Read all of this leaflet carefully before you start taking this

medicine because it contains important information for you.

* Keep this leaflet. You may need to read it again.

* If you have any further questions, ask your doctor or

pharmacist.

* This medicine has been prescribed for you only.

Do not pass it on to others. It may harm them, even if their

signs of illness are the same as yours.

* If you get any side effects talk to your doctor or pharmacist.

This includes any possible side effects not listed in this leaflet.

See section 4.

1-DESCRIPTION

STATIVA is a pink coloured, round shaped, Biconvex, Film coated

tablet.

2-COMPOSITION

Each STATIVA film coated tablet contains:

-Rosuvastatin Calcium BP Eq, to Rosuvastatin 10mg

-Rosuvastatin Calcium BP Eq, to Rosuvastatin 20mg

Excipients: Lactose Monohydarte, Calcium Hydrogen Phosphate,

Microcrystalline cellulose pH 101, Magnesium Stearate, Crospovidone

Coating, HPMC E, Purified Talc, Titanium Dioxide, Red Iron Oxide,

Diethyl Phthalate, PEG 6000

3- THERAPEUTIC INDICATIONS

• Treatment of Hypercholesterolaemia

Adults, adolescents and children aged 6years or older with primary

hypercholesterolaemia (type IIa including heterozygous familial

hypercholesterolaemia) or mixed dyslipidaemia (type IIb) as an

adjunct to diet when response and other non-pharmacological

treatments (exercise,weight reduction) is inadequate.

Adults, adolescents and children or older with homozygous familial

hypercholesterolaemia as an adjunct to diet and other lipid

lowering treatments (ex.LDL apharesis) or if such treatments are not

appropriate.

• Prevention of cardiovascular events

Prevention of major cardiovascular events in patients who are

estimated to have a high risk for a first cardiovascular event, as an

adjunct to correction of other risk factors.

4- PHARMACOLOGICAL PROPERTIES

HMG-coA reductase inhibitor

Mechanism of action: Rosuvastatin is a selective and competitive

inhibitor of HMG-CoA reductase, the rate-limiting enzyme that

converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a

precusor for cholesterol. The primary site of action of rosuvastatin is

the liver, the target organ for cholesterol lowering. Rosuvastatin

increases the number of hepathic LDL receptors on the cell surface,

enhancing uptake and catabolism of LDL and inhibits the hepathic

synthesis of VLDL,thereby reducing the total number of VLDL and LDL

particles.

5- PHARMACOKINETICS

Absorption

Maximum rosuvastatin plasma concentrations are achieved approx.

5hours after oral intake. The absolute bioavailability is approximately

20%.

Distribution

Mean volume of distribution at steady-state of rosuvastatin is

approximately 134 liters. Rosuvastatin is 88% bound to plasma

proteins, mostly albumin. This binding is reversible and independent

of plasma concentrations.

Metabolism

Rosuvastatin is not extensively metabolized; approximately 10% of a

radiolabeled dose is recovered as metabolite. The major metabolite

is N-desmethyl rosuvastatin, which is formed principally by

cytochrome P450 \ 2C9, and in vitro studies have demonstrated that

N-desmethyl rosuvastatin has approximately one-sixth to one-half

the HMG-CoA reductase inhibitory activity of the parent compound.

Overall, greater than 90% of active plasma HMG-CoA reductase

inhibitory activity is accounted for by the parent compound.

Excretion

Following oral administration, rosuvastatin and its metabolites are

primarily excreted in the feces (90%). After an intravenous dose,

approximately 28% of total body clearance was via the renal route,

and 72% by the hepatic route. The elimination half-life of rosuvastatin

is approximately 19 hours.

6- CONTRAINDICATIONS

• In patients with acute liver disease including unexplained, persistent

elevations of serum transaminases elevation exceeding 3xthe upper

limit of normal (ULN).

• In patients with severe renal impairment (creatinine clearance <

30ml/min) in patients with myopathy.

• In patients receiving concomitant combination of sofosbuvir/velpat-

asvir/voxilaprevir

• In patients receiving concomitant ciclosporin

• During pregnancy and lactation and in women of childbearing

potential not using appropriate contraceptive measures.

• In patients with hypersensitivity to rosuvastatin or to any of the

excipients.

7- POSOLOGY AND METHOD OF ADMINISTRATION

Before treatment initiation the patient should be placed on a

standard cholesterol-lowering diet that should continue during

treatment. The dose should be individualized according to the goal of

therapy and patient response,using current consensus guidelines.

STATIVA may be given at any time of day, with or without food.

• Treatment of hypercholesterolaemia

The recommended start dose is 10mg once daily in both statin naïve

or patients switched from another HMGcoA reductase inhibitor. The

choice of start dose should take into account the individual patient’s

cholesterol level and future cardiovascular risk as well as the

potential risk of adverse events. A dose adjustment to the next dose

level can be made after 4 weeks.

• Prevention of Cardiovascular events

In the cardiovascular events risk reduction study, the dose used was

20mg once daily.

• Pediatric

Pediatric use should only be carried out by specialists.

Children and adolescents 6 to 17 years of age heterozygous familial

hypercholesterolaemia, the usual start dose is 5mg daily.

• In children 6 to 9 years of age with heterozygous familial

hypercholesterolaemia, the usual dose range is 5-10mg once daily.

• In children 10 to 17 years of age with heterozygous familial

hypercholesterolaemia ,the usual dose range is 5-20mg orally once

daily.

• Homozygous familial hypercholesterolaemia

In children 6 to 17years of age with homozygous familial

hypercholesterolaemia, the recommended dose is 20mg once daily.

A starting dose of 5 to 10mg once daily depending on age,weight,and

prior statin use is advised. Titration to the maximum dose of 20mg

once daily should be conducted according to the individual response

and tolerability in paediatric patients, as recommended by the

paediatric treatment recommendations. Children and adolescents

should be placed on standard cholesterol lowering diet before

rosuvastatin treatment initiation; this diet should be continued

during rosuvastatin treatment.

• Elderly

A start dose of 5mg is recommended in patients > 70 years. No

other dose adjustment is necessary in relation to age.

• Patients with renal insufficiency

No dose adjustment is necessary in patients with mild to moderate

renal impairment. The recommended start dose is 5mg in patients

with moderate renal impairment (creatinine clearance <60ml/min).

the 40mg is contraindicated in patients with moderate renal

impairment. The use of STATIVA in patient with severe renal

impairment is contraindicated for all doses.

• Patients with hepatic insufficiency

There was no increase in systemic exposure to rosuvastatin in

subjects with Child-Pugh scores of 7 or below. However increased

systemic exposure has been observed in subjects with Child-Pugh

of scores 8 and 9. STATIVA is contraindicated in patients with active

liver disease.

• Race

The recommended start dose is 5mg for patients of Asian ancestry.

Increased systemic exposure has been seen in Asian subjects. The

40mg dose in contraindicated in some of these patients.

• Pregnancy

Discontinue STATIVA when pregnancy is recognized. Alternatively,

consider the ongoing therapeutic needs of the individual patient.

• Lactation

Limited data from case reports in published literature indicate that

STATIVA is present in human milk. There is no available information

on the effects of the drug on the breastfed infant or the effects of

the drug on milk production.

Statins, including STATIVA, decrease cholesterol synthesis and

possibly the synthesis of other biologically active substances

derived from cholesterol and may cause harm to the breastfed

infant. Because of the potential for serious adverse reactions in a

breastfed infant, based on the mechanism of action, advise

patients that breastfeeding is not recommended during treatment

with STATIVA.

8- WARNINGS AND PRECAUTIONS

• Skeletal Muscle effects

Effects on skeletal muscle Myalgia, Myopathy and rarely

Rhabdomyolysis have been reported in STATIVA treated patients

with all doses and in particular with doses > 20mg. Very rare cases

of rhabdomyolysis have been reported with the use of ezetimibe in

combination with HMGcoA reductase inhibitors. The reporting rate

of for rhabdomyolysis associated with STATIVA is higher at the 40mg

dose.

• Renal effects

Proteinuria, detected by dipstick testing, and mostly tubular in origin

has been observed in patients treated with high dose of STATIVA, in

particular 40mg , where its transient or intermittent in most cases.

Proteinuria has not been shown to be predictive of acute or

progressive renal disease. The reported rate of serious renal events

in post-marketing use is higher at the 40mg dose

Creatine Kinase Measurement

Creatine Kinase (CK) should not be measured following strenuous

exercise or in the presence of a plausible alternative cause of CK

increase wich may confound in the interpretation of the result. If CK

levels are significantly elevated at baseline (>5ULN) a confirmatory

test should be carried out within 5-7 days. If the repeat test

confirms a baseline CK> 5ULN, treatment

should not be started.

Before treatment

STATIVA, as with other HMG co A reductaser

inhibitor,should be prescribed with caution

in patients with pre-disposing factors for

myopathy/rhabdomyolysis, Such factors

include:

-Renal impairment Hypothyroidism

-Personal or family history of hereditary

muscular disorders

-Previous history of muscular toxicity with

another HMGcoA reductase inhibitor or

fibrate

-Alcohol abuse

-Age > 70years

-Situations where an increase in plasma

levels may occur

-Concomitant use of fibrates.

While on treatment

Patients should be asked to report

inexplicable muscle pain,weakness or

cramps immediately, particularly if

associated with malaise or fever. CK levels

should be measured in these patients.

Therapy should be discontinued if CK levels

are markedly elevated (>5ULN) or if

muscular symptoms are severe and cause

daily discomfort (even if CK levels are <5

ULN). If symptoms resolve and CK levels

return to normal, then consideration should

be given to re-introducing STATIVA or an

alternative statin at the lowest dose with

close monitoring.

• There have been very rare Immune-Me-

diated Necrotizing Myopathy (IMNM): Rare

reports of IMNM, an autoimmune myopathy,

have been reported with statin use.

Discontinue STATIVA if IMNM is suspected.

• Liver effects:

As with others statins, STATIVA should be

used with caution in patients who consume

excessive quantities of alcohol and/or have

a history liver disease.

Its is recommended that liver function tests

be carried out prior to, and 3 months

following the initiation of treatment. STATIVA

should be discontinued or the dose

reduced if the level of serum transaminases

is greater than 3 ULN. The reporting rate for

serious hepatic events (consisting mainly in

increased hepatic transaminases) in post

marketing use is higher at the 40mg dose.

9- SPECIFIC PATIENT POPULATIONS

• Age and sex

There was no clinically relevant effect of

age or sex on the pharmacokinetics of

rosuvastatin in adults. The exposure in

children and adolescents with heterozygous

familial hypercholesterolaemia appears to

be similar to or lower than that in adult

patients with dyslipidaemia.

• Race

Pharmacokinetic studies show an

approximate 2-fold elevation in median

AUC and Cmax in Asian subjects (Japenese,Chinese,

Filipino,Vietnamese and Koreans) compared with Caucasians;

Asian-Indians show an approximate 1,3 fold elevation in median AUC

and Cmax. A population pharmacokinetic analysis revealed no

clinically relevant differences in pharmacokinetics between

Caucasian and black groups.

• Renal insufficiency

In a study in subjects with varying degrees of renal impairment, mild

to moderate renal disease had no influence on plasma

concentration of rosuvastatin or the N-desmethyl metabolite.

Subjects with severe impairment (CrCl <30ml/min) has a 3-fold

increase in plasma concentration and a 9-fold increase in the

N-desmethyl metabolite concentration compared to healthy

volunteers. Steady-state plasma concentrations of rosuvastatin in

subjects undergoing haemodialysis were approximately 50% greater

compared to healthy volunteers.

• Hepatic insufficiency

In a study with subjects with varying degrees of hepatic impairment,

there was no evidence of increased exposure to rosuvastatin in

subjects with Child-Pugh score 7 or below. However, 2 subjects with

Child-Pugh scores of 8 and 9 showed an increase in systemic

exposure of at least 2-fold compared to subjects with lower

child-pugh scores. There is no experience in subjects with Child-Pugh

scores above 9.

10-DRUG INTERRACTIONS

• Transporter protein inhibitors

Rosuvastatin is a substrate for certain transporter proteins including

the hepatic uptake transporter OATP1B1 and efflux transporter BCRP.

Concomitant administration of STATIVA with medicinal products that

are inhibitors of these transporter proteins may result in increased

rosuvastatin plasma concentrations and an increased risk of

myopathy.

• Ciclosporin

During concomitant treatment with STATIVA and ciclosporin,

rosuvastatin AUC values were on average 7times higher than those

observed in healthy volunteers. STATIVA is contraindicated in patients

receiving concomitant ciclosporin. Concomitant administration did

not affect plasma concentration of ciclosporin.

• Protease Inhibitors

Although the exact mechanism of interaction is unknown,

concomitant protease inhibitor use may strongly increase

rosuvastatin exposure.For instance, in a pharmacokinetic study ,

co-administration of 10mg rosuvastatin and a combinatio

product of two protease inhibitors

(300mg atazanavir/100mg ritonavir) in healthy volunteers was

associated with an approximately three-fold and

seven-fold increase of rosuvastatin AUC and Cmax

respectively. The concomitant use of STATIVA and some protease

inhibitor combinations may be considered after careful consideration

of STATIVA dose adjustments based on the expected increase in

rosuvastatin exposure.

• Gemfibrozil and other lipid-lowering products

Concomitant use of STATIVA and gemfibrozil resulted

in a 2-fold increase in rosuvastatin Cmax and AUC.

Based on data from specific interaction studies no

pharmacokinetic relevant interaction with fenofibrate is

expected, however a pharmacodynamic interaction may occur.

Gemfibrozil, fenofibrate, other fibrates and lipid lowering doses

( > or equal to 1 g/day) of niacin (nicotinic acid) increase the risk of

myopathy when given concomitantly with HMG-CoA reductase

inhibitors, probably because they can produce myopathy when given

alone.

The 40 mg dose is contraindicated with concomitant use

of a fibrate. These patients should also start with the 5 mg dose.



Rosuvastatin Calcium film coated tablets

Data as given as x-fold change represent a simple ratio between

co-administration and rosuvastatine alone. Data given as % change

represent % difference relative to rosuvastatin alone. Increase as

indicated as

↗, decrease as ↘. Several Interaction studies have been

performed at different dosages, the table shows the most significant

ratio.

(AUC= area under the curve, OD= Once daily, BD= Twice daily, TID=

Three times daily, QID= four times daily).

11-ADVERSE REACTIONS

The adverse reactions seen with STATIVA are generally mild and

transient.

Common (≥1/100 to <1/10) : Headache, Dizziness, Constipation, Nausea,

Abdominal pain, Myalgia, Asthenia

Uncommon ( ≥1/1000 to <1/100) Pruritis, Rash, Urticaria

Rare (≥1/10000 to 1/1000) Hypersensitivity reactions including

angioedema, Increased hepatic transaminases, Myopathy (including

myositis), Rhabdomyolysis Lupus-like syndrome, Muscle rupture,

Thrombocytopenia, Pancreatitis.

Very rare (<1/10000) Arthralgia, Polyneuropathy, memory loss,

Jaundice, Hepatitis, Haematuria,Gynaecomastia.

12-PACKAGING AND STORAGE CONDITION

Store Below 30°C in a dry dark place.

Keep this medecine out of the sight and reach of children.

STATIVA tablets are packed in (Alu/Alu) blisters each of 10

tablets. Box of 30 tablets.

• Ezetimibe

Concomitant use of 10 mg STATIVA and 10 mg ezetimibe resulted in a

1.2 fold increase in AUC of rosuvastatin in hypercholesterolaemic

subjects. A pharmacodynamic interaction, in terms of adverse

effects, between STATIVA and ezetimibe cannot be ruled out.

• Antacid

The simultaneous dosing of STATIVA with an antacid suspension

containing aluminium and magnesium hydroxide resulted in a

decrease in rosuvastatin plasma concentration of approximately

50%. This effect was mitigated when the antacid was dosed 2 hours

after STATIVA. The clinical relevance of this interaction has not been

studied.

• Erythromycin

Concomitant use of STATIVA and erythromycin resulted in a 20%

decrease in AUC and a 30% decrease in Cmax of rosuvastatin. This

interaction may be caused by the increase in gut motility caused by

erythromycin.

• Cytochrome P450 enzymes

Results from in vitro and in vivo studies show that rosuvastatin is

neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In

addition, rosuvastatin is a poor substrate for these isoenzymes.

Therefore, drug interactions resulting from cytochrome

P450-mediated metabolism are not expected. No clinicaly relevant

interactions have been observed between rosuvastatin and either

fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an

inhibitor of CYP2A6 and CYP3A4).

•Interactions requiring rosuvastatin dose adjustments (table 1):

When it is necessary to co-administer STATIVA with other medicinal

products known to increase exposure to rosuvastatin, doses of

STATIVA should be adjusted. Start with a 5 mg once daily dose of

STATIVA if the expected increase in exposure (AUC) is approximately

2-fold or higher. The maximum daily dose of STATIVA should be

adjusted so that the expected rosuvastatin exposure would not likely

exceed that of a 40 mg daily dose of STATIVA taken without

interacting medicinal products, for example a 20 mg dose of STATIVA

with gemfibrozil (1.9-fold increase), and a 10 mg dose of STATIVA with

combination ritonavir/atazanavir (3.1-fold increase).

If medicinal product is observed to increase rosuvastatin AUC less

than 2-told, the starting dose need not be decreased but caution

should be taken it increasing the STATIVA dose above 20mg.