Zenon

ZENON 10 mg/10 mg: White to off-white, round, biconvex, film-coated tablets with a diameter about 9.1 mm.
Each film-coated tablet contains 10 mg rosuvastatin (as rosuvastatin calcium) and 10 mg of ezetimibe.
ZENON 20 mg/10 mg: Yellow to light yellow, round, biconvex, film-coated tablets with a diameter about 9.9 mm.
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.
Excipients/Inactive Ingredients: ZENON 10 mg/10 mg: Core: Lactose monohydrate, Microcrystalline cellulose, Sodium laurilsulfate, Povidone, Colloidal silicon dioxide, Crosscarmellose sodium, Magnesium Stearate.
Coating layer: Hypromellose, Macrogol, Titanium dioxide (E-171), Talc.
ZENON 20 mg/10 mg: Core: Lactose monohydrate, Microcrystalline cellulose, Sodium laurilsulfate, Povidone, Colloidal silicon dioxide, Crosscarmellose sodium, Magnesium Stearate.
Coating layer: Hypromellose, Macrogol, Titanium dioxide (E-171), Talc, Iron oxide yellow (E-172).

Pharmacotherapeutic group: HMG-CoA reductase inhibitors in combination with other lipid modifying agents, rosuvastatin and ezetimibe. ATC code: C10BA06.
Pharmacology: Pharmacodynamics: Ezetimibe: Mechanism of action: Ezetimibe inhibits the intestinal absorption of cholesterol and related plant sterols. Ezetimibe is orally active, and has a mechanism of action that differs from other classes of cholesterol-reducing compounds (e.g. statins, bile acid sequestrants [resins], fibric acid derivatives, and plantstanols). The molecular target of ezetimibe is the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is responsible for the intestinal uptake of cholesterol and phytosterols.
Ezetimibe localises at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver; statins reduce cholesterol synthesis in the liver and together these distinct mechanisms provide complementary cholesterol reduction.
Pharmacodynamic effects: A series of preclinical studies was performed to determine the selectivity of ezetimibe for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of [¹⁴C]-cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or fat soluble vitamins A and D.
Rosuvastatin: 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 precursor for cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for cholesterol lowering.
Rosuvastatin increases the number of hepatic LDL receptors on the cell-surface, enhancing uptake and catabolism of LDL and it inhibits the hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles.
Pharmacodynamic effects: Rosuvastatin reduces elevated LDL-cholesterol, total cholesterol and triglycerides and increases HDL-cholesterol. It also lowers ApoB, nonHDL-C, VLDL-C, VLDL-TG and increases ApoA-I. Rosuvastatin also lowers the LDL-C/HDL-C, total C/HDL-C and nonHDL-C/HDL-C and the ApoB/ApoA-I ratios.
Pharmacokinetics: The bioequivalence of ZENON with the co-administration of reference monocomponent formulations has been demonstrated in a bioequivalence study under fasting conditions based on primary free ezetimibe and rosuvastatin pharmacokinetic parameters C_max and AUC_0-72 (ezetimibe), AUC_0-t (rosuvastatin). The 90% geometric confidence intervals of the ratio (A/B) of least-squares means of the in-transformed AUC_0-72, AUC_0-t, and C_max were within 80.00% to 125.00% for ezetimibe/rosuvastatin 10mg/40mg film coated tablet vs. the corresponding reference treatments. This proof of bioequivalence may be extrapolated to dosage strengths 10mg/20mg and 10mg/10mg, since all conditions for the biostudy exemption were met.
No serious adverse events (SAE) and no deaths were reported for any of the subjects enrolled in this study.
Toxicology: Preclinical safety data: In co-administration studies with ezetimibe and statins the toxic effects observed were essentially those typically associated with statins. Some of the toxic effects were more pronounced than observed during treatment with statins alone. This is attributed to pharmacokinetic and pharmacodynamic interactions in co-administration therapy. No such interactions occurred in the clinical studies. Myopathies occurred in rats only after exposure to doses that were several times higher than the human therapeutic dose (approximately 20 times the AUC level for statins and 500 to 2,000 times the AUC level for the active metabolites).
The co-administration of ezetimibe and statins was not teratogenic in rats. In pregnant rabbits a small number of skeletal deformities (fused thoracic and caudal vertebrae, reduced number of caudal vertebrae) were observed.
In a series of in vivo and in vitro assays ezetimibe, given alone or co-administered with statins, exhibited no genotoxic potential.
Ezetimibe: Animal studies on the chronic toxicity of ezetimibe identified no target organs for toxic effects. In dogs treated for four weeks with ezetimibe (≥0.03 mg/kg/day) the cholesterol concentration in the cystic bile was increased by a factor of 2.5 to 3.5. However, in a one-year study on dogs given doses of up to 300 mg/kg/day no increased incidence of cholelithiasis or other hepatobiliary effects were observed. The significance of these data for humans is not known. A lithogenic risk associated with the therapeutic use of ezetimibe cannot be ruled out.
Long-term carcinogenicity tests on ezetimibe were negative.
Ezetimibe had no effect on the fertility of male or female rats, nor was it found to be teratogenic in rats or rabbits, nor did it affect prenatal or postnatal development. Ezetimibe crossed the placental barrier in pregnant rats and rabbits given multiple doses of 1,000 mg/kg/day.
Rosuvastatin: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenicity potential. Specific tests for effects on hERG have not been evaluated. Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels were as follows: In repeated-dose toxicity studies histopathologic liver changes likely due to the pharmacologic action of rosuvastatin were observed in mouse, rat, and to a lesser extent with effects in the gall bladder in dogs, but not in monkeys. In addition, testicular toxicity was observed in monkeys and dogs at higher dosages. Reproductive toxicity was evident in rats, with reduced litter sizes, litter weight and pup survival observed at maternally toxic doses, where systemic exposures were several times above the therapeutic exposure level.

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.

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 Interactions).
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 Precautions). 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 Precautions and Pharmacology: Pharmacokinetics under Actions). ZENON is contraindicated in patients with active liver disease (see Contraindications).
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 Contraindications and Pharmacology: Pharmacokinetics under Actions).
Race: Increased systemic exposure of rosuvastatin has been seen in Asian subjects (see Precautions and Pharmacology: Pharmacokinetics under Actions). 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 Pharmacology: Pharmacokinetics under Actions). For patients who are known to have such specific types of 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 Precautions). 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 Precautions and Interactions).
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 Interactions).
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.

In the event of an overdose, symptomatic and supportive measures should be employed.
Ezetimibe: In clinical studies, administration of ezetimibe, 50 mg/day, to 15 healthy subjects for up to 14 days, or 40 mg/day to 18 patients with primary hypercholesterolaemia for up to 56 days, was generally well tolerated. In animals, no toxicity was observed after single oral doses of 5,000 mg/kg of ezetimibe in rats and mice and 3,000 mg/kg in dogs.
A few cases of overdosage with ezetimibe have been reported: most have not been associated with adverse experiences. Reported adverse experiences have not been serious.
Rosuvastatin: Liver function and CK levels should be monitored. Haemodialysis is unlikely to be of benefit.

Hypersensitivity to the active substances or to any of the excipients listed in Description.
Pregnancy, breast-feeding and in women of childbearing potential not using appropriate contraceptive measures (see Use in Pregnancy & Lactation).
Active liver disease or unexplained persistent elevations in serum transaminases and any serum transaminase elevation exceeding 3x the upper limit of normal (ULN) (see Precautions).
In patients with severe renal impairment (creatinine clearance <30 ml/min) (see Precautions).
In patients with myopathy (see Precautions).
In patients receiving concomitant ciclosporin (see Interactions).

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 Adverse Reactions).
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 Dosage & Administration, Interactions and Pharmacology: Pharmacokinetics under Actions), 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 Interactions and Adverse Reactions).
ZENON should not be used in any patient with an acute, serious condition suggestive of myopathy 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 Pharmacology: Pharmacokinetics under Actions).
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 Adverse Reactions). 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 Adverse Reactions). 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. Consideration should be given both to the benefit of lipid lowering by use of ZENON in HIV patients receiving protease inhibitors and the potential for increased rosuvastatin plasma concentrations when initiating 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 Dosage & Administration and Interactions).
Fibrates: The safety and efficacy of ezetimibe administered with fibrates have not been established (see as previously mentioned and Contraindications and Interactions).
If cholelithiasis is suspected in a patient receiving ZENON and fenofibrate, gallbladder investigations are indicated and this therapy should be discontinued (see Interactions and Adverse Reactions).
Anticoagulants: If ZENON is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalised Ratio (INR) should be appropriately monitored (see Interactions).
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 Interactions). 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 Dosage & Administration, Contraindications and Pharmacology: Pharmacokinetics under Actions).
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'.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed. However, when driving vehicles or operating machines, it should be taken into account that dizziness has been reported.
Use in Children: 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 is contraindicated during pregnancy and breast-feeding (see Contraindications). Women of childbearing potential should use appropriate contraceptive measures.
Pregnancy: No clinical data are available on the use of ezetimibe during pregnancy. Animal studies on the use of ezetimibe in monotherapy have shown no evidence of direct or indirect harmful effects on pregnancy, embryofoetal development, birth or postnatal development (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Since cholesterol and other products of cholesterol biosynthesis are essential for the development of the foetus, the potential risk from inhibition of HMG-CoA reductase outweighs the advantage of treatment during pregnancy. Animal studies provide limited evidence of reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). If a patient becomes pregnant during use of ZENON, treatment should be discontinued immediately.
Breast-feeding: Studies on rats have shown that ezetimibe is secreted into breast milk. It is not known if ezetimibe is secreted into human breast milk.
Rosuvastatin is excreted in the milk of rats. There are no data with respect to excretion in milk in humans (see Contraindications).
Fertility: No clinical trial data are available on the effects of ezetimibe or rosuvastatin on human fertility. Ezetimibe had no effects on the fertility of male or female rats, rosuvastatin at higher doses showed testicular toxicity in monkeys and dogs (see Pharmacology: Toxicology: Preclinical safety data under Actions).

Summary of safety profile: Adverse drug reactions previously reported with one of the individual components (ezetimibe or rosuvastatin) may be potential undesirable effects with ZENON.
In clinical studies of up to 112 weeks duration, ezetimibe 10 mg daily was administered alone in 2,396 patients, with a statin in 11,308 patients or with fenofibrate in 185 patients.
Adverse reactions were usually mild and transient. The overall incidence of side effects was similar between ezetimibe and placebo. Similarly, the discontinuation rate due to adverse experiences was comparable between ezetimibe and placebo.
The adverse events seen with rosuvastatin are generally mild and transient. In controlled clinical trials, less than 4% of rosuvastatin-treated patients were withdrawn due to adverse events.
Tabulated list of adverse reactions: The frequencies of adverse reactions are ranked according to the following convention: 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 (cannot be estimated from the available data). (See Table 1.)


Click on icon to see table/diagram/image


As with other HMG-CoA reductase inhibitors, the incidence of adverse drug reactions tends to be dose dependent.
Renal effects: Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with rosuvastatin. Shifts in urine protein from none or trace to ++ or more were seen in <1% of patients at some time during treatment with 10 and 20 mg, and in approximately 3% of patients treated with 40 mg. A minor increase in shift (from none or trace to +) was observed with the 20 mg dose. In most cases, proteinuria decreases or disappears spontaneously on continued therapy. Review of data from clinical trials and post-marketing experience to date has not identified a causal association between proteinuria and acute or progressive renal disease.
Haematuria has been observed in patients treated with rosuvastatin and clinical trial data show that the occurrence is low.
Skeletal muscle effects: Effects on skeletal muscle e.g. myalgia, myopathy (including myositis) and, rarely, rhabdomyolysis with and without acute renal failure have been reported have been reported in rosuvastatin-treated patients with all doses and in particular with doses >20 mg.
A dose-related increase in CK levels has been observed in patients taking rosuvastatin; the majority of cases were mild, asymptomatic and transient. If CK levels are elevated (>5xULN), treatment should be discontinued (see Precautions).
Liver effects: As with other HMG-CoA reductase inhibitors, a dose-related increase in transaminases has been observed in a small number of patients taking rosuvastatin; the majority of cases were mild, asymptomatic and transient.
The reporting rates for rhabdomyolysis, serious renal events and serious hepatic events (consisting mainly of increased hepatic transaminases) is higher at the 40 mg dose.
The following adverse events have been reported with some statins: Sexual dysfunction; Exceptional cases of interstitial lung disease, especially with long term therapy (see Precautions).
Laboratory values: In controlled clinical monotherapy trials, the incidence of clinically important elevations in serum transaminases (ALT and/or AST ≥3XULN, consecutive) was similar between ezetimibe (0.5%) and placebo (0.3%). In co-administration trials, the incidence was 1.3% for patients treated with ezetimibe co-administered with a statin and 0.4% for patients treated with a statin alone. These elevations were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment (see Precautions).
In clinical trials, CPK>10XULN was reported for 4 of 1,674 (0.2%) patients administered ezetimibe alone vs 1 of 786 (0.1%) patients administered placebo, and for 1 of 917 (0.1%) patients co-administered ezetimibe and a statin vs 4 of 929 (0.4%) patients administered a statin alone. There was no excess of myopathy or rhabdomyolysis associated with ezetimibe compared with the relevant control arm (placebo or statin alone) (see Precautions).
Paediatric population: The safety and efficacy of ZENON in children below the age of 18 years have not yet been established (see Pharmacology: Pharmacodynamics under Actions).
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Contraindicated combinations: Ciclosporin: Concomitant administration of ZENON with ciclosporin is contraindicated because of the rosuvastatin (see Contraindications). During concomitant treatment with rosuvastatin and ciclosporin, rosuvastatin AUC values were on average 7 times higher than those observed in healthy volunteers (see Table 2). 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 Precautions and Adverse Reactions). If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder investigations are indicated and this therapy should be discontinued (see Adverse Reactions). 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 Pharmacology: Toxicology: Preclinical safety data under Actions). 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 C_max and AUC (see Precautions).
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 Contraindications and Precautions).
Protease inhibitors: Although the exact mechanism of interaction is unknown, concomitant protease inhibitor use may strongly increase rosuvastatin exposure (see Table 2). 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 C_max respectively. The concomitant use of rosuvastatin and some protease inhibitor combinations may be considered after careful consideration of rosuvastatin dose adjustments based on the expected increase in rosuvastatin exposure (see Dosage & Administration, Precautions and Table 2 as follows).
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 Dosage & Administration, Precautions and Table 2 as follows).
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.
If treatment with systemic fusidic acid is necessary, rosuvastatin treatment should be discontinued throughout the duration of the fusidic acid treatment. Also see Precautions.
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 not considered 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 low-density lipoprotein cholesterol (LDL C) reduction due to adding ezetimibe to colestyramine may be lessened by this interaction (see Dosage & Administration).
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 Precautions).
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 C_max 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 and an 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.
Interactions requiring rosuvastatin dose adjustments (see also Table 2): When it is necessary to co-administer rosuvastatin with other medicinal products known to increase exposure to rosuvastatin, doses should be adjusted. The maximum daily dose should be adjusted so that the expected rosuvastatin exposure would not likely exceed that of a 40 mg daily dose of rosuvastatin taken without interacting medicinal products, for example a 20 mg dose of rosuvastatin with gemfibrozil (1.9-fold increase), and a 10 mg dose of rosuvastatin with combination ritonavir/atazanavir (3.1-fold increase). (See Table 2.)


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Incompatibilities: Not applicable.
Special precautions for disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Shelf life: 3 years.
Store below 30°C in the original package in order to protect from moisture and light.

Dyslipidaemic Agents

C10BA06 - rosuvastatin and ezetimibe ; Belongs to the class of HMG CoA reductase inhibitors in combination with other lipid modifying agents. Used in the treatment of hyperlipidemia.

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