World of Drugs

World of Drugs - Volume 7, Issue 3 - September 1996

In This Issue ...
 Search Tip 
 Renewal Notice 
 Staff Profile 
 Search Strategies--Current Clinical Issues 
 FDA Drug Approvals 
 Exhibit Schedule 

SEARCH TIP: Searching for Pregnancy Articles Using the Disease Field, Part II

The June issue Search Tip focused on the retrieval of pregnancy related articles from the IDIS database. Use of the pregnancy check tags, V22. and V23., and several specific disease terms identifying pregnancy complications were reviewed. To conclude this topic, disease terms related to ectopic pregnancy, abortion, labor, delivery, and the puerperium will be discussed.

Ectopic Pregnancy
When searching for articles dealing with ectopic pregnancy the term 633. PREGNANCY, ECTOPIC NEC is used to retrieve cases of cervical, cornual, ovarian, interstitial, or unspecified ectopic pregnancy. For articles on ectopic pregnancy located in the fallopian tube 633.1 PREGNANCY, TUBAL is available.

Abortion
Disease terms identifying abortion include:

Complications of spontaneous or therapeutic abortion may be found by placing the following terms in the disease field:

Labor
Complications of labor affecting the mother are identified by the following:

Medical labor induction procedures including amniotomy are indexed under:

Delivery
The disease term describing normal or uncomplicated delivery is 650. DELIVERY.

Another term for delivery, specifically describing delivery of twins, triplets, etc., is 651. DELIVERY, MULTIPLE BIRTH.

The Puerperium
The following disease terms denote events occurring in the puerperium, or the time from termination of labor to complete involution of the uterus (generally accepted to be a period of 42 days).

The grouping of the above terms into their respective categories illustrates the importance of defining the time period (pregnancy, labor, delivery, puerperium) in which the event of interest occurs. Retrieval of articles dealing with specific events and complications of the various stages of pregnancy and the postpartum period can be accomplished more efficiently when these disease term groups are recognized.

Lori Huynh, R.Ph., Pharm.D.


RENEWAL NOTICE!
Renewal materials for the 1997 IDIS database subscription were mailed in early September. We ask that you respond as soon as possible. Your current subscription will expire after the December 1996 update. To avoid interruption of service your renewal must be received by January 10, 1997. Current microfilm subscribers should note a special offer included with their renewal materials. In the event you misplace or fail to receive a renewal form, please contact our office as soon as possible.

IDIS STAFF PROFILE

Jane Heaton

Jane Heaton joined IDIS as the Scanning Secretary in March of 1996. Jane's primary duties are to scan and proofread abstracts for the database and to coordinate its Quality Assurance/Quality Improvement program. She also assists with data entry, answering phones and other office duties.

Through past work experience in publications, Jane has developed an eye for working with detail. An 11-year employee of the University, she has worked as Production Assistant for the alumni magazine and as Editorial Assistant for Health Science Relations. She has also served as copy-editor for 15 books, most of them on health-related topics.

Much of Jane's spare time is devoted to Toastmasters. Having recently completed a term as Area Governor, Jane is making a concentrated effort to improve her speaking skills. She belongs to three Toastmasters clubs and enjoys traveling the state to compete in speech contests and attend conferences. Jane's motto is "Have speech, will travel."


CURRENT CLINICAL ISSUES -- SEARCH STRATEGIES

PREVENTION OF OSTEOPOROSIS

The purpose of this article is to illustrate use of the IDIS database for identifying key primary literature practical for making drug therapy decisions or for preparing a review on prevention of osteoporosis.

When approaching this type of subject, it is frequently helpful to first locate a few good review articles to obtain general background information and to identify all of the key issues that you will want to address. The first step to an effective search in the IDIS database is to identify the valid search term(s). The selected search terms are then input in the appropriate field to execute the search. The search strategy may then be modified based on the results, and additional searches performed to find the specific information needed.

OSTEOPOROSIS OVERVIEW

Search Strategy: Thesaurus: Press <F3> and choose the thesaurus option from the pull down menu. Press enter. Type the term osteoporosis or use the * sign to truncate the term and press enter. The thesaurus contains 13 disease terms related to osteoporosis. Valid terms are followed by the modified ICD-9CM disease number (e.g., OSTEOPOROSIS 733.0). Only valid disease terms or numbers are used to search in the disease field of the field search template.

Search/Results: Press < F3> and select the field search option. Enter the term OSTEOPOROSIS (or the disease number 733.0) in the disease field and press the enter key to execute the search. The 1985-present file contains 657 records and the 1966-1984 file includes 374 records for the search term OSTEOPOROSIS for a total number of 1031 citations in the database on this broad topic.

Search Modification: To find review articles on osteoporosis use the field search template, type OSTEOPOROSIS (or disease number 733.0) in the disease field and add the word review in the descriptor field. You can specify the population of the review using REVIEW ADULT (or descriptor number 6) or REVIEW GERIATRIC (or descriptor number 23) in the descriptor field. Depending on which of these strategies you use you will retrieve 75 to 200 records. After executing the search press <F7> and select index and abstract to view the results. The results will be displayed with the most current articles first. You may select the articles you want to read based on criteria such as: article currentness, journal, recognized authors.

Clinical Information:

Based on the review articles that you have obtained through this first search of the IDIS database you will find that osteoporosis is gaining recognition as a major health problem in industrialized countries and is expected to have an increasing impact due to the aging populations. In the US alone, more than 1.5 million Americans have fractures each year related to osteoporosis. The annual cost to the health care system in the US will exceed $10 billion (Riggs, et al, 1992). These figures are expected to double by the year 2020 if prevention measures are not implemented. Health care providers can have a great impact on this dilemma by identifying individuals at risk for developing osteoporosis and targeting them for cost-effective prevention measures.

The World Health Organization defines osteoporosis as a " disease characterized by low bone mass and micro architectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in the risk of fractures" (Riggs, et al, 1992; Lindsay, 1989). Osteoporosis is becoming more prevalent in men, but it predominantly affects women. Several risk factors have been associated with osteoporosis including: female gender, Caucasian race, low body weight, select endocrine diseases, low calcium intake, early menopause, genetic abnormalities, estrogen deficiency, chronic corticosteroid use, excessive alcohol intake, cigarette smoking and a sedentary life style. There are also a number of other risk factors for the incidence of fractures, such as increased risk of falls, that are important to consider in patients at risk of osteoporosis.

Osteoporosis is a multifactorial health care problem involving issues of education, screening, diagnosis, prevention, treatment and management of the morbidity associated with fractures. A variety of search strategies could be used to locate literature through the IDIS database to address each of these issues specifically and individually. The remainder of this article will present search strategies to locate specific information to address the issues related to the prevention of osteoporosis.

PREVENTION OF OSTEOPOROSIS

Search Strategy:

Thesaurus: Press <F3> and select the thesaurus option from the pull down menu. Type PREVENTION. The entry retrieved shows that PROPHYLAXIS NEC (or disease number V07.) is the valid term for searching the IDIS database.

Search/Results: Press <F3> to return to the field search template; in the disease field enter: PROPHYLAXIS NEC (or disease number V07.) leave a space then type OSTEOPOROSIS (or disease number 733.0). Press the enter key to execute the search. This search strategy will find articles containing both terms. The 1985-present file contains 295 records and nine records in the 1966-84 file.

Search Modification: To find articles on postmenopausal osteoporosis prevention return to the thesaurus. Enter the truncated term POSTMENOPAUS*. The valid term for post menopausal status is DISORDER, MENOPAUSE/POST NEC (or disease number 627.). Select the field search template and enter DISORDER, MENOPAUSE/POST NEC (or 627.), OSTEOPOROSIS (or 733.0), PROPHYLAXIS NEC (or V07.) in the disease field. Place a space between valid disease terms entered. The 1985-present file contains 141 records. Reminder: When using the disease code numbers to search, always enter the decimal point.

Clinical Information: Drug therapy options

After review of selected articles from your search for information on prevention of osteoporosis you will see that several drug therapy options may be considered including: calcium supplementation, vitamin D, estrogen replacement, alendronate, calcitonin, and sodium fluoride. The next step in your project to learn more about the drug therapy issues in the prevention of osteoporosis is to find more specific information about each of these medications.

IDENTIFYING ARTICLES ON SPECIFIC DRUG THERAPY FOR PREVENTION OF OSTEOPOROSIS

CALCIUM SUPPLEMENTATION

Search Strategy:

Thesaurus: Type calcium. There are 166 valid drug terms or cross reference terms linked to calcium. The valid drug terms are in all capital letters and are followed by the modified American Hospital Formulary Service (AHFS) number. If you wish to obtain information on a specific calcium salt use that individual term or number in searching. To retrieve records for all of the calcium salts as a drug class, type the term calcium in the drug field.

Search/Results: Press <F3> and select the field search template. Enter OSTEOPOROSIS (or 733.0), PROPHYLAXIS NEC (or V07.) in the disease field, and calcium in the drug field. The 1985-present file contains 120 records.

Search Modification: A useful search strategy is to restrict your retrieval to controlled studies. You can do this by typing study in the descriptor field. To retrieve only randomized trials, type study random* in the descriptor field. A search for randomized controlled trials of calcium in prevention of osteoporosis will retrieve 10 records in the 1985 to present database.

Clinical Information:

Most experts agree on the need for adequate calcium intake for proper bone formation. The US recommended daily allowance (RDA) is 800 mg to 1200 mg of elemental calcium daily. Studies have shown that in the US, 75% of women between the ages of 18 -30 ingest less than the RDA for calcium (Reid, et al, 1993). The current guidelines from the NIH Consensus Development Conference recommend 1000 mg of elemental calcium daily for postmenopausal women receiving estrogen, 1500 mg for postmenopausal women not receiving estrogen, 1500 mg for anyone over age 65, 1000 mg for adults, 1200-1500 mg for adolescents and young adults and 800-1200 mg for children. The amount of calcium supplementation recommended for an individual should consider the amount of dietary calcium received. There are many resources available (e.g., from the National Osteoporosis Foundation) for estimation of the calcium content of a person's diet. One must also be aware that the elemental calcium content of different calcium salts varies; calcium carbonate is 40% calcium, calcium citrate is 21% and calcium glubionate and gluconate are 6.4 % and 9% calcium respectively (Lindsay, 1993).

VITAMIN D SUPPLEMENTATION

Search Strategy:

Thesaurus: If you type vitamin D in the thesaurus search, you will find that VITAMIN D & DERIVATIVES is the valid drug term. The truncated AHFS number 8816* is the most efficient way to search this entire class of drugs. If you are interested in searching by individual vitamin D derivatives, you can find a list of valid terms by typing 8816* in a thesaurus search.

Search/Results: Select the field search template; use the valid terms for osteoporosis, prophylaxis, etc., as identified above and use 8816* in the drug field.

Clinical Information:

For prevention of osteoporosis, Vitamin D is generally recommended as a supplement of 400-800 IU daily in all individuals who are considered at risk.

ESTROGEN FOR PREVENTION OF OSTEOPOROSIS

Search Strategy:

Thesaurus: ESTROGEN is a valid drug term. To find articles on estrogen as a drug class you may use the truncated AHFS number 681600*. A search in the thesaurus will show you all of the terms which are included in this category.

Search/Results: Use the combination of disease terms as previously presented and include 681600* in the drug field of the field search template. The 1985-present file contains 189 records on the use of estrogen in prevention of osteoporosis.

You may restrict your search to controlled studies or to randomized controlled studies as described above in the search strategy for calcium supplementation. Several descriptor terms may be used to narrow the search to relevant areas of estrogen therapy. For example:

Randomized Controlled Trials (random*)
Transdermal Estrogen (ADM TOPICAL) (or descriptor 65)
Compliance (COMPLIANCE) (or descriptor 103)
Contraindication (CONTRAINDICATION) (or descriptor 52)

The risk of breast cancer from estrogen use is a significant and controversial issue. The concept of drug-induced breast cancer is indexed with the combination of descriptors SIDE EF NEOPLASM CYST (or 76) and SIDE EF ENDOCRINE (or 81). This search would be performed by typing 681600* in the drug field and 76 and 81 with a space between them in the descriptor field.

Clinical Information:

Estrogen is the best current option for the prevention and treatment of osteoporosis in most postmenopausal or perimenopausal patients. Lufkin, et al found that estrogen increased bone mass and decreased the rate of vertebral fracture. The optimal duration of estrogen therapy is undetermined. Some experts recommended that patients at high risk for fractures should receive lifelong therapy (Weiss, et al, 1980; Felson, et al, 1993). An additional significant consideration in the decision to use estrogen replacement therapy is that it may decrease the rate of coronary artery disease by 50% (Stampfer, et al, 1991).

There are several oral estrogen products available in the US, in addition to the transdermal dosage forms. Dosage regimens have included cyclic schedules as well as continuous therapy. For women with an intact uterus, a progestin should be added to decrease the risk of endometrial hyperplasia which occurs with unopposed estrogen (Bouillon, et al, 1991). The progestin may also be given in a cyclic- sequential regimen or continuously. The continuous regimens are gaining favor because of a lower frequency of side effects and the hope for improved compliance. In spite of the significant benefits of estrogens for prevention of osteoporosis, cardiovascular benefits, and reduction of the physiologic changes and symptoms associated with menopause, less than 30% of eligible patients currently are receiving this therapy. The Women's Health Initiative study sponsored by the NIH will hopefully answer many of the remaining questions regarding the optimal use of estrogen replacement therapy.

ALENDRONATE

Search Strategy:

Thesaurus: You will find that ALENDRONATE is the valid drug term.

Search/Results: Use the term OSTEOPOROSIS (or 733.0), PROPHYLAXIS NEC (V07.) in the disease field, ALENDRONATE in the drug field. In the 1985-present file there are no records. There are 27 records in the 1985-present file for alendronate.

Search Modification: There are two special issues involving the use of alendronate. Alendronate is very poorly absorbed, especially if it is taken with food. There are two descriptors that may be useful for this absorption search; DIETARY INTERACTION (or 75) and PKIN ABSORPTION (or 37). These descriptors may be combined (one at a time in separate searches) with ALENDRONATE.

Alendronate has been reported to cause ulcerative esophagitis. To find information on this drug-induced side effect, use the descriptor, SIDE EF DIGESTIVE (or 78), with ALENDRONATE.

Clinical Information:

Alendronate acts by inhibiting bone resorption. A randomized study of 994 postmenopausal women compared alendronate 5 mg, or 10 mg daily vs. placebo. The study found that women receiving alendronate had an increase in bone mass at all skeletal sites. Alendronate was also associated with a 48% decrease in the rate of new vertebral fractures (Liberman, et al, 1995). The FDA approved dosage of alendronate is 10 mg daily. Because of poor absorption it is important to make it clear to patients that they should take the dose in the morning on an empty stomach with a full glass of water and to not have anything to eat or drink for at least 30 minutes. They should also remain upright during this time to reduce the risk of esophagitis (Gertzetal, 1995; Abdelmalek, 1996).

CALCITONIN

Search Strategy:

Thesaurus: The recently marketed nasal spray form of calcitonin is CALCITONIN SALMON.

Search/Results: Use CALCITONIN SALMON in the drug field and the combination of disease terms, as presented above, in the disease field of the field search template. There are 47 records in the 1985-present database on calcitonin salmon for prevention of osteoporosis.

Search Modification: Prior to January 1994 intranasal administration was indexed under ADM EYE EAR NOSE THROAT (or descriptor 68). After Jan 1994 the administration routes became more specific and the term intranasal is currently being indexed under ADM NOSE (or descriptor 126). Select the field search template and enter CALCITONIN SALMON in the drug field, OSTEOPOROSIS (or 733.0) PROPHYLAXIS NEC (or V07.) in the disease field, and ADM NOSE (or 126) in the descriptor field. Using descriptor 126 retrieves 11 records and descriptor 68 retrieves 16 records in the 1985 to present database.

Clinical Information:

Calcitonin salmon is a peptide hormone that acts by interfering with the osteoclasts to inhibit bone resorption. Calcitonin salmon has been available as an injection for many years. Recently an intranasal dosage form was approved by the FDA. In clinical trials it has been shown to increase bone density in the lumbar spine and reduces the risk of vertebral fractures. A randomized trial of 251 postmenopausal women receiving 50 IU of intranasal calcitonin salmon vs. placebo found a 2% increase in spine bone density after two years of calcitonin salmon compared to placebo (Reginster, et al, 1995). The recommended dose for calcitonin salmon is 200 IU per day in one nostril, alternating nostrils every other day. The intranasal route is well tolerated and avoids the gastrointestinal side effects experienced with the parenteral routes.

SODIUM FLUORIDE FOR OSTEOPOROSIS

Search Strategy:

Slow release preparations are found under the descriptor term FORMULATION EFFICACY (or 22). To perform a search, enter SODIUM FLUORIDE in the drug field and FORMULATION EFFICACY (or 22) in the descriptor field and OSTEOPOROSIS (or 733.0) in the disease field of the field search template. The 1985-present file contains 11 records.

Clinical Information:

Sodium fluoride was first studied in 1961 in osteoporosis. There have been conflicting results on its use with some studies finding an increase in fracture risk. A slow release dosage form has recently been studied and has shown some positive results (Pak, et al, 1995). Sodium fluoride, unlike the other drugs mentioned previously, acts to increase bone formation by stimulating osteoblast proliferation. Bone fragility can occur with too much fluoride. Further investigation is needed to determine its role in preventive therapy. The slow release preparation of sodium fluoride is currently undergoing the FDA review process.

IN CONCLUSION

Osteoporosis is emerging as an epidemic in industrialized countries. Prevention of this disease will have a large impact on health care costs and patients' quality of life especially in the elderly. The necessity of exercise and proper diet should be encouraged in the young and these habits should continue throughout life. Pharmacological therapy should focus on prevention and cost-effective treatment. The specificity and flexibility of the IDIS database allows retrieval of key primary literature to address these issues.

Mary Ann Cull , R.Ph.


BIBLIOGRAPHY

Abdelmalek MF, Douglas DD. Alendronate-induced ulcerative esophagitis. AM J GASTROENTEROL 1996; 91:1282-1283 (IDIS Article Number 368262).

Bouillon R, Burckhardt P, Christiansen C, Fleisch HA, Et Al. Consensus development conference: prophylaxis and treatment of osteoporosis. AM J MED 1991; 90:107-110 (IDIS Article Number 277197).

Felson DT, Zhang Y, Hannan MT, Kiel DP, Et Al. The effect of postmenopausal estrogen therapy on bone density in elderly women. N ENGL J MED 1993; 329:1141- 1146 (IDIS Article Number 321057).

Gertz BJ, Holland SD, Kline WF, Matuszewski BK, Et Al. Studies of the oral bioavailability of alendronate. CLIN PHARMACOL THER 1995; 58:288-298 (IDIS Article Number 355285).

Liberman UA, Weiss SR, Broll J, Minne HW, Et Al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N ENGL J MED 1995; 333: 1437-1443 (IDIS Article Number 357030).

Lindsay R. Prevention and treatment of osteoporosis. LANCET 1993; 341:801-805 (IDIS Article Number 312331).

Lindsay R. Osteoporosis: an updated approach to prevention and management. GERIATRICS 1989; 44:45-54 (IDIS Article Number 264144).

Lufkin EG, Wahner HW, O'Fallon WM, Hodgson SF, Et Al. Treatment of postmenopausal osteoporosis with transdermal estrogen. ANN INTERN MED 1992; 117:1-9 (IDIS Article Number 298553).

National Institutes of Health. Consensus Development Conference Statement: Optimal Calcium Intake. Bethesda, MD: National Institutes of Health, JUNE 6-8,1994. URL: WWW.aace.com/guidelines/osteoporosis.html Available from internet. Accessed 1996 June 6.

Pak CY, Sakhaee K, Adams-Huet B, Piziak V, Et Al. Treatment of postmenopausal osteoporosis with slow-release sodium fluoride. ANN INTERN MED 1995; 123:401-408 (IDIS Article Number 353515).

Reginster JY, Deroisy R, Lecart MP, Sarlet N, Et Al. A double-blind, placebo-controlled, dose-finding trial of intermittent nasal salmon calcitonin for prevention of postmenopausal lumbar spine bone loss. AM J MED 1995; 98:452-458 (IDIS Article Number 348268).

Reid IR, Ames RW, Evans MC, Gamble GD, Et Al. Effect of calcium supplementation on bone loss in postmenopausal woman. NEJM 1993; 328:460-464 (IDIS Article Number 309584).

Riggs BL, Melton LJ. The prevention and treatment of osteoporosis. N ENGL J MED 1992; 327:620-627 (IDIS Article Number 300872).

Stampfer MJ, Colditz GA, Willett WC, Manson JE, Et Al. Postmenopausal estrogen therapy and cardiovascular disease: ten year follow-up from nurses' health study. N ENGL J MED 1991; 325:756-762 (IDIS Article Number 284994).

Weiss NS, Ure CL, Ballard JH, Williams AR, Et Al. Decreased risk of fractures of the hip and lower forearm with postmenopausal use of estrogen. N ENGL J MED 1980; 303:1195-1198 (IDIS Article Number 124682).

FDA DRUG APPROVALS

The FDA has already approved twice as many new molecular entities in 1996 as it had at this time last year. At this pace, an unprecedented number of new drugs may be approved in 1996.

This has been a banner year for oncologic agents. Docetaxel was approved May 14 for the treatment of breast cancer (discussed in June issues of World of Drugs). Another three oncologic agents have been approved and several more are likely to be approved before the year ends.

The month of May also saw the approval of topotecan for the treatment of ovarian cancer after failure of first-line chemotherapy and gemcitabine for the treatment of patients with inoperable pancreatic cancer. Gemcitabine received a Treatment IND approval in February 1995. Since that time, more that 2,900 patients have received the drug. The drug is a nucleoside analog that mimics a natural building block of DNA and disrupts cell replication The approval for gemcitabine was based on two clinical trials: a study comparing gemcitabine with 5-fluorouracil (5-FU) in 126 patients; and an open-label study of 63 patients receiving gemcitabine previously treated with 5-FU (not published). Drug labeling noted that 63% of the patients experienced neutropenia. Other common adverse events included nausea and vomiting, fever, edema, rash, flu-like symptoms and hair loss. During the trials, 10% of the gemcitabine patients discontinued treatment because of side effects. The drug is being investigated for use in combination with other anti-cancer drugs and also for possible non-small cell lung cancer (NSCLC) treatment.1,2 NSCLC was the first indication for gemcitabine in several foreign countries. The drug is approved in 19 other countries, seven of which approved it for pancreatic cancer.

1. Abratt RP, Bezwoda WR, Falkson G et al. Efficacy and safety profile of gemcitabine in non-small-cell lung cancer: a phase II study. J Clin Oncol 1994; 12:1535-40. (IDIS Article Number 334284).

2. Anderson H, Lund B, Bach F et al. Single-agent activity of weekly gemcitabine in advanced non-small-cell lung cancer: a phase II study. J Clin Oncol 1994;12:1821-6. (IDIS Article Number 335229).

Topotecan is the first topoisomerase-I inhibitor to be approved in the United States. The cytotoxicity of the drug is thought to be due to DNA damage produced during DNA synthesis when replication enzymes interact with the ternary complex formed by topotecan, topoisomerase I and DNA. Topotecan was approved for treatment of patients with metastatic carcinoma of the ovary after failure of initial or subsequent chemotherapy. Recommended dose is 1.5 mg/m2 intravenously for 30 minutes daily for five days in a 21-day course of therapy. A minimum of four courses is recommended. Neutropenia is the primary dose-limiting toxicity.1,2

1. Hochster H, Liebes L, Speyer J et al. Phase I trial of low-dose continuous topotecan infusion in patients with cancer: an active and well-tolerated regimen. J Clin Oncol 1994: 12:553-9. (IDIS Article Number 327010).

2. Kudelka A P, Tresukosol D, Edwards C L et al. Phase II study of intravenous topotecan as a 5-day infusion for refractory epithelial ovarian carcinoma. J Clin Oncol 1994; 14:1552-7. (IDIS Article Number 366397).

The second topoisomerase-I inhibitor to be approved is irinotecan. It received accelerated approval for the treatment of metastatic colon and rectal cancer. Colorectal cancer is diagnosed in about 134,000 people in the United States each year. In half of these cases, the disease has metastasized. Standard drug therapy for these patients is 5- FU. About 20% of the patients will respond to this therapy, however the cancer eventually progresses in all these cases. Irinotecan has significant single-agent activity against colorectal cancer that has progressed following 5-FU base chemotherapy.1 The recommended starting dose is 125 mg/m2. Severe diarrhea and myelosuppresion have been associated with use of this drug.1,2

1. Rothenberg ML, Eckhardt JR, Kuhn JG et al. Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 1996;14:1128-35. (IDIS Article Number 366500).

2. Conti JA, Kemeny NE, Saltz LB et al. Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol 1996;14:709-15. (IDIS Article Number 361922).

In addition to the approval of irinotecan for the treatment of metastatic carcinoma of the colon or rectum, the new diagnostic imaging agent arcitumomab was approved for use in conjunction with computerized tomography scans to detect recurrent or metastatic colorectal cancer. Arcitumomab is the Fab' fragment of the anticarcinoembryonic antigen murine monoclonal antibody type IMMU-4. The recommended dose is 1 mg of arcitumomab labeled with 20 to 30 mCi of 99m-technetium. Labeling states " when used in conjunction with standard diagnostic modalities, the combination showed an imaging sensitivity of 97%, a specificity of 29%, and accuracy of 93%, a positive predictive value of 96% and a negative predictive value of 33%."

In a blinded prospective study of 34 patient with colorectal adenocarcinoma, Rodriguez-Bigas et al1 found the radioimmunodetection scan with this antibody to be complementary to computed tomographic scan in the examination of patients with colorectal carcinoma. Stomper et al2 compared the sensitivity, specificity and accuracy of imaging with arcitumomab to computed tomography for the detection of pelvic recurrence of colorectal carcinoma in 61 patients. They found sensitivity of antibody scanning to be greater for recurrences larger then 2 cm, serum CEA more than 2.5 ng/mL, and combined planar and SPECT antibody scanning compared to planar scanning alone.

1. Rodriguez-Bigas MA, Bakshi S, Stomper P et al. 99mTc-IMMU-4 monoclonal antibody scan in colorectal cancer: a prospective study. Arch Surg 1992;127:1321-4. (IDIS Article Number 305135).

2. Stomper PC, D'Souza DJ, Bakshi SP et al. Detection of pelvic recurrence of colorectal carcinoma: prospective, blinded comparison of Tc-99m-IMMU-4 monoclonal antibody scanning and CT. Radiology 1995;197:688-92. (IDIS Article Number 358963).

Corticorelin ovine triflutate, a diagnostic agent, was approved for use in patients with ACTH-dependent Cushing's Syndrome. An analog of naturally-occurring human corticotropin-releasing hormone (CRH), the agent can be used to distinguish between Cushing's disease and ectopic ACTH syndrome. Trainer et al1 compared the effects of human and ovine corticotropin-releasing hormone in ten patients with Cushing's disease, ten patients with simple obesity, and ten healthy volunteers and found that pituitary-adrenal responsiveness to ovine CRH is greater and longer than the response to human CRH. Every subject experienced transient mild flushing after CRH treatment, with no difference in severity between human and ovine CRH.

1. Trainer PJ, Faria M, Newell-Price J et al. A comparison of the effects of human and ovine corticotropin-releasing hormone on the pituitary-adrenal axis. J Clin Endocrinol Metab 1995;80:412-7. (IDIS Article Number 347937).

The approval of nevirapine, a non-nucleoside reverse transcriptase inhibitor, adds another antiviral agent to the list of drugs available for treating HIV-1 infected patients. The agent is to be used in combination with nucleoside analogs. Approval was based on three placebo controlled, randomized, double-blind efficacy studies involving 609 patients. In Trial 241,1 triple therapy of nevirapine, zidovudine and didanosine was compared to zidovudine and didanosine in 398 patients with HIV-1 infection. Adding nevirapine to zidovudine and didanosine improved the long-term immunologic and virologic effects of therapy. Triple therapy was associated with severe rash.

1. D'Aquila RT, Hughes MD, Johnson VA et al. Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1996;124:1019-30. (IDIS Article Number 366146).

With the approval of cidofovir for the treatment of CMV retinitis in patients with AIDS, another drug will soon be available for use in AIDS patients. Approval was based on two unpublished studies involving a total of 148 patients. One of these studies showed that disease progression was less rapid in patients treated immediately with cidofovir than in patients whom therapy was delayed. Cidofovir is administered intravenously once weekly for the first two weeks, then once every two weeks thereafter. Renal toxicity, the most significant adverse effect, may be reduced by concurrent administration of probenecid.1

1. Polis MA, Spooner KM, Baird BF et al. Anticytomegaloviral activity and safety of cidofovir in patients with human immunodeficiency virus infection and cytomegalovirus viruria. Antimicrob Agents Chemother 1995;39:882-6. (IDIS Article Number 345410).

The approval of adapalene for topical treatment of acne vulgaris was based on a pivatol Phase III, randomized, multicenter, investigator-blinded trial,1 designed to compare the efficacy and safety of adapalene with tretinoin in facial acne vulgaris. At the end of the 12-week treatment period in 328 patients, adapalene applied once daily was significantly more effective in reducing acne lesions and was better tolerated than tretinoin gel. Unlike tretinoin and azelaic acid, adapalene carries no adverse event listing or warning of hypopigmentation. As with tretinoin, adapalene warns patients to limit exposure to sunlight. Adapalene is rated pregnancy category C.

1. Shalita A, Weiss JS, Chalker DK et al. A comparison of the efficacy and safety of adapalene gel 0.1% and tretinoin gel 0.025% in the treatment of acne vulgaris; a multicenter trial. J Am Acad Dermatol 1996;34:482-5. (IDIS Article Number 364859).

Patients with open-angle glaucoma who are either intolerant of or do not adequately respond to other intraocular pressure-lowering medications, may respond to latanoprost, a prostanoid selective FP receptor agonist. In multicenter trials comparing latanoprost to the current standard glaucoma drug, timolol, the data demonstrated once daily latanoprost was as effective as twice-daily timolol in reducing intraocular pressure.1,2 Once daily dosing may help patients to be more compliant. In addition, latanoprost may be used concomitantly with other topical ophthalmic drugs to lower intraocular pressure. In clinical trials, after six months treatment, 6.8 percent of patients reported a gradual change in eye color to brown (data from manufacturer).

1. Alm A, Stjernschantz J et al. Effects on intraocular pressure and side effects of 0.005% latanoprost applied once daily, evening or morning: a comparison with timolol. Ophthalmology 995;102:1743-52. (IDIS Article Number 358006).

2. Camras CB et al. Comparison of latanoprost and timolol in patients with ocular hypertension and glaucoma: a six-month, masked, multicenter trial in the United States. Ophthalmology 1996;103:138-47. (IDIS Article Number 359594).

Marketed in other countries since 1982 and available in the United States under compassionate use INDs, albendazole received FDA approval in June for neurocysticercosis and hydatid disease. Neurocysticercosis (NCC), caused by pork tapeworm larvae, is considered the leading infectious cause of seizures worldwide. In published open-label studies,1,2 and a retrospective study,3 patients have responded positively to albendazole. Adverse effects of the drug vary between NCC and hydatid disease patients, but usually involve diminished liver function and lower white blood cell counts.

1. Medina MT, Genton P, Montoya MC et al. Effect of anticysticercal treatment on the prognosis of epilepsy in neurocysticercosis: a pilot trial. Epilepsia 1993;34:1024-7. (IDIS Article Number 323460).

2. Rajshekhar V. Albendazole therapy for persistent, solitary cysticercus granulomas in patients with seizures. Neurology 1993:43:1238-40. (IDIS Article Number 316041).

3. Vazquez V and Sotelo J. The course of seizures after treatment for cerebral cysticercosis. N Engl J Med 1992:327:696-701. (IDIS Article Number 301133).

The approval of insulin lispro, rDNA origin, will make a new rapid-acting insulin analog available to the insulin dependent diabetic patient. Insulin lispro may be injected more closely to mealtime than human regular insulin due to more rapid absorption from subcutaneous tissue. Published studies show insulin lispro to be as effective as human insulin and may provide better postprandial metabolic control1,2 Studies have not demonstrated a difference in frequency of adverse events between the two insulins. Insulin lispro should be used in regimens including a longer-acting insulin and is available on prescription only.

1. Howey DC, Bowsher RR, Brunelle RL et al. [Lys(B28), pro(B29)]-human insulin: effect of injection time on postprandial glycemia. Clin Pharmacol Ther 1995;58:459-69. (IDIS Article Number 358235).

2. Pampanelli S, Torlone E, Lalli C et al. Improved postprandial metabolic control after subcutaneous injection of a short-acting insulin analog in IDDM of short duration with residual pancreatic beta-cell function. Diabetes Care 1995;18:1452-9. (IDIS Article Number 355473).

Meropenem is the first carbapenem antibiotic approved in the United States for children, and that can be administered without a dehydropeptidase-I inhibitor. It was approved for the narrow indication of complicated intra-abdominal infections in adults and pediatrics, and for pediatric bacterial meningitis. The company is also seeking FDA approval for the additional indications of lower respiratory tract infections and skin and skin structures infections. A randomized, double-blind clinical trail comparing meropenem to tobramycin plus clindamycin for treatment of intraabdominal infections showed both therapies to be equally effective.1 A slight reduction in hospital stay of one day was shown in a double-blind randomized trial comparing meropenem to tobramycin plus clindamycin for treatment of patients with advanced appendicitis.2 Clinical trials comparing meropenem to imipenem cilastin in intra-abdominal infections show no difference in efficacy.3,4 A randomized study comparing meropenem to cefotaxime, alone and combined with metronidazole or amikacin in hospitalized children with bacterial infections showed the regimen to be equally effective and tolerated.5 Similar efficacy was also shown in an open, multicenter randomized study comparing meropenem to cefotaxime plus metronidazole in the surgical management of intra-abdominal infections.6

1. Condon RE, Walker AP, Sirinek KR et al. Meropenem versus tobramycin plus clindamycin for treatment of intraabdominal infections: results of a prospective, randomized, double-blind clinical trial. Clin Infect Dis 1995;21:544-50. (IDIS Article Number 354815).

2. Berne TV, Yellin AE, Appleman MD et al. Meropenem versus tobramycin with clindamycin in the antibiotic management of patients with advanced appendicitis. J Am Coll Surg 1996;182:403-7. (IDIS Article Number 367606).

3. Geroulanos SJ et al. Meropenem versus imipenem/cilastin in intra-abdominal infections requiring surgery. J Antimicrob Chemother 1995;36(Suppl A):191-205. (IDIS Article Number 353291).

4. Brismar B, Malmborg AS, Tunevall G et al. Meropenem versus imipenem/cilastin in the treatment of intra-abdominal infections. J Antimicrob Chemother 1995;35:139-48. (IDIS Article Number 343753).

5. Schuler D et al. Safety and efficacy of meropenem in hospitalized children: randomized comparison with cefotaxime, alone and combined with metronidazole or amikacin. J Antimicrob Chemother 1995;36(Suppl A):99-108. (IDIS Article Number 353283).

6. Huizinga WKJ, Warren BL, Baker LW et al. Antibiotic monotherapy with meropenem in the surgical management of intra-abdominal infections. J Antimicrob Chemother 1995;36(Suppl A):179-89. (IDIS Article Number 353290).

The FDA's approval of remifentanil, an opioid analgesic, was based on an "interactive" NDA review process that involved the use of data summaries for the primary review. Although complete study data was submitted with the NDA, FDA reviewers were able to save time by basing the primary review on summary efficacy and safety data. Approval came after a 10-month review. The drug has a rapid onset and peak effect and a short duration of action. Labeling notes that within 6 to 10 minutes after discontinuing the drug, no residual opioid activity will be present. Adverse effects are characteristic of mu-opioids. Pharmacokinetic and pharmacodynamic studies comparing remifentanil to alfentanil have been conducted in healthy volunteers.1,2 The pharmacokinetics of remifentanil at clinically relevant doses in anesthetized patients undergoing elective inpatient surgery were studied by Westmoreland et al.3 In a study of volunteer subjects with severe liver disease, the pharmacokinetics of remifentanil were found unchanged.4

1. Egan TD, Minto CF, Hermann DJ et al. Remifentanil versus alfentanil: comparative pharmacokinetics and pharmacodynamics in healthy adult male volunteers. Anesthesiology 1996;84:821-33. (IDIS Article Number 365686).

2. Kapila A, Glass PSA, Jacobs JR et al. Measured context-sensitive half-times of remifentanil and alfentanil. Anesthesiology 1995;83:968-75. (IDIS Article Number 356511).

3. Westmoreland CL, Hoke JF, Sebel PS et al. Pharmacokinetics of remifentanil (GI87084B) and its major metabolite (GI90291) in patients undergoing elective inpatient surgery. Anesthesiology 1993;79:893-903. (IDIS Article Number 322373).

4. Dershwitz M, Hoke JF, Rosow CE et al. Pharmacokinetics and pharmacodynamics of remifentanil in volunteer subjects with severe liver disease. Anesthesiology 1996;84:812-20. (IDIS Article Number 365685).

Mirtazapine, an alpha-2 receptor antagonist antidepressant, is the first in the alpha-2 class to be approved in the United States. The drug is an entotomeric tetracyclic compound not chemically related to tricyclic compounds and has been demonstrated to be a centrally active presynaptic and post-synaptic alpha-2 receptor antagonist. In a double-blind randomized study comparing mirtazapine to amitriptyline in 150 patients with a major depressive episode, mirtazapine was found to be as effective as amitriptyline in the treatment of major depression with advantages regarding improvements of depressed mood, responder rates and safety. 1

1. Bremner JD. A double-blind comparison of Org 3770, amitriptyline, and placebo in major depression. J Clin Psychiatry 1995;56:519-25. (IDIS Article Number 358479).

With the FDA approval of fosphenytoin injection, Warner-Lambert has indicated marketing of IV Dilantin will be discontinued 1 January, 1997. The company stressed that fosphenytoin provides improved infusion site tolerance and more rapid rate of IV administration than Dilantin. In a randomized, double-blind, crossover study, Jamerson et al compared intravenous administration of fosphenytoin to phenytoin. Fosphenytoin administration resulted in significantly less venous irritation and phlebitis compared with an equimolar dose of phenytoin.1

1. Jamerson BD, Dukes GE, Brouwer KLR et al. Venous irritation related to intravenous administration of phenytoin versus fosphenytoin. Pharmacotherapy 1994;14:47-52. (IDIS Article Number 325157).

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

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

Adapalene (1S)**

Differin

Galderma

(May 31)

ADAPALENE

84280011

(2 citations)

Topical treatment of acne vulgaris Acne

706.0

Albendazole (1P)***

Albenza

SmithKline Beecham

(Jun. 11)

ALBENDAZOLE

8080017

(127 citations)

Treatment of neurocysticercosis and cystic hydatid disease Echinococcosis

122.

Cysticercosis

123.1

Arcitumomab

CEA-Scan

Immunomedics

(Jun. 28)

ARCITUMOMAB

82000811

(15 citations)

Use in conjuntion with computerized tomography scans to detect recurrent or metastatic colorectal cancer Neop, Mgn-Rectosigmoid Junct

154.0

Radioisotope Scan, GI

92.04

Cidofovir (1S)

Vistide

Gilead

(Jun. 26)

CIDOFOVIR

8180066

(20 citations)

Treatment of CMV retinitis in patients with AIDS Chorioretinitis NEC

363.2

Disease, Cytomegalic Inclu

078.5

Syn-Acq Immune Deficiency

042.

Corticorelin, Ovine (1P)

Acthrel

Ferring Labs

(May 23)

CORTICORELIN, OVINE

68280095

(108 citations)

An in vivo diagnostic used in patients with ACTH-dependent Cushing's Syndrome Cushing's Syndrome

255.0

Fosphenytoin Sodium (1S)

Cerebyx

Warner-Lambert

(Aug. 5)

FOSPHENYTOIN

28120807

(16 citations)

Control of generalized convulsive status epilepticus and prevention and treatment of seizures during neurosurgery Grand Mal Status

345.3

Prophylaxis NEC

V07.

Epilepsy NEC

345.

Gemcitabine (1P)

Gemzar

Lilly

(May 15)

GEMCITABINE

10080419

(21 citations)

Treatment of patients with inoperable pancreatic cancer Neop, Mgn-Pancreas NEC

157.

Insulin Lispro (1S)

Humalog

Lilly

(Jun. 14)

INSULIN LISPRO

68200821

(4 citations)

For the treatment of diabetes mellitus in patients requiring insulin Diabetes Mellitus

250.

Irinotecan (1P)

Camptosar

Pharmacia & Upjohn

(Jun. 14)

IRINOTECAN

10020004

(22 citations)

For the treatment of patients with metastatic carcinoma of the colon or rectum whose disease has progressed following 5-FU based therapy Neop, Mgn-Intestine, Lg NEC

153.

Neop, Mgn-Rectum/Anus NEC

154.

Latanoprost (1P)

Xalatan

Pharmacia & Upjohn

(Jun. 5)

LATANOPROST

97000004

(6 citations)

To reduce intraocular pressure that occurs in patients with open-angle glaucoma and ocular hypertension who cannot tolerate or have not responded to any other available treatments Glaucoma NEC

365.

Glaucoma, Open-Angle

365.1

Hypertension, Ocular

365.04

Meropenem (1S)

Merrem

Zeneca

(Jun. 21)

MEROPENEM

8122929

(94 citations)

Treatment of complicated intra-abdominal infections in adults and pediatrics, and for pediatric bacterial meningitis Meningitis, Bacterial NEC

320.

Peritonitis

567.

Mirtazapine (1S)

Remeron

Organon

(Jul. 14)

MIRTAZAPINE

28160617

(9 citations)

Treatment of depression Disorder, Depressive NEC

311.

Nevirapine (1P)

Viramune

Boehringer Ingelheim & Roxane Labs

(Jun. 21)

NEVIRAPINE

8180062

(30 citations)

For use in combination with nucleoside analogues for treatment of HIV-1 infected adults who have experienced clinical and/or immunologic deterioration Syn-Acq Immune Deficiency

042.

Infection, HIV, Asymptomatic

V08.

Remifentanil (1S)

Ultiva

Glaxo

(Jul. 12)

REMIFENTANIL

28080850

(15 citations)

Analgesic agent for use during the induction and maintenance of general anesthesia for inpatient and outpatient procedures, and for continuation as an analgesic into the immediate postoperative period, and as an analgesic component of monitored anesthesia Anesthesia/Paresthesia

782.0

Topotecan (1P)

Hycamtin

SmithKline Beecham

(May 28)

TOPOTECAN

10020002

(33 citations)

Treatment of ovarian cancer after failure of first-line chemotherapy Neop, Mgn-Ovary

183.0

*Through August 1996 Update. Complete bibliographic citations will be provided upon request.
**(1S) New Molecular Entity given standard review by FDA.
***(1P) New Molecular Entity given a priority review.

1996 IDIS EXHIBIT SCHEDULE

American Society of Health-System Pharmacists (ASHP)
Midyear Clinical Meeting (MCM)
New Orleans, Louisiana
December 4-8


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