Duplecor^® (Tablets) Instructions for Use

ATC Code

C10BX03 (Atorvastatin and Amlodipine)

Active Substances

Amlodipine (Rec.INN registered by WHO)

Atorvastatin (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antihypertensive and antianginal drug with hypolipidemic activity

Pharmacotherapeutic Group

Antihypertensive and hypolipidemic agent (slow calcium channel blocker and HMG-CoA reductase inhibitor)

Pharmacological Action

A combined medicinal product: Atorvastatin is a hypolipidemic agent, an inhibitor of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase; Amlodipine is a dihydropyridine derivative, a slow calcium channel blocker (CCB). Therapy with the combined preparation leads to a dose-dependent reduction in systolic and diastolic blood pressure and the concentration of low-density lipoprotein cholesterol (LDL-C).

Regarding the effect on systolic and diastolic blood pressure or LDL-C concentration, this combination does not differ significantly from monotherapy with amlodipine and atorvastatin.

Amlodipine blocks the entry of calcium ions through membranes into the smooth muscle cells of the myocardium and blood vessels. The mechanism of the antihypertensive action of amlodipine is due to a direct relaxing effect on vascular smooth muscles. The exact mechanism of action of amlodipine in angina pectoris has not been fully established, but Amlodipine reduces ischemia by dilating peripheral arterioles, which leads to a decrease in systemic vascular resistance, i.e., a reduction in cardiac afterload. Since the heart rate does not change, the reduction in cardiac load leads to a decrease in energy consumption and oxygen demand. Furthermore, the mechanism of action of amlodipine is also likely associated with the dilation of the main coronary arteries and coronary arterioles, both in unchanged and ischemic areas of the myocardium. Their dilation increases oxygen delivery to the myocardium in patients with vasospastic angina (Prinzmetal’s angina or variant angina).

In patients with arterial hypertension, taking amlodipine in a single daily dose provides a clinically significant reduction in blood pressure over 24 hours, both in the supine and standing positions. Due to its slow onset of action, Amlodipine does not cause acute arterial hypotension.

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

In patients with heart failure of functional class II-IV (according to the NYHA classification), the use of amlodipine did not lead to a worsening of the clinical condition (exercise tolerance, left ventricular ejection fraction, and clinical symptoms).

Atorvastatin selectively and competitively inhibits HMG-CoA reductase, which catalyzes the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonic acid, a precursor of steroids, including cholesterol (Ch). Triglycerides and cholesterol in the liver are incorporated into very-low-density lipoprotein cholesterol (VLDL-C), enter the blood plasma, and are transported to peripheral tissues. LDL-C is formed from VLDL-C during interaction with LDL-C receptors, which are characterized by high affinity for these lipoproteins.

Atorvastatin reduces plasma concentrations of Ch and lipoproteins by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL-C receptors on the cell surface, which leads to enhanced uptake and catabolism of LDL-C. Atorvastatin reduces the formation of LDL-C, provides a significant and sustained increase in LDL-C receptor activity, combined with a favorable change in the quality of LDL particles.

It reduces the concentrations of total Ch (30-46%), LDL-C (41-61%), apolipoprotein B (34-50%), and triglycerides (14-33%), while leading to an increase in the concentration of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A1. These results are the same for patients with heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia, as well as mixed hyperlipidemia, including patients with type 2 diabetes mellitus.

Atorvastatin is effective in reducing LDL-C concentration in patients with homozygous familial hypercholesterolemia, i.e., a population usually resistant to therapy with other hypolipidemic agents. It significantly reduces the risk of ischemic complications (including fatal myocardial infarction) by 16%, and the risk of rehospitalization for angina pectoris accompanied by signs of myocardial ischemia by 26%. The effect of atorvastatin on the risk of ischemic outcomes and mortality did not depend on the initial LDL-C concentration and was comparable in patients with non-Q-wave myocardial infarction and unstable angina, men and women, and patients younger and older than 65 years.

Pharmacokinetics

After oral administration, Amlodipine is well absorbed; C_max in plasma is reached after 6-12 hours. Absolute bioavailability is 64-80%. The bioavailability of amlodipine is not altered by food intake. V_d is approximately 21 L/kg. Approximately 97% of circulating amlodipine is bound to plasma proteins. C_ss of amlodipine in plasma is achieved after 7-8 days of regular administration. Amlodipine is metabolized in the liver to form inactive metabolites; 10% of unchanged amlodipine and 60% of metabolites are excreted by the kidneys. Elimination from plasma is biphasic with a terminal T_1/2 of 30-50 hours. In elderly patients, a tendency towards a decrease in the clearance of amlodipine was noted, leading to an increase in AUC and T_1/2. In patients of various age groups with chronic heart failure (CHF), an increase in AUC and T_1/2 was observed. A similar increase in AUC was noted in patients with hepatic insufficiency. In patients with impaired liver function, T_1/2 increases.

Atorvastatin is rapidly absorbed after oral administration; C_max in plasma is reached within 1-2 hours. The degree of absorption increases depending on the dose of atorvastatin. The absolute bioavailability of atorvastatin is approximately 12%, and the systemic bioavailability of inhibitory activity against HMG-CoA reductase is approximately 30%. The low systemic bioavailability is due to presystemic metabolism (absorption) in the gastrointestinal mucosa and/or first-pass metabolism in the liver. The average V_d of atorvastatin is approximately 381 L. Atorvastatin is more than 98% bound to plasma proteins. Atorvastatin is metabolized by cytochrome P450 3A4 isoenzymes to ortho- and para-hydroxylated derivatives and various beta-oxidation products. In addition to other metabolic pathways, these products are further metabolized via glucuronide conjugation. In vitro, inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to the inhibition observed for atorvastatin. Approximately 70% of the reduction in HMG-CoA reductase activity is due to the action of active circulating metabolites. Atorvastatin is excreted mainly in the bile after hepatic and/or extrahepatic metabolism. However, the drug does not appear to undergo significant enterohepatic recirculation. The mean plasma T_1/2 is approximately 14 hours. Due to the action of active metabolites, the half-life of HMG-CoA reductase inhibitory activity is approximately 20-30 hours. Plasma concentrations of atorvastatin and its metabolites in healthy elderly volunteers are higher than in healthy young volunteers, although the hypolipidemic effects are comparable to those in young individuals. The plasma concentration of atorvastatin in women differs from that in men (C_max in women is approximately 20% higher, and AUC is 10% lower); however, no clinically significant differences in the effect of the drug on lipid metabolism between men and women have been identified. Plasma concentrations of atorvastatin and its metabolites are significantly increased (C_max approximately 16 times, AUC 11 times) in patients with chronic liver disease caused by excessive alcohol consumption (Child-Pugh class B).

Indications

Treatment of arterial hypertension in patients with dyslipidemia, whose condition is adequately controlled by taking amlodipine and atorvastatin in the same dosages that are part of the fixed combinations of amlodipine/atorvastatin (with or without clinically expressed coronary artery disease) and who have one of the following diseases: primary hypercholesterolemia, including familial hypercholesterolemia (familial heterozygous hypercholesterolemia), or combined (mixed) hyperlipidemia (corresponding to type IIa and IIb according to the Fredrickson classification); homozygous familial hypercholesterolemia; when hypolipidemic diet and other non-pharmacological methods of treating dyslipidemia are insufficiently or ineffective.

ICD codes

Dosage Regimen

Take one tablet orally once daily at any time of day, with or without food.

This fixed-dose combination is not recommended for initial therapy. Use only in patients whose condition is already controlled on the individual components (amlodipine and atorvastatin) at the same doses contained in this combination tablet.

Select the tablet strength based on the patient’s established therapeutic needs for both amlodipine and atorvastatin.

Do not exceed the maximum recommended daily dose of 10 mg amlodipine and 80 mg atorvastatin.

In patients with severe renal impairment, no dosage adjustment is required.

Use with caution in patients over 65 years of age due to increased atorvastatin exposure.

Contraindicated in patients with active liver disease or unexplained persistent elevations in serum transaminases.

Prior to initiation, measure fasting lipid levels and assess liver function tests (LFTs).

Monitor LFTs before treatment, at 12 weeks after initiation, after any dose increase, and periodically thereafter.

Discontinue therapy if serum transaminase levels persist at more than 3 times the upper limit of normal.

Advise patients to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.

If creatine phosphokinase (CPK) levels are significantly elevated (>5x ULN), discontinue treatment.

Adverse Reactions

Definition of adverse reaction frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000).

Atorvastatin

From the hematopoietic system uncommon – thrombocytopenia.

Allergic reactions common – hypersensitivity; very rare – anaphylactic reactions, angioedema, bullous rash (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis).

From metabolism and nutrition common – hyperglycemia; uncommon – hypoglycemia.

Mental disorders: uncommon – insomnia, nightmares.

From the nervous system: common – headache; uncommon – dizziness, hypoesthesia, dysgeusia, amnesia, paresthesia; rare – peripheral neuropathy (not otherwise specified).

From the hearing organ uncommon – tinnitus.

From the respiratory system: common – chest pain, nasopharyngitis, epistaxis.

From the digestive system common – diarrhea, constipation, flatulence, nausea, dyspepsia, abdominal pain; uncommon – vomiting.

From the hepatobiliary system: rare – hepatitis, cholestatic jaundice, pancreatitis; very rare – hepatic failure.

From the skin and subcutaneous tissue common – skin rash, pruritus; uncommon – alopecia.

From the musculoskeletal system: common – myalgia, arthralgia, back pain; uncommon – myopathy; rare – myositis, rhabdomyolysis, muscle cramps.

From the reproductive system and mammary glands uncommon – erectile dysfunction; very rare – gynecomastia.

General disorders common – increased fatigue, asthenia; uncommon – general weakness; rare – peripheral edema.

Laboratory parameters common – increased activity of liver transaminases, increased activity of serum CPK; uncommon – weight gain.

Amlodipine

From the hematopoietic system: very rare – thrombocytopenia, leukopenia.

Allergic reactions very rare – hypersensitivity, urticaria, angioedema, erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, photosensitivity.

From metabolism and nutrition very rare – hyperglycemia.

Mental disorders: uncommon – insomnia, mood lability (including anxiety), depression; rare – confusion.

From the nervous system: common – somnolence, dizziness, headache (especially at the beginning of treatment); uncommon – syncope, tremor, hypoesthesia, dysgeusia, paresthesia; very rare – muscle hypertonia, peripheral neuropathy.

From the organ of vision: uncommon – visual impairment (including diplopia).

From the hearing organ uncommon – tinnitus.

From the cardiovascular system common – flushing, peripheral edema of the ankles and feet; uncommon – palpitations, marked decrease in blood pressure; very rare – myocardial infarction (including bradycardia, ventricular tachycardia, and atrial fibrillation), vasculitis.

From the respiratory system: uncommon – dyspnea, rhinitis; very rare – cough.

From the gastrointestinal tract common – abdominal pain, nausea; uncommon – vomiting, dyspepsia, intestinal function disorders (constipation or diarrhea), dry mouth; very rare – pancreatitis, gastritis, hypertrophic gingivitis.

From the hepatobiliary system very rare – hepatitis, cholestatic jaundice.

From the skin and subcutaneous tissue uncommon – alopecia, purpura, skin pigmentation disorder, hyperhidrosis, skin rash, pruritus, exanthema.

From the musculoskeletal system: common – ankle swelling; uncommon – arthralgia, myalgia, muscle cramps, back pain.

From the urinary system uncommon – urination disorder, nocturia, pollakiuria.

From the reproductive system and mammary glands uncommon – erectile dysfunction, gynecomastia.

General disorders common – edema, increased fatigue; uncommon – asthenia, chest pain, pain, general malaise.

Laboratory parameters uncommon – increase or decrease in body weight; rare – increased activity of liver transaminases.

Contraindications

Severe arterial hypotension (systolic blood pressure less than 90 mm Hg); shock (including cardiogenic shock); hemodynamically unstable heart failure after acute myocardial infarction; active liver disease or persistent increase in liver enzyme activity more than 3 times the upper limit of normal of unknown etiology; use in women of reproductive age not using adequate contraceptive methods; concomitant use with itraconazole, ketoconazole, and telithromycin; age under 18 years; pregnancy, lactation (breastfeeding); hypersensitivity to amlodipine and other dihydropyridine derivatives, atorvastatin.

With caution

Arterial hypotension, acute myocardial infarction (and within 1 month after it), CHF of non-ischemic etiology III-IV FC according to the NYHA classification, sick sinus syndrome, hypertrophic obstructive cardiomyopathy, impaired liver function, patients who abuse alcohol and/or have a history of liver disease, patients with risk factors for rhabdomyolysis (moderate renal failure /creatinine clearance less than 60 ml/min/, severe disturbances of water and electrolyte balance, endocrine and metabolic disorders, severe acute infections /sepsis/, uncontrolled epilepsy, major surgical interventions, trauma, hypothyroidism, personal or family history of muscle diseases, myotoxicity while taking other HMG-CoA reductase inhibitors or fibrates, conditions accompanied by an increase in the concentration of atorvastatin in the systemic circulation), age over 65 years, because the concentration of atorvastatin increases with age.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

The drug is contraindicated for use in impaired liver function.

Use in Renal Impairment

No dose adjustment of the drug is required.

Pediatric Use

Contraindicated:

• Age under 18 years (efficacy and safety have not been established).

Geriatric Use

With caution: age over 65 years, because the concentration of atorvastatin increases with age.

Special Precautions

In patients with CHF (III-IV FC according to the NYHA classification) of non-ischemic etiology, when using amlodipine, there is a possibility of pulmonary edema. Therefore, caution is required when using this combination.

Before starting treatment with atorvastatin and periodically during treatment, liver function should be monitored. If liver enzyme activity increases, exceeding the upper limit of normal by 3 times, it is recommended to reduce the dose or discontinue use. In patients with impaired liver function, the T_1/2 of amlodipine increases, so caution is required when using this combination.

The diagnosis of myopathy should be considered in patients taking HMG-CoA reductase inhibitors who have unexplained symptoms, such as muscle pain or tenderness, muscle weakness, or muscle cramps. In such cases, monitoring of CPK activity is necessary. CPK activity should not be measured after intense physical exertion or if there is a probable alternative cause for increased CPK activity. If CPK activity is significantly above normal (more than 5 times the upper limit of normal), CPK activity should be determined regularly for 5-7 days to confirm the results.

CPK activity should be determined before starting treatment with atorvastatin in the following situations: impaired renal function; hypothyroidism; personal or family history of muscle diseases; history of myotoxicity while taking other HMG-CoA reductase inhibitors or fibrates; history of liver disease and/or alcohol abuse; in elderly patients (> 65 years) in the presence of risk factors for rhabdomyolysis. The expected benefit and risk of treatment should be carefully weighed, and patients should be regularly monitored. If CPK activity is increased more than 5 times compared to the upper limit of normal, treatment should not be started.

Patients should be informed of the need to immediately report to the doctor any cases of unexpected onset of muscle pain, muscle weakness, or cramps, especially in combination with malaise or fever.

If muscle pain, weakness, or cramps occur during treatment, CPK activity should be monitored. If it is determined that CPK activity has exceeded the upper limit of normal by more than 5 times, treatment should be discontinued.

If muscle symptoms are severe and cause daily discomfort throughout the day, even if CPK activity is increased less than 5 times compared to the upper limit of normal, treatment should be discontinued.

Increased creatine phosphokinase (CPK) activity should be considered in the differential diagnosis of chest pain when assessing the likelihood of myocardial infarction. During treatment with atorvastatin, as with other drugs of this class, rare cases of rhabdomyolysis with acute renal failure due to myoglobinuria have been reported.

Concomitant use of this combination with dantrolene (infusion solution), gemfibrozil, or other fibrates is not recommended.

When used concomitantly with cyclosporine, nicotinic acid in lipid-lowering doses (more than 1 g/day), fibric acid derivatives, macrolide antibiotics including erythromycin, clarithromycin, antifungal agents belonging to the azoles (itraconazole, ketoconazole), nefazodone, as well as HIV protease inhibitors, the risk of myopathy during treatment with HMG-CoA reductase inhibitors increases.

Effect on the Ability to Drive Vehicles and Operate Machinery

Caution should be exercised when driving vehicles and operating machinery while taking drugs containing the Amlodipine/Atorvastatin combination, considering the possibility of excessive blood pressure reduction, dizziness, and fainting.

Drug Interactions

Concomitant use with baclofen enhances the hypotensive effect. Blood pressure monitoring and a reduction in the dose of the antihypertensive drug may be required.

It cannot be excluded that potent inhibitors of the CYP3A4 isoenzyme (e.g., ketoconazole, itraconazole, ritonavir) may increase the plasma concentration of amlodipine.

With antiepileptic drugs (e.g., carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone), rifampicin, due to the induction of amlodipine metabolism, a decrease in the plasma concentration of calcium channel blockers (in particular, amlodipine) can be expected.

α₁-adrenergic receptor blockers (prazosin, alfuzosin, doxazosin, tamsulosin, terazosin): an enhancement of the hypotensive effect with a risk of severe orthostatic hypotension can be expected.

Amifostine: enhancement of the hypotensive effect due to the manifestation of amifostine adverse events.

Tricyclic antidepressants/antipsychotics: the risk of arterial hypotension or orthostatic hypotension increases (additive effect).

Beta-blockers (bisoprolol, carvedilol, metoprolol): risk of arterial hypotension or heart failure in the case of latent or uncontrolled heart failure (the negative inotropic effect of beta-blockers may be enhanced). In the case of concomitant use of amlodipine and beta-blockers, sympathetic reflex reactions manifested as a result of an excessive hemodynamic effect may be weakened.

Corticosteroids, tetracosactide: the hypotensive effect may decrease due to reduced sodium and water absorption caused by corticosteroids.

Other antihypertensive agents: concomitant use of antihypertensive agents (beta-blockers, angiotensin II receptor antagonists, diuretics, ACE inhibitors) may enhance the hypotensive effect of amlodipine. Concurrent use with nitrates or other vasodilators may lead to an additional decrease in blood pressure.

Sildenafil: in primary arterial hypertension, a single 100 mg dose of sildenafil did not affect the pharmacokinetic parameters of amlodipine. When amlodipine is taken in combination with sildenafil, each drug lowers blood pressure independently of the other.

When calcium channel blockers are used concomitantly with lithium preparations, an increase in the manifestation of their neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus) is possible.

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

Itraconazole, ketoconazole: the risk of dose-dependent adverse events, e.g., rhabdomyolysis, increases (atorvastatin metabolism in the liver is reduced).

Telithromycin: the risk of dose-dependent adverse events, e.g., rhabdomyolysis, increases (atorvastatin metabolism in the liver is reduced).

Gemfibrozil and other fibric acid derivatives: the risk of dose-dependent adverse events, e.g., rhabdomyolysis, increases (atorvastatin metabolism in the liver is reduced).

Inhibitors of the CYP3A4 isoenzyme: Atorvastatin is metabolized by the CYP3A4 isoenzyme. Erythromycin, a CYP3A4 inhibitor, increased the plasma concentration of atorvastatin by 40%. Concurrent administration of atorvastatin and CYP3A4 inhibitors, certain macrolide antibiotics (e.g., erythromycin, clarithromycin), immunosuppressants (cyclosporine), antifungal agents belonging to the azoles (e.g., itraconazole, ketoconazole), amiodarone, protease inhibitors or antidepressants, nefazodone, may lead to an interaction resulting in increased plasma concentration of atorvastatin.

Inducers of the CYP3A4 isoenzyme: concurrent use of atorvastatin and inducers of the CYP3A4 isoenzyme (e.g., phenytoin, rifampicin) may lead to a significant decrease in the plasma concentration of atorvastatin. Due to the dual mechanism of interaction of rifampicin (induction of the CYP3A4 isoenzyme and inhibition of the hepatocyte uptake transporter OATP1B1), concomitant use of atorvastatin and rifampicin led to a mean increase in the C_max and AUC parameters of atorvastatin by 12% and 90%, respectively. In contrast, taking atorvastatin some time after taking rifampicin was accompanied by a significant decrease (approximately 80%) in the plasma concentration of atorvastatin.

Warfarin: taking atorvastatin concomitantly with warfarin may lead to an enhancement of the anticoagulant effect with a risk of bleeding. Patients receiving warfarin should be monitored by a physician, as an adjustment of the anticoagulant dose may be required.

Nicotinic acid: hypolipidemic doses of nicotinic acid (more than 1 g/day) may increase the risk of myopathy when taken concomitantly with HMG-CoA reductase inhibitors. Rarely, renal failure may develop as a consequence of rhabdomyolysis and myoglobinuria. Therefore, the benefit/risk ratio of concomitant use of atorvastatin and nicotinic acid in lipid-lowering doses should be considered.

Antacids: concurrent oral administration of a suspension containing magnesium and aluminum hydroxides reduced the plasma concentration of atorvastatin by approximately 35%, but the degree of reduction in LDL-C content did not change.

Grapefruit juice: grapefruit juice contains one or more components that inhibit CYP3A4 and therefore can lead to increased plasma concentrations of drugs metabolized by the CYP3A4 isoenzyme. Consumption of one glass (240 ml) of grapefruit juice led to a 37% increase in the AUC of atorvastatin and a 20.4% decrease in the AUC of the active ortho-hydroxy metabolite of atorvastatin. However, large quantities of grapefruit juice (more than 1.2 l/day for 5 days) increase the AUC of atorvastatin by 2.5 times and the AUC of active HMG-CoA reductase inhibitors (Atorvastatin and metabolites) by 1.3 times. Concurrent intake of large quantities of grapefruit juice and atorvastatin is not recommended.

Oral contraceptives: use of atorvastatin concomitantly with an oral contraceptive containing norethisterone and ethinyl estradiol led to increased plasma concentrations of norethisterone and ethinyl estradiol. This effect should be considered when choosing an oral contraceptive for a woman receiving Atorvastatin.

Colestipol: the hypolipidemic effect of the combination with colestipol is superior to that of each drug separately, despite a 25% reduction in atorvastatin concentration when used concomitantly with colestipol.

Antipyrine (phenazone): concurrent administration of multiple doses of atorvastatin and phenazone revealed a minor effect or no effect on the clearance of phenazone.

During long-term use of digoxin concomitantly with 10 mg of atorvastatin, a slight increase in the steady-state concentrations of digoxin was observed.

Assessment of the effect of amiodarone or verapamil on Atorvastatin has not been conducted. It is known that both drugs – amiodarone and verapamil – suppress the activity of the CYP3A4 isoenzyme, and their concomitant use with atorvastatin may lead to an increase in the concentration of atorvastatin.

Concomitant use of atorvastatin and fusidic acid may lead to the development of rhabdomyolysis.

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.