Microsoft word - livazo master consolidated smpc 18 nov 2011.doc

Pitavastatin 1mg, 2mg & 4mg film-coated tablets
Master Consolidated SmPC

SUMMARY OF PRODUCT CHARACTERISTICS
NAME OF THE MEDICINAL PRODUCT

1mg: Livazo 1mg film-coated tablets.
2mg: Livazo 2mg film-coated tablets.
4mg: Livazo 4mg film-coated tablets.
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
1mg: Each film-coated tablet contains pitavastatin calcium equivalent to 1mg pitavastatin. Excipient(s) include 63.085mg Lactose monohydrate. For a full list of excipients see Section 6.1. 2mg: Each film-coated tablet contains pitavastatin calcium equivalent to 2mg pitavastatin. Excipient(s) include 126.17mg Lactose monohydrate. For a full list of excipients see Section 6.1. 4mg: Each film coated tablet contains pitavastatin calcium equivalent to 4mg pitavastatin. Excipient(s) include 252.34mg Lactose monohydrate. For a full list of excipients see Section 6.1.
3. PHARMACEUTICAL
Round white film-coated tablets embossed ‘KC’ on one face and ‘1’ on the reverse. Round white film-coated tablets embossed ‘KC’ on one face and ‘2’on the reverse. Round white film-coated tablets embossed ‘KC’ on one face and ‘4’on the reverse.
4. CLINICAL
PARTICULARS

4.1 Therapeutic
indications

Livazo is indicated for the reduction of elevated total cholesterol (TC) and LDL-C, in adult patients
with primary hypercholesterolaemia, including heterozygous familial hypercholesterolaemia, and
combined (mixed) dyslipidaemia, when response to diet and other non-pharmacological measures is
inadequate.
4.2
Posology and method of administration
For oral use only and should be swallowed whole. Livazo can be taken at any time of the day with or without food. It is desirable that the patient takes the tablet at the same time each day. Statin therapy is generally more effective in the evening due to the circadian rhythm of lipid metabolism. Patients should be on a cholesterol lowering diet before treatment. It is important that patients continue dietary control during treatment. Pitavastatin 1mg, 2mg & 4mg film-coated tablets The usual starting dose is 1mg once daily. Adjustment of dose should be made at intervals of 4 weeks or more. Doses should be individualized according to LDL-C levels, the goal of therapy and patient response. Most patients will require a 2mg dose (see Section 5.1). The maximum daily dose is 4mg. No dosage adjustment is required (see Sections 5.1 and 5.2). Pitavastatin should not be used in children aged below 18 years because safety and efficacy has not been established. No data are currently available. No dosage adjustment is required in mild renal impairment but pitavastatin should be used with caution. Data with 4mg dose are limited in all grades of impaired renal function. Therefore 4mg dose should ONLY be used with close monitoring after graded dose titration. In those with severe renal impairment 4mg dose is not recommended (see Sections 4.4 and 5.2). The 4mg dose is not recommended in patients with mild to moderate impaired hepatic function. A maximum daily dose of 2mg may be given with close monitoring (see Sections 4.4 and 5.2).
4.3 Contraindications
Livazo is contraindicated:
 in patients with known hypersensitivity to pitavastatin or to any of the excipients or other  in patients with severe hepatic impairment, active liver disease or unexplained persistent elevations in serum transaminases (exceeding 3 times the upper limit of normal [ULN])  in patients receiving concomitant ciclosporin  during pregnancy, while breast feeding and in women of child bearing potential not taking Special warnings and precautions for use

Muscle Effects
In common with other HMG-CoA reductase inhibitors (statins), there is the potential for myalgia,
myopathy and, rarely, rhabdomyolysis to develop. Patients should be asked to report any muscle
symptoms. Creatine kinase (CK) levels should be measured in any patient reporting muscle pain,
muscle tenderness or weakness especially if accompanied by malaise or fever.
Creatine kinase should not be measured following strenuous exercise or in the presence of any other
plausible cause of CK increase which may confound interpretation of the result. When elevated CK
concentrations (>5x ULN) are noted, a confirmatory test should be performed within 5 to 7 days.
Pitavastatin 1mg, 2mg & 4mg film-coated tablets Before Treatment In common with other statins, Livazo should be prescribed with caution in patients with pre-disposing factors for rhabdomyolysis. A creatinine kinase level should be measured, to establish a reference baseline, in the following situations:  personal or family history of hereditary muscular disorders,  previous history of muscular toxicity with a fibrate or another statin,  history of liver disease or alcohol abuse,  elderly patients (over 70 years) with other predisposing risk factors for rhabdomyolysis,
In such situations, clinical monitoring is recommended and the risk of treatment should be considered
in relation to the possible benefit. Treatment with Livazo should not be started if CK values are >5x
ULN.
During Treatment
Patients must be encouraged to report muscle pain, weakness or cramps immediately. Creatine
kinase levels should be measured and treatment stopped if CK levels are elevated (>5x ULN).
Stopping treatment should be considered if muscular symptoms are severe even if CK levels are ≤5x
ULN. If symptoms resolve and CK levels return to normal, then re-introduction of Livazo may be
considered at a dose of 1mg and with close monitoring.
Liver Effects
In common with other statins, Livazo should be used with caution in patients with a history of liver
disease or who regularly consume excessive quantities of alcohol. Liver function tests should be
performed prior to initiating treatment with Livazo and then periodically during treatment. Livazo
treatment should be discontinued in patients who have a persistent increase in serum transaminases
(ALT and AST) exceeding 3x ULN.
Renal Effects
Livazo should be used with caution in patients with moderate or severe renal impairment. Dose
increments should be instituted only with close monitoring. In those with severe renal impairment,
4mg dose is not recommended (see Section 4.2).
Interstitial Lung Disease
Exceptional cases of interstitial lung disease have been reported with some statins, especially with
long term therapy (see Section 4.8). Presenting features can include dyspnoea, non-productive cough
and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has
developed interstitial lung disease, statin therapy should be discontinued.
Other effects
A temporary suspension of Livazo is recommended for the duration of treatment with erythromycin,
other macrolide antibiotics or fusidic acid (see Section 4.5). Livazo should be used with caution in
patients taking drugs known to cause myopathy (e.g. fibrates or niacin see Section 4.5).
The tablets contain lactose. Patients with the rare hereditary problems of galactose intolerance, Lapp
lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Pitavastatin 1mg, 2mg & 4mg film-coated tablets Interaction with other medicinal products and other forms of interaction

Pitavastatin is actively transported into human hepatocytes by multiple hepatic transporters (including
organic anion transporting polypeptide, OATP), which may be involved in some of the following
interactions.
Ciclosporin: Co-administration of a single dose of ciclosporin with Livazo at steady state resulted in
a 4.6-fold increase in pitavastatin AUC. The effect of steady state ciclosporin on steady state Livazo
is not known. Livazo is contraindicated in patients being treated with ciclosporin (see section 4.3).
Erythromycin: Co-administration with Livazo resulted in a 2.8-fold increase in pitavastatin AUC. A
temporary suspension of Livazo is recommended for the duration of treatment with erythromycin or
other macrolide antibiotics.
Gemfibrozil and other fibrates: The use of fibrates alone is occasionally associated with myopathy.
Co-administration of fibrates with statins has been associated with increased myopathy and
rhabdomyolysis. Livazo should be administered with caution when used concomitantly with fibrates
(see Section 4.4). In Pharmacokinetic studies co-administration of Livazo with Gemfibrozil resulted
in a 1.4-fold increase in pitavastatin AUC with Fenofibrate AUC increased 1.2-fold.
Niacin: Interaction studies with Livazo and niacin have not been conducted. The use of niacin alone
has been associated with myopathy and rhabdomyolysis when used as a monotherapy. Thus Livazo
should be administered with caution when used concomitantly with niacin.
Fusidic acid: There have been reports of severe muscle problems such as rhabdomyolysis attributed
to interactions between fusidic acid and statins. A temporary suspension of Livazo is recommended
for the duration of treatment with fusidic acid (see section 4.4).
Rifampicin: Co-administration with Livazo at the same time resulted in a 1.3-fold increase in
pitavastatin AUC due to reduced hepatic uptake
Protease inhibitors: Co-administration with Livazo at the same time may result in minor changes in
pitavastatin AUC.
Ezetimibe and its glucuronide metabolite inhibit the absorption of dietary and biliary cholesterol.
Co-administration of Livazo had no effect on plasma ezetimibe or the glucuronide metabolite
concentrations and ezetimibe had no impact on pitavastatin plasma concentrations.
Inhibitors of CYP3A4: Interaction studies with itraconazole and grapefruit juice, known inhibitors
of CYP3A4, had no clinically significant effect on the plasma concentrations of pitavastatin.
Digoxin, a known P-gp substrate, did not interact with Livazo. During co-administration there was
no significant change in either pitavastatin or digoxin concentrations.
Warfarin: The steady-state pharmacokinetics and pharmacodynamics (INR and PT) of warfarin in
healthy volunteers was unaffected by the co-administration of Livazo 4mg daily. However, as for
other statins, patients receiving warfarin should have their prothrombin time or INR monitored when
Livazo is added to their therapy.
Pitavastatin 1mg, 2mg & 4mg film-coated tablets Pregnancy and lactation

Pregnancy
Livazo is contraindicated during pregnancy (see Section 4.3). Women of childbearing potential must
take appropriate contraceptive precautions during treatment with Livazo. Since cholesterol and other
products of cholesterol biosynthesis are essential for the development of the fetus, the potential risk
for inhibition of HMG-CoA reductase outweighs the advantage of treatment during pregnancy.
Animal studies show evidence of reproductive toxicity, but no teratogenic potential (see Section 5.3).
If the patient is planning to become pregnant, treatment should be stopped at least one month prior to
conception. If a patient becomes pregnant during use of Livazo, treatment must be discontinued
immediately.
Lactation
Livazo is contraindicated during lactation (see Section 4.3). Pitavastatin is excreted in rat milk. It is
not known whether it is excreted in human milk.
4.7
Effects on ability to drive and use machines

There is no pattern of adverse events that suggests that patients taking Livazo will have any
impairment of ability to drive and use hazardous machinery, but it should be taken into account that
there have been reports of dizziness and somnolence during treatment with Livazo.
4.8 Undesirable

Summary of the safety profile
In controlled clinical trials, at the recommended doses, less than 4% of Livazo treated patients were
withdrawn due to adverse events. The most commonly reported pitavastatin related adverse reaction
in controlled clinical trials was myalgia.
Summary of adverse reactions
Adverse reactions and frequencies observed in worldwide controlled clinical trials and extension
studies, at the recommended doses, are listed below by system organ class. 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.
Blood and the lymphatic system disorders
Uncommon: Anaemia
Metabolism and nutrition disorders
Uncommon: Anorexia
Psychiatric disorders
Uncommon: Insomnia
Nervous system disorders
Common: Headache
Uncommon: Dizziness, Dysgeusia, Somnolence
Eye disorders
Rare: Visual acuity reduced
Ear and labyrinth disorders
Uncommon: Tinnitus
Pitavastatin 1mg, 2mg & 4mg film-coated tablets
Gastrointestinal disorders
Common: Constipation, Diarrhoea, Dyspepsia, Nausea
Uncommon: Abdominal Pain, Dry Mouth, Vomiting
Rare: Glossodynia, pancreatitis acute
Hepato-biliary disorders
Uncommon: Transaminases (aspartate aminotransferase, alanine aminotransferase) increased
Rare: Jaundice cholestatic
Skin and subcutaneous tissue disorders
Uncommon: Pruritus, Rash
Rare: Urticaria, Erythema
Musculoskeletal, connective tissue and bone disorders
Common: Myalgia, Arthralgia
Uncommon: Muscle spasms
Renal and urinary disorders
Uncommon: Pollakiuria
General disorders and administration site conditions
Uncommon: Asthenia, Malaise, Fatigue, Peripheral Oedema
Elevated blood creatinine kinase of >3 times the upper limit of normal (ULN) occurred in 49 out of
2800 (1.8%) patients receiving Livazo in the controlled clinical trials. Levels of ≥10 times ULN with
concurrent muscle symptoms were rare and only observed in one patient out of 2406 treated with
4mg Livazo (0.04%) in the clinical trial programme.
Post Marketing Experience
A two year prospective post-marketing surveillance study was conducted in nearly 20,000 patients in
Japan. The overwhelming majority of the 20,000 patients in the study were treated with 1mg or 2mg
pitavastatin and not 4mg. 10.4% of patients reported adverse events for which a causal relationship
to pitavastatin could not be ruled out and 7.4% of patients withdrew from therapy due to adverse
events. The myalgia rate was 1.08%. The majority of adverse events were mild. Adverse event rates
were higher over 2 years in patients with a history of drug allergy (20.4%), or hepatic or renal disease
(13.5%).
Adverse reactions and frequencies observed in the prospective post-marketing surveillance study but
not in worldwide controlled clinical trials, at the recommended doses are listed below.
Hepato-biliary disorders
Rare: Hepatic function abnormal, Liver disorder
Musculoskeletal, connective tissue disorders
Rare: Myopathy, Rhabdomyolysis
In the post-marketing surveillance study there were two reports of rhabdomyolysis requiring
hospitalisation (0.01% of patients).
In addition there are unsolicited post-marketing reports of skeletal muscle effects including myalgia
and myopathy in Livazo treated patients at all recommended doses. Reports of rhabdomyolysis, with
and without acute renal failure, including fatal rhabdomyolysis have also been received.
Pitavastatin 1mg, 2mg & 4mg film-coated tablets
Statin class effects
The following adverse events have been reported with some statins:
 Sleep disturbances, including nightmares  Exceptional cases of interstitial lung disease, especially with long term therapy (see Section 4.4)
4.9 Overdose
There is no specific treatment in the event of overdose. The patient should be treated
symptomatically and supportive measures instituted as required. Liver function and CK levels should
be monitored. Haemodialysis is unlikely to be of benefit.
5. PHARMACOLOGICAL
PROPERTIES

5.1 Pharmacodynamic properties
Pharmacotherapeutic group:

Mechanism of Action
Pitavastatin competitively inhibits HMG-CoA reductase, the rate-limiting enzyme in the biosynthesis
of cholesterol, and inhibits cholesterol synthesis in the liver. As a result the expression of LDL
receptors in the liver is increased, promoting the uptake of circulating LDL from the blood,
decreasing total cholesterol (TC) and LDL-cholesterol (LDL-C) concentrations in the blood. Its
sustained inhibition of hepatic cholesterol synthesis reduces VLDL secretion into the blood, reducing
plasma triglyceride (TG) levels.
Pharmacodynamic Effects
Livazo reduces elevated LDL-C, total cholesterol and triglycerides and increases HDL-cholesterol
(HDL-C). It reduces Apo-B, and produces variable increases in Apo-A1 (see Table 1). It also
reduces non-HDL-C and elevated TC/HDL-C, and Apo-B/Apo-A1 ratios.
Dose response in patients with primary hypercholesterolaemia
(Adjusted mean percent change from baseline over 12 weeks)
1mg 52 -33.3 -22.8 9.4 -14.8 -24.1 8.5 2mg 49 -38.2 -26.1 9.0 -17.4 -30.4 5.6 4mg 50 -46.5 -32.5 8.3 -21.2 -36.1 4.7 *unadjusted
Clinical efficacy
In controlled clinical studies which enrolled a total of 1687 patients with primary
hypercholesterolaemia and mixed dyslipidaemia, including 1239 patients treated at the therapeutic
doses (mean baseline LDL-C about 4.8 mmol/L), Livazo consistently reduced LDL-C, TC, non-
HDL-C, TG and Apo-B concentrations and elevated HDL-C and Apo-A1 concentrations. TC/HDL-
C and Apo-B/Apo-A1 ratios were reduced. LDL-C was reduced by 38 to 39% with Livazo 2mg and
44 to 45% with Livazo 4mg. The majority of patients taking 2mg achieved the European
Atherosclerosis Society (EAS) treatment target for LDL-C (<3 mmol/L).
Pitavastatin 1mg, 2mg & 4mg film-coated tablets
In a controlled clinical trial in 942 patients aged ≥65 years (434 treated with Livazo 1mg, 2mg or
4mg) with primary hypercholesterolaemia and mixed dyslipidaemia (mean baseline LDL-C about 4.2
mmol/L), LDL-C values were reduced by 31%, 39.0% and 44.3%, respectively, and about 90% of
patients reached the EAS treatment target. More than 80% of the patients were taking concomitant
medications, but the incidence of adverse events was similar in all treatment groups and fewer than
5% of patients withdrew from the study due to adverse events. Safety and efficacy findings were
similar in patients in the different age subgroups (65-69, 70-74, and ≥75 years).
In controlled clinical trials which enrolled a total of 761 patients (507 treated with Livazo 4mg) who
had primary hypercholesterolaemia or mixed dyslipidaemia, with 2 or more cardiovascular risk
factors (mean baseline LDL-C about 4.1 mmol/L), or mixed dyslipidaemia with type 2 diabetes
(mean baseline LDL-C about 3.6 mmol/L), approximately 80% achieved the relevant EAS target
(either 3 or 2.5 mmol/L, depending on risk). LDL-C was reduced by 44% and 41%, respectively, in
the patient groups.
In long term studies of up to 60 weeks duration in primary hypercholesterolaemia and mixed
dyslipidaemia, EAS target attainment has been maintained by persistent and stable reductions of
LDL-C, and HDL-C concentrations have continued to increase. In a study in 1346 patients who had
completed 12 weeks of statin therapy (LDL-C reduction 42.3%, EAS target attainment 69%, HDL-C
elevation 5.6%), values after a further 52 weeks of treatment with pitavastatin 4mg were LDL-C
reduction 42.9%, EAS target attainment 74%, HDL-C elevation 14.3%.
A beneficial effect of pitavastatin on cardiovascular morbidity and mortality has not been
demonstrated as no outcome studies were included in the clinical programme.
5.2 Pharmacokinetic
properties

Absorption: Pitavastatin is rapidly absorbed from the upper gastrointestinal tract and peak plasma
concentrations are achieved within one hour after oral administration. Absorption is not affected by
food. Unchanged drug undergoes enterohepatic circulation and is well absorbed from the jejunum
and ileum. The absolute bioavailability of pitavastatin is 51%.
Distribution: Pitavastatin is more than 99% protein bound in human plasma, mainly to albumin and
alpha 1-acid glycoprotein, and the mean volume of distribution is approximately 133 L. Pitavastatin
is actively transported into hepatocytes, the site of action and metabolism, by multiple hepatic
transporters including OATP1B1 and OATP1B3. Plasma AUC is variable with an approximately 4-
fold range between the highest and lowest values. Studies with SLCO1B1 (the gene which encodes
OATP1B1) suggests that polymorphism of this gene could account for much of the variability in
AUC. Pitavastatin is not a substrate for p-glycoprotein.
Metabolism: Unchanged pitavastatin is the predominant drug moiety in plasma. The principal
metabolite is the inactive lactone which is formed via an ester-type pitavastatin glucuronide conjugate
by UDP glucuronosyltransferase (UGT1A3 and 2B7). In vitro studies, using 13 human cytochrome
P450 (CYP) isoforms, indicate that the metabolism of pitavastatin by CYP is minimal; CYP2C9 (and
to a lesser extent CYP2C8) is responsible for the metabolism of pitavastatin to minor metabolites.
Excretion: Unchanged pitavastatin is rapidly cleared from the liver in the bile, but undergoes
enterohepatic recirculation, contributing to its duration of action. Less than 5% of pitavastatin is
excreted in the urine. The plasma elimination half-life ranges from 5.7 hours (single dose) to
8.9 hours (steady state) and the apparent geometric mean oral clearance is 43.4 L/h after single dose.
Effect of food: The maximum plasma concentration of pitavastatin was reduced by 43% when it was
taken with a high-fat meal, but AUC was unchanged.
Pitavastatin 1mg, 2mg & 4mg film-coated tablets
Special populations

Elderly: In a pharmacokinetic study which compared healthy young and elderly (≥65 years)
volunteers, pitavastatin AUC was 1.3-fold higher in elderly subjects. This has no effect on the safety
or efficacy of Livazo in elderly patients in clinical trials.
Gender: In a pharmacokinetic study which compared healthy male and female volunteers,
pitavastatin AUC was increased 1.6-fold in women. This has no effect on the safety or efficacy of
Livazo in women in clinical trials.
Race: There was no difference in the pharmacokinetic profile of pitavastatin between Japanese and
Caucasian healthy volunteers when age and body weight was taken into account.
Paediatric: Pharmacokinetic data in the paediatric population are not available.
Renal insufficiency: For patients with moderate renal disease and those on haemodialysis increases
in AUC values were 1.8-fold and 1.7-fold respectively (see Section 4.2).
Hepatic insufficiency: For patients with mild (Child-Pugh A) hepatic impairment AUC was 1.6
times that in healthy subjects, while for patients with moderate (Child-Pugh B) hepatic impairment
AUC was 3.9-fold higher. Dose restrictions are recommended in patients with mild and moderate
hepatic impairment (see Section 4.2). Livazo is contraindicated in patients with severe hepatic
impairment.
5.3
Preclinical safety data
Non-clinical data reveal no special hazard for humans based on results from conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Indications of renal toxicity were seen in monkeys at exposures greater than those reached in adult humans administered the maximum daily dose of 4mg and urinary excretion plays a far greater role in the monkey than in other animal species. In vitro studies with liver microsomes indicate that a monkey-specific metabolite may be implicated. The renal effects observed in monkeys are unlikely to have clinical relevance for humans, however the potential for renal adverse reactions cannot be completely excluded. Pitavastatin had no effect on fertility or reproductive performance and there was no evidence of teratogenic potential. However, maternal toxicity was observed at high doses. A study in rats indicated maternal mortality at or near term accompanied by fetal and neonatal deaths at doses of 1 mg/kg/day (approximately 4 fold greater than the highest dose in humans on an AUC basis). No studies have been conducted in juvenile animals. Pitavastatin 1mg, 2mg & 4mg film-coated tablets
6. PHARMACEUTICAL
PARTICULARS
List of excipients

Tablet core
Lactose monohydrate
Low substituted hydroxypropylcellulose
Hypromellose (E464)
Magnesium Aluminometasilicate
Magnesium stearate
Film coating
Hypromellose (E464)
Titanium dioxide (E171)
Triethyl citrate (E1505)
Colloidal anhydrous silica
6.2 Incompatibilities
Not applicable.
6.3 Shelf

4 years.
6.4
Special precautions for storage

Do not store above 25ºC.
To protect from light keep blister in the outer carton.
6.5
Nature and contents of container
1mg: White PVdC coated PVC/AL blisters in cartons of 7, 28, 30, 90 or 100 tablets. 2mg: White PVdC coated PVC/AL blisters in cartons of 7, 28, 30, 90 or 100 tablets. 4mg: White PVdC coated PVC/AL blisters in cartons of 7, 28 or 30 tablets. Special precautions for disposal

To protect the environment, do not dispose of via waste water or household waste.
7. MARKETING
AUTHORISATION

Kowa Pharmaceutical Europe Co. Ltd.,
Winnersh Triangle, Wokingham RG41 5RB, UK.
8.
MARKETING AUTHORISATION NUMBER(S)

1mg: PL32363/0011
2mg: PL32363/0001
4mg: PL32363/0002
9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Pitavastatin 1mg, 2mg & 4mg film-coated tablets 1mg: 12/08/2010
2mg: 12/08/2010
4mg: 12/08/2010
10.
DATE OF REVISION OF THE TEXT
1mg: 18/11/2011 2mg: 18/11/2011 4mg: 18/11/2011

Source: http://www.kowapharmaceuticals.eu/_client/pdfs/livazo_smpc.pdf

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