Roxera^® Plus (Tablets) Instructions for Use

Marketing Authorization Holder

Krka d.d., Novo mesto (Slovenia)

ATC Code

C10BA06 (Rosuvastatin and Ezetimibe)

Active Substances

Ezetimibe (Rec.INN registered by WHO)

Rosuvastatin (Rec.INN registered by WHO)

Dosage Forms

	Roxera® Plus	Film-coated tablets, 10 mg+10 mg: 30, 60 or 90 pcs.
		Film-coated tablets, 20 mg+10 mg: 30, 60 or 90 pcs.
		Film-coated tablets, 40 mg+10 mg: 30, 60 or 90 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets light yellow or light brownish-yellow, or light brown-yellow in color, round, slightly biconvex, with an engraving “R2” on one side; fracture view: a rough mass of white or almost white color with a light yellow or light brownish-yellow, or light brown-yellow film coating.

Excipients: microcrystalline cellulose PH-112, lactose, mannitol, crospovidone, type A, croscarmellose sodium, magnesium stearate, povidone K30, sodium lauryl sulfate, colloidal anhydrous silicon dioxide.

Film coating composition: lactose monohydrate, hypromellose, titanium dioxide (E171), triacetin, iron oxide yellow (E172).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Film-coated tablets light pink in color, round, slightly biconvex, with an engraving “R4” on one side; fracture view: a rough mass of white or almost white color with a light pink film coating.

Excipients: microcrystalline cellulose PH-112, lactose, mannitol, crospovidone, type A, croscarmellose sodium, magnesium stearate, povidone K30, sodium lauryl sulfate, colloidal anhydrous silicon dioxide.

Film coating composition: lactose monohydrate, hypromellose, titanium dioxide (E171), triacetin, iron oxide red (E172).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Film-coated tablets from light grayish-violet to light gray-violet in color, round, slightly biconvex, with an engraving “R5” on one side; fracture view: a rough mass of white or almost white color with a film coating from light grayish-violet to light gray-violet in color.

Excipients: microcrystalline cellulose PH-112, lactose, mannitol, crospovidone, type A, croscarmellose sodium, magnesium stearate, povidone K30, sodium lauryl sulfate, colloidal anhydrous silicon dioxide.

Film coating composition: lactose monohydrate, hypromellose, titanium dioxide (E171), triacetin, iron oxide red (E172), iron oxide black (E172).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Clinical-Pharmacological Group

Hypolipidemic agent

Pharmacotherapeutic Group

Hypolipidemic agents; hypolipidemic agents in combinations; combinations of various hypolipidemic agents

Pharmacological Action

Combined hypolipidemic agent (HMG-CoA reductase inhibitor + cholesterol absorption inhibitor).

Rosuvastatin

Rosuvastatin is a hypolipidemic agent from the statin group. A selective competitive inhibitor of HMG-CoA reductase, the enzyme that converts HMG-CoA to mevalonate, a precursor of cholesterol.

Rosuvastatin increases the number of LDL receptors on the surface of hepatocytes, which leads to increased uptake and catabolism of LDL, inhibition of VLDL synthesis, reducing the overall concentration of LDL and VLDL. It reduces the concentrations of LDL-C, non-HDL-C, VLDL-C, TC, TG, VLDL-TG, Apo-B, reduces the ratios of LDL-C/HDL-C, TC/HDL-C, non-HDL-C/HDL-C, Apo-B/apolipoprotein AI (ApoA1), increases the concentrations of HDL-C and ApoA1. The therapeutic effect appears within 1 week after the start of therapy, reaches 90% of the maximum after 2 weeks, reaches a maximum by 4 weeks and thereafter remains constant.

Ezetimibe

Ezetimibe inhibits the absorption of cholesterol in the intestine and is effective when taken orally. The mechanism of action of ezetimibe differs from the mechanism of action of other classes of hypolipidemic agents (for example, HMG-CoA reductase inhibitors (statins), bile acid sequestrants, fibrates and plant stanols). The molecular target of ezetimibe is the transport protein (Niemann-Pick C1-Like 1, NPC1L1), responsible for the absorption of cholesterol and phytosterols in the intestine.

Ezetimibe is localized in the brush border of the small intestine cells and prevents the absorption of cholesterol, leading to a decrease in the flow of cholesterol from the intestine to the liver, thereby reducing its reserves in the liver and increasing absorption from the blood, while statins inhibit the synthesis of cholesterol in the liver. These different mechanisms complement each other, leading to a decrease in its concentration in blood plasma.

Pharmacokinetics

Rosuvastatin

The C_max of rosuvastatin is reached approximately 5 hours after oral administration. The absolute bioavailability of rosuvastatin is approximately 20%.

Rosuvastatin is intensively taken up by liver cells, which is the main site of cholesterol synthesis and LDL-C clearance. The V_d of rosuvastatin is approximately 134 L. Approximately 90% of rosuvastatin is bound to plasma proteins, mainly albumin.

Rosuvastatin is biotransformed in the liver to a small extent (about 10%), as it is a non-profile substrate for cytochrome P450 isoenzymes. The main isoenzyme involved in the metabolism of rosuvastatin is the CYP2C9 isoenzyme. The CYP2C19, CYP3A4 and CYP2D6 isoenzymes are involved in the metabolism to a lesser extent.

The main metabolites of rosuvastatin are N-desmethylrosuvastatin and lactone metabolites. N-desmethylrosuvastatin is approximately 50% less active than Rosuvastatin, the action of lactone metabolites is clinically insignificant. More than 90% of the pharmacological activity for the inhibition of circulating HMG-CoA reductase is provided by rosuvastatin, the rest by its metabolites.

About 90% of the rosuvastatin dose is excreted unchanged through the intestine, the remainder is excreted by the kidneys. T_1/2 is approximately 19 hours and does not change with an increase in the drug dose. The geometric mean plasma clearance is approximately 50 L/h (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, the process of hepatic uptake of the drug involves a specific membrane polypeptide, the OATP-C transporter, which plays an important role in its hepatic elimination.

Ezetimibe

After oral administration, Ezetimibe is rapidly absorbed and intensively conjugated to form a pharmacologically active phenolic glucuronide (Ezetimibe-glucuronide). C_max is reached within 1-2 hours for ezetimibe glucuronide and after 4-12 hours for ezetimibe. The absolute bioavailability of ezetimibe cannot be determined because the substance is practically insoluble in water. Food intake (with high fat content or without) did not affect the bioavailability of ezetimibe when used in tablet form. Ezetimibe can be taken with food or on an empty stomach.

Ezetimibe and Ezetimibe-glucuronide are bound to plasma proteins by 99.7% and 88-92%, respectively.

The metabolism of ezetimibe occurs mainly in the small intestine and liver by conjugation with glucuronide (phase II reaction) followed by excretion in the bile. Ezetimibe is minimally subjected to oxidative metabolism (phase I reaction). The concentrations of ezetimibe and Ezetimibe-glucuronide (the main derivatives of ezetimibe determined in plasma) are 10-20% and 80-90%, respectively, of the total concentration of ezetimibe in plasma. Ezetimibe and Ezetimibe-glucuronide are slowly eliminated from the body in the process of enterohepatic recirculation. T_1/2 for ezetimibe and Ezetimibe-glucuronide is approximately 22 hours.

Indications

Primary hypercholesterolemia (Fredrickson type IIa, including heterozygous familial hypercholesterolemia), homozygous familial hypercholesterolemia (Fredrickson type IIb).

ICD codes

Dosage Regimen

Take orally once daily, with or without food.

Individualize the dose based on the indication, therapeutic response, and current lipid-lowering guidelines.

Select the appropriate tablet strength to achieve the desired rosuvastatin component dose (10 mg, 20 mg, or 40 mg); the ezetimibe dose is fixed at 10 mg.

Initiate therapy only after failure to adequately control hypercholesterolemia with a statin or ezetimibe alone.

For patients switching from rosuvastatin monotherapy, start the combination at the previously administered rosuvastatin dose.

For patients switching from ezetimibe co-administered with a statin, start the combination at the previously administered statin dose.

The maximum recommended daily dose is 40 mg rosuvastatin / 10 mg ezetimibe.

Do not use the 40 mg/10 mg strength as initial therapy.

Exercise caution when initiating the 40 mg/10 mg strength; reserve for patients with severe hypercholesterolemia and high cardiovascular risk who have not achieved target LDL-C on lower doses.

Contraindicate the 40 mg/10 mg strength in patients of Asian ancestry and in those with predisposing factors for myopathy.

Prior to initiation, exclude secondary causes of hyperlipidemia.

Perform liver function tests before starting treatment and thereafter clinically indicated.

Assess renal function before initiating the 40 mg/10 mg strength and during therapy as appropriate.

Adverse Reactions

Blood and lymphatic system disorders rarely – thrombocytopenia.

Immune system disorders rarely – hypersensitivity reactions, including angioedema.

Endocrine disorders often – diabetes mellitus.

Metabolism and nutrition disorders infrequently – decreased appetite.

Psychiatric disorders frequency unknown – depression.

Nervous system disorders often – headache, dizziness; infrequently – paresthesia; very rarely – polyneuropathy, memory impairment; frequency unknown – peripheral neuropathy, sleep disorders (including insomnia and nightmares).

Vascular disorders frequency unknown – flushing, arterial hypertension.

Respiratory, thoracic and mediastinal disorders infrequently – cough.

Gastrointestinal disorders often – constipation, nausea, abdominal pain, diarrhea, abdominal distension; infrequently – dyspepsia, gastroesophageal reflux disease, nausea, dry mouth, gastritis; rarely – pancreatitis.

Hepatobiliary disorders rarely – increased activity of “hepatic” transaminases; very rarely – jaundice, hepatitis; frequency unknown – cholelithiasis, cholecystitis.

Skin and subcutaneous tissue disorders infrequently – pruritus, skin rash, urticaria; frequency unknown – Stevens-Johnson syndrome, erythema multiforme.

Musculoskeletal and connective tissue disorders often – myalgia; infrequently – arthralgia, muscle spasms, neck pain, back pain, muscle weakness, limb pain; rarely – myopathy (including myositis), rhabdomyolysis; very rarely – arthralgia; frequency unknown – immune-mediated necrotizing myopathy, tendon lesions, sometimes complicated by rupture, muscle pain, myopathy, rhabdomyolysis.

Renal and urinary disorders very rarely – hematuria.

Reproductive system and breast disorders very rarely – gynecomastia.

General disorders and administration site conditions often – asthenia, increased fatigue.

Investigations often – increased ALT and/or AST activity; infrequently – increased ALT and/or AST activity, dose-dependent increase in plasma CK concentration, increased GGT activity; abnormal liver function tests.

Contraindications

Pregnancy and breastfeeding; female patients with childbearing potential not using effective methods of contraception; active liver disease or persistent unexplained increase in serum hepatic transaminase activity (more than 3 times the ULN); moderate (7-9 points on the Child-Pugh scale) or severe (more than 9 points on the Child-Pugh scale) hepatic impairment; severe renal impairment (CrCl <30 ml/min); myopathy; simultaneous use with cyclosporine; age under 18 years.

For the dosage of 40 mg + 10 mg

Presence of the following risk factors for the development of myopathy/rhabdomyolysis: moderate renal failure (CrCl <60 ml/min), hypothyroidism, history of myotoxicity while taking other HMG-CoA reductase inhibitors or fibrates, excessive alcohol consumption, conditions that may lead to an increase in the plasma concentration of rosuvastatin, simultaneous use of fibrates; patients of Mongoloid race; history of hereditary muscle diseases, including familial.

With caution

Conditions indicating the development of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (sepsis, arterial hypotension, extensive surgery, trauma, severe metabolic, endocrine and electrolyte disturbances or uncontrolled seizures); hypothyroidism; age over 70 years; conditions in which an increase in the plasma concentration of rosuvastatin has been noted; patients of Mongoloid race; simultaneous use with fibrates, indirect anticoagulants (warfarin) or fluindione; history of myotoxicity while taking other HMG-CoA reductase inhibitors or fibrates; excessive alcohol consumption; history of liver disease or hepatic insufficiency; mild and moderate renal impairment (CrCl >30 ml/min); mild renal impairment (CrCl >60 ml/min) (for the dosage of 40 mg + 10 mg).

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Contraindicated for use in moderate (7-9 points on the Child-Pugh scale) or severe (more than 9 points on the Child-Pugh scale) hepatic impairment.

Use in Renal Impairment

Contraindicated for use in severe renal impairment (CrCl <30 ml/min).

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

With caution: age over 70 years.

Special Precautions

You should consult a doctor immediately if unexpected muscle pain, muscle weakness or cramps appear, especially in combination with malaise and fever. If these conditions occur, it is necessary to determine CK activity. Therapy should be discontinued if CK activity is significantly increased (more than 5 times the ULN), or if muscle symptoms are severe and cause daily discomfort (even if CK activity is increased less than 5 times compared to the ULN). If the symptoms disappear and CK activity returns to normal, the question of re-prescribing rosuvastatin or other HMG-CoA reductase inhibitors in lower doses with careful monitoring of the patient’s condition should be considered.

The drug should not be used in patients with acute, serious conditions indicating the development of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (sepsis, arterial hypotension, extensive surgery, trauma, severe metabolic, endocrine and electrolyte disturbances or uncontrolled seizures).

It is recommended to determine liver function indicators before starting therapy and 3 months after starting therapy. The drug should be discontinued or the dose of the drug should be reduced if the activity of “hepatic” transaminases in the blood plasma exceeds the ULN by 3 times or more.

In patients receiving high doses of rosuvastatin (mainly 40 mg/day), the development of tubular proteinuria was reported, which in most cases was transient. The development of proteinuria did not indicate acute kidney disease or progression of kidney disease. In patients taking the combination Rosuvastatin+Ezetimibe at a dosage of 40 mg+10 mg, it is recommended to regularly monitor renal function indicators during treatment.

When using statins, an increase in blood glucose concentration is possible. In some patients with a high risk of developing diabetes mellitus, such changes may lead to its manifestation, which is an indication for the prescription of hypoglycemic therapy. However, the reduction in the risk of vascular diseases while taking statins exceeds the risk of developing diabetes mellitus, so this factor should not be a reason for discontinuing statin therapy. Patients at risk (fasting blood glucose 5.6-6.9 mmol/L, BMI >30 kg/m², hypertriglyceridemia, history of arterial hypertension) should be placed under medical supervision and biochemical parameters should be regularly monitored.

When using some statins, especially over a long period of time, isolated cases of the development of interstitial lung disease have been reported, which may manifest as shortness of breath, non-productive cough and deterioration in general well-being (weakness, weight loss and fever). If interstitial lung disease is suspected, therapy with the combination Rosuvastatin+Ezetimibe should be discontinued.

Effect on ability to drive vehicles and mechanisms

Due to the likelihood of dizziness when taking the combination Rosuvastatin+Ezetimibe, caution should be exercised when driving vehicles and operating machinery.

Drug Interactions

Contraindicated combinations

Simultaneous use of the combination Rosuvastatin + Ezetimibe with cyclosporine is contraindicated.

Not recommended combinations

Fibrates and other hypolipidemic drugs

Patients receiving fenofibrate and Ezetimibe should be informed about the possible risk of developing cholelithiasis and gallbladder diseases. If cholelithiasis is suspected, it is necessary to examine the gallbladder and discontinue the drug.

Simultaneous use of fenofibrate or gemfibrozil with ezetimibe moderately increased the concentration of total ezetimibe (approximately 1.5 and 1.7 times, respectively).

Gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses of nicotinic acid (more than 1 g per day) increased the risk of myopathy when used simultaneously with HMG-CoA reductase inhibitors, possibly because these agents can themselves cause myopathy when used as monotherapy. Simultaneous use of the drug at a dosage of 40 mg + 10 mg with fibrates is contraindicated.

HIV Protease Inhibitors

Although the precise mechanism of interaction is unknown, concomitant use with HIV protease inhibitors may lead to a significant increase in rosuvastatin exposure. In a pharmacokinetic study, the coadministration of 10 mg rosuvastatin and a combination product containing two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers resulted in an approximately 3-fold and 7-fold increase in rosuvastatin AUC and C_max, respectively. Concomitant use of rosuvastatin and certain combinations of HIV protease inhibitors may be considered after careful dose adjustment based on the expected increase in rosuvastatin plasma concentration.

Transporter Protein Inhibitors

Rosuvastatin is a substrate for certain transporter proteins, including the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant use of rosuvastatin with other medicinal products that are inhibitors of these transporter proteins may lead to increased plasma concentrations of rosuvastatin and an increased risk of myopathy.

Fusidic Acid

The risk of myopathy, including rhabdomyolysis, may be increased with the concomitant use of fusidic acid. If systemic fusidic acid therapy is necessary, Rosuvastatin should be discontinued during this treatment.

Other Interactions

Cytochrome P450 System Isoenzymes

Results from in vivo and in vitro studies show that Rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 system isoenzymes. Furthermore, Rosuvastatin is not a significant substrate for these isoenzymes. Therefore, no interaction with other medicinal products at the level of metabolism by cytochrome P450 system isoenzymes is expected. No clinically significant interaction was observed between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4 isoenzymes) and ketoconazole (an inhibitor of CYP2A6 and CYP3A4 isoenzymes).
Preclinical studies have shown that Ezetimibe does not induce cytochrome P450 isoenzymes. No clinically significant interactions were observed between ezetimibe and other medicinal products at the level of metabolism by CYP1A2, CYP2D6, CYP2C8, CYP2C9, and CYP3A4 isoenzymes or N-acetyltransferase.

Antacids

Concomitant administration of antacids decreased the rate of absorption of ezetimibe but had no effect on its bioavailability. This decrease in absorption rate is not considered clinically significant.
Concomitant use of rosuvastatin and an antacid suspension containing magnesium and aluminum hydroxide resulted in an approximately 50% reduction in rosuvastatin plasma concentration. This effect is less pronounced when antacids are taken 2 hours after rosuvastatin administration. The clinical significance of this interaction has not been studied.

Cholestyramine

Concomitant use of cholestyramine reduced the mean AUC of total ezetimibe (Ezetimibe + ezetimibe glucuronide) by approximately 55%. The LDL-C-lowering effect of adding ezetimibe to cholestyramine may be reduced by this interaction.

Anticoagulants, Vitamin K Antagonists

Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on the bioavailability of warfarin or prothrombin time in a study of 12 healthy adult males. However, there have been post-marketing reports of increased INR in patients taking Ezetimibe concomitantly with warfarin or fluindione. When ezetimibe is added to warfarin (or another coumarin anticoagulant) or fluindione therapy, INR should be monitored.
As with other HMG-CoA reductase inhibitors, initiating therapy with rosuvastatin or increasing its dose in patients concurrently receiving treatment with vitamin K antagonists (e.g., warfarin or another coumarin anticoagulant) may lead to an increase in INR. Discontinuation of rosuvastatin or a decrease in its dose may lead to a reduction in INR. In such cases, regular monitoring of INR is recommended.

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 increased intestinal motility associated with erythromycin use.

Oral Contraceptives/HRT

Concomitant use of rosuvastatin and oral contraceptives increased the AUC of ethinyl estradiol and the AUC of norgestrel by 26% and 34%, respectively. This increase in plasma concentration should be considered when selecting the dose of oral contraceptives.
Pharmacokinetic data on the concomitant use of rosuvastatin and HRT are not available; therefore, a similar effect cannot be ruled out with this combination. However, this combination was widely used during clinical trials and was well tolerated by female patients.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.