World of Drug Information

World of Drug Information - Volume 9, Issue 4 - December 1998

In This Issue ...
 Current Clinical Issues 
 Search Tips 
 WHO Fellows 
 IDIS File Recap 
 IDIS Originator Honored 
 Year 2000 Compliance 
 Perspective From an IDIS Subscriber
 Subscription Renewal Reminder 
 Key References 
 FDA Approvals 
 Staff Profile 

CURRENT CLINICAL ISSUES

Leukotriene Modifiers for Asthma Treatment

Asthma is becoming a major health concern related to increasing morbidity and mortality in the United States. It is estimated that 14 to 15 million Americans have asthma, five to 10% of the population. It is the most common chronic disease of childhood, affecting an estimated 4.8 million US children (Center for Disease Control and Prevention 1995). People with asthma collectively have 100 million days of restricted activity and 470,000 hospitalizations annually. More than 5,000 people die of asthma annually. According to the CDC 1996 report, in the US asthma hospitalization rates are highest among African-Americans and children, and death rates are highest among African-Americans aged 15-24 years.

The NIH guidelines, published in April 1997, classify asthmatics into four groups based on the signs and symptoms of the disease: mild intermittent, mild persistent, moderate persistent and severe persistent. The guidelines define asthma as "a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role, in particular, mast cells, eosinophils, T lymphocytes, neutrophils, and epithelial cells. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough, particularly at night and in the early morning. These episodes are usually associated with widespread, but variable airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an associated increase in the existing bronchial hyperresponsiveness to a variety of stimuli."

The pharmacological approach to treating asthma has changed over the years as the pathophysiology is better understood. Previously, treatment, including epinephrine, atropine-like drugs and some inhaled beta-agonists, was aimed at relieving symptoms of bronchoconstriction, not disease control. When the role of the inflammatory process involved in asthma was better understood, corticosteroids, cromolyn and nedrocromil were used more frequently in treatment. Recent studies have shown the effects of specific immune cells, cytokines and immune mediators in the disease process. This information led to the development of new drugs in the armamentarium of asthma treatment including the leukotriene modifiers.

The leukotrienes are potent biochemical mediators released from mast cells, eosinophils, and basophils that contract airway smooth muscle, increase vascular permeability, increase mucus secretions, and attract and activate inflammatory cells in the airways of patients with asthma.The leukotreine modifiers act to improve lung function, diminish symptoms and the need for inhaled beta-agonists. Three oral leukotriene modifiers are FDA approved for mild-to-moderate persistent asthma: zafirlukast (Accolate), zileuton (Zyflo) and most recently montelukast (Singulair).

Compliance is an issue for the treatment of asthma. Mellins found that 50% of patients on chronic drug therapy are not compliant. Beta-agonists and theophylline are current agents for chronic asthma. Inhaled asthma medications have the advantage of delivering the drug to the site of action. Unfortunately, training and the skill of using a metered inhaler presents compliance problems. The oral agent theophylline has a narrow therapeutic range, requires monitoring and has a significant number of drug-drug interactions associated with it. The 1997 NIH guidelines present leukotriene modifiers as possible alternative first line therapy for mild-to-moderate persistent asthma. More studies are necessary to prove efficacy.

SEARCH STRATEGIES

The IDIS database offers many options for retrieval of primary literature to evaluate the use of the new leukotriene modifiers for the treatment of chronic asthma. Search terms entered in the global field give a broad overview of the number of articles on a subject. Entering asthma in the global field retrieves 44,253 articles (IDIS file 1966-October 1998). Search terms entered in the global field search all the fields. A specific search for bronchial asthma would be more useful. Click on the Thesaurus tab to find the IDIS valid term and code number. In the thesaurus field type asthma and press <ENTER> or click on the Search button. Scrolling through the list, you find that bronchial asthma is under the valid term ASTHMA NEC 493. Return to the Main Search screen. In the disease field, type the valid number 493. (remember that the decimal point is a part of the disease number). Another method is to use the Phrase tab for the disease field. Click on the Phrase tab and type the first few letters of a term. Terms with the same first few letters will appear. Select a term by checking the box beside the term and then click on OK. This will insert your selected term in the disease field. The file contains 8,957 records on asthma (IDIS file 1966-October 1998). If you search with asthma in the disease field, the cross reference will automatically be activated. The records containing other valid asthma terms will also be retrieved. A search combining the drug of interest in the drug field and ASTHMA NEC 493. in the disease field yields the results: zafirlukast and asthma nec = 74 hits, zileuton = 52 hits and montelukast = 31 hits. (IDIS file 1966-October 1998). The IDIS database contains articles about 15 other leukotriene modifiers not yet FDA approved.

The search can be limited to randomized controlled studies by finding the valid descriptor term and code number using the Look Up button at the end of the descriptor field on the Main Search screen. In the Look Up section, the descriptors are listed by category. Scrolling through the list, you find the three randomized study classes based on the age of the study population. 135 STUDY RANDOMIZE ADULT can be selected by clicking on the box next to the term.

The unique mechanism of action for these new drugs may be looked at in detail. Articles explaining the mechanism of action can be found by placing descriptor 41 MECHANISM OF ACTION in the descriptor field and the drug name in the drug field. The major side effects associated with these new drugs are increases in liver enzyme levels and Churg-Strauss syndrome with zafirlukast. To search for articles on the elevation of liver enzymes search descriptor 78 SIDE EF DIGESTIVE. Churg-Strauss syndrome involves pulmonary infiltrates, vasculitis and cardiomyopathy. The thesaurus will help you find the descriptor(s) that can be searched in combination with the drug term to find articles related to this side effect. In the thesaurus type Churg-Strauss.The results show it is searched using descriptors 82, 79 and 83. Return to the Main Search screen, type zafirlukast in the drug field and in the descriptor field the descriptor numbers 82, 79, 83, leaving a space between each code number.

The leukotriene modifiers are being studied in both adult and pediatric patients. To retrieve pediatric articles, use the age tag for pediatrics listed in the disease vocabulary. To find the valid term and code number, consult the thesaurus to find that the pediatrics age tag is under the valid term V85. PEDIATRICS. To do a search type V85. in the disease field in combination with any of the agents.

CLINICAL INFORMATION

Leukotriene Receptor Antagonists

Zafirlukast (Accolate, Zenneca Pharmaceuticals), FDA approved September 26, 1996, is the first oral leukotriene modifier for treatment of patients older than 12 years old for prophylactic and chronic treatment of mild-to-moderate persistent asthma. The drug is a competitive cysteinyl leukotriene receptor antagonist. The cysteinyl leukotrienes are products of arachidonic acid metabolism that increase eosinophil migration, mucus production and airway wall edema and cause bronchoconstriction.

Suissa (1997), in a 13-week randomized placebo-controlled study in mild-to-moderate asthmatics found zafirlukast (20 mg bid) to be effective in FEV-1 improvement, symptom control and economic effectiveness. The zafirlukast group (103/146 patients) had 89% more days without symptoms or beta agonist inhaler use than the placebo group. They also had 55% fewer health care contacts and 55% fewer days of absence from work or school.

The pivotal study on which FDA approval was based, has been published by Fish (1997). It was a 13-week randomized, placebo, double-blind trial in 762 chronic mild asthmatics to determine the efficacy of zafirlukast 20 mg bid. Efficacy was assessed by daytime asthma symptoms, beta-agonist rescue use and pulmonary function. At the trial end, the daytime symptom score decreased 26.5% with zafirlukast and 13.3% for placebo relative to baseline. Zafirlukast reduced beta agonist use 22.3% (3.91 puffs per day) compared to 7% (3.14 puffs per day) on placebo. Pulmonary function was assessed by FEV-1 and PEFR. Zafirulukast FEV-1 and PEFR % changes from baseline were 6.3% and 6.9% respectively (p < 0.05 and p < 0.01, respectively).

The bioavailability of zafirlukast is reduced by food. The manufacturer recommends that the drug be taken one hour before or after meals to ensure adequate drug absorption. (Zafirlukast package insert)

Zafirlukast is available as 20 mg oral tablets and the recommended dose is 20 mg bid in patients older than 12 years of age. Zafirlukast is metabolized by cytochrome P450 and also has shown drug-drug interactions with theophylline, warfarin and other drugs that use cytochrome P450. Drug dosing modifications may be necessary. (Zafirlukast package insert)

Weschler (1998), in a case series report, describes the occurrence of Churg-Strauss syndrome in eight steroid dependent asthmatics who received zafirlukast following steroid withdrawl. Investigators are still debating if this is related to steroid withdrawal or the drug itself.

FDA approved montelukast (Singulair, Merck) is a leukotriene receptor antagonist for oral prophylaxis and chronic treatment of asthma in adults and children at least six years old. Zafirlukast and zileuton are not approved for use in patients under 12 years old. According to the 1997 NIH guidelines for the diagnosis and management of asthma, leukotriene modifiers are not recommended for the treatment of an acute asthma attack.

Reiss (1998), in a 12-week randomized, double-blind placebo controlled study evaluated oral montelukast in adults with chronic mild-to-moderate asthma. The 681 patients received either 10 mg daily oral montelukast or placebo. Montelukast significantly improved (p < .001 compared with placebo) airway obstruction, as shown by an increase in FEV-1 of 13.1% (placebo, 4.2%), in morning PEFR of 24.0 L/min (placebo, 4.6 L/min), and in evening PEFR of 15.9 L/min (placebo, 4.2 L /min). Patient-reported endpoints, daytime asthma symptoms and as needed beta-agonists, significantly improved with montelukast (p < .001 compared with placebo). The most frequently reported side effect was increased levels of alanine aminotransferase (ALT); 2.5% with montelukast and 1.5% with placebo treatment.

Knorr (1998) investigated the efficacy of montelukast in treatment of mild to moderate asthma in patients six to 14 years old. In an eight-week randomized, double-blind study 336 patients received either montelukast 5 mg chewable tablet daily or placebo. Montelukast improved the morning FEV-1, the main outcome measure. Mean morning FEV-1 increased from 1.85 L to 2.01 L (8.23 % change) in the montelukast group and 1.85 L to 1.93 L (3.58% change) in the placebo group (p = < .001) from baseline.

Montelukast is available in 10-mg tablets or 5-mg chewable tablets. The recommended dosage is 5 mg daily in children six to 14 years old and 10 mg daily in adults. The drug can be taken without regard to food. Montelukast does not inhibit the cytochrome- P450 enzymes and is expected to have fewer drug interactions than the two other approved leukotriene modifiers. (Montelukast package insert) The hepatic toxicity, reported with zileuton, has not been found with montelukast, nor has the Churg-Strauss vasculitis found in patients taking zafirlukast.

Leukotriene Synthesis Inhibitor

Zileuton (Zyflo, Abbott) a leukotriene synthesis inhibitor was FDA approved in 1997 for the chronic or prophylactic treatment of mild-to-moderate asthma in patients older than 12 years. Zileuton acts by inhibiting the enzyme 5-lipoxygenase which catalyzes the conversion of arachidonic acid to leukotrienes. Two studies have compared the efficacy of 400 mg qid vs 600 mg qid zileuton for patients with mild chronic asthma. Israel (1996), in a 13-week double-blind randomized trial in 401 patients, found an improvement in FEV-1 at 2 to 4 hours after dosing. The improvement was 15.7%, 13.9% and 7.7% with 600 mg qid, 400 mg qid and placebo, respectively (p = .006). Patients receiving 600 mg qid zileuton also required fewer corticosteroid rescues, 6.1% of patients on 600 mg qid zileuton compared to 15.6% on placebo. Liu (1996) found similar results in a randomized, double-blind, six-month trial in 373 patients with mild-to-moderate asthma. Zileuton improved FEV-1 16% and 12% for patients treated with 600 mg qid and 400 mg qid respectively, compared to 6% for placebo (p < 0.01). Improvements in morning PEFR and steroid rescue were also sustained for six months.

Schwartz (1998) compared zileuton to standard oral theophylline for the treatment of moderate asthma . A 13-week randomized, double-blind study in 377 patients compared zileuton 400 mg qid, zileuton 600 mg and slow-release theophylline 200 or 400 mg bid (dosage adjusted to reach trough theophylline levels of 8 to 15 micrograms/ml). The results found that zileuton 400 mg qid had a significantly greater FEV-1 improvement compared to theophylline. The long term FEV-1 improvement in the groups was 34%, 30.2%, 33.7% for zileuton 400 mg, zileuton 600 mg and theophylline, respectively. Zileuton was more effective than theophylline in improving FEV-1.

Zileuton undergoes cytochrome P450 metabolism. It has been shown to have interactions with warfarin, theophylline, propranolol and other drugs that utilize the cytochrome P450 pathway. The drug has been associated with increase in the alanine aminotransferase activity of three times the normal levels. The manufacturers have recommended monitoring ALT levels prior to therapy, then monthly for three months and then every other month for the first year. (Zileuton package insert)

The leukotriene modifiers offer a new oral option for the treatment of chronic mild-to-moderate asthma. The NIH guidelines offer them as a possible first line therapy for chronic asthma in patients. The drugs are beneficial in the treatment of the inflammatory process of asthma. Research with other drugs that modify the immune mediators is already in progress. Further studies on the efficacy of these drugs compared to current therapy are necessary to clarify the leukotrine modifiersí role in symptom control and disease treatment of asthma.

Mary Ann Cull, R.Ph.

REFERENCES

Centers for Disease Control and Prevention. Asthma mortality and hospitalization amoung children and young adults-United States, 1990-1993.MMWR 1996;45:350-353

Centers for Disease Control and Prevention. Asthma-United States, 1989-1992. MMWR 1995;43:952-5

Fish J, Kemp J, Lockey R et al. Zafirlukast for symptomatic mild-to-moderate asthma: A 13 -Week Multicenter Study. Clin Ther. 1997;19:675-690 (IDIS Article Number 393045)

Israel E, Cohn J, Dube L et al. Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma. JAMA. 1996;275:931-36 (IDIS Article Number 362020)

Kelloway J. Zafirlukast: the first leukotriene-receptor antagonist approved for the treatment of asthma. Ann Pharmacotherapy. 1997;31:1012-21 (IDIS Article Number 391497)

Knorr B, Matz J, Bernstein J et al. Montelukast for chronic asthma in 6- to 14 year-old children. JAMA. 1998; 279:1181-1186 (IDIS Article Number 402889)

Liu M, Dube L, Lancaster J et al. Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: a 6-month randomized multicenter trial. J Allergy Clin Immunol. 1996;98:859-71 (IDIS Article Number 377230)

Mellins RB, Evans D, Zimmerman B et al. Patient compliance. Are we wasting our time and dont know it? Am Rev Respir Dis 1992;146:1376-7

Montelukast package insert. West Point,PA: Merck & Co Inc;1998 Feb.

National Institutes of Health, National Heart, Lung, and Blood Institute. 1997 Highlights of the Expert Panel Report II: Guidelines for the Diagnosis and Management of Asthma. National Institutes of Health, Bethesda , MD [resource on World Wide Web]. URL: http://www.nhlbi.nih.gov/nhlbi/lung/asthma/prof/asthgdln.htm. Available from Internet. Accessed 1997 Nov 15.

Reiss T, Chervinsky P, Dockhorn R et al. Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma. Arch Intern Med. 1998;158:1213-1220 (IDIS Article Number 408567 )

Schwartz H, Petty T, Dube L et al. A randomized controlled trial comparing zileuton with theophylline in moderate asthma. Arch Intern Med. 1998;158:141-148 (IDIS Article Number 399785)

Suissa S, Dennis R, Ernst P et al. Effectiveness of the leukotriene receptor antagonist zafirlukast for mild-to moderate asthma: a randomized, double-blind, placebo-controlled trial. ANN INTERN MED. 1997;126:177-183 (IDIS Article Number 380612)

United States Food and Drug Administration. Summary basis of approval. Zafirlukast: NDA 20-547. Washington, DC: United States Department of Health and Human Services. 1996

Wechsler M, Garpestad E, Flier S et al. Pulmonary infiltrates, eosinophilia, and cardiomyopathy following corticosteroid withdrawal in patients with asthma receiving zafirlukast. JAMA. 1998:279:455-457 (IDIS Article Number 399474)

Zafirlukast package insert. Wilmington, DE: Zeneca Pharmaceuticals; 1996 Sept.

Zileuton package insert. North Chicago, IL: Abbott Laboratories; 1996 Dec.

SEARCH TIPS

IDIS WINDOWS® Enhancements

Viewing Articles

Once a search has been executed, the results are displayed in a split screen format. A click on the highlighted Image tab located at the lower left of the top screen retrieves the article for viewing. Two features have been added to enhance article viewing:

1) The capability to choose an individual page for viewing allows quick access to a specific section of a long article.

2) The capability to rotate a page makes the reading of sideways charts and tables less awkward.


Printing Index Records and Articles

After viewing the index record or the article, a click on the Printer button opens the Print Screen with diverse font options, styles and sizes. IDIS software now supports more printers.

The new feature "Image Page Range" allows printing an image of a specific page or page range from a selected article. An article image will be printed in its entirety if the "Image Page Range" is left blank.


Reinstallation

Previously, re-installation was required with each monthly update. An enhancement of our software allows using the system without re-installation once the November 1998 update is installed. Subscribers will no longer need to re-install unless notified by IDIS staff.

ThaiBinh TonThat
R.Ph. Pharm. D.

Division of Drug Information Services (DDIS) Provides Fellowship Training

Sponsored by the World Health Organization, two Malaysian pharmacists completed four-week training fellowships at DDIS during the Spring of 1998. Mr. Farid Wong Bin Abdullah's fellowship began March 9 and continued through April 3, and Ms. Asma Murshid studied in Iowa City from April 13 through May 8. The fellowships provided customized and individual training at DDIS, The University of Iowa Hospitals and Clinics (UIHC) and Mercy Hospital in Iowa City.

Mr. Farid Wong Bin Abdullah

Mr. Wong and Ms. Murshid had different interests and goals for their fellowships. Mr. Wong came to "to study the setting-up of a computer network for pharmacy-related service in a public hospital with emphasis on clinical pharmacy activities and drug information services" and "to evaluate the suitability of software currently in use for adoption in Malaysia." Ms. Murshid's goals were "to study the drug auditing system being implemented, to identify various intervention strategies used in promoting rational use of drugs and to gain expertise in improving pharmaceutical use in health care."

Ms. Asma Murshid and Dr. ThaiBinh TonThat, IDIS

Ms. Murshid is currently the project coordinator for the Malaysian Rational Use of Drug (MRUD) Programme. She is one of two pharmacists at Pengarah Hospital, Hospital Seberang Jaya, a 314-bed district hospital located in Penang, Malaysia. Mr. Wong is with the pharmacy division of the Ministry of Health in Kuala Lumpur, Malaysia. He received his Bachelor of Pharmacy degree with honors from the Universiti Sains Malaysia, Malaysia's second oldest university.

As part of their training, Mr. Wong and Ms. Murshid gave presentations to the DDIS pharmacists and other staff about pharmacy in their country. Both agree that Malaysia is undergoing a drive towards industrialization and modernization. According to their presentations, the population of Malaysia is approximately 21 million people with 3,000 pharmacies and 150 hospitals. There are two kinds of hospitals: general hospitals employing eight to 20 registered pharmacists and district hospitals that deal with administration and supplies and usually employ one or two registered pharmacists. The Malaysian Health Care system is set up so that the poor and rural residents depend greatly on government health services that either do not charge or charge very nominal fees. Government health services are financed by taxes and other public revenues.

There are three universities and two private colleges (not yet open) available to study pharmacy in Malaysia. Pharmacy is a four-year program leading to a Bachelor of Pharmacy degree. After practicing for one year the pharmacist must pass the forensic examination (in English) and then be registered under the Malaysian Pharmacy Board. Once you pass the exam and register, you are registered for life. A federal Malaysian law called the "Enterprise Law" allows interested people to attend career training at no charge.

In the pharmacy division of the government sector, there are three branches: Regulatory, Enforcement and Pharmaceutical Care. There is a Federal Formulary listing 1,226 drugs. There are also state formularies where hospitals pick their own drugs which are reviewed every three months. There are five classes of drugs, A through E. Malaysian pharmacists can prescribe Class C drugs, e.g., antifungals.

As reported by Mr. Wong and Ms. Murshid, pharmacy practice in Malaysia is very different from that in the United States. The fellowships undertaken in Iowa were their first exposure to pharmacy as it is practiced outside their country. The training they received and knowledge gained have undoubtedly proved invaluable to their practice of pharmacy in Malaysia. The DDIS staff would also like to express gratitude for the insights and thought provoking discussion of the pharmacy profession inspired by Mr. Wong and Ms. Murshid.

Donna Brus, Editor
donna-brus@uiowa.edu

1998 IDIS File Recap

The IDIS database continues to grow. From January 1998 to November 1998 we added:

Drug

The drug thesaurus contains 20,143 terms including over 7,300 valid terms. The fibric acid derivatives and the HMG CoA reductase inhibitors are now two subcategories of the Antilipemic Agents. All antiretrovirals are grouped under a new subcategory ANTIVIRALS-ANTIRETROVIRALS. Specific phytopharmaceutical valid terms were added to cover the rapid expansion of herbal medicines.

Disease

The disease thesaurus has close to 14,000 terms including more than 2,450 defined terms. 1998 activities concentrated around the topic of infection. The emerging trend of quinolone-resistant microorganisms in clinical practice prompted the addition of the defined term RESISTANCE, QUINOLONES V09.5. Before 1998, all streptococcal infections were indexed under the defined global term Infection, Streptococcus. The creation of five additional defined streptococcal infection terms in 1998 allows the retrieval of specific streptococcal serogroup A, B, C, D and G infections. Staphylococcus aureus infection now has a unique defined term to set it apart from other staphylococcal infections.

Descriptor

Clinical algorithm, advisory committee recommendations and position statements developed under the auspices of recognized authoritative organizations are indexed under descriptor 156 Practice Guidelines. They can now be searched in any year in the IDIS database.

Journal

The IDIS journal list is periodically reviewed. Journals from various specialties such as oncology, geriatrics, pharmaceutical care and alternative medicine are being evaluated. MEREK, a newsletter from the United Kingdom, will be added in 1999 and back indexed to 1990.

Thesaurus

The IDIS Thesaurus is a cross-reference of all valid drug, disease and descriptor terms to their synonyms, drug trade names or similar concepts. A total of over 900 entries have been added since January 1998.

ThaiBinh TonThat
R.Ph., Pharm.D.

IDIS Originator Honored

William W. Tester (left) receives the Distinguished Alumni
Award from Dean Gilbert Banker. IDIS Director Hazel Seaba
joins Banker in congratulating Tester.


William W. Tester of Anna Maria, Florida, was one of five alumni recently honored for their professional accomplishments and service to the University of Iowa and the College of Pharmacy. He was honored as a recipient of the UI College of Pharmacy Distinguished Alumni Award at the Collegeís All Alumni Reunion Dinner on October 9.

Mr. Tester served the University of Iowa from 1951 to 1975 in a number of positions, including Director of Hospital Pharmacy Services at the University of Iowa Hospitals and Clinics. In 1965, while executing the provisions of a U.S. Public Health Service grant, "A Study of Patient Care Involving a Unit Dose System," Mr. Tester saw the need for drug information to support the clinical activities of pharmacists practicing in patient care settings. He and other study investigators created the Iowa Drug Information Service database. Published in the College of Pharmacy, it was originally used just in the University of Iowa Hospitals and Clinics. The database was shared with other big ten university hospital pharmacy departments and eventually converted to a subscription service.

Mr. Tester was an early leader in baccalaureate clinical education and multidisciplinary research methodology. His contribution to pharmacy was not simply one of technical innovation, but a vision for a new role for the pharmacist. Placing the pharmacist in the patient care arena changed pharmacistsí role. The drug therapy knowledge of the pharmacist was called into play before the drug was administered. The physical presence of the pharmacist in the patient care domain led to the development of pharmacistsí current clinical, pharmaceutical care role.

When questioned about what he most enjoyed about pharmacy, Mr. Tester replied, "The strong pharmacist-patient relationship and the close interaction with physicians and other health care professionals. Over the years, in this clinical environment, pharmacy has provided and integrated a significant number of patient oriented services."

Donna Brus, Editor
donna-brus@uiowa.edu


IDIS System/CD-ROM and Year 2000 Compliance

IDIS System/CD-ROM is Year 2000 compliant. The publication year is the only date field in the database and is currently in four-digit format. There is no code in the retrieval software which is affected by the system date. Please contact us if you need additional information.


Perspective From an IDIS Subscriber

Editorís Note: From time to time, we publish articles contributed by IDIS subscribers. An article from Dave Mace, B.S.(Pharm.), is included in this issue. Dave Mace is from an institution that is a long-standing IDIS subscriber, utilizing the database on a regular basis. His consult illustrates when the use of the IDIS database contributed directly to patient care outcomes. The responsibility for errors is the authorís alone and does not necessarily represent hospital views and recommendations. We hope you find the information interesting and useful and welcome comments. If you are interested in sharing your experiences using the IDIS database, please contact donna-brus@uiowa.edu.

To: Geriatric Evaluation and Management Team Staff (GEM)

Re: Dementia like syndrome possibly associated with the use of paroxetine, donepezil or their combination in an elderly woman

HPI: The patient is a 78-year-old female who was admitted to GEM unit for evaluation on October 26th for a rapid decline in her cognitive status since May (MMSE: December 1997, 30/30; May 1998, 29/30; and August 1998, 20/30) and for evaluation of her gait disturbance, weakness, increased falls and incontinence. The patient has been on naproxen 500 mg qam, acetaminophen prn for RA, donepezil 10 mg qhs for Alzheimerís disease and paroxetine 20 mg qam for depression. The patient lives with her husband, who is her main caregiver. He reports increasing difficulty in providing her care.

On the patientís eighth hospital day orders were written to discontinue paroxetine and begin tapering donepezil over the next three days. On the morning of the eleventh hospital day, the patient seemed more alert and was able to converse with staff. Her husband considered her to be significantly improved when compared with her status prior to admission. Her improvement continues and she is aware of her continuing deficits. Formal mental status testing results are pending as she was unable to cooperate with testing shortly after admission.

CONSULTS

Neurology: Pending

Gero-Psychiatry: October 27

Differential includes iatrogenic factors (fluoxetine, lorazepam, paroxetine and donepezil - all introduced a few months prior to admission); new stroke; infections and other possible medical etiology. The patient was seen by the physician on 10/28/98 and she was more alert than the day before. (On the previous day she was confused and unable to answer any questions.) In the physicianís judgment, no psychotropic medications were currently needed. The physician was aware the paroxetine and donepezil had been discontinued. The physician described a history of polyneuropathy (which we did not see in history) and recommended adding vitamin B1 and B12 therapy. The physician stressed the patient's poor response to antidepressant(s) in the past prior to the emergence of aggression noted recently.

LITERATURE

Paroxetine (Paxil)

Mirow (1991) described a 60-year-old woman with major depressive disorder who was stable on fluoxetine 20 mg daily. She presented with a nine-month history of memory and learning impairment (e.g., forgetting she made a bank deposit), unaccompanied by depression, sleep disturbance, sedation or anticholinergic signs. She improved slightly about a week after the discontinuation of fluoxetine and was started on nortriptyline 40 mg daily for recurrent depressive episodes. Eighteen days after discontinuing fluoxetine, she was significantly improved and no recurrent cognitive dysfunction was reported.

Lewis and colleagues (1993) reported a 67-year-old mildly mentally handicapped woman with agitated depressive illness. She was started on paroxetine 20 mg and increased to 40 mg daily. She was also on thioridazine 10 mg tid, and trifluoperazine 10 mg for agitation. After three weeks the agitation was improved, and thioridazine and trifluoperazine were discontinued. She began to deteriorate, becoming immobile, unreactive, rarely speaking and occasionally incontinent. The cause of the deterioration was unknown. Two weeks after discontinuing thioridazine and trifluoperazine, paroxetine was discontinued and she completely recovered after five days. Two months later, paroxetine 20 mg daily and haloperidol 3 mg were added because of recurrence of depression. Psychomotor retardation developed again after two weeks and subsided once paroxetine was withdrawn. Whether paroxetine was solely responsible for these adverse effects is unclear. The neuroleptics may have contributed.

Singh and colleagues (1995) studied a 73-year-old man with a diagnosis of major depression who was started on fluoxetine 20 mg daily. The patient developed a fine tremor in his hands, decrease in appetite, slower and stiffer movements, urinary and bowel incontinence and became more withdrawn and disoriented to time, place and person after the second day of therapy. After the fifth day of therapy, fluoxetine was discontinued. On the sixth day, trihexyphenidyl was added and his tremor and rigidity was improved. On the seventh and eighth days, he was able to sit up, walk and communicate.

Donepezil (Aricept)

Bourke and colleague (1998) described an 80-year-old female with Parkinsonís disease who was on tacrine 20 mg qid for more than one month. She was also taking sertraline 25 mg daily. She was admitted to a nursing facility due to worsening balance and falls. On admission she walked freely without assistance. Twenty-seven days after admission her tacrine was changed to donepezil 5 mg daily to avoid potential hepatic toxicity and monitoring requirements. Within 14 days she was reported to be unsteady on her feet, lethargic and required assistance to walk. Eighteen days later she fell while walking. The PE findings included stiffness and tremor. Donepezil was discontinued three days later. She slowly improved after the discontinuation of donepezil. She was also hypothyroid with a TSH of 64. Her T4 dose was increased and no later TSH values were reported. Although hypothyroidism is a risk factor for falls, her ability to walk unassisted dramatically changed after donepezil was added. Sertraline is an inhibitor of both 2D6 and 3A4 hepatic enzymes.

Trzepacz and colleagues (1996) described on 80-year-old male who became increasingly confused after his tacrine was increased to 160 mg daily, after three months of use at lower doses. He became increasingly confused over the next 45 days, with a waxing and waning pattern. After starting a phenytoin regimen (200 mg bid) he became worse, with steady deterioration over the next two weeks. He became bedridden, incontinent of urine and dehydrated. All medications were held on admission. On admission, he was stuporous for the first 36 hours. When he awoke he demonstrated increased tone in his neck and extremities, with an intermittent low-frequency pill rolling tremor (R > L), cogwheeling, masked facies, muscle fasciculations, hyperflexia, miosis, grasp and snout reflexes and a transient heart rate of 60. (Levels of phenytoin and albumin were 22 mg/dl and 2.5 mg/dl, respectively.) Seventy-two hours after admission he became more alert. His level of consciousness continued to change. He required assistance in feeding and could not walk unassisted. Follow-up five months later revealed a functional level decrease from his level prior to the tacrine regimen. Failure to improve after the tacrine dose implies the existence of confounding factors or the possibility of persistent CNS damage.

Woo and colleagues (1996) studied 20 nursing home residents with Alzheimerís dementia who were given tacrine in doses ranging from 40 to 160 mg/day for up to 16 weeks. Tacrine was discontinued in their patients for the following reasons: weight loss and poor appetite (17), ALT levels above the upper limit of normal (9), anorexia (11), weight decrease (9), agitation (7), nausea and vomiting (6), confusion (4) and abdominal pain (3).

The Canadian Adverse Drug Reaction Monitoring Program (from 8/97 to 8/98) received the ADR reports associated with donepezil (Springuel, 1998). There was one report of each of the following: death two days later of unknown cause(s), dyskinesia, abnormal gait, headache and aggressive reaction. There were two reports each of anxiety and confusion.

*Note eight of the ADRs were reported in patients who were on drugs that are known to be 2D6 or 3A4 inhibitors (sertraline, fluoxetine, diltiazem). Paroxetine also inhibits 2D6 and 3A4.

MANUFACTURER

We contacted the medical information staff at SmithKline Beecham concerning reports of paroxetine and worsening dementia. They have no reports of paroxetine associated with the emergence or worsening of dementia syndromes (SmithKline Beecham Pharmaceuticals, 1998). They acknowledge that patients with significant dementia were excluded from paroxetine clinical trials in depression, OCD and panic disorder. A clinical trial compared imipramine and paroxetine in 198 patients with dementia, in which the most common adverse effects associated with paroxetine were somnolence, nausea and insomnia. However, they did not describe specific syndromes in patients who discontinued paroxetine or indicate whether there were any cases of further decline in mental status or functional level (Katone cited in SmithKline Beecham, 1998; original unavailable to us).

COMMENT

The patient has become increasingly confused and periodically incontinent of urine since the start of her donepezil and/or paroxetine. Our original impression was that a drug interaction had occurred between paroxetine and donepezil which reduced donepezil clearance, resulting in higher than expected donepezil levels and the syndrome of confusion/delirium/dementia. The possibility of such an interaction exists, since donepezil is a substrate for both CYP2D6 and CYP3A4 and paroxetine inhibits the metabolism of CYP2D6. We believe it is possible that elevated donepezil levels may have contributed to the patient's decline. Our search resulted in nine cases of parkinsonian features or confusion associated with the use of tacrine or donepezil. Details describing systemic cholinergic effects in most of these patients were lacking. This leads us to believe that the confusion or parkinsonian features emerged in the absence of signs of cholinergic excess, such as nausea, vomiting, sweating and diarrhea. The patient did not have any history of such cholinergic excess. We cannot rule out donepezil as a contributing factor in the patientís recent decline.

The SSRIs, as a group, are becoming more frequently associated with the emergence of parkinsonian side effects, including EPS, akathisia, dystonia and tardive dyskinesia-like syndromes. A recent editorial (Pies, 1997) posed the following question: "Must we now consider SRIs neuroleptics?" Although such side effects had been believed to be infrequent or rare, a retrospective review of EPS in elderly patients exposed to SSRIs found a 6% (4 cases) incidence in a medically ill group, two of whom had preexisting parkinsonism. In each case the EPS remitted after the SSRI was discontinued (Pies, 1997). As of December 31, 1996, Eli Lilly had received the following reports of EPS associated with fluoxetine: akathisia, 403 cases; dystonia, 240 cases; tardive dyskinesia, 81 cases. Over the long history of TCAs there have been few spontaneous reports for all types of EPS. Apparently such syndromes (of neuroleptic-like side effects) are much more common with SSRIs than with TCAs (Breggin, 1994).

It is well known that even low or standard doses of neuroleptics such as haloperidol can result in the clinical deterioration of patients with early dementia or parkinsonian syndromes. Who can say whether or not the SSRIs, by whatever mechanism they cause EPS, could also result in clinical deterioration of patients with early dementia? The few case reports we found support such a possibility. Several other elderly patients with medical problems seen on our unit, who were treated with sertraline, became less active, withdrawn, and their functional status declined without any other known reason(s).

We believe the patientís rapid improvement within a few days of discontinuing paroxetine and donepezil provides support for the probability that the drugs had contributed to her decline. The discontinuation of both drugs in the same time frame makes it difficult to determine whether one of the drugs alone or the combination of drugs contributed to her decline.

You may wish to consider the possibility of a diagnostic rechallenge in the future, with each agent separately.

FOLLOW-UP

On the morning of the patientís eighteenth hospital day, she seems much more alert and she continues to improve in her clinic exercise program. Other staff describe the patientís status as waxing and waning with periods of confusion. She is expected to remain on the unit for several more weeks and will be followed in GEM clinic as an outpatient.

REFERENCES

Bourke D, Druckenbrod RW. Possible association between donepezil and worsening Parkinsonís disease. Ann Pharmacotherapy 1998;32:610-611. (IDIS Article Number 404836)

Breggin PR, Breggin GR. Talking back to Prozac. New York: St. Martinís Press, 1994.

Lewis J, Braganza J, Williams T. Psychomotor retardation and semistuporous state with paroxetine. Br Med J 1993;306:1169. (IDIS Article Number 313777)

Mirow S. Cognitive dysfunction association with fluoxetine. Am J Psychiatry 1991;148:948-949. (IDIS Article Number 284233)

Pies, RW. Must we now consider SRIs neuroleptics? J Clin Psychopharmacol 1997;17:443-445. (IDIS Article Number 397920)

Singh, RK, Gupta AD, Singh B. Acute organic brain syndrome after fluoxetine treatment. Am J Psychiatry 1995;152:295-296. (IDIS Article Number 341580)

SmithKline Beecham Pharmaceuticals. Personal communication from William Cushing Product Information Department, November 9, 1998.

Springuel P. Donepezil: suspected adverse reactions. Can Med Assoc J 1998;159:81. (IDIS Article Number 408522)

Trzepacz PT, Ho V, Mallavarapu H. Cholinergic delirium and neurotoxicity associated with tacrine for Alzheimer's disease. Psychosomatics 1996;37:299-301.

Woo JK, Lantz MS, Marchello V et al. Efficacy and tolerability of tacrine in nursing home residents with Alzheimerís dementia. J Am Geriatr Soc 1996;44:1411-1412. (IDIS Article Number 376597)


Deirdre Fanning, Pharm.D. candidate, prepared the portion of this article concerning donepezil.

Zenaida Quinn, Pharm.D. candidate, prepared the portion of this article concerning paroxetine.

Dave Mace, Drug Information Specialist, revised and edited the article. Mace graduated from the University of Iowa College of Pharmacy in 1967. Since 1982 he has served as the Director of the Drug Information Center at BPVAMC, 10,000 Bay Pines Blvd., Bay Pines, FL 33744. His responsibilities include serving as a preceptor for drug information and Pharm.D. clerkship programs and responding to complex drug information requests from clinical staff.


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KEY REFERENCES

NEW DRUG SELECTED BIBLIOGRAPHY

This new drug selected bibliography provides a selection of key clinical studies of new drugs approved by the FDA during August, September and October 1998. IDIS SYSTEM/CD-ROM was searched to retrieve key articles relevant to the new drugs and their approved uses.

Efavirenz

Carpenter CCJ, Fischl MA, Hammer SM et al. Antiretroviral therapy for HIV infection in 1998. Updated recommendations of the international AIDS society-USA panel. JAMA 1998;280:78-86. (IDIS Article Number 408238). These updated recommendations include guidelines on the use of nonnucleoside reverse transcriptase inhibitors such as efavirenz for antiretroviral therapy.

Infliximab

Targan SR, Hanauer SB, Van Deventer SJH et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohnís disease. N Engl J Med 1997;337:1029-1035. (IDIS Article Number 393095). A 12-week multicenter, randomized, placebo-controlled, double-blind trial was conducted by investigators to compare efficacy of a single two-hour infusion of 5, 10 or 20 mg/kg infliximab with placebo for the treatment of active Crohnís disease in 108 patients with moderate-to-severe disease resistant to treatment.

Leflunomide

Mladenovic V, Domljan Z, Rozman B et al. Safety and effectiveness of leflunomide in the treatment of patients with active rheumatoid arthritis. Arthritis Rheum 1995;38:1595-1603. (IDIS Article Number 358458). This report summarizes the findings of a six-month, randomized, placebo-controlled, triple-blind phase II study comparing 5, 10 or 25 mg daily doses of leflunomide to placebo in 402 patients with active rheumatoid arthritis.

Rotavirus Vaccine

Rennels MB, Glass RI, Dennehy PH et al. Safety and efficacy of high-dose rhesus-human reassortant rotavirus vaccines-report of the national multicenter trial. Pediatrics 1996;98:7-13. (IDIS Article Number 360385). A report of the results of a large, multicenter, randomized, placebo-controlled, double-blind trial of monovalent serotype 1 and tetravalent rhesus-human reassortant rotavirus vaccines in 1,278 healthy infants ages five to 25 weeks. (One of the three pivotal studies on which FDA approval was based.)

Griffiths RI, Anderson GF, Powe NR et al. Economic impact of immunization against rotavirus gastroenteritis: evidence from a clinical trial. Arch Pediatr Adolesc Med 1995;149:407-414. (IDIS Article Number 345533). Investigators conducted a study to estimate the economic impact, from the societal perspective, of immunization against rotavirus gastroenteritis in an infant population in the United States by performing an economic analysis based on data collected alongside the above national multicenter trial.

Santosham M, Moulton LH, Reid R et al. Efficacy and safety of high-dose rhesus-human reassortant rotavirus vaccine in Native American populations. J Pediatr 1997;131:632-638. (IDIS Article Number 397534). In a randomized, double-blind trial, investigators compared the efficacy, safety and immunogenicity of a rhesus rotavirus tetravalent vaccine, a rhesus rotavirus monovalent vaccine, and placebo in 1,185 healthy American Indian infants, aged six to 24 weeks, for two rotavirus seasons. (One of the three pivotal studies on which FDA approval was based.)

Joensuu J, Koskenniemi E, Pang XL et al. Randomized placebo-controlled trial of rhesus-human reassortant rotavirus vaccine for prevention of severe rotavirus gastroenteritis. Lancet 1997;350:1205-1209. (IDIS Article Number 394768). In a randomized, placebo-controlled, double-blind study, investigators assessed the efficacy of rhesus human reassortant rotavirus tetravalent vaccine against severe rotavirus gastroenteritis in 2,400 Finnish infants. (One of the three pivotal studies on which FDA approval was based.)

Sevelamer

Chertow GM, Burke SK, Lazarus M et al. Poly[allylamine hydrochloride] (RenaGel): a noncalcemic phosphate blinder for the treatment of hyperphosphatemia in chronic renal failure. Am J Kidney Dis 1997;29:66-71. (IDIS Article Number 378868). In this eight-week, phase II, randomized, placebo-controlled, double-blind, parallel-design trial, investigators evaluated the efficacy and safety of poly[allylamine hydrochloride] (sevelamer) as a phosphate binder in 36 patients on maintenance hemodialysis.

Technetium Tc-99m Apcitide

Muto P, Lastoria S, Varrella P et al. Detecting deep venous thrombosis with technetium-99m-labeled synthetic peptide P280. J Nucl Med 1995;36:1384-1391. (IDIS Article Number 351465). This study was conducted to determine the feasibility of externally imaging deep vein thrombosis (DVT) with technetium Tc-99m apcitide in nine patients with DVT and to assess the safety and sensitivity of this agent for diagnosing DVT.

Ruth Calloway, R.Ph., M.S.


FDA DRUG/BIOLOGIC APPROVALS

Generic Name

(FDA Therapeutic Classification)

Trade Name

Sponsor

(Approval Date)

Valid IDIS Drug Term

Drug Number

(IDIS Citations)*

Indication/Use

Valid IDIS Disease Term

Modified ICD-9-CM Number

Efavirenz
(1P)**
Sustiva
Dupont Merck Pharmaceutical
(Sept. 17)
EFAVIRENZ
8180401
(7citations)
Treatment of HIV-1 infection Infection, HIV, Asymptomatic
V08.
Syn-Acq Immune
Deficiency
042.
Fomivirsen sodium
(1P)
Vitravene
Isis
(Aug. 26)
FOMIVIRSEN
8180097
(5 citations)
Local treatment of cytomegalovirus (CMV) retinitis in patients with AIDS who are intolerant of or have a contraindication to other treatment(s) for CMV retinitis or who were insufficiently responsive to previous treatments for CMV retinitis Disease, Cytomegalic Incl.
078.5
Chorioretinitis NEC
363.2
Infliximab
Remicade
Centocor, Inc.
(Aug. 24)
INFLIXIMAB
82000446
(11 citations)
Reduction of signs and symptoms of moderately to severely active Crohnís disease in patients who have an inadequate response to conventional therapy, and for reduction in the number of draining enterocutaneous fistula in patients with fistulizing Crohnís disease Enteritis, regional
555.
Leflunomide
(1P)
Arava
Hoechst Marion Roussel
(Sept.10)
LEFLUNOMIDE
95000119
(15 citations)
For the treatment of active rheumatoid arthritis (RA) to reduce signs and symptoms and to retard structural damage as evidenced by X-ray erosions and joint space narrowing Arthritis, Rheumatoid
714.0
Rotavirus Vaccine
RotaShield
Wyeth-Ayerst Laboratories
(Aug. 31)
ROTAVIRUS VACCINE
80120039
(83 citations)
Prevention of rotavirus gastroenteritis caused by rotavirus serotypes 1-4 in infants in a three-dose series at 2, 4, and 6 months of age Infection, Intest, Rotavirus
008.61
Sevelamer Hydrochloride
(1S)***
RenaGel
Geltex Pharmaceuticals
(Oct.30)
ALLYLAMINE
95000019
(1 citation)
Reduction of serum phosphorus in patients with end stage renal disease who are on hemodialysis Disorder, Phosphorus Metab
275.3
Failure, Renal
586.
Hemodialysis
39.95
Technetium TC-99m Apcitide
(1P)
AcuTect
Diatide
(Sept. 14)
TC 99M APCITIDE
78040261
(1 citation)
Scintigraphic imaging of acute venous thrombosis in the lower extremities of patients who have signs and symptoms of acute venous thrombosis Radioisotope Scan NEC
92.0
Embolism/Thrombosis,VN NEC
453.
Trastuzumab
Herceptin
Genentech
(Sept. 25)
TRASTUZUMAB
82000447
(5 citations)
Treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have received one or more chemotherapy regimens for their metastatic disease Neop, MGN-Female Breast
174.
Valrubicin
(1P)
Valstar
Anthra Pharmaceuticals
(Sept. 25)
VALRUBICIN
10030030
(3 citations)
For intravesical therapy of BCG-refractory carcinoma in situ (CIS) of the urinary bladder in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality Neop, MGN-Bladder
188.

* Through November 1998 update. Complete bibliographic citations will be provided upon request.
** (1P) New Molecular Entity given priority review by FDA.
*** (1S) New Molecular Entity given a standard review by FDA.


STAFF PROFILE

                       Deb Abel
Deb Abel joined the staff of IDIS as a Medical Record Administrator I in June of 1998. Prior to being employed with IDIS, Deb worked in the Department of Anesthesia at The University of Iowa Hospitals and Clinics.

Deb's main responsibility with the division is indexing. She also helps with proofing articles. Favorite leisure activities include music, reading and spending time with her children.


World of Drug Information is published quarterly (March, June, September, December) by the Division of Drug Information Service.

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Photographer: David Luck

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IDIN
Iowa Drug Information Network
Telephone: 319-335-4199
U.S. Toll-Free: 800-791-7055
Fax: 319-335-4440
E-mail: IDIN@uiowa.edu
Web Site: http://idin.idis.uiowa.edu

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