Primary Hypercholesterolaemia
Ezechol, co-administered with an HMG-CoA reductase inhibitor (statin) is indicated as adjunctive therapy to
diet for use in patients with primary (heterozygous familial and non-familial) hypercholesterolaemia who are
not appropriately controlled with a statin alone.
Ezechol monotherapy is indicated as adjunctive therapy to diet for use in patients with primary (heterozygous
familial and non-familial) hypercholesterolaemia in whom a statin is considered inappropriate or is not
tolerated.
Homozygous Familial Hypercholesterolaemia (HoFH)
Ezechol co-administered with a statin, is indicated as adjunctive therapy to diet for use in patients with HoFH.
Patients may also receive adjunctive treatments (e.g. LDL apheresis).
Homozygous Sitosterolaemia (phytosterolaemia)
Ezechol is indicated as adjunctive therapy to diet for use in patients with homozygous familial sitosterolaemia.
A beneficial effect of Ezechol on cardiovascular morbidity and mortality has not yet been demonstrated.
 

The patient should be on an appropriate lipid-lowering diet and should continue on this diet during treatment
with Ezechol.
Route of administration is oral. The recommended dose is one Ezechol 10 mg tablet daily. Ezechol can be
administered at any time of the day, with or without food.
When Ezechol is added to a statin, either the indicated usual initial dose of that particular statin or the already
established higher statin dose should be continued. In this setting, the dosage instructions for that particular
statin should be consulted.
Co-administration with bile acid sequestrants
Dosing of Ezechol should occur either ≥2 hours before or ≥4 hours after administration of a bile acid
sequestrant.
Use in the Elderly
No dosage adjustment is required for elderly patients (see section 5.2).
Use in Paediatric Patients
Initiation of treatment must be performed under review of a specialist.
Children and adolescents ≥ 10 years (pubertal status: boys Tanner Stage II and above and girls who are at
least one year post-menarche): No dosage adjustment is required (see section 5.2). The clinical experience in
paediatric and adolescent patients (aged 10-17 years old) is, however, limited.
When Ezechol is administered with a statin, the dosage instructions for the statin, in children should be
consulted.
Children >6 and < 10 years: There is limited data on safety and efficacy in this age group. (see sections 5.1
and 5.2).
Children <6 years: There is no available data on use of Ezechol in this age group.
Use in Hepatic Impairment
No dosage adjustment is required in patients with mild hepatic insufficiency (Child Pugh score 5 to 6).
Treatment with Ezechol is not recommended in patients with moderate (Child Pugh score 7 to 9) or severe
(Child Pugh score >9) liver dysfunction. (See sections 4.4 and 5.2.)
Use in Renal Impairment
No dosage adjustment is required for renal impaired patients (see section 5.2).
 

Hypersensitivity to the active substance or to any of the excipients. When Ezechol is co-administered with a statin, please refer to the SPC for that particular medicinal product. Therapy with Ezechol co-administered with a statin is contraindicated during pregnancy and lactation. Ezechol co-administered with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in serum transaminases.

When Ezechol is co-administered with a statin, please refer to the SPC for that particular medicinal product.
Liver enzymes
In controlled co-administration trials in patients receiving Ezechol with a statin, consecutive transaminase
elevations (≥3 X the upper limit of normal [ULN]) have been observed. When Ezechol is co-administered with a
statin, liver function tests should be performed at initiation of therapy and according to the recommendations
of the statin. (See section 4.8.)
In a controlled clinical study in which over 9000 patients with chronic kidney disease were randomized to
receive Ezechol 10 mg combined with simvastatin 20 mg daily (n=4650) or placebo (n=4620), (median followup period of 4.9 years), the incidence of consecutive elevations of transaminases (>3 X ULN) was 0.7% for
Ezechol combined with simvastatin and 0.6% for placebo (see section 4.8).
Skeletal muscle
In post-marketing experience with Ezechol, cases of myopathy and rhabdomyolysis have been reported. Most
patients who developed rhabdomyolysis were taking a statin concomitantly with Ezechol. However,
rhabdomyolysis has been reported very rarely with Ezechol monotherapy and very rarely with the addition of
Ezechol to other agents known to be associated with increased risk of rhabdomyolysis. If myopathy is
suspected based on muscle symptoms or is confirmed by a creatine phosphokinase (CPK) level >10 times the
ULN, Ezechol, any statin, and any of these other agents that the patient is taking concomitantly should be
immediately discontinued. All patients starting therapy with Ezechol should be advised of the risk of myopathy
and told to report promptly any unexplained muscle pain, tenderness or weakness (see section 4.8).
In a clinical trial in which over 9000 patients with chronic kidney disease were randomized to receive Ezechol
10 mg combined with simvastatin 20 mg daily (n=4650) or placebo (n=4620) (median follow-up 4.9 years),
the incidence of myopathy/rhabdomyolysis was 0.2% for Ezechol combined with simvastatin and 0.1% for
placebo (See section 4.8).
Hepatic insufficiency
Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic
insufficiency, Ezechol is not recommended (see section 5.2).
Paediatric (6 to 17 Years of Age) Patients
Efficacy and safety of Ezechol in patients 6 to 10 years of age with heterozygous familial or non-familial
hypercholesterolemia have been evaluated in a 12-week controlled clinical trial. Effects of ezetimibe for
treatment periods > 12 weeks have not been studied in this age group (see sections 4.2, 4.8, 5.1 and 5.2).
Ezechol has not been studied in patients younger than 6 years of age. (See sections 4.2 and 4.8.)
Efficacy and safety of Ezechol co-administered with simvastatin in patients 10 to 17 years of age with
heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial in adolescent boys
(Tanner stage II or above) and in girls who were at least one year post-menarche.
In this limited controlled study, there was generally no detectable effect on growth or sexual maturation in the
adolescent boys or girls, or any effect on menstrual cycle length in girls. However, the effects of ezetimibe for
a treatment period > 33 weeks on growth and sexual maturation have not been studied (see sections 4.2 and
4.8)
The safety and efficacy of Ezechol co-administered with doses of simvastatin above 40 mg daily have not been
studied in paediatric patients 10 to 17 years of age.
The safety and efficacy of Ezechol co-administered with simvastatin have not been studied in paediatric
patients < 10 years of age (See sections 4.2 and 4.8).
The long-term efficacy of therapy with Ezechol in patients below 17 years of age to reduce morbidity and
mortality in adulthood has not been studied.
Fibrates
The safety and efficacy of Ezechol administered with fibrates have not been established.
If cholelithiasis is suspected in a patient receiving Ezechol and fenofibrate, gallbladder investigations are
indicated and this therapy should be discontinued (see sections 4.5 and 4.8).
Ciclosporin
Caution should be exercised when initiating Ezechol in the setting of ciclosporin. Ciclosporin concentrations
should be monitored in patients receiving Ezechol and ciclosporin (see section 4.5).
Anticoagulants
If Ezechol is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalised
Ratio (INR) should be appropriately monitored (see section 4.5).
Excipient
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption should not take this medicine.
 

Interaction studies have only been performed in adults.
In preclinical studies, it has been shown that ezetimibe does not induce cytochrome P450 drug metabolising
enzymes. No clinically significant pharmacokinetic interactions have been observed between ezetimibe and
drugs known to be metabolised by cytochromes P450 1A2, 2D6, 2C8, 2C9, and 3A4, or N-acetyltransferase.
In clinical interaction studies, ezetimibe had no effect on the pharmacokinetics of dapsone, dextromethorphan,
digoxin, oral contraceptives (ethinyl estradiol and levonorgestrel), glipizide, tolbutamide, or midazolam, during
co-administration. Cimetidine, co-administered with ezetimibe, had no effect on the bioavailability of ezetimibe.
Antacids: Concomitant antacid administration decreased the rate of absorption of ezetimibe but had no effect
on the bioavailability of ezetimibe. This decreased rate of absorption is not considered clinically significant.
Cholestyramine: Concomitant cholestyramine administration decreased the mean area under the curve
(AUC) of total ezetimibe (ezetimibe + ezetimibe glucuronide) approximately 55%. The incremental low-density
lipoprotein cholesterol (LDL-C) reduction due to adding Ezechol to cholestyramine may be lessened by this
interaction (see section 4.2).
Fibrates: In patients receiving fenofibrate and Ezechol, physicians should be aware of the possible risk of
cholelithiasis and gallbladder disease (see section 4.4 and 4.8).
If cholelithiasis is suspected in a patient receiving Ezechol and fenofibrate, gallbladder investigations are
indicated and this therapy should be discontinued (see section 4.8).
Concomitant fenofibrate or gemfibrozil administration modestly increased total ezetimibe concentrations
(approximately 1.5- and 1.7-fold respectively).
Co-administration of Ezechol with other fibrates has not been studied.
Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In animal studies, ezetimibe
sometimes increased cholesterol in the gallbladder bile, but not in all species (see section 5.3). A lithogenic risk
associated with the therapeutic use of Ezechol cannot be ruled out.
Statins: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered
with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin or rosuvastatin.
Ciclosporin: In a study of eight post-renal transplant patients with creatinine clearance of >50 mL/min on a
stable dose of ciclosporin, a single 10-mg dose of Ezechol resulted in a 3.4-fold (range 2.3 to 7.9-fold) increase
in the mean AUC for total ezetimibe compared to a healthy control population, receiving ezetimibe alone, from
another study (n=17). In a different study, a renal transplant patient with severe renal insufficiency who was
receiving ciclosporin and multiple other medications, demonstrated a 12-fold greater exposure to total
ezetimibe compared to concurrent controls receiving ezetimibe alone. In a two-period crossover study in
twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days with a single 100-mg dose of
ciclosporin on Day 7 resulted in a mean 15 % increase in ciclosporin AUC (range 10 % decrease to 51 %
increase) compared to a single 100-mg dose of ciclosporin alone. A controlled study on the effect of coadministered ezetimibe on ciclosporin exposure in renal transplant patients has not been conducted. Caution
should be exercised when initiating Ezechol in the setting of ciclosporin. Ciclosporin concentrations should be
monitored in patients receiving Ezechol and ciclosporin (see section 4.4).
Anticoagulants: Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on
bioavailability of warfarin and prothrombin time in a study of twelve healthy adult males. However, there have
been post-marketing reports of increased International Normalised Ratio (INR) in patients who had Ezechol
added to warfarin or fluindione. If Ezechol is added to warfarin, another coumarin anticoagulant, or fluindione,
INR should be appropriately monitored (see Section 4.4).
 

Pregnancy category: C
Ezechol co-administered with a statin is contraindicated during pregnancy and lactation (see section 4.3),
please refer to the SPC for that particular statin.
Pregnancy:
Ezechol should be given to pregnant women only if clearly necessary. No clinical data are available on the use
of Ezechol during pregnancy. Animal studies on the use of ezetimibe in monotherapy have shown no evidence
of direct or indirect harmful effects on pregnancy, embryofoetal development, birth or postnatal development
(see section 5.3).
Lactation:
Ezechol should not be used during lactation. Studies on rats have shown that ezetimibe is secreted into breast
milk. It is not known if ezetimibe is secreted into human breast milk.
Fertility:
No clinical trial data are available on the effects of ezetimibe on human fertility. Ezetimibe had no effect on the
fertility of male or female rats (see section 5.3).
 

No studies on the effects on the ability to drive and use machines have been performed. However, when
driving vehicles or operating machines, it should be taken into account that dizziness has been reported.
 

a) Summary of safety profile:
Adverse reactions were usually mild and transient. The overall incidence of side effects was similar
between Ezechol and placebo.
b) Tabulated list of adverse reactions:
Clinical Studies and Post-marketing Experience
In clinical studies of up to 112 weeks duration, Ezechol 10 mg daily was administered alone in 2396 patients,
or with a statin in 11,308 patients or with fenofibrate in 185 patients. Adverse reactions were usually mild and
transient. The overall incidence of side effects was similar between Ezechol and placebo. Similarly, the
discontinuation rate due to adverse experiences was comparable between Ezechol and placebo.
Ezechol administered alone or co-administered with a statin:
The following adverse reactions were observed in patients treated with Ezechol (N=2396) and at a greater
incidence than placebo (N=1159) or in patients treated with Ezechol co-administered with a statin (N=11308)
and at a greater incidence than statin administered alone (N=9361). Post-marketing Adverse reactions were
derived from reports containing Ezechol either administered alone or with a statin.
Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to
<1/100); rare (≥1/10,000 to <1/1,000) very rare (<1/10,000) and not known (cannot be estimated from the
available data).

c) Description of selected Adverse reaction:
Not applicable
d) Pediatric Population:
Paediatric (6 to 17 years of age) Patients
In a study involving paediatric (6 to 10 years of age) patients with heterozygous familial or non-familial
hypercholesterolaemia (n = 138), elevations of ALT and/or AST (≥ 3X ULN, consecutive) were observed in
1.1% (1 patient) of the ezetimibe patients compared to 0% in the placebo group. There were no elevations of
CPK (≥ 10X ULN). No cases of myopathy were reported.
In a separate study involving adolescent (10 to 17 years of age) patients with heterozygous familial
hypercholesterolaemia (n = 248), elevations of ALT and/or AST (≥3X ULN, consecutive) were observed in 3%
(4 patients) of the ezetimibe/simvastatin patients compared to 2% (2 patients) in the simvastatin monotherapy
group; these figures were respectively 2% (2 patients) and 0% for elevation of CPK (≥ 10X ULN). No cases of
myopathy were reported.
These trials were not suited for comparison of rare adverse drug reactions.
e) Other special population:
Patients with Chronic Kidney Disease
In the Study of Heart and Renal Protection (SHARP) (see section 5.1), involving over 9000 patients treated
with a fixed dose combination of Ezechol 10 mg with simvastatin 20 mg daily (n=4650) or placebo (n=4620),
the safety profiles were comparable during a median follow-up period of 4.9 years. In this trial, only serious
adverse events and discontinuations due to any adverse events were recorded. Discontinuation rates due to
adverse events were comparable (10.4% in patients treated with Ezechol combined with simvastatin, 9.8% in
patients treated with placebo). The incidence of myopathy/rhabdomyolysis was 0.2% in patients treated with
Ezechol combined with simvastatin and 0.1% in patients treated with placebo. Consecutive elevations of
transaminases (> 3X ULN) occurred in 0.7% of patients treated with Ezechol combined with simvastatin
compared with 0.6% of patients treated with placebo. In this trial, there were no statistically significant
increases in the incidence of pre-specified adverse events, including cancer (9.4% for Ezechol combined with
simvastatin, 9.5% for placebo), hepatitis, cholecystectomy or complications of gallstones or pancreatitis.
Laboratory values
In controlled clinical monotherapy trials, the incidence of clinically important elevations in serum transaminases
(ALT and/or AST ≥3 X ULN, consecutive) was similar between Ezechol (0.5%) and placebo (0.3%). In coadministration trials, the incidence was 1.3% for patients treated with Ezechol co-administered with a statin
and 0.4% for patients treated with a statin alone. These elevations were generally asymptomatic, not
associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued
treatment (See section 4.4.).
In clinical trials, CPK >10 X ULN was reported for 4 of 1,674 (0.2%) patients administered Ezechol alone vs 1
of 786 (0.1%) patients administered placebo, and for 1 of 917 (0.1%) patients co-administered Ezechol and a
statin vs 4 of 929 (0.4%) patients administered a statin alone. There was no excess of myopathy or
rhabdomyolysis associated with Ezechol compared with the relevant control arm (placebo or statin alone) (See
section 4.4.).
To report any side effect(s):

In clinical studies, administration of ezetimibe, 50 mg/day, to 15 healthy subjects for up to 14 days, or 40
mg/day to 18 patients with primary hypercholesterolaemia for up to 56 days, was generally well tolerated. In
animals, no toxicity was observed after single oral doses of 5,000 mg/kg of ezetimibe in rats and mice and
3,000 mg/kg in dogs.
A few cases of overdosage with Ezechol have been reported: most have not been associated with adverse
experiences. Reported adverse experiences have not been serious. In the event of an overdose, symptomatic
and supportive measures should be employed.
 

Pharmacotherapeutic group: Other lipid modifying agents. ATC code: C10A X09
Ezechol is in a new class of lipid-lowering compounds that selectively inhibit the intestinal absorption of
cholesterol and related plant sterols. Ezechol is orally active, and has a mechanism of action that differs from
other classes of cholesterol-reducing compounds (e.g. statins, bile acid sequestrants [resins], fibric acid
derivatives, and plant stanols). The molecular target of ezetimibe is the sterol transporter, Niemann-Pick C1-
Like 1 (NPC1L1), which is responsible for the intestinal uptake of cholesterol and phytosterols.
Ezetimibe localises at the brush border of the small intestine and inhibits the absorption of cholesterol, leading
to a decrease in the delivery of intestinal cholesterol to the liver; statins reduce cholesterol synthesis in the
liver and together these distinct mechanisms provide complementary cholesterol reduction. In a 2-week clinical
study in 18 hypercholesterolaemic patients, Ezechol inhibited intestinal cholesterol absorption by 54%,
compared with placebo.
A series of preclinical studies was performed to determine the selectivity of ezetimibe for inhibiting cholesterol
absorption. Ezetimibe inhibited the absorption of [14C]-cholesterol with no effect on the absorption of
triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or fat soluble vitamins A and D.
Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level
of total-C and LDL-C and inversely with the level of HDL-C.
A beneficial effect of Ezechol on cardiovascular morbidity and mortality has not yet been demonstrated.
CLINICAL TRIALS
In controlled clinical studies, Ezechol, either as monotherapy or co-administered with a statin significantly
reduced total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and
trigylcerides (TG) and increased high-density lipoprotein cholesterol (HDL-C) in patients with
hypercholesterolaemia.
Primary hypercholesterolaemia
In a double-blind, placebo-controlled, 8-week study, 769 patients with hypercholesterolaemia already receiving
statin monotherapy and not at National Cholesterol Education Program (NCEP) LDL-C goal (2.6 to 4.1 mmol/l
[100 to 160 mg/dl], depending on baseline characteristics) were randomised to receive either Ezechol 10 mg or
placebo in addition to their on-going statin therapy.
Among statin-treated patients not at LDL-C goal at baseline (~82%), significantly more patients randomised to
Ezechol achieved their LDL-C goal at study endpoint compared to patients randomised to placebo, 72% and
19% respectively. The corresponding LDL-C reductions were significantly different (25% and 4% for Ezechol
versus placebo, respectively). In addition, Ezechol, added to on-going statin therapy, significantly decreased
total-C, Apo B, TG and increased HDL-C, compared with placebo. Ezechol or placebo added to statin therapy
reduced median C-reactive protein by 10% or 0% from baseline, respectively.
In two, double-blind, randomised placebo-controlled, 12-week studies in 1,719 patients with primary
hypercholesterolaemia, Ezechol 10 mg significantly lowered total-C (13%), LDL-C (19%), Apo B (14%), and TG
(8%) and increased HDL-C (3%) compared to placebo. In addition, Ezechol had no effect on the plasma
concentrations of the fat-soluble vitamins A, D, and E, no effect on prothrombin time, and, like other lipidlowering agents, did not impair adrenocortical steroid hormone production.
In a multicenter, double-blind, controlled clinical study (ENHANCE), 720 patients with heterozygous familial
hypercholesterolemia were randomized to receive ezetimibe 10 mg in combination with simvastatin 80 mg (n =
357) or simvastatin 80 mg (n = 363) for 2 years. The primary objective of the study was to investigate the
effect of ezetimibe/simvastatin combination therapy on carotid artery intima-media thickness (IMT) compared
to simvastatin monotherapy. The impact of this surrogate marker on cardiovascular morbidity and mortality is
still not demonstrated.
The primary endpoint, the change in the mean IMT of all six carotid segments, did not differ significantly
(p=0.29) between the two treatment groups as measured by B-mode ultrasound. With ezetimibe 10 mg in
combination with simvastatin 80 mg or simvastatin 80 mg alone, intima-medial thickening increased by 0.0111
mm and 0.0058 mm, respectively, over the study's 2 year duration (baseline mean carotid IMT 0.68 mm and
0.69 mm respectively).
Ezetimibe 10 mg in combination with simvastatin 80 mg lowered LDL-C, total-C, Apo B, and TG significantly
more than simvastatin 80 mg. The percent increase in HDL-C was similar for the two treatment groups. The
adverse reactions reported for ezetimibe 10 mg in combination with simvastatin 80 mg were consistent with its
known safety profile.
Clinical Studies in Paediatric Patients (6 to 17 years of age)
In a multicentre, double-blind, controlled study, 138 patients (59 boys and 79 girls) 6 to 10 years of age (mean
age 8.3 years) with heterozygous familial or non-familial hypercholesterolaemia (HeFH) with baseline LDL-C
levels between 3.74 and 9.92 mmol/l were randomised to either Ezechol 10 mg or placebo for 12 weeks.
At week 12, Ezechol significantly reduced total-C (-21% vs. 0%), LDL-C (-28% vs. -1%), Apo-B (-22% vs. -
1%), and non-HDL-C (-26% vs. 0%) compared to placebo. Results for the two treatment groups were similar
for TG and HDL-C (-6% vs. +8%, and +2% vs. +1%, respectively).
In a multicentre, double-blind, controlled study, 142 boys (Tanner stage II and above) and 106 postmenarchal
girls, 10 to 17 years of age (mean age 14.2 years) with heterozygous familial hypercholesterolaemia (HeFH)
with baseline LDL-C levels between 4.1 and 10.4 mmol/l were randomised to either Ezechol 10 mg coadministered with simvastatin (10, 20 or 40 mg) or simvastatin (10, 20 or 40 mg) alone for 6 weeks, coadministered Ezechol and 40 mg simvastatin or 40 mg simvastatin alone for the next 27 weeks, and open-label
co-administered Ezechol and simvastatin (10 mg, 20 mg, or 40 mg) for 20 weeks thereafter.
At Week 6, Ezechol co-administered with simvastatin (all doses) significantly reduced total-C (38 % vs 26 %),
LDL-C (49 % vs 34 %), Apo B (39 % vs 27 %), and non-HDL-C (47 % vs 33 %) compared to simvastatin (all
doses) alone. Results for the two treatment groups were similar for TG and HDL-C (-17 % vs -12 % and +7 %
vs +6 %, respectively). At Week 33, results were consistent with those at Week 6 and significantly more
patients receiving Ezechol and 40 mg simvastatin (62 %) attained the NCEP AAP ideal goal (< 2.8 mmol/L [110
mg/dL]) for LDL-C compared to those receiving 40 mg simvastatin (25 %). At Week 53, the end of the open
label extension, the effects on lipid parameters were maintained.
The safety and efficacy of Ezechol co-administered with doses of simvastatin above 40 mg daily have not been
studied in paediatric patients 10 to 17 years of age. The safety and efficacy of Ezechol co-administered with
simvastatin have not been studied in paediatric patients < 10 years of age. The long-term efficacy of therapy
with Ezechol in patients below 17 years of age to reduce morbidity and mortality in adulthood has not been
studied.
Homozygous Familial Hypercholesterolaemia (HoFH)
A double-blind, randomised, 12-week study enrolled 50 patients with a clinical and/or genotypic diagnosis of
HoFH, who were receiving atorvastatin or simvastatin (40 mg) with or without concomitant LDL apheresis.
Ezechol co-administered with atorvastatin (40 or 80 mg) or simvastatin (40 or 80 mg), significantly reduced
LDL-C by 15% compared with increasing the dose of simvastatin or atorvastatin monotherapy from 40 to 80
mg.
Homozygous sitosterolaemia (phytosterolaemia)
In a double-blind, placebo-controlled, 8-week trial, 37 patients with homozygous sitosterolaemia were
randomised to receive Ezechol 10 mg (n=30) or placebo (n=7). Some patients were receiving other treatments
(e.g. statins, resins). Ezechol significantly lowered the two major plant sterols, sitosterol and campesterol, by
21% and 24% from baseline, respectively. The effects of decreasing sitosterol on morbidity and mortality in
this population are not known.
Prevention of Major Vascular Events in Chronic Kidney Disease (CKD)
The Study of Heart and Renal Protection (SHARP) was a multi-national, randomized, placebo-controlled,
double-blind study conducted in 9438 patients with chronic kidney disease, a third of whom were on dialysis at
baseline. A total of 4650 patients were allocated to a fixed dose combination of Ezechol 10 mg with simvastatin
20 mg and 4620 to placebo, and followed for a median of 4.9 years. Patients had a mean age of 62 and 63 %
were male, 72 % Caucasian, 23 % diabetic and, for those not on dialysis, the mean estimated glomerular
filtration rate (eGFR) was 26.5 ml/min/1.73 m2. There were no lipid entry criteria. Mean LDL-C at baseline was
108 mg/dL. After one year, including patients no longer taking study medication, LDL-C was reduced 26 %
relative to placebo by simvastatin 20 mg alone and 38 % by Ezechol 10 mg combined with simvastatin 20 mg.
The SHARP protocol-specified primary comparison was an intention-to-treat analysis of "major vascular events"
(MVE; defined as nonfatal MI or cardiac death, stroke, or any revascularization procedure) in only those
patients initially randomized to the Ezechol combined with simvastatin (n=4193) or placebo (n=4191) groups.
Secondary analyses included the same composite analyzed for the full cohort randomized (at study baseline or
at year 1) to Ezechol combined with simvastatin (n=4650) or placebo (n=4620) as well as the components of
this composite.
The primary endpoint analysis showed that Ezechol combined with simvastatin significantly reduced the risk of
major vascular events (749 patients with events in the placebo group vs. 639 in the Ezechol combined with
simvastatin group) with a relative risk reduction of 16 % (p=0.001).
Nevertheless, this study design did not allow for a separate contribution of the monocomponent ezetimibe to
efficacy to significantly reduce the risk of major vascular events in patients with CKD.
The individual components of MVE in all randomized patients are presented in Table 1. Ezechol combined with
simvastatin significantly reduced the risk of stroke and any revascularization, with non-significant numerical
differences favouring Ezechol combined with simvastatin for nonfatal MI and cardiac death.
Table 1
Major Vascular Events by Treatment Group in all randomized patients in SHARPa

Compared to placebo, ezetimibe/simvastatin 10/40 mg did not significantly reduce the risk of MCE. The
primary outcome occurred in 333 patients (35.3%) in the ezetimibe / simvastatin group and in 355 patients
(38.2%) in the placebo group (hazard ratio in the ezetimibe / simvastatin group, 0.96; 95% confidence
interval, 0.83 to 1.12; p = 0.59). Aortic valve replacement was performed in 267 patients (28.3%) in the
ezetimibe / simvastatin group and in 278 patients (29.9%) in the placebo group (hazard ratio, 1.00; 95% CI,
0.84 to 1.18; p = 0.97). Fewer patients had ischemic cardiovascular events in the ezetimibe / simvastatin
group (n=148) than in the placebo group (n=187) (hazard ratio, 0.78; 95% CI, 0.63 to 0.97; p = 0.02), mainly
because of the smaller number of patients who underwent coronary artery bypass grafting.
Cancer occurred more frequently in the ezetimibe / simvastatin group (105 versus 70, p = 0.01). The clinical
relevance of this observation is uncertain as in the bigger SHARP trial the total number of patients with any
incident cancer (438 in the ezetimibe/ simvastatin versus 439 placebo group) did not differ and therefore the
finding of the SEAS trial could not be confirmed by SHARP.
 

Absorption: After oral administration, ezetimibe is rapidly absorbed and extensively conjugated to a
pharmacologically active phenolic glucuronide (ezetimibe glucuronide). Mean maximum plasma concentrations
(Cmax) occur within 1 to 2 hours for ezetimibe-glucuronide and 4 to 12 hours for ezetimibe. The absolute
bioavailability of ezetimibe cannot be determined as the compound is virtually insoluble in aqueous media
suitable for injection.
Concomitant food administration (high fat or non-fat meals) had no effect on the oral bioavailability of
ezetimibe when administered as Ezechol 10-mg tablets. Ezechol can be administered with or without food.
Distribution: Ezetimibe and ezetimibe-glucuronide are bound 99.7% and 88 to 92% to human plasma
proteins, respectively.
Biotransformation: Ezetimibe is metabolised primarily in the small intestine and liver via glucuronide
conjugation (a phase II reaction) with subsequent biliary excretion. Minimal oxidative metabolism (a phase I
reaction) has been observed in all species evaluated. Ezetimibe and ezetimibe-glucuronide are the major drugderived compounds detected in plasma, constituting approximately 10 to 20 % and 80 to 90 % of the total
drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are slowly eliminated from plasma with
evidence of significant enterohepatic recycling. The half-life for ezetimibe and ezetimibe-glucuronide is
approximately 22 hours.
Elimination: Following oral administration of 14 C-ezetimibe (20 mg) to human subjects, total ezetimibe
accounted for approximately 93% of the total radioactivity in plasma. Approximately 78% and 11% of the
administered radioactivity were recovered in the faeces and urine, respectively, over a 10-day collection period.
After 48 hours, there were no detectable levels of radioactivity in the plasma.
Special populations:
Paediatric patients
The pharmacokinetics of ezetimibe are similar between children ≥6 years and adults. Pharmacokinetic data in
the paediatric population <6 years of age are not available. Clinical experience in paediatric and adolescent
patients includes patients with HoFH, HeFH, or sitosterolaemia.
Geriatric patients
Plasma concentrations for total ezetimibe are about 2-fold higher in the elderly (≥65 years) than in the young
(18 to 45 years). LDL-C reduction and safety profile are comparable between elderly and young subjects
treated with Ezechol. Therefore, no dosage adjustment is necessary in the elderly.
Hepatic insufficiency
After a single 10-mg dose of ezetimibe, the mean AUC for total ezetimibe was increased approximately 1.7-fold
in patients with mild hepatic insufficiency (Child Pugh score 5 or 6), compared to healthy subjects. In a 14-day,
multiple-dose study (10 mg daily) in patients with moderate hepatic insufficiency (Child Pugh score 7 to 9), the
mean AUC for total ezetimibe was increased approximately 4-fold on Day 1 and Day 14 compared to healthy
subjects. No dosage adjustment is necessary for patients with mild hepatic insufficiency. Due to the unknown
effects of the increased exposure to ezetimibe in patients with moderate or severe (Child Pugh score >9)
hepatic insufficiency, Ezechol is not recommended in these patients (see section 4.4).
Renal insufficiency
After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl ≤30
ml/min/1.73m2), the mean AUC for total ezetimibe was increased approximately 1.5-fold, compared to healthy
subjects (n=9). This result is not considered clinically significant. No dosage adjustment is necessary for renal
impaired patients.
An additional patient in this study (post-renal transplant and receiving multiple medications, including
ciclosporin) had a 12-fold greater exposure to total ezetimibe.
Gender
Plasma concentrations for total ezetimibe are slightly higher (approximately 20%) in women than in men. LDLC reduction and safety profile are comparable between men and women treated with Ezechol. Therefore, no
dosage adjustment is necessary on the basis of gender.
 

Animal studies on the chronic toxicity of ezetimibe identified no target organs for toxic effects. In dogs treated
for four weeks with ezetimibe (≥0.03 mg/kg/day) the cholesterol concentration in the cystic bile was increased
by a factor of 2.5 to 3.5. However, in a one-year study on dogs given doses of up to 300 mg/kg/day no
increased incidence of cholelithiasis or other hepatobiliary effects were observed. The significance of these
data for humans is not known. A lithogenic risk associated with the therapeutic use of Ezechol cannot be ruled
out.
In co-administration studies with ezetimibe and statins the toxic effects observed were essentially those
typically associated with statins. Some of the toxic effects were more pronounced than observed during
treatment with statins alone. This is attributed to pharmacokinetic and pharmacodynamic interactions in coadministration therapy. No such interactions occurred in the clinical studies. Myopathies occurred in rats only
after exposure to doses that were several times higher than the human therapeutic dose (approximately 20
times the AUC level for statins and 500 to 2,000 times the AUC level for the active metabolites).
In a series of in vivo and in vitro assays ezetimibe, given alone or co-administered with statins, exhibited no
genotoxic potential. Long-term carcinogenicity tests on ezetimibe were negative.
Ezetimibe had no effect on the fertility of male or female rats, nor was it found to be teratogenic in rats or
rabbits, nor did it affect prenatal or postnatal development. Ezetimibe crossed the placental barrier in pregnant
rats and rabbits given multiple doses of 1,000 mg/kg/day. The co-administration of ezetimibe and statins was
not teratogenic in rats. In pregnant rabbits a small number of skeletal deformities (fused thoracic and caudal
vertebrae, reduced number of caudal vertebrae) were observed. The co-administration of ezetimibe with
lovastatin resulted in embryolethal effects.
 

Lactose monohydrate
Microcrystalline cellulose
Povidone
Croscarmellose sodium
Sodium lauryl sulfate
Magnesium stearate
 

Not applicable.
 

4 years

Store below 30°C.
Blisters: Store in the original package in order to protect from moisture.
 

Al/Al blister packs: 30 tablets
 

No special requirements.