Issue 4 October 2000
Clinical Issues Diuretics vs. Alpha-Blockers for Hypertension Tacrolimus Compared with Cyclosporine in Black Patients	Medication Review Gengraf™ (cyclosporine capsules, USP [Modified] Actonel® (residronate sodium)

Clinical Issues Diuretics vs. Alpha-Blockers for Hypertension The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a randomized, double-blind, controlled study designed to compare outcomes for hypertensive patients treated with various classes of antihypertensive medications. Recently, it was reported that one arm of the study was stopped after an interim analysis revealed worse outcomes for patients treated with the alpha-blocker doxazosin than for patients treated with diuretics. This analysis involved 24,335 patients older than 55 years who had hypertension and at least one other coronary risk factor. These patients were randomly assigned to treatment with either chlorthalidone (12.5 to 25 mg/day) or doxazosin (2 to 8 mg/day). The planned follow-up for the study is 4 to 8 years, but the doxazosin arm was stopped after a median follow-up of 3.3 years. Compared with the diuretic group, the doxazosin group had significantly greater risk for coronary heart disease events (12.0 vs.13.1 events per 100 patients ), stroke (3.6 vs. 4.3 events per 100 patients) and all cardiovascular events (21.8 vs. 25.5 events per 100 patients). In addition, the increased risk for cardiovascular events was apparent in subgroups defined by age, race, and diabetic status. This early report supports that alpha-blockers should not be a first-line antihypertensive therapy, and re-establishes diuretics as the gold standard. ALLHAT is scheduled to also provide comparisons of diuretic therapy with calcium channel blocker or angiotensin-converting-enzyme inhibitor treatment. The complete article can be found in JAMA 2000; 283: 1967- 75. Tacrolimus Compared with Cyclosporine in Black Transplant Recipients Investigators at the University of Illinois at Chicago conducted a prospective, randomized trial in 35 black recipients of primary cadaveric renal transplants comparing tacrolimus plus placebo (n=14) versus cyclosporine plus azathioprine and prednisone (n=21 ). All patients initially received muromonab CD3 (5 mg per day) for seven days. Target levels were 10 to 15 ng/mL for tacrolimus and 150 to 200 ng/mL for cyclosporine. Prednisone was begun at 1 mg/kg/day which was decreased to a maintenance dose of 0.2 mg/kg/day by 6 months. Azathioprine 2 mg/kg/day was given to the cyclosporine patients with dosage adjusted to avoid bone marrow toxicity. The mean age of patients was 45 years (16 to 68 years) and 67% were male. There were no significant differences between the groups in important demographic or disease variables. Patients were followed for mean 12 ± 9 months. Patient and graft survival were similar, 86% (12 of 14) for tacrolimus and 95% (20 of 21) for cyclosporine (p=0.71). Three deaths were associated with cardiovascular events with functioning grafts. Acute rejection occurred in 14% of tacrolimus patients (2 of 14) and 38% (8 of 21) for cyclosporine but this was not significant (p=0.25). Mean serum cholesterol at one year was significantly lower in the tacrolimus group (198 ± 45 mg/dl) compared with cyclosporine (244 ± 49 mg/dl) (p=0.03). Also, mean serum creatinine was significantly lower for the tacrolimus group (1.39 ± 0.38 versus 1.94 ± 0.64 with cyclosporine; p=0.02). This was a relatively small trial that demonstrated lower (but not significant) acute rejection rates with tacrolimus. Tacrolimus was also associated with a lower serum cholesterol and serum creatinine. While the results suggest advantages for tacrolimus, larger studies would be needed before tacrolimus could be recommended for black primary renal transplant patients. The complete article can be found in Am J Surg 1999; 77:299-302.

Medication Review Gengraf™ (cyclosporine capsules, USP [Modified] Gengraf capsules are indicated for the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants. They are available as 100 mg and 25 mg capsules and have been shown to be mg-for-mg bioequivalent to Neoral® capsules (cyclosporine capsules, USP [MODIFIED]). Two studies were conducted to demonstrate bioequivalence with Neoral® in healthy patients. In the first, volunteers participated in a single-dose, open-label, randomized crossover study to compare the bioavailability of Gengraf™ and Neoral® under fasting conditions. In the second, volunteers participated in a single-dose, open-label, randomized, crossover study. The effect of food on Gengraf™ administered under non-fasting conditions was comparable to that of Neoral® administered under non-fasting conditions. In an open-label conversion study, the pharmacokinetics of Gengraf™ capsules were compared to Neoral® capsules in stable renal transplant recipients of at least 6 months. The open-label conversion study consisted of a 1 to 2 week screening period, followed by 2 weeks of dosing Neoral® BID, followed by 2 weeks of dosing Gengraf™ BID, followed by a final week of dosing Neoral® BID. Doses were converted 1:1 in all subjects. Steady state pharmacokinetics were measured on day 14 for Neoral® and day 28 for Gengraf™. Recipients included 17 females and 33 males; racial demographics were 15 African-Americans, 27 Caucasians, 7 Hispanics and 1 Filipino. The results revealed that pharmacokinetics did not change over time after administration of Neoral® or Gengraf™. No cyclosporine dose adjustments were required in any of the 50 recipients evaluated during any of the study periods. Gengraf™ was well tolerated and the adverse events experienced by recipients were generally mild. Headache and infection were the most common adverse events reported for both drugs across the study periods. Principle adverse reactions associated with Gengraf™ are the same as those reported with Neoral®: renal dysfunction, tremor, hirsutism, hypertension, and gum hyperplasia. Dosing conversions from Neoral® to Gengraf™ are on a 1:1, mg-to-mg basis. Currently, pricing for Gengraf™ is less than Neoral®, however, there is no patient assistance program available as of September 2000. For more information, please call Abbott Labs at 1-800-633-9110. Actonel® (risedronate sodium) Actonel®, a new bisphosphonate manufactured by Procter & Gamble and Aventis Pharmaceuticals, is indicated for the treatment and prevention of postmenopausal osteoporosis (PMO), glucocorticoid-induced osteoporosis (GIO), and Paget's Disease. It has been reported that bone loss as a result of corticosteroid use occurs most rapidly in the first six months of therapy and continues for the duration of use. Patients taking more than 7.5 mg daily of prednisone have an increased risk of experiencing hip fractures and are five times more likely to experience a vertebral fracture than people who are not taking steroids. Studies demonstrate that patients who took risedronate 5 mg daily maintained or increased bone mineral density. Vertebral and non-vertebral fractures were also significantly reduced. Since the absorption of risedronate is affected by food and medication, the manufacturer recommends that it should be taken in the morning with a full glass of plain water and at least 30 minutes before the first food, drink or medication of the day. It is important that the medication is taken while in an upright position to facilitate delivery to the stomach. The most common adverse events reported include: infection, back pain, abdominal pain, hypertension, nausea, diarrhea, and arthralgia. Bisphosphonates, as a group, may cause upper gastrointestinal disorders such as dysphagia, esophagitis, and esophageal or gastric ulcer. Contraindications to risedronate use include: hypocalcemia, known hypersensitivity to any component of this product, and inability to stand or sit upright for at least 30 minutes. Risedronate is not recommended in patients with severe renal impairment (creatinine clearance less than 30 mL/min). Risedronate is available in 5 mg or 30 mg film coated tablets. For the treatment of GIO or PMO, the recommended dosage is 5 mg orally every day. For information about risedronate's medication assistance program, call Procter & Gamble Pharmaceuticals at 1-800-830-9049 (open M-F 8:30-5:00 MT).

The MAP newsletter is published quarterly to present topics of interest to the transplant community. If you would like to submit material to be considered for publication in the newsletter, please contact MAP at: Medication Access Program University of Georgia at the Medical College of Georgia Clinical Pharmacy Program CJ-1020 Augusta, Georgia 30912-2450 (706) 721-0131 or 1-800-736-2273 ext. 0131 E-mail - map@mapuga.com

The Medication Access Program is a statewide program for solid-organ transplant patients in Georgia that offers information about medication assistance programs and helps with the enrollment into these programs.