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Asthma Maintenance: An Update on New Medications

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Asthma Maintenance: An Update on New Medications

Abstract and Introduction

Introduction

Uncontrolled asthma has been responsible for 1.8 million emergency department

(ED) visits and almost 500,000 hospitalizations in the United States in 2004

alone.[1,2]

Furthermore, in 2006, the number of physician office, hospital outpatient, and

ED visits with asthma as the primary diagnosis was 13.3 million.[3]

During the last seven years, three asthma maintenance medications have been

approved and marketed: ciclesonide (Alvesco), budesonide/formoterol (Symbicort),

and omalizumab (Xolair).

This article will systematically review the safety, tolerability, efficacy,

price, simplicity of use, and some of the major published studies of the newest

treatment regimens for asthma maintenance.[4]

Ciclesonide

Ciclesonide (Alvesco; Sepracor), an inhaled corticosteroid, was approved by the

FDA in 2006 for maintenance treatment of asthma in patients aged 12 years and

older.[5] Ciclesonide is a prodrug that is hydrolyzed to its active metabolite,

C21-desisobutyryl-ciclesonide, following oral inhalation. Its mechanism of

action includes inflammatory-cell migration and activation, reduced airway

hyperresponsiveness, and blockade of late-phase allergic reactions.[5,6]

Safety

Ciclesonide is not indicated for the treatment of acute bronchospasm or status

asthmaticus, and it is contraindicated in patients with known hypersensitivity

to ciclesonide. Precautions should be taken in patients at risk for worsening

adrenal function, immunosuppression, decreased bone mineral density (BMD),

glaucoma, intraocular pressure, or cataract. The Expert Panel Report 3

acknowledged that long-term use of high-dose inhaled corticosteroids (ICS) can

lead to adverse effects on linear growth; therefore, adolescents receiving ICS

should be consistently monitored for any deviations from predicted growth

patterns.[6] Studies were inconsistent regarding ciclesonide's efficacy in

pediatric patients aged less than 12 years; for this reason, ciclesonide is not

approved for use in this population.[5] Ciclesonide is classified as pregnancy

category C, and the extent of its secretion into breast milk is unknown;

therefore, caution should be exercised in nursing women.[5]

Tolerability

The most common adverse reactions experienced by patients (>3%) taking

ciclesonide are headache, nasopharyngitis, sinusitis, pharyngolaryngeal pain,

upper respiratory infection, arthralgia, nasal congestion, and pain in the back

and extremities. Less common side effects (<1%) include oral candidiasis, cough,

dry mouth and throat, nausea, chest discomfort, and dysphonia. Discontinuation

rates were greater in patients taking ciclesonide 160 mcg once daily compared

with ciclesonide 320 mcg twice daily owing to an increase in asthma

exacerbations.[5,6]

Efficacy

In the U.S., ciclesonide is approved for twice-daily administration for asthma

maintenance. In other countries, the drug is approved for once-daily

administration, and many published clinical trials have investigated this

frequency of administration. A 16-week, randomized, double-blind,

placebo-controlled study examined 691 patients with mild-to-moderate persistent

asthma who had been treated with bronchodilator therapy only. Patients were

randomized to one of four groups: ciclesonide 160 mcg once daily in the morning

for 16 weeks; ciclesonide 80 mcg twice daily for 16 weeks; ciclesonide 80 mcg

twice daily for 4 weeks followed by 160 mcg once daily in the morning for 12

weeks; or placebo for 16 weeks. All ciclesonide regimens showed statistical

improvement in predose forced expiratory volume in 1 second (FEV1) by week 16

compared with placebo. Morning predose FEV1 was greater in patients treated with

80 mcg twice daily versus those taking 160 mcg once daily. Respective increases

in morning predose FEV1 for ciclesonide 160 mcg once daily, 80 mcg twice daily

for 16 weeks, and 80 mcg twice daily for 4 weeks followed by 160 mcg once daily

for 12 weeks were 5%, 10.4%, and 5%.[5]

A phase III, randomized, placebo-controlled trial evaluated 141 patients with

severe, persistent, prednisone-dependent asthma each week to determine whether

their prednisone dose could be reduced. The use of ciclesonide 320 mcg twice

daily and 640 mcg twice daily led to a 47% and 63% reduction in prednisone dose,

respectively, as opposed to a 4% increase in prednisone dose with placebo.[7]

Another randomized, open-label study compared ciclesonide 320 mcg twice daily

and fluticasone propionate 330 mcg twice daily in 528 patients with

moderate-to-severe asthma. Pulmonary function, peak flow, asthma symptoms,

exacerbations requiring oral steroids, use of rescue medications,

discontinuation rates, and quality of life were assessed. The authors concluded

that there were no significant differences between the two corticosteroids in

the measured outcomes.[8]

Price

The monthly cost of ciclesonide metered dose inhaler (MDI) is based on 60

actuations per canister ( TABLE 1 ).[9] In comparison, the cost of mometasone

(Asmanex Twisthaler) is based on 120 actuations per canister. A single canister

of mometasone will last 4 months when administered at 220 mcg once daily or 2

months when administered at 440 mcg twice daily; it is available for $210.19 for

120 actuations.[10] Although mometasone is available only in 120-actuation

increments, this equates to $52.55/month for once-daily dosing and $105.10/month

for twice-daily dosing.

[ CLOSE WINDOW ]

Table 1. Ciclesonide (Alvesco)

Initial Dose Dosage Form Approximate Cost/Month

80 mcg bid 80 or 160 mcg/spray MDI; 60 actuations/canister $154.99; $155.98

MDI: metered dose inhaler.

Source: Reference [9].

Simplicity

Ciclesonide is inhaled twice daily, which is similar to other inhaled

corticosteroids that range from one to four inhalations per day. The inhaler

should be primed prior to first use or if it has not been used for more than 10

days. The inhaler has an indicator display window that counts down the number of

inhalations left in the canister. Patients should use ciclesonide like most oral

inhalers, with the exception that it does not need to be shaken prior to use.

Patients should also be instructed to rinse the mouth with water after each dose

to avoid thrush.[5]

Place in Therapy

ICS are the most potent and effective anti-inflammatory medications available.

Low-dose ICS, which are the preferred maintenance medications, are added to a

patient's quick-relief, short-acting beta2-agonist once the patient has

progressed from intermittent to mild persistent asthma. As a patient progresses

to moderate or severe persistent asthma, the ICS dose generally is increased

before other medications are added to the regimen. ICS for asthma therapy

include beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone,

mometasone, and triamcinolone.[11]

Budesonide/Formoterol

Budesonide/formoterol fumarate dihydrate (Symbicort; AstraZeneca), a combination

MDI, was approved by the FDA in 2006 for the maintenance treatment of asthma in

patients 12 years of age and older. Budesonide is a corticosteroid with

anti-inflammatory properties, and formoterol is a long-acting beta2-agonist

(LABA) that functions as a bronchodilator.[12]

Safety

Budesonide/formoterol is not indicated for the treatment of acute bronchospasm

or status asthmaticus, and it is contraindicated in patients with known

hypersensitivity to budesonide or formoterol.[12] All LABAs carry a black box

warning owing to their potential to increase the risk of asthma-related

death.[12] In February 2010, because of safety concerns, the FDA mandated a

risk-management strategy and class-labeling changes for all LABA-containing

products, including a revised medication guide for patients and a plan to

educate health care professionals about the appropriate use of LABAs. The

requirement is based on findings from several clinical studies--including the

Salmeterol Multicenter Asthma Research Trial, the Salmeterol Nationwide

Surveillance study, and an FDA-initiated meta-analysis of 110 additional

studies--indicating an increased risk of severe exacerbation of asthma symptoms

leading to hospitalization, and even death, in some patients using LABAs for the

prophylactic treatment of asthma.[13–15]

Similar to other corticosteroids, precautions should be taken owing to the

potential for worsening adrenal function, immunosuppression, decreased BMD,

glaucoma, intraocular pressure, cataracts, and adverse effects on growth. The

safety and efficacy of budesonide/formoterol has not been established in

pediatric patients aged less than 12 years. Budesonide/formoterol is classified

as pregnancy category C, and budesonide has been shown to be secreted in human

milk; therefore, it should not be used in nursing women.[12] Drug interactions

that warrant caution include strong CYP450 3A4 inhibitors, tricyclic

antidepressants, beta-blockers, and diuretics.[12]

Tolerability

Common adverse reactions experienced by patients (>3%) using

budesonide/formoterol 80/4.5 mcg or 160/4.5 mcg twice daily include

nasopharyngitis, headache, upper respiratory tract infections, pharyngolaryngeal

pain, sinusitis, influenza, and back pain. Less common side effects include

nasal congestion, stomach discomfort, vomiting, and oral candidiasis.[12]

Patients should be informed of adverse effects associated with LABAs, such as

palpitations, chest pain, rapid heart rate, tremor, and nervousness.[12]

Efficacy

Budesonide/formoterol is approved for twice-daily administration as maintenance

therapy for asthma. In a 6-month, multicenter, parallel-group, double-blind,

double-dummy, randomized trial, 1,391 patients aged 12 years and older with

persistent asthma who had experienced an exacerbation within the past year

received 2 inhalations of budesonide/formoterol 160/4.5 mcg twice daily or 1

inhalation of salmeterol/fluticasone 500/50 mcg twice daily. Patients' mean rate

of exacerbations was similar in both treatment groups. There was a 30% lower

annual rate of moderate or severe exacerbations in the salmeterol/fluticasone

group compared with the budesonide/formoterol group. The authors concluded that

asthma symptoms and lung function were improved in both treatment groups;

however, salmeterol/fluticasone was significantly superior to

budesonide/formoterol in reducing the rate of exacerbations.[16]

Price

The monthly cost of budesonide/formoterol MDI is based on 120 inhalations per

canister ( TABLE 2 ).[17] In comparison, the other available combination MDI,

fluticasone/salmeterol hydrofluoroalkane (Advair HFA)--available in strengths of

45/21 mcg, 115/21 mcg, and 230/21 mcg--is administered as 1 puff twice daily and

costs, respectively, $187.95, $219.40, and $269.91 for a 1-month supply.[18]

[ CLOSE WINDOW ]

Table 2. Budesonide/Formoterol (Symbicort)

Initial Dose Dosage Form Approximate Cost/Month

2 puffs bid 80 or 160/4.5 mcg MDI; 120 actuations/canister $185.10; $217.79

MDI: metered dose inhaler.

Source: Reference [17].

Simplicity

Budesonide/formoterol is administered as 2 inhalations twice daily. The inhaler

should be primed prior to first use or if it has not been used for more than 7

days. Similar to ciclesonide, the inhaler has an indicator display window that

counts down the number of inhalations left in the canister. Patients should use

the inhaler like other MDIs and should shake the inhaler for approximately 5

seconds prior to each use. As with all ICS, patients should be instructed to

rinse the mouth with water after each dose to avoid thrush.[12]

Place in Therapy

Of the adjunctive therapies available, LABAs are the preferred choice to combine

with ICS in patients aged 12 years and older.[11] LABAs are never to be used as

monotherapy. Combination products containing an ICS and an LABA include

fluticasone/salmeterol (Advair) and budesonide/formoterol (Symbicort).[12]

Omalizumab

Omalizumab (Xolair; Genentech) is a novel injectable recombinant DNA-derived

humanized immunoglobulin G monoclonal antibody that binds to human

immunoglobulin E (IgE). It was approved by the FDA in 2003 for maintenance

treatment of moderate-to-severe persistent asthma in patients aged 12 years and

older with a positive skin test or in vitro reactivity to a perennial

aeroallergen and symptoms that are inadequately controlled with ICS.[19]

Omalizumab inhibits the binding of IgE to the high-affinity receptor on the

surface of mast cells and basophils, which limits the release of allergic

response mediators and reduces serum free IgE levels. In clinical studies, total

IgE levels did not return to pretreatment levels for up to 1 year after

discontinuation of omalizumab.[19]

Safety

The product carries a black box warning that anaphylaxis presenting as

bronchospasm, hypotension, syncope, urticaria, and/or angioedema of the throat

or tongue has been reported after administration. Anaphylaxis can occur as early

as after the first dose, but also has occurred beyond 1 year after starting

regularly scheduled treatment, and its frequency is estimated at 0.2%.[19] A

task force investigated the actual incidence of anaphylaxis and determined that

postmarketing reports from 2003 to 2005 corresponded to a rate of 0.09% of

patients.[20] Task force recommendations include observing the patient for 2

hours for the first three injections and 30 minutes thereafter and educating the

patient regarding the signs and treatment of anaphylaxis, including the proper

use of the epinephrine autoinjector. Omalizumab is contraindicated in patients

with a history of severe hypersensitivity reaction.[19]

Malignant neoplasms have been observed in 0.5% of omalizumab-treated patients.

Omalizumab has not been shown to alleviate asthma exacerbations acutely, so is

not indicated to treat acute bronchospasm or status asthmaticus. Some patients

who have had a reduction of oral corticosteroid therapy may present with

systemic eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac

complications, or neuropathy.[19] Omalizumab is classified as pregnancy category

B, and caution should be exercised in nursing women. The concomitant use of

omalizumab with other medications or allergen immunotherapy has not been

evaluated.[19]

The FDA is currently evaluating interim safety findings from the ongoing study

Evaluating the Clinical Effectiveness and Long-Term Safety in Patients with

Moderate to Severe Asthma (EXCELS), an observational study of approximately

5,000 omalizumab-treated patients and a control group of 2,500. The primary

objective of EXCELS is to assess the long-term safety profile of omalizumab in

patients followed for 5 years. Interim data suggest a disproportionate increase

in ischemic heart disease; arrhythmias; cardiomyopathy and cardiac failure;

pulmonary hypertension; cerebrovascular disorders; and embolic, thrombotic, and

thrombophlebotic events.[21] At this time, the FDA is not recommending any

changes to the prescribing information for omalizumab and is not advising

patients to stop taking the drug.

Tolerability

The adverse events most frequently resulting in clinical intervention were

injection-site reaction (45%); viral infections (23%); upper respiratory tract

infection (20%); sinusitis (16%); headache (15%); and pharyngitis (11%). The

most common adverse reactions occurring in more than 1% of omalizumab-treated

patients include body, leg, and arm pain; arthralgia; fatigue; dizziness;

dermatitis; and earache.[19]

Efficacy

Omalizumab reduces the rate of serious asthma exacerbations and the need for ED

treatment and hospitalization in asthma patients.[22] The safety and efficacy of

omalizumab were originally evaluated in three randomized, double-blind,

placebo-controlled, multicenter trials using a maximum dose of 750 mg for 4

weeks.[19] Recently, observational studies have been initiated to determine

safety and effectiveness in clinical practice. The PERSIST study, a prospective,

open-label, observational, multicenter study of severe persistent allergic

asthma, assessed the 16-week and 52-week effectiveness of add-on omalizumab

treatment using physician-rated global evaluation of treatment effectiveness

(GETE).[23] At both 16 and 52 weeks, significant improvement was observed, as

evidenced by good/excellent GETE, better quality of life, percentage of patients

free of severe exacerbations, and reductions in healthcare utilization.[23] As

mentioned previously, the FDA is following the EXCELS study, an ongoing

multicenter, prospective, observational cohort study that will provide

information regarding the clinical safety and effectiveness of omalizumab in a

real-world clinical-practice setting.[24]

Price

The wholesale acquisition cost of one 150-mg vial of omalizumab was $649.16 as

of 2008 ( TABLE 3 ).[25] A patient would pay approximately $10,000 to $20,000

annually for omalizumab therapy, excluding health care provider administration

fees; this rate is much higher than for other available asthma medication

regimens. Genentech offers financial assistance for health care providers and

patients through its Xolair Access Solutions program.

[ CLOSE WINDOW ]

Table 3. Omalizumab (Xolair)

Initial Dose Dosage Form Approximate AWP Cost

150–375 mg SC q2w or q4w 150 mg/5 mL vial $649.16/single-dose vial

AWP: average wholesale price; SC: subcutaneously.

Source: Reference [25].

Simplicity

Dose (150–375 mg) and dosing frequency (2 or 4 weeks) are determined by baseline

serum total IgE level (30–700 IU/mL) and body weight (30–150 kg). Patients must

have a positive skin test or in vitro reactivity to a perennial aeroallergen

with asthma symptoms that are inadequately controlled with ICS.[19] Upon

initiation of omalizumab, ICS should not be abruptly discontinued, and no more

than 150 mg should be subcutaneously injected per site, with a maximum dose of

375 mg every 2 weeks.[19] Administration should occur only in a health care

provider's office to facilitate observation and treatment for anaphylaxis.

Place in Therapy

Omalizumab is the only adjunctive therapy to demonstrate added efficacy to

high-dose ICS plus LABA in patients who have severe persistent allergic asthma;

therefore, it may be considered as additional therapy for severe persistent

asthma patients aged 12 years and older who are not controlled on high-dose ICS

plus LABA.[11] From a pharmacoeconomic standpoint, omalizumab should be used

only in patients with allergic asthma who are poorly controlled despite maximal

therapy.[26]

[ CLOSE WINDOW ]

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US Pharmacist. 2010;35(7):1-5. © 2010 Jobson Publishing