- 1 what is LIPTRUZET medication used for and indication?
- 2 LIPTRUZET Dosage
- 3 Contraindications
- 4 How it works ?
- 5 LIPTRUZET Side Effects
- 6 LIPTRUZET Interactions
- 7 Drive and use machines
- 8 Warnings and Precautions
- 9 PREGNANCY & BREAST-FEEDING & FERTILITY
- 10 What happens if I overdose from LIPTRUZET ?
- 11 What is Forms and Composition ?
what is LIPTRUZET medication used for and indication?
Prevention of cardiovascular events
- LIPTRUZET is indicated to reduce the risk of cardiovascular events (see section 5.1) in patients with coronary artery disease with a history of acute coronary syndrome (ACS), whether or not previously treated with a statin.
LIPTRUZET is indicated as adjunct to diet in adult patients with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidemia when the use of a combination is appropriate:
- Patients not adequately controlled with a statin alone,
- Patients already receiving a statin and ezetimibe.
- Homozygous familial hypercholesterolaemia (HoFH)
- LIPTRUZET is indicated as adjunct to regimen in adult patients with HoFH. These patients may also receive adjuvant therapy (eg LDL apheresis).
Hypercholesterolemia and / or coronary artery disease (with a history of acute coronary syndrome)
- During the entire treatment with LIPTRUZET, the patient should follow an appropriate lipid-lowering regimen.
- The dosage of LIPTRUZET is 10/10 mg per day to 10/80 mg per day. The usual dose is 10/10 mg once a day. The level of low-density lipoprotein (LDL-C) cholesterol, risk factors for coronary artery disease, and the patient’s response to usual cholesterol-lowering therapy will be taken into account when initiating or adjusting therapy. Dosage.
- The dosage of LIPTRUZET should be individualized and take into account the known efficacy of the different strengths of LIPTRUZET (see section Pharmacodynamic properties, Table 4) as well as the response to current lipid-lowering treatment. Dosage adjustments, if necessary, should be made at intervals of 4 weeks or more.
Homozygous familial hypercholesterolaemia
- The dosage of LIPTRUZET in patients with homozygous HF is 10/10 mg to 10/80 mg per day. In these patients LIPTRUZET can be used as an adjunct to other cholesterol lowering therapy (eg LDL apheresis) or when these treatments are not available.
Co-administration with other drugs
- Administration of LIPTRUZET should be either ≥ 2 hours before or ≥ 4 hours after administration of a bile acid sequestrant.
- In patients taking the hepatitis C antiviral drugs elbasvir / grazoprevir concomitantly with LIPTRUZET, the dose of LIPTRUZET should not exceed 10 mg / 20 mg per day (see sections 4.4 and Interactions with other drugs and other forms of interactions).
No dosage adjustment is necessary in elderly patients.
- The safety and efficacy of LIPTRUZET in children have not been established . No data is available.
- LIPTRUZET should be used with caution in patients with hepatic impairment (Pharmacokinetic properties). LIPTRUZET is contraindicated in patients with active liver disease.
- No dose adjustment is necessary in patients with renal impairment .
- Oral route. LIPTRUZET can be given as a single dose at any time of the day, with or without food.
- Ezetimibe hypersensitivity
- Atorvastatin hypersensitivity
- Feeding with milk
- Active liver disease
- Prolonged and unexplained elevation of transaminases> 3 N
- Woman wishing to be pregnant
- Lack of effective female contraception
- Child under 6
- Muscle CPK> 5 N
- Child from 6 to 18 years old
- Moderate or severe hepatic impairment
- Lactose intolerance
Hypersensitivity to the active substances or to any of the excipients listed in the Composition section.
LIPTRUZET is contraindicated during pregnancy and lactation and in women of childbearing potential not using appropriate contraceptive methods (see section Fertility, pregnancy and lactation).
LIPTRUZET is contraindicated in patients with active liver disease or unexplained persistent elevations of serum transaminases greater than 3 times the upper limit of normal (ULN).
LIPTRUZET is contraindicated in patients treated with hepatitis C antivirals glecaprevir / pibrentasvir.
How it works ?
Pharmacotherapeutic group: HMG-CoA reductase inhibitor in
combination with other lipid-lowering drugs, ATC code: C10BA05
(ezetimibe / atorvastatin) is a lipid-lowering agent which
selectively inhibits the intestinal absorption of cholesterol and
related phytosterols and inhibits endogenous synthesis of cholesterol.
plasma cholesterol is derived from intestinal absorption and
endogenous synthesis. LIPTRUZET contains ezetimibe and
atorvastatin, two lipid-lowering drugs with
complementary mechanisms of action . LIPTRUZET lowers high total (C-total)
cholesterol, LDL-cholesterol, apolipoprotein B (Apo B), triglycerides
(TG) and non-low density lipoprotein (non-
HDL-C) cholesterol and increases cholesterol bound to high
density lipoproteins (HDL-C) by the dual inhibition of
cholesterol absorption and synthesis.
inhibits the absorption of cholesterol from the intestine. Ezetimibe is
orally active and has a mechanism of action that differs from that of
other classes of cholesterol lowering drugs (statins, ion exchange resins
, fibrates and plant sterols). The molecular target of
ezetimibe is the sterol transporter NPC1L1 (Niemann-Pick C1-Like 1), which is responsible for the intestinal absorption of cholesterol and phytosterols.
localizes to the brush border of the small intestine and
inhibits the absorption of cholesterol, resulting in a decrease in the
supply of intestinal cholesterol to the liver, while statins
decrease the synthesis of hepatic cholesterol. Thus, these two
molecules administered simultaneously lead, with
distinct mechanisms , to a complementary decrease in cholesterol. A
two-week clinical study in 18
hypercholesterolemic patients showed that ezetimibe inhibited the absorption of
intestinal cholesterol by 54% compared to placebo.
preclinical studies aimed at determining the selectivity of ezetimibe
for the inhibition of cholesterol absorption have been performed.
Ezetimibe inhibits the absorption of [14C] -cholesterol but
has no effect on the absorption of triglycerides, fatty
acids, bile acids, progesterone, ethinyl estradiol or
fat soluble vitamins A and D.
is a selective competitive inhibitor of HMG-CoA reductase, the
step-limiting enzyme responsible for the conversion of
3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a
precursor of sterols, of which cholesterol. In the liver,
triglycerides and cholesterol are incorporated into
very low density lipoproteins (VLDL) and released into plasma for
transport to peripheral tissues. Low
density lipoproteins (LDL) are formed from VLDL and catabolized
primarily through receptors with a
high affinity for LDL (LDL receptors).
decreases plasma cholesterol and serum
lipoprotein levels by inhibiting HMG-CoA reductase and hence
cholesterol biosynthesis in the liver, and increases the number of
LDL receptors on the surface of hepatocytes to enhance
uptake and LDL catabolism.
decreases LDL synthesis and LDL particle number. It
induces a significant and prolonged increase in the activity of
LDL receptors accompanied by an increase in the quality
of the LDL particles in circulation. Atorvastatin is effective in
reducing LDL-C in patients with
homozygous familial hypercholesterolaemia , a population that is difficult to control with
dose-response study showed that atorvastatin reduced the levels of
Total Cholesterol (CT) (from 30% to 46%), LDL-C (from
41% to 61%), apolipoprotein B (by 34%) % to 50%)
and triglycerides (from 14% to 33%) while inducing
variable increases in HDL-C and apolipoprotein A1. These
results are also observed in patients with
heterozygous familial hypercholesterolemia, non-familial forms
of hypercholesterolemia or mixed dyslipidemia, including
patients with non-insulin-dependent diabetes.
Clinical efficacy and safety
controlled clinical studies, LIPTRUZET caused
significant reductions in CT, LDL-C, Apo B, and TG levels and increased HDL-C
in patients with hypercholesterolemia.
placebo- controlled study, 628 patients with dyslipidemia were
randomized to receive placebo, ezetimibe (10 mg),
atorvastatin (10 mg, 20 mg, 40 mg or 80 mg) or
a combination of ezetimibe and atorvastatin equivalent to LIPTRUZET
(10 / 10 mg, 10/20 mg, 10/40 mg and 10/80 mg) for
up to 12 weeks.
patients receiving any dose of LIPTRUZET were compared with those
receiving any dose of atorvastatin. LIPTRUZET induced
significantly greater decreases in CT, LDL-C, ApoB, TG
and non-HDL-C and a significantly greater increase
in HDL-C than atorvastatin monotherapy.
Response to LIPTRUZET in patients with primary dyslipidemia
(Average changea in% at week 12 from baseline before treatmentb)
a For triglycerides, median% change from baseline.
b Initial value, without lipid-lowering treatment.
LIPTRUZET (all doses combined, 10 mg / 10 mg to
10 mg / 80 mg) produced a significant reduction in CT,
LDL-C, Apo B, TG and non-HDL-C and an
increase in significant HDL-C relative to atorvastatin
(all doses combined, 10 to 80 mg).
In a controlled study, the TEMPO study (Titration of Atorvastatin Versus Ezetimibe Add-On to Atorvastatin in Patients with Hypercholesterolaemia),
184 patients with an LDL-C level ≥ 2.6 mmol / L and
≤ 4.1 mmol / L and moderate to high risk of coronary
heart disease received atorvastatin 20 mg for a
minimum of 4 weeks prior to randomization. Patients who
did not achieve LDL-C <2.6 mmol / L were
randomized to receive a combination of ezetimibe and atorvastatin
(equivalent to LIPTRUZET 10/20 mg) or atorvastatin 40 mg
for 6 weeks.
10/20 mg was significantly more effective than doubling
the dose of atorvastatin 40 mg in inducing further reductions
in total cholesterol (-20% versus -7%), LDL-C (-31% versus – 11%), Apo B (‑21% versus ‑8%) and non-HDL-C (‑27% versus ‑10%).
For HDL-C and TG, the results were not significantly
different between the two treatment groups. Likewise, the number of
patients with an LDL-C level <2.6 mmol / L was
significantly higher in the group receiving LIPTRUZET
10/20 mg than in that receiving atorvastatin 40 mg
(84% versus 49 %).
In a controlled study, the EZ-PATH study (Ezetimibe Plus Atorvastatin Versus Atorvastatin Titration in Achieving Lower LDL-C Targets in Hypercholesterolaemic Patients),
556 patients at high cardiovascular risk with an
LDL-C level ≥ 1.8 mmol / L and ≤ 4.1 mmol / L received
atorvastatin 40 mg for a minimum of
4 weeks prior to randomization. Patients who did not
achieve LDL-C <1.8 mmol / L were randomized
to receive a combination of ezetimibe and atorvastatin
(equivalent to LIPTRUZET 10/40 mg) or atorvastatin 80 mg
for 6 weeks.
LIPTRUZET 10/40 mg was
significantly more effective than doubling the dose
of atorvastatin to 80 mg in inducing further reductions
in total cholesterol (‑17% versus ‑7%), LDL-C (‑27% versus – 11%), Apo B (‑18% versus ‑8%), TG (‑12% versus ‑6%) and non-HDL-C (‑23% versus ‑9%).
HDL-C, the results were not significantly different
between the two treatment groups. Similarly, the number of patients
with an LDL-C level <1.8 mmol / L was
significantly higher in the group receiving LIPTRUZET
10/40 mg than in that receiving atorvastatin 80 mg
(74% versus 32 %).
an 8-week controlled study, 308 patients with
hypercholesterolemia treated with atorvastatin who did
not meet the National Cholesterol Education Program
(NCEP) LDL-C target (value-based LDL-C target) initial LDL-C and
coronary risk status) were randomized to receive
ezetimibe 10 mg or placebo in addition to their
current atorvastatin treatment .
patients who did not have the LDL-C target level at baseline
(~ 83%), the number of patients who achieved their
LDL-C target was significantly higher in patients receiving
ezetimibe in combination with atorvastatin than in those who
received placebo in combination with atorvastatin (67% versus
19%) Ezetimibe combined with atorvastatin induced a
significantly greater decrease in LDL-C than
combined placebo at atorvastatin (25% versus 4%) Ezetimibe
combined with atorvastatin also significantly reduced the
levels of CT, Apo B and TG compared to placebo combined with
12-week, phase II controlled study , 1,539
high cardiovascular risk patients with LDL-C levels between 2.6
and 4.1 mmol / L treated with atorvastatin 10 mg daily were
randomized to receive: atorvastatin 20 mg,
rosuvastatin 10 mg or LIPTRUZET 10/10 mg. After
6 weeks of treatment (Period I), patients who
had not achieved LDL-C <2.6 mmol / L with
atorvastatin 20 mg switched to atorvastatin
40 mg or LIPTRUZET 10 / 20 mg for 6 weeks
(period II) and patients receiving rosuvastatin 10 mg
during period I switched to
rosuvastatin 20 mg or LIPTRUZET 10/20 mg. The
LDL-C reductions and comparisons between the LIPTRUZET group and
other treatment groups are shown in Table 5.
to LIPTRUZET * in high-risk patients with baseline LDL-C
between 2.6 and 4.1 mmol / L on
atorvastatin 10 mg per day
* Combination of ezetimibe and atorvastatin equivalent to LIPTRUZET
10/10 mg or LIPTRUZET 10/20 mg.
† M-estimates (based on Huber method), 95% CI and p-value were determined by fitting a robust regression model with terms for treatment and baseline.
Percent changes in geometric mean TG levels from baseline
were calculated based on
exponentiation backtransformation of the model least squares
(LS) means and expressed as (geometric mean
– 1) multiplied by 100.
§ p <0.001 versus LIPTRUZET 10/10
¶ p <0.01 versus LIPTRUZET 10/10
# p <0.05 versus LIPTRUZET 10/10
Þ p <0.001 versus LIPTRUZET 10/20
ß p <0.05 versus LIPTRUZET 10/20
Table 5 contains no data comparing the effects of
LIPTRUZET 10/10 mg and 10/20 mg to doses greater than
40 mg or atorvastatin 20 mg of rosuvastatin.
In a placebo-controlled study, the MIRACL (Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering) study,
patients with acute coronary syndrome (MI without
Q wave or unstable angina) were randomized to receive
atorvastatin 80 mg / day (n = 1,538) or
placebo (n = 1.548). Treatment was started
during the acute phase after hospitalization and lasted
16 weeks. Atorvastatin 80 mg / day induced a
16% (p = 0.048) reduction in the risk of the
primary composite endpoint : death from any cause, non-fatal MI,
cardiac arrest with resuscitation or angina with signs of myocardial ischemia
requiring hospitalization.This result was mainly due to
a 26% reduction in readmissions for angina with
signs of myocardial ischemia (p = 0.018).
LIPTRUZET contains atorvastatin. In a placebo-controlled study, Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOTT-LLA),
the effect of atorvastatin 10 mg on
fatal and non-fatal coronary events was evaluated in 10,305
hypertensive patients. aged 40 to 80 years with a CT level
≤ 6.5 mmol / L and at least three
cardiovascular risk factors . Patients were followed for a median
of 3.3 years. Atorvastatin 10 mg significantly (p <0.001) reduced
the relative risk of: fatal coronary events plus non-
fatal MI by 36% (absolute risk reduction: 1.1%),
total cardiovascular events and revascularization procedures
20% (absolute risk reduction: 1.9%) and
total coronary events by 29% (
absolute risk reduction : 1.4%).
In a placebo-controlled study, the Collaborative Atorvastatin Diabetes Study (CARDS),
the effect of atorvastatin 10 mg on
cardiovascular events was evaluated in 2,838 patients aged 40
to 75 years with type 2 diabetes mellitus or more
cardiovascular risk factors and LDL-C ≤ 4.1 mmol / L
and TG ≤ 6.8 mmol / L. Patients were followed for
a median of 3.9 years.
Atorvastatin 10 mg significantly reduced (P <0.05):
the rate of major cardiovascular events by 37% (
absolute risk reduction : 3.2%), the risk of
stroke by 48% (reduction in the absolute risk: 1.3%) and
the risk of myocardial infarction by 42% (
absolute risk reduction : 1.9%).
Prevention of cardiovascular events
In a multicenter, randomized, double-blind,
active comparator study evaluating the ezetimibe / simvastatin combination,
18,144 patients were included within 10 days of
hospitalization for acute coronary syndrome (ACS;
acute myocardial infarction or angina pectoris). unstable). All patients were randomized
1: 1 to receive either
ezetimibe / simvastatin 10 mg / 40 mg (n = 9.067)
or simvastatin 40 mg (n = 9.077) and were followed for a median of 6.0
patients had a mean age of 63.6 years; 76% were
men, 84% were of Caucasian descent, and 27% were
diabetic. The mean LDL-C value at the time of the event
qualifying for entry into the study was 80 mg / dL (2.1 mmol / L)
for those already on lipid-lowering treatment
(n = 6,390) and 101 mg / dL (2.6 mmol / L) for
those without previous lipid-lowering treatment
(n = 11,594). Before hospitalization for ACS,
qualifying for inclusion in the study, 34% of patients were
on statin therapy. After one year, the mean LDL-C of patients
still on treatment was 53.2 mg / dL (1.4 mmol / L) in the
ezetimibe / simvastatin group and 69.9 mg / dL (1.8 mmol / L) in
the simvastatin monotherapy group.
primary endpoint was a composite endpoint comprising
cardiovascular death, major coronary event (defined
as non-fatal myocardial infarction, documented unstable angina
requiring hospitalization, or
coronary revascularization intervention occurring at least 30 days later. randomization
of treatment groups) and non-fatal stroke. The study demonstrated that
treatment with ezetimibe added to simvastatin provides
additional benefit by reducing the primary composite endpoint comprising
cardiovascular death, major coronary event and
non-fatal stroke, compared to treatment with simvastatin alone
(6.4% relative risk reduction, p = 0.016). The
primary endpoint occurred in 2,572 of
9,067 patients (Kaplan-Meier [KM] 7-year survival rate
32.72%) in the ezetimibe / simvastatin group and in 2,742
of 9,077 patients ( 7-year survival rate according to KM of
34.67%) in the simvastatin alone group (See Figure 1 and
Table 6). This additional benefit is expected to be similar with the
co-administration of ezetimibe and atorvastatin. Total mortality
remained unchanged in this high risk group.
An overall benefit was observed for all strokes; however, there was a small non-significant increase in hemorrhagic stroke in the ezetimibe / simvastatin group compared to the simvastatin alone group .
The risk of hemorrhagic stroke whenezetimibe is co-administered with more potent statins has not been evaluated in long-term studies.
The effect of treatment with ezetimibe / simvastatin was generally consistent with the overall results collected in many subgroups, including sex, age, ethnicity, history of diabetes, baseline lipid levels, treatment previous statin, history of stroke, and hypertension.
1: Effect of ezetimibe / simvastatin on the primary composite endpoint including cardiovascular death, major coronary event or non-fatal stroke.
Major Cardiovascular Events by Treatment Group in All Randomized IMPROVE-IT Patients
* 6% received higher doses of ezetimibe / simvastatin
- † 27% received higher doses of simvastatin 80 mg.
- ‡ Kaplan-Meier 7-year survival rate.
Homozygous familial hypercholesterolaemia (HoFH)
- A randomized, double-blind, 12-week study was performed in patients with homozygous HFHo familial hypercholesterolaemia (clinical and / or genotypic diagnosis).
- The results were analyzed from a subgroup of patients (n = 36) receiving 40 mg of atorvastatin as a starting dose.
- Increasing the dose of atorvastatin from 40 to 80 mg (n = 12) resulted in a reduction in LDL-cholesterol by
2% from baseline with 40 mg atorvastatin. The combination of ezetimibe and atorvastatin equivalent to LIPTRUZET (doses of 10/40 mg and 10/80 mg combined, n = 24) resulted in a reduction in
LDL-cholesterol 19% from baseline with atorvastatin 40 mg. In these patients, the combination of ezetimibe and atorvastatin equivalent doses LIPTRUZET ( 10/80 mg, n = 12) resulted in a reduction of
LDL cholesterol by 25% compared to the initial value with the atorvastatin 40 mg.
- After completing the 12-week study, eligible patients (n = 35) who received atorvastatin 40 mg at inclusion were assigned to receive the combination of ezetimibe and atorvastatin equivalent to LIPTRUZET 10 / 40 mg for an additional 24 months. After at least 4 weeks of treatment, the dose of atorvastatin could be doubled to a maximum dose of 80 mg. At the end of 24 months, LIPTRUZET (doses of 10/40 mg and 10/80 mg combined) had induced a decrease in LDL-C consistent with that observed in the 12 week study .
- The European Medicines Agency has granted an exemption from the obligation to submit the results of studies with LIPTRUZET in all subgroups of the pediatric population in the indication of hypercholesterolemia and mixed dyslipidemia (see section Dosage and method of administration for information on pediatric use).
LIPTRUZET Side Effects
- Allergic rash
- Allergic urticaria
- Decreased appetite
- Sleep disorder
- Peripheral neuropathy
- Blurred vision
- Visual disturbances
- Hearing loss
- Sinus bradycardia
- Laryngopharyngeal pain
- Abdominal discomfort
- Abdominal pain
- Lower abdominal pain
- Upper abdominal pain
- Heavy stools
- Gastric discomfort
- Gastroesophageal reflux
- Dry mouth
- Hepatic insufficiency
- Acute fatal hepatic failure
- Skin rash
- Skin pruritus
- Erythema multiforme
- Bullous dermatosis
- Stevens-Johnson syndrome
- Toxic epidermal necrolysis
- Back pain
- Muscle fatigue
- Muscle spasm
- Muscular weakness
- Pain in extremity
- Muscle breakdown
- Tendon rupture
- Neck pain
- Joint swelling
- Lupus-like syndrome
- Immune-mediated necrotizing myopathy
- Chest pain
- Rebellious bread
- Peripheral edema
- ALAT increased
- ASAT increased
- Alkaline phosphatase increased
- Increase in CPK
- Increased GT gamma
- Increased liver enzymes
- Abnormal liver function tests
- Weight gain
- Sexual dysfunction
- Interstitial lung disease
- Type 2 diabetes
Summary of the safety profile
The safety of LIPTRUZET (or the combination of ezetimibe and atorvastatin equivalent to LIPTRUZET) has been evaluated in over 2,400 patients in 7 clinical studies.
Table of adverse reactions
Adverse reactions observed during clinical studies of LIPTRUZET (or when ezetimibe and atorvastatin equivalent to LIPTRUZET were co-administered) or ezetimibe or atorvastatin or which have been reported since the marketing of LIPTRUZET or Ezetimibe or atorvastatin are listed in Table 3. These adverse reactions are listed by system organ class and frequency. Frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100, <1/10), uncommon (≥ 1/1000, <1/100), rare (≥ 1/10 000, <1/1000); very rare (<1 / 10,000) and not known (cannot be estimated from the available data) Table 3In controlled clinical studies, clinically significant increases in serum transaminases (ALT and / or AST ≥ 3 x ULN, consecutive) were 0.6% for patients treated with LIPTRUZET. These increases are generally asymptomatic, not associated with cholestasis and the values return to their initial value spontaneously or after discontinuation of treatment .
The following adverse events have been reported with some statins:
– exceptional cases of interstitial lung disease, in particular during long-term treatment (see section Warnings and precautions for use);
Type II diabetes: the frequency depends on the presence or absence of risk factors (fasting blood sugar ≥ 5.6 mmol / L, BMI> 30 kg / m2, hypertriglyceridemia, history of high blood pressure).
Many mechanisms may contribute to potential interactions with HMG-CoA reductase inhibitors. Drugs or herbal products that inhibit certain enzymes (eg, CYP3A4) and / or transporters (eg, OATP1B) may increase
atorvastatin plasma concentrations and lead to an increased risk of myopathy / rhabdomyolysis.
Consult the prescribing information of all other co-administered medicinal products for more information on their potential interactions with atorvastatin and / or potential enzyme or transporter changes as well as possible adjustments to dosage and regimen. .
- Atorvastatin is metabolized by cytochrome P450 3A4 (CYP3A4) and is a substrate
of hepatic transporters,
organic anion transporting polypeptides 1B1 (OATP1B1) and 1B3 (OATP1B3).
Atorvastatin metabolites are substrates of OATP1B1. Atorvastatin is
also identified as a substrate of
multidrug resistance protein (MDR1) and
breast cancer resistance protein (BCRP), which may limit the intestinal absorption
and bile clearance of atorvastatin. (see section Pharmacokinetic properties).
Concomitant administration ofatorvastatin and lead to an increased risk of myopathy. The risk
may also be increased when
LIPTRUZET is co-administered with other medicinal products which may induce
myopathies such as fibrates and ezetimibe .
- No clinically significant pharmacokinetic interaction was
observed with the concomitant administration of ezetimibe and
Effects of Other Medicines on LIPTRUZET
- l’administration simultanée d’antiacides diminue le taux d’absorption
d’ézétimibe mais n’a aucun effet sur la biodisponibilité d’ézétimibe.
Cette diminution du taux d’absorption d’ézétimibe n’est pas considérée
comme cliniquement significative.
- l’administration simultanée de cholestyramine diminue d’environ
55 % l’aire sous la courbe (ASC) moyenne de l’ézétimibe total
(ézétimibe + glycuronide d’ézétimibe). La diminution supplémentaire du
LDL-Cholestérol observée liée à l’association LIPTRUZET et
cholestyramine pourrait être réduite par cette interaction (voir
rubrique Posologie et mode d’administration).
- une étude réalisée chez 8 patients transplantés rénaux ayant une
clairance de la créatinine > 50 mL/min, recevant une dose
stable de ciclosporine et une dose unique de 10 mg d’ézétimibe a
montré une augmentation de l’ASC moyenne de l’ézétimibe total de
3,4 fois (2,3 à 7,9 fois) par rapport à des volontaires sains
d’une autre étude (n = 17) recevant de l’ézétimibe seul. Une autre
étude a montré que, chez un patient transplanté rénal ayant une
insuffisance rénale sévère et recevant de la ciclosporine et de
nombreux médicaments, l’exposition totale à l’ézétimibe était 12 fois
supérieure à celle des témoins recevant de l’ézétimibe seul. Dans une
two-period cross-over study in twelve healthy subjects,
administration of 20 mg ezetimibe
daily for 8 days with a single dose of 100 mg ciclosporin on
day 7 resulted in an average increase of 15%
Ciclosporin AUC (varying from 10% decrease to
51% increase) compared to
single dose ciclosporin alone. No controlled studies of the effect of
ezetimibe / ciclosporin have been performed in
kidney transplant patients.
- The caution is required when establishing a LIPTRUZET during
treatment with cyclosporine. Cyclosporin concentrations
should be monitored in patients receiving LIPTRUZET in
combination with ciclosporin (see section 4.4).
- Simultaneous administration of fenofibrate or gemfibrozil increases
total ezetimibe concentrations by approximately 1.5 and 1.7 times, respectively ;
Although these increases are not considered clinically
significant, the combination of LIPTRUZET with fibrates is
not recommended .
- Atorvastatin plasma concentrations are significantly increased
when combined with strong
CYP3A4 inhibitors (see Table 1 and specific information
below). The combination of strong inhibitors of CYP3A4 (such as
cyclosporine, telithromycin, clarithromycin, delavirdine,
stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole,
certain antivirals used in the treatment of HCV (eg
elbasvir / grazoprevir) and inhibitors of HIV protease including
ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.) should be
avoided if possible. In cases where the combination of these
drugs with LIPTRUZET are necessary, a
lower starting dose and a lower maximum dose of LIPTRUZET should be
considered and appropriate clinical monitoring of the patient is
- The moderate CYP3A4 inhibitors (e.g. erythromycin, diltiazem,
verapamil and fluconazole) can increase the concentrations
plasma atorvastatin (see Table 1). An increased risk of
myopathy has been observed when erythromycin is combined with
statins. Interaction studies evaluating the
effects of amiodarone or verapamil on atorvastatin have not been performed .
Amiodarone and verapamil are known inhibitors of CYP3A4 and
combination with LIPTRUZET may increase
atorvastatin exposure . Therefore, a lower maximum dose of
LIPTRUZET should be considered and clinical monitoring of the patient.
is recommended when administered concomitantly with
moderate CYP3A4 inhibitors. Appropriate clinical monitoring is
recommended after initiation or dose adjustment of
Breast Cancer Resistance Protein Inhibitors (BCRP):
- Concomitant use of drugs that inhibit BCRP (such as elbasvir
and grazoprevir) may lead to increased
plasma concentrations of atorvastatin and an increased risk of myopathy; by
Therefore, a dosage adjustment of atorvastatin should be
considered according to the prescribed dose.
Co- administration of elbasvir and grazoprevir with atorvastatin increases
plasma concentrations of atorvastatin by 1.9-fold (see
Table 1); therefore, the dose of LIPTRUZET should not
exceed 10 mg / 20 mg per day in patients receiving
concomitantly with medicinal products containing elbasvir or
Cytochrome P450 3A4 inducers :
- Concomitant administration of atorvastatin with inducers of
cytochrome P450 3A4 (eg efavirenz, rifampicin, St. John’s wort)
may result in varying decreases
in atorvastatin plasma concentrations . Due to the dual mechanism of interaction
of rifampicin (induction of cytochrome P450 3A4 and inhibition of the
hepatic impulse transporter OATP1B1), simultaneous administration
of LIPTRUZET and rifampicin is recommended, as the administration
of atorvastatin is delayed in time with that of rifampicin
was associated with a significant reduction in
plasma concentrations of atorvastatin. The
However, hepatocyte concentrations of atorvastatin are not known
and if the combination cannot be avoided, the efficacy of treatment
should be closely monitored.
Transporter inhibitors :
- Inhibitors of protein transporters (such as ciclosporin)
may increase systemic exposure to atorvastatin (see
Table 1). The effect of inhibition of
hepatocyte transporters on hepatocyte concentrations of atorvastatin
is unknown. If the combination is necessary, the dose of LIPTRUZET
should be reduced and the efficacy of the treatment should be monitored
(see Table 1).
Gemfibrozil / fibrates:
- Treatment with fibrates alone may occasionally cause
muscle adverse events, including rhabdomyolysis. The
risk of these events may be increased with the combination of
fibrates and atorvastatin.
- The use of ezetimibe as monotherapy is associated with
muscle side effects including rhabdomyolysis. The risk of these
side effects may therefore be increased with the combination
of ezetimibe and atorvastatin. Appropriate clinical monitoring of
these patients is recommended.
- Plasma concentrations of atorvastatin and its
active metabolite are reduced (by approximately 25%) when
colestipol and atorvastatin are administered concomitantly. However, the
lipid lowering effects are greater when atorvastatin and
colestipol are administered in combination than when each
drug is administered alone.
- The risk of myopathy, including rhabdomyolysis, may be increased
by the co-administration of systemic fusidic acid and a statin. This
mechanism of interaction (whether pharmacodynamic,
pharmacokinetic or both) is still unknown. Cases of
rhabdomyolysis (some fatal) have been reported in
patients taking this combination.
- If systemic treatment with fusidic acid is required,
treatment with atorvastatin should be discontinued for the duration of
treatment with fusidic acid (see also section 4.4).
- Although no interaction studies between
atorvastatin and colchicine have been performed, cases of myopathy have been
reported with co-administration of atorvastatin and
colchicine and caution should be exercised. imposed when prescribing
atorvastatin with colchicine.
- The risk of myopathy and / or rhabdomyolysis may be increased when HMG-CoA reductase inhibitors are co-administered with daptomycin. Temporary discontinuation of LIPTRUZET should be considered in patients treated with daptomycin unless the benefits of concomitant administration outweigh the risks .
- Atorvastatin exposure is increased when administered with boceprevir. If the combination with LIPTRUZET is necessary, it is recommended to initiate treatment with LIPTRUZET at the
lowest possible dose and then increase the dose under
close monitoring until the desired clinical effect is achieved,
without exceed a daily dose of 10/20 mg. In patients
already receiving LIPTRUZET, the daily dose of LIPTRUZET should not
exceed 10/20 mg during concomitant treatment with
Effects of LIPTRUZET on the Pharmacokinetics of Other Drugs
- Of Preclinical studies have shown that ezetimibe does not induce the enzyme
cytochrome P450 drug metabolism. No
clinically significant pharmacokinetic interaction has been
observed between ezetimibe and drugs known to be
metabolized by cytochromes P450 1A2, 2D6, 2C8, 2C9, and 3A4 or
- In a study in 12 healthy male volunteers,
concomitant administration of ezetimibe (10 mg once
daily) had no significant effect on the bioavailability of
warfarin and on the prothrombin time.
- However, since
marketing, an increase in INR has been reported in
patients taking ezetimibe in combination with warfarin or
fluindione. If LIPTRUZET is combined with warfarin or another
coumarin-derived anticoagulant (AVK), or with fluindione, the INR
should be monitored appropriately.
- Following the concomitant administration of repeated doses of digoxin and
atorvastatin 10 mg, the steady state concentrations of
digoxin are slightly increased. Appropriate monitoring is
necessary in patients treated with digoxin.
- Concomitant administration of atorvastatin with oral contraceptives
increased plasma concentrations of norethisterone and
- In a clinical study in patients receiving
long-term treatment with warfarin, concomitant administration
of atorvastatin 80 mg daily with warfarin resulted in a
small decrease in prothrombin time of approximately 1.7 seconds. during
the first 4 days of treatment; the value
normalized within 15 days of starting
atorvastatin treatment .
- Although only very rare cases of clinically significant interactions with anticoagulants have been
reported, prothrombin time should be determined before initiating treatment with LIPTRUZET in patients receiving coumarin anticoagulants, and quite frequently at the start of
treatment to verify the absence of any significant change in its
value. Once the stability of prothrombin time has been documented,
checks can be performed at the intervals recommended
usually for patients on coumarin anticoagulants. The
same procedure should be followed if the dose of LIPTRUZET is changed or treatment is discontinued.
- Atorvastatin treatment has not been associated with bleeding or changes
in prothrombin time in patients not receiving anticoagulants.
Drive and use machines
Liptruzet has no or negligible influence on the ability to drive and use machines. However, when driving vehicles or using machines, it should be taken into account that dizziness has been reported.
Warnings and Precautions
- Predisposing factor to the occurrence of rhabdomyolysis
- CPK monitoring
- Renal failure
- History of myopathy
- History of muscle toxicity with a statin or fibrate
- History of hepatopathy
- History of excessive alcohol consumption
- Subject over 70 years old
- Increase in CPK
- Unexplained muscle symptoms
- Liver function monitoring
- Transaminases> 3 ULN
- Alcohol consumption
- History of liver damage
- History of hemorrhagic stroke
- History of transient ischemic attack
- History of lacunar infarction
- Interstitial lung disease
- Risk of diabetes
- Mild hepatic impairment
- Woman of childbearing age
Myopathy / Rhabdomyolysis
- Since the marketing of ezetimibe, cases of myopathy and rhabdomyolysis have been reported. Most of the patients who experienced rhabdomyolysis were also taking a statin in combination with ezetimibe. However, cases of rhabdomyolysis have been very rarely reported with ezetimibe as monotherapy, or when ezetimibe has been combined with other drugs known to be linked to an increased risk of rhabdomyolysis.
- LIPTRUZET contains atorvastatin. Like other HMG-CoA reductase inhibitors, atorvastatin may in rare cases cause skeletal muscle damage and cause myalgia, myositis and myopathy which may progress to rhabdomyolysis, a potentially life-threatening condition characterized by by a high level of creatine phosphokinase (CPK) (> 10 x ULN), myoglobinemia and myoglobinuria which may lead to renal failure.
LIPTRUZET should be prescribed with caution in patients with risk factors for rhabdomyolysis. CPK testing should be done before starting treatment in the following cases:
· renal failure,
Personal or family history of hereditary myopathy,
History of muscle toxicity during treatment with a statin or a fibrate,
History of liver disease and / or excessive alcohol consumption,
In elderly patients (> 70 years), the need for CPK testing should be considered based on the presence of other risk factors for rhabdomyolysis,
- situations in which plasma concentrations may be increased, for example due to interactions (see section Interaction with other medicinal products and other forms of interactions) and in special populations including genetic polymorphisms (see section Pharmacokinetic properties).
- In such situations, the risk of treatment should be weighed against the potential benefit and clinical monitoring is recommended.
- If the basal CPK value is significantly elevated (˃ 5 x ULN), treatment should not be initiated.
Determination of creatine phosphokinase
- Creatine phosphokinase (CPK) should not be assayed after intense exercise or in the presence of any other possible cause of increased CPK as this will make interpretation of the results difficult. If the basal CPK level is significantly elevated compared to normal (x 5 x ULN), it should be checked again 5-7 days later to confirm the results.
- Patients should be encouraged to report any muscle pain, cramps or weakness without delay, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after stopping LIPTRUZET.
- If these symptoms occur in a patient during treatment with LIPTRUZET, CPK testing should be performed. If the level is significantly high (> 5 x ULN), the treatment should be stopped.
- If muscle symptoms are severe and cause daily discomfort, discontinuation of treatment should be considered, even if the CPK level is ≤ 5 x ULN.
- If symptoms resolve and CPK levels return to normal, resumption of treatment with LIPTRUZET or another medicine containing a statin may be considered at the lower dose and under careful monitoring.
- – Treatment with LIPTRUZET should be stopped in the event of a clinically significant increase in the level of CPK (> 10 x ULN) or the diagnosis or suspicion of rhabdomyolysis.
- Very rare cases of autoimmune-mediated necrotizing myopathy (IMNM) have been reported during or after treatment with certain statins. Autoimmune-mediated necrotizing myopathy (IMNM) is clinically characterized by proximal muscle weakness and elevations in serum creatinine kinase, which persist despite discontinuation of statin therapy.
- Due to the atorvastatin contained in LIPTRUZET, the risk of rhabdomyolysis is increased when LIPTRUZET is given in combination with certain drugs which may increase the plasma concentration of atorvastatin, such as strong inhibitors of CYP3A4 or protein transporters (for example ciclosporin, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, tipranavir, etc.). The risk of myopathy may also be increased in combination with gemfibrozil and other fibrates antivirals used in the treatment of hepatitis C (HCV) (boceprevir, telaprevir, elbasvir / grazoprevir), erythromycin or niacin.
- If the combination of these drugs with LIPTRUZET is necessary, the risk / benefit ratio of concomitant treatment should be carefully assessed. In patients receiving drugs that increase the plasma concentration of atorvastatin, a lower maximum dose of LIPTRUZET is recommended. In addition, when using strong CYP3A4 inhibitors, a lower starting dose of LIPTRUZET should be considered and appropriate clinical monitoring of these patients is recommended (see section 4.5) .Interactions with other medicinal products and other forms of interaction. ).
- LIPTRUZET should not be administered simultaneously with fusidic acid in systemic form, and for up to 7 days after stopping treatment with fusidic acid. In patients where the use of systemic fusidic acid is considered essential, statin therapy should be discontinued for the duration of fusidic acid therapy. Cases of rhabdomyolysis (some fatal) have been reported in patients receiving fusidic acid and a statin in combination (see section Interactions with other medicinal products and other forms of interactions). Patients should be advised of the need to seek immediate medical attention if they experience symptoms of muscle weakness, pain or tenderness.
- Statin therapy can be restarted seven days after the last dose of fusidic acid.
- In exceptional circumstances, where prolonged treatment with systemic fusidic acid is necessary, e.g. for the treatment of serious infections, the need for co-administration of LIPTRUZET and fusidic acid should only be considered on a case-by-case basis. cases and under close medical supervision.
- Myopathy and / or rhabdomyolysis have been reported with concomitant administration of HMG-CoA reductase inhibitors (such as atorvastatin and ezetimibe / atorvastatin) with daptomycin. Caution is advised when prescribing HMG-CoA reductase inhibitors with daptomycin, as either drug may cause myopathy and / or rhabdomyolysis when taken alone. Temporary discontinuation of LIPTRUZET should be considered in patients treated with daptomycin unless the benefits of concomitant administration outweigh the risks. See the daptomycin prescribing information for more information about this potential interaction with DAP inhibitors.
- In clinical studies, elevations of serum transaminases (> 3 x ULN) have occurred repeatedly in patients receiving ezetimibe and atorvastatin .
- A liver test should be done before starting treatment and regularly thereafter. Liver function should be monitored in patients who develop signs or symptoms suggestive of liver damage. Patients with elevated transaminase levels should be monitored until abnormalities resolve. In the event of a persistent increase in transaminases> 3 x ULN, it is recommended to reduce the dose or to stop treatment with LIPTRUZET.
- LIPTRUZET should be used with caution in patients who consume large amounts of alcohol and / or have a history of liver damage.
- In patients with moderate or severe hepatic impairment, the effects of increased exposure to ezetimibe are not known, LIPTRUZET is not recommended .
- The efficacy and safety of ezetimibe administered with fibrates has not been established; therefore, the combination of LIPTRUZET with fibrates is not recommended (see section Interactions with other medicinal products and other forms of interactions).
- Caution should be taken when initiating LIPTRUZET during treatment with ciclosporin.
- The concentrations of ciclosporin should be monitored in patients receiving LIPTRUZET in combination with ciclosporin (see section Interactions with other medicinal products and other forms of interactions).
If LIPTRUZET is combined with warfarin, or another anti-vitamin K anticoagulant or fluindione, the level of prothrombin expressed in INR should be monitored appropriately (see section Interactions with other medicinal products and other forms of interactions. ).
SPARCL study (Stroke Prevention by Aggressive Reduction in Cholesterol Levels)
- In a post hoc analysis of stroke subtypes in non-coronary patients with a recent history of stroke or transient ischemic attack (TIA), the incidence of hemorrhagic stroke was higher in patients treated with atorvastatin 80 mg than in patients receiving placebo. The increased risk was observed in particular in patients who had a history of hemorrhagic stroke or lacunar infarction at the time of inclusion in the study.
- In these patients, the risk / benefit ratio of atorvastatin 80 mg is uncertain and the potential risk of haemorrhagic stroke should be carefully considered before initiating therapy (see section 5.1).
Interstitial lung disease
- Exceptional cases of interstitial lung disease have been reported with the use of certain statins, especially with long-term treatment (see section 4.8). Symptoms are characterized by dyspnea, non-productive cough, and deterioration in general health (fatigue, weight loss and fever). If interstitial lung disease is suspected in a patient, statin therapy should be discontinued.
- There is some evidence to suggest that statins, as a pharmacological class, increase blood sugar. In some patients at high risk of developing diabetes, statins may cause hyperglycaemia requiring the initiation of diabetes treatment. This risk is nevertheless compensated by the reduction in the vascular risk under statins and therefore, it should not be a reason for stopping statins. Patients at risk (fasting blood glucose between 5.6 and 6.9 mmol / L, BMI> 30 kg / m2, increased triglyceride levels, arterial hypertension) should be monitored clinically and biologically in accordance with national recommendations.
- LIPTRUZET contains lactose. Its use is not recommended in patients with galactose intolerance, Lapp lactase deficiency or glucose or galactose malabsorption syndrome (rare hereditary diseases).
PREGNANCY & BREAST-FEEDING & FERTILITY
Women of childbearing age
Women of childbearing potential should use appropriate contraceptive methods during treatment ( see Contraindications ).
- Atherosclerosis is a chronic disease and in general, stopping lipid-lowering drugs during pregnancy is expected to have little impact on the long-term risk associated with primary hypercholesterolemia.
- Liptruzet is contraindicated during pregnancy ( see Contraindications ). No clinical data are available from the use of Liptruzet during pregnancy.
- Liptruzet should not be used during pregnancy or in a woman planning to become pregnant or in whom pregnancy is suspected. Treatment with Liptruzet should be suspended during pregnancy or until it has been established that the woman is not pregnant ( see Contraindications ).
- Co-administration of ezetimibe and atorvastatin in pregnant rats showed a drug-related increase in the skeletal defect “decreased ossification of sternebrae” in the high-dose ezetimibe / atorvastatin group. This may be related to the observed decrease in fetal weight. In pregnant rabbits, a low incidence of skeletal malformations (fused sternebrae, fused caudal vertebrae, and asymmetric modification of the sternebrae) was observed.
- Safety has not been established in pregnant women. No controlled clinical studies of atorvastatin have been performed in pregnant women. Rare cases of birth defects have been reported after intrauterine exposure to HMG-CoA reductase inhibitors. Studies in animals have shown reproductive toxicity ( see Preclinical Safety ). Treatment of the mother with atorvastatin may reduce the fetal level of mevalonate, which is a precursor of cholesterol biosynthesis.
- No clinical data are available from the use of ezetimibe during pregnancy. Animal studies on the use of ezetimibe as monotherapy have not shown direct or indirect harmful effects on pregnancy, embryonic or fetal development, birth or postnatal development ( cf. Preclinical safety ).
Feeding with milk
- Liptruzet is contraindicated during breast-feeding. Due to the potential risk of serious side effects, women taking Liptruzet should not breast-feed.
- Studies in the spleen have shown that ezetimibe is excreted in human milk. In the rat, plasma concentrations of atorvastatin and its active metabolites are comparable to those observed in milk. It is not known whether the active substances in Liptruzet are excreted in human breast milk ( see Contraindications ).
- Fertility studies with Liptruzet have not been performed.
- In animal studies, atorvastatin had no effect on male or female fertility.
- In rats, ezetimibe had no effect on male or female fertility.
What happens if I overdose from LIPTRUZET ?
- In the event of overdose, symptomatic treatment or even additional measures may be used with monitoring of hepatic function and serum CPK level.
- In clinical studies, administration of ezetimibe at a dose of 50 mg / day in 15 healthy subjects over a period of up to 14 days or 40 mg / day in 18 patients with primary hyperlipidemia over a period of up to 14 days. at 56 days was generally well tolerated. A few cases of overdose have been reported with ezetimibe; most of them have not been associated with adverse events. Serious side effects have not been reported. In animals, no toxicity was observed after single oral doses of 5000 mg / kg of ezetimibe in rats and mice and 3000 mg / kg in dogs.
- Due to the high binding of atorvastatin to plasma proteins, hemodialysis is not expected to significantly increase the clearance of atorvastatin.
What is Forms and Composition ?
|SHAPES and PRESENTATIONS|
10 mg / 10 mg film-coated tablet (capsule-shaped, biconvex, 12.74 mm × 5.10 mm, debossed with “257” on one side; white to off-white), 10 mg / 20 mg ( biconvex capsule-shaped, measuring 14.48 mm × 5.79 mm, debossed with “333” on one side; white to off-white), 10 mg / 40 mg (biconvex capsule-shaped, measuring 16, 38 mm × 6.27 mm, debossed with “337” on one side; white to off-white) and 10 mg / 80 mg (capsule-shaped biconvex, measuring 19.05 mm × 7.94 mm, bearing the words “357” engraved on one side; white to off-white): Boxes of 30 and 90, in blister packs, with nitrogen purge.
|Atorvastatin calcium trihydrate expressed as atorvastatin||10 mg|
Excipients (common): Core: ezetimibe layer: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate; atorvastatin layer: microcrystalline cellulose, lactose monohydrate, hydroxypropylcellulose, croscarmellose sodium, polysorbate 80, calcium carbonate, magnesium stearate, colloidal anhydrous silica. Film coating : hypromellose, macrogol 8000, titanium dioxide (E171), talc.
Excipient with known effect: lactose (153 mg / tab at 10 mg / 10 mg; 179 mg / tab at 10 mg / 20 mg; 230 mg / tab at 10 mg / 40 mg; 334 mg / tab at 10 mg / 80 mg ).
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