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Individualizing inhaled medications for asthma and allergic rhinitis.

INTRODUCTION

Allergic rhinitis (AR) is described as a chronic inflammatory disease of the upper airways characterized by nasal congestion, rhinorrhea, sneezing, and nasal itching. Asthma is characterized by an eosinophilic inflammatory process present throughout the large and small peripheral airways and also by reversible airflow obstruction. (1) Evidence, in the form of links between AR and asthma at the anatomic, physiologic, pathologic, and therapeutic levels, supports the concept of a "unified airway"--the upper and lower airways function as a single unit and that disease processes may be interrelated. (2) Recent surveys indicate that approximately 78% of patients with asthma have AR and 38% of patients with AR have asthma. (3) Several studies have shown that treatment of AR in patients with asthma can improve asthma control and reduce health care costs. (4,5)

ROLE OF INHALED MEDICATIONS IN THERAPY

The pathophysiologic mechanisms involved in asthma and AR lend themselves to management with orally inhaled (asthma) or intranasal (AR) medications. For asthma, inhaled short- and long-acting [beta.sub.2] agonists and corticosteroids are key treatment options, while for AR, intranasal corticosteroids and antihistamines are primary therapeutic options. (6-8) Current asthma treatment guidelines classify orally inhaled corticosteroids (ICS) as low-, mid-, and high-dose based on estimated clinical comparability. (6) Among available intranasal corticosteroids, the overall clinical response appears comparable, and none of the intranasal corticosteroids is generally associated with clinically significant systemic side effects in recommended doses. (8)

Over the past decade and more, numerous [beta.sub.2] agonists and corticosteroid molecules, as well as a wide variety of inhaler devices, have become available. A systematic review suggests that the various inhaler devices available for asthma can work equally well in various clinical settings with patients who can use these devices properly. (9) A consortium of experts has identified over 50 critical inhaler handling errors associated with various inhaler devices that are likely to significantly impair delivery of adequate medication. (10) Of equal concern is that studies have shown that only 15% to 69% of health care professionals can demonstrate correct inhaler use. (10)

The challenge for health care providers is to select the inhaler best suited for an individual patient and teach proper administration technique since these directly impact adherence. In addition, correct administration technique is critical since it is the primary barrier to effectiveness of inhaled medication and achieving the optimal therapeutic response from the drug. (11-14) Clinical consequences of poor inhaler technique include: instability of asthma and increased emergency room visits, hospitalization, and oral medication prescriptions. (13,14)

Assessing potential barriers to effective use of inhaled medications is important at every visit. Patients should demonstrate inhaler technique and be questioned about experiences with unpleasant local side effects such as a bad taste or oral thrush (a potential risk with oral corticosteroid inhalers). (10) Factors that may affect patient satisfaction with and adherence to intranasal medication include nose and throat irritation, medication dripping down the throat, scent, or "wet vs dry" spray. (15) If a barrier is identified, verifying correct inhaler administration or selecting a different inhaler are options.

This article reviews the wide variety of inhaler formulations (oral and intranasal) and devices. Suggestions for individualizing inhaler selection are also provided.

INHALER DEVICES AND FORMULATIONS

In addition to intranasal and orally inhaled formulations, inhalers are available as aqueous or dry powder formulations and as metered-dose or breath-actuated devices.

Nasal inhalers: Aqueous vs aerosol

Most intranasal corticosteroids are available as an aqueous formulation, but hydrofluoroalkane (HFA)-propelled nonaqueous aerosol intranasal corticosteroids have been approved in the last few years (TABLE i). (16) Aqueous products are typically available in a nasal pump dispenser. Proper administration requires the patient to tilt their head back, close the contralateral nostril with a finger, and sniff inward during activation of the spray. Nonaqueous products are delivered through an aerosol device with a metering valve that converts solid or liquid corticosteroid particles into a gaseous suspension using a propellant. The patient closes one nostril with a finger, gently inserts the tip of the nosepiece in the other nostril, and holds the breath while pressing down on the canister to deliver the prescribed number of actuations. (16)

Both formulations appear to have similar efficacy rates. (17) It has been suggested that the HFA formulations may have a preferable sensory profile for some patients in terms of possibly improving some of the bothersome side effects associated with aqueous formulations (such as taste, posterior and anterior runoff, and fragrance), but no study has documented differences in patient adherence by type of formulation. (16)

Oral inhalers: Formulations

Aerosols for inhalation are either solutions, suspensions of solid drug particles in a gas, or dry powder solid particles, which can be generated from devices such as pressurized metered-dose inhalers (pMDIs), dry powder inhalers (DPIs), and nebulizers (TABLE 2); only pMDIs and DPIs are discussed in this article. (11) The efficiency of drug delivery to the lower respiratory tract varies among inhalers based on the type of device, its internal resistance, formulation of the medication, particle size, velocity of the produced aerosol plume, and ease with which patients can use the device. (11)

Aerodynamic diameter is thought to be the most important particle-related factor influencing the deposition pattern of a drug in the lungs, and optimal particle size range for inhalation seems to be 1.5-5 [micro]m, with most particles >5 pm impacting on the oropharynx, and many particles [less than or equal to] 1 [micro]m being exhaled. (18,19) Most current inhalers generate aerosols with a significant proportion of their particles in the 1 to 5 pm range. (18) Several of the newer products generate smaller 'ultrafine' particles which may provide enhanced control because of their improved delivery to the peripheral small airways; however, it is not yet clear that such targeted therapy improves peripheral inflammation/small airway disease over standard ICS MDIs and DPIs. (20) The products generating "ultrafine" particles have been associated with lower oropharyngeal impaction and similar lung deposition when inhaled with either slow or fast inhalation flow, and when actuation and inhalation were not completely coordinated. (21)

Oral inhalers: pMDI vs DPI

The pMDI is the most widely prescribed inhalation device for drug delivery to the respiratory tract to treat asthma (TABLE 3). The canister contains a pressurized suspension or solution of micronized drug particles dispersed in a propellant. A surfactant added to reduce particle agglomeration is also responsible for the characteristic taste of specific inhaler brands. (11) The operation of the pMDI requires pressing the bottom of the canister into the actuator which causes decompression of the formulation within the metering valve, resulting in an explosive generation of aerosol droplets that consist of tiny drug particles contained within a shell of propellant. (11)

A major barrier to effective delivery of medication with a pMDI is the difficulty to coordinate device actuation with inhalation and to maintain a slow rate of inhalation for as long as possible. This is a particular challenge for young children and the elderly. (11,22) To overcome this problem, breath-actuated pMDIs were developed. These devices contain a conventional pressurized canister and have a flow-triggered system driven by a spring, which releases the dose during inhalation, so that firing and inhaling are automatically coordinated. Use of a breath-actuated pMDI results in drug deposition in the lungs comparable to a traditional pMDI used with good coordination. (23) Results of a study in 102 elderly but cognitively intact patients indicate that breath-actuated pMDIs were significantly more likely to be used correctly than a traditional pMDI, plus a spacer. (24) Children and adults using a breath-actuated pMDI may have better asthma control than patients using a traditional pMDI. (25) No breath-activated pMDIs are currently available in the United States.

Dry powder inhalers are breath-actuated and require minimum patient coordination between breathing and actuation of the device to deliver powder medications. The dry powder is formulated either as loose agglomerates of micronized drug particles with aerodynamic particle sizes <5 [micro]m or as carrier-based interactive mixtures with micronized drug particles adherent to the surface of large lactose carriers. (11) The powder is aerosolized through the DPI device where drug particles are separated from the carrier or de-agglomerated. Powder formulation and design of DPI devices significantly affect performance. Higher air flow resistance inhalers are typically more effective in dispersing the dry power during inhalation and, therefore, provide greater lung deposition than lower internal resistance inhalers. Clinical experience shows that most patients can use a high-resistance DPI effectively, even during exacerbations. (11,19) Several studies have demonstrated fewer inhalation errors with DPIs compared with pMDIs. (22,26-28)

[FIGURE OMITTED]

In addition to the availability of breath-actuated devices, other advances are aimed to improve adherence, ease of use, or enhanced deposition of drug particles within the lung. Examples are meters that show how much medication is left and devices that provide feedback to the patient regarding administration technique. (11)

INDIVIDUALIZING THERAPY

An important factor to consider in selecting an oral or intranasal inhaler is patient preference, which can be classified in terms of operational use (eg, ease of learning to use, holding and operating, cleaning, etc), convenience (eg, size, shape, weight, etc) and oral sensation (eg, taste and irritation). Among these, the patient's ability to generate a sufficient (>30 L/min) inspiratory flow rate and to coordinate inhaler actuation and inspiration are critical (FIGURE). (1) For example, in patients with sufficient inspiratory flow but poor coordination, a traditional pMDI alone would not be sufficient and options would include a breath-actuated pMDI, a DPI, or a traditional pMDI with a spacer. Patients who cannot inhale medications consciously, such as elderly patients with cognitive limitations, may be limited to a traditional pMDI with a spacer or a nebulizer. (1) A traditional pMDI with a spacer may be preferred for children, particularly if younger than 7 years of age. (29) Younger patients may prefer smaller, more technical delivery systems while older or disabled patients may benefit from larger devices that can be handled more easily and have clearer displays and larger actuators. (10) Should a patient require more than 1 inhaler, it is suggested to use the same type of inhaler device.

SUMMARY

Inhaled medications are important treatment options for asthma and allergic rhinitis. Selecting among the different formulations and delivery devices is important as it impacts adherence and proper use, both of which affect health-related outcomes. The wide variety of inhalers now available allows individualizing inhaler selection.

Leonard Fromer, MD, FAAFP

Leonard Fromer, MD, FAAFP, Assistant Clinical Professor, Family Medicine, UCLA School of Medicine, Executive Medical Director, The Group Practice Forum, New York, NY

DISCLOSURES

Dr. Fromer discloses that he is on the speakers' bureau for Meda Pharmaceuticals Inc. and Thermo Fischer Scientific, Inc.

ACKNOWLEDGMENT

Editorial support was provided by Angela Cimmino, PharmD; Gregory Scott, PharmD, RPh.

SUPPORT

This article is sponsored by Primary Care Education Consortium and supported by funding from Teva Pharmaceuticals, USA, Inc.

REFERENCES

(1.) Dekhuijzen PN, Vincken W, Virchow JC, et al. Prescription of inhalers in asthma and COPD: towards a rational, rapid and effective approach. Respir Med. 2013;107(12): 1817-1821.

(2.) Lohia S, Schlosser RJ, Soler ZM. Impact of intranasal corticosteroids on asthma outcomes in allergic rhinitis: a meta-analysis. Allergy. 2013;68(5):569-579.

(3.) Meltzer EO, Blaiss MS, Derebery MJ, et al. Burden of allergic rhinitis: results from the Pediatric Allergies in America survey. J Allergy Clin Immunol. 2009; 124 (suppl 3):S43-S70.

(4.) Adams RJ, Fuhlbrigge AL, Finkelstein JA, Weiss ST. Intranasal steroids and the risk of emergency department visits for asthma. J Allergy Clin Immunol. 2002;109(4):636-642.

(5.) Crystal-Peters J, Neslusan C, Crown WH, Torres A. Treating allergic rhinitis in patients with comorbid asthma: the risk of asthma-related hospitalizations and emergency department visits .J Allergy Clin Immunol. 2002;109(l):57-62.

(6.) Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. http://www.ginasthma.org/local/uploads/files/GINA_Pocket_2015. pdf. Updated 2015. Accessed October 13, 2015.

(7.) Brozek JL, Bousquet J, Baena-Cagnani CE, et al; Global Allergy and Asthma European Network; Grading of Recommendations Assessment, Development and Evaluation Working Group. Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision. J Allergy Clin Immunol. 2010;126(3):466-476.

(8.) Wallace DV, Dykewicz MS, Bernstein DI, et al; Joint Task Force on Practice Parameters; American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. The diagnosis and management of rhinitis: an updated practice parameter [published correction appears in J Allergy Clin Immunol. 2008; 122(6): 1237]. J Allergy Clin Immunol. 2008;122(suppl 2):Sl-84.

(9.) Dolovich MB, Ahrens RC, Hess DR, et al; American College of Chest Physicians; American College of Asthma, Allergy, and Immunology. Device selection and outcomes of aerosol therapy: Evidence-based guidelines: American College of Chest Physicians/American College of Asthma, Allergy, and Immunology. Chest. 2005; 127(1):335-371.

(10.) Price D, Bosnic-Anticevich S, Briggs A, et al; Inhaler Error Steering Committee. Inhaler competence in asthma: common errors, barriers to use and recommended solutions. Respir Med. 2013;107(l):37-46.

(11.) Lavorini F, Fontana GA, Usmani OS. New inhaler devices - the good, the bad and the ugly. Respiration. 2014;88(1):3-15.

(12.) Lavorini F, Magnan A, Dubus JC, et al. Effect of incorrect use of dry powder inhalers on management of patients with asthma and COPD. Respir Med. 2008;102(4):593-604.

(13.) Giraud V, Roche N. Misuse of corticosteroid metered-dose inhaler is associated with decreased asthma stability. Eur Respir J. 2002;19(2):246-251.

(14.) Levy ML, Hardwell A, McKnight E, Holmes I. Asthma patients' inability to use a pressurised metered-dose inhaler (pMDI) correctly correlates with poor asthma control as defined by the global initiative for asthma (GINA) strategy: a retrospective analysis. Prim Care Respir J. 2013;22(4):406-411.

(15.) Berger WE, Meltzer EO. Intranasal spray medications for maintenance therapy of allergic rhinitis. Am J Rhinol Allergy. 2015;29(4):273-282.

(16.) Carr WW. New therapeutic options for allergic rhinitis: back to the future with intranasal corticosteroid aerosols. Am J Rhinol Allergy. 2013;27(4):309-313.

(17.) Meltzer EO, Bensch GW, Storms WW. New intranasal formulations for the treatment of allergic rhinitis. Allergy Asthma Proc. 2014;35(s uppl 1):S11-S19.

(18.) Laube BL, Janssens HM, de Jongh FH, et al; European Respiratory Society; International Society for Aerosols in Medicine. What the pulmonary specialist should know about the new inhalation therapies. Eur Respir J. 2011;37(6): 1308-1331.

(19.) Demoly P, Hagedoorn P, de Boer AH, Frijlink HW. The clinical relevance of dry powder inhaler performance for drug delivery. Respir Med. 2014;108(8):1195-1203.

(20.) Stoloff SW, Kelly HW. Updates on the use of inhaled corticosteroids in asthma. Curr Opin Allergy Clin Immunol. 2011; 11 (4):337-344.

(21.) Chrystyn H, Price D. Not all asthma inhalers are the same: factors to consider when prescribing an inhaler. Prim Care Respir I. 2009;18(4):243-249.

(22.) Aydemir Y. Assessment of the factors affecting the failure to use inhaler devices before and after training. Respir Med. 2015;109(4):451-458.

(23.) Leach CL, Davidson PI, Hasselquist BE, Boudreau RJ. Influence of particle size and patient dosing technique on lung deposition of HFA-beclomethasone from a metered dose inhaler. J Aerosol Med. 2005;18(4):379-385.

(24.) Jones V, Fernandez C, Diggory P. A comparison of large volume spacer, breath-activated and dry powder inhalers in older people. Age Ageing. 1999;28(5): 481-484.

(25.) Price D, Thomas M, Mitchell G, Niziol C, Featherstone R. Improvement of asthma control with a breath-actuated pressurised metred dose inhaler (BAI): a prescribing claims study of 5556 patients using a traditional pressurised metred dose inhaler (MDI) or a breath-actuated device. Respir Med. 2003;97(1):12-19.

(26.) Molimard M, Raherison C, Lignot S, Depont F, Abouelfath A, Moore N. Assessment of handling of inhaler devices in real life: an observational study in 3811 patients in primary care. J Aerosol Med. 2003;16(3):249-254.

(27.) Molimard M, Le G, V. Impact of patient-related factors on asthma control. J Asthma. 2008;45(2):109-113.

(28.) Schulte M, Osseiran K, Betz R, et al. Handling of and preferences for available dry powder inhaler systems by patients with asthma and COPD. J Aerosol Med Pulm Drug Delia 2008;21(4):321-328.

(29.) van Aalderen WM, Garcia-Marcos L, Gappa M, et al. How to match the optimal currently available inhaler device to an individual child with asthma or recurrent wheeze. NPJ Prim Care Respir Med. 2015;25:14088.
TABLE 1 Intranasal corticosteroids

Aqueous                                 Nonaqueous

Beclomethasone (Beconase AQ,            Beclomethasone
Vancenase AQ)                           (QNASL Nasal Aerosol)

Budesonide (Rhinocort Aqua)             Ciclesonide
                                        (Zetonna Nasal Aerosol)
Ciclesonide (Omnaris)

Flunisolide (Nasalide, Nasarel)

Fluticasone furoate (Veramyst)

Fluticasone propionate (Flonase)

Mometasone (Nasonex)

Triamcinolone (Nasacort AQ)

Fluticasone propionate/azelastine (a)
(Dymista)

(a) Combination corticosteroid and antihistamine.

Source: US Food and Drug Administration. Drugs@FDA.
www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

TABLE 2 Orally inhaled medications for asthma

Device             Generic name              Brand/device name
type/drug class

pMDIs (traditional)

[Beta.sub.2]-      Albuterol                 ProAir HFA; Proventil
adrenergic                                   HFA; Ventolin HFA;
agonists                                     Xopenex HFA

Corticosteroids    Beclomethasone HFA        QVAR

                   Ciclesonide               Alvesco

                   Flunisolide HFA           Aerospan

                   Fluticasone propionate    Flovent HFA

                   Mometasone furoate        Asmanex HFA

Combinations       Budesonide/formoterol     Symbicort

                   Fluticasone               Advair HFA
                   propionate/salmeterol

                   Mometasone                Dulera
                   furoate/formoterol

BA-pMDIs

[Beta.sub.2]-      None in the US
adrenergic
agonists

Corticosteroids    None in the US

DPIs

[Beta.sub.2]-      Albuterol                 ProAir RespiClick
adrenergic
agonists

                   Formoterol                Foradil Aerolizer

                   Salmeterol                Serevent Diskus

Corticosteroids    Budesonide                Pulmicort Flexhaler

                   Fluticasone propionate    Flovent Diskus

                   Fluticasone furoate       Arnuity Ellipta

                   Mometasone furoate        Asmanex Twisthaler

Combinations       Fluticasone               Breo Ellipta
                   furoate/vilanterol

                   Fluticasone               Advair Diskus
                   propionate/salmeterol

Device             Comments
type/drug class

pMDIs (traditional)

[Beta.sub.2]-      SABA
adrenergic
agonists

Corticosteroids    Emits ultra-fine particles

                   Emits ultra-fine particles

Combinations       corticosteroid/LABA

                   corticosteroid/LABA

                   corticosteroid/LABA

BA-pMDIs

[Beta.sub.2]-
adrenergic
agonists

Corticosteroids

DPIs

[Beta.sub.2]-      SABA
adrenergic
agonists

                   LABA; low resistance DPI

                   LABA; medium resistance DPI

Corticosteroids

                   medium resistance DPI

                   high resistance DPI

Combinations       corticosteroid/LABA

                   corticosteroid/LABA; medium resistance DPI

Abbreviations: BA-pMDI, breath-activated pMDI; DPI, dry powder
inhaler; HFA, hydrofluoroalkane; LABA, long-acting [beta.sub.2]-
agonist; pMDI, pressurized metered dose inhaler; SABA, short-
acting [beta.sub.2]-agonist.

Source: US Food and Drug Administration. Drugs@FDA.
www.accessdata.fda.gov/soripts/cder/drugsatfda/index.cfm.

TABLE 3 Advantages and disadvantages of inhaler devices (18)

Type          Advantages                   Disadvantages

HFA-pMDIs     * Portable and compact       * Coordination of
(suspension                                actuation and inhalation
and           * No contamination risk      needed
solution)
              * High reproducibility       * Most patients inhale too
              between doses                fast

                                           * Low lung deposition and
                                           high oropharyngeal
                                           deposition

                                           * Important to prime
                                           before use if new or not
                                           used in some time, and to
                                           shake before use

                                           * Must be kept upright
                                           during inhalation

                                           * With most devices, the
                                           number of doses remaining
                                           is difficult to determine;
                                           not all pMDIs have dose
                                           counters

HFA-pMDIs     * As above for pMDIs         * Only two corticosteroid
(extra-fine                                products available
particles)    * Higher lung deposition     (QVAR and Alvesco)
              and lower oropharyngeal
              deposition, compared with
              pMDIs that are used alone

              * Good for inhaled
              corticosteroids

              * Corticosteroid dose
              should be halved if
              prescribed for patients
              previously using other
              traditional corticosteroid
              pMDI

              * Optimal inhalation
              technique less important
              than with traditional
              pMDIs

pMDI +        * Less need for              * More expensive and less
spacer        coordination of actuation    portable than a pMDI alone
              and inhalation compared
              with a pMDI alone            * Prone to reduced or
                                           inconsistent dosing
              * Reduced oropharyngeal      because of electrostatic
              deposition compared with a   charge associated with
              pMDI alone                   plastic spacers

              * Improves lung deposition   * Special washing
              if this is poor with pMDI    instructions
              alone
                                           * Some patients find
              * Useful for maintaining     inhalation with a spacer
              efficient drug delivery      more complex and dose
              during acute exacerbations   delivered may be lower if
                                           not used correctly
              * Can use tidal breathing
              if the spacer has a valve    * Some children like to
                                           make the noise, and if
              * Some spacers make a        they do, they will be
              noise to indicate that the   inhaling too fast
              inhalation flow is too
              fast

BA-pMDIs      * May be useful for          * Patients sometimes stop
              patients who cannot          inhaling once actuation
              coordinate inhalation and    occurs
              actuation; may be useful
              for the elderly              * Can only be used with a
                                           drug that is dispensed
              * Should not be used with    with the device; no
              a spacer                     substitutions

DPIs          * Portable and compact;      * Single-dose devices
              many are multi-dose          require repeat loading.
                                           which can lead to error;
              * Some are single-dose       two separate inhalations
              with doses kept separately   are required for each dose
              in sealed package
                                           * DPI delivery can result
              * Breath-actuated, so no     in high oropharyngeal
              need to coordinate actua-    deposition because a
              tion and inhalation, which   forceful inhalation is
              is required with a pMDI      needed to aerosolize the
                                           particles
              * Most multi-dose devices
              have a dose counter          * Flow-dependent dose
                                           emission for some designs;
                                           poor quality (or no) dose
                                           emitted if inspiratory
                                           flow is too slow

                                           * Patients need to exhale
                                           into the room to func-
                                           tional residual capacity
                                           before inhaling from the
                                           DPI; patients should not
                                           exhale into the device
                                           once the dose has been
                                           prepared for inhalation,
                                           or the dose could be blown
                                           out of the devices

                                           * Must be upright when
                                           preparing the dose for
                                           inhalation; must be kept
                                           upright or turned hori-
                                           zontally for inhalation

                                           * Need to be stored in
                                           cool, dry place

Abbreviations: BA-pMDI, breath-activated pMDI; DPI, dry powder
inhaler; HFA, hydrofluoroalkane; pMDI, pressurized metered dose
inhaler.

Adapted by permission from Macmillan Publishers Ltd: Primary Care
Respiratory Journal, Chrystyn H, Price D, Not all asthma inhalers
are the same: factors to consider when prescribing an inhaler,
2009;18(4):243-249, copyright 2009.
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Title Annotation:Hot Topics in Primary Care
Author:Fromer, Leonard
Publication:Journal of Family Practice
Article Type:Clinical report
Geographic Code:1USA
Date:Dec 1, 2015
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