| Considerations When Dosage Changes | |
As the control of patient’s disease improves, or if serious side effects develop, the healthcare provider may decrease steroid dose by tapering the dose to prevent “breakthrough” symptoms and to allow the adrenal glands time to function again. If patient has been taking steroids long-term they should not stop steroids abruptly. Follow the healthcare provider’s recommendations.
As the body adjusts to a lower steroid dose, patients may notice some withdrawal side effects. These may include an increase in breathing difficulty due to worsening of their disease, fatigue, weakness, depression and muscle and joint pain. If breathing difficulty occurs, or if any of the above symptoms are severe, notify your healthcare provider. The non-respiratory side effects usually disappear within a few weeks or months.
If patient’s steroid dose has recently been decreased or stopped and you have a serious illness, surgery or injury, they may require a short steroid burst. During this time, the patient’s adrenal glands may not be functioning at full capacity and cannot handle stress to the body. This is important if they have taken routine steroid pills within the last year or completed a burst within the past two weeks. Patients should inform all of their healthcare providers that they have been on steroid treatment.
Some people do not react normally to steroid medicine. Special testing may be required and the medicine dose may need to be adjusted.
Frequently people have concerns about taking corticosteroid (“steroid”) medicine. Patients should discuss concerns about steroid use with your healthcare provider. Discuss all medicines and herbal supplements with healthcare provider to make sure they don’t interact with the steroids you take. It is important that patients follow their healthcare provider’s directions when taking steroids.
This information has been approved by David Tinkelman, MD (October 2003).
Apr. 29, 1998: Three corticosteroids used intranasally reduced overnight urinary cortisol levels in 16 healthy volunteers, according to new data just published in the Journal of Allergy and Clinical Immunology (1998; 101: 470-4). The reductions “which indicate systemic availability of nasally administered steroids” were significant only for fluticasone 200 mcg/day (43%), while reductions from triamcinolone 220 mcg/day (23%) and beclomethasone 336 mcg/day (21%) did not reach significance.
The researchers also measured the subjects’ response to low-dose ACTH, another marker of adrenal suppression. Serum cortisol concentrations before and after ACTH administration did not indicate significant impact on adrenal response. The authors conclude that, based on the results of this four-day study, further investigation into the systemic effects of intranasal corticosteroids is needed, including whether these effects are additive.
Reprints: B. J. Lipworth, Clin. Pharmacology and Therapeutics, Ninewells Hosp. and Med. Sch., U. Dundee, Dundee DD1 9SY, Scotland, U.K
A manufacturer’s labeling information in 2005 illustrates the types of problems that can be seen:
The replacement of a systemic corticosteroid with BECONASE Inhalation Aerosol can be accompanied by signs of adrenal insufficiency.
Careful attention must be given when patients previously treated for prolonged periods with systemic corticosteroids are transferred to BECONASE Inhalation Aerosol. This is particularly important in those patients who have associated asthma or other clinical conditions where too rapid a decrease in systemic corticosteroids may cause a severe exacerbation of their symptoms.
Studies have shown that the combined administration of alternate-day prednisone systemic treatment and orally inhaled beclomethasone increases the likelihood of HPA suppression compared to a therapeutic
dose of either one alone. Therefore, treatment with BECONASE Inhalation Aerosol should be used with caution in patients already on alternate-day prednisone regimens for any disease.
If recommended doses of intranasal beclomethasone are exceeded or if individuals are particularly sensitive or predisposed by virtue of recent systemic steroid therapy, symptoms of hypercorticism may occur, including very rare cases of menstrual irregularities, acneiform lesions, cataracts, and cushingoid features. If such changes occur, BECONASE Inhalation Aerosol should be discontinued slowly consistent with accepted procedures for discontinuing oral steroid therapy.
Persons who are on drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in nonimmune children or adults on corticosteroids. In such children or adults who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affects the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.
General: During withdrawal from oral steroids, some patients may experience symptoms of withdrawal, e.g., joint and/or muscular pain, lassitude, and depression.
Rare instances of nasal septum perforation have been spontaneously reported.
Rare instances of wheezing, cataracts, glaucoma, and increased intraocular pressure have been reported following the intranasal use of beclomethasone dipropionate.
In clinical studies with beclomethasone dipropionate administered intranasally, the development of localized infections of the nose and pharynx with Candida albicans has occurred only rarely. When such an infection develops, it may require treatment with appropriate local therapy or discontinuation of treatment with BECONASE Inhalation Aerosol.
Beclomethasone dipropionate is absorbed into the circulation. Use of excessive doses of BECONASE Inhalation Aerosol may suppress HPA function.
BECONASE Inhalation Aerosol should be used with caution, if at all, in patients with active or quiescent tuberculous infections of the respiratory tract; untreated fungal, bacterial, or systemic viral infections; or ocular herpes simplex.
For BECONASE Inhalation Aerosol to be effective in the treatment of nasal polyps, the aerosol must be able to enter the nose. Therefore, treatment of nasal polyps with BECONASE Inhalation Aerosol should be considered adjunctive therapy to surgical removal and/or the use of other medications that will permit effective penetration of BECONASE Inhalation Aerosol into the nose. Nasal polyps may recur after any form of treatment.
As with any long-term treatment, patients using BECONASE Inhalation Aerosol over several months or longer should be examined periodically for possible changes in the nasal mucosa.
Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal septum ulcers, nasal surgery, or trauma should not use a nasal corticosteroid until healing has occurred.
Although systemic effects have been minimal with recommended doses, this potential increases with excessive doses. Therefore, larger than recommended doses should be avoided.
July 24, 1998: From the Archives of Diseases in Children (1998; 79) come two studies assessing steroid therapy in asthma and proper treatment of recurrent cough in children.
Increasing the dosage of inhaled corticosteroids at the beginning of an asthmatic exacerbation is “ineffective and should not be included in asthma self management plans,” concludes the first article (pp. 12-7). The report considers 18 exacerbations that occurred in 28 children aged 6-14 years with mild to moderate asthma over a six-month period. Compared with inhaled placebo, steroid inhalations had no significant effect on peak expiratory flow, diurnal peak flow variability, symptoms scores over the following two weeks, or parents’ opinions of the effectiveness of asthma medications.
Reprints: D. Holdaway, Paediatrics and Child Health, Dunedin Sch. of Med., P.O. Box 913, U. Otago Med. Sch., Dunedin, New Zealand.
Neither salbutamol nor beclomethasone was beneficial in children with recurrent cough but with no other evidence of airway obstruction, concludes a second group of authors (pp. 6-11). The study included 43 children aged 6-17 years who received either salbutamol or placebo for five to seven days and then either beclomethasone or placebo for either four to five weeks or eight to nine weeks. The drugs had no significant effect on cough frequency or scores, regardless of whether airway hyperresponsiveness was present.
Reprints: A. B. Chang, Resp. Med., Mater Children’s Hosp., South Brisbane, Queensland 4101, Australia; achang@mater.org.au.
Tradename Intal
Manufacturer Fisons
Treatment Class Respiratory
Indication Cough due to ACE inhibitor therapy
From the February 1994 issue of Medical Sciences Bulletin , published by Pharmaceutical Information Associates, Ltd.
Indication: Cough due to ACE
inhibitor therapy
Drug Tradename: Intal
Manufacturer: Fisons
Angiotensin-converting enzyme (ACE) inhibitors are widely used to treat hypertension and congestive heart failure and have also proved effective for early left ventricular dysfunction and diabetic nephropathy. Although ACE inhibitors are generally well tolerated, a major side effect is a persistent, nonproductive, irritating cough. This appears to be inherent in the mechanism of action of ACE inhibitors (ACE itself is located in the endothelial lining of the vasculature of the lungs). In some patients, the cough is severe enough to lead to drug withdrawal. Various therapies have been tried — theophylline, nonsteroidal antiinflammatory drugs, and even inhaled local anesthetics — but response has been inconsistent.
Recently cardiologist M. Hargreaves reported that inhaled cromolyn sodium (Intal/Fisons) may be effective for suppressing cough in patients taking ACE inhibitors. Hargreaves described five men aged 65 to 82 who experienced cough 2 to 7 days after drug therapy initiation with captopril or lisinopril. Coughing disappeared after ACE inhibitor withdrawal, then returned immediately upon rechallenge. When cromolyn sodium was given by inhalation (20 mg 4 times daily), coughing disappeared in three patients, was much improved in the fourth patient, and was unchanged in the fifth. A literature review turned up seven additional cases of ACE inhibitor-induced cough treated with cromolyn sodium; cough was completely suppressed in four patients, partially suppressed in two patients, and unchanged in one patient. How cromolyn sodium protects against ACE inhibitor cough is not known, said Hargreaves, who nevertheless concludes that the value of cromolyn inhalation therapy should be examined further.
1. Hargreaves M. Brit J Clin Pract. 1993; 47: 319-320.
In 1997, the Annals of Pharmacotherapy: Vol. 31, No. 6, pp. 773-775, the following was reported:
TL Allen and ML Gora-Harper
There are several theories on the cause of ACE inhibitor-induced cough, but the exact mechanism is not known. In many patients, if cough develops, the ACE inhibitor can be discontinued and a drug in another therapeutic class used in its place. However, in patients with CHF, diabetic nephropathy, and patients who have experienced a myocardial infarction, discontinuing the ACE inhibitor may not be in the best interest of the patient. In this patient population it would be reasonable to try cromolyn sodium to treat cough, while continuing the ACE inhibitor. Data are not available to support the efficacy of cromolyn sodium to treat cough in patients with diabetic nephropathy, but these patients clearly benefit from the use of an ACE inhibitor. Other factors not addressed in the case reports and the clinical trial such as patient adherence, cost, and quality of life should also play a role in the decision to use cromolyn sodium. Cromolyn sodium has been effective for the treatment of ACE inhibitor-induced cough in many case reports and has had mild success in one small clinical trial. Although none of the reports adequately assessed adverse effects, studies examining cromolyn for other indications have demonstrated a relatively benign adverse effect profile. It is difficult to recommend an exact dose to use because of the dosing variability in the case reports. The majority of the case reports and the one clinical trial used dosages similar to recommendations for bronchial asthma (i.e., 2 puffs [1.6 mg] 4 times daily via MDI or 20-mg capsules 4 times daily via breath-activated inhalation). At this time, the use of cromolyn sodium is a viable option, but more controlled studies are needed to fully elucidate its role in the treatment of ACE inhibitor-induced cough.
The following is taken from the “Highlights of the 1997 Meeting of the American Academy of Allergy, Asthma & Immunology”
Recently, we have seen the development of many new asthma therapies, each attempting to target a different mechanism through which to combat this chronic inflammatory disease of the airways. The combination of short-term and long-term (acute and chronic) medications is important for the successful management of asthma.
Long-term control medications include corticosteroids, cromolyn sodium and nedocromil, long-acting beta2-agonists, methylxanthines, and leukotriene modifiers. Quick-relief medications include short-acting beta2-agonists, anticholinergics, and systemic corticosteroids. Despite the recognized value of these therapies, new approaches are constantly being identified. For example:
Intravenous Immunoglobulin (IVIG) has numerous immunomodulatory and anti-inflammatory activities. One study used IVIG for the treatment of severe asthma and showed it was significantly effective in allowing for steroid reduction in the subgroup of patients who had higher steroid requirements. This suggests that IVIG should be reserved for the treatment of severely afflicted asthmatic patients.
Hydroxychloroquine (HCQ) was tested for its use in antiallergic, antiasthmatic therapy. HCQ is a generally well tolerated and safe immunomodulating drug. Its proven efficacy in the treatment of rheumatic diseases suggests potential utility in the treatment of non-steroid-dependent asthma. Findings suggest that a late improvement in symptoms occurs in the HCQ group, which is consistent with its known slow onset of action. Additional studies are needed to confirm the antiasthmatic, antiallergic, and possibly disease-modifying effects of HCQ.
Montelukast, a leukotriene receptor antagonist, was shown to decrease peripheral blood eosinophils and improve signs and symptoms of asthma over a 3-month period. Researchers have concluded that montelukast caused a significant improvement in symptoms of chronic asthma, which correlates with changes in peripheral blood eosinophil levels.
Many new products have come to market for the treatment of seasonal allergic rhinitis (SAR), perennial allergic rhinitis (PAR), and nonallergic rhinitis (PNAR). Allergic rhinitis is an immunologically mediated disease in which histamine plays a central mediator role in producing most of the typical ocular and nasal signs and symptoms such as sneezing, nasal stuffiness, and postnasal drip.
Mometasone furoate (NasonexTM) is an aqueous nasal spray in which 200 mcg QD is shown to be as effective and as well tolerated as 400 mcg of beclomethasone dipropionate in treating symptomatic SAR and PAR. Fluticasone propionate is also an aqueous nasal spray and is used in the treatment of PNAR. This condition is etiologically different from allergic rhinitis and is often refractory to treatment with antihistamines, decongestants, and mast cell inhibitors. PNAR is, however, characterized by symptoms that may respond to intranasal corticosteroids such as fluticasone propionate. Antihistamines such as cetirizine and ebastine (not currently available in the United States) have been used for treating PAR; in a study comparing the two, cetirizine was shown to provide total relief in a greater number of patients and was also more effective than ebastine in relieving nasal obstruction. Levocabastine nasal spray is another antihistamine that is used for the treatment of SAR.
In the March 2000 Discover, Carrie Hoppe wrote in an article entitled Advances In Treating Asthma And Allergic Diseases - new therapies, and continuing research, in the treatment of allergies and asthma:
“Last spring, seven-year-old Ashley Collom rushed home from school with a piece of paper in hand, eagerly anticipating sharing her accomplishment with her family. Straight As couldn’t compare to the perfect attendance certificate she grasped in her hands. For the last six weeks of first grade in her Piano, Tex., school, Ashley had not missed a single day of school or woken up in the middle of the night struggling to breathe. Her certificate marked not only the end of the school year, but a fresh start.
“That perfect attendance certificate was like gold for her,” said Karen Collom, Ashley’s mother. “She took it to her allergist immediately to show him. That’s how proud she was of putting up with the therapies until we finally found something that worked for her.” Ashley, like millions of other American children, had suffered from debilitating allergies and asthma for years until she found treatment.
Asthma, like Ashley’s, can flare up at any moment. As a chronic lung disease, asthma causes inflammation of the lower airways and obstructs airflow into the lungs. Airways become swollen and inflamed, and mucus can block air from reaching the lungs. In asthmatics, airways remain in this condition to some degree all the time, even when there are no obvious symptoms, such as wheezing, shortness of breath and chest tightness. When attacks do occur, airways narrow, making it difficult, and in some cases, impossible to breathe. Many times, attacks are brought on by allergic reactions to inhaled or ingested allergens, or even weather changes or exercise.
Nearly two years ago, Ashley’s allergist tried a new approach in the management of the disease and prescribed tandem therapy for her allergic asthma, utilizing a combination of a bronchodilator with long-acting beta2-agonists and inhaled corticosteroids to keep her asthma in check. He also began a series of allergy shots, or immunotherapy, to control her environmental allergies, which helped to trigger her asthma attacks. Since starting the drug combination and immunotherapy, Ashley’s life has turned around. “We didn’t know what was causing anything so we were afraid to do anything,” Karen said. “This year has been light years different. It’s like a whole new world for her. She’s actually participating with the other kids in school and living like any other kid.” Now in second grade, she has not missed a day of school, participates regularly in gym class, goes outside for recess and plays on her local soccer team. “A year ago she saw herself as a sick kid. Now she’s just any other kid in the hallway at school,” Karen said. “As a parent, I feel that’s a tremendous thing.”
COMBINATION THERAPIES
One of the most effective of today’s growing arsenal of allergic disease treatments is combination, or tandem, therapies. Together, inhaled corticosteroids and long-acting beta2 agonists or a new drug, leukotriene modifiers, help millions of individuals to breathe easier.
Inhaled corticosteroids (not to be mistaken for bodybuilding anabolic steroids) have become the most widely used and effective method to reduce airway inflammation in asthmatics. Available in both oral and inhaled form, the inhaled version of this medication is most often preferred, since it puts the drug directly into the lungs in lower doses, keeping side effects to a minimum. An anti-inflammatory medication, the drugs work directly on the body’s bronchi, the main branches leading from the throat to the lungs in the airways, to reduce inflammation and asthma symptoms. Available widely for now more than 30 years, the drugs decrease swelling in the bronchial tubes, mucus production and the overall chain of hyperreactivity in the airways.
While corticosteroids quell inflammation, most asthmatics need another medication to keep airways open when attacks occur and to stave off future attacks. Inhaled bronchodilators act as rescue medication to immediately open airways by relaxing constricted muscles that squeeze airways shut during an attack. The first generation of this class of drugs hit the pharmaceutical market about 40 years ago. Since then, refinements and advancements have created a second generation of the drug, known as short-acting beta2 agonists, which can offer immediate relief during an asthma attack. In combination with inhaled corticosteroids, these drugs can offer patients a new lease on life.
Long-acting beta2 agonists remain effective for at least 12 hours, keeping asthma symptoms, especially nocturnal and exercise-induced asthma, in check for long periods of time. Their unique makeup allows the drug to remain on the airway cell membranes and activate receptors to keep airway muscle contractions at bay. Studies have found the drugs to be very effective in reducing overall airway inflammation levels. This combination approach helps make long-term management of persistent asthma possible.
Combination therapy continues to be the focus of many of today’s research studies and drug development initiatives. This past November, a Food and Drug Administration (FDA) committee recommended approval of a new combination inhaler device which puts both inhaled corticosteroids and a long-acting bronchodilator in one inhaler device.
Ease of use, coupled with reduced side effects, is paramount in fostering patient compliance with drug regimens, said Paul M. O’Byrne, M.D., E.J. Moran Campbell Professor of Medicine and Head of the Division of Respiratory Medicine at McMaster University in Hamilton, Ontario, Canada. The surge of patients turning to combination therapy is partially a reaction to undue concern over the possible long-term effects of corticosteroids on growth, he said. Combination therapy is very appealing to many patients, since it can allow for reduced doses of inhaled steroids, O’Byrne said. “It is sometimes difficult to convince parents how safe these drugs really are. They are concerned about side effects and growth retardation, but the latest studies suggest this shouldn’t be a concern,” O’Byrne said.
Combination therapy is not limited to only inhaled steroids and bronchodilators. The development of leukotriene modifiers has also opened up new doors in the long-term management of asthma. First introduced in 1996, the drugs reduce the production of leukotrienes -- chemical compounds occurring naturally in white blood cells that produce allergic and inflammatory reactions. In asthma, the compounds are released by mast cells and eosinophils, and cause blood vessels to dilate and bronchial muscles to contract. (Inhaled corticosteroids treat symptoms, but do not reduce the production of leukotrienes). The new drugs help to block their action during an asthma attack and can aid in the long-term management of the disease. Easy to administer since they are taken orally, leukotriene modifiers are gaining acceptance among many physicians and patients. Simple drug regimens, such as once or twice a day dosing, have also helped to increase patient compliance in using these drugs.
While the jury is still out on the long-term benefits of leukotriene modifiers and their exact role in combination therapy, the drugs do offer another weapon in the war against allergic disease, O’Byrne said. “While steroids work on one portion of the inflammatory process, leukotriene modifiers work on other aspects,” he said. “In the next three to five years, we’ll learn if we can prevent the progress of the disease in some patients, and now we have very effective therapies. Asthma is now a disease that can be very well controlled.”
NEW TREATMENTS COULD HOLD KEY
While much of today’s drug arsenal can keep allergies and asthma in check for many patients, researchers are still seeking out new treatments which could ease suffering across the board.
Possibly one of the most promising of these new treatments is anti-IgE therapy. The theory behind anti-IgE therapy is that an antibody can “short circuit” the first steps of the allergic response, thus preventing symptoms caused by allergen exposure. In allergic disease, researchers have focused their efforts on blocking the naturally occurring antibody Immunoglobulin E, known as IgE, which plays a major role in diseases such as asthma, anaphylaxis and seasonal allergic rhinitis (hay fever). Those with allergic disease harbor larger quantities of IgE than non-allergic individuals.
When a person prone to allergies inhales certain allergens, such as ragweed pollen or animal dander, IgE directed against that allergen is synthesized in the body and binds to specialized cells called mast cells. When the person comes in contact with the same allergen in the future, the allergen binds to the IgE antibody now seated on the mast cell. This connection triggers the release of inflammatory mediators from cells, such as histamine, prostaglandins and leukotrienes, which cause the recognizable symptoms of allergic reactions, such as a runny nose, watery eyes, sneezing, wheezing, hives or coughing.”
Nearly 10% of the US population, some 18 million Americans suffer from asthma, a respiratory condition characterized by airway inflammation, airway obstruction (at least partially reversible), and airway hyperresponsiveness to such stimuli as environmental allergens, viral respiratory-tract infections, irritants, drugs, food additives, exercise, and cold air. The major underlying pathology in asthma is airway inflammation. Inflammatory cell — eosinophils, CD4+ lymphocytes, macrophages, and mast cells — release a broad range of mediators, including interleukins, leukotrienes, histamine, granulocyte-colony-stimulating factor, and platelet aggregating factor. These mediators are responsible for the bronchial hyperreactivity, bronchoconstriction, mucus secretion, and sloughing of endothelial cells. Because asthma is an inflammatory disease, early treatment with inhaled glucocorticoids is recommended for optimum long-term control. Beta-agonists, while effective for symptomatic control in the short term, do not control the inflammation; indeed, there is evidence that excessive use may exacerbate asthma and contribute to its worldwide increase in prevalence, morbidity, and mortality. (Barnes PJ. Br Med J.)
Glucocorticoid Therapy: Inhalation vs Oral Inhalation Therapy with anti-inflammatory glucocorticoids is recommended for the initial treatment of asthma, with the addition of beta-agonists as needed. Glucocorticoids reduce the risk of fatal and near fatal asthma in both children and adults, and administration by inhalation (compared with oral administration) reduces the risk of systemic side effects. This is because the glucocorticoids available for inhalation therapy are highly active topically and only weakly active systemically, which minimizes effects on the pituitary-adrenal axis, the skin, and the eye. Side effects associated with inhalation therapy are primarily oropharyngeal candidiasis and dysphonia (due to atrophy of laryngeal muscles). Both side effects are less common when a spacer is used because less drug is deposited in the oropharynx and larynx. Oral glucocorticoids cause atrophy of the dermis — with thin skin, striae, and ecchymoses — but inhaled glucocorticoids do not cause similar changes in the respiratory tract.
Another advantage of inhaled over oral administration is that the direct deposition of steroid in the airways generally provides more predictable administration. The oral doses required for adequate control vary substantially, whereas inhaled glucocorticoids are usually effective within a narrower range. There are, however, a number of factors that influence the availability of inhaled glucocorticoids: extent of airway inflammation; degree of lung metabolism; amount of drug swallowed and metabolized in the GI tract; the patient’s ability to coordinate the release and inspiration of the medication; type of glucocorticoid; and the delivery system. (When a spacer is used between the inhaler and the mouth, the inhaler is easier to manipulate and more drug reaches the lungs.)
The most widely used aerosol glucocorticoids are beclomethasone dipropionate (Vanceril/Schering) and budesonide (Rhinocort/Astra, similar to beclomethasone). These agents have a high affinity for intracellular glucocorticoid receptors but are rapidly metabolized to biologically inactive compounds. In one study comparing the efficacy of inhaled versus oral therapy for reducing respiratory symptoms and improving airway function, the ratio of the potency of inhaled budesonide versus oral prednisone was about 40 to 1. There is no evidence that efficacy diminishes with time. Asthma can usually be controlled with beclomethasone or budesonide 200 to 800 microgram inhaled daily. Doses up to 1000 microgram daily have little effect on pituitary-adrenal secretion in adults; larger doses may cause some (variable) dose-dependent suppression of secretion. Doses of 2000 microgram/day in adults have been associated with thinning of the skin, slight glucose intolerance, psychiatric disturbances (rarely), and cataracts (with long-term therapy). Beclomethasone in doses of 1000 to 2000 microgram/day (long term) has been associated with decreases in bone density. Flunisolide (AeroBid/Forest) and triamcinolone (Azmacort/Rorer) are also available for inhalation therapy in the United States, but they haven’t been studied as extensively. (Utiger RD. N Engl J Med. 1993; 329: 1731-1733.)
| Considerations When Dosage Changes | |