Twynsta^® (Tablets) Instructions for Use

ATC Code

C09DB04 (Amlodipine and Telmisartan)

Active Substances

Telmisartan (Rec.INN registered by WHO)

Amlodipine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Combined antihypertensive agent (CCB + angiotensin II receptor antagonist)

Pharmacological Action

A combined antihypertensive drug containing two active components with complementary action, allowing for blood pressure control in patients with arterial (essential) hypertension: an angiotensin II receptor antagonist (Telmisartan) and a slow calcium channel blocker, a dihydropyridine derivative (amlodipine).

The combination of these substances has an additive antihypertensive effect, reducing blood pressure to a greater extent than each component separately.

The drug Twynsta^®, taken once daily, leads to effective and sustained reduction of blood pressure over 24 hours.

Telmisartan

Telmisartan is a specific angiotensin II receptor antagonist (type AT₁), effective when administered orally.

It has high affinity for the AT₁ receptor subtype of angiotensin II, through which the action of angiotensin II is mediated.

It displaces angiotensin II from binding to the receptor, having no agonist action on this receptor.

Telmisartan binds only to the AT₁ receptor subtype of angiotensin II. The binding is long-lasting.

It has no affinity for other receptors, including the AT₂ receptor.

It reduces the concentration of aldosterone in the blood, does not inhibit plasma renin, and does not block ion channels.

Telmisartan does not inhibit ACE (kininase II) – an enzyme that also breaks down bradykinin, therefore an increase in bradykinin-mediated side effects is not expected.

In patients, Telmisartan at a dose of 80 mg completely blocks the hypertensive effect of angiotensin II.

The onset of the antihypertensive effect is noted within 3 hours after the first dose of telmisartan.

The effect of the drug persists for 24 hours and remains significant for up to 48 hours.

A pronounced antihypertensive effect usually develops after 4-8 weeks of regular use.

In patients with arterial hypertension, Telmisartan reduces systolic and diastolic blood pressure without affecting heart rate.

In case of abrupt withdrawal of telmisartan, blood pressure gradually returns to the baseline level without the development of withdrawal syndrome.

Amlodipine

Amlodipine is a dihydropyridine derivative, belonging 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 the antihypertensive action of amlodipine is associated with a direct relaxing effect on vascular smooth muscle cells, leading to a decrease in peripheral vascular resistance and a reduction in blood pressure.

In patients with arterial hypertension, the use of amlodipine once daily provides a clinically significant reduction in blood pressure over 24 hours.

Orthostatic arterial hypotension is not characteristic when using amlodipine due to the slow onset of action of the drug.

In patients with arterial hypertension and normal renal function, amlodipine in therapeutic doses led to a decrease in renal vascular resistance, an increase in glomerular filtration rate and effective renal plasma flow, without changes in filtration fraction or proteinuria.

Amlodipine does not cause any adverse metabolic effects or changes in plasma lipid levels, making it 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 (does not reduce exercise tolerance, does not reduce left ventricular ejection fraction).

Pharmacokinetics

The rate and extent of absorption of the drug Twynsta^® are equivalent to the bioavailability of telmisartan and amlodipine when administered separately.

Telmisartan

Absorption

When taken orally, it is rapidly absorbed from the gastrointestinal tract. Bioavailability is 50%. When taken simultaneously with food, the reduction in AUC ranges from 6% (when used at a dose of 40 mg) to 19% (when used at a dose of 160 mg). Three hours after oral administration, the plasma concentration levels off, regardless of food intake. C_max in plasma and, to a lesser extent, AUC increase disproportionately to the dose size.

Distribution

Plasma protein binding is 99.5%, mainly with albumin and alpha₁-glycoprotein. The mean apparent V_d at steady-state concentration is 500 L. There are no data on clinically significant accumulation of telmisartan.

Metabolism

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

Excretion

T_1/2 is more than 20 hours. It is excreted unchanged in the feces, excretion in the urine is less than 2%. Total plasma clearance is high (900 ml/min) compared to hepatic blood flow (about 1500 ml/min).

Pharmacokinetics in special clinical cases

A difference in plasma concentrations of telmisartan is observed between men and women. C_max and AUC were approximately 3 and 2 times higher, respectively, in women compared to men without a significant effect on efficacy.

The pharmacokinetics of telmisartan in elderly patients does not differ from the pharmacokinetics in young patients.

Telmisartan binds to plasma proteins and is not removed by hemodialysis in patients with renal failure. Lower plasma concentrations of telmisartan are also noted, T_1/2 does not change.

Pharmacokinetic studies conducted in patients with impaired liver function showed that the absolute bioavailability of telmisartan increases to almost 100%. T_1/2 in patients with impaired liver function does not change.

Amlodipine

Absorption

After oral administration of amlodipine in therapeutic doses, C_max in plasma is reached after 6-12 hours. The absolute bioavailability ranges from 64% to 80%. Food intake does not affect the bioavailability of amlodipine.

Distribution

The V_d of amlodipine is approximately 21 L/kg. In vitro studies have shown that in patients with arterial hypertension, approximately 97.5% of circulating amlodipine is bound to plasma proteins. Steady-state plasma concentrations are achieved after continuous use of the drug for 7-8 days.

Metabolism

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

Excretion

The elimination of amlodipine from plasma is biphasic. T_1/2 is approximately 30-50 hours. Amlodipine is excreted in the urine both unchanged (10%) and as metabolites (60%).

Pharmacokinetics in special clinical cases

In elderly patients, there is a tendency for a decrease in the clearance of amlodipine, leading to an increase in AUC and T_1/2.

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

In patients with hepatic insufficiency, the clearance of amlodipine decreased, leading to an increase in the AUC value by approximately 40-60%.

Indications

For the treatment of arterial hypertension

• In patients whose blood pressure is inadequately controlled by telmisartan or amlodipine used as monotherapy;
• In patients for whom combination therapy is indicated;
• In patients receiving Telmisartan and amlodipine as separate tablets, as a replacement for this therapy.

ICD codes

Dosage Regimen

Tablets

Adults

The drug Twynsta^® should be taken once daily, orally, regardless of meals.

Twynsta^® can be prescribed to patients receiving the same doses of telmisartan and amlodipine as separate tablets, for the convenience of therapy and to increase treatment adherence.

Twynsta^® can be prescribed 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 experience adverse reactions limiting drug intake, for example, peripheral edema, can switch to taking Twynsta^® at a dose of 40/5 mg once daily, which will reduce the dose of amlodipine but will not reduce the overall expected antihypertensive effect.

Treatment of arterial hypertension in a patient can be started with the use of Twynsta^® in cases where it is assumed that achieving blood pressure control with any single drug is unlikely. The usual initial dose of Twynsta^® is 40/5 mg once daily. Patients who require a more significant reduction in blood pressure can start taking Twynsta^® at a dose of 80/5 mg once daily.

If, after at least 2 weeks of treatment, additional blood pressure reduction is required, the dose of the drug can be gradually increased to the maximum dose of 80/10 mg once daily.

Twynsta^® can be used together with other antihypertensive drugs.

Renal impairment

In patients with renal impairment, including patients on hemodialysis, no dosage adjustment is required. Amlodipine and Telmisartan are not removed from the body during hemodialysis.

Hepatic impairment

In patients with mild or moderate hepatic impairment, the drug Twynsta^® should be used with caution. The dose of telmisartan should not exceed 40 mg once daily.

Elderly patients

The dosage regimen does not require changes.

Features of the drug action upon first administration or upon its withdrawal

After the first dose of telmisartan, the hypotensive effect gradually develops within the first 3 hours and the effect of the drug persists for 24 hours and remains significant for up to 48 hours.

In case of abrupt withdrawal of telmisartan, blood pressure gradually returns to the baseline level without the development of withdrawal syndrome.

Adverse Reactions

Within system-organ classes, the frequency of adverse effects is classified as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data).

Undesirable adverse reactions are classified by organs and systems in accordance with MedDRA terms.

¹ expected based on experience with telmisartan

² expected based on experience with amlodipine

³ expected with simultaneous use of telmisartan and amlodipine

Additional information regarding individual components

Side effects previously reported with the use of one of the components of the drug (amlodipine or telmisartan) may be enhanced when using the drug 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 less frequently in patients who received the combination of telmisartan and amlodipine than in patients receiving amlodipine alone.

Contraindications

• Obstructive biliary tract diseases;
• Severe arterial hypotension;
• Obstruction of the left ventricular outflow tract (including severe aortic stenosis);
• Hemodynamically unstable heart failure after acute myocardial infarction;
• Severe hepatic impairment;
• Shock;
• Concomitant use with aliskiren in patients with diabetes mellitus or renal impairment (GFR less than 60 ml/min/1.73 m²);
• Fructose intolerance and glucose/galactose malabsorption syndrome or sucrase/isomaltase deficiency;
• Pregnancy;
• Breastfeeding period;
• Age under 18 years (efficacy and safety not established);
• Hypersensitivity to the active components or excipients;
• Hypersensitivity to other dihydropyridine derivatives.

With caution, the drug should be prescribed for impaired liver function, renovascular arterial hypertension, primary aldosteronism, stenosis of the aortic and mitral valves, hypertrophic obstructive cardiomyopathy, heart failure, diabetes mellitus, unstable angina, acute myocardial infarction, impaired renal function, condition after kidney transplantation, reduced blood volume and/or hyponatremia, hyperkalemia, other conditions characterized by activation of the RAAS.

Use in Pregnancy and Lactation

No specific studies have been conducted on the use of the drug Twynsta^® during pregnancy and lactation. Effects related to the individual components of the drug are described below.

Pregnancy

Telmisartan

The use of angiotensin II receptor antagonists is contraindicated during pregnancy. If pregnancy occurs, the use of the drug should be discontinued immediately. If necessary, alternative therapy should be prescribed.

Preclinical studies of telmisartan did not reveal teratogenic properties but established the presence of fetotoxicity.

It is known that the use of angiotensin II receptor antagonists in the II and III trimesters of pregnancy has a fetotoxic effect (impaired renal function, oligohydramnios, delayed ossification of the fetal skull), and neonatal toxicity (renal failure, arterial hypotension and hyperkalemia) is also observed.

In women planning pregnancy, angiotensin II receptor antagonists should be replaced with other antihypertensive drugs that have an established safety profile for use in pregnant women (unless continuation of treatment with angiotensin II receptor antagonists is considered necessary).

If angiotensin II receptor antagonists are used during pregnancy, then, starting from the second trimester of pregnancy, it is recommended to perform ultrasound of the fetal kidneys and skull bones. Newborns whose mothers received angiotensin II receptor antagonists should be carefully monitored for the development of arterial hypotension.

Amlodipine

The available limited data regarding the effects of amlodipine or other calcium channel blockers do not indicate a negative effect on the fetus. However, there is a possible risk of slowing down the labor process.

Breastfeeding period

No specific studies have been conducted on the excretion of telmisartan and/or amlodipine in breast milk in women. In experimental studies on animals, it was found that Telmisartan is excreted in the milk of lactating animals. Given the possible adverse reactions, the decision to continue breastfeeding or to discontinue therapy should be made taking into account its importance for the mother.

No studies have been conducted on the effect of the drug on human fertility.

Use in Hepatic Impairment

In patients with mild to moderate hepatic impairment, the drug Twynsta^® should be used with caution. The dose of telmisartan should not exceed 40 mg once daily.

Use in Renal Impairment

In patients with impaired renal function, including patients on hemodialysis, no dose adjustment of the drug is required. Amlodipine and Telmisartan are not removed from the body during hemodialysis.

With caution, the drug should be prescribed for impaired renal function, condition after kidney transplantation.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age (efficacy and safety have not been established).

Geriatric Use

In elderly patients, the dosage regimen does not require changes.

Special Precautions

During treatment with drugs that affect the RAAS, especially in the presence of impaired renal function and/or heart failure, hyperkalemia may occur. In such patients, regular monitoring of serum potassium levels is recommended. Patients with impaired renal function are also recommended to periodically monitor serum creatinine concentrations. In some patients, due to suppression of the RAAS, especially when using a combination of agents acting on this system (for example, adding an ACE inhibitor or aliskiren, a direct renin inhibitor, to angiotensin II receptor antagonists), renal function is impaired (including acute renal failure). Therapy accompanied by such dual blockade of the RAAS is not recommended and therefore should be limited and carried out strictly individually with careful monitoring of renal function.

In cases where vascular tone and renal function depend predominantly on the activity of the RAAS (for example, in patients with chronic heart failure or kidney disease, including renal artery stenosis), the prescription of drugs affecting this system may be accompanied by the development of acute arterial hypotension, hyperazotemia, oliguria, and, in rare cases, acute renal failure.

In patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney taking drugs that affect the RAAS, there is an increased risk of developing severe arterial hypotension and renal failure.

In patients with primary aldosteronism, antihypertensive drugs whose mechanism of action is to inhibit the RAAS are generally not effective. Thus, the use of telmisartan in such cases is not recommended.

In patients with aortic or mitral stenosis, or with obstructive hypertrophic cardiomyopathy, the use of the drug Twynsta^®, as well as other vasodilators, requires special caution.

A clinical study found that the use of amlodipine in patients with heart failure of non-ischemic etiology of functional class III and IV (according to the NYHA classification) was accompanied by a more frequent development of pulmonary edema (despite the absence of significant differences in the frequency of worsening heart failure compared with placebo).

In patients with diabetes mellitus, coronary artery disease may be asymptomatic, and therefore may be undiagnosed. Patients with diabetes mellitus should undergo appropriate examination for the diagnosis and treatment of coronary artery disease (for example, an exercise test) before starting treatment with the drug Twynsta^®. In patients with diabetes mellitus with concomitant coronary artery disease, the likelihood of fatal myocardial infarction and sudden cardiovascular death may be increased when treated with such antihypertensive agents as angiotensin II receptor antagonists and ACE inhibitors.

There are no data on the use of the drug Twynsta^® in patients with unstable angina, in the acute period and within one month after myocardial infarction.

Restriction of salt intake, intensive diuretic therapy, diarrhea or vomiting can lead to a decrease in blood volume and/or hyponatremia, which may result in the development of symptomatic arterial hypotension, especially after taking the first dose of the drug. Before using the drug Twynsta^®, such conditions require correction.

There is no experience with the use of the drug Twynsta^® in patients who have recently undergone kidney transplantation. Amlodipine and Telmisartan are not removed by hemodialysis. Patients with impaired renal function are recommended to periodically monitor serum potassium and creatinine levels.

Dosage recommendations for patients with impaired liver function have not been developed, so caution should be exercised.

The drug Twynsta^® is effective in treating patients of the Black race (in this population, blood renin activity is usually reduced).

Effect on the ability to drive vehicles and machinery

Studies of the effect on the ability to drive vehicles and operate machinery have not been conducted. However, it should be taken into account that during treatment, adverse effects such as fainting, drowsiness or dizziness may occur. Therefore, caution should be exercised or potentially hazardous activities such as driving vehicles or operating machinery should be avoided.

Overdose

No cases of overdose have been identified. Possible symptoms are a combination of symptoms of overdose of individual components of the drug.

Symptoms of telmisartan overdose: tachycardia, possibly bradycardia, dizziness, increased serum creatinine concentration, acute renal failure.

Symptoms of amlodipine overdose: excessive decrease in blood pressure with possible development of reflex tachycardia and symptoms of excessive peripheral vasodilation (risk of developing severe and persistent arterial hypotension, including with the development of shock and death).

Treatment: symptomatic and supportive therapy, monitoring of the patient’s condition. Methods such as induction of vomiting, gastric lavage, and the use of activated charcoal may be used. In case of a pronounced decrease in blood pressure, the patient should be placed in a horizontal position with a low headboard; administration of plasma-substituting solutions is recommended. To counteract calcium channel blockade, intravenous administration of calcium gluconate is indicated. Hemodialysis is not effective.

Drug Interactions

No interaction between the two active components included in fixed doses in this drug was identified in clinical studies.

No specific drug interaction studies of the drug Twynsta^® with other drugs have been conducted.

Combination of active components

When used concomitantly with other antihypertensive drugs, the antihypertensive effect of the drug Twynsta^® may be enhanced.

It can be expected that some drugs (for example, baclofen and amifostine), due to their pharmacological properties, will enhance the hypotensive effect of all antihypertensive agents, including the drug Twynsta^®. In addition, orthostatic hypotension may be enhanced by ethanol, barbiturates, narcotics, or antidepressants.

When used concomitantly with corticosteroids (for systemic use), a decrease in the antihypertensive effect is possible.

Based on experience with other drugs affecting the RAAS, concomitant use of the drug Twynsta^® and potassium-sparing diuretics, potassium-containing supplements, potassium-containing food salt, and other agents that increase blood potassium levels (for example, heparin) may lead to hyperkalemia. Therefore, the use of such combinations requires caution and monitoring of blood potassium levels.

Telmisartan

When used concomitantly with other antihypertensive drugs, an enhancement of the hypotensive effect is possible. In one study, with the combined use of telmisartan and ramipril, an increase in AUC_0-24 and C_max of ramipril and ramiprilat by 2.5 times was observed. The clinical significance of this interaction has not been established.

Dual blockade of the RAAS (for example, simultaneous use of an ACE inhibitor or aliskiren, a direct renin inhibitor, with angiotensin II receptor antagonists) is not recommended due to possible impairment of renal function (including acute renal failure).

A reversible increase in lithium concentration in the blood, accompanied by toxic phenomena, has been observed with simultaneous use with ACE inhibitors. In rare cases, similar changes have been reported with the prescription of angiotensin II receptor antagonists, in particular, telmisartan. When lithium preparations and angiotensin II receptor antagonists are used concomitantly, it is recommended to determine the lithium content in the blood.

NSAIDs, including acetylsalicylic acid (in doses used as an anti-inflammatory agent), COX-2 inhibitors and non-selective NSAIDs can cause the development of acute renal failure in patients with reduced blood volume. Drugs that affect the activity of the RAAS, including Telmisartan, may have a synergistic effect. In patients receiving NSAIDs and Telmisartan, blood volume should be compensated and renal function should be examined at the beginning of treatment.

When NSAIDs and antihypertensive drugs similar to telmisartan are used concomitantly, a decrease in the antihypertensive effect has been reported due to inhibition of the vasodilatory effect of prostaglandins.

No clinically significant interaction with digoxin, warfarin, hydrochlorothiazide, glibenclamide, simvastatin, ibuprofen, paracetamol and amlodipine has been identified. An increase in the average plasma concentration of digoxin by an average of 20% (in one case by 39%) was noted. When telmisartan and digoxin are used concomitantly, it is advisable to periodically determine the concentration of digoxin in the blood.

Amlodipine

Concomitant use of the drug Twynsta^® with grapefruit or grapefruit juice is not recommended, as in some patients, as a result of increased bioavailability of amlodipine, its antihypertensive effect may be enhanced.

A study in elderly patients showed that diltiazem inhibits the metabolism of amlodipine, probably affecting CYP3A4 (amlodipine plasma concentrations increase by approximately 50% and the effect of amlodipine is enhanced). It cannot be excluded that more potent CYP3A4 inhibitors (such as ketoconazole, itraconazole, ritonavir) may increase amlodipine plasma concentrations to a greater extent than diltiazem.

Concomitant use with inducers of the CYP3A4 isoenzyme (anticonvulsants (for example, carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone), rifampicin, St. John’s wort (Hypericum perforatum)) may lead to a decrease in amlodipine plasma concentrations. Regular medical supervision is indicated. During the use of CYP3A4 inducers, as well as after their discontinuation, a change in the dose of amlodipine is recommended (if possible).

Concomitant use of simvastatin at a dose of 80 mg with amlodipine, regardless of the dose, contributes to an increase in the exposure of simvastatin by up to 77% compared with simvastatin monotherapy. Therefore, the dose of simvastatin should not exceed 20 mg/day.

When used concomitantly, amlodipine may increase the systemic exposure of cyclosporine or tasocitinib. In such cases, regular monitoring of the concentration of cyclosporine or tasocitinib in the blood and dose adjustment if necessary is recommended.

The safety of concomitant use of amlodipine with thiazide diuretics, beta-blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, NSAIDs, antibiotics and oral hypoglycemic drugs has been established.

When amlodipine and sildenafil were used concomitantly, it was shown that each drug had an independent antihypertensive effect.

Additional information

Concomitant use in 20 healthy volunteers of 240 ml of grapefruit juice with a single oral dose of amlodipine 10 mg did not lead to a significant effect on the pharmacokinetic properties of amlodipine.

Concomitant use of amlodipine with cimetidine did not have a significant effect on the pharmacokinetics of amlodipine.

Concomitant use of amlodipine with atorvastatin, digoxin or warfarin did not significantly affect the pharmacokinetics or pharmacodynamics of these drugs.

Storage Conditions

The drug should be stored in the original packaging, out of the reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. The drug should not be used after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

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.