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Rosiglitazone was initially approved for type 2 diabetes monotherapy. We tested health-outcomes modeling as an aid to regulatory decision making by quantifying the incremental net benefit (INB) value of rosiglitazone (relative to a comparator), both at the time of first approval (1999) and at the FDA advisory committee review (2007). Using 1999 data, rosiglitazone was projected to provide an additional 0.639 years of life (0.373 quality-adjusted life years (QALYs)) relative to placebo but a loss of 0.312 years (0.173 QALYs) relative to glyburide, with uncertainty in reduction of hemoglobin A1c (HbA1c) level having the greatest impact on the benefit–risk profile. By 2007, rosiglitazone was projected to provide an additional 0.222 years (0.091 QALYs) vs. glyburide and 0.026 years vs. metformin (0.009 QALYs). Modeling suggested that the use of rosiglitazone as monotherapy was not initially warranted, given the uncertainty with regard to benefit. Despite similar net benefit (NB) as metformin shown in postmarketing data, residual cardiovascular (CV) concerns did not support the use of rosiglitazone as first-line therapy. We adapted a mathematical diabetes model to estimate NB and uncertainty of diabetes monotherapy. Clinical Pharmacology & Therapeutics (2011) 89 3, 429–436. doi:10.1038/clpt.2010.350

Objective To describe implementation of a collaborative drug therapy protocol to screen and counsel women for safe use of hormonal contraceptives prescribed by community pharmacists. Design Community-based intervention study. Setting Metropolitan Seattle, Wash., from June 2003 to December 2005. Participants 26 community pharmacists and 214 women enrollees. Intervention Pharmacists identified women at risk of unintended pregnancy and offered to evaluate them to determine whether they could safely use oral contraceptives, contraceptive patches, or the contraceptive vaginal ring. Interested women self-administered medical and contraceptive history questionnaires. Pharmacists measured weight and blood pressure and prescribed hormonal contraceptives according to the protocol guidelines. Study interviewers followed up with women via telephone at 1, 6, and 12 months. Main Outcome Measures Effectiveness of pharmacist interventions was measured by continuation of hormonal methods by women. Feasibility was determined by measuring acceptability and sustainability. Acceptability was measured by interviewing women and pharmacists. Sustainability was measured by evidence of willingness to pay for the services. Results 195 women (91%) were prescribed hormonal contraceptives by participating pharmacists. A self-administered screening tool and physical measurement of weight and blood pressure enabled pharmacists to evaluate women for safe use of contraceptives. Most women (87%) were experienced users of hormonal contraceptives. More than 80% of women paid for the pharmacists' services out of pocket. After 12 months, 70% of women responding to an interview reported continuing use of hormonal contraceptives. Women reported that they would want to obtain a gynecologic exam within 3-year intervals while taking hormonal contraceptives. Both women and pharmacists were satisfied with the experience. Nearly all respondents expressed willingness to continue to see pharmacist prescribers and to receive other services from them. Conclusion Community pharmacists can efficiently screen women for safe use of hormonal contraceptives and select appropriate products. Women and pharmacists were satisfied with the services, and women were willing to pay for them.

Objective The purpose of this study is to measure the accessibility to purchase oral and transdermal contraceptives over the Internet for low- and high-risk individuals. Methods The Internet was used to search for and order both oral and transdermal contraceptives. Using the “Google™” search engine to locate online pharmacies by entering the term “purchase contraception,” we proceeded to purchase either oral contraceptives or contraceptive patches without a prescription. We first posed as a healthy 25-year-old woman, then as a 35-year-old woman who was obese and a heavy tobacco user, and finally, as a 35-year-old smoker on an antihypertensive medication. Results Our attempts to order both combination oral contraceptives, as well as contraceptive patches, over the Internet without a prescription were successful for all three risk profiles. We ordered from three different Web sites, two within the United States and one international site. The two U.S. Web sites required us to complete a medical questionnaire to obtain a prescription from the site provider, but the foreign site had no questionnaire or risk information posted on the Web site. Despite entering known risk factors for estrogen use, we received all the medications. There was no medical follow-up to these sales except for offers to sell more products. Conclusions Both oral and transdermal contraceptives are easy to obtain over the Internet without a physical appointment with a health care provider to obtain a prescription.

Nearly one half of all pregnancies in the United States are unintended despite the availability of safe and effective contraceptives. The morbidity and mortality from unintended pregnancy are not insignificant. Currently available hormonal contraceptives are very effective, safe, and available for most American women. National and international institutions have removed the pelvic examination as a requirement for initiating the prescription for hormonal contraceptives, substituting instead a medical history and a blood pressure measurement. However, problems with uneven access, prescription requirements, conflicting information on the package instructions for initiating and continuing use, and incorrect perceptions of excess risk of contraceptive products may lead women to use them less than effectively or not at all. Newer progestins have been shown to have more risk of thrombosis than older formulations, instead of improved safety. In considering how hormonal contraceptives might be made safer, recommendations are made for improved availability and effective use. These include expanding the numbers and types of providers and the compensation for these services; reconsidering the need for prescription; revising labels to reflect the safety of the current formulations; communicating the safety of the current formulations; encouraging the use of the older progestins; exploring alternate schedules, such as extended or continuous oral contraceptive (OC) use; promoting same-day initiation of methods rather than waiting for menses; and ensuring universal access to emergency contraception as an adjunct to effective ongoing contraceptive methods.

A validation study evaluated the accuracy of self-reported use of commonly used medications among older women. Within a case-control study of breast cancer, drug information was ascertained by interview. Pharmacy records from 1990 to 1999 were obtained from a Washington State health maintenance organization (66% of subjects) and retail pharmacies (34% of subjects) on a sample of subjects (212 cases, 191 controls) and used as the "gold standard." Recall accuracy was assessed for 6-month, 2-year, and 8-year time windows. Sensitivity of antihypertensive use was 92% (95% confidence interval (CI): 85, 96) for cases and controls in the 6-month period and slightly lower for the 2-year (90% (95% CI: 82, 94) and 87% (95% CI: 78, 92)) and 8-year (80% (95% CI: 69, 88) and 79% (95% CI: 68, 88)) periods. For statins, sensitivity was 83% (95% CI: 64, 93) for cases and 93% (95% CI: 69, 99) for controls in the 6-month period, 75% (95% CI: 55, 88) and 86% (95% CI: 60, 96) in the 2-year period, and 67% (95% CI: 42, 85) and 75% (95% CI: 41, 93) in the 8-year period. For self-report of antidepressants, sensitivities ranged from 66% (95% CI: 47, 80) in the 6-month period to 44% (95% CI: 30, 60) in the 8-year period. Specificity was high among all drug classes, ranging from 91% to 100%. Recall did not differ by case-control status. Trivial changes in estimates were observed when health maintenance organization records alone were used as the gold standard. Self-reported use of antihypertensives and statins appears to be relatively accurate among older women.

BACKGROUND: With the introduction of atypical neuroleptic medications into the marketplace, the use of conventional neuroleptics has fallen, attendant with the perception of a more favorable side-effect profile for the atypical neuroleptics. OBJECTIVE: The purpose of this study was to determine the risk of tardive dyskinesia (TD) associated with atypical and conventional neuroleptics. METHODS: Subjects were adult users of the Veterans Administration Puget Sound Health Care System (VA-PSHCS) who received ≥1 prescription for neuroleptic medications during the study period. Electronic medical and pharmacy records were used to obtain neuroleptic drug exposure, exclusionary diagnosis, diagnosis for TD, and select demographic data. Medical records were reviewed to collect demographic data not available electronically. Controls were randomly selected from a cohort of neuroleptic users without TD. The case-defining event was the diagnosis of TD. RESULTS: There were 42 cases and 160 controls for the final analysis. The only demographic difference found was a higher proportion of Caucasians (90%) in the TD group compared to the control group (76%). There was no significant difference in the risk of TD for patients on conventional neuroleptics compared to the atypical neuroleptic users (OR=1.29; 95% CI=0.71-2.34). After adjusting for age, gender, race, schizophrenia, schizoaffective disorder, depression, and anti-Parkinson drugs, there was still no significant difference in risk of TD between cases and controls (OR=1.02; 95% CI=0.465-2.232). CONCLUSION: This study did not find a statistically significant difference in the risk of TD for users of conventional neuroleptics versus users of atypical neuroleptics.

Unintended pregnancy and subsequent abortion remain major public health issues in many countries, despite evidence that post-coital emergency contraceptives have a good safety profile, are easy to use, and are effective in preventing unwanted pregnancies. Although emergency contraceptives have been prescribed in developed countries for more than 25 years, abortion rates have continued to rise steadily in many jurisdictions. Barriers to the use of emergency contraceptives reduce ready access of women to this birth control option. Because the effectiveness of emergency contraceptives is time dependent, establishing prescribing and dispensing mechanisms that are convenient to women is crucial to their ability to use the therapy in a timely manner. Emergency contraceptives in developed countries are traditionally prescribed by physicians in organized healthcare settings. In these countries, pharmacists are ideally situated to improve patient access to emergency contraceptives, since community pharmacies are widely available in both urban and rural settings and are open extended hours. Innovative initiatives using a variety of regulatory mechanisms now allow pharmacists a greater role in prescribing and distributing emergency contraceptives. In Washington State, USA, pharmacists entering into a collaborative drug therapy agreement with a physician or nurse practitioner can initiate emergency contraceptives based on a prescribing protocol. Several local programs in the United Kingdom have utilized accredited community pharmacists to supply emergency contraceptives using a patient group directive. In British Columbia, Canada, specially-certified pharmacists with independent prescriptive authority utilize an informed consent during the interactive consultation with the potential emergency contraceptive user. In yet other jurisdictions, emergency contraceptives have been transferred to over-the-counter (OTC) status. Relevant public health research questions can now be posed. Future studies will be able to compare the effectiveness of various regulatory mechanisms to expand access, to identify and address potential drawbacks of pharmacist-initiated1 emergency contraceptives, and to explore whether pharmacist-initiated prescriptions represent expanded access or simply a transfer of the prescribing of these agents from physicians to pharmacists. Countries with OTC emergency contraceptives will be able to explore the relationship between varying levels of pharmacist interaction with emergency contraceptive users and health outcomes, and to investigate whether the change in prescriptive status has resulted in unintentional barriers to access for populations such as teenagers and those with restricted discretionary income. These findings will provide valuable new information on the impact of initiatives designed to expand access to emergency contraceptives.

Objective To describe how prescribers and pharmacists view the Emergency Contraceptive Pills (ECP) program, and to evaluate pharmacists' performance through the use of a consumer survey. Design Self-administered provider satisfaction surveys were mailed 6 months after the program's inception. Consumer satisfaction surveys were distributed at the point of ECP service for return by mail. Setting The program encouraged pharmacists and prescribers in western Washington to enter into collaborative prescribing agreements, increasing consumers' access to ECP. Patients or Other Participants Pharmacists who had attended ECP training sessions, prescribers who had authorized pharmacists to prescribe ECP, and women who had been prescribed ECP by pharmacists. Main Outcome Measures Providers' reasons for participating, attitudes toward the ECP program, and experiences with ECP as a result of the program; feedback from women receiving ECP from pharmacists. Results 309 pharmacist surveys and 55 prescriber surveys were sent, of which 159 (51%) and 27 (49%), respectively, were returned. Meeting patient needs and having a professional responsibility to participate were commonly reported reasons for ECP program involvement. Both pharmacists and prescribers (92%) reported being "satisfied" or "very satisfied" with their prescribing agreements. On the 470 consumer surveys returned out of 7,000 distributed (6.5%), pharmacists were rated highly satisfactory for their interactions with patients and the quality of information about ECP use given, but less satisfactory for information about adverse effects, recognition and follow-up of ECP failure, and regular contraceptive methods. Conclusion All participants expressed satisfaction with the ECP program. This example should support the initiation of similar programs in other states.

A program designed to curb increases in drug costs in an HMO by substituting esterified for conjugated estrogens was developed and studied. Patients were voluntarily switched from conjugated to esterified estrogens at an HMO in Washington State. Women were informed about the conversion through newsletters and during clinic and pharmacy visits and received physician and pharmacist counseling. Cost savings were estimated, and patient acceptance was evaluated by interviewing women in four groups, including women who were switched from conjugated to esterified estrogens and then switched back (C-E-C group), women who were not switched (C-C group), and women who were switched to esterified estrogens and not switched back (C-E group). During the first six months, 14,601 (89.2%) of 16,364 women taking conjugated estrogens were switched to esterified estrogens; of these, 13,654 (93.5%) continued taking esterified estrogens for at least six months. The HMO avoided $653,119 of an expected $750,000 cost increase for oral estrogen therapy during the first year of the program. A total of 754 women were interviewed; 65.8% in the C-E-C group and 78.4% in the C-E group reported being satisfied with the information they received. The conversion experience was rated as positive by 28.3% of women in the C-E-C group and 41.5% of women in the C-E group, negative by 25.1%, and 8.9%, and neutral by 46.6% and 49.6%. An HMO avoided a large increase in drug costs by substituting esterified for conjugated estrogens; only 6.5% of patients were switched back to conjugated estrogens at their physicians' or their own request; most patients thought the conversion was a neutral or positive experience.

The Upjohn Consumer Health Survey (UCHS) was a prospective, observational study designed to comply with the US FDA's request that 10,000 users of ROGAINE (REGAINE in international markets) Topical Solution 2% (2% minoxidil solution) be systematically studied in the first year following the product's approval. Members of the Drug cohort were recruited at the time they filled prescriptions for 2% minoxidil solution at cooperating retail pharmacies in the United States. To meet the need for rapid identification of a cooperative comparison group, the Comparator cohort was selected by stratified random sampling from members of a commercial consumer panel. Group matching of Comparators to the Drug cohort on four variables--age, sex, race, and geography of residence--was accomplished prior to recruitment on the basis of information available from the consumer panel records; education was obtained via consent procedures and was also used as a group matching variable. Data collection was accomplished by participant interviews and confirmation of participant-reported medical events. Interviewing costs averaged 18.88 US dollars/completed interview. A commercial consumer panel offers a pool of rapidly identifiable subjects with known demographic characteristics and established willingness to participate in research for efficient cohort recruitment.

Objective To describe a school of pharmacy–community pharmacy collaborative model for medication therapy management (MTM) service and training. Setting University of Washington (UW) School of Pharmacy (Seattle), from July to December 2008. Practice description MTM services and training. Practice innovation A campus-based MTM pharmacy was established for teaching, practice, and collaboration with community pharmacies to provide comprehensive medication reviews (CMRs) and MTM training. Main outcome measures Number of collaborating pharmacies, number of patients contacted, number of CMRs conducted, and estimated cost avoidance (ECA). Results UW Pharmacy Cares was licensed as a Class A pharmacy (nondispensing) and signed "business associate" agreements with six community pharmacies. During July to December 2008, 10 faculty pharmacists completed training and 5 provided CMR services to 17 patients (5 telephonic and 12 face-to-face interviews). A total of 67 claims (17 CMRs and 50 CMR-generated claims) were submitted for reimbursement of $1,642 ($96.58/CMR case). Total ECA was $54,250, averaging $3,191.19 per patient. Seven student pharmacists gained CMR interview training. Conclusion Interest in collaboration by community pharmacies was lower than expected; however, the campus–community practice model addressed unmet patient care needs, reduced outstanding MTM CMR case loads, increased ECA, and facilitated faculty development and training of student pharmacists.

BACKGROUND: Over two thirds of women who need contraception in Uganda lack access to modern effective methods. This study was conducted to estimate the potential cost-effectiveness of achieving universal access to modern contraceptives in Uganda by implementing a hypothetical new contraceptive program (NCP) from both societal and governmental (Ministry of Health (MoH)) perspectives. METHODOLOGY/PRINCIPAL FINDINGS: A Markov model was developed to compare the NCP to the status quo or current contraceptive program (CCP). The model followed a hypothetical cohort of 15-year old girls over a lifetime horizon. Data were obtained from the Uganda National Demographic and Health Survey and from published and unpublished sources. Costs, life expectancy, disability-adjusted life expectancy, pregnancies, fertility and incremental cost-effectiveness measured as cost per life-year (LY) gained, cost per disability-adjusted life-year (DALY) averted, cost per pregnancy averted and cost per unit of fertility reduction were calculated. Univariate and probabilistic sensitivity analyses were performed to examine the robustness of results. Mean discounted life expectancy and disability-adjusted life expectancy (DALE) were higher under the NCP vs. CCP (28.74 vs. 28.65 years and 27.38 vs. 27.01 respectively). Mean pregnancies and live births per woman were lower under the NCP (9.51 vs. 7.90 and 6.92 vs. 5.79 respectively). Mean lifetime societal costs per woman were lower for the NCP from the societal perspective ($1,949 vs. $1,987) and the MoH perspective ($636 vs. $685). In the incremental analysis, the NCP dominated the CCP, i.e. it was both less costly and more effective. The results were robust to univariate and probabilistic sensitivity analysis. CONCLUSION/SIGNIFICANCE: Universal access to modern contraceptives in Uganda appears to be highly cost-effective. Increasing contraceptive coverage should be considered among Uganda's public health priorities.

Background The demand for induced abortions in Uganda is high despite legal and moral proscriptions. Abortion seekers usually go to illegal, hidden clinics where procedures are performed in unhygienic environments by under-trained practitioners. These abortions, which are usually unsafe, lead to a high rate of severe complications and use of substantial, scarce healthcare resources. This study was performed to estimate the costs associated with induced abortions in Uganda. Methods A decision tree was developed to represent the consequences of induced abortion and estimate the costs of an average case. Data were obtained from a primary chart abstraction study, an on-going prospective study, and the published literature. Societal costs, direct medical costs, direct non-medical costs, indirect (productivity) costs, costs to patients, and costs to the government were estimated. Monte Carlo simulation was used to account for uncertainty. Results The average societal cost per induced abortion (95% credibility range) was $177 ($140-$223). This is equivalent to $64 million in annual national costs. Of this, the average direct medical cost was $65 ($49-86) and the average direct non-medical cost was $19 ($16-$23). The average indirect cost was $92 ($57-$139). Patients incurred $62 ($46-$83) on average while government incurred $14 ($10-$20) on average. Conclusion Induced abortions are associated with substantial costs in Uganda and patients incur the bulk of the healthcare costs. This reinforces the case made by other researchers--that efforts by the government to reduce unsafe abortions by increasing contraceptive coverage or providing safe, legal abortions are critical.

Objective To measure agreement between women's self-administered risk factor questionnaire and their providers' evaluation of their medical eligibility for hormonal contraceptive use. Methods This was an anonymous cross-sectional study. Participants were women 15–45 years old who completed a 20-item self-administered questionnaire. Women were recruited from six public health family planning clinics in the Seattle Metropolitan area. A matching medical evaluation questionnaire was completed concurrently by each participant's health care provider. Using provider evaluation as the “gold standard” against which we compared self-reported medical history, we calculated participant–provider agreement with point estimates and 95% confidence interval (CI). Results Of 399 participant and provider pairs, participant–provider agreement was obtained for 392 participant pairs. The majority of the participants (90.3%) were 15–30 years old and 77.7% had used a hormonal contraceptive method for more than 1 year. The estimated proportion of the overall agreement was 96% (95% CI, 0.92–0.98). Women were more likely to report severe headaches (12.4% vs. 3.3%), possible pregnancy (7.3% vs. 3.5%) and smoking (6.2% vs. 2.1%) than providers, but less likely to report smoking more than 15 cigarettes per day (2.6% vs. 9.2%) and irregular menses (6.5% vs. 9.9%). Conclusion Overall, a high proportion of the women in this study completed our medical history questionnaire in concordance with their health care providers' same-day medical evaluation. Agreement on critical medical eligibility criteria such as hypertension was well above 90%. For criteria on which there was disagreement, women were more likely to identify contraindications than were their providers.

Purpose An evaluation was made of the effectiveness in changing prescribing behavior of ‘Dear Health Professional (DHP)’ letters mailed by the manufacturer to physicians and other health professionals advising them of safety information on co-prescribing of tramadol and antidepressants. Methods A retrospective cohort analysis of prescription claims of all plan members from 12 UnitedHealth Group-affiliated health plans who received a first prescription for tramadol between 1 April 1995 and 31 December 1996. The prevalence of co-prescribing of antidepressants and tramadol relative to the date of the ‘DHP’ communication was determined. Results 9218 plan members received an initial prescription for tramadol within the observation period. Prior to the date of the ‘DHP’ communication 1061/4774 (22.2%) members received a prescription for an antidepressant within 30 days of their first prescription for tramadol. Following the date of the communication 844/4444 (19.0%) of members received an antidepressant within 30 days of their first prescription for tramadol. An overall decreasing linear trend in antidepressant co-prescribing was evident over the observation period, but there was no statistically significant acceleration in the decrease following this communication. Conclusions The mailed ‘DHP’ advisory letter did not affect the rate of co-prescribing of tramadol with antidepressants. Copyright © 2004 John Wiley & Sons, Ltd.

BACKGROUND Statin use has increased dramatically in the U.S. in the past decade. Animal and mechanistic studies suggested that statins may have an inhibitory effect on cancer proliferation, including breast carcinoma. However, statins have been found to be carcinogenic in rodents and one clinical trial found an excess of breast carcinoma cases in the treatment group. METHODS The current study assessed whether the use of statins altered the risk of breast carcinoma in older women. The population-based, case–control study comprised female residents from three western Washington State counties. Cases included 975 women identified from the Cancer Surveillance System who were diagnosed with primary invasive breast carcinoma between 1997–1999, whose names appeared on a list of Social Security recipients provided by the Centers for Medicare and Medicaid Services. The cases were ages 65–79 years at the time of diagnosis. The comparison group was comprised of 1007 women without breast carcinoma who were randomly selected from the same list of Social Security recipients. Information pertaining to statin use, medical history, and health behaviors was ascertained through an in-person interview. RESULTS Compared with nonusers, women who were currently using statins or had ever used statins were not found to be at an increased risk for breast carcinoma (odds ratios [OR] = 0.9; 95% confidence interval [95% CI], 0.7–1.2). There was some indication that long-term statin use (> 5 years) was related to a slight decrease in breast carcinoma risk (OR = 0.7; 95% CI, 0.4–1.0). CONCLUSIONS The results of the current study provided some degree of reassurance to the increasing numbers of women using statins that such use is not associated with an increased risk of breast carcinoma. Although the data gave some support to a reduced risk of breast carcinoma among long-term users of statins, further research is needed to confirm this association. Cancer 2004. © 2004 American Cancer Society.

Objective: To assess the effect of a structured program of pharmaceutical care on changes in disease control, functional status, and health services utilization for pediatric and adolescent patients with moderate-to-severe asthma.Design: Randomized, controlled trial.Setting: Community and clinic pharmacies (14 intervention and 18 usual care pharmacies) in western Washington State.Patients: Three hundred thirty children, aged 6 to 17 years, with asthma.Intervention: Structured training for the intervention group pharmacists to provide individualized asthma management services during patient-pharmacist encounters for up to 1 year following the patient's enrollment into the study.Main Outcome Measures: The primary outcome measure was change in pulmonary function as measured by peak expiratory flow rate and spirometry. Secondary outcome measures included changes in functional status and use of asthma-related health care services.Results:The intervention had no significant effect on the health or health services use outcomes of study subjects. When compared with the usual care group, there was no evidence that patients from the intervention group experienced improvements in pulmonary function, functional status, quality of life, asthma management, or satisfaction with care. In addition, there were no differences between groups in use of anti-inflammatory medications, total or asthma-related medical care utilization, or total or asthma-related school days lost.Conclusion: This pharmaceutical care intervention had no significant effect on the health or health services use outcomes of pediatric patients with asthma. The intervention may not have been powerful enough to significantly affect pharmacists' behaviors and asthma patients' outcomes in community pharmacy settings, and there is evidence that the pharmacists' compliance with the study protocol was low due, in part, to patient- and practice-related obstacles.

Study Objective: To increase knowledge about adolescents who obtained emergency contraceptive pills (ECP) directly from a pharmacist without first contacting a physician. Design: Cross-sectional self-administered survey. Setting: Fifteen randomly selected pharmacies providing ECP in western Washington State. Participants: Adolescents 15–21 years old (n = 126) who obtained ECP directly from a pharmacist. Outcome Measures: Responses to a 20-item questionnaire examining adolescents' reasons for seeking care from a pharmacist, need for additional medical evaluation, risk for not receiving additional medical care, and satisfaction with care provided by the pharmacist. Results: The most common reasons for using the pharmacy were convenience (44%), lack of knowledge about alternatives (38%), and privacy (31%). If the pharmacy service were not available, 58% said they would see a doctor, 22% said they would wait to see if they got pregnant, and 20% did not know. Based on self-report, 81% of adolescents needed a new method of ongoing contraception, an evaluation for sexually transmitted disease, or both. Among these adolescents, 36% had risk factors for not receiving this care. Adolescents were satisfied with the pharmacy service; 94% said they would recommend the service to a friend. Conclusions: ECP provision by pharmacists is a useful way to increase access to emergency contraception. However, many adolescents using ECP need additional medical care. Programs designed to increase ECP access should use these opportunities to link adolescents with more comprehensive reproductive health care services.

Objectives. This study investigated the effect on the risk and cost of unintended pregnancies of emergency contraceptive pills obtained directly from a pharmacist. Methods. We used a decision model to compare outcomes for private and public payers following unprotected intercourse from. Results. Obtaining emergency contraceptive pills from a pharmacy, compared with obtaining them from a physician or clinic, resulted in a $158 (95% confidence interval (CI) = $76, $269) reduction in costs for private payers and a $48 (95% CI = $16, $93) reduction for public payers. Conclusions. Our findings suggest that under varied assumptions, obtaining emergency contraceptive pills directly from a pharmacist reduces the number of unintended pregnancies and is cost saving.

Study Objective. To investigate the occurrence of tramadol-associated seizures. Design. Retrospective cohort and case-control studies. Setting. UnitedHealth Group-affiliated independent practice model health plans, from different regions of the United States, contracting with large networks of physicians. Intervention. Analysis of administrative data from a large U.S. managed care population. Patients. A cohort of 9218 adult tramadol users and 37,232 concurrent nonusers. Measurements and Main Results. Fewer than 1% of users (80) had a presumed incident seizure claim after the first tramadol prescription. Risk of seizure claim was increased 2- to 6-fold among users adjusted for selected comorbidities and concomitant drugs. Risk was highest among those aged 25–54 years, those with more than four tramadol prescriptions, and those with history of alcohol abuse, stroke, or head injury. A case-control study among users was conducted to validate incident seizure outcomes from medical records. Only eight cases were confirmed, and all had cofactors associated with increased seizure risk. Conclusion. In a general population, risk of seizure may be associated with long-term therapy with tramadol or the presence of cofactors, or confined to a small sensitive population subset.

We evaluated the acceptability of a systematic estrogen replacement therapy (ERT) substitution program in a large U.S. health maintenance organization (HMO). Prescriptions for 14,601 enrollees were converted from Premarin tablets (PR) to Estratab tablets (ES). At the end of 6 months, 93.5% of the women continued to use ES, and 6.5% reverted to use of PR. We report the results of a telephone survey that included women randomly selected from three groups who participated in the substitution program. The groups were women whose prescriptions were converted from PR to ES (n = 253), women whose prescriptions were converted from PR to ES and back to PR (n = 250), and women who continued to use PR without converting to ES (n = 251). Two thirds of women who did not revert to use of PR were still using ES 3 years after conversion of their prescriptions. Women whose prescriptions were converted but who returned to use of PR cited both return of menopausal symptoms and development of new symptoms as reasons. Women who continued to use ES did not report return of menopausal symptoms after the conversion. Our evidence supports the conclusion that the substitution of Estratab tablets for Premarin tablets among users of ERT was well tolerated and acceptable to most affected women in this HMO setting.

BACKGROUND The pre- and peri-natal drug exposures reported by women participating in a case-control study of children in Colorado were examined for association with infant craniosynostosis. METHODS Mothers of case and control children underwent a standardized telephone interview and obstetric and newborn medical record review. The interview included questions on the use of prescription and non-prescription drugs, nutritional supplements, recreational and drugs of abuse. The mother's obstetric record was abstracted for information about pharmacologic agents taken before and during the antepartum period. RESULTS There were no statistically significant risk ratios associating craniosynostosis with prenatal exposure to hydantoin, valproic acid, or cocaine. Mothers of four case children and one control child reported specific exposure to retinoic acid. There were no statistically significant increases in the odds ratio (OR) for any suture type among children exposed to hypoxigenic agents, sympathomimetic or parasympatholytic agents, or metal-containing agents. The OR was 1.87 (lower bound of the two-sided 95% test-based confidence interval (CI): 1.08) among children with sagittal/lambdoid suture synostosis who were exposed to nitrosatable drugs chlorpheniramine, chlordiazepoxide, and nitrofurantoin compared to controls. CONCLUSIONS Certain nitrosatable drugs may be associated with increased risk of infant sagittal/lambdoid craniosynostosis. A possible mechanism related to ischaemia/reperfusion injury is suggested.

Objective: This article describes requisite components of a community pharmacy·based vaccine administration program and provides resources for obtaining training and materials to facilitate implementation in the pharmacy. Data Sources: Published medical literature accessed via Medline; interviews of pharmacists who initiated vaccine administration programs; government publications; professional publications including manuals and newsletters; and the resources of the Washington State Board of Pharmacy. Data Synthesis: Pharmacists in several states have initiated vaccine-administration programs for adults, adolescents, and children within their pharmacies with acceptance by patients, third party payers, and other health professionals. In some states, collaborative prescribing agreements between physicians or nurse-practitioners and pharmacists enable pharmacists to implement high-volume immunization clinics as well as individual patients services. Standardized training is available from several sources, and in most settings vaccine administration services can be implemented with low initial investment. Conclusion: Vaccine administration may soon become an integral function in community pharmacists' responsibilities for the health and well-being of patients. Acknowledgments: Many thanks to Don Downing for editorial review.

Five patients with chronic nonmalignant pain were transferred from other analgesics to oral methadone. The method of transferring to oral methadone is described and issues of cost effectiveness; convenience, improved analgesia, and adverse effects are discussed. Oral methadone may provide a cost-effective alternative to other optoid analgesics and may provide improved, pain control in certain patients, even when compared with other opioids administered parenlerally.

In 1997, the U.S. Food and Drug Administration endorsed the use of a combination estrogen and progestin oral contraceptive for emergency postcoital contraception.' In 1998, the agency approved the first dedicated emergency contraceptive product for use in the United States, and in 1999 it approved the first progestin-only emergency contraceptive pill.2 Despite emergency contraception's safety, effectiveness and unique ability to reduce unintended pregnancy, it has been vastly underused. One study conducted in 1997 found that only one in 10 health professionals routinely discussed emergency contraception with their clients, and that 41% of Americans were completely unaware of its existence.3 The Institute of Medicine advocates an aggressive effort to reduce the number of unintended pregnancies, by increasing access to contraceptive information and services and by broadening the range of health care professionals and institutions that promote and provide contraceptive services.4 In response to this mandate, five organizations in Washington State-the nonprofit organization Program for Appropriate Technology in Health (PATH), the Washington State Pharmacists Association, the University of Washington Department of Pharmacy, the Washington State Board of Pharmacy and the Seattle office of the advertising firm DDB World

To the Editor: Glasier and Baird (July 2 issue)1 found that emergency contraception was used responsibly by women who were given the appropriate medication to keep at home. Making emergency contraception available in this way is consistent with the objectives of a project implemented in community pharmacies in Washington State. Under collaborative drug-therapy agreements developed jointly by physicians and pharmacists, women may obtain emergency contraceptive pills in advance of or in response to an immediate need directly from pharmacists without first contacting their health care providers. This program does not make emergency contraception available without prescription but rather, after a . . .

women's awareness and use of emergency contraception by utilizing pharmacists to increase its availability. We also discuss the impact that their expanded role is having on access to emergency contraception, and thereby the potential impact of the program on rates of unintended pregnancy.

We describe a quantitative method of analysis for assessing stability of human monoclonal antibody production by hybridomas. Clones derived from fusion between the SHM-D33 heteromyeloma line and EBV-stimulated human lymphocytes were studied for antibody presence using a fluorescent labelling technique. Frequencies of antibody-negative variants in clonal populations were measured, and measurements on parallel clonal populations were subjected to Luria-Delbrück fluctuation analysis to compute rates of generations of antibody-negative cells. Independent hybridoma clones exhibited a range of stabilities and the corresponding rates varied between 5 X 10(-4) and 6 X 10(-2) cell-1 generation-1. Rates of generation of antibody-negative variants for the more stable heteromyeloma hybridomas compared well with those of 2 established mouse hybridoma lines tested (less than 10(-3) cell-1 generation-1). There was a positive correlation between frequency of antibody-negative variants measured in clonal populations grown to large numbers of cells (greater than 10(7) per culture) and their rate of loss of antibody production. Large variations in frequency of antibody-negative variants were observed in parallel clonal populations, suggesting that loss of ability to produce antibody is due to random, mutation-like events including chromosome loss (Luria and Delbrück, 1943). High frequencies of antibody-negative variants may indicate imminent loss of antibody-producing capacity by a clone growing in suspension culture.

To the Editor.— Regarding the article by Gifford et al (1980;243:1532) on the postmarket surveillance (PMS) of cimetidine, if the goals of postmarket surveillance as outlined in the article can be realized, PMS programs can be of value to individual clinicians, the pharmaceutical industry, and federal agencies. Some questions arose that we think were not completely addressed in the article. These pertain to the method employed by Gifford and his group in the reporting of adverse effects. Perhaps the most important was the method of assigning causality in assessing the reports of deaths. We refer specifically to the statement that "deaths that occurred after stopping treatment were clearly unrelated to cimetidine." In assessing the possible drug relatedness of these deaths, one must consider whether the onset of the precipitating event leading to death was within the prescribing time frame. To consider only the end point of death could lead to

To the Editor.— We concur with Rossi et al 1 that alert physicians and others spontaneously reporting their suspicions of adverse drug reactions is critical to the discovery of rare effects of marketed drugs. Spontaneous reporting is an essential element of the multicomponent postmarketing surveillance systems established by pharmaceutical manufacturers and the Food and Drug Administration. However, we disagree with the assumption that the reason for conducting systematic postmarketing drug surveillance is to identify unusual or unexpected adverse effects. The purpose of systematic surveillance is to quantify the occurrence of both beneficial and adverse effects, which is not possible with spontaneous reporting systems. Even expected effects that are occurring with reasonable frequency need to be quantified, particularly if they occur with a different frequency among previously unidentified subgroups of users. Furthermore, the failure of adversity to appear at a statistically significant level in the observation of 10,000 persons does not