The medical letter on drugs and therapeutics march 28 2016

The Medical Letter

®

on Drugs and Therapeutics
Volume 58

ISSUE
ISSUE
No.

1433
1491
Volume 56

March 28, 2016

IN THIS ISSUE

Seebri Neohaler and Utibron Neohaler for COPD ................................................................ p 39
Lumacaftor/Ivacaftor (Orkambi) for Cystic Fibrosis........................................................... p 41
Cobimetinib (Cotellic) for Metastatic Melanoma ................................................................ p 43
A Recombinant C1 Esterase Inhibitor (Ruconest) for Hereditary Angioedema .........online only
Inhibitors and Inducers of CYP Enzymes and P-Glycoprotein ...................................online only
In Brief: Dinutuximab (Unituxin) for High-Risk Neuroblastoma ................................online only
In Brief: Uridine Triacetate (Xuriden) for Hereditary Orotic Aciduria .........................online only

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The Medical Letter

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on Drugs and Therapeutics
Volume 58

March 28, 2016
Take CME Exams
ALSO IN THIS ISSUE

ISSUE

ISSUE No.

1433
1491
Volume 56

▶

Lumacaftor/Ivacaftor (Orkambi) for Cystic Fibrosis........................................................... p 41
Cobimetinib (Cotellic) for Metastatic Melanoma ................................................................ p 43
A Recombinant C1 Esterase Inhibitor (Ruconest) for Hereditary Angioedema .........online only
Inhibitors and Inducers of CYP Enzymes and P-Glycoprotein ...................................online only
In Brief: Dinutuximab (Unituxin) for High-Risk Neuroblastoma ................................online only
In Brief: Uridine Triacetate (Xuriden) for Hereditary Orotic Aciduria .........................online only

Seebri Neohaler and Utibron
Neohaler for COPD

Table 2. Long-Acting Anticholinergic/Beta2-Adrenergic
Agonist Combination Inhalers: Ease of Use
Anoro Ellipta

The FDA has approved two new inhalers for longterm maintenance treatment of chronic obstructive
pulmonary disease (COPD). Seebri Neohaler
(Novartis) contains the long-acting anticholinergic
glycopyrrolate. Utibron Neohaler (Novartis) contains
both glycopyrrolate and the long-acting beta2adrenergic agonist (LABA) indacaterol. Glycopyrrolate/
indacaterol is the third fixed-dose combination of a
long-acting anticholinergic and a LABA to become
available in the US; umeclidinium/vilanterol (Anoro
Ellipta)1 and tiotropium/olodaterol (Stiolto Respimat)2

were approved earlier.
Pronunciation Key
Glycopyrrolate : glye" koe pir' oh late
Seebri : see' bree
Indacaterol : in" da ka' ter ol
Utibron : yoo tee' bron

▶ Dry powder inhaler; drug delivery to the lungs is dependent
upon ability to perform a rapid, deep inhalation

▶ Once-daily dosing
▶ No assembly or priming required
▶ Indicator shows how many doses are left
▶ Doses may be wasted if inhaler is opened/closed accidentally
Stiolto Respimat

▶ Inhalation spray inhaler; drug delivery to the lungs is not
dependent on strength of breath intake

▶ Once-daily dosing
▶ Assembly may be difficult for some patients
▶ Indicator shows approximately how many doses are left
Utibron Neohaler

▶ Dry powder inhaler; drug delivery to the lungs is dependent
upon ability to perform a rapid, deep inhalation

▶ Twice-daily dosing
▶ Removal of the capsule from the foil pack and insertion of the
capsule into the inhaler may be difficult for some patients

▶ Transparent capsules may be helpful in determining if the full
dose was inhaled

GLYCOPYRROLATE — Glycopyrrolate has been
available for many years in a parenteral formulation
for multiple indications. An oral formulation is available
for reduction of chronic severe drooling in children
with certain neurologic conditions.
MAINTENANCE TREATMENT OF COPD — In patients
with moderate to severe COPD, regular treatment
Table 1. Pharmacology
Glycopyrrolate

Indacaterol

Class

Long-acting
anticholinergic

Long-acting beta2adrenergic agonist

Route

Oral inhalation

Oral inhalation

Tmax

5 minutes

15 minutes

Metabolism

Multiple CYP enzymes

UGT1A1 and CYP3A4

Elimination

Urine (60-70%)

Feces (54% unchanged)

Half-life

33-53 hours

40-56 hours

with an inhaled long-acting bronchodilator (an
anticholinergic or a beta2-adrenergic agonist) can relieve symptoms, improve lung function, and reduce the
frequency of exacerbations. For patients inadequately
controlled with a single agent, combining a LABA and
a long-acting anticholinergic has resulted in additional
improvement in lung function. For patients with
severe COPD who experience frequent exacerbations

despite treatment with a long-acting anticholinergic
and a LABA, addition of an inhaled corticosteroid is
recommended.3,4
CLINICAL STUDIES — Glycopyrrolate – In two
unpublished, double-blind trials (summarized in
the package insert), 867 patients with moderate
to severe COPD were randomized to twice-daily
treatment with inhaled glycopyrrolate or placebo.
39

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The Medical Letter

March 28, 2016

Vol. 58 (1491)

®

Table 3. Some Inhaled Drugs for Maintenance Treatment of COPD
Drug

Formulation

Delivery Device

Usual Adult Dosage

Cost1

400 mcg/inh
15.6 mcg/cap2
18 mcg/cap2

DPI (30, 60 inh/unit)
DPI (60 inh/unit)
DPI (5, 30, 90 inh/unit)

1 inh bid
1 inh bid3
1 inh once/d3

$301.10
297.80
315.70

2.5 mcg/inh
62.5 mcg/inh

ISI (60 inh/unit)
DPI (7, 30 inh/unit)

2 inh once/d
1 inh once/d

315.70
252.60

1 inh once/d3
2 inh once/d

213.60
155.70

1 inh bid

322.60

1 inh bid3

297.80

2 inh once/d

315.70

1 inh once/d

315.70

Long-Acting Anticholinergics
Aclidinium – Tudorza Pressair (AstraZeneca)
Glycopyrrolate – Seebri Neohaler (Novartis)
Tiotropium – Spiriva HandiHaler
(Boehringer Ingelheim)
Spiriva Respimat
Umeclidinium – Incruse Ellipta (GSK)
Long-Acting Beta2-Adrenergic Agonists

Indacaterol – Arcapta Neohaler (Novartis)
75 mcg/cap2
DPI (30 inh/unit)
Olodaterol – Striverdi Respimat
2.5 mcg/inh
ISI (28, 60 inh/unit)
(Boehringer Ingelheim)
Salmeterol – Serevent Diskus (GSK)
50 mcg/blister
DPI (28, 60 inh/unit)
Long-Acting Anticholinergic/Long-Acting Beta2-Adrenergic Agonist Combinations
Glycopyrrolate/indacaterol – Utibron Neohaler 15.6 mcg/27.5 mcg/cap2
DPI (6, 60 inh/unit)
(Novartis)
Tiotropium/olodaterol – Stiolto Respimat
2.5 mcg/2.5 mcg/inh
ISI (60 inh/unit)
(Boehringer Ingelheim)
Umeclidinium/vilanterol – Anoro Ellipta (GSK)
62.5 mcg/25 mcg/blister
DPI (7, 30 inh/unit)

inh = inhalation; DPI = dry powder inhaler; cap = capsule; ISI = inhalation spray inhaler
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 an actual transactional price. Source: AnalySource® Monthly. March 5, 2016. Reprinted with permission by First
Databank, Inc. All rights reserved. ©2016. www.fdbhealth.com/policies/drug-pricing-policy.
2. Capsules should not be swallowed.
3. Multiple inhalations from the same capsule may be needed to deliver the full dose.

After 12 weeks, patients treated with glycopyrrolate

had significantly larger mean increases from
baseline in FEV1 AUC0-12 (forced expiratory volume in
1 second area under the curve from 0-12 hours); the
difference between glycopyrrolate and placebo was
139 mL in trial 1 and 123 mL in trial 2.
Glycopyrrolate/Indacaterol – In two double-blind
trials (FLIGHT 1 and FLIGHT 2), a total of 2038
patients with moderate to severe COPD were randomized to twice-daily glycopyrrolate/indacaterol,
glycopyrrolate alone, indacaterol alone, or placebo.
At 12 weeks, the combination increased FEV1 AUC0-12
significantly more than glycopyrrolate or indacaterol
alone: by 98 and 94 mL in trial 1 and 79 and 112 mL
in trial 2. Patients treated with glycopyrrolate/
indacaterol also had a significant reduction in rescue
inhaler use compared to those treated with placebo.
The combination improved scores on a healthrelated quality of life questionnaire significantly more
than placebo.5
ADVERSE EFFECTS — The most common adverse
effects reported in clinical trials were upper respiratory
tract infection and nasopharyngitis with glycopyrrolate alone and nasopharyngitis and hypertension
with glycopyrrolate/indacaterol.
Systemic absorption of inhaled anticholinergics could
cause urinary retention and increased intraocular
40

pressure, but glycopyrrolate is minimally bioavailable
and systemic adverse effects are unlikely to occur with
inhaled use.
Systemic adverse effects of inhaled beta2-adrenergic
agonists include palpitations, tachycardia, chest

pain, tremor, nervousness, insomnia, QTc interval
prolongation, hypokalemia, and hyperglycemia.
Tolerance to the therapeutic effects of these drugs
may occur with chronic use.
PREGNANCY
—
Inhaled
glycopyrrolate
and
glycopyrrolate/indacaterol are classified as category C
(no teratogenic effects in animals given high doses; no
adequate studies in pregnant women) for use during
pregnancy. Beta2-adrenergic agonists may interfere
with uterine contractility during labor.
DRUG INTERACTIONS — The hypokalemic effects of
indacaterol may be potentiated by concomitant use
of a corticosteroid, a non-potassium-sparing diuretic,
or a xanthine derivative such as theophylline. Use of
indacaterol with monoamine oxidase (MAO) inhibitors,
tricyclic antidepressants, or other drugs that prolong
the QTc interval could result in additive effects.
Concomitant use of beta blockers can decrease the
effectiveness of indacaterol.
DOSAGE AND ADMINISTRATION — Both products are
supplied with a Neohaler inhalation device and 60
blister-packaged capsules containing 15.6 mcg of


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glycopyrrolate alone (Seebri Neohaler) or combined
with 27.5 mcg of indacaterol (Utibron Neohaler). The
recommended dosage of Seebri Neohaler or Utibron
Neohaler is twice-daily inhalation of the contents of
one capsule.
The device is prepared for administration by placing
one capsule inside the Neohaler chamber. The patient
pushes buttons on both sides of the device at the same
time to puncture the capsule and then exhales fully
before taking deep, rapid but steady breaths through
the mouthpiece until there is no powder remaining in
the capsule; this requires 1 or 2 inhalations for most
patients. After inhaling the contents of the capsule, the
patient should remove the inhaler from his/her mouth
and wait at least 5-10 seconds before exhaling.
CONCLUSION — New inhalers containing the longacting anticholinergic glycopyrrolate alone (Seebri

▶

Lumacaftor/Ivacaftor (Orkambi) for
Cystic Fibrosis

The FDA has approved a fixed-dose combination
of lumacaftor and ivacaftor (Orkambi – Vertex) for
oral treatment of cystic fibrosis (CF) in patients
≥12 years old who are homozygous for the F508del
mutation. About 50% of patients in the US with
CF are homozygous for the F508del (also called

Phe508del) mutation. This is the first approved
indication for lumacaftor; ivacaftor is available
alone as Kalydeco for treatment of CF in patients
≥2 years old with other mutations.1 Orkambi is the
first drug to be approved in the US for treatment of
patients with the F508del mutation.
Pronunciation Key
Lumacaftor : loo" ma kaf' tor
Orkambi : or kam' bee
Ivacaftor : eye" va kaf' tor

MECHANISM OF ACTION — The cystic fibrosis
transmembrane conductance regulator (CFTR)
protein functions as a regulated chloride channel.
The F508del mutation causes CFTR protein misfolding, a reduced quantity of CFTR protein at the
cell surface, and decreased stability of the CFTR
protein. Lumacaftor improves the conformational
stability of the protein and increases the amount
of CFTR protein at the cell surface. Ivacaftor is a
CFTR potentiator that increases chloride transport
through CFTR channels.

Vol. 58 (1491)

March 28, 2016

Neohaler) or in combination with the long-acting beta2adrenergic agonist indacaterol (Utibron Neohaler) can
improve lung function in patients with moderate to
severe COPD. How they compare in efficacy and safety
with other inhaled drugs for this indication remains to

be determined, but some of the older products offer
the advantage of once-daily dosing. ■
1. Anoro Ellipta: an inhaled umeclidinium/vilanterol combination
for COPD. Med Lett Drugs Ther 2014; 56:30.
2. Tiotropium/olodaterol (Stiolto Respimat) for COPD. Med Lett
Drugs Ther 2015; 57:161.
3. Global Initiative for Chronic Obstructive Lung Disease (GOLD).
Global strategy for the diagnosis, management, and prevention
of COPD. Available at www.goldcopd.org. Accessed March 17,
2016.
4. Drugs for asthma and COPD. Treat Guidel Med Lett 2013; 11:75.
5. DA Mahler et al. FLIGHT1 and FLIGHT2: efficacy and safety
of QVA149 (indacaterol/glycopyrrolate) versus its monocomponents and placebo in patients with chronic obstructive
pulmonary disease. Am J Respir Crit Care Med 2015; 192:1068.

Table 1. Pharmacology
Lumacaftor

Ivacaftor

Tmax

~4 hours (with food)

~4 hours (with food)

Metabolism

Not extensive (mainly
by oxidation and

glucuronidation)

Primarily hepatic
by CYP3A

Elimination

Feces (51% unchanged);
urine (8.6%)

Feces (87.8%);
urine (6.6%)

Half-life

~26 hours (CF patients)

~9 hours (healthy
subjects)

CLINICAL STUDIES — In clinical trials, neither
ivacaftor nor lumacaftor alone has been shown to
be effective in patients with CF who are homozygous
for the F508del mutation.2,3
Approval of the lumacaftor/ivacaftor combination
was based on the results of two 24-week, doubleblind trials (TRAFFIC and TRANSPORT) in a total
of 1108 patients ≥12 years old with stable CF who
were homozygous for the F508del mutation and had
a forced expiratory volume in 1 second (FEV1) that
was 40-90% of the predicted normal value. Patients

were randomized to receive ivacaftor (250 mg every
12 hours) plus lumacaftor (400 mg every 12 hours or
600 mg once daily) or placebo.
In a pooled analysis, lumacaftor 400 mg/ivacaftor
250 mg every 12 hours (the FDA-approved dosage)
produced statistically significant improvements from
baseline in the absolute change in percent predicted
FEV1 (a difference from placebo of +2.8 percentage
41


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®

points). The rate of pulmonary exacerbations,
including those leading to hospitalization and use of
IV antibiotics, was significantly lower in patients taking
lumacaftor/ivacaftor than in those taking placebo.
Patients taking the combination also had greater
placebo-corrected increases from baseline in BMI.4
ADVERSE EFFECTS — The most common adverse
effects of lumacaftor/ivacaftor in clinical trials
(occurring in ≥10% of patients and more frequently
than with placebo) were dyspnea, nasopharyngitis,
nausea, diarrhea, and upper respiratory tract infection.
More patients taking the combination discontinued
treatment because of adverse effects (4.2% vs 1.6%
with placebo).
Increases in hepatic transaminase and bilirubin levels

have occurred during treatment with lumacaftor/
ivacaftor. Hepatic encephalopathy has been reported
in patients with advanced liver disease taking
the combination.
DRUG INTERACTIONS — Lumacaftor is a strong
inducer of CYP3A. The combination can reduce the
serum concentrations and efficacy of the many drugs
that are metabolized by this enzyme, including some
corticosteroids and azole antifungals. Lumacaftor/
ivacaftor may also decrease the efficacy of hormonal
contraceptives; use of a nonhormonal contraceptive is
recommended during treatment.
Lumacaftor may inhibit and induce P-glycoprotein
(P-gp); serum concentrations of P-gp substrates
such as digoxin may increase or decrease if taken with
lumacaftor/ivacaftor. Lumacaftor may also induce
CYP2B6, 2C8, 2C9, and 2C19 and inhibit CYP2C8 and
2C9; serum concentrations of drugs metabolized by
these pathways may increase or decrease if taken
concurrently with lumacaftor/ivacaftor.
Ivacaftor is a CYP3A substrate. Concurrent
administration of a CYP3A inhibitor and lumacaftor/
ivacaftor is not expected to significantly increase
steady-state ivacaftor concentrations because of the
CYP3A-inducing effects of lumacaftor. Concurrent
administration of a strong CYP3A inducer and
lumacaftor/ivacaftor can decrease ivacaftor serum
concentrations and is not recommended.5 In laboratory studies, prolonged exposure to ivacaftor reduced
the efficacy of lumacaftor.6
DOSAGE, ADMINISTRATION, AND COST — Orkambi

tablets contain 200 mg of lumacaftor and 125 mg of
ivacaftor. The recommended dosage of lumacaftor/
ivacaftor is 2 tablets taken every 12 hours. The
42

Vol. 58 (1491)

March 28, 2016

combination should be taken with fat-containing
food, which increases lumacaftor exposure 2-fold and
ivacaftor exposure 3-fold.
Liver function should be measured before starting
treatment, quarterly during the first year of treatment,
and annually thereafter. Treatment with the combination should be interrupted if significant increases
occur in hepatic transaminase and bilirubin levels.
Patients with moderate hepatic impairment should
take two tablets in the morning and one in the evening. Although the combination has not been studied
in patients with severe hepatic impairment, the manufacturer recommends a starting dosage of one tablet in
the morning and one in the evening for such patients.
Patients starting lumacaftor/ivacaftor treatment, or
resuming treatment after an interruption of >7 days,
who are currently taking a strong CYP3A inhibitor
should take one tablet once daily for 7 days (to
allow for induction of CYP3A by lumacaftor) before
continuing with the usual recommended dosage. If a
dose is missed, it should be skipped unless ≤6 hours
have passed since the scheduled dosing time. One
year of treatment with Orkambi at the usual dosage
costs about $260,000.7

CONCLUSION — The fixed-dose combination of
lumacaftor and ivacaftor (Orkambi) is the first
disease-modifying therapy to be approved for the
50% of patients with cystic fibrosis who are homozygous for the F508del mutation. Orkambi improves
pulmonary function and reduces exacerbations, but
its long-term efficacy and safety have not been
established, it interacts with many other drugs, and it
is very expensive. ■
1. Ivacaftor (Kalydeco) for cystic fibrosis. Med Lett Drugs Ther
2012; 54:29.
2. PA Flume et al. Ivacaftor in subjects with cystic fibrosis who
are homozygous for the F508del-CFTR mutation. Chest 2012;
142:718.
3. JP Clancy et al. Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis
homozygous for the F508del-CFTR mutation. Thorax 2012; 67:12.
4. CE Wainwright et al. Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med
2015; 373:220.
5. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2016; 58:e46.
6. PB Davis. Another beginning for cystic fibrosis therapy. N Engl
J Med 2015; 373:274.
7. 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. March 5, 2016. Reprinted
with permission by First Databank, Inc. All rights reserved. ©2016.
www.fdbhealth.com/policies/drug-pricing-policy.


The Medical Letter

▶

Vol. 58 (1491)

®

Cobimetinib (Cotellic) for Metastatic
Melanoma

The FDA has approved the mitogen-activated
extracellular signal-regulated kinase (MEK) inhibitor
cobimetinib (Cotellic – Genentech) for use in combination with the BRAF kinase inhibitor vemurafenib
(Zelboraf) for treatment of unresectable or metastatic
melanoma with a BRAF V600E or V600K mutation.
Pronunciation Key
Cobimetinib : koe" bi me' ti nib
Cotellic : koe tel' ik

STANDARD TREATMENT — BRAF mutations are present in about 50% of melanomas; BRAF V600E accounts
for 70-80% of these mutations and BRAF V600K for
5-15%. The BRAF inhibitors vemurafenib and dabrafenib (Tafinlar) have been highly effective in treating
BRAF mutation-positive unresectable or metastatic
melanoma.1,2 Adding the MEK inhibitor trametinib
(Mekinist) improved overall survival compared with
use of a BRAF inhibitor alone.3 Immunotherapy with
the programmed death receptor-1 (PD-1) inhibitors
pembrolizumab (Keytruda) or nivolumab (Opdivo),
or with nivolumab plus ipilimumab (Yervoy) has also
been effective for treatment of unresectable or metastatic melanoma with BRAF V600 mutations.4-6
MECHANISM OF ACTION — Cobimetinib and
vemurafenib act on two different kinases in the

same signaling pathway. The combination was more

March 28, 2016

Table 1. Pharmacology
Formulation

20 mg tablets

Route

Oral

Tmax

2.4 hours

Metabolism

Primarily by CYP3A oxidation and
UGT2B7 glucuronidation

Elimination

Feces (76%); urine (18%)

Half-life

23-70 hours

effective than either drug alone in inducing apoptosis
in vitro and reducing tumor growth in mouse models of
melanoma cells with BRAF V600E mutations.
PHARMACOLOGY — Cobimetinib is well absorbed
after oral administration, but extensive intestinal firstpass metabolism limits its systemic exposure.7
CLINICAL STUDIES — FDA approval of cobimetinib was
based on the results of a randomized trial comparing
the combined use of vemurafenib and cobimetinib
with vemurafenib alone in 495 patients with previously
untreated, unresectable, locally advanced or metastatic
BRAF V600 mutation-positive melanoma. Median
progression-free survival, the primary endpoint, was
9.9 months with the combination and 6.2 months with
vemurafenib alone (p<0.001).8 After a median followup of 18.5 months, median overall survival was 22.3
months with vemurafenib plus cobimetinib and 17.4
months with vemurafenib alone (p=0.005); two-year
overall survival rates were 48% with the combination
and 38% with monotherapy.9

Table 2. Kinase Inhibitors for Metastatic Melanoma
Drug

Class

Indication1

Median PFS

Usual Dosage

Cost2

Dabrafenib –
Tafinlar (GSK)
Vemurafenib –
Zelboraf (Genentech)
Trametinib –
Mekinist (GSK)
Cobimetinib –
Cotellic (Genentech)

BRAF inhibitor

Melanoma with BRAF
V600E mutation
Melanoma with BRAF
V600E mutation
Melanoma with BRAF
V600E or V600K mutations
Melanoma with BRAF
V600E or V600K mutations6

5.1 mos vs 2.7 mos
with dacarbazine3
5.3 mos vs 1.6 mos
with dacarbazine5
See combination therapy

150 mg PO
bid4

960 mg PO
bid
2 mg PO
once/d4
60 mg PO
once/d7

$26,393.90

BRAF inhibitor
MEK inhibitor
MEK inhibitor

See combination therapy

32,552.40
30,214.00
18,185.30

Combination Therapy
Dabrafenib plus
trametinib

BRAF inhibitor/
MEK inhibitor

Melanoma with BRAF
V600E or V600K mutations

11.4 mos vs 7.3 mos

with vemurafenib8
9.4 mos vs 5.8 mos
with dabrafenib9

See individual
drugs

56,607.90

Vemurafenib plus
cobimetinib

BRAF inhibitor/
MEK inhibitor

Melanoma with BRAF
V600E or V600K mutations

9.9 mos vs 6.2 mos
with vemurafenib10

See individual
drugs

50,737.70

PFS = progression-free survival
1. FDA-approved for use in patients with unresectable or metastatic melanoma.
2. Approximate WAC for 3 months' 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. March 5, 2016. Reprinted with permission by First

Databank, Inc. All rights reserved. ©2016. www.fdbhealth.com/policies/drug-pricing-policy.
3. A Hauschild et al. Lancet 2012; 380:358.
4. Taken at least 1 hour before or at least 2 hours after a meal.
5. PB Chapman et al. N Engl J Med 2011; 364:2507.
6. Only approved for use in combination with vemurafenib.
7. On days 1-21 of each 28-day treatment cycle.
8. C Robert et al. N Engl J Med 2015; 372:30.
9. KT Flaherty et al. N Engl J Med 2012; 367:1694.
10. J Larkin et al. N Engl J Med 2014; 371:1867.

43


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®

ADVERSE EFFECTS — In the clinical trial, severe
(grade 3-4) adverse effects occurred in 58% of patients
treated with vemurafenib alone and in 62% of those
taking vemurafenib and cobimetinib. Diarrhea, nausea,
elevated CPK levels, decreased ejection fraction, and
retinal detachment, all class effects of MEK inhibitors,
occurred more frequently with the combination than
with vemurafenib alone. Photosensitivity reactions
and elevated hepatic transaminases were also
more common in patients taking the combination.
MEK inhibitors appear to protect, however, against
development of cutaneous squamous-cell carcinoma,
a known effect of BRAF inhibitors, which occurred in

6 patients (2%) treated with both vemurafenib and
cobimetinib and in 27 (11%) of those treated with
vemurafenib alone.
PREGNANCY — Cobimetinib has not been studied in
pregnant women. It was teratogenic and embryotoxic
in pregnant rats at doses 0.9-1.4 times the
recommended human dose.
DRUG INTERACTIONS — Cobimetinib is a substrate of
CYP3A. It should not be administered concurrently with
strong or moderate CYP3A inhibitors or inducers.10
Cobimetinib is also a substrate of the drug transporter
P-glycoprotein (P-gp); drugs that inhibit P-gp may
increase its concentrations.10
DOSAGE — Cobimetinib is available as 20-mg tablets.
The recommended dosage is 60 mg once daily (with or
without food) for the first 21 days of each 28-day cycle.
If administration with a moderate CYP3A inhibitor is
unavoidable in patients taking cobimetinib 60 mg,
the dosage can be reduced to 20 mg once daily for
a maximum of 14 days. The package insert contains
detailed instructions for reducing the dose and/or
withholding the drug in patients who experience
certain adverse reactions.
CONCLUSION — In patients with unresectable or
metastatic melanoma with BRAF V600E or V600K
mutations, addition of the MEK inhibitor cobimetinib
(Cotellic) to the BRAF inhibitor vemurafenib (Zelboraf)
has produced improvements in survival that are similar
to those achieved with combined use of dabrafenib
(Tafinlar) and trametinib (Mekinist). Both combinations

are significantly more effective than treatment with
a BRAF inhibitor alone. Some adverse effects occur
more frequently with combined use of a BRAF inhibitor
and a MEK inhibitor, but MEK inhibitors appear to
reduce the risk of developing cutaneous squamouscell carcinomas induced by BRAF inhibitors. ■
44

March 28, 2016

Vol. 58 (1491)

1. Vemurafenib (Zelboraf) for metastatic melanoma. Med Lett
Drugs Ther 2011; 53:77.
2. Dabrafenib (Tafinlar) and trametinib (Mekinist) for metastatic
melanoma. Med Lett Drugs Ther 2013; 55:62.
3. C Robert et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 2015; 372:30.
4. Pembrolizumab (Keytruda) for metastatic melanoma. Med Lett
Drugs Ther 2014; 56:e114.
5. J Larkin et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015; 373:23.
6. J Larkin et al. Efficacy and safety of nivolumab in patients with
BRAF V600 mutant and BRAF wild-type advanced melanoma: a
pooled analysis of 4 clinical trials. JAMA Oncol 2015; 1:433.
7. RH Takahashi et al. Absorption, metabolism, excretion, and the
contribution of intestinal metabolism to the oral disposition of
[14C] cobimetinib, a MEK inhibitor in humans. Drug Metab Dispos 2016; 44:28.
8. J Larkin et al. Combined vemurafenib and cobimetinib in BRAFmutated melanoma. N Engl J Med 2014; 371:1867.
9. V Atkinson et al. Improved overall survival (OS) with cobimetinib (COBI) + vemurafenib (V) in advanced BRAF-mutated
melanoma and biomarker correlates of efficacy. Late breaking
abstract presented at the Society for Melanoma Research International Congress, San Francisco, November 18-21, 2015.
10. Inhibitors and inducers of CYP enzymes and P-glycoprotein.

Med Lett Drugs Ther 2016; 58:e46.

Online Only Articles
A Recombinant C1 Esterase Inhibitor (Ruconest) for
Hereditary Angioedema
www.medicalletter.org/TML-article-1491d
Inhibitors and Inducers of CYP Enzymes and P-Glycoprotein
www.medicalletter.org/TML-article-1491e
In Brief: Dinutuximab (Unituxin) for High-Risk Neuroblastoma
www.medicalletter.org/TML-article-1491f
In Brief: Uridine Triacetate (Xuriden) for Hereditary Orotic
Aciduria
www.medicalletter.org/TML-article-1491g

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Enstilar – A New Formulation of Calcipotriene/Betamethasone
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Which Oral Anticoagulant?
Ciprofloxacin (Otiprio) for Tympanostomy Tube Insertion
Anthrasil and BioThrax for Inhalation Anthrax

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Volume 58 (Issue 1491)

▶

March 28, 2016

A Recombinant C1 Esterase
Inhibitor (Ruconest) for Hereditary
Angioedema

The FDA has approved Ruconest (Salix), a recombinant
analog of human complement component 1 esterase
inhibitor (C1INH), for treatment of acute attacks in
patients with hereditary angioedema (HAE).
Pronunciation Key
Ruconest : roo' ko" nest

THE DISEASE — HAE, a rare autosomal dominant

disorder (estimated prevalence 1:10,000-50,000),
is usually caused by a mutation of the C1-inhibitor
gene. C1INH suppresses the activity of the serine
protease plasma kallikrein, preventing generation
of bradykinin, a vasoactive substance that
increases vascular permeability and causes acute
angioedema attacks. Patients with HAE are deficient
in endogenous or functional C1INH, which leads to

an overproduction of bradykinin. They experience
recurrent and frequently unpredictable attacks of
angioedema lasting 2-5 days, typically involving the
extremities, gastrointestinal tract, genitalia, face,
oropharynx, and/or larynx.
OTHER PRODUCTS FOR HAE — Two other C1INH
products are available in the US: Cinryze is approved for
prophylaxis and Berinert is approved for treatment of
acute angioedema attacks.1 Both of these products are
derived from human plasma; Ruconest is purified from
the milk of transgenic rabbits. The kallikrein inhibitor
ecallantide (Kalbitor) and the selective bradykinin B2
receptor antagonist icatibant (Firazyr)2 are also FDAapproved for treatment of acute angioedema attacks.
Ecallantide is administered subcutaneously, but is not
approved for self-administration. The other approved
products can be self-administered, but icatibant is the
only one of these that is given subcutaneously rather
than intravenously.

Table 1. Some Products for Hereditary Angioedema
FDA-Approved

Indication

Dosage

SelfAdministration

Agent

Class

Cost1

Ruconest (Salix)

Recombinant human C1
esterase inhibitor
purified from milk of
transgenic rabbits

Treatment of acute
attacks in adults
and adolescents2

<84 kg: 50 IU/kg IV3
≥84 kg: 4200 IU IV3

Yes

$11,416.60

Cinryze (Shire)

Human plasma-derived
C1 esterase inhibitor

Prophylaxis in adults
and adolescents

1000 Units IV
q3-4 days

Yes

5356.90

Berinert (CSL Behring)

Human plasma-derived
C1 esterase inhibitor

Treatment of acute
attacks affecting
face, abdomen,
and larynx in adults
and adolescents

20 IU/kg IV

Yes

8055.00

Ecallantide –
Kalbitor (Dyax)

Recombinant human
plasma kallikrein
inhibitor produced in
Pichia pastoris yeast cells

Treatment of acute
attacks in patients
≥12 years old

10 mg SC x 3 in
the abdomen,
thigh, or upper arm3

No4

11,910.00

Icatibant –
Firazyr (Shire)

Bradykinin B2
receptor antagonist

Treatment of acute
attacks in patients

≥18 years old

30 mg SC in
the abdomen5

Yes

9440.80

1. Approximate WAC for one dose for a 70-kg patient. 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. March 5, 2016. Reprinted with permission
by First Databank, Inc. All rights reserved. ©2016. www.fdbhealth.com/policies/drug-pricing-policy.
2. Efficacy not established for laryngeal attacks.
3. One additional dose can be given within a 24-hour period.
4. Eligible patients can receive a visit from a nurse who will administer ecallantide infusions at the patient’s preferred location at an additional cost. Not
appropriate for treatment of laryngeal attacks.
5. Two additional doses can be given (at 6-hour intervals) within a 24-hour period.

e44

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CLINICAL STUDIES — Approval of Ruconest was based
on the results of a randomized, double-blind trial in
75 patients ≥13 years old with HAE experiencing a

moderate to severe peripheral, abdominal, facial, and/
or oropharyngeal-laryngeal angioedema attack. The
median time to beginning of symptom relief at the
primary attack location, the primary endpoint, was
significantly shorter in patients who received Ruconest
than in those who received placebo (90 vs 152 minutes).
Only 2 patients with a primary oropharyngeal-laryngeal
attack were treated with the active drug.3 In an openlabel extension of the trial, 44 patients were treated with
Ruconest for a total of 224 subsequent attacks. The
median time to beginning of symptom relief for the first
5 attacks was 75 minutes; in almost all cases, only one
dose of Ruconest was required.4
ADVERSE EFFECTS — Ruconest was well tolerated in
clinical trials. Serious hypersensitivity reactions have
occurred in patients taking C1 esterase inhibitors.
Ruconest is contraindicated for use in patients with a
history of allergy to rabbits or rabbit-derived products.
Use of plasma-derived C1 esterase inhibitors has been
associated with thromboembolic adverse events in
patients with risk factors; no thrombotic events were
reported in clinical studies with Ruconest. Antibody
testing in 205 patients treated with Ruconest for 650
acute attacks found that none developed anti-C1INH
neutralizing antibodies.

Vol. 58 (1491)

PREGNANCY — Ruconest is classified as category B
(embryotoxicity in rabbits but not rats; no adequate
studies in women) for use during pregnancy.

DOSAGE AND ADMINISTRATION — The recommended
dosage of Ruconest is 50 IU/kg for patients who
weigh <84 kg and 4200 IU for those weighing ≥84 kg,
administered as an IV injection over approximately 5
minutes. A second dose may be given if necessary;
no more than 2 doses should be administered in a 24hour period.
CONCLUSION — Ruconest, a recombinant C1 esterase
inhibitor, is effective for treatment of acute attacks
of hereditary angioedema (HAE). Whether it is more
effective or safer than human plasma-derived C1
esterase inhibitors or any other drug approved for
this indication remains to be determined. Its efficacy
for treatment of laryngeal attacks has not been
established. ■
1. Three new drugs for hereditary angioedema. Med Lett Drugs
Ther 2010; 52:66.
2. In brief: Icatibant (Firazyr) for hereditary angioedema. Med Lett
Drugs Ther 2011; 53:96.
3. MA Riedl et al. Recombinant human C1-esterase inhibitor relieves symptoms of hereditary angioedema attacks: phase 3,
randomized, placebo-controlled trial. Ann Allergy Asthma Immunol 2014; 112:163.
4. HH Li et al. Recombinant human-C1 inhibitor is effective and
safe for repeat hereditary angioedema attacks. J Allergy Clin
Immunol Pract 2015; 3:417.

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on Drugs and Therapeutics
Volume 58 (Issue 1491)

March 28, 2016

IN BRIEF

Dinutuximab (Unituxin) for High-Risk
Neuroblastoma
The FDA has approved use of dinutuximab (Unituxin
[yoo ni tux' in] – United Therapeutics) in combination
with interleukin-2 (IL-2), granulocyte-macrophage
colony-stimulating factor (GM-CSF), and isotretinoin for
treatment of children with high-risk neuroblastoma who
previously responded to first-line therapies. Dinutuximab
is a monoclonal antibody that binds to GD2, a glycolipid
that is overexpressed on the surface of neuroblastoma
cells.1
Dinutuximab received a priority review and orphan

drug designation. Approval was based on the results
of an open-label trial in 226 patients with high-risk
neuroblastoma that had at least a partial response
to induction chemotherapy, autologous stem cell
transplantation, and radiation. Patients were randomized
to receive a combination of dinutuximab, GM-CSF, IL-2,
and isotretinoin, or isotretinoin alone. At 2 years, the
event-free survival rate, the primary endpoint, was 66%
with the dinutuximab regimen and 46% with isotretinoin
alone (p<0.01). The overall survival rate was 86% with the
dinutuximab regimen compared to 75% with isotretinoin
alone (p<0.02).2
The recommended dose of dinutuximab is 17.5 mg/m2
daily infused IV over 10-20 hours for 4 consecutive
days for up to 5 cycles. Dinutuximab can cause lifethreatening infusion reactions, severe pain requiring
treatment with IV opioids, peripheral neuropathy,
capillary leak syndrome, visual disturbances, hemolyticuremic syndrome, and other serious adverse effects. The
cost for one 17.5 mg single-use vial is $7,500.3 ■
1. S Dhillon. Dinutuximab: first global approach. Drugs 2015; 75:
923.
2. AL Yu et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and
isotretinoin for neuroblastoma. N Engl J Med 2010; 363:1324.
3. Approximate WAC. WAC = wholesaler acquisition cost, or manufacturer’s published price to wholesalers; WAC represents published
catalogue or list prices and may not represent an actual transactional price. Source: AnalySource® Monthly. March 5, 2016. Reprinted with permission by First Databank, Inc. All rights reserved.
©2016. www.fdbhealth.com/policies/drug-pricing-policy.

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on Drugs and Therapeutics
Volume 58 (Issue 1491)

March 28, 2016

IN BRIEF

Uridine Triacetate (Xuriden) for
Hereditary Orotic Aciduria
The FDA has approved the pyrimidine analog
uridine triacetate (Xuriden [zur' uh den] – Wellstat
Therapeutics) for treatment of hereditary orotic aciduria,
a rare autosomal recessive disorder (estimated birth
prevalence: <1:1,000,000) in infants and children caused
by a deficiency in uridine 5’-monophosphate (UMP)
synthase. This deficiency prevents synthesis of uridine
nucleotides and causes developmental delays, failure to

gain weight, hematologic abnormalities, and excessive
urinary excretion of orotic acid, which can lead to urinary
obstruction.1 Xuriden is the first drug to be approved in the
US for this indication. Uridine triacetate is also available
as Vistogard for treatment of fluorouracil (5-FU) or
capecitabine (Xeloda, and generics) overdose or severe or
life-threatening toxicity.
In an unpublished, single-arm, 6-week trial with a
6-month extension (summarized in the package insert),
4 patients 3-19 years old with hereditary orotic aciduria
were treated with uridine triacetate 60 mg/kg once daily
for 6 weeks, followed by 60-120 mg/kg once daily for
6 months. After 6 months of treatment, hematologic
parameters (neutrophil count, WBC count, or mean
corpuscular volume) either improved or remained
stable and orotic acid levels remained stable in all 4
patients. Weight growth either improved or remained
stable and height growth remained stable in 3 patients
measured after 6 months of treatment. No adverse
effects were reported.
Xuriden is available as oral granules in 2-gram single-use
packets. The recommended starting dosage is 60 mg/
kg once daily. The dose can be increased to 120 mg/kg
(max 8 grams) once daily if urine orotic acid levels
increase or remain above normal, or for worsening
disease. The granules should be mixed in applesauce,
pudding, yogurt, milk, or infant formula and swallowed
immediately, without chewing. Once the packet is
opened, any unused granules should be discarded. The
cost for 30 2-gram packets of Xuriden is $22,500.2 ■

1. S Balasubramaniam et al. Inborn errors of pyrimidine metabolism:
clinical update and therapy. J Inherit Metab Dis 2014: 37:687.
2. Approximate WAC = wholesaler acquisition cost, or
manufacturer’s published price to wholesalers; WAC represents
published catalogue or list prices and may not represent an
actual transactional price. Source: AnalySource® Monthly.
March 5, 2016. Reprinted with permission by First Databank, Inc.
All rights reserved. ©2016. www.fdbhealth.com/policies/drugpricing-policy.

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Seebri Neohaler and Utibron Neohaler for COPD
1. In two 12-week trials supporting the efficacy of glycopyrrolate/
indacaterol for COPD, the combination was shown to:
a. increase the FEV1 AUC0-12 compared to indacaterol
b. increase the FEV1 AUC0-12 compared to glycopyrrolate
c. improve scores on a health-related quality of life
questionnaire more than placebo
d. all of the above
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b. it is an inhalation spray inhaler
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Lumacaftor/Ivacaftor (Orkambi) for Cystic Fibrosis
4.    Which of the following drugs has been effective in clinical trials
for treatment of cystic fibrosis in patients who are homozygous
for the F508del mutation?
a. ivacaftor alone
b. lumacaftor alone
c. lumacaftor/ivacaftor
d. all of the above
 5. Lumacaftor/ivacaftor has only been shown to be effective for
cystic fibrosis patients who are homozygous for the F508del
mutation. What is the approximate prevalence of this genotype
among patients with the disease?
a. 5%
b. 20%
c. 50%
d. 90%

6. The mother of a 13-year-old girl with cystic fibrosis with the
F508del mutation recently saw an advertisement for lumacaftor/
ivacaftor (Orkambi) and asks if her daughter should receive the
new drug. Which of the following should you tell her?
a. Orkambi has not been shown to improve respiratory
function in patients with the F508del mutation
b. Orkambi should be taken every 12 hours with fatcontaining food
c. Orkambi has no significant drug interactions and can be
taken concurrently with most other drugs
d. all of the above

7.  In clinical trials, lumacaftor/ivacaftor:
a. increased predicted FEV1
b. increased BMI
c. reduced the rate of pulmonary exacerbations
d. all of the above
Cobimetinib (Cotellic) for Metastatic Melanoma
8. BRAF mutations are present in what percentage of melanomas?
a. 10%
b. 30%
c. 50%
d. 80%
9. In the clinical trial comparing vemurafenib alone with
vemurafenib plus cobimetinib, the difference between the
two groups in median number of months of progression-free
survival was:
a. 2.2
b. 3.7
c. 6.2
d. 9.9
10. Adding a MEK inhibitor to a BRAF inhibitor appears to protect
against:
a. photosensitivity reactions
b. cutaneous squamous-cell carcinoma
c. hepatotoxicity
d. all of the above

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