The medical letter on drugs and therapeutics march 28 2016

1491 on Drugs and Therapeutics Seebri Neohaler and Utibron Neohaler for COPD ...p 39 Lumacaftor/Ivacaftor Orkambi for Cystic Fibrosis ...p 41 Cobimetinib Cotellic for Metastatic Melanoma

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IN THIS ISSUE

ISSUE

1433

Volume 56

Published by The Medical Letter, Inc • A Nonprofi t Organization

ISSUE No

1491

on Drugs and Therapeutics

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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39

Take CME Exams

ISSUE

1433

Volume 56

ISSUE No

1491 Lumacaftor/Ivacaftor (Orkambi) for Cystic Fibrosis Cobimetinib (Cotellic) for Metastatic Melanoma p 41p 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

ALSO IN THIS ISSUE

Seebri Neohaler and Utibron

Neohaler for COPD

▶

The FDA has approved two new inhalers for

long-term maintenance treatment of chronic obstructive

pulmonary disease (COPD) Seebri Neohaler

(Novartis) contains the long-acting anticholinergic

glycopyrrolate Utibron Neohaler (Novartis) contains

-adrenergic agonist (LABA) indacaterol Glycopyrrolate/

indacaterol is the third fi xed-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

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

with an inhaled long-acting bronchodilator (an

re-lieve 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

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

Table 1 Pharmacology

Glycopyrrolate Indacaterol

Class Long-acting Long-acting beta2

anticholinergic adrenergic 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

Table 2 Long-Acting Anticholinergic/Beta 2 -Adrenergic Agonist Combination Inhalers: Ease of Use

Anoro Ellipta

▶ 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

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After 12 weeks, patients treated with glycopyrrolate

had significantly larger mean increases from

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

ran-domized to twice-daily glycopyrrolate/indacaterol,

glycopyrrolate alone, indacaterol alone, or placebo

signifi cantly 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 signifi cant reduction in rescue

inhaler use compared to those treated with placebo

The combination improved scores on a

health-related quality of life questionnaire signifi cantly more

ADVERSE EFFECTS — The most common adverse

effects reported in clinical trials were upper respiratory

tract infection and nasopharyngitis with

glycopyr-rolate alone and nasopharyngitis and hypertension

with glycopyrrolate/indacaterol

Systemic absorption of inhaled anticholinergics could

cause urinary retention and increased intraocular

pressure, but glycopyrrolate is minimally bioavailable and systemic adverse effects are unlikely to occur with inhaled use

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 classifi ed as category C (no teratogenic effects in animals given high doses; no adequate studies in pregnant women) for use during

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

Table 3 Some Inhaled Drugs for Maintenance Treatment of COPD

Long-Acting Anticholinergics

Aclidinium – Tudorza Pressair (AstraZeneca) 400 mcg/inh DPI (30, 60 inh/unit) 1 inh bid $301.10

Glycopyrrolate – Seebri Neohaler (Novartis) 15.6 mcg/cap 2 DPI (60 inh/unit) 1 inh bid 3 297.80

Tiotropium – Spiriva HandiHaler 18 mcg/cap 2 DPI (5, 30, 90 inh/unit) 1 inh once/d 3 315.70 (Boehringer Ingelheim)

Spiriva Respimat 2.5 mcg/inh ISI (60 inh/unit) 2 inh once/d 315.70

Umeclidinium – Incruse Ellipta (GSK) 62.5 mcg/inh DPI (7, 30 inh/unit) 1 inh once/d 252.60

Long-Acting Beta 2 -Adrenergic Agonists

Indacaterol – Arcapta Neohaler (Novartis) 75 mcg/cap 2 DPI (30 inh/unit) 1 inh once/d 3 213.60

Olodaterol – Striverdi Respimat 2.5 mcg/inh ISI (28, 60 inh/unit) 2 inh once/d 155.70 (Boehringer Ingelheim)

Salmeterol – Serevent Diskus (GSK) 50 mcg/blister DPI (28, 60 inh/unit) 1 inh bid 322.60

Long-Acting Anticholinergic/Long-Acting Beta 2 -Adrenergic Agonist Combinations

Glycopyrrolate/indacaterol – Utibron Neohaler 15.6 mcg/27.5 mcg/cap2 DPI (6, 60 inh/unit) 1 inh bid 3 297.80 (Novartis)

Tiotropium/olodaterol – Stiolto Respimat 2.5 mcg/2.5 mcg/inh ISI (60 inh/unit) 2 inh once/d 315.70 (Boehringer Ingelheim)

Umeclidinium/vilanterol – Anoro Ellipta (GSK) 62.5 mcg/25 mcg/blister DPI (7, 30 inh/unit) 1 inh once/d 315.70

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.

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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: effi cacy and safety

of QVA149 (indacaterol/glycopyrrolate) versus its mono-components and placebo in patients with chronic obstructive pulmonary disease Am J Respir Crit Care Med 2015; 192:1068.

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

long-acting anticholinergic glycopyrrolate alone (Seebri

Lumacaftor/Ivacaftor (Orkambi) for

Cystic Fibrosis

▶

Pronunciation Key Lumacaftor : loo" ma kaf' tor Orkambi : or kam' bee

Ivacaftor : eye" va kaf' tor

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

first drug to be approved in the US for treatment of

patients with the F508del mutation

CLINICAL STUDIES — In clinical trials, neither

ivacaftor nor lumacaftor alone has been shown to

be effective in patients with CF who are homozygous

Approval of the lumacaftor/ivacaftor combination was based on the results of two 24-week, double-blind 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

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 signifi cant improvements from baseline in the absolute change in percent predicted

Lumacaftor Ivacaftor

Tmax ~4 hours (with food) ~4 hours (with food) Metabolism Not extensive (mainly Primarily hepatic

by oxidation and by CYP3A glucuronidation)

Elimination Feces (51% unchanged); Feces (87.8%);

urine (8.6%) urine (6.6%) Half-life ~ 26 hours (CF patients) ~9 hours (healthy

subjects)

Neohaler) or in combination with the long-acting beta2

-adrenergic agonist indacaterol (Utibron Neohaler) can

improve lung function in patients with moderate to severe COPD How they compare in effi cacy and safety with other inhaled drugs for this indication remains to

be determined, but some of the older products offer

MECHANISM OF ACTION — The cystic fibrosis

transmembrane conductance regulator (CFTR)

protein functions as a regulated chloride channel

The F508del mutation causes CFTR protein

mis-folding, 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

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points) The rate of pulmonary exacerbations,

including those leading to hospitalization and use of

IV antibiotics, was signifi cantly lower in patients taking

lumacaftor/ivacaftor than in those taking placebo

Patients taking the combination also had greater

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 effi cacy of the many drugs

that are metabolized by this enzyme, including some

corticosteroids and azole antifungals Lumacaftor/

ivacaftor may also decrease the effi cacy 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 signifi cantly 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

labora-tory studies, prolonged exposure to ivacaftor reduced

the effi cacy 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

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 fi rst year of treatment, and annually thereafter Treatment with the combi-nation should be interrupted if signifi cant increases occur in hepatic transaminase and bilirubin levels Patients with moderate hepatic impairment should take two tablets in the morning and one in the eve-ning Although the combination has not been studied

in patients with severe hepatic impairment, the manu-facturer 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

CONCLUSION — The fi xed-dose combination of

lumacaftor and ivacaftor (Orkambi) is the fi rst

disease-modifying therapy to be approved for the 50% of patients with cystic fi brosis who are

homoz-ygous for the F508del mutation Orkambi improves

pulmonary function and reduces exacerbations, but its long-term effi cacy and safety have not been established, it interacts with many other drugs, and it

1 Ivacaftor (Kalydeco) for cystic fi brosis Med Lett Drugs Ther 2012; 54:29.

2 PA Flume et al Ivacaftor in subjects with cystic fi brosis 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 investi-gational CFTR corrector compound, in subjects with cystic fi brosis homozygous for the F508del-CFTR mutation Thorax 2012; 67:12.

4 CE Wainwright et al Lumacaftor-ivacaftor in patients with cys-tic fi brosis 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 fi brosis therapy N Engl

J Med 2015; 373:274.

7 Approximate WAC WAC = wholesaler acquisition cost or manufac-turer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual

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Cobimetinib (Cotellic) for Metastatic

Melanoma

▶

Pronunciation Key Cobimetinib : koe" bi me' ti nib Cotellic : koe tel' ik

The FDA has approved the mitogen-activated

extracellular signal-regulated kinase (MEK) inhibitor

cobimetinib (Cotellic – Genentech) for use in

combi-nation with the BRAF kinase inhibitor vemurafenib

(Zelboraf) for treatment of unresectable or metastatic

melanoma with a BRAF V600E or V600K mutation

STANDARD TREATMENT — BRAF mutations are

pres-ent 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

dab-rafenib (Tafi nlar) have been highly effective in treating

BRAF mutation-positive unresectable or metastatic

(Mekinist) improved overall survival compared 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

MECHANISM OF ACTION — Cobimetinib and

vemurafenib act on two different kinases in the

same signaling pathway The combination was more

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 fi

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

follow-up 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

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

Table 2 Kinase Inhibitors for Metastatic Melanoma

Dabrafenib – BRAF inhibitor Melanoma with BRAF 5.1 mos vs 2.7 mos 150 mg PO $26,393.90

Tafinlar (GSK) V600E mutation with dacarbazine 3 bid 4

Vemurafenib – BRAF inhibitor Melanoma with BRAF 5.3 mos vs 1.6 mos 960 mg PO 32,552.40

Zelboraf (Genentech) V600E mutation with dacarbazine 5 bid

Trametinib – MEK inhibitor Melanoma with BRAF See combination therapy 2 mg PO 30,214.00

Mekinist (GSK) V600E or V600K mutations once/d 4

Cobimetinib – MEK inhibitor Melanoma with BRAF See combination therapy 60 mg PO 18,185.30

Cotellic (Genentech) V600E or V600K mutations 6 once/d 7

Combination Therapy

Dabrafenib plus BRAF inhibitor/ Melanoma with BRAF 11.4 mos vs 7.3 mos See individual 56,607.90 trametinib MEK inhibitor V600E or V600K mutations with vemurafenib 8 drugs

9.4 mos vs 5.8 mos with dabrafenib 9

Vemurafenib plus BRAF inhibitor/ Melanoma with BRAF 9.9 mos vs 6.2 mos See individual 50,737.70 cobimetinib MEK inhibitor V600E or V600K mutations with vemurafenib 10 drugs

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.

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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

Cobimetinib is also a substrate of the drug transporter

P-glycoprotein (P-gp); drugs that inhibit P-gp may

DOSAGE — Cobimetinib is available as 20-mg tablets

The recommended dosage is 60 mg once daily (with or

without food) for the fi rst 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

(Tafi nlar) and trametinib (Mekinist) Both combinations

are signifi cantly 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

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

1 Vemurafenib (Zelboraf) for metastatic melanoma Med Lett Drugs Ther 2011; 53:77.

2 Dabrafenib (Tafi nlar) and trametinib (Mekinist) for metastatic melanoma Med Lett Drugs Ther 2013; 55:62.

3 C Robert et al Improved overall survival in melanoma with com-bined 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 mono-therapy in untreated melanoma N Engl J Med 2015; 373:23.

6 J Larkin et al Effi cacy 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 Dis-pos 2016; 44:28.

8 J Larkin et al Combined vemurafenib and cobimetinib in BRAF-mutated melanoma N Engl J Med 2014; 371:1867.

9 V Atkinson et al Improved overall survival (OS) with cobi-metinib (COBI) + vemurafenib (V) in advanced BRAF-mutated melanoma and biomarker correlates of effi cacy Late breaking abstract presented at the Society for Melanoma Research In-ternational Congress, San Francisco, November 18-21, 2015.

10 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2016; 58:e46.

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Trang 8

e44

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)

A Recombinant C1 Esterase

Inhibitor (Ruconest) for Hereditary

Angioedema

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

derived from human plasma; Ruconest is purifi ed from

the milk of transgenic rabbits The kallikrein inhibitor

ecallantide (Kalbitor) and the selective bradykinin B2

FDA-approved 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

esterase inhibitor attacks in adults ≥84 kg: 4200 IU IV 3

purifi ed from milk of and adolescents 2

transgenic rabbits

C1 esterase inhibitor and adolescents q3-4 days

C1 esterase inhibitor attacks affecting

face, abdomen,

and larynx in adults and adolescents Ecallantide – Recombinant human Treatment of acute 10 mg SC x 3 in No 4 11,910.00

Kalbitor (Dyax) plasma kallikrein attacks in patients the abdomen,

inhibitor produced in ≥12 years old thigh, or upper arm 3

Icatibant – Bradykinin B2 Treatment of acute 30 mg SC in Yes 9440.80

Firazyr (Shire) receptor antagonist attacks in patients the abdomen 5

≥18 years old

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

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.

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 defi cient

in endogenous or functional C1INH, which leads to

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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

signifi cantly shorter in patients who received Ruconest

than in those who received placebo (90 vs 152 minutes)

Only 2 patients with a primary oropharyngeal-laryngeal

open-label 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 fi rst

5 attacks was 75 minutes; in almost all cases, only one

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

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 re-lieves symptoms of hereditary angioedema attacks: phase 3, randomized, placebo-controlled trial Ann Allergy Asthma Im-munol 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

PREGNANCY — Ruconest is classifi ed 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 24-hour 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 effi cacy for treatment of laryngeal attacks has not been

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e48

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 fi rst-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

life-threatening infusion reactions, severe pain requiring

treatment with IV opioids, peripheral neuropathy,

capillary leak syndrome, visual disturbances,

hemolytic-uremic syndrome, and other serious adverse effects The

cost for one 17.5 mg single-use vial is $7,500.3 ■

1 S Dhillon Dinutuximab: fi rst 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

manufac-turer’s published price to wholesalers; WAC represents published

catalogue or list prices and may not represent an actual

transac-tional price Source: AnalySource® Monthly March 5, 2016

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