P&T News: September 1995, Vol. 16, No. 3
Elizabeth A. Beltz, Pharm.D.
Peer Review Status: Internally Peer Reviewed by Joel N.
Kline, M.D., Assistant Professor, Division of Pulmonary Disease,
Department of Internal Medicine
Although mortality from asthma is relatively uncommon, the rate of mortality is on the rise. There were 4360 deaths from asthma in the U.S. in 1987, which was 31% more than in 1980.1 Increases in mortality have also been reported in Canada, Australia, England and Wales, and Denmark.3,4 The reasons for these increases in mortality are unknown, but some associations have been made. An increase in deaths in patients over 55 years old may simply be a result of the aging population as a whole. Increased mortality among blacks in the U.S. may be a result of lack of access to medical care.4 Inadequate patient education, lack of a timely diagnosis of asthma, and/or undertreatment of diagnosed asthma may also contribute to deaths.3-5 An increase in reporting asthma deaths or changes in the way asthma deaths are coded by the International Classification of Diseases (ICD-9) have also been implicated in this rise in mortality.3
The Role of Inhaled Beta Agonists in Asthma Therapy
Beta adrenergic-agonists stimulate beta-2 adrenergic receptors in
smooth airway muscles with resultant bronchodilation. Bronchodilation
improves the airflow obstruction that occurs in asthma and may also
facilitate expectoration of secretions. Stimulation of
beta-adrenergic receptors on mast cells inhibits the secretion of
inflammatory mediators. Effects on beta-1 receptors may produce
undesirable effects such as tachycardia and palpitations. To minimize
these effects, agents with more beta-2 receptor selectivity, such as
albuterol, are frequently prescribed, and these drugs are
administered by inhalation rather than orally (Table 1). Inhaled
therapy also has a more rapid onset of action than oral therapy. l
There has been a great deal of interest in the potential contribution that the use of inhaled beta-2 agonists may have on mortality associated with asthma. Areas of controversy include whether inhaled beta-2 agonists should be given on a regular schedule or only on an as-needed basis, and whether long-acting inhaled beta-2 agonists such as salmeterol are safe for routine therapy.
Inhaled beta-2 agonists are considered first-line therapy for the treatment of acute asthma symptoms. l Beta-2 agonists used for this indication should be short-acting (such as albuterol) and have a quick onset of action (minutes). Patients who have frequent symptoms (e.g., more than two times per week) also require preventive therapy. l Preventive therapy usually consists of an anti-inflammatory agent such as inhaled corticosteroids or cromolyn, although theophylline or regularly administered inhaled beta-2 agonists may also be used. Short-acting beta-2 agonists have a duration of up to 4 to 6 hours. Therefore, when they are used for maintenance therapy, patients may have breakthrough symptoms, especially at the end of the night, when bronchoconstriction may be most severe.6
|
Table 1. Inhaled Beta Agonists Stocked at UIHC | ||
|
BETA AGONIST |
DOSE |
RECEPTOR ACTIVITY |
|
Albuterol MDI |
2 puffs q4-6hrs |
beta-2 > > beta-1 |
|
Epinephrine MDI |
1-2 puffs prn |
alpha, beta-l and 2 |
|
Isoproterenol MDI |
1-2 puffs q4-6hrs |
beta-1 and beta-2 |
|
Metaproterenol MDI |
2-3 puffs q3-4hrs |
beta-2 > beta-1 |
|
Salmeterol MDI |
2 puffs ql2hrs |
beta-2 > > beta-1 |
|
Terbutaline MDI |
2 puffs q4-6hrs |
beta-2 > > beta-1 |
|
MDI = Metered dose inhaler |
|
|
Epidemiologic Safety Studies
The suggestion that inhaled beta-2 agonists may worsen asthma and
increase mortality associated with this disease is not new. In the
1960s an association was found between increased asthma mortality and
the use of Isoprenaline "Forte(D" metered dose inhaler, a
high-potency isoproterenol product that was never released in the
U.S.7
Fenoterol Studies
More recently, a group in New Zealand published three case control
studies that examined the hypothesis that fenoterol (a beta-agonist
not available in the U.S.) increases the risk of death in patients
with asthma.7~9 The case groups were patients between the ages of 5
and 45 years who died of asthma. The first study looked at deaths
between August 1981 and July 1983; the second study looked at deaths
between 1977 and 1981; and the third study covered the years 1981 to
1987. In all three studies, four controls (asthma admissions to the
hospital to which the case patient would have been admitted had he or
she survived) were matched to each case.
All three studies found an increased risk of mortality in patients who had received a prescription for fenoterol. Three subgroups of patients with markers which may indicate more severe asthma had an even greater risk of mortality. The three groups included: patients who had three or more categories of asthma drugs prescribed; patients with a documented hospital admission for asthma within the previous 12 months; or patients who were prescribed oral corticosteroids. The greatest risk was found with patients who had a hospital admission during the previous 12 months and had received a prescription for oral corticosteroids. Both of these markers could be indicative of someone with severe asthma.
The authors concluded in all three studies that the use of inhaled fenoterol increased the risk of death in patients with severe asthma. They attempted to better control for severity of asthma between case patients and their controls in the second study by using controls who had been hospitalized for asthma in the previous 12 months. In the third study they used two control groups, one group included patients with a previous hospitalization for asthma in the preceding 12 months and one without. Despite these modifications, there are at least two major problems with these studies. First, the studies were retrospective and the information was retrieved from many different sources by different individuals. Secondly, the studies only examined prescribed medications and made no attempt to ascertain compliance with prescribed regimens, particularly how much fenoterol was actually administered.
A Saskatchewan epidemiology study was published in 1992 by Spitzer et al.10 They matched 129 case patients who had experienced fatal or near-fatal asthma events with 655 controls who had received medications for asthma, but had not had fatal or near-fatal events. They were matched for region of residence, age, receipt of social assistance, and previous hospitalizations for asthma. They found an increased risk of death or near-death from asthma associated with beta-2 agonists, especially fenoterol; although, when analyzed for death alone, there was no difference between fenoterol and albuterol. The risk increased as the number of canisters dispensed to the patient over a 12-month period increased. There was also an increased risk seen with administration of theophylline and oral corticosteroids. This study did look at amount of drugs dispensed, but as with the New Zealand studies, actual patient compliance was not ascertained. The fact that an increased risk was also found with theophylline and oral corticosteroid usage may indicate that the risk of death or near-death is related more to the severity of the asthma rather than the medications administered.
It is not possible to draw specific conclusions from either the New Zealand studies or the Saskatchewan study since specifics are not known about medication compliance. A placebo-controlled, cross-over study was conducted by Sears et al comparing regular versus on-demand inhaled fenoterol.11 Based on morning and evening peak expiratory flow rate, symptom diaries, use of additional inhaled bronchodilators, and need for short courses of prednisone, 70% of the 64 patients had better control with on-demand inhaled fenoterol during a six month period than with scheduled fenoterol given four times daily for six months. Mean airway responsiveness to methacholine challenge increased slightly during the fenoterol period. The authors concluded that regular inhalation of a beta-2 agonist was associated with deterioration of asthma control, regardless of concomitant therapy. Although other investigators have shown similar results with terbutaline,l2nl3 and with albuterol or ipratropium bromide,l4 critics argue that assumptions made by Sears et al, as well as by other investigators, are incorrect.
Other Beta-2 Agonist Studies
Caution should be exercised when extrapolating these studies done
with fenoterol to all beta-2 agonists.15 Fenoterol is a more potent
agent than albuterol, yet it is marketed in doses two times higher
than albuterol and has been shown to have a higher incidence of
adverse effects, including tachycardia and hypokalemia, than
albuterol or terbutaline at doses that provide similar
bronchodilation.16 These effects alone could contribute to increased
morbidity or mortality. In addition, the results of the study by
Sears et al have not been reproduced by all investigators.l7sl8
Another important issue is whether these results may be extrapolated to agents which are commonly used in the U.S. such as albuterol. The New Zealand studies did not show the same risk of mortality with albuterol as with fenoterol. The Sasketchewan study did show an increased risk of morbidity and mortality with albuterol, although the odds ratio was half that for fenoterol.
As a follow-up to their earlier three studies, the authors who reported the New Zealand data conducted a case-control study to determine whether there was an association with asthma mortality and albuterol.l9 They examined 17 deaths from asthma between 1969 and 1976, the first years after albuterol was introduced, hypothesizing that if the association between fenoterol and asthma deaths occurred because patients with unstable asthma were switched to fenoterol after it was introduced in 1976, a similar pattern would have occurred after albuterol was introduced in 1969. They used two groups of controls as they had in their third study.9 The same association was not found between albuterol and deaths from asthma as was with fenoterol, but the authors cautioned that the very small number of evaluable cases (17) made it difficult to draw conclusions from the study.
Morbidity/Mortality Risks Associated with Beta-2 Agonist
Use
Recently, Pearce et al, reported that since the New Zealand
Department of Health issued warnings about the safety of fenoterol
and limited its availability, the asthma mortality rates in New
Zealand have decreased by half.20 They found that the sales of beta-2
agonists as a group increased slightly between 1988 and 1990 despite
a decrease in sales of fenoterol and asthma deaths. Additionally,
sales of inhaled corticosteroids remained constant during this period
so that increased use of maintenance anti-inflammatory agents was
probably not the reason for the decrease in deaths. It is possible
that an apparent relationship between increased asthma mortality and
beta-2 agonists may be related to fenoterol rather than to the class
of medications as a whole.
Other epidemiologic studies have shown an association between mortality and indicants of more severe asthma or worsening asthma. 21-23 Suissa et al found an association between mortality and the rise of either albuterol and/or fenoterol use in excess of recommended limits (>2 canisters per month)21 and an increased risk of fatal or near-fatal asthma in patients with a profile of increasing beta-agonist use.22
Sly examined the rates of death from asthma in the U.S. between 1988 and 1991 as well as the sales of all inhaled antiasthmatic drugs.23 He found a moderation in asthma deaths during this period while sales of beta agonists continue to climb, concluding that increases in death rates from asthma might have been due to undertreatment.
One explanation for the potential worsening of asthma in patients on beta-2 agonists is the development of tolerance or "down-regulation" of the beta-2 receptors.4,13,14,17 Studies show that while airway responsiveness may not diminish, a tolerance may develop to the effect on beta receptors on the mast cells, potentially causing an increase in release of inflammatory mediators.4,13,14,17,18,24 Thus, patients may not seek medical attention in a timely manner. If this is true, there might be a special concern with using long-acting beta-2 agonists such as salmeterol.
These studies indicate that increased mortality rates from asthma may be due to undertreatment or failure to seek medical attention in a timely manner when asthma symptoms worsen, rather than to the medications used.21~23 In particular, agents commonly prescribed in the U.S., such as albuterol, have not been implicated to the degree that fenoterol has.
Salmeterol
Approximately one year ago salmeterol, the first long-acting inhaled
beta-2 agonist available in the U.S., was approved by the Food and
Drug Administration. Salmeterol is indicated for the maintenance
treatment of asthma and the prevention of bronchospasm in patients 12
years of age or older including patients with symptoms of nocturnal
asthma who require regular treatment with inhaled short-acting beta-2
agonists. It is also indicated for the prevention of exercise-induced
bronchospasm. It is beta-2 selective and, when dosed as two puffs (42
mcg) twice daily, the bronchodilating effects last up to 12 hours.
Because the onset of action is approximately 30 minutes,
salmeterol is indicated for maintenance therapy, but is not
appropriate for the treatment of acute asthma symptoms. Patients must
also have a short-acting beta-2 agonist available to treat acute
symptoms.25
Studies have demonstrated mixed results on the effects of salmeterol on airway hyperresponsiveness. Cheung et al found that a tolerance developed to the protective effects of salmeterol against a bronchoconstrictor stimulus, methacholine, despite well-maintained bronchodilation and, therefore, cautioned against monotherapy with beta-2 agonists.2fi On the other hand, Booth et al found a continued protection against methacholine-induced bronchoconstriction 12 hours after administration of salmeterol and showed no rebound upon stopping treatment.27 of note, most patients in this study received inhaled corticosteroids, while patients in the study by Cheung et al did not receive inhaled corticosteroids. A large surveillance study (>25,000 patients) in Great Britain found no evidence of increased mortality in patients who received salmeterol.28
It appears that salmeterol is safe and effective therapy for patients who require maintenance therapy, particularly those with nocturnal symptoms. Those patients who require maintenance therapy should also receive an inhaled anti-inflammatory agent.
Another safety issue involving salmeterol therapy is the appropriate use of the medication by patients. A recent Letter to the Editor in The New England Journal of Medicine reported that two elderly patients with moderately severe asthma who suffered fatal respiratory arrests at home were found holding their salmeterol inhalers.29 According to the author, both had been told that salmeterol would have a delayed onset of action and that they should use their albuterol inhaler for emergencies. This example emphasizes the need for physicians, pharmacists, and nurses to provide clear and comprehensive counselling to patients receiving salmeterol. Additionally, it emphasizes the need to provide these patients with a prescription for a short-acting beta-2 agonist such as albuterol and the knowledge to know when to use it. In December 1994, the manufacturer revised the patient instruction leaflet (Table 2) to better instruct patients in the proper use of salmeterol.30
|
Table 2. Patient Instructions for Proper Use of Salmeterol |
|
1. Do not use more than a dosage of 2 puffs twice daily approximately 12 hours apart. 2. Do not use salmeterol to relieve sudden asthma symptoms (e.g., sudden severe onset or worsening of wheezing, cough, chest tightness, and/or shortness of breath that have been diagnosed as due to asthma). If these symptoms occur, they should be treated with a short-acting bronchodilator such as albuterol, metaproterenol, or terbutlaine. 3. If you do not have an inhaled, short-acting bronchodilator, contact your physician to have one prescribed for you. 4. Notify your physician immediately if:
5. Use other inhaled medications only as prescribed by your doctor. 6. Do not use salmeterol as a substitute for oral or inhaled corticosteroids. Do not change your corticosteroid dose without talking to your doctor. 7. To prevent exercise-induced bronchospasm, inhale your salmeterol dose at least 30 to 60 minutes before exercise. ______ Adapted from Patient's Instructions for Use, Serevent (E)(salmeterol xinafoate) Inhalation Aerosol. December 1994 |
Summary
While the controversy over whether or not to administer beta-2
agonists continues, recommendations can be made (Table 3). Patients
with mild asthma (intermittent, brief episodes, <2 times weekly)
should use beta-2 agonists on an was needed" basis. If patients have
two or more episodes per week (moderate asthma), maintenance therapy
with an inhaled anti-inflammatory agent, (e.g., inhaled
corticosteroids) should be instituted. In most situations, beta-2
agonists administered on a regular basis should only be used in
conjunction with an inhaled anti-inflammatory agent. Salmeterol may
be useful, especially for patients with nocturnal symptoms, but it is
imperative that these patients be cautioned not to use salmeterol to
treat acute symptoms. Inhalers of salmeterol, dispensed by the
Pharmacy Department of The University of Iowa Hospitals and Clinics,
are labelled with an auxiliary sticker stating, "THE DOSAGE OF THIS
MEDICATION SHOULD NOT EXCEED 2 INHALATIONS TWICE DAILY UNDER ANY
CIRCUMSTANCES." Patients on salmeterol MUST also have a short-acting,
quick-onset beta-2 agonist inhaler available to treat these acute
symptoms. Patients should also be advised to seek medical attention
if their beta-2 agonist requirement increases. Pharmacists and
physicians should monitor the usage of beta-2 agonists to attempt to
detect those patients who may require additional maintenance therapy.
|
Table 3. Guidelines for the Use of Beta-2 Agonists in Adult Asthmatics |
|
1. Administer beta-2 agonists on an "as needed" basis in patients with mild (less than two symptomatic episodes of symptoms per week) asthma. 2. Institution of an inhaled anti-inflammatory agent (such as an inhaled corticosteroid) should be considered for patients who have moderate (two or more symptomatic episodes per week) asthma. Beta-2 agonists administered on a scheduled basis may be used in conjunction with the anti-inflammatory agents. 3. Salmeterol may be considered for patients with nocturnal symptoms or exercise-induced bronchospasm. 4. Patients on salmeterol must be cautioned not to use it to treat acute symptoms and must have a short-acting bronchodilator available to treat acute symptoms. 5. Usage of beta-2 agonists should be monitored to detect patients who may require further maintenance therapy. Metered dose inhalers typically contain enough actuations to last approximately one month when used at the recommended doses. Thus, unless the patient has been instructed to use higher doses, requests for refills more frequently than approximately every 4 weeks may indicate inadequate control of asthma symptoms, as may the purchase of over-the-counter medications for relief of asthma symptoms. 6. Patients should be counseled to seek medical consultation if their usage of these medications increases or if they no longer obtain relief with dosages that were previously adequate. |
References
Douglas E. Morgan, M.S.
Peer Review Status: Internally Peer Reviewed by Raymond
J. Hohl, M.D., Assistant Professor, Division of Hematology/Oncology,
Department of Internal Medicine and Jack T. Stapleton, M.D.,
Associate Professor, Division of Infectious Diseases, Department of
Internal Medicine
An increasing number of candidal infections has accompanied the growth of bone marrow and solid organ transplantation more intensive (and immunosuppressive) chemotherapy and the worldwide rise in numbers of HIV-infected individuals.1,2>3 This review will summarize general treatment strategies for oral candidiasis and focus on the appropriate selection of oral azole antifungals (e.g., ketoconazole, fluconazole) with suggested guidelines.
Efficacy
Appropriate management of oral candidiasis is determined by the
severity of infection (Table 1) and the severity or character of
underlying concurrent immunodeficiency.1s3X4 Treatment with
clotrimazole troches or nystatin suspension is strongly recommended
as initial therapy for mild to moderate oral candidiasis.3R4 Systemic
therapy with an oral azole antifungal is recommended for severe oral
candidiasis, for poor response to topical therapy, or for cases with
esophageal lesions or symptoms suggesting candidal esophagitis. l,3,4
|
Table 1. Management of Oral Candidiasis[a] | ||||||||||||
|
Disease Severity |
Drug of Choice |
Dosage Regimen |
Alternate Therapy | |||||||||
|
Mild to moderate oral candidiasis |
| |||||||||||
|
Severe oral candidiasis |
| |||||||||||
|
Oral candidiasis with esophagitis |
| |||||||||||
|
_____________ | ||||||||||||
Topical therapy should be considered the initial first-line therapy, for mild to moderate oral candidiasis, even in patients with profound immune suppression.3R4 Pons et al treated oral candidiasis in 334 HIV-positive patients with either oral fluconazole 100 mg daily or clotrimazole troches 10 mg 5 times daily for 14 days. Clinical cure rates did not differ between groups (91 % versus 85 %, respectively) and side effects were similar.5 Clinical failure of topical therapy may be the most practical marker to determine when therapy should be changed to oral azole therapy. The presence of severe mucosal damage at presentation or AIDS patients with CD4<200 cells/ul may warrant initial use of systemic oral azole therapy.1v3v4 Intravenous fluconazole is reserved for patients unable to take oral azole therapy when indicated, particularly those patients with extreme risk of malabsorption. Intravenous amphotericin B is generally indicated when systemic azole therapy fails to control severe oral or esophageal candidiasis.6
Increased use of fluconazole in the HIV-infected patient population may also be attributed to its utility in the management of cryptococcal disease.3 Fluconazole, with effective blood-brain barrier penetration, has been used to treat cryptococcal meningitis and has been found useful as secondary prophylaxis following initial central nervous system infections.7 Fluconazole has also been used for primary prophylaxis to prevent cryptococcal disease, although the cost-effectiveness of this strategy has not been evaluated.
Widespread use of fluconazole, especially long-term suppressive therapy in HIV-positive patients, has been associated with emergence of fluconazole-resistant candidial strains.9~# This development argues for the possible benefits of reserving oral azole therapy in uncomplicated oral candidiasis to those cases refractory to topical clotrimazole or nystatin. Concerns of resistance may also be partly responsible for a shift from chronic suppressive azole therapy to episodic use of azole therapy, retreating each severe symptomatic relapse.11 Fungal susceptibility testing suggests that cross-resistance among azole antifungals occurs. The clinical relevance of this finding is not clear since there is anecdotal evidence that oral candidiasis refractory to one azole antifungal may respond to a different azole antifungal.11
Drug Interactions and Precautions
All three oral azole antifungals share important drug-drug
interactions with several medications.l2 The intensity of the adverse
interactions and the clinical significance may vary among the three
antifungals. The clinician should be familiar with the details of
these interactions before prescribing one azole over another, or
changing the medications listed in Table 2 to alternative
therapy.
|
Table 2. Drugs Which May Interact with Azole Antifungals |
|
Guidelines for Use
A lack of definitive superiority of one oral azole antifungal over
anotherl6^l7 mandates selection based on drug-specific limitations,
adverse effect profiles, and cost-effectiveness considerations. When
oral azole therapy is indicated, ketoconazole is the preferred agent
for these conditions, except in the following circumstances:
1. Ketoconazole requires a low gastric pH for good absorption and should be avoided in patients with achlorhydria, hypochlorhydria, and in patients receiving omeprazole or H2receptor antagonists (e.g., cimetidine).
2. Ketoconazole absorption may be impaired if given with antacids, sucralfate, or didanosine. Avoid concurrent use or give ketoconazole two hours or more prior to these medications.
3. When documented drug-drug interactions clearly favor alternative oral azole antifungals over ketoconazole.
Summary
Topical antifungal therapy remains the initial treatment of choice
for mild to moderate oral candidiasis; oral azole antifungals should
be considered second-line therapy for this indication. For severe
oral candidiasis or oral candidiasis with esophagitis, preferential
use of ketoconazole over fluconazole, whenever possible, permits
equally effective therapy at less expense. The duration of short-term
antifungal therapy is typically 7 to 14 days for uncomplicated cases
of oral candidiasis, while a minimum of 2 to 3 weeks is suggested
when esophagitis is also present.3,4 Concurrent drug therapy and
possible drug-drug interactions may influence the decision to use one
azole antifungal over another. Prolonged, continuous azole therapy
has been used to prevent relapse in patients with severe immune
dysfunction, but may lead to fungal resistance.
References
Drugs Added to Stock
DORZOLAMIDE Ophthalmic Solution: 2% Dorzolamide (Trusopt t)- MSD) ophthalmic solution is a topical carbonic anhydrase inhibitor indicated for the treatment of elevated intraocular pressure, including open angle glaucoma.
FLUVASTATIN Capsules: 20 mg, 40 mg Fluvastatin (Lescol @- Sandoz) is an HMG-CoA reductase inhibitor indicated as an adjunct to diet for the treatment of elevated total cholesterol and LDL-cholesterol levels in patients with primary hypercholesterolemia . NOTE: Fluvastatin is significantly less expensive than the other agents in this drug class.
LOSARTAN Tablets: 25 mg, 50 mg Losartan (Cozaar(D- MSD) is an angiotensin II receptor antagonist indicated for the treatment of hypertension.
MYCOPHENOLATE Capsules: 250 mg Mycophenolate (MMF, CellCept @>- Roche) is an immunosuppressive agent indicated for prophylaxis of organ rejection in patients receiving allogenic renal transplants; it is used in conjunction with cyclosporine and corticosteroids. NOTE: Mycophenolate has been designated as a protocol drug by the Pharmacy and Therapeutics Subcommittee with its use restricted to renal transplant patients at high risk of organ rejection.
SKIN REFRIGERANT, TOPICAL SPRAY Fluori Methane(R) is a topical skin refrigerant containing dichlorodifluoromethane 15% and trichloromonofluoromethane 85 % . This product is nonflammable and has not been associated with significant systemic absorption or toxicity.
Drugs Deleted From Stock
ADSORBOTEAR[R] This brand of artificial tears has been discontinued by the manufacturer. Other brands of artificial tears are available.
ATROPINE 0.5% OPHTHALMIC OINTMENT Discontinued by the manufacturer. The 1 7c ointment is available.
GENTAMICIN 2 mg/ml INTRATHECAL INJECTION Discontinued by the manufacturer. Preservative-free 10 mg/ml gentamicin injection is available.
MICONAZOLE INJECTION Discontinued due to low use. Amphotericin B and fluconazole injections are available.
Additional Actions
The following additional dosage strengths have also been added to stock:
ERYTHROMYCIN 333 mg delayed-release tablets.
MAGNESIUM OXIDE 400 mg tablets.
VITAMIN E 400 IU capsules.