1. NAME OF THE MEDICINAL PRODUCT

ZENON 10 mg/10 mg film-coated tablets ZENON 20 mg/10 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

ZENON 10 mg/10 mg: Each film-coated tablet contains 10 mg rosuvastatin (as rosuvastatin calcium) and 10 mg of ezetimibe.

ZENON 20 mg/10 mg: Each film-coated tablet contains 20 mg of rosuvastatin (as rosuvastatin calcium) and 10 mg of ezetimibe.

Excipients with known effect:

ZENON 10 mg/10 mg: Each film-coated tablet contains 222.0 mg of lactose monohydrate and a maximum of 2.4 mg of sodium.

ZENON 20 mg/10 mg: Each film-coated tablet contains 283.0 mg of lactose monohydrate and a maximum of 2.7 mg of sodium.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet

ZENON 10 mg/10 mg: white to off-white, round, biconvex, film-coated tablets with a diameter about 9.1 mm.

ZENON 20 mg/10 mg: yellow to light yellow, round, biconvex, film-coated tablets with a diameter about 9.9 mm.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Primary Hypercholesterolaemia/Homozygous Familial Hypercholesterolaemia (HoFH)

ZENON is indicated for substitution therapy in adult patients who are adequately controlled with rosuvastatin and ezetimibe given concurrently at the same dose level as in the fixed combination, but as separate products, as adjunct to diet for treatment of primary hypercholesterolaemia (heterozygous familial) or homozygous familial hypercholesterolaemia. ROSUVASTATIN/EZETIMIBE fixed dose combination should not be used as initial therapy.

4.2 Posology and method of administration

Posology

The patient should be on an appropriate lipid-lowering diet and should continue on this diet during treatment with ZENON. ZENON is not suitable for initial therapy. Treatment initiation or dose adjustment if necessary should only be done with the monocomponents and after setting the appropriate doses the switch to the fixed dose combination of the appropriate strength is possible.

Patient should use the strength corresponding to their previous treatment. The recommended dose is one ZENON tablet daily.

The dose of 5/10 mg can be met by using a single product of each of the approved active substance which marketed in Indonesia, which are rosuvastatin 5 mg and ezetimibe 10 mg. For patients who need higher LDL cholesterol reduction, dosage can be adjusted. After initiation or dosage titration of ZENON, lipid level should be analysis after 4 weeks or more, then dosage can be adjusted according to those analysis result.

Co-administration with bile acid sequestrants

Dosing of ZENON should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant (see section 4.5).

Paediatric population

The safety and efficacy of ZENON in children below the age of 18 years have not yet been established..

Elderly

A start dose of 5 mg rosuvastatin is recommended in patients >70 years (see section 4.4). The combination is not suitable for initial therapy. Treatment initiation or dose adjustment if necessary should only be done with the monocomponents and after setting the appropriate doses the switch to the fixed dose combination of the appropriate strength is possible.

Hepatic impairment

No dosage adjustment is required in patients with mild hepatic impairment (Child Pugh score 5 to 6). Treatment with ZENON is not recommended in patients with moderate (Child Pugh score 7 to 9) or severe (Child Pugh score>9) liver dysfunction (see sections 4.4 and 5.2). ZENON is contraindicated in patients with active liver disease (see section 4.3).

Renal impairment

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

The recommended start dose is rosuvastatin 5 mg in patients with moderate renal impairment (creatinine clearance <60 ml/min).

The 40 mg/10 mg dose (not available in the Indonesia) is contraindicated in patients with moderate renal impairment.

The use of ZENON in patients with severe renal impairment is contraindicated for all doses (see sections 4.3 and 5.2).

Race

Increased systemic exposure of rosuvastatin has been seen in Asian subjects (see sections 4.4 and 5.2). The recommended start dose is rosuvastatin 5 mg for patients of Asian ancestry. The fixed dose combination is not suitable for initial therapy. Monocomponent preparations should be used to start the treatment or to modify the dose. Combination of 40 mg/10 mg film-coated tablets (not available in the Indonesia) are contraindicated in these patients

Genetic polymorphisms

Specific types of genetic polymorphisms are known that can lead to increased rosuvastatin exposure (see section 5.2). For patients who are known to have such specific typesof polymorphisms, a lower daily dose of ZENON is recommended.

Dosage in patients with pre-disposing factors to myopathy

The recommended start dose is rosuvastatin 5 mg in patients with pre-disposing factors to myopathy (see section 4.4). The fixed dose combination is not suitable for initial therapy. Monocomponent preparations should be used to start the treatment or to modify the dose.

Concomitant therapy

Rosuvastatin is a substrate of various transporter proteins (e.g. OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) is increased when ZENON is administered concomitantly with certain medicinal products that may increase the plasma concentration of rosuvastatin due to interactions with these transporter proteins (e.g. ciclosporin and certain protease inhibitors including combinations of ritonavir with atazanavir, lopinavir, and/or tipranavir; see sections 4.4 and 4.5).

Whenever possible, alternative medications should be considered, and, if necessary, consider temporarily discontinuing ZENON therapy. In situations where co-administration of these medicinal products with ZENON is unavoidable, the benefit and the risk of concurrent treatment and rosuvastatin dosing adjustments should be carefully considered (see section 4.5).

Method of administration

Route of administration is oral. ZENON can be administered at any time of the day, with or without food. The tablet should be swallowed whole with a drink of water.

1.1 Contraindications

· Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

· Pregnancy, breast-feeding and in women of childbearing potential not using appropriate contraceptive measures (see section 4.6).

· Active liver disease or unexplained persistent elevations in serum transaminases and any serum transaminase elevation exceeding 3x the upper limit of normal (ULN) (see section 4.4).

· In patients with severe renal impairment (creatinine clearance <30 ml/min) (see section 4.4).

· In patients with myopathy (see section 4.4).

· In patients receiving concomitant ciclosporin (see section 4.5).

1.2 Special warnings and precautions for use

Skeletal muscle effects

Effects on skeletal muscle e.g. myalgia, myopathy and, rarely, rhabdomyolysis have been reported in rosuvastatin-treated patients with all doses and in particular with doses >20 mg. As with other HMG-CoA reductase inhibitors, the reporting rate for rhabdomyolysis associated with rosuvastatin in post- marketing use is higher at the 40 mg dose.

In post-marketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported. However, rhabdomyolysis has been reported very rarely with ezetimibe monotherapy and very rarely with the addition of ezetimibe to other agents known to be associated with increased risk of rhabdomyolysis.

If myopathy is suspected based on muscle symptoms or is confirmed by a creatine phosphokinase (CPK) level, ZENON and any of these other agents that the patient is taking concomitantly should be immediately discontinued. All patients starting therapy with ZENON should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness (see section 4.8).

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 which may confound interpretation of the result. If CK levels are significantly elevated at baseline (>5xULN) a confirmatory test should be carried

out within 5-7 days. If the repeat test confirms a baseline CK >5xULN, treatment should not be started.

Before treatment

Caution should be exercised 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 HMG-CoA reductase inhibitor or fibrate,

- alcohol abuse,

- age >70 years,

- situations where an increase in plasma levels may occur (see sections 4.2, 4.5 and 5.2),

- concomitant use of fibrates.

In such patients the risk of treatment should be considered in relation to possible benefit and clinical monitoring is recommended. If CK levels are significantly elevated at baseline (>5xULN) treatment should not be started.

Whilst 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 (>5xULN) or if muscular symptoms are severe and cause daily discomfort (even if CK levels are </=5x ULN). If symptoms resolve and CK levels return to normal, then consideration should be given to re- introducing rosuvastatin or an alternative HMG-CoA reductase inhibitor at the lowest dose with close monitoring of the patient. Routine monitoring of CK levels in asymptomatic patients is not warranted.

There have been very rare reports of an immune-mediated necrotizing myopathy (IMNM) during or after treatment with statins, including rosuvastatin. IMNM is clinically characterised by proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.

In clinical trials there was no evidence of increased skeletal muscle effects in the small number of patients dosed with rosuvastatin and concomitant therapy. However, an increase in the incidence of myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitors together with fibric acid derivatives including gemfibrozil, cyclosporin, nicotinic acid, azole antifungals, protease inhibitors and macrolide antibiotics.

Gemfibrozil increases the risk of myopathy when given concomitantly with some HMG-CoA reductase inhibitors. Therefore, the combination of rosuvastatin and gemfibrozil is not recommended. The benefit of further alterations in lipid levels by the combined use of rosuvastatin with fibrates or niacin should be carefully weighed against the potential risks of such combinations. The 40 mg dose of rosuvastatin is contraindicated with concomitant use of a fibrate (see sections 4.5 and 4.8).

ZENON should not be used in any patient with an acute, serious condition suggestive ofmyopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g. sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders; or uncontrolled seizures).

Liver effects

In controlled co-administration trials in patients receiving ezetimibe with statin, consecutive transaminase elevations (≥3 × the upper limit of normal [ULN]) have been observed.

It is recommended that liver function tests be carried out prior to, and 3 months following, the initiation of treatment. Rosuvastatin should be discontinued or the dose reduced if the level of serum transaminases is greater than 3 times the upper limit of normal.

In patients with secondary hypercholesterolaemia caused by hypothyroidism or nephrotic syndrome, the underlying disease should be treated prior to initiating therapy with rosuvastatin.

Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic impairment, ZENON is not recommended (see section 5.2).

Liver disease and alcohol

As with other HMG-CoA reductase inhibitors, rosuvastatin should be used with caution in patients who consume excessive quantities of alcohol and/or have a history of liver disease.

Renal effects

Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with higher doses of rosuvastatin, in particular 40 mg, where it was transient or intermittent in most cases. Proteinuria has not been shown to be predictive of acute or progressive renal disease (see section 4.8). The reporting rate for serious renal events in post-marketing use is higher at the 40 mg dose. An assessment of renal function should be considered during routine follow-up of patients treated with a dose of 40 mg

Diabetes mellitus

Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/l, BMI > 30 kg/m², raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.

In the JUPITER study, the reported overall frequency of diabetes mellitus was 2.8% in rosuvastatin and 2.3% in placebo, mostly in patients with fasting glucose 5.6 to 6.9 mmol/l.

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.

Protease inhibitors

Increased systemic exposure to rosuvastatin has been observed in subjects receiving rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Considerationshould be given both to the benefit of lipid lowering by use of ZENON in HIV patients receivingprotease inhibitors and the potential for increased rosuvastatin plasma concentrations wheninitiating and

up titrating rosuvastatin doses in patients treated with protease inhibitors. The concomitant use with certain protease inhibitors is not recommended unless the dose of rosuvastatin is adjusted (see sections 4.2 and 4.5).

Fibrates

The safety and efficacy of ezetimibe administered with fibrates have not been established (see above and sections 4.3 and 4.5).

If cholelithiasis is suspected in a patient receiving ZENON and fenofibrate, gallbladder investigations are indicated and this therapy should be discontinued (see sections 4.5 and 4.8).

Anticoagulants

If ZENON is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalised Ratio (INR) should be appropriately monitored (see section 4.5).

Fusidic acid

ZENON must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination (see section 4.5). The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness.

Statin therapy may be re-introduced seven days after the last dose of fusidic acid.

In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g., for the treatment of severe infections, the need for co-administration of ZENON and fusidic acid should only be considered on a case by case basis and under close medical supervision.

Race

Pharmacokinetic studies show an increase in exposure of rosuvastatin in Asian subjects compared with Caucasians (see sections 4.2, 4.3 and 5.2).

Paediatric population

ZENON is not recommended for use in children and adolescents of less than 18 years of age, due to insufficient data on safety and efficacy.

ZENON contains lactose monohydrate and sodium

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

1.1 Interaction with other medicinal products and other forms of interaction

Contraindicated combinations:

Ciclosporin: Concomitant administration of ZENON with ciclosporin is contraindicated because of the rosuvastatin (see section 4.3). During concomitant treatment with rosuvastatin and ciclosporin, rosuvastatin AUC values were on average 7 times higher than those observed in healthy volunteers (see Table 1). Concomitant administration did not affect plasma concentrations of ciclosporin.

In a study of eight post-renal transplant patients with creatinine clearance of>50 ml/min on a stable dose of ciclosporin, a single 10-mg dose of ezetimibe resulted in a 3.4-fold (range 2.3 to 7.9-fold)

increase in the mean AUC for total ezetimibe compared to a healthy control population,receiving ezetimibe alone, from another study (n=17). In a different study, a renal transplant patient with severe renal impairment who was receiving ciclosporin and multiple other medications, demonstrated a 12-fold greater exposure to total ezetimibe compared to concurrent controls receiving ezetimibe alone. In a two-period crossover study in twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days with a single 100 mg dose of ciclosporin on Day 7 resulted in a mean 15 % increase in ciclosporin AUC (range 10 % decrease to 51 % increase) compared to a single 100 mg dose of ciclosporin alone. A controlled study on the effect of co- administered ezetimibe on ciclosporin exposure in renal transplant patients has not been conducted.

Not-recommended combinations:

Fibrates and other lipid-lowering products: In patients receiving fenofibrate and ezetimibe, physicians should be aware of the possible risk of cholelithiasis and gallbladder disease (see sections 4.4 and 4.8). If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder investigations are indicated and this therapy should be discontinued (see section 4.8). Concomitant fenofibrate or gemfibrozil administration modestly increased total ezetimibe concentrations (approximately 1.5- and 1.7-fold respectively).

Co-administration of ezetimibe with other fibrates has not been studied. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In animal studies, ezetimibe sometimes increased cholesterol in the gallbladder bile, but not in all species (see section 5.3). A lithogenic risk associated with the therapeutic use of ezetimibe cannot be ruled out.

Concomitant use of rosuvastatin and gemfibrozil resulted in a 2-fold increase in rosuvastatin Cmax and AUC (see section 4.4).

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 1g/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/10 mg dose (not available in the Indonesia) is contraindicated with concomitant use of a fibrate (see sections 4.3 and 4.4).

Protease inhibitors: Although the exact mechanism of interaction is unknown, concomitant protease inhibitor use may strongly increase rosuvastatin exposure (see Table 1). In a pharmacokinetic study, co-administration of 10 mg rosuvastatin and a combination product of two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers was associated with an approximately three-fold and seven-fold increase in rosuvastatin AUC and Cmax respectively. The concomitant use of rosuvastatin and some protease inhibitor combinationsmay be considered after careful consideration of rosuvastatin dose adjustments based on the expected increase in rosuvastatin exposure (see sections 4.2, 4.4 and 4.5 Table 1).

Transporter protein inhibitors: Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter OATP1B1 and efflux transporter BCRP. Concomitant administration of rosuvastatin with medicinal products that are inhibitors of these transporter proteins may result in increased rosuvastatin plasma concentrations and an increased risk of myopathy (see sections 4.2, 4.4 and 4.5 Table 1).

Fusidic acid: The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination.

Other interactions:

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 clinically relevant interactions have been observed between rosuvastatin and either fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).

In preclinical studies, it has been shown that ezetimibe does not induce cytochrome P450 drug metabolising enzymes. No clinically significant pharmacokinetic interactions have been observed between ezetimibe and drugs known to be metabolised by cytochromes P450 1A2, 2D6, 2C8, 2C9, and 3A4, or N-acetyltransferase.

Antacids: Concomitant antacid administration decreased the rate of absorption of ezetimibe but had no effect on the bioavailability of ezetimibe. This decreased rate of absorption is notconsidered clinically significant.

The simultaneous dosing of rosuvastatin 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 rosuvastatin. The clinical relevance of this interaction has not been studied.

Colestyramine: Concomitant colestyramine administration decreased the mean area under the curve (AUC) of total ezetimibe (ezetimibe + ezetimibe glucuronide) approximately 55%. The incremental lowdensity lipoprotein cholesterol (LDL C) reduction due to adding ezetimibe to colestyramine may be lessened by this interaction (see section 4.2).

Anticoagulants, Vitamin K antagonists: Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability of warfarin and prothrombin time in a study of twelve healthy adult males. However, there have been post-marketing reports of increased International Normalised Ratio (INR) in patients who had ezetimibe added to warfarin or fluindione. If ZENON is added to warfarin, another coumarin anticoagulant, or fluindione, INR should be appropriately monitored (see section 4.4).

As with other HMG-CoA reductase inhibitors, the initiation of treatment or dosage up-titration of rosuvastatin in patients treated concomitantly with vitamin K antagonists (e.g. warfarin or another coumarin anticoagulant) may result in an increase in International Normalised Ratio (INR). Discontinuation or down-titration of rosuvastatin may result in a decrease in INR. In such situations, appropriate monitoring of INR is desirable.

Erythromycin: Concomitant use of rosuvastatin and erythromycin resulted in a 20% decrease in AUC(0-t) and a 30% decrease in Cmax of rosuvastatin. This interaction may be caused by the increase in gut motility caused by erythromycin.

Oral contraceptive/hormone replacement therapy (HRT): Concomitant use of rosuvastatin andan oral contraceptive resulted in an increase in ethinyl estradiol and norgestrel AUC of 26% and 34%, respectively. These increased plasma levels should be considered when selecting oral contraceptive doses. There are no pharmacokinetic data available in women taking concomitant rosuvastatin and HRT and therefore a similar effect cannot be excluded. However, the combination has been extensively used in women in clinical trials and was well tolerated.

In clinical interaction studies, ezetimibe had no effect on the pharmacokinetics of oral contraceptives (ethinyl estradiol and levonorgestrel).

Other medicinal products: Based on data from specific interaction studies with rosuvastatin no clinically relevant interaction with digoxin is expected. In clinical interaction studies, ezetimibe had no effect on the pharmacokinetics of dapsone, dextromethorphan, digoxin, glipizide, tolbutamide, or midazolam, during co-administration. Cimetidine, co-administered with ezetimibe, had no effect on the bioavailability of ezetimibe.

Zenon