Issue 14 April 2003
Rhabdomyolysis Associated with Statin Therapy	New Medications: Actonel® Weekly (risedronate) ; Zetia® (ezetimide)	American Transplant Congress (Transplant 2003)

Rhabdomyolysis Associated with Statin Therapy Rhabdomyolysis is associated with a CK (creatine kinase) elevation of more than 10 times the normal upper limit, and is not common in the general population (less than 0.1%). Rhabdomyolysis can lead to myoglobinuria, acute renal necrosis, elevated ASAT (aspartate amino transferase), and LDH (lactate dehydrogenase). Rhabdomyolysis, in association with statins such as fluvastatin, atorvastatin, lovastatin, simvastatin, and pravastatin, is more common in patients with multi-system diseases (i.e. renal failure), hypothyroidism, hypoalbuminemia, the elderly and some medication combinations including fibric acids. Modest elevations in liver function tests (LFTs) are not an absolute contraindication for the use of statins. A baseline LFT should be acquired and people at risk should be monitored more closely. If a patient has symptoms of generalized muscle weakness and/or pain, tenderness, and brown urine with elevations of CK that are 10 times above normal or greater, the statin should be discontinued and the patient should be monitored for normalization of CK levels. CK elevations are usually associated with higher doses of statins. For more information, the ACC/AHA/NHLBI published a Clinical Advisory on the Use and Safety of Statins in Circulation (2002;106;1024-1028). Authored by Roseann Johnston

New Medications Actonel® Weekly (risedronate) Once weekly Actonel® (risedronate), manufactured by Procter and Gamble, was approved in May 2002 for the prevention and treatment of postmenopausal osteoporosis. Actonel® is a bisphosphonate that inhibits bone resorption by binding to the mineral surface of bone and decreasing osteoclast activity. Once weekly Actonel® is available as a 35 mg tablet. There are also 5 mg and 30 mg tablets available as once daily regimens for the treatment of osteoporosis and Paget’s disease, respectively. Once daily risedronate 5 mg is effective and well tolerated for preventing and treating both postmenopausal and glucocorticoid induced osteoporosis. The pharmacokinetics and mechanism of action of risedronate suggest that administration less often than once daily may have similar effects on bone mineral density (BMD). In one clinical trial, the efficacy and tolerability of once weekly risedronate (35 mg and 50 mg) was compared to daily risedronate (5 mg) in women with osteoporosis. The mean change in lumbar spine BMD after 12 months was 4% in the 5 mg daily group, 3.9% in the 35 mg weekly group, and 4.2% in the 50 mg weekly group. Average changes in femoral neck and total hip BMD were similar in the three groups. The percentage of adverse effects was similar between all three groups with the most common being infection, arthralgia, and upper GI complaints. Since the 35 mg and the 50 mg dose provided the same efficacy and safety, the lower dose is considered optimal for postmenopausal women with osteoporosis (Brown JP et al, Calcif Tissue Int 2002; 71:103-111). Actonel® is contraindicated in patients with known hypersensitivity to the active ingredient, other bisphosphonates, or any component of the formulation. It is also contraindicated in patients with hypocalcemia, abnormalities of the esophagus that delay esophageal emptying, or an inability to stand or sit upright for at least 30 minutes. Common adverse effects include headache, rash, diarrhea, abdominal pain, arthralgia, and flu-like syndrome. The recommended dose of Actonel® is 35 mg once a week for the prevention and treatment of postmenopausal or glucocorticoid induced osteoporosis. It should be administered 30 to 60 minutes prior to food, drink, or other medications orally to avoid interference with absorption. It should be taken on an empty stomach with a full glass of plain water and the patient should avoid lying down for 30 minutes after swallowing the tablet. A patient assistance program is available for Actonel®. For further information, please contact the MAP office at (706) 721-0131 or Procter and Gamble at (800) 830-9049. Zetia® (ezetimide) Zetia® (ezetimide), manufactured by Merck/Schering-Plough, was FDA approved in October 2002 for monotherapy or for combination with HMG-CoA reductase inhibitors for hypercholesterolemia. The mechanism of action of ezetimide is quite different from any other cholesterol-lowering agent because it lowers cholesterol by preventing its intestinal absorption through the inhibition of cholesterol transport across the intestinal wall. Ezetimide is available in 0.25 mg, 1 mg, 5 mg, and 10 mg tablets. When used as monotherapy, each once daily dose of ezetimide has been shown to decrease LDL cholesterol by approximately 10%, 13%, 17%, and 19%, respectively. Clinical trials have shown up to a 20% greater reduction in LDL cholesterol when used in combination with statin therapy. The recommended maintenance dose of ezetimide is 10 mg once daily. Ezetimide has not been shown to interfere with the cytochrome P-450 enzyme system. There has been a noted interaction with ezetimide and bile acid sequestrants, therefore, the manufacturer recommends taking ezetimide at least 2 hours before or 4 hours after the administration of a bile acid sequestrant. Clinical trials have shown ezetimide to be comparable to placebo with regards to the side-effect profile. Some of the more common side effects include headache, viral infection, arthralgias, and upper respiratory tract infection. Ezetimide appears to be a useful addition to the choice of medications that are available for hyperlipidemia. One of the primary advantages to this medication is the drug-drug interaction and side-effect profile. This is definitely an advantage in certain patient populations where the potential for drug-drug interactions and adverse events is potentially overwhelming. Many transplant patients are taking medications that are metabolized by the cytochrome P-450 system. For instance, some transplant patients are on cyclosporine, tacrolimus, or sirolimus, which are substrates of the cytochrome 3A4 enzyme system. The majority of the HMG-CoA reductase inhibitors are inhibitors of 3A4 enzymatic system, which could possibly lead to toxic levels of each of these agents. Use of a medication like Zetia® that does not interfere with the cytochrome P-450 system could minimize the side-effect profile that is caused by drug-drug interactions in transplant patients. A patient assistance program is available for this medication. For more information concerning the patient assistance program contact the MAP office at 706-721-0131 or Merck/Schering-Plough at (800) 347-7503. Authored by Bridget Maner, Pharm.D.

American Transplant Congress (Transplant 2003) Meeting To Be Held in Washington, D.C. May 30 – June 4, 2003 The American Society of Transplant Surgeons (ASTS) and the American Society of Transplantation (AST) will be hosting their annual joint meeting, the American Transplant Congress Meeting, in Washington D.C. on May 30 – June 4, 2003. This meeting serves as a forum for the exchange of scientific and clinical information, ideas, and opinions for those who are interested in the research aspects of solid organ and tissue transplantation. Physicians, surgeons, scientists, nurses, organ procurement personnel, and pharmacists are invited to attend workshops and meetings, present abstracts and posters, as well as participate in group sessions in an effort examine and discuss issues and objectives that are relevant to organ and tissue transplantation. The meeting will be held at the Marriott Wardman Park Hotel in Washington D.C. For more information, contact the American Transplant Congress 2003 staff at (856) 439-0880, or visit their web site at www.atcmeeting.org.

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.