Fluoroquinolone use for uncomplicated urinary tract infections in women: a retrospective cohort study.

OBJECTIVES: The United States Food & Drug Administration released an advisory in 2016 that fluoroquinolones be relegated to second-line agents for uncomplicated urinary tract infections (UTIs) given reports of rare but serious side effects; similar warnings have followed from Health Canada and the European Medicines Agency. The objective was to determine whether alternative non-fluoroquinolone agents are as effective as fluoroquinolones in the treatment of UTIs. METHODS: We conducted a retrospective population-based cohort study using administrative health data from six Canadian provinces. We identified women (n = 1 585 997) receiving antibiotic treatment for episodes of uncomplicated UTIs (n = 2 857 243) between January 1 2005 and December 31 2015. Clinical outcomes within 30 days from the initial antibiotic dispensation were compared among patients treated with a fluoroquinolone versus non-fluoroquinolone agents. High-dimensional propensity score adjustments were used to ensure comparable treatment groups and to minimize residual confounding. RESULTS: Fluoroquinolone use for UTI declined over the study period in five of six Canadian provinces and accounted for 22.3-48.5% of treatments overall. The pooled effect across the provinces indicated that fluoroquinolones were associated with fewer return outpatient visits (OR 0.89, 95%CI 0.87-0.92), emergency department visits (OR 0.74, 95%CI 0.61-0.89), hospitalizations (OR 0.83, 95%CI 0.77-0.88), and repeat antibiotic dispensations (OR 0.77, 95%CI 0.75-0.80) within 30 days. CONCLUSIONS: Fluoroquinolones are associated with improved clinical outcomes among women with uncomplicated UTIs. This benefit must be weighed against the risk of fluoroquinolone resistance and rare but serious fluoroquinolone side effects when selecting first-line treatment for these patients.

Effectiveness of the STOPP/START (Screening Tool of Older Persons' potentially inappropriate Prescriptions/Screening Tool to Alert doctors to the Right Treatment) criteria: systematic review and meta-analysis of randomized controlled studies.

WHAT IS KNOWN AND OBJECTIVE: STOPP/START are explicit screening tools that identify potentially inappropriate prescribing in older adults. Our objective was to update our 2013 systematic review that showed limited evidence of impact, using new evidence from randomized controlled trials (RCTs) assessing clinical, humanistic and economic outcomes in older adults. METHODS: We performed a search of PubMed, EMBASE, CINAHL, Web of Science and grey literature for RCTs published in English since the previous review through June 2014. The Cochrane Risk of Bias Tool was used. We performed a meta-analysis on the effect of STOPP on potentially inappropriate medication (PIM) rates and a narrative synthesis on other outcomes. RESULTS AND DISCUSSION: Four RCTs (n = 1925 adults) from four countries were included, reporting both acute (n = 2) and long-term care (n = 2) patients. Studies differed in implementation. Two studies were judged to have low risk, and two to have moderate-to-high risk of bias in key domains. Meta-analysis found that the STOPP criteria reduced PIM rates in all four studies, but study heterogeneity (I(2) = 86·7%) prevented the calculation of a meaningful statistical summary. We found evidence that use of the criteria reduces falls, delirium episodes, hospital length-of-stay, care visits (primary and emergency) and medication costs, but no evidence of improvements in quality of life or mortality. WHAT IS NEW AND CONCLUSION: STOPP/START may be effective in improving prescribing quality, clinical, humanistic and economic outcomes. Additional research investigating these tools is needed, especially in frail elderly and community-living patients receiving primary care.

Concordance with a STOPP (Screening Tool of Older Persons' Potentially Inappropriate Prescriptions) Criterion in Nova Scotia, Canada: Benzodiazepine and Zoplicone Prescription Claims by Older Adults with Fall-related Hospitalizaions.

BACKGROUND: Optimization of prescribing in older adults is needed. The STOPP criteria provide a systematic way of identifying potentially inappropriate prescribing in this population. Previous research indicates poor concordance between benzodiazepine prescribing and STOPP. OBJECTIVES: To determine the extent and predictors of benzodiazepine and zopiclone (BZD-Z) pharmacy dispensations in older adults with a history of a recent fall, in concordance with STOPP. METHODS: Prescription claims data from the Nova Scotia Seniors' Phamacare Program were linked with fall-related injury data from the CIHI Discharge Abstract Database. Adults aged ≥ 66 years making a claim for a BZD-Z in the 100 days prior to fall-related hospitalization were identified. Their BZD-Z claims in the 100 days following discharge were also identified. Descriptive statistics, trend tests and logistical regression modelling were performed to examine predictors for continued use of BZD-Z post-fall. RESULTS: Over 5 years, from a pool of 8,271 older adults discharged following a fall-related hospitalization, 1,789 (21.6%) had made a claim for a BZD-Z in the 100 days prior to admission. Of these, 82% were women. Younger age and female sex were predictors of continuing BZD-Z dispensations post-fall. In the 100 days following discharge, 74.2% (n=1327) made a claim for at least one BZD-Z. CONCLUSION: BZD-Z use continued in 74% of patients following discharge from a fall-related hospitalization, representing limited concordance with the STOPP criterion. Such hospitalizations and follow-up care present an opportunity to address an ongoing modifiable risk factor.

Prescribing indicators: what can Canada learn from European countries?

BACKGROUND: Drug therapy can improve patients' quality of life and health outcomes; however, underuse, overuse and inappropriate use of drugs can occur. Systematic examination of potential opportunities for improving prescribing and medication use is needed. OBJECTIVE: To convene a diverse group of stakeholders to learn about and discuss advantages and limitations of data sources, tools and methods related to drug prescribing indicators; foster methods to assess safe, appropriate and cost-effective prescribing; increase awareness of international organizations who develop and apply performance indicators relevant to Canadian researchers, practitioners and decision-makers; and provide opportunities to apply information to the Canadian context. METHODS: Approximately 50 stakeholders (health system decision-makers, senior and junior researchers, healthcare professionals, graduate students) met June 1-2, 2009 in Halifax, Canada. Four foundational presentations on evaluating quality of prescribing were followed by discussion in pre-assigned breakout groups of a prepared case (either antibiotic use or prescribing for seniors), followed by feedback presentations. RESULTS: Many European countries have procedures to develop indicators for prescribing and quality use of medicines. Indicators applied in diverse settings across the European Union use various mechanisms to improve quality, including financial incentives for prescribers. CONCLUSION: Further Canadian approaches to develop a system of Canadian prescribing indicators would enable federal/provincial/territorial and international comparisons, identify practice variations and highlight potential areas for improvement in prescribing, drug use and health outcomes across Canada. A more standardized system would facilitate cross-national research opportunities and enable Canada to examine how European countries use prescribing indicators, both within their country and across the European Union.

Disease progression among multiple sclerosis patients before and during a disease-modifying drug program: a longitudinal population-based evaluation.

Randomized controlled trials have demonstrated the efficacy of disease-modifying drugs (DMDs) in persons with relapsing-remitting multiple sclerosis (MS) and secondary progressive MS with superimposed relapses. However, these brief studies of selected patients have focused mainly on reducing attacks and must be complemented by evaluations in 'realworld' clinical settings to establish the effectiveness of DMD programs in slowing disease progression and to inform health policy and program decision-making. We assessed the effectiveness of DMDs as administered in a comprehensive publicly funded drug insurance program that provides DMDs to a geographically defined population of MS patients who meet specific eligibility criteria. Data from 1752 MS patients (10,312 assessments) seen between 1980 and 2004 at a regional MS Clinic serving the entire population of Nova Scotia, Canada were analysed. Using survival methods we observed a statistically significant reduction in disease progression to specific Expanded Disability Status Scale endpoints following the introduction of this program. Subgroup analyses of patients eligible for treatment using hierarchical linear regression methods also suggested that disease progression was slowed in patients treated with the first DMD prescribed. These findings provide evidence supporting DMD program effectiveness that can be used to inform the broader implementation of such programs.

How effective are disease-modifying drugs in delaying progression in relapsing-onset MS?

OBJECTIVE: Our objective was to estimate the effectiveness of disease-modifying drugs (DMDs) in delaying multiple sclerosis (MS) disability progression in relapsing-onset (R-onset) definite MS patients under "real-world" conditions. METHODS: Treatment effect size, for DMDs as a class, was estimated in absolute terms and relative to MS natural history. A basic model estimated annual Expanded Disability Status Scale (EDSS) change before and after treatment. An expanded model estimated annual EDSS change in pretreatment years, treatment years on first drug, treatment years after drugs were switched, and in years after treatment stopped. Models were populated with 1980 through 2004 clinical data, including 1988 through 2004 data for all Nova Scotians treated with DMDs. Estimates were made for relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and R-onset groups. RESULTS: Estimated pretreatment annual EDSS increases were approximately 0.10 of one EDSS point for the RRMS group, 0.31 for the SPMS group, and 0.16 for the R-onset group. Estimates of EDSS increase avoided per treatment year on the first drug were significant for the RRMS group (-0.103, 0.000), the SPMS group (-0.065, 0.011), and the R-onset group (-0.162, 0.000); relative effect size estimates were 112%, 21%, and 105%. Estimated EDSS progression was faster in years after drug switches and treatment stops. CONCLUSIONS: Our estimates of disease-modifying drug (DMD) relative treatment effect size, in the context of "real-world" clinical practice, are similar to DMD treatment efficacy estimates in pivotal trials, though our findings attained statistical significance. DMDs, as a class, are effective in delaying Expanded Disability Status Scale progression in patients with relapsing-onset definite multiple sclerosis (MS) (90%), although effectiveness is much better for relapsing-remitting MS than for secondary progressive MS groups.

The impact of socioeconomic and demographic factors on the utilization of smoking cessation medications in patients hospitalized with cardiovascular disease in Nova Scotia, Canada.

OBJECTIVE: To determine whether any demographic or socioeconomic factors affect the use of smoking cessation medications in patients hospitalized with heart disease. METHOD: Data were obtained from the Improving Cardiovascular Outcomes in Nova Scotia (ICONS) Canada database, which includes a registry of all hospitalized patients with a diagnosis of ischaemic heart disease, congestive heart failure, or atrial fibrillation since October 1997. Patients agreeing to provide follow-up were sent an enrollment survey to determine demographic and socioeconomic factors including household income, educational background and private drug insurance plans. RESULTS: Between 15 October 1997 and 31 December 2000, 5442 patients who were current smokers and 270 patients using a smoking cessation medication were admitted to hospital registered in the ICONS database. An enrollment survey was completed by 1071 current smokers and 77 patients using a smoking cessation agent. CONCLUSION: Higher education level, presence of private drug insurance plans, and less difficulty paying for basic needs were associated with higher use of smoking cessation medications.

A comparison of health utility measures for the evaluation of multiple sclerosis treatments.

OBJECTIVES: To evaluate the practical application and psychometric properties of three health utility measures in a sample of MS patients with a broad range of neurological disability as measured by the Extended Disability Status Scale (EDSS). METHODS: Patients randomly selected from two MS clinic registries were assessed using standard clinical methods and completed three generic measures of health utility (EQ-5D, HUI Mark III, SF-6D). The proportion of missing data, test/retest reliability, and construct validity of each health utility measure were examined. RESULTS: The assessments were completed by 187 patients. Less than 10% of data were missing for the subscales of the SF-6D (< 3.2%), HUI Mark III (<1.6%), and EQ-5D (< or =7.5%). Severely disabled patients were more likely to omit physical function questions for the SF-6D (20%), and EQ-5D (43%). Retest reliability for the SF-6D (ICC = 0.83), EQ-5D (ICC = 0.81), and HUI Mark III (ICC = 0.87) were adequate for population surveys. Correlations between assessment of clinical function and each health utility measure were strongest for the HUI Mark III (HUI Mark III EDSS rho = -0.77, HUI Mark III ambulation index rho = -0.76, HUI Mark III timed 25 foot walk rho = -0.73, HUI Mark III nine hole peg test rho = -0.65). CONCLUSIONS: The health utility measures were generally feasible and reliable but the HUI Mark III demonstrated highest concordance with the EDSS across the full range of neurological disability. Of the three measures studied, the HUI Mark III may be the most appropriate for cost effectiveness evaluations of MS therapies.

Variation in pharmacy prescription refill adherence measures by type of oral antihyperglycaemic drug therapy in seniors in Nova Scotia, Canada.

OBJECTIVE: To examine the association between pharmacy prescription refill adherence by type of oral antihyperglycaemic medications used in seniors in Nova Scotia, Canada. RESEARCH DESIGN AND METHODS: Pharmacy and health care utilization data from April 1993 to March 1996 for Nova Scotia Seniors' Pharmacare beneficiaries treated with 1st and 2nd generation sulphonylureas and biguanides was analysed. Refill adherence was quantified by two proportions: number of days beneficiaries had a medication surplus compared with the total period of observation and gaps in treatment compared with the total period of observation. Analysis examined association of type of oral antihyperglycaemic agent and dosing on refill adherence, after adjustment for age, gender and hospital use. RESULTS: A total of 3358 beneficiaries met the study criteria. The mean refill adherence rate [continuous multiple-interval measure of medication availability (CMA)] was 86 +/- 0.4% SE and continuous measure of medication gaps (CMG) was 16 +/- 0.4% SE. Use of biguanides was associated with lower odds of having a medication surplus. The use of 2nd generation sulphonylureas and biguanides, and use of agents with a dosage frequency of more than one dose per day was associated with medication gaps. CONCLUSIONS: Many beneficiaries taking antihyperglycaemic agents adhered well to prescribed therapy. The proportion of days not covered by medications averaged 16%. Beneficiaries taking medications once a day were more likely to have good refill adherence. Further work is needed to compare prescription refill adherence rates with other adherence measures and clinical outcomes. These methods are useful for establishing baseline adherence, monitoring the success of programmes designed to improve adherence, and determining cost-effectiveness of drug regimens.

Impact of a limited fluoroquinolone reimbursement policy on antimicrobial prescription claims.

OBJECTIVE: To examine the influence on administrative pharmacy claims of a policy that limited the reimbursement of the fluoroquinolones and other antimicrobials in the senior population within Nova Scotia, Canada. METHODS: The administrative claims database of the Nova Scotia Seniors' Pharmacare Program was used to identify all prescription claims for orally administered antibiotics and urinary antiinfectives. The number of beneficiaries receiving antimicrobials and the number, duration, and cost of prescriptions for antimicrobials were measured monthly. Descriptive time-series plots were used to compare antimicrobial use for two 12-month periods before the institution of the policy (December 1, 1994-November 30, 1995, and December 1, 1995-November 30, 1996) and the 12 months after the policy took effect (January 1, 1997-December 31, 1997). RESULTS: Following the implementation of the fluoroquinolone reimbursement policy, the number of patients using antimicrobials decreased by 2.2% and the number of prescriptions for antimicrobials decreased by 3.4%. Fluoroquinolone prescriptions decreased by 80.2%; prescriptions for sulfonamides and trimethoprim increased by 34.9%, cephalosporins by 17.0%, and macrolides and lincosamides by 16.5%. The only prescription duration to change was the fluoroquinolones, which increased by 25%. The average cost per antimicrobial user/year decreased from $35.24 during prepolicy period 2 to $27.51 during the postpolicy period. CONCLUSIONS: Prescription claims for fluoroquinolones in seniors decreased following the introduction of the policy. Total antimicrobial use also decreased, although this may be related to other factors. The effect of this policy change on patient outcomes requires further study.

Cost-effectiveness of interferon beta-1b in slowing multiple sclerosis disability progression. First estimates.

OBJECTIVE: To estimate the cost-effectiveness (CE) of interferon beta-1b (IFN beta-1b) in slowing disability progression in persons with relapsing-remitting multiple sclerosis (RRMS). METHODS: Treatment program costs and health outcomes are modeled for cohorts of 1,000 females and 1,000 males followed 40 years from onset. Fifteen scenarios model MS natural history progression, treatment efficacy, direct treatment costs, and MS healthcare costs. A single randomized placebo-controlled trial of IFN beta-1b found reduced disease activity by MRI, reduced frequency and severity of exacerbations, and a tendency toward slower disability progression. Disability years avoided are modeled as the primary health outcome analyzed. A ministry of health (MOH) perspective is adopted, using Nova Scotia population-based data. Annual IFN beta-1b direct treatment costs (Can $16,685) are high relative to both MOH healthcare costs per person with MS (Can $2,000) and estimated MOH costs avoided. RESULTS: Given "reference case" assumptions for women with RRMS, treatment reduces lifetime disability years by 10%. Cost per disability year avoided before discounting is Can $189,230 (US $124,892), and Can $274,842 (US $181,395) after discounting at 5%. Estimates for alternative scenarios vary greatly, leaving main findings unchanged. CONCLUSIONS: Using the Expanded Disability Status Scale, cost per disability year avoided due to interferon beta-1b treatment in RRMS is quite high. Comparable CE estimates, using MS-specific or generic health-related quality-of-life outcome measures, are even higher. Further research is required to better measure treatment effects, modification of MS natural history, and net societal costs of IFN beta-1b in RRMS.

Underuse of acetylsalicylic acid in individuals with myocardial infarction, ischemic heart disease or stroke: data from the 1995 population-based Nova Scotia Health Survey.

OBJECTIVE: To determine current patterns of acetylsalicylic acid (ASA) use in Nova Scotia for individuals with self-reported myocardial infarction, stroke or ischemic heart disease. DESIGN: Descriptive, cross-sectional, population-based study using data from the 1995 Nova Scotia Health Survey (NSHS). The NSHS was based on a probability sample and was representative of the Nova Scotia adult population by age, sex and region. Survey data were obtained by standardized home interviews conducted by trained public health nurses. SETTING: The province of Nova Scotia in 1995. PARTICIPANTS: Survey respondents who reported having a myocardial infarction, stroke or ischemic heart disease were assessed. RESULTS: Among those who reported a history of myocardial infarction, stroke or ischemic heart disease, 55% (95% CI 47% to 63%), 49% (95% CI 38% to 61%) and 54% (95% CI 39% to 68%), respectively, reported using ASA at the time of the survey. Overall, only 53% of those with cardiovascular disease were using ASA. Exclusion of persons with potential contraindications to ASA did not significantly increase these proportions. CONCLUSIONS: ASA appears to be underused in those at high risk for future vascular events. Further research is required to investigate determinants of ASA use and to increase appropriate use of ASA.

Possible role of the intestinal P-450 enzyme system in a cyclosporine-clarithromycin interaction.

Clarithromycin is a macrolide antibiotic similar in structure to erythromycin, but suggested to have fewer drug interactions. Although a pharmacokinetic interaction between clarithromycin and cyclosporine was recently reported, its magnitude and mechanism have not been explored. A 43-year-old renal transplant recipient receiving cyclosporine was treated with clarithromycin because of pneumonia. A cyclosporine pharmacokinetic study was performed 8 days after the initiation of the clarithromycin and 14 days after stopping the drug. Clarithromycin coadministration caused an approximately 2-fold increase in the area under the whole blood concentration versus time curve of cyclosporine. The oral clearance of cyclosporine was halved by clarithromycin, but the terminal elimination rate constant decreased only 15% and mean residence time 20%. These observations suggest that clarithromycin inhibits not only the hepatic metabolism but also the intestinal metabolism of cyclosporine. Caution is advised when administering the two drugs concurrently, and additional studies are necessary to elucidate the mechanism of this interaction.

Drug therapy in multiple sclerosis: a study of Nova Scotia senior citizens.

We conducted a study to determine the types and costs of drugs used by Nova Scotia senior citizens with multiple sclerosis (MS) compared with the types and costs of drugs used by all senior citizens in Nova Scotia. Administrative claims databases from the Nova Scotia Seniors Pharmacare program for persons aged 65 years or older were linked to the Dalhousie Multiple Sclerosis Research Unit (DMSRU) clinical database (1980-1994). Analyses compared persons with MS aged 65 years or older who attended the DMSRU at least once with the general population of senior citizens. Not all persons with MS attended the DMSRU. In aggregate, Pharmacare costs in 1993-1994 for patients with MS aged 65 years or older (N = 52) were $975.00 Canadian per capita compared with $590.00 Canadian for all senior citizens in Nova Scotia (N = 108,646). Thus average drug costs for the senior citizens with MS were 65% greater than those for all senior citizens covered by Nova Scotia's comprehensive, publicly funded Pharmacare program. Compared with other senior citizens, those with MS more frequently received alpha-blockers, anticholinergics, cholinergics, tricyclic antidepressants, anticonvulsants, antifatigue agents, antispasticity agents, and antibiotics for bladder infections.

Prescribing patterns of antilipemic drugs and prevalence of hypercholesterolemia in the Nova Scotia population more than 65 years old.

OBJECTIVE: To examine the prevalence of antilipemic drug use, demographic characteristics of patients using these drugs, and the prevalence of hypercholesterolemia in the Nova Scotia population over 65 years of age. DESIGN: Information was collected on the prescribing of antilipemic drugs using Nova Scotia Medical Services Insurance Pharmacare program data from October 1991 through March 1992. Pharmacare data were compared with prevalence data on increased low-density lipoprotein (LDL) cholesterol concentrations obtained from the Nova Scotia Heart Health Survey (NSHHS). SETTING: Pharmacare is a centrally administered drug insurance system maintained in computerized claims files since 1974. It provides prescription drugs to all residents of Nova Scotia who are at least 65 years old and who are insured under the provincial Medicare program. PARTICIPANTS: In the 1991-1992 fiscal year, 47,000 men and 65,700 women were eligible for Pharmacare. The NSHHS was administered to a probability sample of 2,108 individuals, representative of the 1986 population aged 18-74 years. MAIN OUTCOME MEASURES: Prescriptions for antilipemic agents. RESULTS: The NSHHS data indicated that 3.7% of women and 2.3% of men at least 65 years old and 4.8% of women and 2.8% of men 65-74 years old received a prescription for antilipemic drugs.

Delirium probably induced by clarithromycin in a patient receiving fluoxetine.

BACKGROUND: Clarithromycin is a macrolide antibiotic very similar to erythromycin in structure and spectrum of activity. It has gained increasing use since its release in Canada in May 1992, partly because it is promoted as having less potential for drug interactions and adverse effects. However, as with all new medications, a high degree of vigilance for unreported adverse effects is advisable. CASE SUMMARY: A healthy 53-year-old lawyer was receiving long-term fluoxetine 80 mg hs and nitrazepam 10 mg hs for depression and mild sleep apnea. Subsequent to initiation of treatment with clarithromycin for a respiratory infection, he rapidly developed delirium, which cleared quickly after stopping all 3 medications. The delirium and psychosis did not recur when the infection was treated with erythromycin alone or after restarting fluoxetine and nitrazepam therapy at previous dosages in the absence of antibiotics. DISCUSSION: This man's delirium is consistent with fluoxetine intoxication, which appears to have resulted from inhibition of hepatic cytochrome P450 metabolism by clarithromycin. Undiagnosed, this serious drug reaction could have lead to serious medical and social consequences. CONCLUSIONS: As the use of clarithromycin increases, the potential for interactions with other drugs metabolized by the P450 enzyme system may be realized. Clinicians should consider which other medications a patient is receiving before prescribing clarithromycin or any macrolide antibiotic with potential to influence the P450 system.

Effect of calcium-channel blockers on cyclosporine clearance and use in renal transplant patients.

OBJECTIVE: To determine the effect of calcium-channel blockers (CCBs) on cyclosporine dose, clearance, and cost, and their effect on kidney graft function and survival in patients who underwent kidney transplant. DESIGN: A total of 176 adults receiving 177 transplants were studied retrospectively. Patients were stratified as follows: no CCB (n = 57), diltiazem (n = 13), nifedipine (n = 37), and verapamil (n = 70). Patients received cyclosporine 3-4 mg/kg by continuous infusion for 5 days followed by cyclosporine 10 mg/kg/d po to maintain initial whole blood concentrations of 300-400 ng/mL. Clearance of intravenously administered cyclosporine was calculated following at least 48 hours of the same dose by continuous infusion. The amount and cost of cyclosporine used during the first 10 days of oral therapy were also calculated. RESULTS: Patients receiving diltiazem, but not verapamil or nifedipine, had decreased clearance of intravenously administered cyclosporine compared with that of the mean control group. The mean clearance of intravenously administered cyclosporine +/- SD in patients receiving no CCB was 5.1 +/- 1.5 mL/min/kg, diltiazem was 3.7 +/- 0.8 mL/min/kg, nifedipine was 6.4 +/- 1.9 mL/min/kg, and verapamil was 5.2 +/- 2.2 mL/min/kg. The amount and cost of 10 days of oral cyclosporine therapy was decreased in the verapamil group (5.7 +/- 1.5 g and $257 +/- 69) compared with that of the control group (6.7 +/- 1.6 g and $304 +/- 72) (p < 0.001). There was no significant difference among the groups with respect to immediate graft function, 1-year serum creatinine concentration, or 1-year graft survival. CONCLUSIONS: Diltiazem decreased the clearance of intravenously administered cyclosporine. Although verapamil did not decrease the clearance of intravenously administered cyclosporine, it allowed a significant reduction in oral cyclosporine cost without apparent adverse effects on graft function. Further work is needed to determine the effect of CCBs on cyclosporine pharmacokinetics, especially with respect to their metabolism by gut and hepatic cytochrome P-450 enzymes, and their effect on patient outcome.