Issue 8 October 2001
CURE Trial	New Medications Lantus® (Insulin glargine) Advair™ Diskus® (salmeterol and fluticasone propionate)	Updates Baycol® (cerivastatin) Withdrawn

CURE Trial Recurrent ischemic events, precipitated by thrombosis, are major risks for patients presenting with acute coronary syndromes. Many different medicines, including aspirin, heparin, glycoprotein IIb/IIIa receptor blockers, and low molecular weight heparins, have been proven effective for short term prevention. Thienopyridine derivatives, such as clopidogrel, could be beneficial in combination with aspirin because they inhibit platelet aggregation by a complementary mechanism. The investigators of the CURE trial, Clopidogrel in Unstable Angina to Prevent Recurrent Events, compared the safety and efficacy of clopidogrel plus aspirin versus aspirin alone over a twelve month period. This double-blind, placebo controlled study enrolled over 12,500 patients with acute coronary syndromes and no ST-segment elevation. Patients were given clopidogrel, loading dose of 300mg followed by 75mg/day, and aspirin 75-325mg/day or matching placebo and aspirin. Approximately 9% of the clopidogrel group died from cardiovascular causes, nonfatal myocardial infarction, or stroke compared to 11% of the placebo group (p<0.001). Similar results favoring the clopidogrel group were also seen in subgroups receiving other drugs, such as antihypertensives or ACE inhibitors, and subgroups using different doses of aspirin. Bleeding occurred more often in those using clopidogrel (3.7% vs. 2.7%; p=0.001), but there was no difference in the rate of life threatening bleeding. Combination antiplatelet therapy may be an emerging treatment strategy in secondary prevention of ischemic events. For more information concerning this trial refer to the study (NEJM 2001;345:494). Authored by Jason VanLandingham

New Medications Lantus® (Insulin glargine) Lantus® (Insulin glargine), manufactured by Aventis, is a new long-lasting insulin analog approved by the FDA for treatment of both type 1 and type 2 diabetes. A randomized prospective 28-week trial was done with type 1 diabetes patients (n=534). In this study, insulin glargine was given once daily at bedtime and compared to NPH insulin, which was given once or twice daily. All patients also received regular human insulin at mealtimes. The study showed that reductions in glycosaturated hemoglobin from baseline levels were similar in both groups. However, insulin glargine produced a greater reduction in fasting glucose levels and less symptomatic hypoglycemia (40% vs. 49%) or nocturnal hypoglycemia (18% vs. 27%) (RE Ratner et al, Diabetes Care; 23:639). Another 16 week study with type 1 diabetes patients (n=619) was done with insulin glargine given once daily at bedtime compared to NPH insulin given once or twice daily as basal treatment, with all patients receiving rapid-acting insulin lispro at mealtime. This study showed that patients taking insulin glargine had lower fasting blood glucose levels, but there was no difference in hypoglycemia or other adverse events. The only exception was a higher incidence of mild pain at the injection site with insulin glargine (6% vs. 0.3% with NPH). Also, mean weight gain was less (0.12 kg vs. 0.54 kg) with insulin glargine (P Raskin et al, Diabetes Care 2000; 23:1666) The most common adverse effects of insulin glargine are hypoglycemia and mild pain occurring at the injection site. The long-term safety of this new product remains to be established. Insulin glargine is supplied in the US only in 10-ml vials that contain 100 units per ml. It cannot be diluted or mixed with any other insulin or solution. When patients change from a once-daily dosage of NPH or ultralente insulin to insulin glargine, once daily at bedtime, the initial dose remains the same. When patients change from a twice-daily dosage of NPH to insulin glargine, the initial dose should be reduced by about 20% and then adjusted based on the patient's response. In patients who have not previously been treated with insulin, the recommended initial dosage is 10 units given once daily at bedtime. This dosage should be adjusted as needed. The dosage range in clinical trials has extended from 2 to 100 units per day. A patient assistance program is available for Lantus®. For further information please contact MAP at 706-721-0131 or Aventis at 1-800-221-4025. ADVAIRTM™ DISKUS® ADVAIRTM™ DISKUS®, a combination salmeterol/fluticasone propionate inhaler approved by the FDA in August 2000, was released to pharmacies on April 16, 2001. ADVAIRTM™ is marketed by GlaxoWellcome and is indicated for the treatment of both the inflammation and the bronchoconstriction of asthma. ADVAIRTM™ is available in three strengths, each strength containing 50mcg of salmeterol combined with 100mcg, 250mcg, or 500mcg of fluticasone propionate. In a 12-week, double-blind, triple-dummy study, 608 patients stopped their inhaled corticosteroid and were randomized to one of three treatment groups. Patients were evenly divided and received either salmeterol/fluticasone in com- bination, fluticasone alone or triamcinolone. The patients taking the combination product showed an overall improvement in forced expiratory volume in 1 second (FEV1) of 0.58L (27%). These patients also reported less adverse effects, greater peak expiratory flow (PEF), and a higher percentage of rescue free days. Recommended dosing for ADVAIRTM™ for patients not previously on, or on low doses of inhaled corticosteroids, is 100mcg/50mcg inhaled twice daily. For patients on medium to high dosages of inhaled corticosteroids, the dose of ADVAIRTM™ is 250mcg/50mcg or 500mcg/50mcg inhaled twice daily. The maximum recommended daily dose of ADVAIRTM™ is 500mcg/50mcg twice daily. All patients should be titrated to the lowest possible dosage after they are stabilized on ADVAIRTM™ therapy. It is recommended that prescribing physicians and pharmacists emphasize to patients that the ADVAIRTM™ inhaler is not meant to replace fast acting rescue inhalers. Patients need to rely on these fast acting inhalers for emergency situations. A patient assistance program is available for ADVAIRTM™. For further information please contact GlaxoWellcome Patient Assistance Program at 1-800-722-9294. Authored by Lori A. Carithers

Updates Baycol® Withdrawn In August 2001, Bayer Corporation voluntarily withdrew Baycol® (cerivastatin) as a result of its link with rhabdomylolysis. This adverse effect was actually more commonly associated with the co-administration of Baycol® and another antihyperlipidemic, gemfibrozil. Rhabdomylolysis occurs when muscle cells breakdown and release their contents into the blood stream. This may result in kidney damage and other end organ damage. One of the major laboratory indicators of muscle breakdown is CPK (creatinine phosphokinase). Signs and symptoms of rhabdomylolysis include muscle pain, weakness, tenderness, malaise, fever, dark urine, nausea, vomiting and elevated CPK. Authored by Dr. Leslie Roebuck

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.