Twynsta, pills 5+80mg, 28pcs

Composition

1 tablet contains:

active ingredients:

amlodipine bezylate 6.935 mg, which corresponds to the content of amlodipine 5 mg, telmisartan 40 and 80 mg;

excipients:

sodium hydroxide,

povidone K 25,

meglumine,

sorbitol,

magnesium stearate,

microcrystalline cellulose,

pregelated starch,

corn starch,

colloidal silicon dioxide,

dye mixture*.

composition of the dye mixture: iron oxide black (E172) – 76%, iron oxide yellow (e172) – 4%, FD & C blue No. 1 (diamond blue FCF aluminum varnish), aluminum pigment (E 133) – 20%

Pharmacological action

The drug Twynsta is a combined drug containing two antihypertensive substances with complementary effects, allowing you to control blood pressure in patients with arterial (essential) hypertension: angiotensin II receptor antagonist, telmisartan, and slow calcium channel blocker, dihydropyridine derivative, amlodipine. The combination of these substances has an additive hypotensive effect, reducing blood pressure to a greater extent than each individual component. The drug, taken once a day, leads to an effective and sustained reduction in blood pressure for 24 hours.

Telmisartan is a specific angiotensin II receptor antagonist (type AT1), effective when taken orally. It has a high affinity for the AT1 subtype of angiotensin II receptors, through which the action of angiotensin II is realized. Displaces angiotensin II from binding to the receptor, without having an agonist effect on this receptor. Telmisartan binds only to the AT1 subtype of angiotensin II receptors. The relationship is long-term. It has no affinity for other receptors, including the AT2 receptor. Reduces the concentration of aldosterone in the blood, does not inhibit renin in the blood plasma and does not block ion channels. Telmisartan does not inhibit the angiotensin-converting enzyme (kininase I) (an enzyme that also breaks down bradykinin). Therefore, an increase in bradykinin-induced side effects is not expected. In patients, telmisartan 80 mg completely blocks the hypertensive effect of angiotensin II.

The onset of antihypertensive action is noted within 3 hours after the first use of telmisartan. The effect of the drug persists for 24 hours and remains significant for up to 48 hours. A pronounced hypotensive effect usually develops 4-8 weeks after regular use. In patients with arterial hypertension, telmisartan reduces systolic and diastolic blood pressure( BP) without affecting the heart rate (HR). In the case of abrupt withdrawal of telmisartan, blood pressure gradually returns to its original level without the development of “withdrawal”syndrome.

Amlodipine, a dihydropyridine derivative, belongs to the class of “slow” calcium channel blockers. It inhibits the transmembrane influx of calcium ions into cardiomyocytes and vascular smooth muscle cells. The mechanism of antihypertensive action of amlodipine is associated with a direct relaxing effect on vascular smooth muscle cells, which leads to a decrease in peripheral vascular resistance and a decrease in blood pressure. In patients with arterial hypertension, the use of amlodipine once a day provides a clinically significant reduction in blood pressure for 24 hours. Orthostatic hypotension is not characteristic during the use of amlodipine due to the slow onset of action of the drug.

In patients with hypertension and normal renal function, amlodipine at therapeutic doses resulted in reduced renal vascular resistance, increased glomerular filtration rate, and effective renal plasma flow, without changing filtration or proteinuria. Amlodipine does not lead to any metabolic adverse effects or changes in plasma lipids, and therefore is suitable for use in patients with bronchial asthma, diabetes mellitus and gout. The use of amlodipine in patients with heart failure is not accompanied by a negative inotropic effect (exercise tolerance does not decrease, the left ventricular ejection fraction does not decrease). Pharmacokinetics. Pharmacokinetics of the combination of fixed doses. The rate and degree of absorption of the drug is equivalent to the bioavailability of telmisartan and amlodipine when used as separate tablets.

Pharmacokinetics

Pharmacokinetics of the fixed dose combination

The rate and degree of absorption of Twynsta is equivalent to the bioavailability of telmisartan and amlodipine when used as separate tablets.

Pharmacokinetics of individual components

Telmisartan

Suction

When taken orally, it is rapidly absorbed from the gastrointestinal tract. Bioavailability – 50%. When taken simultaneously with food, the decrease in AUC ranges from 6% (at a dose of 40 mg) to 19% (at a dose of 160 mg).3 hours after ingestion, the concentration in the blood plasma is equalized, regardless of food intake.

Distribution

Binding to plasma proteins is 99.5%, mainly with albumin and alpha-1 glycoprotein. The average value of the visible V_d at an equilibrium concentration of 500 l.

Metabolism

Telmisartan is metabolized by conjugation with glucuronic acid. The metabolites are pharmacologically inactive.

Elimination

T_1/2 – more than 20 h_{. Cmax} in blood plasma and, to a lesser extent, AUC increase disproportionately to the dose. There is no evidence of clinically significant accumulation of telmisartan. It is excreted through the intestines in unchanged form, excretion by the kidneys is less than 2%. Total plasma clearance is high (900 ml / min) compared to hepatic blood flow (about 1500 ml / min).

Amlodipine

Suction

After oral use of amlodipine in therapeutic doses_{, cmax} in blood plasma is reached in 6-12 hours. Absolute bioavailability ranges from 64% to 80%. Food intake does not affect the bioavailability of amlodipine.

The Vd distribution_of amlodipine is approximately 21 l / kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine binds to plasma proteins in patients with hypertension.

Metabolism

Amlodipine is largely (approximately 90%) metabolized in the liver to form inactive metabolites.

Deduction

The elimination of amlodipine from the blood plasma occurs in two phases. T_1/2 is approximately 30-50 hours. Stable blood plasma levels are achieved after continuous use of the drug for 7-8 days. Amlodipine is excreted by the kidneys both unchanged (10%) and as metabolites (60%).

Pharmacokinetics in special clinical cases:

There is a difference in plasma concentrations in men and women. _Cmax and AUC were approximately 3 and 2 times higher in women compared to men, respectively, with no significant effect on efficacy.

The pharmacokinetics of telmisartan in elderly patients do not differ from young patients. No dose adjustment is required. In elderly patients, there is a tendency to decrease the clearance of amlodipine, which leads to an increase in AUC and T_1/2.

No dose adjustment of telmisartan is required in patients with renal insufficiency, including patients undergoing hemodialysis. Telmisartan is not removed by hemodialysis.

The pharmacokinetics of amlodipine in patients with impaired renal function do not change significantly.

Pharmacokinetic studies conducted in patients with impaired liver function have shown that the absolute bioavailability of telmisartan increases to almost 100%. T_1/2 in patients with impaired liver function does not change. In patients with hepatic insufficiency, the clearance of amlodipine decreased, which led to an increase in the AUC value by about 40-60%.

Indications

• arterial hypertension (for patients whose blood pressure is insufficiently controlled by telmisartan or amlodipine in monotherapy);
• arterial hypertension (for patients who are indicated for combination therapy);
• patients with arterial hypertension receiving telmisartan and amlodipine in the form of separate tablets, as a substitute for this therapy.

Use during pregnancy and lactation

Special studies of the drug Twynsta during pregnancy and lactation have not been conducted. The effects associated with individual components of the drug are described below.

Pregnancytelmisartan The use of angiotensin II receptor antagonists (ARA II) is contraindicated during pregnancy. If pregnancy is diagnosed, the drug should be stopped immediately. If necessary, alternative therapy should be prescribed. It is known that the use of ARA II during the second and third trimesters of pregnancy has a fetotoxic effect (decreased renal function, oligohydramnion, slowing of ossification of the fetal skull), and neonatal toxicity (renal failure, hypotension and hyperkalemia) is also observed. Amlodipine: Although there are limited data on the effects of amlodipine or other calcium receptor antagonists, there is no evidence of adverse effects on the fetus. However, there may be a risk of slowing down the delivery process.

Breast-feeding periodspecial studies on the excretion of telmisartan and / or amlodipine in breast milk in women have not been conducted. Animal studies have shown that telmisartan is excreted in the milk of lactating animals. Taking into account possible adverse reactions, the decision to continue breast-feeding or discontinue therapy should be made taking into account its significance for the mother. Studies of the effect on human fertility have not been conducted.

Contraindications

• obstructive disease of the biliary tract;
• severe arterial hypotension;
• obstruction of the output tract of the left ventricle (including a high degree of aortic stenosis);
• hemodynamically unstable heart failure after acute myocardial infarction;
• severe liver failure;
• shock;
• fructose intolerance and malabsorption syndrome glucose/galactose or sucrase deficiency/isomaltase;
• pregnancy;
• the breast-feeding period;
• the age of 18 years (effectiveness and safety not established);
• hypersensitivity to the active components or auxiliary substances;
• increased sensitivity to others, a derivative of dihydropyridine.

Twynsta of the drug should be administered with caution to patients with:

• obstructive diseases of the biliary tract or hepatic impairment;
• bilateral renal artery stenosis or stenosis of the artery to a solitary kidney;
• condition after kidney transplantation;
• reduced BCC and/or hyponatremia;
• dual blockade of the renin-angiotensin-aldosterone system (RAAS);
• in other States, characterized by the activation of the RAAS;
• primary aldosteronism;
• stenosis of the aortic and mitral valve disease, obstructive hypertrophic cardiomyopathy;
• heart failure;
• hyperkalemia;
• diabetes mellitus with additional cardiovascular risk (i. e., concomitant disease of the coronary arteries /coronary artery disease/);
• after 1 month after acute myocardial infarction and unstable angina.

Side effects

Within the organ-system classes, the following categories are used for the frequency of side effects: very common (≥1/10); common (≥1/100, < 1/10); infrequent (≥1/1000, < 1/100); rare (≥1/10 000,

Additional information on individual components Side effects previously reported with one of the components of the drug (amlodipine or telmisartan) may increase with the use of Twynsta, even if they were not observed in clinical studies or during the post-marketing period. Additional information regarding the combination of components Peripheral edema, a dose-dependent side effect of amlodipine, was observed in patients who received a combination of telmisartan and amlodipine, less often than in patients who received amlodipine alone.

Interaction

Interactions between the two active components included in fixed doses of this drug were not observed in clinical studies. Special studies of drug interactions of the drug Twynsta with other drugs have not been conducted.

Combination of Active ingredients When using Twynsta concomitantly with the following medications, the following information should be taken into account. Other antihypertensive drugs When used concomitantly with other antihypertensive drugs, the antihypertensive effect of Twynsta may be enhanced. Some medications, such as baclofen and amifostin, can be expected to enhance the antihypertensive effect of all antihypertensive agents, including Twynsta, due to their pharmacological properties. In addition, orthostatic hypotension may be aggravated by ethanol, barbiturates, narcotic drugs or antidepressants. Corticosteroids (systemic use)It is possible to reduce the hypotensive effect.

Telmisartan Concomitant use of telmisartan with:

• other antihypertensive agents: may increase the hypotensive effect. In one study, the combined use of telmisartan and ramipril resulted in a 2.5-fold increase in AUC0-24 and Cmax of ramipril and ramiprilate. The clinical significance of this interaction has not been established.
• digoxin, warfarin, hydrochlorothiazide, glibenclamide, simvastatin and amlodipine: no clinically significant interaction was detected. There was an increase in the average concentration of digoxin in blood plasma by an average of 20% (in one case by 39%). With simultaneous use of telmisartan and digoxin, it is advisable to periodically determine the concentration of digoxin in the blood.
• lithium preparations: there was a reversible increase in the concentration of lithium in the blood, accompanied by toxic phenomena when taking ACE inhibitors. In rare cases, such changes have been reported with the use of angiotensin II receptor antagonists, in particular, telmisartan. When prescribing lithium preparations and angiotensin II receptor antagonists at the same time, it is recommended to determine the lithium content in the blood.
• NSAIDs, including acetylsalicylic acid in doses used as an anti-inflammatory agent, cyclooxygenase-2 (COX-2) inhibitors, and non-selective NSAIDs, may cause acute renal failure in patients with reduced BCC. Drugs that affect the activity of the renin-angiotensin system, including telmisartan, may have a synergistic effect. In patients receiving NSAIDs and telmisartan, BCC should be compensated and renal function monitored at the beginning of treatment.

Concomitant use of NSAIDs and antihypertensive drugs such as telmisartan has been reported to reduce the antihypertensive effect by inhibiting the vasodilator effect of prostaglandins.

Amlodipine Concomitant use of amlodipine with:

• grapefruit and grapefruit juice: concomitant use of the drug with grapefruit or grapefruit juice is not recommended, because in some patients, as a result of increased bioavailability of amlodipine, its antihypertensive effects may increase.
• inhibitors of the CYP3A4 isoenzyme: in a study in elderly patients, diltiazem was shown to inhibit the metabolism of amlodipine, probably affecting CYP3A4 (plasma concentrations of amlodipine increase by about 50% and the effect of amlodipine is enhanced). It cannot be ruled out that more active CYP3A4 inhibitors (such as ketoconazole, itraconazole, and ritonavir) may increase plasma concentrations of amlodipine to a greater extent than diltiazem.
• inducers of the CYP3A4 isoenzyme-anticonvulsants (for example, carbamazepine, phenobarbital, phenytoin, phosphenytoin, primidone), rifampicin, St. John’s wort (Hypericum perforatum): combined use may lead to a decrease in plasma concentrations of amlodipine. Regular medical supervision is indicated. During the use of CYP3A4 inducers, as well as after their withdrawal, it is recommended (if possible) to change the dose of amlodipine.
• Co-use of simvastatin 80 mg with amlodipine, regardless of the dose, increases exposure to simvastatin by up to 77% compared to simvastatin monotherapy. Therefore, the dose of simvastatin should not exceed 40 mg / day.

Concomitant use of the following medications should take into account the following Information The safety of co-use of amlodipine with thiazide diuretics, beta-blockers, ACE inhibitors, long-acting nitrates, nitroglycerin (used sublingually), NSAIDs, antibiotics and hypoglycemic agents for oral use has been established. Concomitant use of amlodipine and sildenafil showed that each drug had an independent antihypertensive effect. Additional Information The simultaneous use of 240 ml of grapefruit juice in 20 healthy volunteers with a single dose of amlodipine 10 mg, taken orally, did not significantly affect the pharmacokinetic properties of amlodipine. Concomitant use of amlodipine with cimetidine did not significantly affect the pharmacokinetics of amlodipine. Concomitant use of amlodipine with atorvastatin, digoxin, warfarin or cyclosporine did not significantly affect the pharmacokinetics or pharmacodynamics of these drugs. Based on the experience of using other drugs that affect the RAAS, the simultaneous use of the drug Twynsta and potassium-sparing diuretics, potassium-containing supplements, potassium-containing food salt, and other drugs that increase the content of potassium in the blood (for example, heparin) can lead to hyperkalemia, so this indicator should be monitored in patients. In this regard, their simultaneous use with telmisartan requires caution.

How to take, course of use and dosage

The drug Twynsta should be taken 1 time/day, inside, regardless of food intake. Twynsta can be given to patients receiving the same doses of telmisartan and amlodipine as separate tablets, for ease of treatment and to increase adherence to treatment.

Twynsta may be given to patients in whom the use of amlodipine alone or telmisartan alone does not lead to adequate blood pressure control. Patients taking amlodipine at a dose of 10 mg, who have observed adverse reactions that limit the use of the drug, for example, peripheral edema, can switch to taking the drug Twynsta at a dose of 40/5 mg 1 time / day, which will reduce the dose of amlodipine, but will not reduce the overall expected antihypertensive effect.

Treatment of arterial hypertension in a patient can begin with the use of the drug Twynsta in the case when it is assumed that achieving blood pressure control with any one drug is unlikely. The usual initial dose of Twynsta is 40/5 mg once a day. Patients who need a more significant reduction in blood pressure can start taking the drug Twynsta at a dose of 80/5 mg 1 time/day. If an additional reduction in blood pressure is required after at least 2 weeks of treatment, the dose of the drug can be gradually increased to a maximum dose of 80/10 mg 1 time / day. Twynsta can be used together with other antihypertensive drugs.

Renal impairment in patients with impaired renal function, including patients undergoing hemodialysis, no dosage changes are required. Amlodipine and telmisartan are not removed from the body during hemodialysis.

Hepatic impairment In patients with mild to moderate hepatic impairment, Twynsta should be used with caution. The dose of telmisartan should not exceed 40 mg once a day.

Elderly patients The dosage regimen does not require any changes.

Features of the drug’s action at the first dose or when it is canceled after the first dose of telmisartan, the hypotensive effect gradually develops during the first 3 hours and the drug’s effect persists for 24 hours and remains significant until 48 hours. In the case of abrupt withdrawal of telmisartan, blood pressure gradually returns to its original level without the development of withdrawal syndrome.

Overdose

Symptoms and overdose were not detected. Possible symptoms of overdose consist of symptoms from the individual components of the drug. Telmisartan – marked decrease in blood pressure, tachycardia, possibly bradycardia, dizziness, increased serum creatinine concentration, acute renal failure. Amlodipine – excessive peripheral vasodilation and possibly reflex tachycardia. There may be severe and probably prolonged systemic hypotension, up to the development of shock with a fatal outcome. Treatment Hemodialysis is not effective.Monitoring of the patient’s condition, therapy should be symptomatic and supportive. Intravenous use of calcium gluconate may be useful to counteract calcium channel blockage. Methods of treating overdose can be used, such as induction of vomiting, gastric lavage, the use of activated charcoal, placing the patient in a “lying position with raised legs” and the introduction of plasma-substituting solutions in case of a pronounced decrease in blood pressure.

Special instructions

The drug should be administered with caution if the patient has the following conditions::

• impaired liver function;
• bilateral renal artery stenosis or stenosis of the artery of a single kidney, severe renal dysfunction. In some patients, due to the suppression of RAAS, especially when using a combination of agents acting on this system, renal function is impaired (including acute renal failure). Therefore, therapy accompanied by such a double blockade of the RAAS should be carried out strictly individually and with careful monitoring of renal function (including periodic monitoring of serum potassium and creatinine). In cases based on vascular tone and renal function primarily from the activity of the RAAS (e. g., patients with congestive heart failure, or kidney diseases, including stenosis of the renal arteries or stenosis of the artery to a solitary kidney), the appointment of drugs that affect this system may be accompanied by the development of acute arterial hypotension, hyperazotemia, oliguria, and, in rare cases, acute renal failure;
• condition after kidney transplantation (experience of missing);
• a decrease in BCC and/or hyponatremia as a result of prior diuretic therapy, restriction of salt, diarrhea or vomiting;
• dual blockade of the RAAS;
• other conditions characterized by activation of the RAAS;
• primary aldosteronism;
• stenosis of the aortic and mitral valve disease, idiopathic hypertrophic subaortic stenosis;
• heart failure;
• hyperkalemia;
• hereditary fructose intolerance;
• in patients with diabetes and additional cardiovascular risk ie, patients with diabetes and concomitant coronary artery disease (CAD), the risk of fatal myocardial infarction and unexpected cardiovascular death may be increased when treatment antihypertensives, such as receptor antagonists of angiotensin II and ACE inhibitors. In patients with diabetes mellitus, CHD may be asymptomatic and therefore not be diagnosed. Patients with diabetes mellitus should undergo appropriate diagnostics, such as a physical activity test, to diagnose and treat CHD, as appropriate, before starting treatment with Twynsta.

Other indications Lead is less effective in the treatment of black patients (this population usually has reduced blood renin activity). There are no data on the use of the drug Twynsta in patients with unstable angina, acute myocardial infarction and in the period one month after the development of myocardial infarction.

Influence on the ability to drive motor vehicles and manage mechanicsstudies of the influence on the ability to drive motor vehicles and manage mechanisms have not been conducted. However, it should be taken into account that undesirable effects such as fainting, drowsiness or dizziness may occur during treatment. Therefore, care should be taken when driving vehicles or mechanisms. If patients experience these sensations, they should avoid performing potentially dangerous activities such as driving vehicles or operating machinery.

Form of production

Tablets

Storage conditions

At a temperature not exceeding 25 °C, in the original packaging

Shelf life

3 years

Active ingredient

Amlodipine, Telmisartan

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

For adults as directed by your doctor

Indications

Hypertension