Amlodipine, Atorvastatin

Pharmacological properties

Cadova 5/10 and cadova 10/10 have a double mechanism of action; the effect of amlodipine as a dihydropyridine calcium antagonist (calcium ion antagonist or slow calcium channel blocker) and for the suppression of atmorvastatin gmg-coa reductase. the amlodipine component of the drugs drops 5/10 and drops 10/10 inhibits the transmembrane flow of calcium ions into the cells of the smooth muscles of blood vessels and heart muscles. The atorvastatin component is a potent selective inhibitor of HMG-COA reductase, a key enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme and mevalonate, a precursor of sterols, including xc.

For the drugs Cadova 5/10 and Cadova 10/10, no modification of the effect of amlodipine on systolic blood pressure was noted compared with monotherapy with amlodipine.

Similarly, for Kaduet 5/10 and Kaduet 10/10, no modification of the effect of atorvastatin on LDL cholesterol was detected in comparison with atorvastatin monotherapy.

The Anglo-Scandinavian study of the results of heart disease (ASCOT) is a randomized, 2 × 2-factor design study to compare two antihypertensive regimens in 19,257 patients (ASCOT-BPLA group for lowering blood pressure) and to study the effect of adding 10 mg of atorvastatin compared to placebo in 10 305 patients (lipid lowering group - ASCOT-LLA) for lethal and non-lethal coronary attacks.

The effect of atorvastatin on lethal and non-lethal coronary attacks was evaluated in a randomized, double-blind, placebo-controlled study (ASCOT-LLA) in 10,305 hypertensive patients aged 40–79 years without previous myocardial infarction or angina pectoris and with a total cholesterol level of ≤6.5 mmol / l (251 mg / dl). All patients had at least 3 of the following predefined cardiovascular risk factors: male gender, age (≥55 years), smoking, diabetes, early history of IHD in the immediate family, total HDL cholesterol ≥6, peripheral vascular disease, left hypertrophy ventricle, previous cerebrovascular disorder, specific abnormalities of the ECG, proteinuria / albuminuria.

Patients were treated using antihypertensive regimens based on amlodipine (5–10 mg) or atenolol (50–100 mg). To achieve the planned BP in the future (140/90 mm Hg in patients without diabetes, 130/80 mm Hg in patients with diabetes), perindopril (4-8 mg) could be added in the amlodipine group, and the atenolol group is potassium bendroflumethiazide (1.25–2.5 mg). The third-line therapy in both groups was doxazosin GITS (4–8 mg). The atorvastatin group consisted of 5168 patients (2584 people received amlodipine and 2584 atenolol), and the placebo group consisted of 5137 patients (2554 people received amlodipine and 2583 atenolol).

The combination of amlodipine with atorvastatin led to a significant reduction in risk in the composite primary endpoint of lethal coronary artery disease and non-lethal myocardial infarction:

• 53% (95% confidence interval (CI) 31–68%; p0,0001) compared with the combination of amlodipine + placebo;
• 39% (95% CI 8–59%; p0.016) compared with the combination of atenolol + atorvastatin.

Blood pressure decreased significantly with both treatment regimens and significantly more for the amlodipine + atorvastatin-based regimen than for the atenolol + atorvastatin-based regimen (respectively –26.5 / –15.6 mm Hg vs. –24.7 / –13 , 6 mmHg). For differences between the two groups, p = 0.0036 (for systolic blood pressure) and 0.0001 (for diastolic blood pressure).

A study of antihypertensive and lipid-lowering treatments to prevent heart attacks (ALLHAT). To compare the efficacy of amlodipine or lisinopril with the efficacy of chlortalidone as a first-line therapy in patients with mild to moderate severity hypertension, a randomized, double-blind, double-blind, antihypertensive and lipid-lowering treatment to prevent heart attacks (ALLHAT) was performed.

A total of 33,357 patients with hypertension aged ≥55 years were randomized and were observed on average for 4.9 years. These patients had at least one additional risk factor for coronary heart disease, including: a previous myocardial infarction or stroke (less than 6 months before inclusion in the study) or other documented atherosclerotic cardiovascular disease (51.5% in total), type II diabetes mellitus ( 36.1%), HDL cholesterol 35 mg / dl (11.6%), left ventricular hypertrophy diagnosed by ECG or echocardiography (20.9%), current cigarette smoking (21.9%).

The primary endpoint was a combination of lethal coronary artery disease or non-lethal myocardial infarction. In the amlodipine group, the primary endpoint reached 11.3% of patients compared to 11.5% in the chlortalidone group (relative risk (RR) 0.98; 95% CI 0.90–1.07; p = 0.65).

Among the secondary endpoints: the mortality rate for all reasons was 17.3% in the chlortalidone group and 16.8% in the amlodipine group (amlodipine compared to chlortalidone, RR 0.96; 95% CI 0.89–1.02; p = 0.20).

The frequency of heart failure (a composite composite cardiovascular endpoint component) was significantly higher in the amlodipine group compared with the chlortalidone group (10.2% versus 7.7%; RR 1.38; 95% CI 1.25–1.52 ; p0.001).

The study did not show the benefits of any drug relative to the primary endpoint; a posteriori analysis of the results showed that amlodipine reduces the number of deaths in coronary heart disease and non-lethal myocardial infarction of the main endpoint and mortality for all reasons of the secondary main endpoint to the same extent as chlortalidone.

The study “Prevention of Stroke by Aggressively Lowering Cholesterol Levels” (SPARCL) in 4731 patients who had a stroke or transient ischemic attack (TIA) in the previous 6 months without a history of IHD, evaluated the effect of 80 mg of atorvastatin daily or placebo on stroke. 60% of the patients were men aged 21–92 years (mean age 63 years); at the inclusion stage, they had an average LDL level of 133 mg / dL (3.4 mmol / L). The average LDL cholesterol level was 73 mg / dl (1.9 mmol / L) during treatment with atorvastatin and 129 mg / dl (3.3 mmol / L) - placebo. Median follow-up - 4.9 years.

80 mg of atorvastatin reduced the risk of a primary endpoint of a fatal or non-lethal stroke by 15% (RR 0.85; 95% CI 0.72–1.00; p = 0.05 or RR 0.84; 95% CI 0.71– 0.99; p = 0.03 after statistical correction for initial stage factors) compared with placebo. For all reasons, mortality was 9.1% (216/2365) for atorvastatin compared with 8.9% (211/2366) for placebo.

In a post-hoc analysis, 80 mg of atorvastatin reduced the incidence of ischemic attack (218/2365, 9.2% versus 274/2366, 11.6%; p = 0.01) and increased the incidence of hemorrhagic stroke (55/2365, 2, 3% versus 33/2366, 1.4%; p = 0.02) compared with placebo.

The risk of hemorrhagic stroke increased in patients who were included in the study with a previous hemorrhagic stroke (7/45 for atorvastatin versus 2/48 for placebo; RR 4.06; 95% CI 0.84–19.57), and the risk of ischemic the attack for these groups was similar (3/45 for atorvastatin versus 2/48 for placebo; RR 1.64; 95% CI 0.27–9.82).

The risk of hemorrhagic stroke increased in patients who were included in the study with a previous lacunar infarction (20/708 for atorvastatin versus 4/701 for placebo; RR 4.99; 95% CI 1.71-14.61), the risk of ischemic an attack in these patients (79/708 for atorvastatin versus 102/701 for placebo; RR 0.76; 95% CI 0.57–1.02). Perhaps the risk of stroke increased in patients with previous lacunar infarction who received 80 mg / day of atorvastatin.

For all reasons, mortality was 15.6% (7/45) for atorvastatin versus 10.4% (5/48) in a subgroup of patients with a previous hemorrhagic stroke. For all reasons, mortality was 10.9% (77/708) for atorvastatin versus 9.1% (64/701) for placebo in a subgroup of patients with previous lacunar infarction.

Pharmacokinetics

Data for Kaduet 5/10 and Kaduet 10/10. After oral administration, two distinct peaks of plasma concentrations were noted. The first, within 1-2 hours after administration, is due to atorvastatin; the second, 6-12 hours after administration, is due to amlodipine.The rate and extent of absorption (bioavailability) of amlodipine and atorvastatin from Kaduet 5/10 and Kaduet 10/10 is not significantly different from the bioavailability of amlodipine and atorvastatin when combined with amlodipine and atorvastatin tablets.

The bioavailability of amlodipine from Kaduet 5/10 and Kaduet 10/10 was not affected by taking the drug after meals. Although food reduces the rate and extent of absorption of atorvastatin from Kaduet 5/10 and Kaduet 10/10 by approximately 32 and 11%, respectively, C estimates_max and AUC, a similar decrease in plasma concentrations after meals was noted for atorvastatin without a decrease in exposure to LDL cholesterol (see below).

Data for Amlodipine

Suction. Following oral administration of therapeutic doses of amlodipine alone, absorption led to the appearance of C_max within 6-12 hours after taking a dose of the drug. According to estimates, the absolute bioavailability was in the range of 64–80%. The volume of distribution is about 21 l / kg body weight. The bioavailability of amlodipine does not change with food intake.

Distribution. In vitro amlodipine studies have shown that in patients with hypertension, about 97.5% of the circulating drug binds to plasma proteins.

Biotransformation. Amlodipine is intensively converted (≈90%) to inactive metabolites by hepatic metabolism.

Excretion. The elimination of amlodipine from blood plasma is a two-phase process with a final T_½ about 30–50 hours. Plasma levels of a stable state were achieved after 7–8 days of continuous administration of the drug. 10% of the initial amlodipine and 60% of its metabolites were excreted in the urine.

Data for Atorvastatin

Suction. Atorvastatin is rapidly absorbed, plasma C_max achieved within 1-2 hours. The degree of absorption increases in proportion to the dose of atorvastatin. The absolute bioavailability of atorvastatin (the parent drug) is about 12%, and the systemic bioavailability for the inhibition of HMG-CoA reductase is about 30%. Low systemic bioavailability is associated with presystemic clearance in the gastrointestinal mucosa and / or presystemic hepatic metabolism. Although food reduces the rate and extent of absorption by about 25% and 9%, respectively, C estimates_max and AUC, the decrease in LDL cholesterol is the same regardless of whether atorvastatin is taken with or without food. Atorvastatin plasma concentrations lower (approximately 30% for C_max and AUC) after an evening intake of the drug compared to the morning. However, the decrease in LDL cholesterol is the same, regardless of the time of day of taking the drug.

Distribution. The average volume of distribution of atorvastatin is about 381 liters. More than 95% of atorvastatin binds to plasma proteins.

Biotransformation. Atorvastatin is extensively metabolized to ortho- and para-hydroxylated derivatives and various beta-oxidation products. The in vitro suppression of HMG-CoA reductase by ortho and para-hydroxylated metabolites is equivalent to the same inhibition of atorvastatin. About 70% of the inhibitory activity with respect to circulating HMG-CoA reductase is associated with active metabolites.

Excretion. Atorvastatin and its metabolites are excreted mainly with bile after hepatic and / or extrahepatic metabolism. However, this drug obviously does not undergo significant enterohepatic recirculation. Average T_½ atorvastatin from plasma in humans is about 14 hours, and T_½ inhibitory activity for HMG-CoA reductase - 20-30 hours due to the contribution of active metabolites. After taking atorvastatin, 2% of the dose is excreted in the urine.

Amlodipine and atorvastatin data in special populations

Elderly patients. Time to reach C_max amlodipine in blood plasma is similar in both elderly patients and younger people. Amlodipine clearance tends to decrease, leading to an increase in AUC and T_½ in elderly patients. Increased AUC and T_½ in patients with congestive heart failure corresponded to that expected for patients of the studied age group.

Atorvastatin plasma concentrations in healthy elderly (over 65) were higher (approximately 40% for C_max and 30% for AUC) than in young people. Clinical data suggest a greater decrease in LDL levels in the elderly population compared with young people at any dose of atorvastatin.

Children. The pharmacokinetic data of the pediatric population are not available.

Floor. Atorvastatin plasma concentrations in women are different from those in men (approximately 20% higher for C_max and 10% lower for AUC). These differences were not clinically significant and did not cause significant clinical differences in lipid effects for men and women.

Renal failure. Renal failure does not significantly affect the pharmacokinetics of amlodipine. Amlodipine is not dialyzed. Therefore, patients with renal failure may take the usual initial dose of amlodipine.

In studies using atorvastatin, renal failure did not affect plasma concentrations of atorvastatin or a decrease in LDL cholesterol, so there is no need to adjust the dose of atorvastatin for patients with renal dysfunction.

Liver failure. In patients with liver failure, amlodipine clearance is reduced, which leads to an increase in AUC by approximately 40-60%. Moderate to severe hepatic dysfunction does not affect the patients therapeutic response to atorvastatin, but the exposure of this drug is significantly increased. Atorvastatin plasma concentrations in patients with chronic alcoholic liver disease (Child-Pugh class B) increase markedly (approximately 16-fold for C_max and 11-fold for AUC).

Polymorphism SLCO1B1. The metabolism of all HMG-CoA reductase inhibitors in the liver, including atorvastatin, occurs with the participation of the transport protein OATP1B1. In patients with SLCO1B1 polymorphism, there is a risk of increased exposure of atorvastatin, which may lead to an increased risk of rhabdomyolysis (see SPECIAL INSTRUCTIONS). Polymorphism of the gene encoding OATP1B1 (SLCO1B1 c.521CC) is associated with an increase in atorvastatin exposure (AUC) 2.4 times higher than in individuals without this genotype variant (c.521TT). Genetic impairment of liver absorption of atorvastatin is also possible in these patients. The effect on effectiveness is unknown.

Indications

For the prevention of cardiovascular events in patients with antigens, with three concomitant cardiovascular risk factors, with normal to moderately elevated levels of cholesterol, without the clinical manifestations of ischemic heart disease, and when, in accordance with current treatment recommendations, the combined use of amlodipine and low dose of atorvastatin.

In case of insufficient effectiveness of the lipid-lowering diet and other non-pharmacological measures.

Application

Cadova 5/10 and cadova 10/10 are intended for oral use.

The usual starting dose is 5 mg / 10 mg once daily. If the patient requires more effective control of blood pressure, you can take 10 mg / 10 mg 1 time per day.

The drug can be taken at any time of the day with or without food.

Cadova 5/10 and Cadova 10/10 can be used both separately and in combination with antihypertensive drugs, but it can not be used with another calcium channel blocker or with another statin.

Patients with renal failure: dose adjustment is not required for patients with impaired renal function.

Patients with liver failure: Cadova 5/10 and Cadova 10/10 contraindicated in patients with active liver disease.

Elderly patients: there is no need for dose adjustment for elderly patients.

With simultaneous use with cyclosporine, the dose of atorvastatin should not exceed 10 mg (see INTERACTIONS).

Children. Safety and efficacy of drugs Cadova 5/10 and Cadova 10/10 for children have not been established, so they are not recommended for use in this category of patients. Pharmacokinetic data on the use in children are absent.

Contraindications

• Hypersensitivity to dihydropyridines *, active substances - amlodipine and atorvastatin or any other auxiliary substances; active liver diseases or a constant level of serum transaminases, which is 3 times higher than the upper limit of normal (VGN); severe arterial hypotension; shock (including cardiogenic); obstruction of the outflow tract from the left ventricle (for example, high grade aortic stenosis); hemodynamically unstable heart failure after acute myocardial infarction; in patients with unstable angina and within 8 days after myocardial infarction.

The drug can not be used in pregnant women; women who are planning a pregnancy, or women of reproductive age who do not use appropriate contraceptives.

* Amlodipine is a calcium channel blocker, a derivative of dihydropyridine.

Side effects

Cadova 5/10 and cadova 10/10 were evaluated for safety in 1092 patients who were treated for concomitant ag and dyslipidemia in double-blind, placebo-controlled studies. in clinical studies using cadova 5/10 and cadova 10/10 there were no adverse events inherent in this combination. adverse events were limited to those previously reported for amlodipine and / or atorvastatin (the following tables of adverse events are given below).

In controlled clinical trials, discontinuation of treatment due to adverse clinical events or due to abnormal laboratory test results was necessary only for 5.1% of patients treated with amlodipine in combination with atorvastatin, compared with 4% of patients receiving placebo.

The following adverse events, given according to the organ-system classes and frequency of MedDRA, appear separately for amlodipine and atorvastatin.

Very often: ≥1 / 10, often: ≥1 / 100 and 1/10, infrequently: ≥1 / 1000 and 1/100, single: ≥1 / 10,000 and 1/100, rarely: 1/10 000, unknown (impossible to estimate from the available data).

* Cases of diabetes mellitus with the use of certain statins have been reported: the frequency depends on the presence or absence of risk factors (fasting blood glucose ≥5.6 mmol / l, body mass index 30 kg / m², an increased level of TG, AH in history).

special instructions

Heart failure. patients with heart failure should be prescribed with caution. in a long-term placebo-controlled study of patients with severe heart failure (nyha class iii and iv), the incidence of pulmonary edema in patients treated with amlodipine was higher than in those taking placebo (see pharmacological properties). calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular complications and mortality.

Effect on the liver.The results of hepatic tests must be determined before starting treatment, periodically after treatment, as well as in patients who exhibit any signs or symptoms that suggest a liver lesion. In the case of elevated levels of transaminases, it is necessary to monitor them until normalization.

T_½ of amlodipine prolonged and higher in patients with impaired liver function, dosage recommendations have not been investigated.

If elevated ALAT levels are supported and