1232 Cardiovascular Drugs

Bezafibrate (BAN, USAN, rINN) 7. Buse JB, et al. Primary prevention of cardiovascular diseases in
people with diabetes mellitus: a scientific statement from the
myoglobinuria leading to renal failure, has also been reported but
appears to be rare. Patients with renal impairment, and possibly
American Heart Association and the American Diabetes Asso-
Betsafibraatti; Bezafibrát; Bezafibrat; Bezafibratas; Bézafibrate; Be- ciation. Circulation 2007; 115: 114–26. Also published in Dia- with hypothyroidism, may be at increased risk of muscle toxicity.
zafibrato; Bezafibratum; BM-15075; LO-44. 2-[4-(2-p-Chlo- betes Care 2007; 30: 162–72. The UK CSM has advised1 that patients treated with fibrates
robenzamidoethyl)phenoxy]-2-methylpropionic acid. 8. Tenenbaum A, et al. Effect of bezafibrate on incidence of type should consult their doctor if they develop muscle pain, tender-
2 diabetes mellitus in obese patients. Eur Heart J 2005; 26: ness, or weakness, and treatment should be stopped if muscle
Безафибрат 2032–8.
9. Tenenbaum A, et al. Peroxisome proliferator-activated receptor toxicity is suspected clinically or if creatine phosphokinase is
C 19 H 20 ClNO 4 = 361.8. markedly raised or progressively rising.
ligand bezafibrate for prevention of type 2 diabetes mellitus in
C AS — 41859-67-0. patients with coronary artery disease. Circulation 2004; 109: Other lipid regulating drugs, particularly the statins, have also
ATC — C10AB02. 2197–2202. been associated with myopathy and the risk of muscle toxicity is
10. Klein J, et al. Recurrent hypoglycaemic episodes in a patient
ATC Vet — QC10AB02. with type 2 diabetes under fibrate therapy. J Diabetes Compli- increased if fibrates and statins are taken together (see Lipid Reg-
cations 2002; 16: 246–8. ulating Drugs under Interactions of Simvastatin, p.1393); combi-
11. Konttinen A, et al. The effect of gemfibrozil on serum lipids in nation therapy may be appropriate in some patients but careful
O COOH diabetic patients. Ann Clin Res 1979; 11: 240–5. monitoring is required.2
O Effects on the kidneys. Small increases in creatinine concen- 1. Committee on Safety of Medicines/Medicines Control Agency.
H 3C CH3 tration are common during treatment with bezafibrate and have Rhabdomyolysis associated with lipid-lowering drugs. Current
also been reported with other fibrates,1 although possibly not Problems 1995; 21: 3. Available at:
N http://www.mhra.gov.uk/home/idcplg?IdcService=GET_
H with gemfibrozil. There have also been reports of acute renal fail- FILE&dDocName=CON2015618&RevisionSelectionMethod=
Cl
ure associated with treatment with bezafibrate,2 and with clofi- LatestReleased (accessed 30/05/08)
brate,3,4 and an accelerated decline in renal function has been re- 2. Shek A, Ferrill MJ. Statin-fibrate combination therapy. Ann
ported with bezafibrate in patients with chronic renal failure.5 Pharmacother 2001; 35: 908–917.
Pharmacopoeias. In Eur. (see p.vii) and Jpn. Renal failure may also occur due to rhabdomyolysis in patients
Ph. Eur. 6.2 (Bezafibrate). A white or almost white, crystalline Gallstones. Fibrates, including fenofibrate1-3 and gemfibrozil4
receiving fibrates, including gemfibrozil (see Effects on Skeletal have been reported to increase indices of bile lithogenicity, and
powder. It exhibits polymorphism. Practically insoluble in water; Muscle, below).
sparingly soluble in alcohol and in acetone; freely soluble in some studies5,6 have suggested an increased risk of gallstones in
1. Broeders N, et al. Fibrate-induced increase in blood urea and patients receiving fibrates. However, in the Helsinki Heart
dimethylformamide; it dissolves in dilute solutions of alkali hy- creatinine: is gemfibrozil the only innocuous agent? Nephrol
droxides. Study7 no significant increase in gallstone operations was report-
Dial Transplant 2000; 15: 1993–9.
2. Lipkin GW, Tomson CRV. Severe reversible renal failure with ed among 2051 patients taking gemfibrozil compared with 2030
bezafibrate. Lancet 1993; 341: 371. taking placebo, although a follow-up study8 reported that chole-
Adverse Effects and Precautions 3. Dosa S, et al. Acute-on-chronic renal failure precipitated by clof- cystectomies were consistently more common in those receiving
The commonest adverse effects of bezafibrate therapy ibrate. Lancet 1976; i: 250. gemfibrozil during the entire 8.5-year observation period.
4. Cumming A. Acute renal failure and interstitial nephritis after
are gastrointestinal disturbances including anorexia, clofibrate treatment. BMJ 1980; 281: 1529–30.
1. Brown WV. Treatment of hypercholesterolaemia with fenofi-
brate: a review. Curr Med Res Opin 1989; 11: 321–30.
nausea, and gastric discomfort. Other adverse effects 5. Williams AJ, et al. The short term effects of bezafibrate on the 2. Blane GF. Comparative toxicity and safety profile of fenofibrate
reported to occur less frequently include headache, diz- hypertriglyceridaemia of moderate to severe uraemia. Br J Clin and other fibric acid derivatives. Am J Med 1987; 83 (suppl 5B):
Pharmacol 1984; 18: 361–7. 26–36.
ziness, vertigo, fatigue, skin rashes, pruritus, photosen- 3. Palmer RH. Effects of fibric acid derivatives on biliary lipid
Effects on the nervous system. Adverse effects on the pe-
sitivity, alopecia, impotence, anaemia, leucopenia, and ripheral nervous system have been reported with fibrates. Periph- composition. Am J Med 1987; 83 (suppl 5B): 37–43.
thrombocytopenia. Raised serum-aminotransferase 4. Leiss O, et al. Effect of gemfibrozil on biliary lipid metabolism
eral neuropathy has been reported1 with bezafibrate, and was in normolipemic subjects. Metabolism 1985; 34: 74–82.
concentrations have occasionally been reported. Ele- substantiated by nerve conduction studies. There have also been 5. Mamdani MM, et al. Is there an association between lipid-low-
vated creatine phosphokinase concentrations during reports of peripheral neuropathy with clofibrate,2 and with fenof- ering drugs and cholecystectomy? Am J Med 2000; 108: 418–21.
bezafibrate therapy may be associated with a syndrome ibrate,3 which resolved when therapy was withdrawn. In addi- 6. Caroli-Bosc F-X, et al. Role of fibrates and HMG-CoA reduct-
tion, by 1993, the Adverse Drug Reactions Advisory Committee ase inhibitors in gallstone formation: epidemiological study in an
of myositis, myopathy, and rarely rhabdomyolysis; pa- in Australia had received reports of paraesthesia occurring in 6 unselected population. Dig Dis Sci 2001; 46: 540–4.
7. Frick MH, et al. Helsinki Heart Study: primary-prevention trial
tients with hypoalbuminaemia resulting from nephrot- patients in association with gemfibrozil treatment.4 with gemfibrozil in middle-aged men with dyslipidemia: safety
ic syndrome or with renal impairment may be at in- 1. Ellis CJ, et al. Peripheral neuropathy with bezafibrate. BMJ of treatment, changes in risk factors, and incidence of coronary
1994; 309: 929. heart disease. N Engl J Med 1987; 317: 1237–45.
creased risk. Bezafibrate should not be given with 2. Gabriel R, Pearce JMS. Clofibrate-induced myopathy and neu- 8. Huttunen JK, et al. The Helsinki Heart Study: an 8.5-year safety
statins in patients with risk factors for myopathy. Bez- ropathy. Lancet 1976; ii: 906. and mortality follow-up. J Intern Med 1994; 235: 31–9.
afibrate may increase the lithogenic index, and there 3. Corcia P, et al. Severe toxic neuropathy due to fibrates. J Neurol
Neurosurg Psychiatry 1999; 66: 410. Headache. Severe recurrent headaches have been reported1 in
have been isolated reports of gallstones, although the 4. Anonymous. Paraesthesia and neuropathy with hypolipidaemic a patient receiving bezafibrate. The headaches started about 24
risk from fibrates as a class is unclear (see Gallstones, agents. Aust Adverse Drug React Bull 1993; 12: 6. hours after therapy with bezafibrate began, and recurred about 1
below). Effects on the pancreas. Acute pancreatitis has been hour after each dose. Headaches occurred 30 to 90 minutes after
reported1 in a patient receiving bezafibrate, and recurred on 2 oc- each dose of gemfibrozil in 2 patients.2,3 In both patients, the
Bezafibrate should not be given to patients with severe casions when bezafibrate was restarted. There has also been a headaches were accompanied by dry mouth, and in 1 also by
hepatic impairment or significant liver disease, gall- report2 of acute pancreatitis in a patient receiving both fenofi- blurred vision. The headaches stopped when gemfibrozil was
stones or gallbladder disorders, or hypoalbuminaemic brate and simvastatin, although simvastatin was considered more withdrawn and recurred one week after re-exposure.
likely to be responsible. An increased incidence of pancreatitis 1. Hodgetts TJ, Tunnicliffe C. Bezafibrate-induced headache. Lan-
states such as nephrotic syndrome. It should be used cet 1989; i: 163.
with caution in renal impairment and is contra-indicat- was also reported with fenofibrate in the FIELD study,3 although
2. Arellano F, et al. Gemfibrozil-induced headache. Lancet 1988; i:
the number of cases was small. 705.
ed if creatinine clearance is below 15 mL/minute un- 1. Gang N, et al. Relapsing acute pancreatitis induced by re-expo- 3. Alvarez-Sabin J, et al. Gemfibrozil-induced headache. Lancet
less the patient is on dialysis (see under Uses and Ad- sure to the cholesterol lowering agent bezafibrate. Am J Gastro- 1988; ii: 1246.
ministration, below). enterol 1999; 94: 3626–8.
2. McDonald KB, et al. Pancreatitis associated with simvastatin Hyperhomocysteinaemia. Hyperhomocysteinaemia has
◊ Reviews. plus fenofibrate. Ann Pharmacother 2002; 36: 275–9. been associated with an increased risk for cardiovascular disease.
1. Davidson MH, et al. Safety considerations with fibrate therapy.
3. The FIELD study investigators. Effects of long-term fenofibrate Small studies have found that both bezafibrate 1,2 and
therapy on cardiovascular events in 9795 people with type 2 di- fenofibrate1,3 increase plasma-homocysteine concentrations, al-
Am J Cardiol 2007; 99 (Issue 6 suppl 1): 3C–18C. abetes mellitus (the FIELD study): randomised controlled trial.
Lancet 2005; 366: 1849–61. Corrections. ibid. 2006; 368: 1415
though the clinical significance of this is not clear.4 Folic acid and
Effects on glucose metabolism. Use of fibrates in diabetic vitamin B12 have been given4,5 with fenofibrate to reduce homo-
and 1420.
patients has generally been reported to either improve1-3 or have cysteine concentrations, but the role of such treatment is not es-
no effect4-6 on insulin sensitivity and glucose metabolism, and Effects on sexual function. Sexual dysfunction has occurred tablished.
they are considered a suitable treatment for type 2 diabetics with with some fibrates. Erectile dysfunction and loss of libido has 1. Dierkes J, et al. Serum homocysteine increases after therapy
hypertriglyceridaemia.7 There is also some evidence that fibrates been reported in 3 patients1-3 during gemfibrozil treatment. In 2 with fenofibrate or bezafibrate. Lancet 1999; 354: 219–20.
may reduce the incidence or delay the onset of diabetes in pa- of the men1,2 bezafibrate did not produce this adverse effect. The 2. Jonkers IJAM, et al. Implication of fibrate therapy for homo-
tients with obesity8 or impaired glucose tolerance.9 However, UK CSM was reported to be aware of a further 6 cases.2 Of a cysteine. Lancet 1999; 354: 1208.
there has been a report10 of recurrent hypoglycaemia in a type 2 further 3 cases of erectile dysfunction associated with gemfibro- 3. de Lorgeril M, et al. Lipid-lowering drugs and homocysteine.
zil reported from Spain, 1 patient had previously reacted similar- Lancet 1999; 353: 209–10.
diabetic when gemfibrozil was added to high-dose insulin thera- 4. Dierkes J, et al. Fenofibrate-induced hyperhomocysteinaemia:
py although eventually a reduced insulin dosage, with fibrate ly to clofibrate.4 A systematic review,5 including these and other clinical implications and management. Drug Safety 2003; 26:
therapy, produced good glucose control. Gemfibrozil is contra- reports, supported the conclusion that fibrates could cause erec- 81–91.
indicated in patients receiving repaglinide due to the risk of se- tile dysfunction. 5. Melenovsky V, et al. Effect of folic acid on fenofibrate-induced
vere hypoglycaemia (see p.458). Conversely, a study in 20 dia- Gynaecomastia was reported6 in a 56-year-old man receiving elevation of homocysteine and cysteine. Am Heart J 2003; 146:
betic patients11 given gemfibrozil reported a slight increase in re- fenofibrate and recurred on rechallenge; there were no other ef- 110. Full version available at:
http://download.journals.elsevierhealth.com/pdfs/journals/
quirements for antidiabetic therapy (oral hypoglycaemics or fects on sexual function. 0002-8703/PIIS0002870303001224.pdf (accessed 30/05/08)
insulin) in 9 and a decrease in 1. 1. Pizarro S, et al. Gemfibrozil-induced impotence. Lancet 1990;
1. Ogawa S, et al. Bezafibrate reduces blood glucose in type 2 di- 336: 1135. Photosensitivity. Fibrates have been associated with photo-
abetes mellitus. Metabolism 2000; 49: 331–4. 2. Bain SC, et al. Gemfibrozil-induced impotence. Lancet 1990; sensitivity reactions1 and there may be cross-sensitivity with ke-
2. Jones IR, et al. Lowering of plasma glucose concentrations with 336: 1389. toprofen (see under Adverse Effects of Ketoprofen, p.73).
bezafibrate in patients with moderately controlled NIDDM. Di- 3. Bharani A. Sexual dysfunction after gemfibrozil BMJ 1992; 305: 1. Serrano G, et al. Photosensitivity induced by fibric acid deriva-
abetes Care 1990; 13: 855–63. 693. tives and its relation to photocontact dermatitis to ketoprofen J
3. Notarbartolo A, et al. Effects of gemfibrozil in hyperlipidemic 4. Figueras A, et al. Gemfibrozil-induced impotence. Ann Pharma- Am Acad Dermatol 1992; 27: 204–8.
patients with or without diabetes. Curr Ther Res 1993; 53: cother 1993; 27: 982.
381–93. 5. Rizvi K, et al. Do lipid-lowering drugs cause erectile dysfunc-
4. Leaf DA, et al. The hypolipidemic effects of gemfibrozil in type tion? A systematic review. Fam Pract 2002; 19: 95–8. Interactions
V hyperlipidemia. JAMA 1989; 262: 3154–60. 6. Gardette V, et al. Gynecomastia associated with fenofibrate. Ann Bezafibrate and other fibrates are highly protein-bound
5. Pagani A, et al. Effect of short-term gemfibrozil administration Pharmacother 2007; 41: 508–11.
on glucose metabolism and insulin secretion in non-insulin-de-
and may displace other drugs from protein binding
Effects on skeletal muscle. Muscle disorders including my-
pendent diabetics. Curr Ther Res 1989; 45: 14–20.
ositis and myopathy are well known to occur with lipid regulat-
sites. Interactions may also occur through changes in
6. Hernández-Mijares A, et al. Ciprofibrate effects on carbohy- the activity of cytochrome P450 isoenzymes, particu-
drate and lipid metabolism in type 2 diabetes mellitus subjects. ing drugs such as fibrates.1 Rhabdomyolysis, presenting as mus-
Nutr Metab Cardiovasc Dis 2000; 10: 1–6. cle pain with elevated creatine phosphokinase and larly CYP3A4.
 Bezafibrate 1233
Fibrates may enhance the effects of oral anticoagu- and type V hyperlipoproteinaemias. Bezafibrate and (p.1164). Although the evidence is less good than for statins, sev-
lants; the dose of anticoagulant should be reduced other fibrates reduce triglycerides by reducing the con- eral studies have shown that fibrates may reduce both the pro-
gression of atherosclerosis and the incidence of cardiovascular
when treatment with a fibrate is started, and then ad- centration of very-low-density lipoprotein (VLDL). events.1
justed gradually if necessary. Recommendations vary; They reduce low-density lipoprotein (LDL)-cholester- In the Bezafibrate Coronary Atherosclerosis Intervention Trial
licensed product information for bezafibrate suggests a ol to a lesser extent, although the effect is variable, and (BECAIT)2,3 treatment with bezafibrate for 5 years in young
reduction of up to 50% in the dosage of anticoagulant. may also increase high-density lipoprotein (HDL)- men (less than 45 years of age) after myocardial infarction result-
The mechanism of the interaction is unclear; fibrates cholesterol. Although evidence that this leads to a re- ed in fewer coronary events and slowed the progression of focal
coronary atherosclerosis when compared with placebo. Howev-
have been reported to displace warfarin from protein duction in cardiovascular events is less good than for er, in older men with peripheral vascular disease,4 bezafibrate
binding sites but other mechanisms are probably also statins, some fibrates may have a role in cardiovascular had no effect on the incidence of coronary events and stroke to-
involved. risk reduction (see below). gether, although the severity of intermittent claudication was re-
Other drugs that may be displaced from plasma pro- Bezafibrate is given in a usual oral dose of 200 mg duced and, in men under 65 years, there were fewer non-fatal
coronary events. In the Diabetes Atherosclerosis Intervention
teins by fibrates include tolbutamide and other sulfony- three times daily taken with or after food; gastrointes- Study (DAIS),5 fenofibrate reduced the angiographic progres-
lurea antidiabetics, phenytoin, and, in patients with hy- tinal disturbances may be reduced in susceptible pa- sion of coronary atherosclerosis in type 2 diabetics, and there
poalbuminaemia, furosemide. The interaction with tients by increasing the dose gradually over 5 to 7 days; were also fewer clinical events in those receiving fenofibrate;
antidiabetics is complex since fibrates may alter glu- 200 mg twice daily may occasionally be adequate for further analysis showed6 reduced progression to microalbuminu-
cose tolerance in diabetic patients (see Effects on Glu- maintenance particularly in the treatment of hypertrig- ria in the fenofibrate group. However, another study in type 2
diabetics, the FIELD study,7 found no reduction in the risk of
cose Metabolism, above). The dosage of antidiabetics lyceridaemia. A modified-release tablet is also availa- major coronary events with fenofibrate, although there were
may need adjusting during bezafibrate therapy. ble and is given as a single daily dose of 400 mg. fewer non-fatal myocardial infarctions and revascularisations. A
There is an increased risk of myopathy if fibrates are The dose of bezafibrate should be reduced in patients meta-analysis8 of studies including type 2 diabetics concluded
with renal impairment (see below). that fibrates reduce the incidence of cardiovascular events, but
used with statins (see Lipid Regulating Drugs under In- the effect on mortality was not significant.
teractions of Simvastatin, p.1393). ◊ General reviews. The best evidence for a reduction in cardiovascular events is for
Fibrates may interact with ciclosporin, although re- 1. Goa KL, et al. Bezafibrate: an update of its pharmacology and gemfibrozil. The Helsinki Heart Study9 assessed gemfibrozil for
use in the management of dyslipidaemia. Drugs 1996; 52: the primary prevention of ischaemic heart disease in 4081 mid-
ports have been conflicting (see p.1827). However, 725–53.
nephrotoxicity associated with increased ciclosporin 2. Goldenberg I, et al. Update on the use of fibrates: focus on bez- dle-aged men with hyperlipidaemia. There was an overall reduc-
afibrate. Vasc Health Risk Manag 2008; 4: 131–41. tion of 34% in the incidence of fatal and non-fatal myocardial
concentrations has been reported with bezafibrate and infarctions and cardiac deaths in the gemfibrozil group compared
renal function should be monitored. Action. Bezafibrate is a typical member of the fibric acid deriv-
with the placebo group, with the greatest reduction seen during
ative group of drugs (the fibrates) used in the treatment of hyper-
Cholestasis has been reported in a patient given fenof- years 3 to 5. Follow-up for a further 3.5 years10 suggested that
lipidaemias (p.1169). One of the primary actions of the fibrates
long-term treatment with gemfibrozil seemed to postpone coro-
ibrate with raloxifene (see p.2128). is to promote the catabolism of triglyceride-rich lipoproteins, in
nary events for about 5 years. The Veterans Affairs High-Density
particular very-low-density lipoproteins (VLDL), apparently
◊ Reviews. mediated by an enhanced activity of lipoprotein lipase.1 They
Lipoprotein Cholesterol Intervention Trial (VA-HIT)11 assessed
1. Lozada A, Dujovne CA. Drug interactions with fibric acids. gemfibrozil for the secondary prevention of ischaemic heart dis-
may also interfere with the synthesis of VLDL, possibly by in-
Pharmacol Ther 1994; 63: 163–76. ease in 2531 older men (mean age 64 years) whose primary lipid
hibiting hepatic acetyl coenzyme A carboxylase. The effect of
Lipid regulating drugs. The bioavailability of gemfibrozil abnormality was a low HDL-cholesterol level. There was an
fibrates on low-density lipoprotein (LDL)-cholesterol depends
was reduced by colestipol, but was unaffected when gemfibrozil overall reduction of 22% in the incidence of fatal and non-fatal
on the overall lipoprotein status of the patient but concentrations
was taken either 2 hours before or 2 hours after colestipol.1 myocardial infarctions and cardiac deaths in the gemfibrozil
tend to decrease if high at baseline and increase if low at baseline.
group compared with the placebo group, with the beneficial ef-
For discussion of the interaction between fibrates and statins, see High-density lipoprotein (HDL)-cholesterol concentrations are
fects of gemfibrozil becoming apparent about 2 years after ran-
p.1393. increased, although there have been a few reports of unexpected
domisation. There was also a reduction in the incidence of
1. Forland SC, et al. Apparent reduced absorption of gemfibrozil falls in HDL-cholesterol with bezafibrate2,3 and ciprofibrate.4,5
stroke.12
when given with colestipol. J Clin Pharmacol 1990; 30: 29–32. Fibrates have three actions on sterol metabolism:1 they inhibit 1. Després J-P, et al. Role of fibric acid derivatives in the manage-
NSAIDs. Acute renal failure due to rhabdomyolysis in a patient the synthesis of cholesterol, they inhibit the synthesis of bile ment of risk factors for coronary heart disease. Drugs 2004; 64:
has been attributed to an interaction between ciprofibrate and acids, and they enhance the secretion of cholesterol in bile. It is 2177–98.
ibuprofen.1 Ibuprofen was believed to have displaced ciprofi- these latter two effects which are responsible for the raised cho- 2. Ericsson C-G, et al. Angiographic assessment of effects of bez-
lesterol saturation of bile, which may lead to the formation of afibrate on progression of coronary artery disease in young male
brate from protein binding sites. The use of radiological contrast postinfarction patients. Lancet 1996; 347: 849–53.
media may also have been a contributory factor. gallstones in some patients (see Gallstones, under Adverse Ef- 3. Ericsson C-G, et al. Effect of bezafibrate treatment over five
1. Ramachandran S, et al. Acute renal failure due to rhabdomyoly- fects, above). years on coronary plaques causing 20% to 50% diameter nar-
sis in presence of concurrent ciprofibrate and ibuprofen treat- The effects of fibrates are mediated by their agonist action at per- rowing (The Bezafibrate Coronary Atherosclerosis Intervention
ment. BMJ 1997; 314: 1593. oxisome proliferator-activated receptors (PPARs).6,7 Fibrates are Trial (BECAIT)). Am J Cardiol 1997; 80: 1125–9.
4. Meade T, et al. Bezafibrate in men with lower extremity arterial
agonists of PPAR-α, which plays an important role in fatty acid disease: randomised controlled trial. BMJ 2002; 325: 1139–43.
Pharmacokinetics metabolism; some, such as bezafibrate, may also activate other 5. Diabetes Atherosclerosis Intervention Study Investigators. Ef-
Bezafibrate is readily absorbed from the gastrointesti- receptors including PPAR-γ (which plays a role in glucose ho- fect of fenofibrate on progression of coronary-artery disease in
moeostasis).7 type 2 diabetes: the Diabetes Atherosclerosis Intervention
nal tract. Plasma protein binding is about 95%. The 1. Grundy SM, Vega GL. Fibric acids: effects on lipids and lipopro-
Study, a randomised study. Lancet 2001; 357: 905–910. Correc-
tion. ibid.; 1890.
plasma elimination half-life is about 1 to 2 hours. Most tein metabolism. Am J Med 1987; 83 (suppl 5B): 9–20. 6. Ansquer J-C, et al. Fenofibrate reduces progression to micro-
of a dose is excreted in the urine, about half as un- 2. Capps NE. Lipid profiles on fibric-acid derivatives. Lancet albuminuria over 3 years in a placebo-controlled study in type 2
1994; 344: 684–5. diabetes: results from the Diabetes Atherosclerosis Intervention
changed drug, the remainder as metabolites including 3. McLeod AJ, et al. Abnormal lipid profiles on fibrate derivatives. Study (DAIS). Am J Kidney Dis 2005; 45: 485–93.
20% as glucuronides. A small proportion (about 3%) Lancet 1996; 347: 261. 7. The FIELD study investigators. Effects of long-term fenofibrate
4. Chandler HA, Batchelor AJ. Ciprofibrate and lipid profile. Lan- therapy on cardiovascular events in 9795 people with type 2 di-
of the dose appears in the faeces. Elimination may be cet 1994; 344: 128–9. abetes mellitus (the FIELD study): randomised controlled trial.
increased by forced diuresis. The drug is not dialysa- 5. McLeod AJ, et al. Ciprofibrate and lipid profile. Lancet 1994; Lancet 2005; 366: 1849–61. Corrections. ibid. 2006; 368: 1415
344: 955. and 1420.
ble. 6. Fruchart J-C, Duriez P. Mode of action of fibrates in the regula- 8. Allemann S, et al. Fibrates in the prevention of cardiovascular
◊ References. tion of triglyceride and HDL-cholesterol metabolism. Drugs To- disease in patients with type 2 diabetes mellitus: meta-analysis
day 2006; 42: 39–64. of randomised controlled trials. Curr Med Res Opin 2006; 22:
1. Abshagen U, et al. Disposition pharmacokinetics of bezafibrate 7. Robinson JG. Should we use PPAR agonists to reduce cardiovas- 617–23.
in man. Eur J Clin Pharmacol 1979; 16: 31–8. cular risk? PPAR Res 2008; 2008: 891425. 9. Frick MH, et al. Helsinki Heart Study: primary-prevention trial
2. Abshagen U, et al. Steady-state kinetics of bezafibrate and clof- with gemfibrozil in middle-aged men with dyslipidemia: safety
ibrate in healthy female volunteers. Eur J Clin Pharmacol 1980; Administration in renal impairment. Bezafibrate is mainly of treatment, changes in risk factors, and incidence of coronary
17: 305–8. excreted in the urine and dosage alterations may be necessary in heart disease. N Engl J Med 1987; 317: 1237–45.
patients with renal impairment; fibrates may also impair renal 10. Heinonen OP, et al. The Helsinki Heart Study: coronary heart
The elderly. In a study comparing the pharmacokinetics of be- disease incidence during an extended follow-up. J Intern Med
zafibrate in 19 elderly patients with younger healthy subjects,1 function (see Effects on the Kidneys under Adverse Effects, 1994; 235: 41–9.
maximum plasma concentrations were 1.6 times higher in the above). Modified-release preparations are contra-indicated in pa- 11. Bloomfield Rubins H, et al. Gemfibrozil for the secondary pre-
elderly group (median 12.1 mg/litre against 7.7 mg/litre) and tients with creatinine clearance (CC) below 60 mL/minute and vention of coronary heart disease in men with low levels of
the dosage of conventional-release formulations should be re- high-density lipoprotein cholesterol. N Engl J Med 1999; 341:
half-life was increased by 3.8 times (median 6.6 hours against 410–18.
1.7 hours). The differences could not be attributed solely to di- duced depending on CC, as follows:
12. Bloomfield Rubins H, et al. Reduction in stroke with gemfibro-
minished renal function in elderly patients. Dosage adjustments • CC 40 to 60 mL/minute: 400 mg daily zil in men with coronary heart disease and low HDL cholesterol:
in elderly patients should not therefore be based on renal function • CC 15 to 40 mL/minute: 200 mg daily or on alternate days The Veterans Affairs HDL Intervention Trial (VA-HIT). Circu-
alone. lation 2001; 103: 2828–33.
• CC less than 15 mL/minute unless on dialysis: contra-indicat-
1. Neugebauer G, et al. Steady-state kinetics of bezafibrate retard in ed Dementia. For reference to a possible reduction in the inci-
hyperlipidemic geriatric patients. Klin Wochenschr 1988; 66: • dialysis patients: 200 mg every 3 days, with careful monitor- dence of dementia associated with lipid regulating drugs, includ-
250–6. ing ing fibrates, see under Uses of Simvastatin, p.1395.
Renal impairment. The half-life of bezafibrate may be pro- In a study in patients with renal impairment1 the half-life of bez- Preparations
longed in patients with renal impairment (see under Uses and afibrate was reported to be prolonged to 4.6 hours in 3 patients BP 2008: Bezafibrate Tablets.
Administration, below). with CC greater than 40 mL/minute, 7.8 hours in 8 patients with
CC of 20 to 40 mL/minute, and 20.1 hours in a patient with CC Proprietary Preparations (details are given in Part 3)
Arg.: Bezacur; Bezalip; Elpi Lip; Nebufur; Austria: Bezacur; Bezalip; Bezare-
Uses and Administration of 13 mL/minute. tard; Bezastad; Belg.: Cedur; Eulitop; Braz.: Cedur; Canad.: Bezalip;
Bezafibrate, a fibric acid derivative, is a lipid regulat- 1. Anderson P, Norbeck H-E. Clinical pharmacokinetics of bezafi- Chile: Nimus; Oralipin; Cz.: Regadrin B; Fin.: Bezalip; Fr.: Befizal; Ger.:
brate in patients with impaired renal function. Eur J Clin Phar- Azufibrat†; Befibrat; Beza; Beza-Puren†; Bezabeta; Bezacur†; Bezadoc; Bez-
ing drug. It is used to reduce total cholesterol and trig- macol 1981; 21: 209–14. agamma; Bezamerck†; Bezapham†; Cedur; Lipox; Regadrin B†; Sklerofi-
lycerides in the management of hyperlipidaemias brat†; Gr.: Bezalip; Getup†; Verbital; Hong Kong: Bezalip; Zafibral†;
Cardiovascular risk reduction. Lipid lowering therapy has Hung.: Bezalip; India: Beza†; Bezalip; Israel: Bezalip; Norlip; Ital.: Bezalip;
(p.1169), including type IIa, type IIb, type III, type IV, an important role in patients at risk of cardiovascular disease Hadiel; Jpn: Bezalip; Malaysia: Bezalip; Mex.: Befitec; Bexalcor; Bezafisal;

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)
1234 Cardiovascular Drugs
Bezalex; Bezalip; Bifaren; Bionolip; Colser; Fazebit; Klestran†; Lesbest; Lipoc- about 90%. Peak plasma concentrations are reached 2 Incompatibility. The manufacturer of bivalirudin states that it
in; Neptalip; Nivetril; Redalip; Solibay†; Zaf; Neth.: Bezalip; NZ: Bezalip; is incompatible with: alteplase, amiodarone hydrochloride, am-
Fibalip; Philipp.: Bezastad; Pol.: Bezamidin; Port.: Bezalip; S.Afr.: Bezalip; to 4 hours after oral doses. Bisoprolol is about 30%
photericin B, chlorpromazine hydrochloride, diazepam, prochlo-
Singapore: Bezalip; Zafibral; Spain: Difaterol; Eulitop; Reducterol†; Swed.: bound to plasma proteins. It has a plasma elimination rperazine edisilate, reteplase, streptokinase, and vancomycin
Bezalip; Switz.: Cedur; Thai.: Bezalip; Bezamil; Polyzalip; Raset†; UAE: Li-
pitrol; UK: Bezagen; Bezalip; Bezalip Mono; Fibrazate; Zimbacol; Venez.: half-life of 10 to 12 hours. Bisoprolol is moderately hydrochloride.
Bezalip; Detrex†. lipid-soluble. It is metabolised in the liver and excreted
in urine, about 50% as unchanged drug and 50% as Adverse Effects and Precautions
metabolites. As for Lepirudin, p.1323.
Binifibrate (rINN)
Binifibrato; Binifibratum. 2-(4-Chlorophenoxy)-2-methylpropi- Uses and Administration Interactions
onic acid ester with 1,3-dinicotinoyloxypropan-2-ol. Bisoprolol is a cardioselective beta blocker (p.1225). It As for Lepirudin, p.1323.
Бинифибрат is reported to be devoid of intrinsic sympathomimetic
C 25 H 23 ClN 2 O 7 = 498.9. and membrane-stabilising properties.
C AS — 69047-39-8. Pharmacokinetics
Bisoprolol is given as the fumarate in the management Bivalirudin is partly metabolised and partly excreted
of hypertension (p.1171) and angina pectoris (p.1157). by the kidney. When given intravenously the plasma
It is also used as an adjunct to standard therapy in pa- half-life is about 25 minutes in patients with normal re-
H3C O Cl tients with stable chronic heart failure (p.1165). nal function but is prolonged in renal impairment. Bi-
In hypertension or angina pectoris the usual dose of valirudin does not bind to plasma proteins and is re-
H 3C O N bisoprolol fumarate is 5 to 10 mg orally as a single dai- moved by haemodialysis.
O ly dose; the maximum recommended dose is 20 mg ◊ References.
daily. A reduction in dose may be necessary in patients 1. Robson R, et al. Bivalirudin pharmacokinetics and pharmacody-
O namics: effect of renal function, dose, and gender. Clin Pharma-
with hepatic or renal impairment (see below).
O O col Ther 2002; 71: 433–9.
In heart failure the initial oral dose of bisoprolol fu-
O marate is 1.25 mg once daily. If tolerated, the dose Uses and Administration
should be doubled after 1 week, and then increased Bivalirudin, an analogue of the peptide hirudin
N gradually at 1 to 4 week intervals to the maximum dose (p.1305), is a direct thrombin inhibitor with actions
tolerated; this should not exceed 10 mg once daily. similar to Lepirudin, p.1323. It is used as an anticoag-
◊ References. ulant in patients undergoing percutaneous coronary in-
Profile 1. Johns TE, Lopez LM. Bisoprolol: is this just another beta-block- terventions, including those with, or at risk of, heparin-
Binifibrate, a derivative of clofibrate (p.1246) and nicotinic acid er for hypertension or angina? Ann Pharmacother 1995; 29:
(p.1957), is a lipid regulating drug that has been used in the treat- 403–14.
induced thrombocytopenia. It is also used in patients
ment of hyperlipidaemias. 2. CIBIS-II Investigators and Committees. The Cardiac Insuffi- with acute coronary syndromes in whom early inter-
Preparations
ciency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet vention is planned, and has been investigated in pa-
1999; 353: 9–13.
Proprietary Preparations (details are given in Part 3) 3. McGavin JK, Keating GM. Bisoprolol: a review of its use in tients with acute coronary syndromes treated medical-
Spain: Antopal†; Biniwas†. chronic heart failure. Drugs 2002; 62: 2677–96. ly (see Ischaemic Heart Disease, under Uses and
Administration in hepatic or renal impairment. US Administration of Lepirudin, p.1323).
licensed product information recommends that the initial dose of Some preparations state that bivalirudin is present as
bisoprolol fumarate for hypertension should be 2.5 mg daily and
Bisoprolol Fumarate that the dose should be increased cautiously in patients with se- the hydrate of the trifluoroacetate salt but doses are giv-
(BANM, USAN, rINNM) ⊗ vere hepatic impairment or renal impairment (creatinine clear- en in terms of bivalirudin.
ance less than 40 mL/minute). UK licensed product information In the management of patients undergoing planned
Bisoprolol Fumarat; Bisoprolol, Fumarate de; Bisoprolol Hemifu- recommends a maximum dose of 10 mg daily for both angina
marate; Bisoprolol, hémifumarate de; Bisoprololfumarat; Biso- pectoris and hypertension in patients with severe hepatic impair-
percutaneous coronary intervention (PCI), the ini-
prololi Fumaras; Bisoprololi hemifumaras; Bisoprololifumaraatti; ment or with a creatinine clearance of less than 20 mL/minute. tial dose of bivalirudin is 750 micrograms/kg by intra-
CL-297939; EMD-33512 (bisoprolol or bisoprolol fumarate); Bisoprolol is not dialysable. venous injection followed immediately by an intrave-
Fumarato de bisoprolol. 1-[4-(2-Isopropoxyethoxymethyl)phe- nous infusion of 1.75 mg/kg per hour; the activated
noxy]-3-isopropylaminopropan-2-ol fumarate. Preparations clotting time should be measured 5 minutes after the
Бизопролола Фумарат USP 31: Bisoprolol Fumarate and Hydrochlorothiazide Tablets; Bisoprolol
Fumarate Tablets. initial injection and a second injection of
(C 18H 31 NO 4 ) 2 ,C 4 H 4 O 4 = 767.0. 300 micrograms/kg should be given if anticoagulation
Proprietary Preparations (details are given in Part 3)
C AS — 66722-44-9 (bisoprolol); 66722-45-0 (bisoprolol Arg.: Concor; Corbis; Lostaprolol; Austral.: Bicor; Austria: Bisocor; Bisos- is inadequate. The infusion should be given for the du-
fumarate); 104344-23-2 (bisoprolol fumarate). tad; Bisotyrol†; Cardiocor; Concor; Darbalan; Nanalan; Rivacor; Belg.:
Bisoprotop; Docbisopro; Emconcor; Isoten; Braz.: Concor; Canad.: ration of the procedure and may be continued for up to
ATC — C07AB07.
ATC Vet — QC07AB07.
Monocor; Chile: Concor; Cz.: Bisoblock; Bisocard; Bisogamma; Bivaxol; 4 hours afterwards; licensed prescribing information in
Concor; Concor Cor; Kordobis; Rivocor; Denm.: Bisocor; Cardicor; Em-
concor; Fin.: Bisomerck; Bisopral; Emconcor; Orloc; Fr.: Cardensiel; Cardi- the USA allows the infusion to then be continued at a
ocor; Detensiel; Soprol†; Ger.: Biso; Biso Lich; Biso-Puren; BisoAPS; Biso- lower dose of 200 micrograms/kg per hour for up to 20
O CH3 beta; Bisobloc†; Bisogamma; Bisohexal; Bisomerck; Concor; Cordalin†;
CH3 O Fondril; Jutabis; Gr.: Abitrol; Blocatens; Pactens; Speridol; Hong Kong: hours if required.
Concor; Hung.: Bisoblock; Bisocard; Bisogamma; Bisogen; Concor; Concor As part of the management of patients with acute cor-
CH3 Cor; Coviogal; India: Concor; Indon.: B-Beta; Concor; Hapsen; Lodoz;
H 3C N O onary syndromes, the initial dose of bivalirudin is
H Maintate; Irl.: Bisocor; Bisopine; Cardicor; Emcolol; Emcor; Soprol; Israel:
OH Bisolol; Cardiloc; Concor; Ital.: Cardicor; Concor; Congescor; Pluscor; Se- 100 micrograms/kg by intravenous injection, followed
quacor ; Jpn: Maintate; Malaysia: Concor ; Mex.: Concor; Neth.:
(bisoprolol) Bisobloc†; Bisoblock; Cardicor†; Emcor; Norw.: Emconcor; Philipp.: Con- by an intravenous infusion of 250 micrograms/kg per
core; Pol.: Bisocard; Bisohexal; Bisopromerck; Bisoratio; Concor; Corectin; hour. In patients managed medically, the infusion may
Port.: Concor; Libracor; Rus.: Biprol (Бипрол); Bisocard (Бисокард); Bi-
Pharmacopoeias. In Eur. (see p.vii) and US. sogamma (Бисогамма); Concor (Конкор); Corbis (Корбис); S.Afr.: Adco- be continued for up to 72 hours. For those who proceed
Bisocor; Bilocor; Bisohexal; Cardicor; Concor; Singapore: Concor; Spain: to PCI or coronary artery bypass surgery without car-
Ph. Eur. 6.2 (Bisoprolol Fumarate). A white or almost white, Emconcor; Euradal; Godal; Swed.: Bisomerck; Emconcor; Switz.: Bilol;
slightly hygroscopic powder. It exhibits polymorphism. Very Concor; Thai.: Concor; Novacor; Turk.: Concor; UK: Bipranix†; Cardi- diopulmonary bypass, a further intravenous injection
soluble in water; freely soluble in methyl alcohol. Store in air- cor; Emcor; Monocor†; Soloc†; Vivacor; USA: Zebeta; Venez.: Concor. of 500 micrograms/kg should be given, and the infu-
tight containers. Protect from light. Multi-ingredient: Arg.: Corbis D; Ziac; Austria: Bisocombin; Bisoprolol sion should be increased to 1.75 mg/kg per hour for the
USP 31 (Bisoprolol Fumarate). A white crystalline powder. Very comp; Bisoprolol-HCT; Bisostad plus; Concor Plus; Darbalan Plus; Nanalan
soluble in water and in methyl alcohol; freely soluble in alcohol, Plus; Rivacor Plus; Belg.: Co-Bisoprolol; Emcoretic; Lodoz; Maxsoten; Mer- duration of the procedure; after PCI, the infusion may
ck-Co-Bisoprolol; Braz.: Biconcor; Chile: Ziac; Cz.: Concor Plus†; Lodoz; be continued at a dose of 250 micrograms/kg per hour
in chloroform, and in glacial acetic acid; slightly soluble in Tebis Plus H; Fin.: Bisoprolol Comp; Emconcor Comp; Orloc Comp; Fr.:
acetone and in ethyl acetate. Store in airtight containers. Protect Lodoz; Wytens; Ger.: Biso comp; Biso-Puren comp; Bisobeta comp; Biso- for a further 4 to 12 hours if required. For those who
from light. hexal plus; BisoLich comp; Bisomerck Plus; Bisoplus; Bisoprolol Comp; Biso- proceed to coronary artery bypass surgery with cardi-
prolol HCT; Bisoprolol Plus; Concor Plus; Fondril HCT; Hong Kong: Lo-
doz; Hung.: Concor Plus; Lodoz; India: Lodoz; Ital.: Lodoz; Mex.: opulmonary bypass, the infusion should be stopped 1
Adverse Effects, Treatment, and Precau- Biconcor; Neth.: Emcoretic; Norw.: Lodoz; Philipp.: Ziac; Port.: Concor hour before the procedure and the patient should be
tions Plus; S.Afr.: Ziak; Singapore: Lodoz; Spain: Emcoretic; Switz.: Concor
Plus; Lodoz; Thai.: Lodoz; USA: Ziac; Venez.: Biconcor; Ziac. treated with unfractionated heparin.
As for Beta Blockers, p.1226.
The dose of bivalirudin should be reduced in patients
Interactions with renal impairment (see below).
The interactions associated with beta blockers are dis- Bivalirudin (BAN, USAN, rINN) ◊ References.
cussed on p.1228. BG-8967; Bivalirudina; Bivalirudine; Bivalirudinum; Hirulog. 1. Carswell CI, Plosker GL. Bivalirudin: a review of its potential
place in the management of acute coronary syndromes. Drugs
Бивалирудин 2002; 62: 841–70.
Pharmacokinetics C 98 H 138N 24 O 33 = 2180.3. 2. Sciulli TM, Mauro VF. Pharmacology and clinical use of biva-
Bisoprolol is almost completely absorbed from the C AS — 128270-60-0. lirudin. Ann Pharmacother 2002; 36: 1028–41.
gastrointestinal tract and undergoes only minimal first- 3. Moen MD, et al. Bivalirudin: a review of its use in patients un-
ATC — B01AE06. dergoing percutaneous coronary intervention. Drugs 2005; 65:
pass metabolism resulting in an oral bioavailability of ATC Vet — QB01AE06. 1869–91.