Amlodipine, Perindopril

Brand Krka dd Novo mesto AO

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Available since: 2019-09-19

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Clinical Pharmacology

Dalneva - combined antihypertensive drug.

Perindopril

Perindopril - an ACE inhibitor. ACE or kininase II is an exopeptidase that converts angiotensin I into a vasoconstrictor, angiotensin II, and besides, ACE destroys bradykinin, which has a vasodilator, to an inactive hectapeptide. Suppression of the activity of ACE leads to a decrease in angiotensin II, an increase in the activity of renin in the blood plasma and a decrease in the secretion of aldosterone. Since ACE also destroys bradykinin, ACE suppression also leads to an increase in the activity of the kallikrein-kinin system.

Perindopril acts through its active metabolite, perindoprilat. Other metabolites have no inhibitory effect on ACE in vitro. Perindopril has a therapeutic effect in any degree of hypertension, reducing systolic and diastolic blood pressure in the supine and standing position.

Decreases round fist, resulting in increased peripheral blood flow without changes in heart rate.

The kidney blood flow usually increases, while the SCF does not change.

The antihypertensive effect reaches its maximum 4-6 hours after a single dose of perindopril inside and lasts for 24 hours. The hypotensive effect 24 hours after a single dose is about 87-100% of the maximum hypotensive effect.

Decrease in blood pressure is developing rapidly. The therapeutic effect occurs in less than 1 month from the start of therapy and is not accompanied by tachycardia.

Termination of therapy does not lead to the development of withdrawal syndrome.

Perindopril has a vasodilating effect, helps to restore the elasticity of large arteries and the structure of the vascular wall of small arteries, and also reduces left ventricular hypertrophy.

Amlodipine

Derivative of dihydropyridine - a blocker of slow calcium channels, has antianginal and hypotensive effects. Blocks calcium channels, reduces the transmembrane transition of calcium ions into the cell (to a greater extent in vascular smooth muscle cells than in cardiomyocytes).

Antianginal action due to the expansion of the coronary and peripheral arteries and arterioles: with angina reduces the severity of myocardial ischemia; expanding peripheral arterioles, reduces OPSS, reduces myocardial afterload, reduces myocardial oxygen demand, expanding coronary arteries and arterioles in unchanged and ischemic myocardial areas, increases oxygen supply to the myocardium (especially with vasospastic angina); prevents spasm of the coronary arteries (including caused by smoking). In patients with stable angina, a single daily dose increases exercise tolerance, increases the time before the onset of an attack of angina and ischemic depression of the ST segment on the ECG, reduces the frequency of strokes and the consumption of nitroglycerin and other nitrates.

It has a long dose-dependent hypotensive effect. The hypotensive effect is due to the direct vasodilating effect on vascular smooth muscle. In case of arterial hypertension, a single dose provides a clinically significant reduction in blood pressure for 24 hours (in the position of the patient lying and standing). Orthostatic hypotension with the appointment of amlodipine is quite rare. Does not cause a decrease in the left ventricular ejection fraction.

Reduces the degree of hypertrophy of the left ventricular myocardium. Does not affect the contractility and conductivity of the myocardium, does not cause a reflex increase in heart rate, inhibits platelet aggregation, increases GFR, has a weak natriuretic effect. In diabetic nephropathy does not increase the severity of microalbuminuria. It does not have any adverse effect on the metabolism and plasma lipid concentration and can be used in the treatment of patients with bronchial asthma, diabetes mellitus and gout.A significant decrease in blood pressure is observed after 6-10 hours, the duration of the effect is 24 hours.

Pharmacokinetics

The amount of absorption of amlodipine and perindopril when using the drug Dalnev is not significantly different from that when using monodrugs.

Perindopril

Suction

After oral administration, perindopril is rapidly absorbed and reaches Cmax in the blood plasma within 1 hour. Eating reduces the bioavailability of perindopril, so the drug should be taken 1 time / day, in the morning, before eating.

There is a linear dependence of the concentration of perindopril in plasma on the magnitude of its dose.

Distribution

Binding of perindoprilat with plasma proteins (mainly with ACE) is 20%, and depends on its concentration. Vd of free perindoprilat is approximately 0.2 l / kg.

Metabolism

Perindopril does not possess pharmacological activity, is a prodrug. Approximately 27% of the total amount of perindopril ingested enters the bloodstream as an active metabolite, perindoprilat. In addition to perindoprilat, 5 more metabolites are formed that do not possess pharmacological activity. Cmax of perindoprilat in blood plasma is reached 3-4 h after ingestion.

Removal

T1 / 2 perindopril from plasma is approximately 1 hour.

Perindoprilat is excreted by the kidneys, T1 / 2 of the unbound fraction is approximately 17 hours, so Css is achieved within 4 days after ingestion.

Pharmacokinetics in special clinical situations

Removal of perindoprilat is slowed down in elderly patients and in patients with cardiac and renal failure, therefore, monitoring of such patients should include regular monitoring of plasma creatinine and potassium concentrations.

The dialysis clearance of perindoprilat is 70 ml / min.

The pharmacokinetics of perindopril is changed in patients with cirrhosis of the liver: the hepatic clearance decreases by 2 times, but the amount of perindoprilat formed does not decrease, therefore, dose adjustment is not required.

Amlodipine

Suction

Amlodipine is well absorbed when taken orally in therapeutic doses. Cmax in plasma is reached in 6-12 hours. Absolute bioavailability is 64-80%. Eating does not affect the bioavailability of amlodipine.

Distribution

Vd is approximately 21 L / kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is associated with plasma proteins.

Metabolism and excretion

Amlodipine is metabolized in the liver to form inactive metabolites. The final T1 / 2 from blood plasma - 35-50 h, which allows you to take the drug 1 time / day.

Approximately 60% of the dose taken is excreted by the kidneys, 10% - unchanged.

Pharmacokinetics in special clinical situations

The time to reach Cmax in plasma is the same in elderly and young patients. There is a tendency to reduce the clearance of amlodipine in elderly patients, which is accompanied by an increase in AUC. The recommended dosing regimen for elderly patients is the same as for younger patients, although the dose should be increased with caution.

Amlodipine T1 / 2 is lengthened in patients with impaired liver function.

Indications

Arterial hypertension and / or ischemic heart disease: stable exertional angina in patients who require perindopril and amlodipine.

Composition

Active substances: Amlodipine besyata 5 mg; perindopril erbumine A substance granules 4 mg;

Excipients: microcrystalline cellulose; pregelatinized starch; carboxymethyl starch sodium; sodium bicarbonate; colloidal silicon dioxide; magnesium stearate

Amlodipine, Perindopril is marketed under different brands and generic names, and comes in different dosage forms:

Brand name	Manufacturer	Country	Dosage form
Dalneva	Krka dd Novo mesto AO	Slovenia	pills
Prestance	Servier	France	pills

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Dosage and Administration

For oral use 1 tablet once a day, preferably in the morning before meals.

Dose of the drug Dalneva^® It is selected after a previous titration of doses of individual components of the drug - perindopril and amlodipine - in patients with arterial hypertension and stable angina.

If necessary, the dose of the drug Dalneva^® can be changed on the basis of individual selection of doses of individual components: (amlodipine 5 mg + perindopril 4 mg) or (amlodipine 10 mg + perindopril 4 mg), or (amlodipine 5 mg + perindopril 8 mg), or (amlodipine 10 mg + perindopril 8 mg).

The maximum daily dose of amlodipine 10 mg + perindopril 8 mg.

Impaired renal function.Drug Dalneva^® can be used in patients with Cl creatinine more than 60 ml / min. Drug Dalneva^® contraindicated for use in patients with Cl creatinine less than 60 ml / min.

Such patients are recommended individual selection of doses of perindopril and amlodipine. Changes in the concentration of amlodipine in the blood plasma do not correlate with the severity of renal failure.

Liver failure.Care must be taken when using the drug Dalneva^® in patients with liver failure, because there are no recommendations for the drug doses in these patients.

Elderly patients.When using the drug Dalneva^® Elderly patients dose adjustment is not required.

Children and teenagers.Drug Dalneva^® should not be given to children and adolescents under 18 years of age. because There are no data on the efficacy and safety of perindopril and amlodipine in these groups of patients, both in monotherapy and as part of combination therapy.

Adverse reactions

From the circulatory and lymphatic systems: very rarely - leukopenia / neutropenia, agranulocytosis, pancytopenia, thrombocytopenia, hemolytic anemia in patients with congenital glucose-6-phosphate dehydrogenase deficiency, decreased hemoglobin and hematocrit.

On the part of the immune system: infrequently - urticaria.

Metabolic disorders: infrequently - weight gain, weight loss; very rarely - hyperglycemia; frequency unknown - hypoglycemia.

From the nervous system: often - drowsiness, dizziness, headache, paresthesias, vertigo; infrequently - insomnia, mood lability, sleep disturbance, tremor, hypoesthesia; very rarely - peripheral neuropathy, confusion.

From the senses: often - visual disturbances, tinnitus.

From the CCC: often - a feeling of heartbeat, "flushes" of blood to the skin of the face, a pronounced decrease in blood pressure; infrequently - fainting; rarely - pain behind the sternum; very rarely - stenocardia, myocardial infarction, possibly due to an excessive decrease in blood pressure in patients from the high risk group, arrhythmias (including bradycardia, ventricular tachycardia and atrial fibrillation), stroke, possibly due to an excessive decrease in blood pressure in patients from the high risk, vasculitis.

On the part of the respiratory system: often - shortness of breath, cough; infrequently - rhinitis, bronchospasm; very rarely - eosinophilic pneumonia.

From the digestive system: often - abdominal pain, nausea, vomiting, dyspepsia, diarrhea, constipation; infrequently - dryness of the oral mucosa, a violation of taste perception, a change in the rhythm of defecation; very rarely - pancreatitis, gingival hyperplasia, gastritis, hepatitis, cholestatic jaundice, cytolytic or cholestatic hepatitis.

On the part of the skin: often - pruritus, skin rash; infrequently - angioedema of the face, extremities, lips, mucous membranes, tongue, vocal folds and / or larynx, alopecia, hemorrhagic rash, photosensitization, increased sweating; very rarely - angioedema, erythema multiforme, Stevens-Johnson syndrome.

From the musculoskeletal system: often - muscle spasms; infrequently - arthralgia, myalgia, back pain.

From the urinary system: infrequently - urination disorder, nocturia, frequent urination, renal failure; very rarely, acute renal failure.

From the reproductive system: infrequently - impotence, gynecomastia.

Other: often - peripheral edema, asthenia, fatigue; infrequently - chest pain, malaise.

Laboratory indicators: rarely, increased bilirubin concentration; very rarely - increased activity of hepatic transaminases (ACT, ALT) (most often in combination with cholestasis); unknown frequency - increase in the concentration of urea and creatinine in the blood serum.

Additional data on amlodipine: isolated cases of extrapyramidal syndrome with the use of BPC.

Perindopril

Contraindications

hypersensitivity to perindopril or other ACE inhibitors;
angioedema (angioedema) in history (including against the background of taking other ACE inhibitors);
hereditary / idiopathic angioedema;
age up to 18 years (efficacy and safety have not been established).

Amlodipine

hypersensitivity to amlodipine or other dihydropyridine derivatives;
severe arterial hypotension (SAD less than 90 mm Hg), shock, including cardiogenic;
obstruction of the output tract of the left ventricle (including pronounced aortic stenosis);
unstable angina (with the exception of Prinzmetal stenocardia);
hemodynamically unstable heart failure after acute myocardial infarction;
age up to 18 years (efficacy and safety have not been established).

Dalneva^®

hypersensitivity to excipients that are part of the drug;
renal failure (Cl creatinine less than 60 ml / min);
age up to 18 years (efficacy and safety have not been established).

Carefully: liver failure; chronic heart failure; aortic and / or mitral stenosis; hypertrophic obstructive cardiomyopathy (GOKMP); elderly age; bilateral stenosis of the renal arteries; arterial stenosis of the only functioning kidney; renal failure (Cl creatinine less than 60 ml / min); Systemic diseases of the connective tissue (including systemic lupus erythematosus, scleroderma), therapy with immunosuppressants, allopurinol, procainamide (risk of developing neutropenia, agranulocytosis), reduced BCC (diuretic administration, diet restricted in table salt, vomiting, diarrhea), atherosclerosis, cerebrovascular diseases, renovascular hypertension, diabetes mellitus, use of dantrolen, estramustine, potassium-saving diuretics, potassium preparations, potassium-containing salt substitutes and lithium preparations, hyperkalemia; surgery / general anesthesia; Negroid patients; hemodialysis using high-flow polyacrylonitrile membranes - the risk of anaphylactoid reactions; before the procedure of LDL apheresis using dextran sulfate, simultaneous desensitization therapy with allergens (eg hymenoptera), the state after kidney transplantation (no clinical data).

Drug interactions

Perindopril

Simultaneous use not recommended

Potassium-sparing diuretics, potassium preparations or potassium-containing food salt substitutes:Although serum potassium remains within the normal range, hyperkalemia may occur in some patients with perindopril. Potassium-sparing diuretics (for example, spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes can lead to a significant increase in plasma potassium levels, and therefore their use at the same time as ACE inhibitors is not recommended.If simultaneous therapy is necessary (in the case of confirmed hypokalemia), care should be taken to regularly monitor plasma potassium and ECG parameters.

Lithium preparations: with the simultaneous use of lithium preparations and ACE inhibitors, there have been cases of a reversible increase in the concentration of lithium in the blood serum and the associated toxic effects. Simultaneous therapy with perindopril and lithium preparations is not recommended. If necessary, such a combination therapy should be carried out under the regular control of the concentration of lithium in the blood plasma.

Estramustine: simultaneous use is accompanied by an increased risk of angioedema.

Simultaneous use requiring special care

NSAIDs, incl. COX-2 inhibitors, acetylsalicylic acid in high doses (more than 3 g / day) and non-selective NSAIDs: the use of NSAIDs can lead to a decrease in the diuretic, natriuretic and hypotensive action of ACE inhibitors. The simultaneous use of ACE inhibitors and NSAIDs can lead to a deterioration in renal function, including the development of acute renal failure and an increase in serum potassium, especially in patients with reduced renal function. Care should be taken when using this combination, especially in elderly patients. Patients in this case need to compensate for fluid loss, carefully monitor kidney function, both at the beginning and during the treatment process.

Hypoglycemic drugs (oral and / or insulin hypoglycemic agents):the use of ACE inhibitors may enhance the hypoglycemic effect of insulin or sulfonylurea derivatives in patients with diabetes mellitus.

The development of episodes of hypoglycemia was noted very rarely (perhaps there is an increase in glucose tolerance, leading to a decrease in the need for insulin).

Simultaneous application requiring attention

Diuretics (thiazide and loop): in patients taking diuretics, especially with excessive removal of fluid and / or electrolytes, at the beginning of the use of ACE inhibitors a significant decrease in blood pressure can be observed. The risk of arterial hypotension can be reduced by eliminating diuretic, increasing fluid intake and / or salt before starting therapy, starting therapy with low doses of perindopril with their further gradual increase.

Sympathomimetics: sympathomimetics can weaken the hypotensive effect of ACE inhibitors.

Gold preparations: in patients receiving simultaneous injection therapy with gold preparations (sodium aurothiomalate) and ACE inhibitors, including perindopril, nitrate-like reactions are rarely observed (“flushes” of blood to the skin of the face, nausea, vomiting, decrease in blood pressure).

Allopurinol, cytostatic and immunosuppressive agents, corticosteroids (with systemic use) and procainamide: simultaneous use with ACE inhibitors may be accompanied by an increased risk of leukopenia.

General anesthesia drugs: the simultaneous use of ACE inhibitors and agents for general anesthesia can lead to an increase in the hypotensive effect.

Amlodipine

Simultaneous use not recommended

Dantrolene (w / in the introduction): in animal experiments after the introduction of verapamil and dantrolen (iv), cases of fatal ventricular fibrillation and cardiovascular insufficiency associated with hyperkalemia were observed. Given the risk of developing hyperkalemia, the simultaneous use of amlodipine and dantrolen should be avoided.

Simultaneous use requiring special care

Inductors CYP3A4 (rifampicin, Hypericum perforatum drugs, anticonvulsants, such as carbamazepine, phenobarbital, phenytoin, phosphenytoin, primidone): possible decrease in plasma concentration of amlodipine due to increased metabolism in the liver. Care should be taken with the simultaneous use of amlodipine and microsomal oxidation inducers and, if necessary, adjust the dose of amlodipine.

Strong and mild inhibitors of CYP3A4 isoenzyme (protease inhibitors, azole antifungal drugs (itraconazole and ketoconazole), macrolides, such as erythromycin and clarithromycin, verapamil and diltiazem): possible increase in plasma concentration of amlodipine and increased risk of side effects, especially in elderly patients. Care should be taken with simultaneous use and, if necessary, adjust the dose of amlodipine.

Simultaneous application requiring attention

The simultaneous use of β-blockers (bisoprolol, metoprolol) and α-and β-blocker carvedilol used in CHF: increases the risk of arterial hypotension and worsening of CHF in patients with uncontrolled or latent CHF (increased negative inotropic effect). In addition, β-adrenergic blockers can reduce excessive reflex cardiac sympathetic activation against the background of concomitant CHF.

There is no interaction of the following drugs with amlodipine:

- with simultaneous use of amlodipine and cimetidine pharmacokinetic parameters of amlodipine did not change;

- with simultaneous use of amlodipine and sildenafil, there is no marked increase in the hypotensive effect of each of the drugs.

Grapefruit juice: taking 240 ml of grapefruit juice with a single dose of amlodipine (10 mg orally) did not have a significant effect on the pharmacokinetics of amlodipine.

Amlodipine does not affect the pharmacokinetics of the following drugs:

- atorvastatin: receiving repeated doses of amlodipine 10 mg in combination with atorvastatin at a dose of 80 mg does not lead to a significant change in the equilibrium pharmacokinetic parameters of atorvastatin;

- digoxin: simultaneous use of amlodipine and digoxin is not accompanied by a change in the concentration of digoxin in the blood serum and the renal clearance of digoxin in healthy volunteers;

- warfarin: in healthy male volunteers who took warfarin, the addition of amlodipine does not have a significant effect on the change in the rate of PV due to warfarin;

- cyclosporine: amlodipine does not have a significant effect on the pharmacokinetic parameters of cyclosporine.

Dalneva^®

Simultaneous application requiring special attention.

Baclofen: potentiation of hypotensive action is possible. It is necessary to control blood pressure and kidney function, as well as dose adjustment of amlodipine.

Simultaneous application requiring attention

Antihypertensive drugs (eg β-blockers) and vasodilators: may increase the hypotensive effect of perindopril and amlodipine. Care should be taken when applying at the same time.with nitroglycerin, other nitrates or other vasodilators, because it may further decrease blood pressure.

Corticosteroids (mineralocorticosteroids and GCS), tetracosactide: reduction of hypotensive action (fluid and sodium ion retention due to corticosteroids).

α-blockers (prazosin, alfuzosin, doxazosin, tamsulosin, terazosin): increased hypotensive action and increased risk of orthostatic hypotension.

Amifostine: can potentiate the hypotensive effect of amlodipine.

Tricyclic antidepressants / neuroleptics / general anesthetics: increased hypotensive effect and increased risk of orthostatic hypotension.

Pregnancy and Lactation

Dalnev drug use^® contraindicated in pregnancy. Drug Dalneva^® should not be used in the first trimester of pregnancy.When planning a pregnancy or its occurrence on the background of the use of the drug Dalneva^® it is necessary to stop taking the drug as soon as possible and to prescribe another antihypertensive therapy approved for use during pregnancy. Appropriate controlled studies of the use of ACE inhibitors in pregnant women have not been conducted. The limited data available on the effect of the drug on the fetus in the first trimester of pregnancy indicate that the use of ACE inhibitors does not lead to fetal malformations, but an increased risk of their occurrence cannot be excluded. It is known that the effect of ACE inhibitors on the fetus in the II and III trimesters of pregnancy can lead to a violation of its development (decreased renal function, oligohydramnios, slowing down of ossification of the skull bones) and the development of complications in the newborn (renal failure, arterial hypotension, hyperkalemia). If the patient received ACE inhibitors in the II or III trimester of pregnancy, it is recommended to conduct an ultrasound to assess the state of the bones of the skull and the kidney function of the fetus.

Newborns whose mothers received ACE inhibitors during pregnancy should be under close medical supervision because of the risk of hypotension, oliguria, and hyperkalemia.

Do not use the drug Dalneva^® during lactation, because there is no relevant clinical experience with the use of amlodipine and perindopril both in monotherapy and in combination therapy. If necessary, use the drug Dalneva^® during lactation, breastfeeding should be discontinued.