Mertenil

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MERTENIL (MERTENIL®)

Composition:

Active ingredient: rosuvastatin;

One tablet contains rosuvastatin 5 mg, 10 mg, or 20 mg, equivalent to 5.2 mg, 10.4 mg, or 20.8 mg of rosuvastatin calcium;

Excipients: lactose monohydrate, microcrystalline cellulose, magnesium hydroxide, crospovidone, magnesium stearate; film coating: polyvinyl alcohol, titanium dioxide (E 171), macrogol, talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Mertenil, film-coated tablets, 5 mg: white or almost white, round, biconvex film-coated tablets, approximately 5.5 mm in diameter. One side of the tablet is engraved with "C33".

Mertenil, film-coated tablets, 10 mg: white or almost white, round, biconvex film-coated tablets, approximately 7 mm in diameter. One side of the tablet is engraved with "C34".

Mertenil, film-coated tablets, 20 mg: white or almost white, round, biconvex film-coated tablets, approximately 9 mm in diameter. One side of the tablet is engraved with "C35".

Pharmacotherapeutic group. Hypolipidemic agents, single-component. HMG-CoA reductase inhibitors. Rosuvastatin. ATC code C10AA07.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the enzyme that catalyzes the rate-limiting step in the conversion of 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. The primary site of action of rosuvastatin is the liver—the target organ for cholesterol-lowering agents. Rosuvastatin increases the number of LDL receptor molecules on the surface of liver cells, enhancing the uptake and catabolism of LDL, and inhibits LDL synthesis in the liver, thereby reducing the total number of LDL and VLDL particles.

Pharmacodynamic effects.

Rosuvastatin reduces elevated levels of LDL-cholesterol, total cholesterol, and triglycerides (TG), while increasing HDL-cholesterol levels. It also decreases levels of ApoB, non-HDL-cholesterol, LDL-cholesterol, TG-rich LDL, and increases ApoA-I levels. Rosuvastatin reduces the ratios of LDL-C/HDL-C, total cholesterol/HDL-C, non-HDL-C/HDL-C, and ApoB/ApoA-I.

Dose-response in patients with primary hypercholesterolemia (type IIa and IIb) (adjusted mean percent change from baseline)

Dose	N	LDL-C	Total Cholesterol	HDL-C	Triglycerides	Non-HDL-C	Apo B	Apo A-I
Placebo	13	-7	-5	3	-3	-7	-3	0
5 mg	17	-45	-33	13	-35	-44	-38	4
10 mg	17	-52	-36	14	-10	-48	-42	4
20 mg	17	-55	-40	8	-23	-51	-46	5
40 mg	18	-63	-46	10	-28	-60	-54	0

The therapeutic effect becomes apparent within one week after initiation of therapy; after 2 weeks of treatment, the effect reaches 90% of the maximum possible. Maximum effect is generally achieved after 4 weeks and is maintained thereafter.

Pharmacokinetics.

Absorption. Maximum plasma concentration of rosuvastatin is reached approximately 5 hours after oral administration. Absolute bioavailability is approximately 20%.

Distribution. Rosuvastatin is significantly taken up by the liver, which is the primary site of cholesterol synthesis and LDL-cholesterol clearance. The volume of distribution of rosuvastatin is approximately 134 L. Approximately 90% of rosuvastatin is bound to plasma proteins, primarily albumin.

Biological transformation. Rosuvast inflamm undergoes limited metabolism (approximately 10%).
In vitro studies of metabolism using human hepatocytes indicate that rosuvastatin is a weak substrate for metabolism by cytochrome P450 enzymes. CYP2C9 is the main isoenzyme involved in metabolism, while CYP2C19, CYP3A4, and CYP2D6 isoenzymes play a lesser role. The main metabolites are N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, while lactone metabolites are pharmacologically inactive. More than 90% of the pharmacological activity related to inhibition of circulating HMG-CoA reductase is provided by rosuvastatin.

Elimination. Approximately 90% of the administered dose of rosuvastatin is excreted unchanged via the intestine (including both absorbed and unabsorbed rosuvastatin), and the remainder is excreted unchanged by the kidneys. Approximately 5% is excreted unchanged in urine. The plasma elimination half-life (T½) is 19 hours and does not increase with higher doses of the drug. The mean geometric value of plasma clearance is approximately 50 L/hour (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, the hepatic uptake of rosuvastatin involves the membrane transporter OATP-C. This transporter plays a significant role in the hepatic elimination of rosuvastatin.

Linearity. Systemic exposure to rosuvastatin increases proportionally with dose. No changes in pharmacokinetic parameters are observed with multiple daily dosing.

Special patient groups

Age and gender. No clinically significant effect of age or gender on the pharmacokinetics of rosuvastatin has been observed in adults. Exposure in children and adolescents with heterozygous familial hypercholesterolemia was similar to or lower than exposure in adult volunteers (see section "Children" below).

Race. Comparative pharmacokinetic studies showed an approximately 2-fold increase in mean AUC and Cmax values in patients of Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese, and Koreans) compared to those in Caucasian patients. In Indians, an increase of approximately 1.3-fold in mean AUC and Cmax values was observed. Analysis of pharmacokinetic parameters for the entire study group did not reveal clinically significant differences in the pharmacokinetics of the drug between Caucasians and Black patients.

Renal impairment. In a study of patients with various degrees of renal impairment, plasma concentrations of rosuvastatin or its N-desmethyl metabolite did not change in patients with mild to moderate renal impairment. In patients with severe renal impairment (creatinine clearance <30 mL/min), plasma concentrations of rosuvastatin increased 3-fold and N-desmethyl metabolite concentrations increased 9-fold compared to healthy volunteers. Plasma concentrations of rosuvastatin in patients undergoing hemodialysis were approximately 50% higher than in healthy volunteers.

Hepatic impairment. In a study of patients with various degrees of hepatic impairment, no data indicated increased systemic exposure to rosuvastatin in individuals with a Child–Pugh score of 7 or lower. However, in patients with a Child–Pugh score of 8 or 9, systemic exposure was at least doubled compared to patients with lower Child–Pugh scores. There is no experience with the use of rosuvastatin for the treatment of patients with hepatic impairment exceeding a Child–Pugh score of 9.

Genetic polymorphism

The distribution of HMG-CoA reductase inhibitors, including rosuvastatin, involves transport proteins OATP1B1 and BCRP. Patients with polymorphisms in the SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) genes have an increased risk of elevated rosuvastatin exposure. With specific polymorphisms SLCO1B1 c.521CC and ABCG2 c.421AA, rosuvastatin exposure (AUC) is increased compared to genotypes SLCO1B1 c.521TT or ABCG2 c.421CC. Routine genotyping is not required in clinical practice; however, patients with such polymorphisms are recommended to receive a lower daily dose of rosuvastatin.

Children

Drug exposure in children aged 10 to 17 or 6 to 17 years with heterozygous familial hypercholesterolemia is similar to or lower than exposure in adult patients. Rosuvastatin exposure was dose-proportional and consistent over a period of more than 2 years.

Clinical characteristics.

Indications.

Treatment of hypercholesterolemia.

For adults, adolescents, and children aged 6 years and older with primary hypercholesterolemia (type IIa, including heterozygous familial hypercholesterolemia) or mixed dyslipidemia (type IIb), as an adjunct to diet, when dietary measures and other non-pharmacological interventions (e.g., physical exercise, weight reduction) are insufficient.

For adults, adolescents, and children aged 6 years and older with homozygous familial hypercholesterolemia, as an adjunct to diet and other lipid-lowering treatments (e.g., LDL apheresis), or when such therapy is not sufficiently effective.

Prevention of cardiovascular events

Prevention of major cardiovascular events in patients estimated to be at high risk of a first cardiovascular event (see section "Pharmacodynamics"), as an adjunct to correction of other risk factors.

Contraindications.

• Patients with hypersensitivity to rosuvastatin or to any of the excipients listed in the "Composition" section;
• Patients with active liver disease, including cases of unknown etiology, with persistent elevations in liver transaminase activity, or with serum levels of any transaminase exceeding three times the upper limit of normal (ULN);
• Patients with severe renal impairment (creatinine clearance < 30 mL/min);
• Patients with myopathy;
• Patients receiving concomitant combination therapy with sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other forms of interaction");
• Patients receiving concomitant cyclosporine;
• During pregnancy and breastfeeding, as well as in women of childbearing potential who are not using reliable contraceptive methods.

Administration of the 40 mg dose is contraindicated in patients with factors predisposing to myopathy/rhabdomyolysis. These factors include:

• Moderate renal impairment (creatinine clearance < 60 mL/min);
• Hypothyroidism;
• Personal or family history of hereditary muscle disorders;
• History of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;
• Alcohol abuse;
• Conditions that may lead to increased plasma concentrations of rosuvastatin;
• Belonging to the Mongoloid race;
• Concomitant use of fibrates (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Effect of concomitant medicinal products on rosuvastatin

Inhibitors of transporter proteins

Rosuvastatin is a substrate for certain transporter proteins, including the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant use of rosuvastatin with medicinal products that inhibit these transporter proteins may increase plasma concentrations of rosuvastatin and increase the risk of myopathy (see sections "Posology and method of administration", "Special warnings and precautions for use", "Interaction with other medicinal products and other forms of interaction", Table 1).

Cyclosporine

During concomitant use of rosuvastatin and cyclosporine, rosuvastatin AUC values were on average approximately 7 times higher than those observed in healthy volunteers (see Table 1). Rosuvastatin is contraindicated in patients receiving cyclosporine (see section "Contraindications").

Concomitant use did not affect cyclosporine plasma concentrations.

Protease inhibitors

Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors may significantly increase rosuvastatin exposure (see Table 1). For example, in a pharmacokinetic study, concomitant administration of 10 mg rosuvastatin and a combination drug containing two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers resulted in approximately 3-fold and 7-fold increases in rosuvastatin AUC and Cmax, respectively. Concomitant use of rosuvastatin with certain protease inhibitor combinations may be possible after careful consideration of rosuvastatin dose adjustment based on the expected increase in rosuvastatin exposure (see sections "Posology and method of administration", "Special warnings and precautions for use", "Interaction with other medicinal products and other forms of interaction", Table 1).

Gemfibrozil and other lipid-lowering agents

Concomitant use of rosuvastatin and gemfibrozil resulted in a 2-fold increase in rosuvastatin AUC and Cmax (see section "Special warnings and precautions for use").

Based on data from specific studies, no pharmacokinetically significant interaction with fenofibrate is expected; however, pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and lipid-lowering doses of niacin (> or = 1 g/day) increase the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, likely because they may cause myopathy when used alone. The 40 mg dose of rosuvastatin is contraindicated when used concomitantly with fibrates (see sections "Contraindications" and "Special warnings and precautions for use"). Such patients should also initiate therapy with a 5 mg dose.

Ezetimibe

Concomitant administration of 10 mg rosuvastatin and 10 mg ezetimibe to patients with hypercholesterolemia resulted in a 1.2-fold increase in rosuvastatin AUC (Table 1). However, a pharmacodynamic interaction between rosuvastatin and ezetimibe cannot be excluded, which may lead to adverse effects (see section "Special warnings and precautions for use").

Antacid agents

Concomitant use of rosuvastatin with antacid suspensions containing aluminum and magnesium hydroxide reduces rosuvastatin plasma concentration by approximately 50%. This effect was less pronounced when antacids were administered 2 hours after rosuvastatin. The clinical significance of this interaction has not been studied.

Erythromycin

Concomitant use of rosuvastatin and erythromycin reduced rosuvastatin AUC(0-t) by 20% and Cmax by 30%. This interaction may be due to enhanced intestinal motility caused by erythromycin.

Cytochrome P450 enzymes

Results from in vitro and in vivo studies indicate that rosuvastatin does not inhibit or induce cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate of these isoenzymes. Therefore, drug interactions mediated by P450 metabolism are not expected. No clinically significant interactions were observed between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).

Ticagrelor

Ticagrelor may affect renal excretion of rosuvastatin, increasing the risk of its accumulation. Although the exact mechanism is unknown, in some cases, concomitant use of ticagrelor and rosuvastatin has led to impaired renal function, elevated creatine phosphokinase levels, and rhabdomyolysis.

Interactions with medicinal products requiring rosuvastatin dose adjustment (see also Table 1)

When rosuvastatin must be used concomitantly with medicinal products capable of increasing rosuvastatin exposure, the rosuvastatin dose should be adjusted. When prescribing Mertenil with other medicinal products, the respective product information should be consulted. If rosuvastatin exposure (AUC) is expected to increase approximately 2-fold or more, treatment should be initiated with a 5 mg once-daily dose. The maximum daily dose of rosuvastatin should be adjusted so that the expected rosuvastatin exposure does not exceed that observed with a 40 mg/day dose in the absence of interacting medicinal products; for example, when used with gemfibrozil, the rosuvastatin dose should be 20 mg (1.9-fold increase in exposure), and when used with ritonavir/atazanavir combination, 10 mg (3.1-fold increase in exposure).

If a medicinal product increases rosuvastatin AUC by less than 2-fold, dose reduction is not required initially; however, caution should be exercised when increasing the Mertenil dose above 20 mg.

Table 1. Effect of concomitant medicinal products on rosuvastatin exposure (AUC; in descending order of magnitude) based on published clinical study data.

Increased AUC of rosuvastatin by 2-fold or more
Dosing regimen of the interacting drug	Dosing regimen of rosuvastatin	Change in rosuvastatin AUC*
Sofosbuvir/velpatasvir/voxilaprevir (400 mg–100 mg–100 mg) + voxilaprevir (100 mg) once daily for 15 days	10 mg, single dose	↑ 7.4-fold
Cyclosporine, from 75 mg twice daily to 200 mg twice daily, 6 months	10 mg once daily, 10 days	↑ 7.1-fold
Darolutamide 600 mg twice daily, 5 days	5 mg, single dose	↑ 5.2-fold
Regorafenib 160 mg once daily, 14 days	5 mg, single dose	↑ 3.8-fold
Atazanavir 300 mg/ritonavir 100 mg once daily, 8 days	10 mg, single dose	↑ 3.1-fold
Velpatasvir 100 mg once daily	10 mg, single dose	↑ 2.7-fold
Obitasvir 25 mg/paritaprevir 150 mg/ritonavir 100 mg once daily + dasabuvir 400 mg twice daily, 14 days	5 mg, single dose	↑ 2.6-fold
Teriflunomide	Data not available	↑ 2.5-fold
Grazoprevir 200 mg/elbasvir 50 mg once daily, 11 days	10 mg, single dose	↑ 2.3-fold
Glecaprevir 400 mg/pibrentasvir 120 mg once daily, 7 days	5 mg once daily, 7 days	↑ 2.2-fold
Lopinavir 400 mg/ritonavir 100 mg twice daily, 17 days	20 mg once daily, 7 days	↑ 2.1-fold
Capmatinib 400 mg twice daily	10 mg, single dose	↑ 2.1-fold
Clopidogrel 300 mg loading dose, then 75 mg for 24 hours	20 mg once daily	↑ 2-fold
Fostamatinib 100 mg twice daily	20 mg, single dose	↑ 2.0-fold
Febuxostat 120 mg once daily	10 mg, single dose	↑ 1.9-fold
Gemfibrozil 600 mg twice daily, 7 days	80 mg, single dose	↑ 1.9-fold
Increased AUC of rosuvastatin less than 2-fold
Dosing regimen of the interacting drug	Dosing regimen of rosuvastatin	Change in rosuvastatin AUC*
Elotrombopag 75 mg once daily, 5 days	10 mg, single dose	↑ 1.6-fold
Darunavir 600 mg/ritonavir 100 mg twice daily, 7 days	10 mg once daily, 7 days	↑ 1.5-fold
Tipranavir 500 mg/ritonavir 200 mg twice daily, 11 days	10 mg, single dose	↑ 1.4-fold
Dronedarone 400 mg twice daily	Data not available	↑ 1.4-fold
Itraconazole 200 mg once daily, 5 days	10 mg single dose	↑ 1.4-fold**
Ezetimibe 10 mg once daily, 14 days	10 mg once daily, 14 days	↑ 1.2-fold**
Decreased AUC of rosuvastatin
Dosing regimen of the interacting drug	Dosing regimen of rosuvastatin	Change in rosuvastatin AUC*
Erythromycin 500 mg four times daily, 7 days	80 mg, single dose	↓ 20%
Baicalin 50 mg three times daily, 14 days	20 mg, single dose	↓ 47%
No clinically significant effect on rosuvastatin AUC ratio
Dosing regimen of the interacting drug	Dosing regimen of rosuvastatin	Change in rosuvastatin AUC*
Fosamprenavir 700 mg/ritonavir 100 mg twice daily, 8 days	10 mg, single dose	↔
Aleglitazar 0.3 mg, 7 days	40 mg, 7 days	↔
Silymarin 140 mg three times daily, 5 days	10 mg, single dose	↔
Fenofibrate 67 mg three times daily, 7 days	10 mg, 7 days	↔
Rifampicin 450 mg once daily, 7 days	20 mg, single dose	↔
Ketoconazole 200 mg twice daily, 7 days	80 mg, single dose	↔
Fluconazole 200 mg once daily, 11 days	80 mg, single dose	↔

*Data presented as fold change represent a simple ratio between rosuvastatin used in combination and rosuvastatin used alone. Data presented as % change represent % difference relative to values with rosuvastatin used alone.

An increase is indicated by ↑, no change by ↔, and a decrease by ↓.

**Several interaction studies were conducted at different rosuvastatin doses; the most significant ratios are presented in Table 1.

Effect of rosuvastatin on concomitant medicinal products

Vitamin K antagonists

As with other HMG-CoA reductase inhibitors, initiation of treatment with rosuvastatin or increasing its dose in patients concurrently taking vitamin K antagonists (e.g., warfarin or other coumarin anticoagulants) may lead to an increase in the international normalized ratio (INR). Upon discontinuation or dose reduction of rosuvastatin, INR may decrease. In such cases, appropriate monitoring of INR is recommended.

Oral contraceptives / hormone replacement therapy (HRT)

Concomitant use of rosuvastatin and oral contraceptives resulted in a 26% and 34% increase in AUC of ethinylestradiol and norgestimate, respectively. This increase in plasma levels should be considered when selecting the dose of oral contraceptives. There are no data on the pharmacokinetics of medicinal products in patients concurrently taking rosuvastatin and HRT; therefore, the possibility of interaction cannot be excluded. However, this combination has been widely used in women in clinical trials and was well tolerated.

Other medicinal products

Digoxin

Based on specific interaction studies, no clinically significant interaction with digoxin is expected.

Fusidic acid

Interaction studies between rosuvastatin and fusidic acid have not been conducted. The risk of developing myopathy, including rhabdomyolysis, may be increased when systemic fusidic acid is used concomitantly with statins. The mechanism of this interaction (pharmacodynamic, pharmacokinetic, or both) is currently unknown. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving this combination.

If treatment with systemic fusidic acid is necessary, rosuvastatin therapy should be discontinued for the entire duration of fusidic acid treatment (see section "Special precautions for use").

Children

Interaction studies have been conducted only in adults. The extent of interaction in children is unknown.

Special precautions for use.

Severe skin adverse reactions

Severe skin adverse reactions, including Stevens-Johnson syndrome (SJS) and drug-induced eosinophilia with systemic symptoms (DRESS syndrome), have been reported with rosuvastatin use, which may be life-threatening or result in death (see section "Adverse reactions"). Patients should be informed about the signs and symptoms of severe skin reactions and closely monitored during treatment. If signs or symptoms suggestive of such reactions occur, Mertenil should be discontinued immediately and alternative therapy considered.

If a patient develops a serious reaction such as SJS or DRESS syndrome associated with the use of Mertenil, treatment must be discontinued immediately and the drug must never be used again.

Renal effects

Proteinuria (detected by dipstick testing), predominantly of tubular origin and mostly transient or intermittent, has been observed in patients receiving Mertenil, particularly at high doses such as 40 mg. However, proteinuria was not indicative of acute or progressive renal disease (see section "Adverse reactions"). Serious renal adverse events in the post-marketing period have been reported more frequently with the 40 mg dose. Renal function should be regularly monitored in patients taking the 40 mg dose.

Effects on skeletal muscle

Skeletal muscle disorders such as myalgia, myopathy, and rarely rhabdomyolysis, have been observed in patients receiving any dose of Mertenil, particularly at doses exceeding 20 mg. Cases of rhabdomyolysis have been very rarely reported with the use of ezetimibe in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be excluded (see section "Interaction with medicinal products and other forms of interaction"), therefore such combination should be used with caution.

As with other HMG-CoA reductase inhibitors, the frequency of post-marketing reports of rhabdomyolysis associated with rosuvastatin has been higher with the 40 mg dose.

Neuromuscular effects

There have been isolated reports that statins may induce de novo or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). If symptoms worsen, treatment with Mertenil should be discontinued. Recurrences have been reported upon re-challenge with the same or another statin.

Creatine kinase measurement

Creatine kinase (CK) levels should not be measured following significant physical exertion or in the presence of possible alternative causes of elevated CK, which may complicate interpretation of results. If baseline CK levels are markedly elevated (> 5 times the upper limit of normal [ULN]), a repeat test should be performed within 5–7 days to confirm the results. If the repeat test confirms baseline CK levels exceeding 5 times ULN, treatment should not be initiated.

Before starting treatment

Mertenil, like other HMG-CoA reductase inhibitors, should be prescribed with caution in patients predisposed to myopathy/rhabdomyolysis. Such risk factors include:

• renal impairment;
• hypothyroidism;
• personal or family history of hereditary muscle disorders;
• history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;
• alcohol abuse;
• age > 70 years;
• conditions that may lead to increased plasma levels of the drug (see sections "Dosage and administration", "Interaction with other medicinal products and other forms of interaction", and "Pharmacokinetics");
• concomitant use of fibrates.

In such patients, the benefit-risk ratio should be carefully assessed, and patient monitoring is recommended. Treatment should not be initiated if baseline CK levels are significantly elevated (> 5 times ULN).

During treatment

Patients should be advised to promptly report unexplained muscle pain, weakness, or cramps, especially if accompanied by malaise or fever. In such patients, CK levels should be measured. Treatment should be discontinued if CK levels are markedly elevated (> 5 × ULN) or if muscle symptoms are severe and interfere with daily activities (even if CK ≤ 5 × ULN). If symptoms resolve and CK levels return to normal, Mertenil or an alternative HMG-CoA reductase inhibitor may be cautiously reintroduced at the lowest dose under medical supervision. Routine monitoring of CK levels in patients without the aforementioned symptoms is not required. Very rare cases of immune-mediated necrotizing myopathy (IMNM) have been reported during or after statin therapy, including with rosuvastatin. Clinical features of IMNM include proximal muscle weakness and elevated serum creatine kinase levels that persist even after discontinuation of statin therapy.

Clinical trials have not shown increased skeletal muscle effects in a small number of patients receiving rosuvastatin with concomitant medications. However, increased incidence of myositis and myopathy has been observed in patients receiving other HMG-CoA reductase inhibitors concomitantly with fibric acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid, azole antifungals, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used concomitantly with certain HMG-CoA reductase inhibitors; therefore, rosuvastatin is not recommended to be used in combination with gemfibrozil. The benefit of further lipid-lowering with rosuvastatin in combination with fibrates or niacin should be carefully weighed against the potential risks associated with such combinations. Concomitant use of rosuvastatin 40 mg and fibrates is contraindicated (see sections "Interaction with medicinal products and other forms of interaction" and "Adverse reactions").

Mertenil should not be used concomitantly with systemic fusidic acid or within 7 days after discontinuation of fusidic acid treatment. In patients for whom systemic fusidic acid is considered necessary, statin therapy should be discontinued for the entire duration of fusidic acid treatment. Cases of rhabdomyolysis (including several fatal cases) have been reported in patients receiving concomitant fusidic acid and statins (see section "Interaction with other medicinal products and other forms of interaction"). Patients should seek immediate medical attention if they experience any symptoms of muscle weakness, pain, or tenderness.

Statin therapy may be restarted 7 days after the last dose of fusidic acid. In exceptional cases where prolonged systemic fusidic acid treatment is required, e.g., for the treatment of severe infections, the need for concomitant use of Mertenil and fusidic acid should be considered on a case-by-case basis under close medical supervision.

Mertenil should not be used in patients with acute, serious conditions indicating myopathy or risk of renal failure due to rhabdomyolysis (such as sepsis, arterial hypotension, major surgery, trauma, severe metabolic, endocrine, and electrolyte disturbances, or uncontrolled seizures).

Hepatic effects

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

Liver function tests should be performed before initiating treatment and again after 3 months of therapy. Mertenil should be discontinued or the dose reduced if serum transaminase levels exceed three times the upper limit of normal. The frequency of post-marketing reports of serious hepatic events (mainly elevated liver transaminases) was higher with the 40 mg dose.

In patients with secondary hypercholesterolemia due to hypothyroidism or nephrotic syndrome, treatment of the underlying condition should be initiated before starting Mertenil.

Race

Pharmacokinetic studies indicate approximately twofold higher exposure in Mongolian race patients compared to Caucasians (see sections "Dosage and administration", "Contraindications", and "Pharmacokinetics").

Protease inhibitors

Increased systemic exposure to rosuvastatin has been observed when rosuvastatin is used concomitantly with various protease inhibitors in combination with ritonavir. Both the benefit of lipid-lowering with rosuvastatin in HIV patients receiving protease inhibitors and the potential for increased plasma concentrations of rosuvastatin at the initiation of therapy or dose escalation should be considered. Concomitant use of the medicinal product with protease inhibitors is not recommended unless the rosuvastatin dose is adjusted (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction").

Lactose intolerance

The medicinal product Mertenil contains lactose monohydrate. This medicinal product should not be used in patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

Interstitial lung disease

Isolated cases of interstitial lung disease have been reported with the use of some statins, particularly with long-term therapy (see section "Adverse reactions"). Manifestations may include dyspnea, non-productive cough, and deterioration in general health (fatigue, weight loss, fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Diabetes mellitus

Some evidence suggests that statins may increase blood glucose levels and may induce hyperglycemia requiring treatment in some patients at high risk of developing diabetes. However, this risk is outweighed by the reduction in vascular risk with statin use, and therefore should not be a reason to discontinue statin therapy. Patients at risk (fasting glucose 5.6–6.0 mmol/L, BMI >30 kg/m², elevated triglycerides, arterial hypertension) should be monitored clinically and biochemically according to national guidelines.

In the JUPITER study, the overall incidence of diabetes was 2.8% in the rosuvastatin group and 2.3% in the placebo group, predominantly in patients with fasting glucose levels between 5.6 and 6.9 mmol/L.

Children

Assessment of linear growth (height), body weight, BMI (body mass index), and development of secondary sexual characteristics according to Tanner in children aged 6 to 17 years receiving rosuvastatin is limited to a 2-year period. After 2 years of investigational treatment, no effect on growth, body weight, BMI, or sexual maturation was observed (see section "Pharmacodynamics").

In a clinical study in children and adolescents receiving rosuvastatin for 52 weeks, CK elevations >10 times ULN and muscle-related symptoms after physical exertion or increased physical activity were observed more frequently than in adults (see section "Adverse reactions").

Use during pregnancy or breastfeeding

Rosuvastatin is contraindicated during pregnancy and breastfeeding.

Women of childbearing potential

Women of childbearing potential should use reliable contraceptive methods.

Pregnancy

Since cholesterol and other products of cholesterol biosynthesis are essential for fetal development, the potential risk of HMG-CoA reductase inhibition outweighs any potential benefit of using the drug during pregnancy. If a patient becomes pregnant while receiving this medicinal product, treatment should be discontinued immediately.

Breastfeeding

Rosuvastatin is excreted into rat milk. There are no data on excretion into human breast milk (see section "Contraindications").

Ability to affect reaction speed when driving or operating machinery

No studies have been conducted to assess the effect of rosuvastatin on the ability to drive or operate machinery. However, given the pharmacodynamic properties of the drug, it is unlikely that Mertenil will affect this ability. Dizziness during treatment should be considered when driving or operating machinery.

Method of Administration and Dosage

Before initiating treatment, patients should be placed on a standard cholesterol-lowering diet, which must be continued during treatment.

Method of Administration

Mertenil is administered orally, at any time of day, independent of food intake.

Dosage

The dose should be individually adjusted depending on the therapeutic goal and the patient's response to treatment, following recommendations of current widely accepted guidelines.

Treatment of Hypercholesterolemia

The recommended initial dose is 5 or 10 mg orally once daily, both for patients who have not previously used statins and for those who have previously used other HMG-CoA reductase inhibitors. When selecting the initial dose, the patient's individual cholesterol levels, risk of cardiovascular complications, and potential risk of adverse reactions should be considered. If necessary, the dose may be increased to the next level after 4 weeks (see section "Pharmacodynamics"). Since adverse reactions occur more frequently with the 40 mg dose than with lower doses (see section "Adverse Reactions"), the maximum dose of 40 mg should be titrated only in patients with severe hypercholesterolemia and high cardiovascular risk (particularly patients with familial hypercholesterolemia) who have not achieved the desired response with a 20 mg dose and who will be under regular specialist supervision (see section "Special Precautions"). Specialist monitoring is recommended when initiating treatment with the 40 mg dose.

Prevention of Cardiovascular Events

In clinical trials evaluating cardiovascular risk reduction, the drug was administered at a dose of 20 mg once daily (see section "Pharmacodynamics").

Elderly Patients

The recommended initial dose for patients aged over 70 years is 5 mg (see section "Special Precautions"). No other dose adjustment based on age is required.

Patients with Renal Impairment

No dose adjustment is required for patients with mild or moderate renal impairment.

The recommended initial dose for patients with moderate renal impairment (creatinine clearance <60 mL/min) is 5 mg. The 40 mg dose is contraindicated in patients with moderate renal impairment. Mertenil is contraindicated in patients with severe renal impairment at any dose (see sections "Contraindications" and "Pharmacokinetics").

Patients with Hepatic Impairment

In patients with hepatic impairment scoring 7 or less on the Child-Pugh scale, no increase in systemic exposure to rosuvastatin was observed. However, in patients scoring 8 or 9 on the Child-Pugh scale, systemic exposure increased (see section "Pharmacokinetics"). Renal function should be assessed in these patients (see section "Special Precautions"). Experience with the drug in patients scoring 9 or more on the Child-Pugh scale is lacking. Mertenil is contraindicated in patients with active liver disease (see section "Contraindications").

Race

Increased systemic exposure to the drug has been observed in patients of Mongolian race (see sections "Contraindications", "Special Precautions", and "Pharmacokinetics"). The recommended initial dose for patients of Asian origin is 5 mg; the 40 mg dose is contraindicated in these patients.

Genetic Polymorphism

Certain types of genetic polymorphism may lead to increased rosuvastatin exposure (see section "Pharmacokinetics"). Patients known to have such polymorphism types should be prescribed a lower daily dose of rosuvastatin.

Patients with Predisposition to Myopathy

The recommended initial dose for patients with risk factors for myopathy is 5 mg (see section "Special Precautions").

The 40 mg dose is contraindicated in some of these patients (see section "Contraindications").

Concomitant Use

Rosuvastatin is a substrate for various transporter proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) increases when rosuvastatin is co-administered with certain medicinal products capable of increasing rosuvastatin plasma concentrations via interaction with these transporter proteins (e.g., cyclosporine and certain protease inhibitors, including ritonavir combinations with atazanavir, lopinavir, and/or tipranavir; see sections "Special Precautions" and "Interaction with Other Medicinal Products and Other Forms of Interaction"). When prescribing Mertenil with other medicinal products, their instructions for medical use should be consulted. Alternative therapy should be considered whenever possible, and, if necessary, rosuvastatin treatment should be temporarily discontinued. In situations where concomitant use of these medicinal products with rosuvastatin cannot be avoided, the benefits and risks of combination therapy should be carefully weighed, and rosuvastatin dose should be carefully selected (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Children

The use of the drug in children should be performed only by a specialist.

Children and Adolescents Aged 6 to 17 Years (Tanner Stage ˂II-V)

Heterozygous Familial Hypercholesterolemia

The usual initial daily dose for children and adolescents with heterozygous familial hypercholesterolemia is 5 mg once daily.

• In children aged 6 to 9 years with heterozygous familial hypercholesterolemia, the recommended dose is 5 mg to 10 mg orally once daily. The safety and efficacy of doses exceeding 10 mg in this patient group have not been studied.
• In children aged 10 to 17 years with heterozygous familial hypercholesterolemia, the recommended dose is 5 mg to 20 mg orally once daily. The safety and efficacy of doses exceeding 20 mg in this patient group have not been studied.

The dose should be increased according to the individual child's response to treatment and drug tolerability, following recommendations for pediatric treatment (see section "Special Precautions"). Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard cholesterol-lowering diet, which must be continued during treatment.

Homologous Familial Hypercholesterolemia

In children aged 6 to 17 years with homozygous familial hypercholesterolemia, the maximum recommended dose is 20 mg once daily.

The recommended initial dose is 5 mg to 10 mg once daily, depending on age, body weight, and prior statin use. The dose may be increased up to the maximum dose of 20 mg once daily according to the individual child's response to treatment and drug tolerability, following recommendations for pediatric treatment (see section "Special Precautions"). Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard cholesterol-lowering diet, which must be continued during treatment.

Experience with doses exceeding 20 mg in this population is limited.

The 40 mg tablets are not used in children.

Children Under 6 Years of Age

Safety and efficacy in children under 6 years of age have not been studied. Therefore, Mertenil is not recommended for use in children under 6 years of age.

Overdose

There is no specific antidote for overdose. In case of overdose, symptomatic and supportive treatment is recommended. Liver function and CK levels should be monitored. Hemodialysis is unlikely to be effective.

Adverse reactions

Adverse reactions observed during rosuvastatin use are generally mild and transient. In controlled clinical studies, less than 4% of patients receiving rosuvastatin discontinued treatment due to adverse reactions.

List of adverse reactions in table format

The table below presents the adverse reaction profile of rosuvastatin based on data from clinical studies and extensive post-marketing experience. Adverse reactions are classified by frequency and by system organ classes (SOC).

Adverse reactions are categorized by frequency as follows: common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), and not known (cannot be estimated from available data).

Table 2. Adverse reactions based on clinical studies and post-marketing experience

System organ class	Common	Uncommon	Occasional	Rare	Frequency not known
Blood and lymphatic system disorders			Thrombocytopenia
Immune system disorders			Hypersensitivity reactions, including angioneurotic edema
Endocrine disorders	Diabetes mellitus1
Psychiatric disorders					Depression
Nervous system disorders	Headache, dizziness			Polyneuropathy, memory loss	Peripheral neuropathy, sleep disorders (including insomnia and nightmares), myasthenia gravis
Eye disorders					Ocular myasthenia
Respiratory, thoracic and mediastinal disorders					Cough, dyspnea
Gastrointestinal disorders	Constipation, nausea, abdominal pain		Pancreatitis		Diarrhea
Hepatobiliary disorders			Elevated liver transaminase levels	Jaundice, hepatitis
Skin and subcutaneous tissue disorders		Pruritus, rash, urticaria			Stevens-Johnson syndrome, drug-induced eosinophilia with systemic symptoms (DRESS syndrome)
Musculoskeletal and connective tissue disorders	Myalgia		Myopathy (including myositis), rhabdomyolysis, muscle rupture, lupus-like syndrome	Arthralgia	Tendon disorders, sometimes complicated by ruptures, immune-mediated necrotizing myopathy
Renal and urinary disorders				Hematuria
Reproductive system and breast disorders				Gynecomastia
General disorders and administration site conditions	Asthenia				Edema

1Frequency depends on the presence of risk factors (fasting blood glucose ≥ 5.6 mmol/L, body mass index >30 kg/m², elevated triglyceride levels, history of arterial hypertension).

As with other HMG-CoA reductase inhibitors, the frequency of adverse reactions depends on the dose.

Effect on kidneys

Proteinuria, predominantly of tubular origin (detected by test strips), has been observed in patients treated with rosuvastatin. Changes in urinary protein content from none or trace to "++" or higher were reported in <1% of patients receiving 10 mg and 20 mg doses, and in approximately 3% of patients receiving 40 mg rosuvastatin. A slight increase in the frequency of proteinuria from none or trace to "+" was observed with the 20 mg dose. In most cases, the degree of proteinuria decreased or resolved spontaneously during continued treatment. Based on clinical studies and post-marketing surveillance data, to date there is no causal relationship established between proteinuria and acute or progressive kidney disease.

Hematuria has been observed in patients treated with rosuvastatin; however, clinical trial data indicate a low incidence of its occurrence.

Effect on skeletal muscle

Skeletal muscle-related events such as myalgia, myopathy (including myositis), and rarely rhabdomyolysis, with or without acute renal failure, have been observed during treatment with any dose of rosuvastatin, particularly with doses >20 mg.

In patients treated with rosuvastatin, dose-dependent increases in creatine kinase (CK) levels have been observed; in most cases, this was mild, asymptomatic, and transient. If CK levels are elevated (more than 5 times the upper limit of normal (ULN)), treatment should be discontinued (see section "Dosage and Administration").

Effect on liver

As with other HMG-CoA reductase inhibitors, dose-dependent increases in transaminase levels have been observed in a small number of patients treated with rosuvastatin; in most cases, this was mild, asymptomatic, and transient.

With the use of some statins, the following adverse events have been reported:

• sexual dysfunction;
• isolated cases of interstitial lung disease, particularly with long-term use (see section "Dosage and Administration").

The frequency of reports of rhabdomyolysis, serious renal and hepatic adverse events (mainly increased hepatic transaminase activity) was higher with the 40 mg dose of the medicinal product.

Children

Elevated creatine kinase levels >10 times above ULN and muscle-related symptoms following physical exertion or increased physical activity were observed more frequently in a 52-week study involving children and adolescents compared to adults (see section "Dosage and Administration"). However, the safety profile of rosuvastatin in children and adolescents was similar to that in adults.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, as well as patients or their legal representatives should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. Store in the original packaging to protect from light. No special temperature storage conditions are required for this medicinal product.

Keep out of reach of children.

Packaging. 10 tablets per blister; 3 blisters per cardboard pack.

Prescription status. Prescription only.

Manufacturer. Gedeon Richter Plc., Hungary.

Manufacturer's address. H-1103 Budapest, 19-21 Demrédi Street, Hungary.