· Consider drugs used to treat asthmatic patients including long-term control and quick relief treatment options for patients. Think about the impact these drugs might have on patients including adults and children.

FIGURE 4–7. ASSESSING ASTH MA CONTROL AN D ADJUSTING THERAPY IN YOUTHS ≥ 12 YEARS OF AGE AND ADULTS  0−1/year ≥2/year (see note) • Consider short course of oral systemic corticosteroids, • Step up 1−2 steps, and • Reevaluate in 2 weeks. • For side effects, consider alternative treatment options. • Step up 1 step and • Reevaluate in 2−6 weeks. • For side effects, consider alternative treatment options. • Maintain current step. • Regular followups every 1−6 months to maintain control. • Consider step down if well controlled for at least 3 months. Recommended Action for Treatment (see figure 4−5 for treatment steps) Evaluation requires long-term followup care Medication side effects can vary in intensity from none to very troublesome and worrisome. The level of intensity does not correlate to specific levels of control but should be considered in the overall assessment of risk. Treatment-related adverse effects Risk Progressive loss of lung function Validated questionnaires Symptoms ≤2 days/week >2 days/week Throughout the day Impairment 3–4 N/A ≤15 1–2 ≥1.5 16−19 0 ≤0.75* ≥20 ATAQ ACQ ACT <60% predicted/ personal best 60−80% predicted/ personal best >80% predicted/ personal best FEV1 or peak flow Short-acting beta ≤2 days/week >2 days/week Several times per day 2-agonist use for symptom control (not prevention of EIB) Consider severity and interval since last exacerbation Exacerbations requiring oral systemic corticosteroids Classification of Asthma Control (≥12 years of age) Components of Control Interference with normal activity None Some limitation Extremely limited Nighttime awakenings ≤2x/month 1−3x/week ≥4x/week Very Poorly Controlled Not Well Controlled Well Controlled — *ACQ values of 0.76–1.4 are indeterminate regarding well-controlled asthma. — Key: EIB, exercise-induced bronchospasm; ICU, intensive care unit Notes:  The stepwise approach is meant to assist, not replace, the clinical decisionmaking required to meet individual patient needs.  The level of control is based on the most severe impairment or risk category. Assess impairment domain by patient’s recall of previous 2–4 weeks and by spirometry/or peak flow measures. Symptom assessment for longer periods should reflect a global assessment, such as inquiring whether the patient’s asthma is better or worse since the last visit.  At present, there are inadequate data to correspond frequencies of exacerbations with different levels of asthma control. In general, more frequent and intense exacerbations (e.g., requiring urgent, unscheduled care, hospitalization, or ICU admission) indicate poorer disease control. For treatment purposes, patients who had ≥2 exacerbations requiring oral systemic corticosteroids in the past year may be considered the same as patients who have not-well-controlled asthma, even in the absence of impairment levels consistent with not-well-controlled asthma.  Validated Questionnaires for the impairment domain (the questionnaires do not assess lung function or the risk domain) ATAQ = Asthma Therapy Assessment Questionnaire© (See sample in “Component 1: Measures of Asthma Assessment and Monitoring.”) ACQ = Asthma Control Questionnaire© (user package may be obtained at www.qoltech.co.uk or juniper@qoltech.co.uk) ACT = Asthma Control Test™ (See sample in “Component 1: Measures of Asthma Assessment and Monitoring.”) Minimal Important Difference: 1.0 for the ATAQ; 0.5 for the ACQ; not determined for the ACT.  Before step up in therapy: — Review adherence to medication, inhaler technique, environmental control, and comorbid conditions. — If an alternative treatment option was used in a step, discontinue and use the preferred treatment for that step. Section 4, Managing Asthma Long Term—Youths ≥12 Years of Age and Adults 346 August 28, 2007 FIGURE 4–8a. USUAL DOSAGE S FOR LONG-TERM CONTROL MEDICATIONS FOR YOUTHS ≥ 12 YEARS OF AGE AND ADULTS Medication Dosage Form Adult Dose Comments Inhaled Corticosteroids (ICS) (See figure 4–8b, “Estimated Comparative Daily Dosages for Inhaled Corticosteroids.”) Systemic Corticosteroids (Applies to all three corticosteroids) Methylprednisolone 2, 4, 8, 16, 32 mg tablets Prednisolone 5 mg tablets, 5 mg/5 cc, 15 mg/5 cc Prednisone 1, 2.5, 5, 10, 20, 50 mg tablets; 5 mg/cc, 5 mg/5 cc 7.5–60 mg daily in a single dose in a.m. or qod as needed for control Short-course “burst”: to achieve control, 40–60 mg per day as single or 2 divided doses for 3– 10 days  For long-term treatment of severe persistent asthma, administer single dose in a.m. either daily or on alternate days (alternate-day therapy may produce less adrenal suppression). Short courses or “bursts” are effective for establishing control when initiating therapy or during a period of gradual deterioration.  There is no evidence that tapering the dose following improvement in symptom control and pulmonary function prevents relapse. Inhaled Long-Acting Beta2-Agonists (LABA)  Should not be used for symptom relief or exacerbations. Use with ICS. Salmeterol DPI 50 mcg/ blister 1 blister q 12 hours  Decreased duration of protection against EIB may occur with regular use. Formoterol DPI 12 mcg/ single-use capsule 1 capsule q 12 hours  Each capsule is for single use only; additional doses should not be administered for at least 12 hours.  Capsules should be used only with the Aerolizor™ inhaler and should not be taken orally. Combined Medication Fluticasone/Salmeterol DPI 100 mcg/50 mcg, 250 mcg/50 mcg, or 500 mcg/50 mcg HFA 45 mcg/21 mcg 115 mcg/21 mcg 230 mcg/21 mcg 1 inhalation bid; dose depends on severity of asthma  100/50 DPI or 45/21 HFA for patient not controlled on low- to medium-dose ICS 250/50 DPI or 115/21 HFA for patients not controlled on medium- to high-dose ICS Budesonide/ Formoterol HFA MDI 80 mcg/4.5 mcg 160mcg/4.5 mcg 2 inhalations bid; dose depends on severity of asthma  80/4.5 for patients who have asthma not controlled on low- to mediumdose ICS  160/4.5 for patients who have asthma not controlled on medium- to highdose ICS  Section 4, Managing Asthma Long Term—Youths ≥12 Years of Age and Adults 347 August 28, 2007 FIGURE 4–8a. USUAL DOSAGE S FOR LONG-TERM CONTROL MEDICATIONS FOR YOUTHS ≥ 12 YEARS OF AGE AND ADULTS (CONTINUED) Medication Dosage Form Adult Dose Comments Cromolyn and Nedocromil MDI 0.8 mg/puff Cromolyn 2 puffs qid Nebulizer 20 mg/ampule 1 ampule qid Nedocromil MDI 1.75 mg/puff 2 puffs qid  4–6 week trial may be needed to determine maximum benefit.  Dose by MDI may be inadequate to affect hyperresponsiveness.  One dose before exercise or allergen exposure provides effective prophylaxis for 1–2 hours. Not as effective for EIB as SABA.  Once control is achieved, the frequency of dosing may be reduced. Leukotriene Modifiers Leukotriene Receptor Antagonists Montelukast 4 mg or 5 mg chewable tablet 10 mg tablet 10 mg qhs  Montelukast exhibits a flat doseresponse curve. Doses >10 mg will not produce a greater response in adults. Zafirlukast 10 or 20 mg tablet 40 mg daily (20 mg tablet bid)  For zafirlukast, administration with meals decreases bioavailability; take at least 1 hour before or 2 hours after meals.  Monitor for signs and symptoms of hepatic dysfunction. 5-Lipoxygenase Inhibitor Zileuton 600 mg tablet 2,400 mg daily (give tablets qid)  For zileuton, monitor hepatic enzymes (ALT). Methylxanthines Theophylline Liquids, sustainedrelease tablets, and capsules Starting dose 10 mg/ kg/day up to 300 mg maximum; usual maximum 800 mg/day  Due to wide interpatient variability in theophylline metabolic clearance, routine serum theophylline level monitoring is important.  See next page for factors that can affect theophylline levels. Immunomodulators Omalizumab Subcutaneous injection, 150 mg/1.2 mL following reconstitution with 1.4 mL sterile water for injection 150–375 mg SC q 2–4 weeks, depending on body weight and pretreatment serum IgE level  Do not administer more than 150 mg per injection site.  Monitor for anaphylaxis for 2 hours following at least the first 3 injections. Key: DPI, dry powder inhaler; EIB, exercise-induced bronchospasm; HFA, hydrofluoroalkane; IgE, immunoglobulin E; MDI, metered-dose inhaler; SABA, short-acting beta2-agonist Adjust dosage to achieve serum concentration of 5–15 mcg/mL at steady-state (at least 48 hours on same dosage).  Section 4, Managing Asthma Long Term—Youths ≥12 Years of Age and Adults 348 August 28, 2007 FIGURE 4–8a. USUAL DOSAGE S FOR LONG-TERM CONTROL MEDICATIONS FOR YOUTHS ≥ 12 YEARS OF AGE AND ADULTS (CONTINUED) Factors Affecting Serum Theophylline Concentrations* Factor Decreases Theophylline Concentrations Increases Theophylline Concentrations Recommended Action Food È or delays absorption of some sustained-release theophylline (SRT) products Ç rate of absorption (fatty foods) Select theophylline preparation that is not affected by food. Diet Ç metabolism (high protein) È metabolism (high carbohydrate) Inform patients that major changes in diet are not recommended while taking theophylline. Systemic, febrile viral illness (e.g., influenza) È metabolism Decrease theophylline dose according to serum concentration. Decrease dose by 50 percent if serum concentration measurement is not available. Hypoxia, cor pulmonale, and decompensated congestive heart failure, cirrhosis È metabolism Decrease dose according to serum concentration. Age Ç metabolism (1–9 years) È metabolism (<6 months, elderly) Adjust dose according to serum concentration. Phenobarbital, phenytoin, carbamazepine Ç metabolism Increase dose according to serum concentration. Cimetidine È metabolism Use alternative H2 blocker (e.g., famotidine or ranitidine). Macrolides: erythromycin, clarithromycin, troleandomycin È metabolism Use alternative macrolide antibiotic, azithromycin, or alternative antibiotic or adjust theophylline dose. Quinolones: ciprofloxacin, enoxacin, perfloxacin È metabolism Use alternative antibiotic or adjust theophylline dose. Circumvent with ofloxacin if quinolone therapy is required. Rifampin Ç metabolism Increase dose according to serum concentration. Ticlopidine È metabolism Decrease dose according to serum concentration. Smoking Ç metabolism Advise patient to stop smoking; increase dose according to serum concentration. *This list is not all inclusive; for discussion of other factors, see package inserts.  Section 4, Managing Asthma Long Term—Youths ≥12 Years of Age and Adults 349 August 28, 2007 FIGURE 4–8b. ESTIMATED CO MPARATIVE DAILY DOSAGES FOR INHALED CORTICOSTEROIDS FOR YOUTHS ≥ 12 YEARS OF AGE AND ADULTS Drug Low Daily Dose Medium Daily Dose High Daily Dose Adult Adult Adult Beclomethasone HFA 40 or 80 mcg/puff 80–240 mcg >240–480 mcg >480 mcg Budesonide DPI 90, 180, or 200 mcg/inhalation 180–600 mcg >600–1,200 mcg >1,200 mcg Flunisolide 250 mcg/puff 500–1,000 mcg >1,000–2,000 mcg >2,000 mcg Flunisolide HFA 80 mcg/puff 320 mcg >320–640 mcg >640 mcg Fluticasone HFA/MDI: 44, 110, or 220 mcg/puff 88–264 mcg >264–440 mcg >440 mcg DPI: 50, 100, or 250 mcg/inhalation 100–300 mcg >300–500 mcg >500 mcg Mometasone DPI 200 mcg/inhalation 200 mcg 400 mcg >400 mcg Triamcinolone acetonide 75 mcg/puff 300–750 mcg >750–1,500 mcg >1,500 mcg Key: DPI, dry powder inhaler; HFA, hydrofluoroalkane; MDI, metered-dose inhaler Notes:  The most important determinant of appropriate dosing is the clinician’s judgment of the patient’s response to therapy. The clinician must monitor the patient’s response on several clinical parameters and adjust the dose accordingly. The stepwise approach to therapy emphasizes that once control of asthma is achieved, the dose of medication should be carefully titrated to the minimum dose required to maintain control, thus reducing the potential for adverse effect.  Some doses may be outside package labeling, especially in the high-dose range.  MDI dosages are expressed as the actuator dose (the amount of the drug leaving the actuator and delivered to the patient), which is the labeling required in the United States. This is different from the dosage expressed as the valve dose (the amount of drug leaving the valve, not all of which is available to the patient), which is used in many European countries and in some scientific literature. DPI doses are expressed as the amount of drug in the inhaler following activation.  Comparative dosages are based on published comparative clinical trials (Adams et al. 2005; Barnes et al. 1998; Kelly 1998; Lasserson et al. 2005; Pedersen and O’Byrne 1997). The rationale for some key comparisons is summarized as follows: — The high dose is the dose that appears likely to be the threshold beyond which significant hypothalamic-pituitaryadrenal (HPA) axis suppression is produced, and, by extrapolation, the risk is increased for other clinically significant systemic effects if used for prolonged periods of time (Martin et al. 2002; Szefler et al. 2002). — The low- and medium-doses reflect findings from dose-ranging studies in which incremental efficacy within the low- to medium-dose ranges was established without increased systemic effect as measured by overnight cortisol excretion. The studies demonstrated a relatively flat dose-response curve for efficacy at the medium-dose range; that is, increasing the dose of high-dose range did not significantly increase efficacy but did increase systemic effect (Adams et al. 2001; Martin et al. 2002; Szefler et al. 2002). — The dose for budesonide and fluticasone MDI or DPI are based on recently available comparative data. These new data, including meta-analyses, show that fluticasone requires one-half the microgram dose of budesonide DPI to achieve comparable efficacy (Adams et al. 2005; Barnes et al. 1998; Nielsen and Dahl 2000). Section 4, Managing Asthma Long Term—Youths ≥12 Years of Age and Adults 350 August 28, 2007 FIGURE 4–8b. ESTIMATED CO MPARATIVE DAILY DOSAGES FOR INHALED CORTICOSTEROIDS FOR YOUTHS ≥ 12 YEARS OF AGE AND ADULTS (CONTINUED) — The dose for beclomethasone in HFA inhaler should be approximately one-half the dose for beclomethasone in chlorofluorocarbon (CFC) inhaler for adults and children, based on studies demonstrating that the different pharmaceutical properties of the medications result in enhanced lung delivery for the HFA (a less forceful spray from the HFA propellant and a reengineered nozzle that allows a smaller particle size) and clinical trials demonstrating similar potency to fluticasone at 1:1 dose ratio (Boulet et al. 2004; Busse et al. 1999; Gross et al. 1999; Lasserson et al. 2005; Leach et al. 1998; Pedersen et al. 2002; Szefler et al. 2002; Thompson et al. 1998). — The dose for mometasone DPI is based on product information and current literature (Bousquet et al. 2000; Fardon et al. 2004; Kemp et al. 2000; O’Connor et al. 2001). Mometasone is approved for once daily administration. Mometasone furoate by dry powder achieved effects similar to twice the dose of budesonide by dry powder (Bousquet et al. 2000) and comparable to a slightly higher dose of fluticasone propionate by dry powder (O’Connor et al. 2001). — The dose for flunisolide HFA is based on product information and current literature (Corren et al. 2001; Gillman et al. 2002; Richards et al. 2001).  Bioavailability Both the relative potency and the relative bioavailability (systemic availability) determine the potential for systemic activity of an ICS preparation. As illustrated here, the bioavailability of an ICS is dependent on the absorption of the dose delivered to the lungs and the oral bioavailability of the swallowed portion of the dose received. — Absorption of the dose delivered to the lungs: ♦ Approximately 10–50 percent of the dose from the MDI is delivered to the lungs. This amount varies among preparations and delivery devices. ♦ Nearly all of the amount delivered to the lungs is bioavailable. — Oral bioavailability of the swallowed portion of the dose received: ♦ Approximately 50–80 percent of the dose from the MDI without a spacer/holding chamber is swallowed. ♦ The oral bioavailability of this amount varies: Either a high first-pass metabolism or the use of a spacer/holding chamber with an MDI can decrease oral bioavailability, thus enhancing safety (Lipworth 1995). The approximate oral bioavailability of ICSs has been reported as: beclomethasone dipropionate 20 percent; flunisolide, 21 percent; triamcinolone acetonide, 10.6 percent; budesonide, 11 percent; fluticasone propionate, 1 percent; mometasone, <1 percent (Affrime et al. 2000; Chaplin et al. 1980; Check and Kaliner 1990; Clissold and Heel 1984; Davies 1993; Harding 1990; Heald et al. 1995; Martin et al. 1974; Mollmann et al. 1985; Szefler 1991; Wurthwein and Rohdewald 1990).  Potential drug interactions A number of the ICSs, including fluticasone, budesonide, and mometasone, are metabolized in the gastrointestinal tract and liver by CYP 3A4 isoenzymes. Potent inhibitors of CYP 3A4, such as ritonavir and ketoconazole, have the potential for increasing systemic concentrations of these ICSs by increasing oral availability and decreasing systemic clearance. Some cases of clinically significant Cushing syndrome and secondary adrenal insufficiency have been reported (Johnson et al. 2006; Samaras et al. 2005). Inactivation in the liver or gut wall “first pass” Inactivation in gut Section 4, Managing Asthma Long Term—Youths ≥12 Years of Age and Adults 351 August 28, 2007 FIGURE 4–8c.USUAL DOSAGES FOR QUICK-RELIEF MEDICATIONS FOR YOUTHS ≥ 12 YEARS OF AGE AND ADULTS Medication Dosage Form Adult Dose Comments Inhaled Short-Acting Beta2-Agonists (SABA) MDI Applies to all four SABAs Albuterol CFC 90 mcg/puff, 200 puffs/canister Albuterol HFA 90 mcg/puff, 200 puffs/canister Pirbuterol CFC 200 mcg/puff, 400 puffs/canister Levalbuterol HFA 45 mcg/puff, 200 puffs/canister  2 puffs 5 minutes before exercise  2 puffs every 4–6 hours as needed  An increasing use or lack of expected effect indicates diminished control of asthma.  Not recommended for long-term daily treatment. Regular use exceeding 2 days/week for symptom control (not prevention of EIB) indicates the need to step up therapy.  Differences in potency exist, but all products are essentially comparable on a per puff basis.  May double usual dose for mild exacerbations.  Should prime the inhaler by releasing 4 actuations prior to use.  Periodically clean HFA activator, as drug may block/plug orifice.  Nonselective agents (i.e., epinephrine, isoproterenol, metaproterenol) are not recommended due to their potential for excessive cardiac stimulation, especially in high doses. Nebulizer solution Albuterol 0.63 mg/3 mL 1.25 mg/3 mL 2.5 mg/3 mL 5 mg/mL (0.5%) 1.25–5 mg in 3 cc of saline q 4–8 hours as needed  May mix with budesonide inhalant suspension, cromolyn or ipratropium nebulizer solutions. May double dose for severe exacerbations. Levalbuterol (R-albuterol) 0.31 mg/3 mL 0.63 mg/3 mL 1.25 mg/0.5 mL 1.25 mg/3 mL 0.63 mg–1.25 mg q 8 hours as needed  Compatible with budesonide inhalant suspension. The product is a sterilefilled, preservative-free, unit dose vial.  Section 4, Managing Asthma Long Term—Youths ≥12 Years of Age and Adults 352 August 28, 2007 FIGURE 4–8c. USUAL DOSAGES FOR QUICK-RELIEF MEDICATIONS FOR YOUTHS ≥ 12 YEARS OF AGE AND ADULTS (CONTINUED) Medication Dosage Form Adult Dose Comments Anticholinergics MDI Ipratropium HFA 17 mcg/puff, 200 puffs/canister 2–3 puffs q 6 hours Nebulizer solution 0.25 mg/mL (0.025%) 0.25 mg q 6 hours  Evidence is lacking for anticholinergics producing added benefit to beta2-agonists in long-term control asthma therapy. MDI Ipratropium with albuterol 18 mcg/puff of ipratropium bromide and 90 mcg/puff of albuterol 2–3 puffs q 6 hours 200 puffs/canister Nebulizer solution 0.5 mg/3 mL ipratropium bromide and 2.5 mg/3 mL albuterol 3 mL q 4–6 hours  Contains EDTA to prevent discoloration of the solution. This additive does not induce bronchospasm. Systemic Corticosteroids Applies to the first three corticosteroids Methylprednisolone 2, 4, 6, 8, 16, 32 mg tablets  Short course “burst”: 40–60 mg/day as single or 2 divided doses for 3–10 days  Short courses or “bursts” are effective for establishing control when initiating therapy or during a period of gradual deterioration. Prednisolone 5 mg tablets, 5 mg/5 cc, 15 mg/5 cc Prednisone 1, 2.5, 5, 10, 20, 50 mg tablets; 5 mg/cc, 5 mg/5 cc  The burst should be continued until symptoms resolve and the PEF is at least 80 percent of personal best. This usually requires 3–10 days but may require longer. There is no evidence that tapering the dose following improvement prevents relapse. Repository injection (Methylprednisolone acetate) 40 mg/mL 80 mg/mL 240 mg IM once  May be used in place of a short burst of oral steroids in patients who are vomiting or if adherence is a problem. Key: CFC, chlorofluorocarbon; EIB, exercise-induced bronchospasm; HFA, hydrofluoroalkane; IM, intramuscular; MDI,

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