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Drugs affecting lipid metabolism
I. Aursnes
44
Drugs affecting lipid metabolism
(SED-13, 1324; SEDA-18, 426; SEDA-19, 407)
FIBRATES
The frequency of adverse effects with the newly developed micronized fenofibrate is comparable with the frequency with the usual formulation. In 7235 patients with dyslipidemia of types IIa, IIb, or IV, treated with micronized fenofibrate 200 mg/day for 12 weeks, 335 adverse events were reported by a total of 289 patients (4%) (1R). T h e most frequently reported adverse events were those affecting the digestive system (2%), followed by adverse events associated with the skin and appendages (0.7%), nervous system (0.5%), or the body as a whole (0.5%). A total of 34 adverse events (10% of all adverse events) were classified as serious. Three of the serious events were reported to be possibly related to the study drug (two cases of cholelithiasis, one case of jaundice). In another study of 1334 patients in the same review, there was one case of epistaxis with concomitant oral anticoagulant therapy, two episodes of acute pancreatitis, and one of hepatitis. Hepatic enzyme activities were increased in under 2% of 1334 patients in another series after 6 months of t r e a t m e n t (1R).
Skin Photosensitivity is a problem with the fibrates (SEDA-21, 458) and there is crossreactivity between ketoprofen and fenofibrate, believed to be due to chemical similarities between these two drugs (2c). Risk factors Hypothyroidism predisposes to rhabdomyolysis in patients taking hypolipidemic drugs and it has been suggested that one should screen thyroid function before starting 9 1999 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 22 J.K. Aronson, ed.
490
therapy (SEDA-21, 458). This has been recently supported by a report of thyroid myopathy in a 69-year-old man taking fenofibrate 200 mg/day, when his hyperthyroidism was treated with radioiodine (3c). Interactions Acute renal insufficiency has been seen in a 29-year-old man taking ciprofibrate 100mg and ibuprofen 400mg (4c). Both drugs are highly protein bound and contain propionic acid groups; ibuprofen may therefore displace ciprofibrate. Several interactions of warfarin with hypolipidemic drugs have been described (SEDA21, 459). This now also includes a clinically important potentiation of bezafibrate by warfarin (5c).
HMG COENZYME-A REDUCTASE INHIBITORS
(STATINS) (SED-13,
1327; SEDA-19, 408; SEDA-20, 408; SEDA-21, 459) Museuloskeletal
Symptoms, predominantly
stiffness and tenderness of proximal limb muscles and difficulty in rising from a low chair, can develop within a month of starting statin therapy and most cases develop within 3 months. Most patients recover after withdrawal. Sometimes a corticosteroid is needed to reverse the myopathy. In a 42-year-old man muscle biopsies showed that the myopathy was at least partly due to an inflammatory reaction (6c). Skin and appendages A case of ichthyosiform eruptions on the abdomen and back was observed in a 42-year-old Korean woman after 3 months of lovastatin therapy and disappeared on withdrawal (7c).
Drugs affecting lipid metabolism
Chapter44
With the exception of fluvastatin and pravastatin, the statins are metabolized by CYP3A4. Other drugs metabolized by this enzyme can greatly enhance the concentrations of statins in the body and can thereby precipitate rhabdomyolysis, for example the macrolide antibiotic erythromycin (SED-13, 1328). This has now also been observed when patients taking long-term statins were given a course of the similar drugs clarithromycin and azithromycin (8c). It has also been observed with the antidepressant nefazodone (9c). Other drugs that are metabolized by CYP3A4, such as cimctidine, have not been reported to cause this effect. Cyclosporin also increases the risk of rhabdomyolysis, the risk varying from statin to statin. This effect is at least partly due to differences in kinetic interactions. For example, cyclosporin increased the A U C of pravastatin (20 mg/day) 5-fold and the A U C of Iovastatin (20 mg/day) 20-fold (10c). Furthermore, lovastatin accumulated during steady-state therapy and pravastatin did not. Hepatotoxicity is another problem when various drugs are combined. In one study of 389 patients, combined pravastatin or simvastatin with gemfibrozil or ciprofibrate for 29 months in patients with refractory familial combined hyperlipidemia, five patients (1.3%) were withdrawn because their transaminase activities were increased more than 3-fold. The investigators concluded that rare drug-induced reversible hepatotoxicity calls for close monitoring (11c). Potassium-depleting diuretics, but not indapamide, have been reported to attenuate the effect of lovastatin on blood lipid concentrations (12c). Interactions
I N D I V I D U A L STATINS
491 Atorvastatin
(( SEDA-20, 409)
There was no difference in adverse effects in 177 patients randomized for 52 weeks to either simvastatin or atorvastatin (13c). Museuloskeletal Myopathy has not been reported in patients taking atorvastatin, but experience with it has been limited (14R). Myalgia was reported in 3% of the atorvastatin group in one study of 133 patients, but no patient had persistent increases in creatine phosphokinase activity over 10 times the normal limit (14R). After 1 year of treatment with atorvastatin, there was no evidence of lens opacities. Special senses
Mean prothrombin times fell slightly in 12 patients taking maintenance warfarin who took atorvastatin 80 mg/day for 2 weeks, but only during the first few days (15c). Thus, atorvastatin had no consistent effect on the anticoagulant activity of warfarin and adjustments in warfarin dosing should not be necessary. Interactions
Cerivastatin Cerivastatin is the most potent statin mg for mg. Rhabdomyolysis, myoglobinemia, and acute renal insufficiency have not been reported, but it has only recently been introduced. Serum aminotransferase activities rose more than 3-fold in under 1% of patients, a figure similar to that found with other statins (16R). In other respects too the tolerability of this drug is similar to that of other statins (17R).
Fluvastatin (SEDA-19, 408; SEDA-20, 409; SEDA-21, 460)
Although there may be differences in the degree of interaction with, for instance, cyclosporin (see above), the general impression is that the frequencies of adverse effects connected with the various statins are the same.
Experience with fluvastatin in over 1800 patients treated for an average of 61 weeks has shown it to be safe and well tolerated (SEDA19, 408).
Chapter 44
492 Museuloskeletal There have been no reports of myopathy with fluvastatin in any studies. Some cases of myalgia have been reported, mainly after exercise, but the increases in creatine kinase were less than 3-fold, rather than the 10-fold change that is used to define myopathy (SEDA-19, 408). There are, however, good reasons to believe that myopathy is a class effect and should be expected even with this drug. Indeed, of 85 spontaneous reports about fluvastatin in Australia in 1996, 30 described muscle disorders (18c).
Interactions Three patients who had taken warfarin and fluvastatin 20 mg/day for 1-2 weeks had raised international normalized ratios (19c).
Simvastatin (SED-13, 1329; SEDA-18,
1. Aursnes
NICOTINIC ACID DERIVATIVES N i a c i n (SED-13, 1329) A wide range of adverse effects have been reported with niacin (22R). In a recent comparison of modified-release with normal-release niacin in 29 men with hyperlipidemia and coronary artery disease, there were differences in tolerability but not in adverse effects (23c). The men took daily regular niacin 1 g, lovastatin 40 mg, and colestipol 20 g for 1 year, followed by two random-sequence crossover phases (8 months each) alternating regular with modified-release niacin. Compliance was significantly higher with modified-release niacin (95 vs 85%). The modified-release niacin was preferred by 21 patients and the regular niacin by four. There were no differences in uric acid, glucose, or insulin concentrations or aspartate aminotransferase activities. The two niacin formulations did not differ in extent of toxicity.
MISCELLANEOUS DRUGS
428) Skin and appendages A hypersensitivity purpura-like eruption occurred in a 62-year-old man with cirrhosis of the liver who took simvastatin 20 mg/day (20c).
Severe rhabdomyolysis occurred in a 52-year-old woman who took a combination of gemfibrozil and simvastatin (21c).
Interactions
Probucol Altogether 16 cases' of tachydysrhythmias, especially torsade de pointes, have been reported in association with probucol, 15 in women; prolongation of the QT interval is seen (SEDA-21, 460). Since the Probucol Quantitative Regression Swedish Trial (PQRST) showed no improvement in lumen volume of the femoral artery in patients given probucol plus cholestyramine compared with those given cholestyramine alone, doubts have been raised about its efficacy (24R).
REFERENCES/ 1. Adkins JC, Faulds D. Micronised fenofibrate: a review of its pharmacodynamic properties and clinical efficacy in the management of dyslipidaemia. Drugs 1997;54:615-33. 2. Leroy D, Dompmartin A, Szczurko C, Michel M, Louvet S. Photodermatitis from ketoprofen with cross-reactivity to fenofibrate and benzophenones. Photodermatol Photoimmunol Photomed 1997;13:93-7.
3. Schlienger JL, Goichot B, Grunenberger F, Pradignac A. Revelation d'une myopathie thyroidienne par un fibrate. Rev Med Interne 1997; 18:169-70. 4. Ramachandran S, Giles PD, Hartland A. Acute renal failure due to rhabdomyolysis in presence of concurrent ciprofibrate and ibuprofen treatment. Br Med J 1997;314:1593. 5. Beringer TRO. Warfarin potentiation with bezafibrate. Postgrad Med J 1997;73:657-8.
Drugs affecting lipid metabolism
Chapter 44
6. Giordano N, Senesi M, Mattii G, Battisti E, Villanov M, Gennari C. Polymyositis associated with simvastatin. Lancet 1997;349:1600-1. 7. Soeong-Jea-Jeong, Young-Tae-Kim. A case of acquired ichthyosis developed during cholesterollowering treatment. Korean J Dermatol 1997; 35:546-50. 8. Grunden JW, Fisher KA. Lovastatin-induced rhabdomyolysis possibly associated with clarithromycin and azithromycin. Ann Pharmacother 1997;31:859-63. 9. Jacobson RH, Wang P, Glueck C J, Jody DN. Myositis and rhabdomyolysis associated with concurrent use of simvastatin and nefazodone. J Am Med Assoc 1997;277:296-7. 10. Olbricht C, Wanner C, Eisenhauer T, Kliem V, Doll R, Boddaert M, O'Grady P, Krekler M, Mangold B, Christians U. Accumulation of lovastatin, but not pravastatin, in the blood of cyclosporine-treated kidney graft patients after multiple doses. Clin Pharmacol Ther 1997; 62:311-21. 11. Athyros VG, Papageorgiou AA, Hatzikonstandinou HA, Didangelo TP, Carina MV, Kranitsas DF, Kontopoulos AG. Safety and efficacy of long-term statin-fibrate combinations in patients with refractory familial combined hyperlipidemia. Am J Cardiol 1997;80:608-13. 12. Aruna AS, Akula SK, Sarpong DF. Interaction between potassium-depleting diuretics and lovastatin in hypercholesterolemic ambulatory care patients. J Pharm Technol 1997;13:21-6. 13. Dart A, Jerums G, Nicholson G, D'Emden M, Hamilton-Craig I, Tallis G, Best J, West M, Sullivan D, Bracs P, Black D. A multicenter, double-blind, one-year study comparing safety and efficacy of atorvastatin versus simvastatin in patients with hypercholesterolemia. Am J Cardiol 1997;80:39-44.
493 14. Lea AP, McTavish D. Atorvastatin. A review of its pharmacology and therapeutic potential in the management of hyperlipidaemias. Drugs 1997 ;53: 828-47. 15. Stern R, Abel R, Gibson GL, Besserer J. Atorvastatin does not alter the anticoagulant activity of warfarin. J Clin Pharmacol 1997;37:10624. 16. Anonymous. Cerivastatin for hypercholesterolemia. Med Lett Drugs Ther 1998;40:13-14. 17. McLellan K J, Wisemann LR, McTavish D. Cerivastatin. Drugs 1998;55:415-20. 18. Anonymous. WHO Drug Information 1997; 11:68. 19. Kline SS, Harrell CC. Potential warfarin-fluvastatin interaction. Ann Pharmacother 1997; 31:790. 20. Horiuchi Y, Maruok H. Petechial eruptions due to simvastatin in a patient with diabetes mellitus and liver cirrhosis. J Dermatol 1997;24:54951. 21. Tal A, Rajeshawari M. Isley W. Rhabdomyolysis associated with simvastatin-gemfibrozil therapy. South Med J 1997;90:546-7. 22. Britton ML, Bradberry JC, Letassy NA, McKenney JM, Sirman SM. ASHP therapeutic position statement on the safe use of niacin in the management of dyslipidemias. Am J Health Syst Pharm 1997;54:2815-19. 23. Brown B G, Bardsley J, Poulin D, Hillger LA, Dowdy A, Maher V M G, Zhao XQ, Albers J J, Knopf RH. Moderate dose three-drug therapy with niacin, lovastatin, and colestipol to reduce low-density lipoprotein cholesterol <100 mg/dl in patients with hyperlipidema and coronary artery disease. Am J Cardiol 1997;80:111-15. 24. Sasich LD, Sukkar SR. Probucol--lack of efficacy and market withdrawals. Saudi Pharm J 1997;5:72-3.
44
Drugs affecting lipid metabolism
(SED-13, 1324; SEDA-18, 426; SEDA-19, 407)
FIBRATES
The frequency of adverse effects with the newly developed micronized fenofibrate is comparable with the frequency with the usual formulation. In 7235 patients with dyslipidemia of types IIa, IIb, or IV, treated with micronized fenofibrate 200 mg/day for 12 weeks, 335 adverse events were reported by a total of 289 patients (4%) (1R). T h e most frequently reported adverse events were those affecting the digestive system (2%), followed by adverse events associated with the skin and appendages (0.7%), nervous system (0.5%), or the body as a whole (0.5%). A total of 34 adverse events (10% of all adverse events) were classified as serious. Three of the serious events were reported to be possibly related to the study drug (two cases of cholelithiasis, one case of jaundice). In another study of 1334 patients in the same review, there was one case of epistaxis with concomitant oral anticoagulant therapy, two episodes of acute pancreatitis, and one of hepatitis. Hepatic enzyme activities were increased in under 2% of 1334 patients in another series after 6 months of t r e a t m e n t (1R).
Skin Photosensitivity is a problem with the fibrates (SEDA-21, 458) and there is crossreactivity between ketoprofen and fenofibrate, believed to be due to chemical similarities between these two drugs (2c). Risk factors Hypothyroidism predisposes to rhabdomyolysis in patients taking hypolipidemic drugs and it has been suggested that one should screen thyroid function before starting 9 1999 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 22 J.K. Aronson, ed.
490
therapy (SEDA-21, 458). This has been recently supported by a report of thyroid myopathy in a 69-year-old man taking fenofibrate 200 mg/day, when his hyperthyroidism was treated with radioiodine (3c). Interactions Acute renal insufficiency has been seen in a 29-year-old man taking ciprofibrate 100mg and ibuprofen 400mg (4c). Both drugs are highly protein bound and contain propionic acid groups; ibuprofen may therefore displace ciprofibrate. Several interactions of warfarin with hypolipidemic drugs have been described (SEDA21, 459). This now also includes a clinically important potentiation of bezafibrate by warfarin (5c).
HMG COENZYME-A REDUCTASE INHIBITORS
(STATINS) (SED-13,
1327; SEDA-19, 408; SEDA-20, 408; SEDA-21, 459) Museuloskeletal
Symptoms, predominantly
stiffness and tenderness of proximal limb muscles and difficulty in rising from a low chair, can develop within a month of starting statin therapy and most cases develop within 3 months. Most patients recover after withdrawal. Sometimes a corticosteroid is needed to reverse the myopathy. In a 42-year-old man muscle biopsies showed that the myopathy was at least partly due to an inflammatory reaction (6c). Skin and appendages A case of ichthyosiform eruptions on the abdomen and back was observed in a 42-year-old Korean woman after 3 months of lovastatin therapy and disappeared on withdrawal (7c).
Drugs affecting lipid metabolism
Chapter44
With the exception of fluvastatin and pravastatin, the statins are metabolized by CYP3A4. Other drugs metabolized by this enzyme can greatly enhance the concentrations of statins in the body and can thereby precipitate rhabdomyolysis, for example the macrolide antibiotic erythromycin (SED-13, 1328). This has now also been observed when patients taking long-term statins were given a course of the similar drugs clarithromycin and azithromycin (8c). It has also been observed with the antidepressant nefazodone (9c). Other drugs that are metabolized by CYP3A4, such as cimctidine, have not been reported to cause this effect. Cyclosporin also increases the risk of rhabdomyolysis, the risk varying from statin to statin. This effect is at least partly due to differences in kinetic interactions. For example, cyclosporin increased the A U C of pravastatin (20 mg/day) 5-fold and the A U C of Iovastatin (20 mg/day) 20-fold (10c). Furthermore, lovastatin accumulated during steady-state therapy and pravastatin did not. Hepatotoxicity is another problem when various drugs are combined. In one study of 389 patients, combined pravastatin or simvastatin with gemfibrozil or ciprofibrate for 29 months in patients with refractory familial combined hyperlipidemia, five patients (1.3%) were withdrawn because their transaminase activities were increased more than 3-fold. The investigators concluded that rare drug-induced reversible hepatotoxicity calls for close monitoring (11c). Potassium-depleting diuretics, but not indapamide, have been reported to attenuate the effect of lovastatin on blood lipid concentrations (12c). Interactions
I N D I V I D U A L STATINS
491 Atorvastatin
(( SEDA-20, 409)
There was no difference in adverse effects in 177 patients randomized for 52 weeks to either simvastatin or atorvastatin (13c). Museuloskeletal Myopathy has not been reported in patients taking atorvastatin, but experience with it has been limited (14R). Myalgia was reported in 3% of the atorvastatin group in one study of 133 patients, but no patient had persistent increases in creatine phosphokinase activity over 10 times the normal limit (14R). After 1 year of treatment with atorvastatin, there was no evidence of lens opacities. Special senses
Mean prothrombin times fell slightly in 12 patients taking maintenance warfarin who took atorvastatin 80 mg/day for 2 weeks, but only during the first few days (15c). Thus, atorvastatin had no consistent effect on the anticoagulant activity of warfarin and adjustments in warfarin dosing should not be necessary. Interactions
Cerivastatin Cerivastatin is the most potent statin mg for mg. Rhabdomyolysis, myoglobinemia, and acute renal insufficiency have not been reported, but it has only recently been introduced. Serum aminotransferase activities rose more than 3-fold in under 1% of patients, a figure similar to that found with other statins (16R). In other respects too the tolerability of this drug is similar to that of other statins (17R).
Fluvastatin (SEDA-19, 408; SEDA-20, 409; SEDA-21, 460)
Although there may be differences in the degree of interaction with, for instance, cyclosporin (see above), the general impression is that the frequencies of adverse effects connected with the various statins are the same.
Experience with fluvastatin in over 1800 patients treated for an average of 61 weeks has shown it to be safe and well tolerated (SEDA19, 408).
Chapter 44
492 Museuloskeletal There have been no reports of myopathy with fluvastatin in any studies. Some cases of myalgia have been reported, mainly after exercise, but the increases in creatine kinase were less than 3-fold, rather than the 10-fold change that is used to define myopathy (SEDA-19, 408). There are, however, good reasons to believe that myopathy is a class effect and should be expected even with this drug. Indeed, of 85 spontaneous reports about fluvastatin in Australia in 1996, 30 described muscle disorders (18c).
Interactions Three patients who had taken warfarin and fluvastatin 20 mg/day for 1-2 weeks had raised international normalized ratios (19c).
Simvastatin (SED-13, 1329; SEDA-18,
1. Aursnes
NICOTINIC ACID DERIVATIVES N i a c i n (SED-13, 1329) A wide range of adverse effects have been reported with niacin (22R). In a recent comparison of modified-release with normal-release niacin in 29 men with hyperlipidemia and coronary artery disease, there were differences in tolerability but not in adverse effects (23c). The men took daily regular niacin 1 g, lovastatin 40 mg, and colestipol 20 g for 1 year, followed by two random-sequence crossover phases (8 months each) alternating regular with modified-release niacin. Compliance was significantly higher with modified-release niacin (95 vs 85%). The modified-release niacin was preferred by 21 patients and the regular niacin by four. There were no differences in uric acid, glucose, or insulin concentrations or aspartate aminotransferase activities. The two niacin formulations did not differ in extent of toxicity.
MISCELLANEOUS DRUGS
428) Skin and appendages A hypersensitivity purpura-like eruption occurred in a 62-year-old man with cirrhosis of the liver who took simvastatin 20 mg/day (20c).
Severe rhabdomyolysis occurred in a 52-year-old woman who took a combination of gemfibrozil and simvastatin (21c).
Interactions
Probucol Altogether 16 cases' of tachydysrhythmias, especially torsade de pointes, have been reported in association with probucol, 15 in women; prolongation of the QT interval is seen (SEDA-21, 460). Since the Probucol Quantitative Regression Swedish Trial (PQRST) showed no improvement in lumen volume of the femoral artery in patients given probucol plus cholestyramine compared with those given cholestyramine alone, doubts have been raised about its efficacy (24R).
REFERENCES/ 1. Adkins JC, Faulds D. Micronised fenofibrate: a review of its pharmacodynamic properties and clinical efficacy in the management of dyslipidaemia. Drugs 1997;54:615-33. 2. Leroy D, Dompmartin A, Szczurko C, Michel M, Louvet S. Photodermatitis from ketoprofen with cross-reactivity to fenofibrate and benzophenones. Photodermatol Photoimmunol Photomed 1997;13:93-7.
3. Schlienger JL, Goichot B, Grunenberger F, Pradignac A. Revelation d'une myopathie thyroidienne par un fibrate. Rev Med Interne 1997; 18:169-70. 4. Ramachandran S, Giles PD, Hartland A. Acute renal failure due to rhabdomyolysis in presence of concurrent ciprofibrate and ibuprofen treatment. Br Med J 1997;314:1593. 5. Beringer TRO. Warfarin potentiation with bezafibrate. Postgrad Med J 1997;73:657-8.
Drugs affecting lipid metabolism
Chapter 44
6. Giordano N, Senesi M, Mattii G, Battisti E, Villanov M, Gennari C. Polymyositis associated with simvastatin. Lancet 1997;349:1600-1. 7. Soeong-Jea-Jeong, Young-Tae-Kim. A case of acquired ichthyosis developed during cholesterollowering treatment. Korean J Dermatol 1997; 35:546-50. 8. Grunden JW, Fisher KA. Lovastatin-induced rhabdomyolysis possibly associated with clarithromycin and azithromycin. Ann Pharmacother 1997;31:859-63. 9. Jacobson RH, Wang P, Glueck C J, Jody DN. Myositis and rhabdomyolysis associated with concurrent use of simvastatin and nefazodone. J Am Med Assoc 1997;277:296-7. 10. Olbricht C, Wanner C, Eisenhauer T, Kliem V, Doll R, Boddaert M, O'Grady P, Krekler M, Mangold B, Christians U. Accumulation of lovastatin, but not pravastatin, in the blood of cyclosporine-treated kidney graft patients after multiple doses. Clin Pharmacol Ther 1997; 62:311-21. 11. Athyros VG, Papageorgiou AA, Hatzikonstandinou HA, Didangelo TP, Carina MV, Kranitsas DF, Kontopoulos AG. Safety and efficacy of long-term statin-fibrate combinations in patients with refractory familial combined hyperlipidemia. Am J Cardiol 1997;80:608-13. 12. Aruna AS, Akula SK, Sarpong DF. Interaction between potassium-depleting diuretics and lovastatin in hypercholesterolemic ambulatory care patients. J Pharm Technol 1997;13:21-6. 13. Dart A, Jerums G, Nicholson G, D'Emden M, Hamilton-Craig I, Tallis G, Best J, West M, Sullivan D, Bracs P, Black D. A multicenter, double-blind, one-year study comparing safety and efficacy of atorvastatin versus simvastatin in patients with hypercholesterolemia. Am J Cardiol 1997;80:39-44.
493 14. Lea AP, McTavish D. Atorvastatin. A review of its pharmacology and therapeutic potential in the management of hyperlipidaemias. Drugs 1997 ;53: 828-47. 15. Stern R, Abel R, Gibson GL, Besserer J. Atorvastatin does not alter the anticoagulant activity of warfarin. J Clin Pharmacol 1997;37:10624. 16. Anonymous. Cerivastatin for hypercholesterolemia. Med Lett Drugs Ther 1998;40:13-14. 17. McLellan K J, Wisemann LR, McTavish D. Cerivastatin. Drugs 1998;55:415-20. 18. Anonymous. WHO Drug Information 1997; 11:68. 19. Kline SS, Harrell CC. Potential warfarin-fluvastatin interaction. Ann Pharmacother 1997; 31:790. 20. Horiuchi Y, Maruok H. Petechial eruptions due to simvastatin in a patient with diabetes mellitus and liver cirrhosis. J Dermatol 1997;24:54951. 21. Tal A, Rajeshawari M. Isley W. Rhabdomyolysis associated with simvastatin-gemfibrozil therapy. South Med J 1997;90:546-7. 22. Britton ML, Bradberry JC, Letassy NA, McKenney JM, Sirman SM. ASHP therapeutic position statement on the safe use of niacin in the management of dyslipidemias. Am J Health Syst Pharm 1997;54:2815-19. 23. Brown B G, Bardsley J, Poulin D, Hillger LA, Dowdy A, Maher V M G, Zhao XQ, Albers J J, Knopf RH. Moderate dose three-drug therapy with niacin, lovastatin, and colestipol to reduce low-density lipoprotein cholesterol <100 mg/dl in patients with hyperlipidema and coronary artery disease. Am J Cardiol 1997;80:111-15. 24. Sasich LD, Sukkar SR. Probucol--lack of efficacy and market withdrawals. Saudi Pharm J 1997;5:72-3.