Bezafibrate
adverse Effects
The commonest side-effects of bezafibrate therapy
are gastro-intestinal upsets including anorexia, naus-
ia and gastric discomfort. Other adverse effects re-
ported to occur less frequently include headache ,di-
zziness. vertigo, fatigue, skin rashes, pruritus. alo-
pecia, impotence, and anaemia and leucopenia.
Raised serum-aminotransferase concentrations have occasionally
been reported. Elevated creatine phosphokinase concentrations
during bezafibrate therapy
may be associated with a syndrome of myositis, my-
opathy. and rarely rhabdomyolysis; patients with
hypoalbuminaemia resulting from the nephrotic
syndrome or other renal impairment may be at in-
creased risk. Bezafibrate may increase the lithogenic
index, but although there have been isolated reports
of gallstones there is no evidence that the adminis-
tration of bezafibrate is associated with an increased
frequency of this adverse effect.
Effects on hypoglycaemic control. Reductions in fasting
blood-glucose concentrations of between 4 and 10% occurred
during long-term therapy with bezafibrate in hyperlipidaemic
diabetic patients.l2 Jones et al.~ suggested that bezafibrate
could be considered as additional or alternative therapy in pa-
tients with type 2 diabetes mellitus.
Effects on the nervous system. Peripheral neuropathy
occurred in a patient given bezafibrate and was substantiated
by nerve conduction studies.
Effects on skeletal muscle. The UK Committee on Safety
of Medicines has noted that myositis and myopathy are well
known to occur with lipid regulating drugs such as fibrates
and statins. Rhabdomyolysis, presenting as muscle pain with
elevated creatine phosphokinase and myoglobinuria leading
to renal failure, has also been reported but appears to be rare.
Worldwide reporting did not indicate marked differences in
the risk of the reactions with individual drugs. Patients with
renal impairment, and possibly with hypothyroidism. may be
at increased risk of muscle toxicity.
Headache. Severe recurrent headaches were associated with
bezafibrate administration in one patient.' The headaches
started about 24 hours after therapy with bezafibrate began,
and recurred about 1 hour after each dose.
Precautions
Bezafibrate should not be given to patients with
severe liver or kidney impairment, primary biliary
cirrhosis, gallstones or gallbladder disorders, or
hypoalbuminaemic states such as the nephrotic syn-
drome.
Patients with renal impairment and possibly with hypothy-
roidism may be at increased risk of the muscle toxicity asso-
ciated with fibrates and statins (see Adverse Effects, above).
Combined treatment with a fibrate and a statin may increase
the risk of serious muscle toxicity. The UK Committee on
Safety of Medicines' has advised that patients treated with
these drugs should consult their doctor if they develop muscle
pain, tenderness, or weakness and treatment should be
stopped if muscle toxicity is suspected clinically or if
creatine phosphokinase is markedly raised or progressively
rising.
Diabetes mellitus. See Effects on Hypoglycaemic Control
under Adverse Effects, above.
Renal Impairment. See under Uses and Administration
below.
Interactions
Bezafibrate and other fibrates may enhance the ef
fects of oral anticoagulants: the dose of anticoagu
lant should be reduced when treatment with a fibrate
is started, and then adjusted gradually if necessary
Recommendations concerning the amount that the
anticoagulant dose should be reduced by vary be
tween the manufacturers of the differing fibrates and
are sometimes not even specified; the manufacturers
of bezafibrate suggest a reduction of up to 50% in
the dosage of anticoagulant. The mechanism of the interaction
has not yet been determined. Fibrates
have been reported to displace warfarin from protein
binding sites but other mechanisms are probably
also involved.
A number of other drugs may be displaced from
plasma proteins by fibrates including tolbutamide
and other sulphonylurea antidiabetics, phenytoin,
and. in patients with hypoalbuminaemia, frusemide.
The interaction with antidiabetics is complex since
bezafibrate has been shown to alter glucose toler-
ance in both diabetic and non-diabetic patients. The
dosage of antidiabetics may need adjusting during
concomitant bezafibrate therapy.
There is an increased risk of myopathy if fibrates are
given concurrently with statins.
Increased cyclosporin concentrations and associated
nephrotoxicity have been reported when the drug
was administered concomitantly with bezafibrate.
Pharmacokineties
Bezafibrate is readily absorbed from the gastro-in-
testinal tract. Plasma protein binding is about 95%.
The plasma elimination half-life is about 2 hours.
Most of a dose is excreted in the urine, about half as
unchanged drug, the remainder as metabolites in-
cluding the glucuronide conjugate. A small propor-
tion of the dose appears in the faeces.
Old age. In a study comparing the pharmacokinetics of bez-
afibrate in 19 elderly patients with younger healthy subjects.'
maximum plasma concentrations were 1.6 times higher in the
elderly group (median 12.1 mg per litre against 7.7 mg per
litre) and half-life was increased by 3.8 times (median 6.6
hours against 1.7 hours). The differences could not be attrib-
uted solely to diminished renal function in elderly patients.
Dosage adjustments in elderly patients should not therefore
be based on renal function alone.
Renal impairment. For a report of the half-life of bezafi-
brate in patients with impaired renal function, see under Uses
and Administration, below.
Uses and Administration Bezafibrate. a fibric acid derivative, is a lipid regu-ating drug.
It is used in the treatment of type lla, type llb. type III, type IV, and type V hyperlipoproteinaemias.
It reduces elevated plasma concentrations of triglycerides by reducing the concentration
of very-low-density lipoproteins (VLDL). It reduces
elevated plasma concentrations of cholesterol to a
lesser extent, but the effect is variable.
Bezafibrate is given in a usual dose of 200 mg three
times daily by mouth taken with or after food;
200 mg twice daily may occasionally be adequate
for maintenance particularly in the treatment of
hypertriglyceridaemia. A 400-mg modified-release
tablet is also available and is given as a single daily dose of 400 mg.
Administration In renal Impairmmt. Bezafibrate is
generally contra-indicated in severe renal dysfunction but the
manufacturer has stated that it may be given to patients with
renal impairment depending on creatinine clearance. Sug-
gested doses are: creatinine clearance 40 to 60 mL per
minute, 400 mg daily: 15 to 40 mL per minute. 200 mg daily
or on alternate days: less than 15 mL per minute and dialysis
patients, 200 mg on every third day.
In a study in patients with impaired renal function' the half-
life of bezafibrate was reported to be prolonged to 4.6 hours
in 3 patients with creatinine clearance greater than 40 mL per
minute, 7.8 hours in 8 patients with creatinine clearance of 20
to 40 mL per minute, and 20.1 hours in a patient with creati-
nine clearance of 13 mL per minute. Williams et al} reported
an accelerated decline in renal function in 2 patients with ad-
vanced chronic renal failure during bezafibrate therapy, and
suggested that further dosage reductions would be necessary
to avoid excessive plasma-bezafibrate concentrations in urae-
mic patients.
Hyperlipidaemia . Bezalibrate is a typical member of the
fibric acid derivative group of drugs (the fibrates) used in
the treatment of hyperlipidaemias . One of the primary
actions of the fibrates is to promote the catabolism of
triglyceride rich lipoproteins, in particular very-low-density
lipo-proteins (VLDL). apparently mediated by an enhanced
activity of lipoprotein lipase.' They may also interfere with
the synthesis of VLDL. possibly by inhibiting hepatic acetyl
coenzyme A carboxylase. The effect of fibrates on low-densi-
ty lipoprotein-cholesterol (LDL-cholesterol) depends on the
overall lipoprotein status of the patient. In
hypertriglyceridaemic patients the response depends on
underlying LDL-cholesterol concentrations and the type of
lipoprotein abnor-mality, while in normotnglyceridaemic patients
with type lla- hyperlipoproteinaemia the LDL-cholesterol tends to de-
crease. In these patients bezafibrate and fenofibrate may re-
duce LDL-cholcsterol concentrations more effectively than
clofibrate or gemftbrozil. High-density lipoprolein-cholester-
ol (HDL-cholestero!) concentrations are increased by fibrate
therapy in both hypertriglyceridaemic and normotriglyceri-
daemic patients, although there have been a few reports of
unexpected fails in HDL-cholesterol with bezafibrate' and
ciprofibrate. Fibrates have three actions on sterol metabolism:' they
inhibit the synthesis of cholesterol, they inhibit the synthesis of
bile acids, and they enhance the secretion of cholesterol in bile.
It is these latter two effects which are responsible for the raised
cholesterol saturation of bile. which may lead to the forma-
tion of gallstones in some patients. However, other factors
appear to be necessary since gallstones only develop in relatively few patients.
Bezafibrate has been shown to reduce cholesterol and
triglyceride concentrations in patients with type lla. llb, and IV
hyperlipoproteinaemias and in diabetic patients with lipid
abnormalities. Comparative studies have shown it to be atleast as effective as clofibrate and fenofibrate. and to be more
so than gernfibrozil in the short, but possibly not long term.
It is less effective than ciprofibrate (except for effects on HDL-cholesterol).
The influence of long-term bezafibrate administration on
mortality from Ischaemic heart disease has been investigated. In the Bezafibrate Coronary Atherosclerosis Intervention
Trial (BECAIT)56 treatment for 5 years in young men (less
than 45 years of age) following myocardial infarction resulted
in fewer coronary events and. slowed the progression of focal
coronary atherosclerosis when compared with placebo.