Roxera^® Combi (Tablets) Instructions for Use

Marketing Authorization Holder

Krka, D.D. (Slovenia)

ATC Code

C10BX09 (Rosuvastatin and Amlodipine)

Active Substances

Amlodipine (Rec.INN registered by WHO)

Rosuvastatin (Rec.INN registered by WHO)

Dosage Forms

	Roxera® Combi	Film-coated tablets, 5 mg+10 mg: 28, 30, 60, 84 or 90 pcs.
		Film-coated tablets, 5 mg+15 mg: 28, 30, 60, 84 or 90 pcs.
		Film-coated tablets, 5 mg+20 mg: 28, 30, 60, 84 or 90 pcs.
		Film-coated tablets, 10 mg+10 mg: 28, 30, 60, 84 or 90 pcs.
		Film-coated tablets, 10 mg+15 mg: 28, 30, 60, 84 or 90 pcs.
		Film-coated tablets, 10 mg+20 mg: 28, 30, 60, 84 or 90 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets brownish-yellow, round, slightly biconvex, with a bevel, on one side an embossed engraving “10-5”; appearance on the break: a rough mass of white or almost white color with a brownish-yellow film coating.

Excipients: microcrystalline cellulose – 123.08 mg, anhydrous lactose – 56 mg, crospovidone – 10.5 mg, colloidal silicon dioxide – 0.46 mg, magnesium stearate – 2.63 mg.

Film coating composition: Opadry II 85F220163 yellow – 6.3 mg (polyvinyl alcohol – 2.968 mg, macrogol 3350 – 1.766 mg, titanium dioxide (E171) – 0.911 mg, talc – 0.425 mg, iron oxide yellow dye (E172) – 0.23 mg).

7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (12) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Film-coated tablets light pinkish-brown, round, slightly biconvex, with a bevel, on one side an embossed engraving “15-5”; appearance on the break: a rough mass of white or almost white color with a light pinkish-brown film coating.

Excipients: microcrystalline cellulose – 188.09 mg, anhydrous lactose – 84 mg, crospovidone – 15.75 mg, colloidal silicon dioxide – 0.69 mg, magnesium stearate – 3.95 mg.

Film coating composition: Opadry II 85F270036 tan – 10 mg (polyvinyl alcohol – 4.821 mg, macrogol 3350 – 2.869 mg, titanium dioxide (E171) – 1.479 mg, talc – 0.69 mg, iron oxide yellow dye (E172) – 0.1 mg, iron oxide red dye (E172) – 0.028 mg, iron oxide black dye (E172) – 0.014 mg).

7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (12) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Film-coated tablets light yellow, round, slightly biconvex, with a bevel, on one side an embossed engraving “20-5”; appearance on the break: a rough mass of white or almost white color with a light yellow film coating.

Excipients: microcrystalline cellulose – 253.1 mg, anhydrous lactose – 112 mg, crospovidone – 21 mg, colloidal silicon dioxide – 0.92 mg, magnesium stearate – 5.26 mg.

Film coating composition: Opadry II 85F220164 yellow – 12.6 mg (polyvinyl alcohol – 6.122 mg, macrogol 3350 – 3.643 mg, titanium dioxide (E171) – 1.878 mg, talc – 0.876 mg, iron oxide yellow dye (E172) – 0.08 mg).

7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (12) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Film-coated tablets light pink, round, slightly biconvex, with a bevel, on one side an embossed engraving “10-10”; appearance on the break: a rough mass of white or almost white color with a light pink film coating.

Excipients: microcrystalline cellulose – 256.56 mg, anhydrous lactose – 112 mg, crospovidone – 21 mg, colloidal silicon dioxide – 0.92 mg, magnesium stearate – 5.26 mg.

Film coating composition: Opadry II 85F230120 orange – 12.6 mg (polyvinyl alcohol – 6.132 mg, macrogol 3350 – 3.649 mg, titanium dioxide (E171) – 1.881 mg, talc – 0.878 mg, iron oxide yellow dye (E172) – 0.025 mg, iron oxide red dye (E172) – 0.035 mg).

7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (12) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Film-coated tablets pink, round, slightly biconvex, with a bevel, on one side an embossed engraving “15-10”; appearance on the break: a rough mass of white or almost white color with a pink film coating.

Excipients: microcrystalline cellulose – 181.15 mg, anhydrous lactose – 84 mg, crospovidone – 15.75 mg, colloidal silicon dioxide – 0.69 mg, magnesium stearate – 3.39 mg.

Film coating composition: Opadry II 85F265068 brown – 10 mg (polyvinyl alcohol – 4.821 mg, macrogol 3350 – 2.869 mg, titanium dioxide (E171) – 1.479 mg, talc – 0.69 mg, iron oxide yellow dye (E172) – 0.1 mg, iron oxide red dye (E172) – 0.028 mg, iron oxide black dye (E172) – 0.014 mg).

7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (12) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Film-coated tablets white, round, slightly biconvex, with a bevel, on one side an embossed engraving “20-10”; appearance on the break: a rough mass of white or almost white color with a white film coating.

Excipients: microcrystalline cellulose – 245.16 mg, anhydrous lactose – 112 mg, crospovidone – 21 mg, colloidal silicon dioxide – 0.92 mg, magnesium stearate – 5.26 mg.

Film coating composition: Opadry II white 85F280010 – 12.6 mg (polyvinyl alcohol – 6.161 mg, macrogol 3350 – 3.667 mg, titanium dioxide (E171) 1.89 mg, talc – 0.882 mg).

7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (12) – cardboard packs.
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

Antihypertensive + hypolipidemic agent

Pharmacological Action

A combined preparation containing Amlodipine – a slow calcium channel blocker and Rosuvastatin – a hypolipidemic agent, an HMG-CoA reductase inhibitor (statin), intended for therapy in patients with arterial hypertension and dyslipidemia.

Amlodipine

Amlodipine is a dihydropyridine derivative, blocks slow calcium channels, reduces the transmembrane flow of calcium ions into cardiomyocytes and vascular smooth muscle cells.

The mechanism of the antihypertensive action of amlodipine is due to a direct relaxing effect on vascular smooth muscle cells.

The mechanism of the antianginal action is not fully understood; presumably, the reduction of myocardial ischemia is associated with two effects.

• Amlodipine dilates peripheral arterioles and thus reduces total peripheral resistance (afterload). Since the heart rate remains unchanged, the load on the heart decreases, and the myocardial demand for energy and oxygen decreases;
• The mechanism of action of amlodipine also probably includes the dilation of the main coronary arteries and coronary arterioles in both unchanged and ischemic areas of the myocardium, which increases oxygen supply to the myocardium in patients with coronary artery spasm (Prinzmetal’s angina or variant angina), and prevents coronary artery spasm (including that caused by smoking).

In patients with arterial hypertension, taking amlodipine once a day provides a clinically significant reduction in blood pressure in the supine and standing positions for 24 hours. Due to the slow development of the antihypertensive effect, Amlodipine does not cause acute arterial hypotension.

In patients with angina, taking amlodipine once a day increases exercise tolerance, time to onset of angina attack and time to 1 mm ST segment depression, and also reduces the frequency of angina attacks and the need for nitroglycerin intake.

Amlodipine does not have an adverse effect on metabolism, on plasma lipid concentrations and can be used in patients with bronchial asthma, diabetes mellitus and gout.

Rosuvastatin

Rosuvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. The main target of rosuvastatin action is the liver, where cholesterol synthesis and LDL catabolism take place.

Rosuvastatin increases the number of LDL receptors on the surface of hepatocytes, increasing the uptake and catabolism of LDL, which in turn leads to inhibition of VLDL synthesis and a decrease in the total amount of LDL and VLDL.

Pharmacokinetics

Amlodipine

After oral administration in therapeutic doses, Amlodipine is well absorbed, C_max in plasma is noted after 6-12 hours. Absolute bioavailability ranges from 64 to 80%. V_d is about 21 L/kg. In vitro studies have shown that about 97.5% of circulating amlodipine is bound to plasma proteins. Simultaneous food intake does not affect the bioavailability of amlodipine.

The terminal T_1/2 of amlodipine from plasma is approximately 35-50 hours, which allows the drug to be taken once a day. Amlodipine is extensively metabolized in the liver to form inactive metabolites, 60% of the administered dose is excreted by the kidneys as inactive metabolites, 10% – unchanged, and 20-25% – through the intestine with bile.

Rosuvastatin

C_max of rosuvastatin in plasma is reached approximately 5 hours after oral administration. Absolute bioavailability is about 20%.

Rosuvastatin is metabolized mainly by the liver, which is the main site of cholesterol synthesis and LDL cholesterol metabolism. V_d of rosuvastatin is about 134 L. Approximately 90% of rosuvastatin is bound to plasma proteins, mainly albumin.

The systemic exposure of rosuvastatin increases in proportion to the dose. Pharmacokinetic parameters do not change with daily administration.

Rosuvastatin undergoes limited metabolism (about 10%). In vitro studies using human hepatocytes have shown that Rosuvastatin is a non-specific substrate for metabolism mediated by the cytochrome P450 system. The main isoenzyme involved in the metabolism of rosuvastatin is the CYP2C9 isoenzyme. The CYP2C19, CYP3A4 and CYP2D6 isoenzymes are involved to a lesser extent. The main identified metabolites of rosuvastatin are N-desmethyl and lactone metabolites. N-desmethyl is approximately 50% less active than Rosuvastatin, lactone metabolites are pharmacologically inactive. More than 90% of the pharmacological activity for inhibiting 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 (including absorbed and unabsorbed Rosuvastatin), the remainder is excreted by the kidneys. About 5% of the administered dose is excreted unchanged by the kidneys. T_1/2 from plasma is about 19 hours. T_1/2 does not change with increasing rosuvastatin dose. The geometric mean plasma clearance is about 50 L/h (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, the membrane cholesterol transporter is involved in the hepatic uptake of rosuvastatin, playing an important role in the hepatic elimination of rosuvastatin.

Pharmacokinetics in special patient groups

Patient sex and age do not have a clinically significant effect on the pharmacokinetics of rosuvastatin. The pharmacokinetics of rosuvastatin in children and adolescents with heterozygous familial hypercholesterolemia was similar to that in adult volunteers. The time required to reach C_max of amlodipine in plasma is practically independent of age. In elderly patients, there is a tendency for a decrease in the clearance of amlodipine, leading to an increase in AUC and T_1/2. The increase in AUC and T_1/2 in patients with chronic heart failure corresponds to the expected value for this age group.

Pharmacokinetic studies showed an approximately two-fold increase in the median AUC and C_max of rosuvastatin in patients of Mongoloid race (Japanese, Chinese, Filipino, Vietnamese, and Korean) compared with similar indicators in patients of Caucasian race. In Indians, an increase in median AUC and C_max of approximately 1.3 times was noted. Population pharmacokinetic analysis did not reveal clinically significant differences in pharmacokinetics between patients of Caucasian and Negroid race.

Renal impairment does not significantly affect the kinetics of amlodipine. Amlodipine is not removed by hemodialysis. In patients with mild to moderate renal impairment, the plasma concentration of rosuvastatin or the N-desmethyl metabolite does not change significantly. In patients with severe renal impairment (creatinine clearance less than 30 ml/min), the plasma concentration of rosuvastatin is 3 times higher, and the concentration of the N-desmethyl metabolite is 9 times higher than in healthy volunteers. The plasma concentration of rosuvastatin in patients on hemodialysis was approximately 50% higher than in healthy volunteers.

Data on the use of amlodipine in patients with hepatic impairment are limited. In patients with hepatic impairment, a decrease in the clearance of amlodipine is noted, leading to a prolongation of T_1/2 and an increase in AUC by approximately 40-60%. In patients with hepatic impairment of 7 points and below on the Child-Pugh scale, no prolongation of the T_1/2 of rosuvastatin was noted. In two patients with hepatic impairment of 8 and 9 points on the Child-Pugh scale, a prolongation of T_1/2 of at least 2 times was noted. There is no experience with the use of rosuvastatin in patients with hepatic impairment of more than 9 points on the Child-Pugh scale.

HMG-CoA reductase inhibitors, including Rosuvastatin bind to the transport proteins OATP1B1 (organic anion transporting polypeptide involved in the uptake of statins by hepatocytes) and BCRP (efflux transporter). In carriers of the SLC01B1 (OATP1B1) C.521CC and ABCG2 (BCRP) C.421AA genotypes, an increase in the exposure (AUC) of rosuvastatin of 1.6 and 2.4 times, respectively, was noted, compared with carriers of the SLC01B1 C.521TT and ABCG2 C.421CC genotypes.

Indications

The drug is indicated for therapy in patients with arterial hypertension and dyslipidemia; in patients with arterial hypertension who are at risk of developing cardiovascular complications (for the prevention of major cardiovascular events), whose condition is adequately controlled by simultaneous administration of rosuvastatin and amlodipine in the same doses as in the combined preparation.

ICD codes

Dosage Regimen

The drug is taken orally, once a day, at any time, regardless of meals. The tablet should be swallowed whole, not chewed or crushed, with water.

Before starting therapy with the drug, the patient should begin following a standard hypocholesterolemic diet and continue to adhere to it during therapy.

The recommended dose of the drug is 1 tablet/day.

Before using the drug, it is necessary to achieve blood pressure control through the simultaneous intake of the two active components of the drug in stable doses. The dose is selected after prior titration of the doses of the individual components of the drug. If a change in the dose of one of the active substances in the fixed combination drug is required (for example, due to a newly diagnosed disease, a change in the patient’s condition, or a drug interaction), an individual selection of doses of the individual components is necessary.

In patients with mild or moderate renal impairment, dose adjustment is not required. The use of the drug is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 ml/min).

The use of the drug in patients with active liver disease is contraindicated.

In elderly patients, dose adjustment is not required.

The safety of using the drug in children and adolescents under 18 years of age has not been established, therefore it is not recommended to use the drug in this group of patients.

When studying the pharmacokinetic parameters of rosuvastatin in patients belonging to different ethnic groups, an increase in the systemic concentration of rosuvastatin was noted among Japanese and Chinese individuals. This fact should be taken into account when using the drug in these patient groups. The recommended initial dose of rosuvastatin for patients of Mongoloid race is 5 mg/day. The use of rosuvastatin at a dose of 40 mg is contraindicated in patients of Mongoloid race.

Carriers of the SLC01B1 (OATP1B1) c.521CC and ABCG2 (BCRP) c.421AA genotypes showed an increase in exposure (AUC) to rosuvastatin compared to carriers of the SLC01B1 c.521TT and ABCG2 c.421CC genotypes. For patients who are carriers of the c.521CC or c.421AA genotypes, the recommended maximum dose of rosuvastatin is 20 mg once daily.

Rosuvastatin binds to various transport proteins (in particular, OATP1B1 and BCRP). When the drug is used concomitantly with drugs that increase the plasma concentration of rosuvastatin due to interaction with transport proteins (such as cyclosporine, some HIV protease inhibitors, including the combination of ritonavir with atazanavir, lopinavir and/or tipranavir), the risk of myopathy (including rhabdomyolysis) may increase. In such cases, the possibility of prescribing alternative therapy or temporarily discontinuing the combined drug should be assessed. If it is necessary to use the drugs mentioned above, the benefit-risk ratio of concomitant therapy with the combined drug should be assessed and the possibility of adjusting the rosuvastatin dose should be considered.

Adverse Reactions

WHO classification of frequency of adverse effects: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10,000 to <1/1000), very rare (<1/10,000), frequency unknown (cannot be estimated from the available data).

Amlodipine

Blood and lymphatic system disorders very rare – leukopenia, thrombocytopenia.

Immune system disorders: very rare – allergic reactions, angioedema, urticaria.

Metabolism and nutrition disorders very rare – hyperglycemia.

Psychiatric disorders uncommon – insomnia, mood swings (including anxiety), increased excitability, unusual dreams, depression; rare – confusion; very rare – apathy, agitation, ataxia.

Nervous system disorders common – dizziness, headache, drowsiness; uncommon – tremor, dysgeusia, hypoesthesia, paresthesia, peripheral neuropathy; very rare – migraine, memory loss, parosmia.

Eye disorders uncommon – visual impairment (including diplopia), accommodation disorder, xerophthalmia, conjunctivitis, eye pain.

Ear and labyrinth disorders uncommon – tinnitus.

Cardiac disorders common – palpitations, flushing; uncommon – marked decrease in blood pressure; very rare – myocardial infarction, syncope, development or worsening of chronic heart failure, cardiac arrhythmias (including bradycardia, ventricular tachycardia and atrial fibrillation), orthostatic hypotension, vasculitis.

Respiratory, thoracic and mediastinal disorders uncommon – dyspnea, rhinitis, epistaxis; very rare – cough.

Gastrointestinal disorders abdominal pain, nausea; uncommon – constipation, anorexia, vomiting, dyspepsia, flatulence, dry mouth, thirst, diarrhea; rare – increased appetite, gingival hyperplasia; very rare – gastritis, pancreatitis, hepatitis, jaundice, hyperbilirubinemia, increased activity of hepatic transaminases.

Renal and urinary disorders uncommon – painful urination, nocturia, frequent urination; very rare – dysuria, polyuria.

Reproductive system and breast disorders uncommon – erectile dysfunction, gynecomastia.

Skin and subcutaneous tissue disorders uncommon – purpura, skin discoloration, increased sweating, exanthema, skin itching, rash; very rare – alopecia, erythema multiforme, exfoliative dermatitis, xeroderma, cold sweat, photosensitivity.

Musculoskeletal and connective tissue disorders uncommon – muscle cramps, myalgia, arthrosis, arthralgia; rare – myasthenia.

General disorders and administration site conditions common – increased fatigue, peripheral edema; uncommon – asthenia, back pain, weight gain, weight loss; very rare – chest pain.

Rosuvastatin

Blood and lymphatic system disorders frequency unknown – thrombocytopenia.

Immune system disorders uncommon – urticaria; rare – hypersensitivity reactions, including angioedema.

Endocrine disorders common – type 2 diabetes mellitus¹.

Psychiatric disorders frequency unknown – depression.

Nervous system disorders common – dizziness, headache; very rare – memory loss, peripheral neuropathy.

Respiratory, thoracic and mediastinal disorders frequency unknown – dyspnea, cough.

Gastrointestinal disorders common – abdominal pain, nausea, constipation; rare – pancreatitis, increased activity of hepatic transaminases; very rare – hepatitis, jaundice; frequency unknown – diarrhea.

Skin and subcutaneous tissue disorders uncommon – skin itching, rash; frequency unknown – Stevens-Johnson syndrome.

Musculoskeletal and connective tissue disorders common – myalgia; rare – myopathy (including myositis), rhabdomyolysis; very rare – arthralgia; frequency unknown – immune-mediated necrotizing myopathy.

Renal and urinary disorders very rare – hematuria.

Reproductive system and breast disorders frequency unknown – gynecomastia.

General disorders and administration site conditions common – asthenia; frequency unknown – peripheral edema.

¹ Frequency depends on the presence or absence of risk factors (fasting blood glucose ≥5.6 mmol/L, BMI >30 kg/m², elevated plasma triglycerides, history of arterial hypertension).

Isolated cases of extrapyramidal syndrome have been reported with the use of amlodipine.

As with other HMG-CoA reductase inhibitors, the frequency of adverse reactions with rosuvastatin use is dose-dependent.

The following side effects have been reported with the use of some HMG-CoA reductase inhibitors: depression, sleep disorders including insomnia and nightmares, sexual dysfunction. Isolated cases of interstitial lung disease have been reported, especially with long-term use of the drugs.

Description of selected adverse reactions with rosuvastatin use

Renal and urinary disorders

Proteinuria may be detected with the use of rosuvastatin. Changes in urine protein levels (from none or trace amounts to ++ or more) are observed in less than 1% of patients receiving Rosuvastatin at a dose of 10-20 mg/day, and in about 3% of patients receiving Rosuvastatin at a dose of 40 mg/day. In most cases, proteinuria decreases or disappears during therapy and does not indicate the occurrence of an acute or progressive concomitant kidney disease.

Musculoskeletal and connective tissue disorders

The following effects on the musculoskeletal system have been reported with the use of rosuvastatin at all doses, and especially at doses exceeding 20 mg/day: myalgia, myopathy (including myositis), and in rare cases, rhabdomyolysis with or without acute renal failure.

A dose-dependent increase in CPK activity is observed in a small number of patients taking Rosuvastatin. In most cases, it was minor, asymptomatic and temporary. If CPK activity increases (more than 5 times the upper limit of normal), therapy should be suspended.

Hepatobiliary disorders

As with other HMG-CoA reductase inhibitors, a dose-dependent increase in hepatic transaminase activity is observed in a small number of patients using rosuvastatin. In most cases, it is minor, asymptomatic and temporary.

Investigations

With the use of rosuvastatin, increases in CPK activity, plasma glucose, glycosylated hemoglobin, bilirubin, GGT activity, ALP, and changes in plasma concentrations of thyroid hormones have also been observed.

Contraindications

Severe arterial hypotension (systolic BP less than 90 mm Hg); hemodynamically unstable heart failure after acute myocardial infarction; left ventricular outflow tract obstruction (including severe aortic stenosis); active liver disease (including persistent elevation of hepatic transaminases and any elevation of serum hepatic transaminases more than 3 times the upper limit of normal); severe renal impairment (creatinine clearance less than 30 ml/min); myopathy; use in patients predisposed to the development of myotoxic complications; concomitant use of cyclosporine; pregnancy, breastfeeding period, use in women of childbearing potential not using adequate contraception; age under 18 years (efficacy and safety not established); hypersensitivity to amlodipine, other dihydropyridine derivatives, rosuvastatin.

With caution hepatic insufficiency, history of liver disease, chronic heart failure of non-ischemic etiology NYHA class III-IV, unstable angina, aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy, acute myocardial infarction (and within 1 month after it), sick sinus syndrome (severe tachycardia, bradycardia), arterial hypotension, concomitant use with inhibitors or inducers of the CYP3A4 isoenzyme, presence of risk factors for myopathy/rhabdomyolysis (renal failure, hypothyroidism, personal or family history of hereditary muscle diseases) and previous history of muscle toxicity with other HMG-CoA reductase inhibitors or fibrates, excessive alcohol consumption, conditions in which an increase in plasma concentration of rosuvastatin has been noted, concomitant use with fibrates, sepsis, major surgery, trauma, severe metabolic, endocrine or electrolyte disturbances or uncontrolled seizures, racial background (Mongoloid race), age over 65 years.

Use in Pregnancy and Lactation

The drug is contraindicated during pregnancy and breastfeeding.

Pregnancy

Women of reproductive potential should use adequate contraceptive methods.

Since cholesterol and other products of cholesterol biosynthesis are important for fetal development, the potential risk of HMG-CoA reductase inhibition outweighs the benefit of using the drug during pregnancy. Data on the reproductive toxicity of rosuvastatin obtained from animal studies are limited.

If pregnancy occurs during therapy, the drug should be discontinued immediately.

The safety of amlodipine use during pregnancy has not been established. In animal studies, reproductive toxicity was observed with the use of high doses of amlodipine. Use during pregnancy is only possible if the potential benefit to the mother outweighs the possible risk to the fetus.

Breastfeeding period

There are no data on the excretion of amlodipine in breast milk. However, it is known that other slow calcium channel blockers – dihydropyridine derivatives – are excreted in breast milk.

Data on the excretion of rosuvastatin in human breast milk are lacking; it is known that Rosuvastatin is excreted in the milk of lactating rats.

Fertility

Some patients using calcium channel blockers have experienced reversible biochemical changes in the sperm head. No effect of amlodipine on fertility was observed in a study in rats.

Use in Hepatic Impairment

The use of the drug in patients with active liver disease is contraindicated.

With caution hepatic insufficiency, history of liver disease.

Use in Renal Impairment

The use of the drug is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 ml/min).

Pediatric Use

The use of the drug is contraindicated under 18 years of age (efficacy and safety not established).

Geriatric Use

With caution age over 65 years.

Special Precautions

The patient should be informed of the need to immediately consult a doctor in case of unexpected onset of muscle pain, muscle weakness or cramps, especially in combination with malaise and fever. In such patients, CPK activity should be determined. Therapy should be discontinued if CPK activity is significantly increased (more than 5 times the upper limit of normal) or if musculoskeletal symptoms are severe and cause daily discomfort (even if CPK activity is not more than 5 times the upper limit of normal). If symptoms disappear and CPK activity returns to normal, the possibility of resuming the use of the combined drug or other HMG-CoA reductase inhibitors at lower doses under close medical supervision should be considered. Monitoring CPK activity in the absence of symptoms is not advisable.

Very rare cases of immune-mediated necrotizing myopathy with clinical manifestations of persistent proximal muscle weakness and increased serum CPK activity during therapy or upon discontinuation of HMG-CoA reductase inhibitors, including rosuvastatin, have been reported. Additional investigations of the muscular and nervous systems, serological tests, and therapy with immunosuppressive agents may be required. No signs of increased effects on skeletal muscle with the use of rosuvastatin and concomitant therapy have been noted. However, an increased number of cases of myositis and myopathy have been reported in patients taking other HMG-CoA reductase inhibitors in combination with fibric acid derivatives (e.g., gemfibrozil), cyclosporine, nicotinic acid in lipid-lowering doses (more than 1 g/day), azole antifungal agents, HIV protease inhibitors and macrolide antibiotics.

When used concomitantly with some HMG-CoA reductase inhibitors, gemfibrozil increases the risk of myopathy. Thus, concomitant use of the drug and gemfibrozil is not recommended. The benefits of further modification of plasma lipid concentrations with the combined use of the drug with fibrates or nicotinic acid in lipid-lowering doses should be carefully weighed against the possible risk.

Due to the increased risk of rhabdomyolysis, the drug should not be used in patients with acute conditions that may lead to myopathy or conditions predisposing to the development of renal failure (e.g., sepsis, arterial hypotension, major surgery, trauma, severe metabolic, endocrine or electrolyte disturbances or uncontrolled seizures).

Maintenance of dental hygiene and observation by a dentist is necessary (to prevent soreness, bleeding and gingival hyperplasia).

The following effects on the musculoskeletal system have been reported with the use of rosuvastatin at all doses, but especially at doses exceeding 20 mg/day: myalgia, myopathy, and in rare cases rhabdomyolysis. Very rare cases of rhabdomyolysis have been reported with the concomitant use of HMG-CoA reductase inhibitors and ezetimibe. Such a combination should be used with caution, as a pharmacodynamic interaction cannot be excluded.

CPK activity should not be determined after intense physical exertion and in the presence of other possible causes of its increase, as this may lead to misinterpretation of the results. If the baseline CPK activity is significantly elevated (5 times above the upper limit of normal), a repeat test should be performed after 5-7 days. Therapy should not be started if the repeat test confirms the initial high CPK activity (more than 5 times the upper limit of normal).

During the use of amlodipine in patients with chronic heart failure NYHA class III-IV of non-ischemic origin, an increased incidence of pulmonary edema was noted, despite the absence of signs of worsening heart failure. Caution should be exercised when conducting therapy in patients with chronic heart failure (NYHA class III-IV).

In patients with renal impairment, dose adjustment of amlodipine is not required. Changes in the plasma concentration of amlodipine are not related to the degree of renal impairment.

In patients receiving high doses of rosuvastatin (in particular 40 mg/day), tubular proteinuria was observed, which was detected by dipstick tests and in most cases was intermittent or short-term. Such proteinuria does not indicate an acute or progressive concomitant kidney disease.

As with other drugs containing an HMG-CoA reductase inhibitor, caution should be exercised when using the drug in patients with excessive alcohol consumption and/or a history of liver disease. It is recommended to perform liver function tests before starting therapy and 3 months after its initiation. The drug should be discontinued or the dose reduced if serum hepatic transaminase activity exceeds 3 times the upper limit of normal.

In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, therapy for the underlying diseases should be carried out before starting treatment with the drug.

In pharmacokinetic studies, an increase in the plasma concentration of rosuvastatin was noted in representatives of the Mongoloid race compared to representatives of the Caucasian race.

With the use of some HMG-CoA reductase inhibitors, especially over a long period, isolated cases of interstitial lung disease have been reported. Manifestations of the disease may include dyspnea, non-productive cough and deterioration in general health (weakness, weight loss and fever). If interstitial lung disease is suspected, therapy with the drug should be discontinued.

In patients with a glucose concentration from 5.6 to 6.9 mmol/L, rosuvastatin therapy was associated with an increased risk of developing type 2 diabetes mellitus.

The safety and efficacy of amlodipine in hypertensive crisis have not been established.

The drug contains lactose, therefore it should not be used in the following conditions: lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

Effect on the Ability to Drive Vehicles and Operate Machinery

During therapy with the drug, caution should be exercised when driving vehicles and working with other technical devices requiring increased concentration and speed of psychomotor reactions, taking into account the risk of developing a pronounced decrease in blood pressure, dizziness, drowsiness and other adverse reactions, especially at the beginning of treatment and when increasing the dose.

Drug Interactions

Amlodipine

With the simultaneous use of diltiazem at a dose of 180 mg and amlodipine at a dose of 5 mg in elderly patients with arterial hypertension (from 69 to 87 years old), an increase in the systemic exposure of amlodipine by 57% was noted. Simultaneous use of amlodipine and erythromycin in healthy volunteers (from 18 to 43 years old) does not lead to significant changes in amlodipine exposure (increase in AUC by 22%). Although the clinical significance of these effects is not fully understood, they may be more pronounced in elderly patients.

Potent inhibitors of the CYP3A4 isoenzyme (e.g., ketoconazole, itraconazole) may lead to an increase in the plasma concentration of amlodipine to a greater extent than diltiazem. Amlodipine and inhibitors of the CYP3A4 isoenzyme should be used with caution.

In patients taking clarithromycin (an inhibitor of the CYP3A4 isoenzyme) and Amlodipine simultaneously, there is an increased risk of lowering blood pressure. Patients taking such a combination are recommended to be under careful medical supervision.

There are no data on the effect of inducers of the CYP3A4 isoenzyme on the pharmacokinetics of amlodipine. Simultaneous use of inducers of the CYP3A4 isoenzyme (e.g., rifampicin, St. John’s wort) may reduce the plasma concentration of amlodipine. Caution should be exercised when using amlodipine concomitantly with inducers of the CYP3A4 isoenzyme.

When used concomitantly with amlodipine, there is a risk of increasing the plasma concentration of tacrolimus. To avoid tacrolimus toxicity when used concomitantly with amlodipine, the plasma concentration of tacrolimus should be monitored in patients and the dose of tacrolimus should be adjusted if necessary.

Simultaneous use of amlodipine for the treatment of arterial hypertension with thiazide diuretics, alpha-, beta-blockers, nitrates or ACE inhibitors is considered safe. In patients with stable angina pectoris, Amlodipine can be used simultaneously with other antianginal agents, for example, with long-acting or short-acting nitrates, beta-blockers.

Unlike other slow calcium channel blockers, no clinically significant interaction of amlodipine was found when used concomitantly with NSAIDs, including indomethacin.

Enhancement of the antianginal and antihypertensive effects of slow calcium channel blockers is possible with simultaneous use with thiazide and “loop” diuretics, ACE inhibitors, beta-blockers and nitrates, as well as enhancement of the antihypertensive effect with simultaneous use with alpha₁-blockers, antipsychotics.

Although a negative inotropic effect was not usually observed in studies of amlodipine, nevertheless, some slow calcium channel blockers may enhance the severity of the negative inotropic effect of antiarrhythmic agents causing QT interval prolongation (e.g., amiodarone and quinidine).

Simultaneous use of amlodipine with antibiotics and oral hypoglycemic agents is considered safe.

A single dose of sildenafil 100 mg in patients with essential hypertension does not affect the pharmacokinetic parameters of amlodipine.

Repeated use of amlodipine 10 mg and atorvastatin 80 mg is not accompanied by significant changes in the pharmacokinetic parameters of atorvastatin.

Simultaneous multiple use of amlodipine 10 mg and simvastatin 80 mg leads to an increase in simvastatin exposure by 77%. In such patients, the dose of simvastatin should be limited to 20 mg/day.

Amlodipine, when used as a single dose and repeatedly at a dose of 10 mg, does not affect the pharmacokinetics of ethanol.

Antiviral agents (ritonavir) increase the plasma concentrations of slow calcium channel blockers, including amlodipine.

Antipsychotics and isoflurane enhance the antihypertensive effect of dihydropyridine derivatives.

Calcium preparations may reduce the effect of slow calcium channel blockers.

When slow calcium channel blockers are used concomitantly with lithium preparations (data for amlodipine are not available), an increase in the manifestations of neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus) is possible.

Studies of the simultaneous use of amlodipine and cyclosporine were conducted only in a group of patients after kidney transplantation. The use of this combination may either have no effect or increase the C_max of cyclosporine to varying degrees up to 40%. The plasma concentration of cyclosporine should be monitored in this group of patients when amlodipine and cyclosporine are used simultaneously.

When used concomitantly, Amlodipine does not affect the serum concentration and renal clearance of digoxin.

Amlodipine does not significantly affect the action of warfarin.

Cimetidine does not affect the pharmacokinetics of amlodipine.

In in vitro studies, Amlodipine does not affect the plasma protein binding of digoxin, phenytoin, warfarin and indomethacin.

Simultaneous single oral administration of 240 mg of grapefruit juice and 10 mg of amlodipine is not accompanied by a significant change in the pharmacokinetics of amlodipine. Nevertheless, it is not recommended to use grapefruit juice and Amlodipine simultaneously, because with genetic polymorphism of the CYP3A4 isoenzyme, an increase in the bioavailability of amlodipine and, consequently, an enhancement of the antihypertensive effect is possible.

Aluminum-, magnesium-containing antacids with a single dose do not have a significant effect on the pharmacokinetics of amlodipine.

Rosuvastatin

Rosuvastatin is a substrate for some transport proteins, in particular OATP1B1 and BCRP. Simultaneous use of drugs that are inhibitors of these transport proteins may be accompanied by an increase in the plasma concentration of rosuvastatin and an increased risk of developing myopathy.

With the simultaneous use of rosuvastatin and cyclosporine, the AUC of rosuvastatin is on average 7 times higher than the value observed in healthy volunteers. Simultaneous use with rosuvastatin does not affect the plasma concentration of cyclosporine. The use of rosuvastatin is contraindicated in patients taking cyclosporine.

Simultaneous use of HIV protease inhibitors can significantly increase the exposure of rosuvastatin. Simultaneous use of 20 mg rosuvastatin and a combination of two HIV protease inhibitors (400 mg lopinavir/100 mg ritonavir) is accompanied by an increase in the steady-state AUC_{0-24 h} and C_max of rosuvastatin by 2 and 5 times, respectively. Therefore, the simultaneous use of rosuvastatin and HIV protease inhibitors is not recommended.

Simultaneous use of rosuvastatin and gemfibrozil leads to an increase in C_max and AUC of rosuvastatin in plasma by 2 times. Based on specific interaction data, no pharmacokinetically significant interaction with fenofibrate is expected; a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses of nicotinic acid (doses greater than 1 g/day) increased the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, possibly because they can cause myopathy when used as monotherapy. In such patients, therapy should be started at a dose of 5 mg/day. Simultaneous use of fibrates and rosuvastatin at a daily dose of 40 mg is contraindicated.

Simultaneous use of rosuvastatin 10 mg and ezetimibe 10 mg was accompanied by an increase in the AUC of rosuvastatin in patients with hypercholesterolemia. A pharmacodynamic interaction between rosuvastatin and ezetimibe, manifested by an increased risk of adverse reactions, cannot be excluded.

Simultaneous use of rosuvastatin and antacids containing aluminum and magnesium hydroxide leads to a decrease in the plasma concentration of rosuvastatin by approximately 50%. This effect is less pronounced if antacids are taken 2 hours after taking rosuvastatin.

Simultaneous use of rosuvastatin and erythromycin leads to a decrease in the AUC_(0-t) of rosuvastatin by 20% and its C_max by 30%. This interaction may occur as a result of increased intestinal motility caused by the use of erythromycin.

Results of in vivo and in vitro studies have shown that Rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. Furthermore, Rosuvastatin is a weak substrate for this system of isoenzymes. Therefore, no interaction of rosuvastatin with other drugs at the level of metabolism involving cytochrome P450 isoenzymes is expected.

No clinically significant interaction between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4 isoenzymes) and ketoconazole (an inhibitor of CYP2A6 and CYP3A4 isoenzymes) was noted.

As with other statins, post-marketing reports of cases of rhabdomyolysis have been received with the combined use of rosuvastatin and fusidic acid. Patients should be closely monitored. If necessary, temporary discontinuation of rosuvastatin may be possible.

The dose of rosuvastatin should be adjusted if it is necessary to use it simultaneously with drugs that increase the exposure of rosuvastatin.

As with other HMG-CoA reductase inhibitors, initiation of rosuvastatin therapy or an increase in its dose in patients taking vitamin K antagonists (e.g., warfarin) concomitantly may lead to an increase in INR. Discontinuation of rosuvastatin or a decrease in its dose may lead to a decrease in INR. In such cases, monitoring of INR is recommended.

Simultaneous use of rosuvastatin and oral contraceptives increases the AUC of ethinyl estradiol and norgestrel by 26% and 34%, respectively. Such an increase in plasma concentration should be taken into account when selecting the dose of hormonal contraceptives.

Pharmacokinetic data on the simultaneous use of rosuvastatin and HRT drugs are not available, therefore, a similar effect with the use of this combination cannot be excluded. However, this combination was widely used during clinical trials and was well tolerated by patients.

No clinically significant interaction of rosuvastatin with digoxin is expected.

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.