The medical letter on drugs and therapeutics april 27 2015

The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959
Volume 57

ISSUE
ISSUE
No.

1433
1467
Volume 56

April 27, 2015

IN THIS ISSUE

Carbidopa/Levodopa Extended-Release Capsules (Rytary) ........................................ p 59
Netupitant/Palonosetron (Akynzeo) for Chemotherapy-Induced Nausea
and Vomiting ........................................................................................................... p 61
Umeclidinium (Incruse Ellipta) for COPD ................................................................... p 63
Glyxambi — A New Combination for Type 2 Diabetes ................................................. p 65
Addendum: Diet, Drugs, and Surgery for Weight Loss................................................. p 66

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The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959
Volume 57

ISSUE

ISSUE No.

1433
1467

Volume 56

▶

April 27, 2015
Take CME Exams
ALSO IN THIS ISSUE

Netupitant/Palonosetron (Akynzeo) for Chemotherapy-Induced Nausea
and Vomiting ........................................................................................................................p 61
Umeclidinium (Incruse Ellipta) for COPD .............................................................................p 63
Glyxambi — A New Combination for Type 2 Diabetes .........................................................p 65
Addendum: Diet, Drugs, and Surgery for Weight Loss ........................................................p 66

Carbidopa/Levodopa ExtendedRelease Capsules (Rytary)

The FDA has approved a new formulation of carbidopa/
levodopa (Rytary – Impax) in extended-release capsules for treatment of Parkinson’s disease (PD).
Pronunciation Key
Carbidopa: kar" bi doe' pa
Rytary: rye tar' ee
Levodopa: lee" voe doe' pa

CARBIDOPA/LEVODOPA — The combination of
levodopa and carbidopa is still the most effective
pharmacologic treatment for symptomatic relief
of PD.1 It has been available for many years as
immediate- and sustained-release tablets (Sinemet,
Sinemet CR, and generics), orally disintegrating
tablets, and in combination with the COMT inhibitor

entacapone (Stalevo, and generics). Sustainedrelease tablets have a slower and less predictable
onset of action than immediate-release tablets. Many
patients must take a half or a whole immediate-release
tablet concomitantly with sustained-release tablets,
particularly with the first dose of the day. Some small
studies in patients with PD fluctuations have found no
significant difference in "off" time between sustainedrelease and immediate-release formulations.2
A PHARMACOKINETIC STUDY — Rytary capsules
contain a combination of immediate- and extendedrelease beads. In an open-label pharmacokinetic
study, levodopa plasma concentrations increased
at a similar rate following administration of a single
dose of either immediate-release carbidopa/levodopa
or the new extended-release capsules. Serum

Table 1. Pharmacology of Rytary
Carbidopa

Levodopa

Class

Decarboxylase
inhibitor

Dopamine precursor

Metabolism

Glucuronidation

Decarboxylation,
O-methylation

Tmax

3 hours

1 hour

Excretion

30% unchanged
in urine

Urine as metabolites,
6% unchanged

Half-life (terminal)

~2 hours

~2 hours

concentrations remained higher than 50% of levodopa
Cmax significantly longer with the extended-release
formulation (4.0 vs 1.4 hours).3
CLINICAL STUDIES — FDA approval of Rytary was
based on two clinical trials. The first, a 30-week trial,
found that extended-release carbidopa/levodopa
capsules were significantly more effective than

placebo in treating levodopa-naive patients with PD.4
The second was a 22-week comparison of extendedand immediate-release carbidopa/levodopa in
patients with advanced PD and motor fluctuations;
the extended-release capsules produced a greater
reduction in “off” time as a percentage of waking hours
(-13.06% vs -6.21%), a greater reduction in daily “off”
time (-2.18 vs -1.01 hours), and about one more hour
of “on” time with no or non-troublesome dyskinesia
(11.8 vs 10.9 hours), all significant differences, with
fewer daily doses (mean 3.6 vs 5.0).5
In a third trial in patients with advanced PD, those
taking extended-release carbidopa/levodopa capsules had a lower percentage of “off” time than those
taking immediate-release carbidopa/levodopa plus
entacapone (24.0% vs 32.5%).6
59

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


The Medical Letter

Vol. 57 (1467)

®

April 27, 2015

Table 2. Some Carbidopa/Levodopa Combinations for Parkinson’s Disease
Drug

Some Available Formulations

Usual Daily Dosage

Cost1

23.75/95, 36.25/145
48.75/195, 61.25/245 mg caps2

285-1170 mg levodopa,
divided3

$207.00

immediate-release – generic
Sinemet (Merck)

10/100, 25/100, 25/250 mg tabs

300-1500 mg levodopa,
divided

25.20
87.00

orally disintegrating – generic

10/100, 25/100, 25/250 mg tabs

300-1500 mg levodopa,

divided

70.00

sustained-release – generic4
Sinemet CR (Merck)

25/100, 50/200 mg tabs

400-1600 mg levodopa,
divided

60.50
141.00

12.5/50/200, 18.75/75/200,
25/100/200, 31.25/125/200,
37.5/150/200, 50/200/200 mg tabs

300-1500 mg levodopa,
divided

272.10
497.90

Carbidopa/levodopa
extended-release – Rytary (Impax)

Carbidopa/levodopa/entacapone – generic
Stalevo (Orion)

1. Approximate WAC for 30 days’ treatment with the lowest recommended 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. Capsules may be opened, and the contents sprinkled on 1-2 tablespoons of applesauce and taken immediately.
3. Dosages of Rytary are not interchangeable with those of other carbidopa/levodopa products. See Table 3.
4. Generic sustained-release tablets are bioequivalent to Sinemet CR sustained-release tablets, but they are called "carbidopa and levodopa extended-release
tablets" in their package inserts.

ADVERSE EFFECTS — The tolerability of the new
extended-release capsules appears to be similar to
that of other carbidopa/levodopa formulations. The
most common adverse effects reported in clinical
trials were nausea, dizziness, and headache.

should first be converted to the appropriate Rytary
dose using the conversion table below. If patients are
converting from carbidopa/levodopa plus entacapone
(or another COMT inhibitor), the starting dosage may
need to be higher.

DOSAGE AND ADMINISTRATION — Rytary capsules
are not interchangeable with immediate-release
or sustained-release formulations of carbidopa/
levodopa; the strengths were intentionally made
different by the manufacturer to avoid confusion
with other available products. In levodopa-naive
patients, the recommended starting dosage of the
new formulation is 23.75/95 mg three times daily
for the first three days, which can be increased to

36.25/145 mg three times daily starting on day 4 and
then, if needed, increased to 97.5/390 mg three times
daily. The dosing frequency may then be increased to
five times daily if necessary. The total daily dose of
Rytary should not exceed 612.5/2450 mg.

The capsules should be swallowed whole and can
be taken with or without food. For patients who have
difficulty swallowing, the contents of the capsules can
be sprinkled on 1-2 tablespoons of applesauce and
taken immediately.

To switch patients from immediate-release carbidopa/
levodopa to Rytary, the daily immediate-release dose
Table 3. Conversion from IR Carbidopa/Levodopa to Rytary1
Total Daily IR
Levodopa Dose

Total Daily Rytary
Levodopa Dose
Rytary Starting Dosage

400-549 mg

855 mg

3 caps of 23.75/95 mg TID

550-749 mg

1140 mg

4 caps of 23.75/95 mg TID

750-949 mg

1305 mg

3 caps of 36.25/145 mg TID

950-1249 mg

1755 mg

3 caps of 48.75/195 mg TID

2205 mg
or 2340 mg

3 caps of 61.25/245 mg TID
or 4 caps of 48.75/195 mg TID

≥1250 mg

1. RA Hauser. 2015. How to dose Rytary (carbidopa and levodopa extendedrelease) [White paper]. National Parkinson Foundation. Available at www.
parkinson.org. Accessed April 15, 2015.

60

CONCLUSION — Extended-release carbidopa/levodopa

capsules (Rytary) can decrease “off” time and dosing
frequency compared to immediate-release tablets.
Dosages of Rytary are not interchangeable with those
of other carbidopa/levidopa products. ■
1. Drugs for Parkinson’s disease. Med Lett Drugs Ther 2013;
11:101.
2. R Pahwa et al. Practice Parameter: treatment of Parkinson
disease with motor fluctuations and dyskinesia (an evidencebased review): report of the Quality Standards Subcommittee
of the American Academy of Neurology. Neurology 2006;
66:983.
3. RA Hauser et al. Crossover comparison of IPX066 and a
standard levodopa formulation in advanced Parkinson’s
disease. Mov Disord 2011; 26:2246.
4. R Pahwa et al. Randomized trial of IPX066, carbidopa/
levodopa extended release, in early Parkinson’s disease.
Parkinsonism Relat Disord 2014; 20:142.
5. RA Hauser et al. Extended-release carbidopa-levodopa
(IPX066) compared with immediate-release carbidopalevodopa in patients with Parkinson’s disease and motor
fluctuations: a phase 3 randomised, double-blind trial. Lancet
Neurol 2013; 12:346.
6. F Stocchi et al. Comparison of IPX066 with carbidopalevodopa plus entacapone in advanced PD patients.
Parkinsonism Relat Disord 2014; 20:1335.


The Medical Letter

▶

®

Netupitant/Palonosetron (Akynzeo)
for Chemotherapy-Induced Nausea
and Vomiting

The FDA has approved Akynzeo (Helsinn/Eisai), an oral
fixed-dose combination of the substance P/neurokinin 1 (NK1) receptor antagonist netupitant and the
serotonin-3 (5-HT3) receptor antagonist palonosetron,
for prevention of acute and delayed nausea and
vomiting associated with cancer chemotherapy
in adults. Akynzeo is the first product to combine
drugs from these two classes. Palonosetron (Aloxi)
is also available as a single agent for prevention of
chemotherapy-induced and postoperative nausea
and vomiting.1 Netupitant is the second substance
P/NK1 receptor antagonist to be approved in the US;
aprepitant (Emend) was the first.2
Pronunciation Key
Netupitant: ne tue' pi tant
Akynzeo: a kin' zee oh
Palonosetron: pal" oh noe' se tron

STANDARD TREATMENT — Current guidelines recommend that patients undergoing highly emetogenic
chemotherapy receive a 3-drug regimen consisting
of aprepitant, a 5-HT3 receptor antagonist, and
dexamethasone for prevention of acute and delayed
nausea and vomiting.3,4 Palonosetron administered in
combination with dexamethasone is recommended
for patients receiving moderately emetogenic
chemotherapy. Granisetron or ondansetron (Zofran,
and generics) may be substituted if palonosetron is

not available.
Table 1. Pharmacology of Akynzeo
Class

Netupitant

Palonosetron

Substance P/NK1
receptor antagonist

5-HT3 receptor antagonist

Metabolism Primarily by CYP3A4,
and to a lesser extent
by CYP2C9 and 2D6

Primarily by CYP2D6,
and to a lesser extent by
CYP3A4 and 1A2

Tmax

5 hours

5 hours

Excretion

Feces (~71% in 14 days);

urine (~4% in 14 days)

Urine (85%-93%);
feces (5%-8%)

Half-life

96 hrs (healthy subjects); 44 hrs (healthy subjects);
~ 80 hrs (cancer patients) ~ 48 hrs (cancer patients)

MECHANISM OF ACTION — Palonosetron has a higher
affinity for 5-HT3 receptors than other available 5-HT3
receptor antagonists. Netupitant selectively inhibits
NK1 receptors and blocks the action of substance
P, a neuropeptide that binds to NK1 receptors in the
gut, brainstem, and area postrema, all of which are
involved in the emetic response. The combination of

Vol. 57 (1467)

April 27, 2015

palonosetron and netupitant may block the action of
substance P synergistically.5
CLINICAL STUDIES — FDA approval of netupitant/
palonosetron was based on two double-blind
controlled trials. The first was a dose-ranging trial
that randomized 694 chemotherapy-naive patients
undergoing highly emetogenic (cisplatin-based)
chemotherapy to a single oral dose of netupitant

100, 200, or 300 mg plus palonosetron 0.5 mg, or to
a single oral dose of palonosetron 0.5 mg alone. Oral
aprepitant for 3 days plus IV ondansetron on day 1
was included as an “exploratory arm” that was only
to be compared to palonosetron. All groups also
received oral dexamethasone on days 1-4.6
The second trial randomized 1455 chemotherapynaive patients undergoing moderately emetogenic
(anthracycline-cyclophosphamide) chemotherapy to
a single oral dose of netupitant 300 mg plus palonosetron 0.5 mg or a single oral dose of palonosetron 0.5 mg
alone. Both groups also received oral dexamethasone
on day 1.7
Table 2. Netupitant/Palonosetron Clinical Trials
Netupitant/
Palonosetron1

Palonosetron2

Aprepitant +
Ondansetron3

Highly Emetogenic Chemotherapy Trial4 (n=694)
Complete Response5
Acute Phase
98.5%
(0-24 h)
Delayed Phase
90.4%
(25-120 h)
Overall Phase
89.6%

(0-120 h)

89.7%

94.8%

80.1%

88.8%

76.5%

86.6%

Moderately Emetogenic Chemotherapy Trial6 (n=1455)
Complete Response5
Acute Phase
88.4%
(0-24 h)
Delayed Phase
76.9%
(25-120 h)
Overall Phase
74.3%
(0-120 h)

85.0%

—

69.5%

—

66.6%

—

1. The dosage of netupitant/palonosetron was 300 mg/0.5 mg once.
Patients in the highly emetogenic chemotherapy trial also received oral
dexamethasone 12 mg once on day 1 and 4 mg twice daily on days 2-4.
Patients in the moderately emetogenic chemotherapy trial received oral
dexamethasone 20 mg on day 1.
2. Palonosetron was administered as a single oral 0.5-mg dose. Patients in
the highly emetogenic chemotherapy trial received oral dexamethasone
20 mg on days 1 and 8 mg twice daily on days 2-4. Patients in the
moderately emetogenic chemotherapy trial received oral dexamethasone
20 mg on day 1.
3. Administered as oral aprepitant 125 mg, IV ondansetron 32 mg, and oral
dexamethasone 12 mg on day 1, followed by oral aprepitant 80 mg once
daily and oral dexamethasone 4 mg twice daily on days 2-3, then oral
dexamethasone 4 mg twice daily on day 4.
4. Patients undergoing cisplatin-based chemotherapy (PJ Hesketh et al. Ann
Oncol 2014; 25:1340).
5. Defined as no emesis and no use of rescue medication.
6. Patients undergoing chemotherapy containing cyclophosphamide and an
anthracycline; this combination is now classified as highly emetogenic (M
Aapro et al. Ann Oncol 2014; 25:1328).

61

The Medical Letter

Vol. 57 (1467)

®

April 27, 2015

Table 3. Some Drugs for Chemotherapy-Induced Nausea and Vomiting
Some Available Formulations

Usual Adult Dosage for Highly
Emetogenic Chemotherapy1

Dolasetron – Anzemet (Sanofi)

50, 100 mg tabs

PO : 100 mg once

$95.50

Granisetron – generic

1 mg tabs; 1 mg/mL,3 4 mg/4 mL vials;
0.1 mg/mL preservative-free vials
52 cm2 patch5

PO : 2 mg once
IV : 1 mg or 0.01 mg/kg once
1 patch 24 hours before
chemotherapy6

31.20
19.704
435.50

4, 8, 16, 24 mg tabs;
4 mg/5 mL oral soln; 2 mg/mL vials3;
4 mg/2 mL syringes
4, 8, 24 mg tabs; 4 mg/5 mL
oral soln; 2 mg/mL vials3

PO : 24 mg once or 8 mg
twice/d x 1 day
IV : 8 mg or 0.15 mg/kg once
PO : 24 mg once or 8 mg
twice/d x 1 day
IV : 8 mg or 0.15 mg/kg once

3.607

4, 8 mg tabs

ODT: 24 mg once

4, 8 mg oral films

24 mg 30 minutes before
chemotherapy

0.075 mg/1.5 mL, 0.25 mg/5 mL
single-use vials

IV : 0.25 mg once

411.00

Aprepitant – Emend (Merck)

40, 80, 125 mg caps

PO : 125 mg on day 1, then
80 mg on days 2-3

495.109

Fosaprepitant – Emend (Merck)

150 mg vials (lyophilized powder)

IV : 150 mg once

257.00

PO : 300 mg/0.5 mg once

499.80

Drug

Cost2

5-HT3 Receptor Antagonists

transdermal patch – Sancuso
(Prostrakan)
Ondansetron – generic
Zofran (GSK)

orally disintegrating tablet – generic
Zofran ODT (GSK)
oral soluble film – Zuplenz (Galena)
Palonosetron – Aloxi (Helsinn/Eisai)

2.008
110.607
42.708
5.80
104.40
75.20

Substance P/NK1 Receptor Antagonists

Substance P/NK1 Receptor Antagonist and 5-HT3 Receptor Antagonist Combination
Netupitant/palonosetron – Akynzeo
(Helsinn/Eisai)

300 mg/0.5 mg caps

ODT = orally disintegrating tablet
1. For single-day chemotherapy.
2. Approximate WAC for one dose. WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or
list price and may not represent an actual transactional price. Source: AnalySource® Monthly. April 5, 2015. Reprinted with permission by First Databank, Inc. All
rights reserved. ©2015. www.fdbhealth.com/policies/drug-pricing-policy.
3. Also available as preservative-free solution.
4. Cost for 1 mg.
5. Each patch contains 34.3 mg of granisetron and releases 3.1 mg of granisetron per 24 hours for up to 7 days.
6. Remove the patch a minimum of 24 hours after chemotherapy. It may be worn for up to 7 days.
7. Cost for three 8-mg tablets.
8. Cost for 8 mg.
9. Cost for one 125-mg capsule and two 80-mg capsules.

In both trials, complete response rates (no emesis
and no use of rescue medication) were significantly
higher with netupitant plus palonosetron than with
palonosetron alone (see Table 2).
Another study in 413 patients undergoing moderately
or highly emetogenic chemotherapy found that complete response rates with netupitant/palonosetron
were maintained over multiple cycles of chemotherapy
and appeared to be similar to those achieved with
aprepitant/palonosetron.8
ADVERSE EFFECTS — The most common adverse
effects of netupitant/palonosetron (occurring in ≥3% of
patients) were headache, asthenia, dyspepsia, fatigue,
constipation, and erythema. Serotonin syndrome has
been reported with use of 5-HT3 receptor antagonists.
Elevations in liver enzymes and total bilirubin have

occurred rarely.
PREGNANCY – Akynzeo is classified as category C
(embryofetal toxicity in animals; no adequate studies
in women) for use during pregnancy.
62

DRUG INTERACTIONS — Netupitant is a moderate
inhibitor of CYP3A4 and can increase serum concentrations of drugs that are substrates of CYP3A4,
such as dexamethasone, midazolam, and some
chemotherapy agents. As with aprepitant, a lower dose
of dexamethasone should be used in combination with
netupitant/palonosetron. Netupitant is a substrate of
CYP3A4; concurrent use with CYP3A4 inducers, such
as rifampin, should be avoided.9
Serotonin syndrome has been reported with concurrent
use of 5-HT3  receptor antagonists and other serotonergic
drugs, including selective serotonin reuptake inhibitors
(SSRIs) and serotonin and norepinephrine reuptake
inhibitors (SNRIs).
DOSAGE AND ADMINISTRATION — The recommended dosage of Akynzeo is one capsule (netupitant
300 mg/palonosetron 0.5 mg) approximately 1 hour
before the start of chemotherapy. Patients receiving
highly emetogenic chemotherapy should also take
oral dexamethasone 12 mg 30 minutes before chemo-


The Medical Letter

®

Table 4. Emetogenicity of Some IV Chemotherapy Drugs1,2
Highly Emetogenic Drugs
Carmustine (BiCNU)
Cisplatin (Platinol)3
Cyclophosphamide4 (Cytoxan)3
Dacarbazine (DTIC-Dome)3
Moderately Emetogenic Drugs
Azacitidine (Vidaza)3
Alemtuzumab (Campath)
Bendamustine (Treanda)
Carboplatin (Paraplatin)3
Clofarabine (Clolar)
Cyclophosphamide4 (Cytoxan)3
Cytarabine6 (Cytosar-U)3

Dactinomycin (Cosmegen)3
Mechlorethamine (Mustargen)
Streptozocin (Zanosar)

Daunorubicin5 (Cerubidine)3
Doxorubicin5 (Adriamycin)3
Epirubicin5 (Ellence)3
Idarubicin5 (Idamycin)3
Ifosfamide (Ifex)3
Irinotecan (Camptosar)3
Oxaliplatin (Eloxatin)3

Mildly Emetogenic Drugs
Bortezomib (Velcade)
Cabazitaxel (Jevtana Kit)

Cytarabine6 (Cytosar-U)3
Docetaxel (Taxotere)3
Doxorubicin, liposomal (Doxil)3
Etoposide (Vepesid)3
Fluorouracil (Adrucil)3
Gemcitabine (Gemzar)3
Ixabepilone (Ixempra Kit)

Methotrexate (Folex)3
Mitomycin (Mutamycin)3
Mitoxantrone (Novantrone)3
Paclitaxel (Taxol)3
Panitumumab (Vectibix)
Pemetrexed (Alimta)
Temsirolimus (Torisel)
Topotecan (Hycamtin)3
Trastuzumab (Herceptin)

1. E Basch et al. J Clin Oncol 2011; 29:4189; F Roila et al. Ann Oncol 2010;
21:v232.
2. Antineoplastics are often given in combination. Dose, route, and schedule
of administration also affect the incidence and intensity of nausea and
vomiting.
3. Available generically .
4. Doses of cyclophosphamide ≥1500 mg/m2 are classified as highly emetogenic and doses <1500 mg/m2 are classified as moderately emetogenic.
5. Considered highly emetogenic when used in combination with cyclophosphamide.
6. Doses of cytarabine >1000 mg/m2 are classified as moderately emetogenic
and doses ≤1000 mg/m2 are classified as mildly emetogenic.

therapy on day 1 and 8 mg once daily on days 2-4.

Patients receiving moderately emetogenic chemotherapy should take oral dexamethasone 12 mg 30
minutes before chemotherapy on day 1.
CONCLUSION — The oral fixed-dose combination
of netupitant and palonosetron (Akynzeo) is more
effective than oral palonosetron alone and appears
to be similar to the currently recommended regimen
of aprepitant plus a 5-HT3 receptor antagonist for
prevention of acute and delayed nausea and vomiting
in adult patients undergoing highly and moderately
emetogenic chemotherapy. ■
1. Palonosetron (Aloxi) for prevention of nausea and vomiting due
to cancer chemotherapy. Med Lett Drugs Ther 2004; 46:27.
2. Aprepitant (Emend) for prevention of nausea and vomiting due
to cancer chemotherapy. Med Lett Drugs Ther 2003; 45:62.
3. E Basch et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2011;
29:4189.
4. F Roila et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea
and vomiting: results of the Perugia consensus conference.
Ann Oncol 2010; 21 (suppl 5):v232.
5. C Rojas et al. Molecular mechanisms of 5-HT3 and NK1 receptor antagonists in prevention of emesis. Eur J Pharmacol 2014;
722:26.
6. PJ Hesketh et al. Efficacy and safety of NEPA, an oral

Vol. 57 (1467)

April 27, 2015

combination of netupitant and palonosetron, for prevention of
chemotherapy-induced nausea and vomiting following highly
emetogenic chemotherapy: a randomized dose-ranging pivotal

study. Ann Oncol 2014; 25:1340.
7. M Aapro et al. A randomized phase III study evaluating the
efficacy and safety of NEPA, a fixed-dose combination of
netupitant and palonosetron, for prevention of chemotherapyinduced nausea and vomiting following moderately emetogenic
chemotherapy. Ann Oncol 2014; 25:1328.
8. RJ Gralla et al. A phase III study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and
palonosetron, for prevention of chemotherapy-induced nausea
and vomiting over repeated cycles of chemotherapy. Ann Oncol
2014; 25:1333.
9. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2013; 55:e44.

▶

Umeclidinium (Incruse Ellipta)
for COPD

The FDA has approved Incruse Ellipta (GSK), a
single-agent inhaler containing the long-acting
anticholinergic umeclidinium, for once-daily maintenance treatment of chronic obstructive pulmonary
disease (COPD). Umeclidinium was initially approved
in combination with the long-acting beta2-adrenergic
agonist vilanterol as Anoro Ellipta.1
Pronunciation Key
Umeclidinium: ue mek" li din' ee um
Incruse Ellipta: in' cruise ee lip' ta

MAINTENANCE TREATMENT — In patients with
moderate to severe COPD, regular treatment with
an inhaled long-acting bronchodilator (a beta2agonist or an anticholinergic) can relieve symptoms,

improve lung function, and reduce the frequency of
exacerbations. A combination of a beta2-agonist
and an anticholinergic can be used for patients
inadequately controlled on a single agent.2
CLINICAL STUDIES — In a 12-week, double-blind
trial, 206 patients with moderate to very severe COPD
were randomized to receive once-daily umeclidinium
62.5 mcg or 125 mcg, or placebo. After 12 weeks,
the mean improvement in trough forced expiratory
volume in 1 second (FEV1) from baseline was
Table 1. Pharmacology
Class

Anticholinergic

Formulation

Dry powder inhaler containing 30 doses

Route

Oral inhalation

Tmax

5-15 minutes

Metabolism

Primarily by CYP2D6

Elimination

92% (feces), <1% (urine)

Half-life

11 hours

63


The Medical Letter

April 27, 2015

Vol. 57 (1467)

®

Table 2. Dosage and Cost of Some Inhaled Drugs for Maintenance Treatment of COPD
Drug

Formulations

Delivery Device

Usual Adult Dosage

Cost1

$281.40

Long-Acting Anticholinergics
Aclidinium – Tudorza Pressair (Actavis)

400 mcg/inhalation

DPI (30, 60 inh/unit)

400 mcg bid

Tiotropium – Spiriva HandiHaler
(Boehringer Ingelheim)
Spiriva Respimat (Boehringer Ingelheim)
Umeclidinium – Incruse Ellipta (GSK)

18 mcg/capsule

DPI (5, 30, 90 inh/unit)

18 mcg once/d

297.80

2.5 mcg/inhalation
62.5 mcg/inhalation

MDI (28, 60 inh/unit)
DPI (7, 30 inh/unit)

5 mcg once/d
62.5 mcg once/d

297.80
224.80

DPI (7, 30 inh/unit)

62.5/25 mcg once/d

297.80

Long-Acting Anticholinergic/Long-Acting Beta2-Agonist Combination
Umeclidinium/vilanterol – Anoro Ellipta
(GSK/Theravance)

62.5/25 mcg/blister

DPI = dry powder inhaler; MDI = metered-dose inhaler; inh = inhalation
1. Approximate WAC for 30 days’ treatment. WAC = wholesaler acquisition cost, or manufacturer’s published price to wholesalers; WAC represents published
catalogue or list prices 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.

significantly greater with both doses of umeclidinium
than with placebo.3
In a 24-week, double-blind trial, 1532 patients with
moderate to severe COPD were randomized to receive
once-daily umeclidinium 62.5 mcg, vilanterol 25 mcg,
umeclidinium/vilanterol 62.5/25 mcg, or placebo.
Compared to placebo, pre-dose trough FEV1 increased

by 115 mL with umeclidinium, by 72 mL with vilanterol,
and by 167 mL with umeclidinium/vilanterol, all
statistically significant differences.4
ADVERSE EFFECTS — In clinical trials, the most
common adverse effects of umeclidinium were
nasopharyngitis, upper respiratory tract infection,
cough, and arthralgia. Atrial fibrillation occurred
in <1% of patients, but was more common among
patients treated with umeclidinium than in those
treated with placebo. In a 52-week safety study, the
Table 3. Long-Acting Anticholinergic Inhalers: Ease of Use
Tudorza Pressair (aclidinium)
▶ Dry powder inhaler; delivery of drug dependent upon
inhalation technique
▶ Easy to use
▶ Dosed twice daily
Spiriva HandiHaler (tiotropium)
▶ Dry powder inhaler; delivery of drug dependent upon
inhalation technique
▶ Inserting capsules into the device may be difficult for
some patients
▶ Dosed once daily
Spiriva Respimat (tiotropium)
▶ Metered dose inhaler; inhalation spray may improve drug
delivery to the lungs
▶ Assembly of the inhaler may be difficult for some patients
▶ Dosed once daily
Incruse Ellipta (umeclidinium)
▶ Dry powder inhaler; delivery of drug dependent upon
inhalation technique

▶ Doses may be wasted if opened accidentally
▶ Dosed once daily
64

incidences of some atrial arrhythmias were at least
2% greater with umeclidinium 125 mcg (higher than
the FDA-approved dose) than with placebo.5
Anticholinergics like umeclidinium should be used
with caution in patients with narrow-angle glaucoma
and in those with prostatic hyperplasia or bladderneck obstruction. Inhaled medications can cause
paradoxical bronchospasm, which can be fatal.
PREGNANCY — Umeclidinium is classified as category C (risk cannot be ruled out; no adequate studies
in women) for use during pregnancy.
DOSAGE AND ADMINISTRATION — The recommended
dosage of umeclidinium is one 62.5-mcg inhalation
once daily. Each Incruse Ellipta dry powder inhaler
contains 30 doses of the drug and has a counter to track
the number of doses that have been used. Opening the
inhaler cover readies a dose for administration and
causes the counter to count down by 1. Closing the
cover without inhaling the medication wastes that
dose, which will remain in the device but will no longer
be usable.
CONCLUSION — Umeclidinium (Incruse Ellipta), inhaled
orally once daily, has improved lung function in patients
with chronic obstructive pulmonary disease (COPD).
How it compares with other inhaled anticholinergics in
efficacy and safety remains to be determined. ■
1. Anoro Ellipta: an inhaled umeclidinium/vilanterol combination
for COPD. Med Lett Drugs Ther 2014; 56:30.

2. Drugs for asthma and COPD. Treat Guidel Med Lett 2013; 11:75.
3. R Trivedi et al. Umeclidinium in patients with COPD: a randomised, placebo-controlled study. Eur Respir J 2014; 43:72.
4. JF Donohue et al. Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD. Respir Med 2013; 107: 1538.
5. JF Donohue et al. Safety and tolerability of once-daily umeclidinium/vilanterol 125/25 mcg and umeclidinium 125 mcg in
patients with chronic obstructive pulmonary disease: results
from a 52-week, randomized, double-blind, placebo-controlled
study. Respir Res 2014; 15:78.


The Medical Letter

▶

Vol. 57 (1467)

®

Glyxambi – A New Combination for
Type 2 Diabetes

The FDA has approved Glyxambi (Boehringer
Ingelheim/Lilly), a fixed-dose combination of empagliflozin (Jardiance) and linagliptin (Tradjenta), for oral
treatment of type 2 diabetes in adults. It is the first
combination of a sodium-glucose co-transporter 2
(SGLT2) inhibitor and a dipeptidyl peptidase-4 (DPP4) inhibitor to be approved in the US.
Pronunciation Key
Empagliflozin: em" pa gli floe' zin
Glyxambi: glik sam' bee
Linagliptin: lin" a glip' tin

STANDARD TREATMENT — Used alone, oral antihyperglycemic drugs generally lower glycated
hemoglobin (HbA1c) by 0.5%-1.5%. In the absence
of contraindications, metformin is the preferred firstline agent.1 If metformin does not achieve the desired
goal, a second drug is usually added. If maximum
doses of 2 drugs prove insufficient, a third can be
added. Most patients with type 2 diabetes eventually
require multi-drug therapy or insulin to achieve
glycemic control. Some diabetes experts favor early
use of insulin if HbA1c remains poorly controlled on
maximal-dose single-drug therapy.2
MECHANISM OF ACTION — Empagliflozin inhibits
SGLT2, a membrane protein expressed mainly in the
kidney that transports filtered glucose from urine in
the proximal renal tubule into tubular epithelial cells.
SGLT2 inhibitors decrease renal tubular reabsorption
of glucose and increase urinary glucose excretion,
resulting in a reduction in blood glucose levels.3
Linagliptin inhibits DPP-4, an enzyme that inactivates
and degrades incretin hormones, cytokines, and other

April 27, 2015

peptides. Incretin hormones, released in response
to meals, potentiate insulin release and decrease
glucagon production, lowering serum glucose
concentrations.4
A CLINICAL STUDY — Approval of Glyxambi was
based on a double-blind, active-controlled trial
in 686 patients with type 2 diabetes inadequately
controlled on metformin alone (HbA1c 7%-10.5%).

Following a 2-week placebo run-in period, patients
were randomized to one of the 5 active treatment
arms shown in Table 2. At week 24, addition of the
empagliflozin/linagliptin combination reduced HbA1c
and fasting plasma glucose significantly more than
either drug alone. Significantly more patients taking
the combination achieved an HbA1c <7%.5
View our detailed online table: SGLT-2 Inhibitors
ADVERSE EFFECTS — The most common adverse
effects reported in patients taking empagliflozin
and linagliptin in clinical trials were urinary tract
infection, nasopharyngitis, and upper respiratory
tract infection.
Empagliflozin, like other SGLT2 inhibitors, has
been associated with urinary and genital mycotic
infections. SGLT2 inhibitors have a modest diuretic
effect that could lead to dehydration, hypovolemia,
and hypotension, particularly in elderly patients who
have renal dysfunction or are also taking a diuretic.
Use of empagliflozin has been associated with
modest increases in serum creatinine and decreases
in eGFR, especially in patients with moderate renal
impairment. The efficacy of the drug decreases with
worsening renal function; neither empagliflozin alone
nor this new combination should be used in patients
with an eGFR <45 mL/min/1.73 m2. Increases in LDL

Table 1. Dosage and Cost of SGLT2 Inhibitors and DPP-4 Inhibitors
Drug

Formulations

Usual Adult Dosage

Cost1
$342.80

SGLT2 Inhibitors
Canagliflozin – Invokana (Janssen)

100, 300 mg tabs

100-300 mg once daily

Dapagliflozin – Farxiga (AstraZeneca)

5, 10 mg tabs

5-10 mg once daily

342.90

Empagliflozin – Jardiance (Boehringer Ingelheim/Lilly)

10, 25 mg tabs

10-25 mg once daily

342.80

DPP-4 Inhibitors
Alogliptin – Nesina (Takeda)

6.25, 12.5, 25 mg tabs

25 mg once daily

312.00

Linagliptin – Tradjenta (Boehringer Ingelheim/Lilly)

5 mg tabs

5 mg once daily

330.70

Saxagliptin – Onglyza (AstraZeneca)

2.5, 5 mg tabs

5 mg once daily

324.90

Sitagliptin – Januvia (Merck)

25, 50, 100 mg tabs

100 mg once daily

330.70

10/5, 25/5 mg tabs

10/5-25/5 mg once daily

480.00

SGLT2 Inhibitor/DPP-4 Inhibitor Combination
Empagliflozin/linagliptin – Glyxambi
(Boehringer Ingelheim/Lilly)

1. Approximate WAC for 30 days’ treatment at the lowest 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.

65


The Medical Letter

Vol. 57 (1467)

®

Table 2. Glyxambi Clinical Study Results at 24 Weeks1

Regimen

FPG
HbA1c
Change
Change (%)2,3 (mg/dL)2

HbA1c
<7% (%)4

Metformin
+ empagliflozin 10 mg
(n=140)

-0.66

-20.8

28.0

Metformin
+ empagliflozin 25 mg
(n=141)

-0.62

-18.8

32.6

Metformin
+ linagliptin 5 mg

(n=132)

-0.70

-13.1

36.1

-1.08

-32.2

57.8

-1.19

-35.3

61.8

Metformin
+ empagliflozin 10 mg/
linagliptin 5 mg
(n=136)
Metformin
+ empagliflozin 25 mg/
linagliptin 5 mg
(n=137)

FPG = Fasting plasma glucose

1. RA DeFronzo et al. Diabetes Care 2015; 38:384.
2. Mean change from baseline
3. The primary endpoint.
4. Percentage of patients who achieved HbA1c <7%.

cholesterol and hematocrit have been reported in
patients taking empagliflozin.
As with other DPP-4 inhibitors, hypersensitivity reactions such as angioedema, urticaria, localized
skin exfoliation, and bronchial hyperreactivity have
been reported with linagliptin. There have been
postmarketing reports of acute pancreatitis in patients taking a DPP-4 inhibitor; a cause and effect
relationship has not been established. In one study,
use of the DPP-4 inhibitor saxagliptin (Onglyza) was
associated with an increased risk of hospitalization
due to heart failure.6
The long-term safety of both SGLT2 and DPP-4
inhibitors is unknown.
PREGNANCY — Glyxambi is classified as category C
(evidence of toxicity in animals; no adequate studies
in women) for use during pregnancy.
DRUG INTERACTIONS — Hypoglycemia can occur
if Glyxambi is used with insulin or a sulfonylurea; a
reduction in the dosage of insulin or the sulfonylurea
may be needed. Concurrent use with a diuretic can
increase the risk of volume depletion. Linagliptin
is a weak to moderate inhibitor of CYP3A4 and
a substrate of P-glycoprotein (P-gp); strong inducers of CYP3A4 or P-gp such as rifampin can
decrease serum concentrations of linagliptin to
subtherapeutic levels.7

66

April 27, 2015

DOSAGE AND ADMINISTRATION — The recommended
starting dosage of Glyxambi is 10 mg empagliflozin/
5 mg linagliptin once daily, taken in the morning with
or without food. If tolerated, the dose can be increased
to 25 mg empagliflozin/5 mg linagliptin once daily.
The combination should not be started in patients
with an eGFR <45 mL/min/1.73 m2 and should be
discontinued if the eGFR falls and remains persistently
below this level.
CONCLUSION — The fixed-dose combination of
empagliflozin and linagliptin (Glyxambi) is less expensive and should be more convenient than taking
the same drugs separately, but the reduction in HbA1c
is modest and the long-term safety of these drugs is
unknown. ■
1. American Diabetes Association. Standards of medical care in
diabetes–2015. Diabetes Care 2015; 38 (Suppl 1):S1.
2. Drugs for type 2 diabetes. Treat Guidel Med Lett 2014; 12:17.
3. Empagliflozin (Jardiance) for diabetes. Med Lett Drugs Ther
2014; 56:99.
4. Linagliptin (Tradjenta) – a new DPP-4 inhibitor for type 2
diabetes. Med Lett Drugs Ther 2011; 53:49.
5. RA DeFronzo et al. Combination of empagliflozin and linagliptin
as second-line therapy in subjects with type 2 diabetes
inadequately controlled on metformin. Diabetes Care 2015;
38:384.
6. BM Scirica et al. Saxagliptin and cardiovascular outcomes

in patients with type 2 diabetes mellitus. N Engl J Med 2013;
369:1317.
7. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2013; 55:e44.

Addendum: Diet, Drugs, and Surgery for Weight Loss
In the article on Diet, Drugs, and Surgery for Weight
Loss in the February 16, 2015 issue of The Medical
Letter (volume 57), the mean weight loss listed in table 1
included, at the lower end of the range, the mean weight
loss reported with a lower than FDA-approved dose of
lorcaserin (Belviq). The placebo-corrected weight loss
reported with FDA-approved doses of lorcaserin is 2.93.6 kg. This change has been made in the article as it
appears online.

Coming Soon in The Medical Letter:
Pegylated Beta Interferon (Plegridy) for Multiple Sclerosis
Extended-Release Hydrocodone (Hysingla ER) for Pain
Concentrated Insulin Glargine (Toujeo) for Diabetes
Ceftazidime/Avibactam (Avycaz) – A New Intravenous
Antibiotic
Drugs for Psoriasis and Psoriatic Arthritis


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1.
Review the efficacy and safety of the new extended-release capsule formulation of carbidopa/levodopa (Rytary) for treatment of Parkinson’s disease.
2.
Review the efficacy and safety of the fixed-dose combination of netupitant and palonosetron (Akynzeo) for prevention of chemotherapy-induced nausea and vomiting.
3.
Review the efficacy and safety of inhaled umeclidinium (Incruse Ellipta) for treatment of COPD.
4.
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Issue 1467 Questions

(Correspond to questions #81-90 in Comprehensive Exam #72, available July 2015)
Carbidopa/Levodopa Extended-Release Capsules (Rytary)

Umeclidinium (Incruse Ellipta) for COPD

1. In the pharmacokinetic study, the duration of time with serum
concentrations higher than 50% of levodopa Cmax with extendedrelease carbidopa/levodopa capsules was:
a. 2 hours
b. 4 hours
c. 6 hours
d. 8 hours

6. All available inhaled long-acting anticholinergics are dosed once per
day except:
a. Tudorza Pressair
b. Spiriva HandiHaler

c. Spiriva Respimat
d. Incruse Ellipta

2. The daily reduction in “off” time with extended-release carbidopa/
levodopa capsules in the 22-week clinical trial compared to
immediate-release carbidopa/levodopa tablets was about:
a. 1 hour
b. 2 hours
c. 3 hours
d. 4 hours
3. A 71-year-old man with advanced Parkinson’s disease has been
taking 1200 mg of levodopa in an immediate-release carbidopa/
levodopa formulation, but recently he has noticed a disturbing
increase in “off” time, and he would like to switch to the new
extended-release capsules. What would be the appropriate dosing
regimen of Rytary for this patient?
a. 3 capsules of 36.25/145 mg TID
b. 3 capsules of 48.75/195 mg TID
c. 3 capsules of 61.25/245 mg TID
d. none of the above
Netupitant/Palonosetron (Akynzeo) for Chemotherapy-Induced Nausea
and Vomiting
4. Which of the following statements about the netupitant/
palonosetron combination is true?
a. It has produced a complete response (no emesis and no use
of rescue medication) in close to or more than 90% of patients
treated with highly emetogenic chemotherapy.
b. It has maintained complete response rates over multiple
cycles of chemotherapy.
c. It should be administered with oral dexamethasone.

d. all of the above
5. Which of the following drugs is classified as highly emetogenic?
a. carboplatin
b. daunorubicin
c. cisplatin
d. all of the above

7. In the 24-week study supporting the efficacy of umeclidinium for
COPD, the drug was shown to:
a. increase FEV1
b. reduce COPD exacerbations
c. reduce mortality
d. all of the above
Glyxambi – A New Combination for Type 2 Diabetes
8. In the clinical trial in patients with type 2 diabetes inadequately
controlled on metformin alone, addition of linagliptin 5 mg and
empagliflozin 10 mg resulted in a change in HbA1c of about:
a. 0.5%
b. 0.7%
c. 0.9%
d. 1.1%
9. A 79-year-old man with type 2 diabetes is beginning treatment with
Glyxambi. His current medications include metformin, enalapril, and
chlorthalidone. His HbA1c is 9.5% and his eGFR is 57 mL/min/1.73 m2.
Which of the following statements about the use of Glyxambi in this
patient is correct?
a. He cannot take Glyxambi because his eGFR is <60 mL/
min/1.73 m2.
b. Based on the efficacy of Glyxambi in clinical trials, it is likely he
will achieve an HbA1c <7%.

c. He may be at increased risk of hypovolemia and hypotension
because of his concomitant medications and baseline renal
function.
d. all of the above
10. SGLT2 inhibitors such as empagliflozin:
a. increase urinary glucose excretion
b. can cause genital mycotic infections
c. have reduced efficacy in patients with renal dysfunction
d. all of the above

ACPE UPN: Per Issue Exam: 0379-0000-15-467-H01-P; Release: April 27, 2015, Expire: April 27, 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; 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
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Copyright and Disclaimer: The Medical Letter, Inc. is an independent nonprofit organization that provides healthcare professionals with unbiased drug prescribing recommendations. The editorial
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