequately to methotrexate,
infliximab-dyyb, compared to Remicade, was:
a. significantly less effective in producing ACR20 responses
b. significantly less effective in preventing radiographic
progression of disease
c. similarly effective in producing ACR20 responses and in
preventing radiographic progression
d. more effective in preventing radiographic progression

2. As an add-on drug in patients inadequately controlled on metformin,
how did once-daily lixisenatide compare to twice-daily exenatide in
reducing A1C? Lixisenatide was:
a. superior to exenatide
b. noninferior to exenatide
c. inferior to exenatide
d. superior to exenatide in one study, inferior in another
3. A 64-year-old woman with a BMI of 31 and type 2 diabetes has been
taking metformin but needs another drug to achieve her A1C goal. You
would like to add a GLP-1 receptor agonist. In clinical studies, liraglutide:
a. has been significantly more effective than lixisenatide in
reducing A1C

b. has been shown to reduce cardiovascular risk, while
lixisenatide to date has not
c. has been similar to lixisenatide in reducing weight
d. all of the above
4. The fixed-ratio combination of insulin glargine and lixisenatide
(Soliqua 100/33) has been shown to be more effective in reducing
A1C than:
a. either of its components alone
b. insulin glargine plus liraglutide
c. insulin degludec plus liraglutide
d. all of the above
Pembrolizumab (Keytruda) for First-Line Treatment of Metastatic NSCLC
5. In patients with NSCLC that highly expresses PD-L1, median
progression-free survival was how much longer with pembrolizumab
than with platinum-based chemotherapy?
a. 2.6 months
b. 4.3 months
c. 6.3 months
d. 8.2 months
6. About what percentage of patients have advanced NSCLC that highly
expresses PD-L1?
a. 10%
b. 25%
c. 50%
d. >60%

8. You have a 13-year-old male patient with severe Crohn’s disease
that has not responded to Remicade. His mother asks you if
Inflectra might be more effective. You could tell her that:
a. Inflectra has not been approved by the FDA for treatment of

Crohn’s disease in children.
b. In a randomized, double-blind trial comparing the two drugs
in children with severe Crohn’s disease, Remicade was more
effective than Inflectra.
c. In one study, patients with Crohn’s disease who switched from
Remicade to Inflectra had a higher rate of disease worsening
than those who stayed on Remicade.
d. all of the above
Yosprala – A Combination of Aspirin and Omeprazole
9. Yosprala contains:
a. immediate-release aspirin and delayed-release omeprazole
b. delayed-release aspirin and delayed-release omeprazole
c. delayed-release aspirin and immediate-release omeprazole
d. immediate-release aspirin and immediate-release omeprazole
Drug Interaction: Dabigatran (Pradaxa) and Statins
10. A 70-year-old man taking dabigatran etexilate for atrial fibrillation
now requires treatment for hyperlipidemia. Based on the results of a
recent population-based, case-controlled study, which of the following statins might interact with dabigatran and increase his risk of
major hemorrhage?
a. atorvastatin
b. simvastatin
c. fluvastatin
d. rosuvastatin

ACPE UPN: Per Issue Exam: 0379-0000-17-513-H01-P; Release: January 30, 2017, Expire: January 30, 2018
Comprehensive Exam 76: 0379-0000-17-076-H01-P; Release: July 2017, Expire: July 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,
Pharm.D.; ASSOCIATE EDITORS: Susan M. Daron, Pharm.D., Amy Faucard, MLS, Corinne Z. Morrison, Pharm.D., Michael P. Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M. Shah,
Pharm.D., F. Peter Swanson, M.D.

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Sunnybrook Health Sciences Centre; Richard B. Kim, M.D., University of Western Ontario; Franco M. Muggia, M.D., New York University Medical Center; Sandip K. Mukherjee,
M.D., F.A.C.C., Yale School of Medicine; Dan M. Roden, M.D., Vanderbilt University School of Medicine; Esperance A.K. Schaefer, M.D., M.P.H., Harvard Medical School; F. Estelle
R. Simons, M.D., University of Manitoba; Neal H. Steigbigel, M.D., New York University School of Medicine; Arthur M. F. Yee, M.D., Ph.D., F.A.C.R., Weill Medical College of Cornell
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