LIPTRUZET Uses, Dosage, Side Effects, Precautions & Warnings

Generic drug of the Therapeutic class: Metabolism and Nutrition
Active ingredients: ezetimibe , Atorvastatin

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.

Hypercholesterolemia

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).

LIPTRUZET Dosage

Dosage

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).

Older subjects

No dosage adjustment is necessary in elderly patients.

Pediatric population

• The safety and efficacy of LIPTRUZET in children have not been established . No data is available.

Hepatic insufficiency

• LIPTRUZET should be used with caution in patients with hepatic impairment (Pharmacokinetic properties). LIPTRUZET is contraindicated in patients with active liver disease.

Renal failure

• No dose adjustment is necessary in patients with renal impairment .

Administration mode

• Oral route. LIPTRUZET can be given as a single dose at any time of the day, with or without food.

Contraindications

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 ?

Class
Pharmacotherapeutic group: HMG-CoA reductase inhibitor in
combination with other lipid-lowering drugs, ATC code: C10BA05

LIPTRUZET

(ezetimibe / atorvastatin) is a lipid-lowering agent which
selectively inhibits the intestinal absorption of cholesterol and
related phytosterols and inhibits endogenous synthesis of cholesterol.

Action mechanism

LIPTRUZET

The
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.

Ezetimibe
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.

Ezetimibe
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.

Several
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.

Atorvastatin
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).

Atorvastatin
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.

Atorvastatin
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
lipid-lowering drugs.

A
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

In
controlled clinical studies, LIPTRUZET caused
significant reductions in CT, LDL-C, Apo B, and TG levels and increased HDL-C
in patients with hypercholesterolemia.

Primary hypercholesterolemia

In a
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.

The
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.

Table 4

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.

c
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.

LIPTRUZET
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%).

For
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 %).

In
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 .

Among
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
atorvastatin.

In a
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.

Table 5

Response
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

The
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
years old.

The
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.

The
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.

Figure

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
10/80 mg.

• † 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

LIPTRUZET Interactions

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

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.

Before treatment

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,

· hypothyroidism,

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.

During treatment

• 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.

Daptomycin

• 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.

Liver enzymes

• 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.

Hepatic insufficiency

• In patients with moderate or severe hepatic impairment, the effects of increased exposure to ezetimibe are not known, LIPTRUZET is not recommended .

Fibrates

• 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).

Ciclosporin

• 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).

Anti coagulants

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.

Diabetes

• 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.

Excipients

• 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 ).

Pregnancy

Feeding with milk 

What happens if I overdose from LIPTRUZET ?

What is  Forms and Composition ?

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.

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 ).

NOT’s

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general information:

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Additional information:

• General explanation about dealing with the medicine: how to take the medicine, the doses and times of it, the start and duration of its effectiveness, the recommended diet during the period of taking the medicine, the method of storage and storage, recommendations in cases for forgetting the dose and instructions to stop taking the drug and take additional doses.

Special warnings:

• For pregnant and breastfeeding women, the elderly, boys and drivers, and use before surgery.

Side effects:

• It treats possible side effects and drug interactions that require attention and its effect on continuous use.
• The information contained in this medicine is based on medical literature, but it is not a substitute for consulting a doctor.