Telmista AM, tablets 5 mg+40 mg 28 pcs

Pharmacotherapeutic group:

Hypertensive combined agent (slow calcium channel blocker + angiotensin II receptor antagonist).

ATX code:

C09DB04

Pharmacological properties

Pharmacodynamics

. The combination drug Telmista® AM contains two hypotensive agents with complementary actions to control blood pressure (BP) in patients with arterial (essential) hypertension: The angiotensin II receptor antagonist (ARA II) telmisartan and the slow calcium channel blocker (CMCB) dihydropyridine derivative amlodipine.

The combination of these substances has an additive antihypertensive effect, reducing BP to a greater extent than each component separately. A combination drug consisting of amlodipine and telmisartan, taken once daily, results in effective and sustained BP lowering within 24 hours.

Amlodipine

Amlodipine is a dihydropyridine derivative and belongs to the class of PBMCs. It inhibits transmembrane transition of calcium ions in cardiomyocytes and smooth muscle cells of the vascular wall.

The antihypertensive effect of amlodipine is due to a direct relaxant effect on the smooth muscle cells of the vascular wall resulting in reduction of peripheral vascular resistance and decrease of BP.

In patients with arterial hypertension once daily administration of amlodipine provides clinically significant BP reduction within 24 hours. The antihypertensive effect develops slowly, so the development of acute arterial hypotension is uncommon.

In patients with arterial hypertension and normal renal function therapeutic doses of amlodipine resulted in decrease of renal vascular resistance, increase of glomerular filtration rate (GFR) and effective renal plasma blood flow without change in filtration or proteinuria.

Amlodipine has no adverse metabolic effects and does not affect plasma lipid concentrations. Therefore, the drug may be used in patients with concomitant bronchial asthma, diabetes mellitus and gout.

The use of amlodipine in patients with cardiac insufficiency is not associated with negative inotropic effect (no decrease of exercise tolerance and left ventricular ejection fraction).

Telmisartan

Telmisartan is a specific ARA II (type AT1) that is effective when taken orally. It has high affinity for the AT1 subtype of angiotensin II receptors, through which the action of angiotensin II is realized. It displaces angiotensin II from binding to the receptor, having no agonist effect against this receptor. Telmisartan binds only to the AT1 subtype of angiotensin II receptor. The binding is long-lasting. It has no affinity for other receptors, including the AT2 receptor. Reduces aldosterone concentration, does not inhibit plasma renin activity and does not block ion channels. Telmisartan does not inhibit angiotensin-converting enzyme (ACE) or kininase II, an enzyme that also degrades bradykinin. Therefore, an increase in bradykinin-induced adverse reactions (HP) is not expected.

At a dose of 80 mg, telmisartan completely blocks the hypertensive effects of angiotensin II. The onset of antihypertensive action is observed within 3 hours after the first telmisartan administration. The action of the drug persists for 24 hours and remains significant up to 48 hours. A pronounced antihypertensive effect usually develops 4-8 weeks after regular use.

Telmisartan reduces systolic and diastolic BP in patients with arterial hypertension without affecting heart rate (HR).

In case of abrupt telmisartan withdrawal, BP gradually returns to baseline levels without development of “withdrawal” syndrome.

The incidence of dry cough was significantly lower in patients treated with telmisartan compared to ACE inhibitors.

The two large randomized controlled trials ONTARGET (Global Endpoints in Telmisartan Monotherapy and Ramipril) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes Study, conducted by the US Department of Veterans Affairs) studied ACE inhibitor combination with ARA II. The ONTARGET study was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes with confirmed target organ damage. The VA NEPHRON-D study was a study in patients with type 2 diabetes and diabetic nephropathy.

These studies showed no significant beneficial effects on renal and/or cardiovascular outcomes and mortality, whereas an increased risk of hyperkalemia, acute renal failure (ARF) and/or arterial hypotension was observed compared to monotherapy. Given the similar pharmacodynamic properties, these results are also relevant for other ACE inhibitors and ARA II.

Therefore, ACE inhibitors and ARA II should not be used simultaneously in patients with diabetic nephropathy.

The ALTITUDE (Aliskiren Use in Patients with Type 2 Diabetes with Assessment of Cardiovascular and Renal Endpoints) was a study designed to test the benefit of adding aliskiren to standard treatment with an ACE inhibitor or ARA II in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease or both. The study was terminated early due to an increased risk of adverse outcomes. Cardiovascular death and stroke were more frequently reported in the aliskiren group than in the placebo group, and adverse events (AEs) and serious adverse events (SAEs) (hyperkalemia, arterial hypotension, and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group. There is a difference in plasma concentrations of telmisartan in men and women. The values of maximum concentration (Cmax) and area under the pharmacokinetic concentration-time curve (AUC) were approximately 3 and 2 times higher in women compared to men, respectively, with no significant effect on efficacy.

Pharmacokinetics

Combination of fixed doses of amlodipine and telmisartan

The magnitude and rate of absorption of amlodipine and telmisartan when used as part of a combination drug are not significantly different from those when they are used as monotherapies.

Amlodipine

Intake

Amlodipine is well absorbed when taken orally at therapeutic doses and reaches Cmax after 6-12 hours. Absolute bioavailability is 64-80%. Food intake does not affect the bioavailability of amlodipine.

Distribution

The volume of distribution is approximately 21 l/kg. Results of in vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.

Metabolism

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

The excretion of amlodipine from blood plasma is biphasic with a half-life (T1/2) of approximately 30-50 hours. Stable concentration in blood plasma is reached after continuous drug administration for 7-8 days. Amlodipine is excreted by the kidneys both as unchanged (10%) and as metabolites (60%).

Telmisartan

Intake

In oral administration, telmisartan is rapidly absorbed from the gastrointestinal tract (GIT). Absolute bioavailability is 50%. When taken concomitantly with food, AUC decreases from 6% (at a dose of 40 mg) to 19% (at a dose of 160 mg). In 3 hours after oral administration the plasma concentration becomes similar to that of telmisartan on an empty stomach.

Distribution

Binding to plasma proteins >99.5% (mainly to albumin and alpha-1-acid glycoprotein). The average value of the apparent volume of distribution in the equilibrium state is 500 l.

Metabolism

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

The T1/2 is greater than 20 hours. The values of Cmax and, to a lesser extent, AUC increase disproportionately to the dose. There is no evidence of clinically significant cumulation of telmisartan. It is excreted unchanged in the intestine, renal excretion is less than 1%. Total plasma clearance is high (approximately 1000 ml/min) compared to hepatic blood flow (about 1500 ml/min).

Particular patient groups

Elderly patients

In elderly patients there is a tendency for amlodipine clearance to decrease, resulting in increased AUC and T1/2 values.

The pharmacokinetics of telmisartan does not differ in elderly and younger patients.

Renal dysfunction

The pharmacokinetics of amlodipine in patients with renal dysfunction are not significantly altered.

Telmisartan is bound to plasma proteins and is not eliminated by hemodialysis in patients with renal impairment. Plasma concentrations of telmisartan are doubled in patients with renal impairment. However, telmisartan concentrations are lower in patients on hemodialysis and the T1/2 is unchanged.

Hepatic impairment

In patients with hepatic impairment, the clearance of amlodipine was decreased, resulting in an increase in AUC of approximately 40-60%.

Pharmacokinetic studies performed in patients with hepatic impairment have shown that the absolute bioavailability of telmisartan is increased to almost 100%. The T1/2, in patients with hepatic dysfunction is not altered.

Indications

Arterial hypertension (for patients whose blood pressure is not sufficiently controlled with amlodipine or telmisartan in monotherapy).

Arterial hypertension (for patients for whom combination therapy is indicated). Patients with arterial hypertension receiving amlodipine and telmisartan in the form of separate tablets as a replacement for this therapy.

Pharmacological effect

Pharmacotherapeutic group:

antihypertensive combination drug (slow calcium channel blocker + angiotensin II receptor antagonist).

ATX Code:

C09DB04

Pharmacological properties

Pharmacodynamics

The combined drug Telmista® AM contains two antihypertensive substances with a complementary effect, which allows you to control blood pressure (BP) in patients with arterial (essential) hypertension: an angiotensin II receptor antagonist (ARA II) – telmisartan and a blocker of “slow” calcium channels (SCBC), a dihydropyridine derivative – amlodipine.

The combination of these substances has an additive antihypertensive effect, reducing blood pressure to a greater extent than either component alone. A combination drug containing amlodipine and telmisartan, taken once a day, leads to an effective and sustained reduction in blood pressure over 24 hours.

Amlodipine

Amlodipine is a dihydropyridine derivative and belongs to the BMCC class. Inhibits the transmembrane transition of calcium ions into cardiomyocytes and smooth muscle cells of the vascular wall.

The antihypertensive effect of amlodipine is due to a direct relaxing effect on the smooth muscle cells of the vascular wall, which leads to a decrease in peripheral vascular resistance and a decrease in blood pressure.

In patients with arterial hypertension, taking amlodipine once a day provides a clinically significant reduction in blood pressure within 24 hours. The antihypertensive effect develops slowly, and therefore the development of acute arterial hypotension is uncharacteristic.

In patients with arterial hypertension and normal renal function, the use of amlodipine at therapeutic doses resulted in a decrease in renal vascular resistance, an increase in glomerular filtration rate (GFR) and effective plasma blood flow in the kidneys without changes in filtration or proteinuria.

Amlodipine does not have adverse metabolic effects and does not affect the concentration of plasma lipids. In this regard, the drug can be used in patients with concomitant 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 is not reduced, and the left ventricular ejection fraction is not reduced).

Telmisartan

Telmisartan is a specific ARA II (type AT1), effective when taken orally. It has a high affinity for the AT1 receptor subtype of angiotensin II, through which the action of angiotensin II is realized. Displaces angiotensin II from its connection with the receptor, without having an agonist effect on this receptor. Telmisartan binds only to the AT1 receptor subtype of angiotensin II. The connection is long-term. It has no affinity for other receptors, including the AT2 receptor. Reduces the concentration of aldosterone, does not inhibit the activity of renin in the blood plasma and does not block ion channels. Telmisartan does not inhibit angiotensin-converting enzyme (ACE) or kininase II, an enzyme that also breaks down bradykinin. Therefore, an increase in bradykinin-induced adverse reactions (HP) is not expected.

At a dose of 80 mg, telmisartan completely blocks the hypertensive effect of angiotensin II. The onset of antihypertensive action is observed within 3 hours after the first dose of telmisartan. The effect of the drug lasts for 24 hours and remains significant for up to 48 hours. A pronounced antihypertensive effect usually develops 4-8 weeks after regular use.

Telmisartan reduces systolic and diastolic blood pressure in patients with arterial hypertension without affecting heart rate (HR).

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

The incidence of dry cough was significantly lower in patients receiving telmisartan compared with ACE inhibitors.

Two large randomized controlled trials, ONTARGET (Telmisartan Alone and in Combination with Ramipril Global Endpoints Study) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes Study), examined the use of a combination of an ACE inhibitor and an ARB II. The ONTARGET study was a study conducted in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes mellitus with documented end-organ damage. The VA NEPHRON-D study was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies did not show significant beneficial effects on renal and/or cardiovascular outcomes and mortality, whereas an increased risk of hyperkalemia, acute renal failure (ARF) and/or hypotension was observed compared with monotherapy. Given the similar pharmacodynamic properties, these results are also relevant for other ACE inhibitors and ARB II.

Therefore, ACE inhibitors and ARB II should not be used simultaneously in patients with diabetic nephropathy.

The ALTITUDE study (Aliskiren Trial in Patients with Type 2 Diabetes with Cardiovascular and Renal Endpoints Evaluated) was a study designed to test the benefit of adding aliskiren to standard treatment with an ACE inhibitor or an ACE II inhibitor in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. The study was stopped early due to an increased risk of adverse outcomes. Cardiovascular death and stroke were reported more frequently in the aliskiren group than in the placebo group, and adverse events (AEs) and serious adverse events (SAEs) (hyperkalemia, hypotension, and renal dysfunction) were reported more frequently in the aliskiren group than in the placebo group. There is a difference in plasma concentrations of telmisartan in men and women. Maximum concentration (Cmax) and area under the concentration-time curve (AUC) values ​​were approximately 3-fold and 2-fold, respectively, higher in women compared to men, with no significant effect on efficacy.

Pharmacokinetics

Fixed dose combination of amlodipine and telmisartan

The magnitude and rate of absorption of amlodipine and telmisartan when used as part of a combination drug does not differ significantly from that when used as single drugs.

Amlodipine

Suction

Amlodipine is well absorbed when taken orally in therapeutic doses and reaches Cmax after 6-12 hours. Absolute bioavailability is 64-80%. Food intake does not affect the bioavailability of amlodipine.

Distribution

The volume of distribution is approximately 21 l/kg. The results of in vitro studies showed that approximately 97.5% of circulating amlodipine is bound to plasma proteins.

Metabolism

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

Removal

The elimination of amlodipine from blood plasma occurs in two phases, the half-life (T1/2) is approximately 30-50 hours. Stable plasma concentrations are achieved after continuous administration of the drug for 7-8 days. Amlodipine is excreted by the kidneys both unchanged (10%) and in the form of metabolites (60%).

Telmisartan

Suction

When taken orally, telmisartan is rapidly absorbed from the gastrointestinal tract (GIT). Absolute bioavailability – 50%. When taken simultaneously with food, the reduction in AUC values ​​ranges from 6% (at a dose of 40 mg) to 19% (at a dose of 160 mg). 3 hours after oral administration, the concentration in the blood plasma becomes similar to the concentration when taking telmisartan on an empty stomach.

Distribution

Plasma protein binding >99.5% (mainly albumin and alpha-1-acid glycoprotein). The average value of the apparent volume of distribution at equilibrium is 500 l.

Metabolism

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

Removal

T1/2 is more than 20 hours. Cmax and, to a lesser extent, AUC values ​​increase disproportionately with dose. There is no data on clinically significant accumulation of telmisartan. Excreted through the intestines unchanged, excretion by the kidneys is less than 1%. Total plasma clearance is high (approximately 1000 ml/min) compared to hepatic blood flow (approximately 1500 ml/min).

Special patient groups

Elderly patients

In elderly patients, there is a tendency to decrease the clearance of amlodipine, which leads to an increase in AUC and T1/2 values.

The pharmacokinetics of telmisartan do not differ between elderly and young patients.

Renal dysfunction

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

Telmisartan binds to plasma proteins and is not removed by hemodialysis in patients with renal failure. The plasma concentration of telmisartan in patients with renal failure is doubled. However, in patients on hemodialysis, lower concentrations of telmisartan are observed, T1/2 does not change.

Liver dysfunction

In patients with hepatic impairment, the clearance of amlodipine was reduced, resulting in an increase in AUC by approximately 40-60%.

Pharmacokinetic studies conducted in patients with impaired liver function showed that the absolute bioavailability of telmisartan increases to almost 100%. T1/2 does not change in patients with impaired liver function.

Special instructions

Amlodipine

Cardiovascular diseases

The effectiveness and safety of amlodipine in hypertensive crisis has not been established.

In acute myocardial infarction, the use of amlodipine is possible only after stabilization of hemodynamic parameters.

In rare cases, in patients with coronary artery disease (especially with severe obstructive lesions of the coronary arteries), an increase in the frequency, duration and/or severity of angina attacks was observed after starting the use of BMCC or after increasing their dosage.

Although in general BMCC should be used with caution in patients with CHF, amlodipine did not increase mortality or the incidence of cardiovascular events in patients with CHF in short- and long-term clinical studies. During the use of amlodipine in patients with CHF (III and IV functional class according to the NYHA classification) of non-ischemic origin, an increase in the incidence of pulmonary edema was observed, despite the absence of signs of progression of heart failure.

Aortic stenosis, mitral stenosis, HOCM

As with all drugs that have a vasodilating effect, amlodipine should be used with caution in patients with aortic stenosis, mitral stenosis or HOCM. In patients with left ventricular outflow tract obstruction (including severe aortic stenosis), the use of the drug is contraindicated.

Withdrawal syndrome

Despite the absence of withdrawal syndrome in BMCC, it is advisable to discontinue treatment with amlodipine by gradually reducing the dose of the drug. Amlodipine does not prevent the development of withdrawal syndrome after abrupt cessation of beta-blockers.

Peripheral edema

Mild to moderate peripheral edema was the most common adverse event reported with amlodipine in clinical studies. The incidence of peripheral edema increases with increasing dose (when using amlodipine at a dose of 2.5 mg, 5 mg and 10 mg per day, edema occurred in 1.8%, 3% and 10.8% of patients, respectively). Peripheral edema associated with the use of amlodipine should be carefully differentiated from symptoms of progression of left ventricular heart failure.

Liver dysfunction

Controlled studies have not been conducted in patients with impaired liver function. In a small number of patients with mild to moderate liver failure, an increase in T1/2 of amlodipine was noted. Patients with liver failure, if it is necessary to use amlodipine, should be under medical supervision. In some cases (for example, with moderate liver failure), the use of a lower initial dose of amlodipine (2.5 mg per day) is recommended.

Elderly patients

In elderly patients, T1/2 may increase and amlodipine clearance may decrease. In clinical studies, the incidence of AEs in patients aged >65 years was approximately 6% higher than in younger patients. No changes in amlodipine doses are required, but more careful monitoring of patients in this category is necessary.

Other

During amlodipine therapy, it is necessary to monitor body weight and salt intake, and the appointment of an appropriate diet is indicated.

It is necessary to maintain dental hygiene and follow-up with a dentist (to prevent pain, bleeding and gum hyperplasia).

Telmisartan

Pregnancy

ARA II should not be started during pregnancy. Unless continued treatment is considered necessary, in patients planning pregnancy, these drugs should be replaced with alternative antihypertensive drugs that have an established safety profile for use during pregnancy. If pregnancy is diagnosed, treatment with ARA II should be stopped immediately and, if necessary, alternative treatment initiated.

Renovascular hypertension

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

Double blockade of the RAAS

There is evidence that the simultaneous use of ACE inhibitors, ARB II or aliskiren increases the risk of arterial hypotension, hyperkalemia and decreased renal function (including acute renal failure). Therefore, double blockade of the RAAS by combined use of ACE inhibitors, ARB II or aliskiren is not recommended.

If dual blockade of the RAAS is considered necessary, it should only be performed under specialist supervision and subject to careful monitoring of renal function, electrolyte concentrations and blood pressure.

The simultaneous use of ARA II with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients.

The simultaneous use of ACE inhibitors and ARB II is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Other conditions characterized by activation of the RAAS

In cases where vascular tone and renal function depend primarily on the activity of the RAAS (for example, in patients with CHF or kidney diseases, including renal artery stenosis), the prescription of drugs that affect it may be accompanied by the development of acute arterial hypotension, hyperazotemia, oliguria, and, in rare cases, acute renal failure.

Liver failure

Telmisartan should not be used in patients with cholestasis, biliary obstruction or severe liver dysfunction (Child-Pugh class C), since telmisartan is excreted primarily in the bile. It is assumed that in such patients the hepatic clearance of telmisartan is reduced.

Primary hyperaldosteronism

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

Diabetes mellitus

In patients with diabetes mellitus with additional cardiovascular risk (i.e., with concomitant CAD), the risks of fatal myocardial infarction and sudden cardiovascular death may be increased when treated with antihypertensive agents such as II receptor antagonists and ACE inhibitors.

When using telmisartan in patients with diabetes mellitus receiving insulin or other hypoglycemic drugs, hypoglycemia may occur. Therefore, appropriate monitoring of blood glucose concentrations should be considered in such patients; Dosage adjustments of insulin or hypoglycemic medications may be required if necessary.

Hyperkalemia

During treatment with drugs that affect the RAAS, especially in the presence of impaired renal function and/or heart failure, hyperkalemia may occur. Hyperkalemia may be fatal in elderly patients, in patients with renal impairment, in patients with diabetes mellitus, in patients concomitantly receiving other drugs that may increase serum potassium levels, and/or in patients with intercurrent events.

Before considering the possibility of simultaneous use of drugs that affect the RAAS, it is necessary to assess the benefit-risk ratio. The main risk factors for the development of hyperkalemia are:

diabetes mellitus, renal dysfunction, age (>70 years);
combination with one or more other drugs that affect the RAAS and/or nutritional supplements containing potassium. Drugs or therapeutic classes of drugs that may precipitate hyperkalemia include potassium salts, potassium-sparing diuretics, ACE inhibitors, ARBs, NSAIDs (including selective COX-2 inhibitors), heparin, immunosuppressants (cyclosporine or tacrolimus), and trimethoprim;
intercurrent events, in particular, dehydration, acute cardiac decompensation, metabolic acidosis, deterioration of renal function, sudden deterioration of renal disease (eg, infectious diseases), cell lysis (eg, limb ischemia, rhabdomyolysis, major trauma).

In these patients, serum potassium levels should be carefully monitored.

Amlodipine + telmisartan

Liver failure

Telmista® AM should be used with caution in patients with liver failure.

Renal dysfunction and conditions after kidney transplantation

There is no experience with the use of a combination drug containing amlodipine and telmisartan in patients who have recently undergone kidney transplantation. Amlodipine and telmisartan are not removed by hemodialysis. In patients with impaired renal function, periodic monitoring of potassium levels and serum creatinine concentrations is recommended.

Reduced blood volume and/or hyponatremia

Due to limited salt intake, intensive diuretic therapy, diarrhea or vomiting, symptomatic arterial hypotension may develop, especially after taking the first dose of the drug. Before using Telmista® AM, such conditions require correction. If arterial hypotension occurs during the use of Telmista® AM, the patient should be placed in the supine position and, if necessary, intravenous saline should be administered. Treatment can be continued after blood pressure has stabilized.

Stenosis of the aortic and mitral valves, HOCM

In patients with aortic or mitral stenosis or HOCM, the use of Telmista® AM, as well as other vasodilators, requires special caution.

Unstable angina, acute myocardial infarction

There is no data on the use of Telmista® AM in patients with unstable angina, in the acute period and within one month after myocardial infarction.

Other

A marked decrease in blood pressure in patients with ischemic cardiomyopathy or coronary artery disease can lead to the development of myocardial infarction or stroke.

The drug Telmista® AM is effective in the treatment of patients of the Negroid race (in this population, renin activity in the blood plasma is usually reduced).

Special information on excipients

The composition of the drug Telmista® AM, along with other excipients, includes sorbitol and lactose monohydrate (see section “Composition”), and therefore its use is contraindicated in patients with fructose intolerance, galactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

Impact on the ability to drive vehicles and machinery

Studies of the effect on the ability to drive vehicles and machinery have not been conducted. However, it should be taken into account that adverse reactions such as fainting, drowsiness or dizziness may occur during treatment. Therefore, caution should be exercised when operating vehicles or machinery. If patients experience these sensations, they should avoid performing potentially dangerous activities such as driving vehicles or using machinery.

Active ingredient

Amlodipine, Telmisartan

Composition

For 1 tablet:

First layer

Active ingredient: telmisartan 40.00 mg

Excipients: meglumine, sodium hydroxide, povidone K30, lactose monohydrate, sorbitol, yellow iron oxide dye (E172), magnesium stearate, sodium stearyl fumarate

Second layer

Active ingredient: amlodipine besilate 6.94 mg, equivalent to amlodipine 5.00 mg

Excipients: mannitol, colloidal silicon dioxide, stearic acid

Pregnancy

Telmista® AM is contraindicated during pregnancy and breastfeeding.

There have been no special studies of the combination drug amlodipine and telmisartan during pregnancy and breastfeeding. The effects associated with taking individual components of the drug are described below.

Pregnancy

Amlodipine

The limited data available regarding the effects of amlodipine or other CBMCs do not indicate adverse effects on the fetus. However, there may be a risk of labor slowing down.

Telmisartan

The use of ARA II is contraindicated during pregnancy. If pregnancy is diagnosed, telmisartan should be stopped immediately. If necessary, alternative therapy should be used.

Preclinical studies of telmisartan did not reveal teratogenic properties, but established the presence of fetotoxicity. It is known that the use of ARA II during the II and III trimesters of pregnancy has a fetotoxic effect (decreased renal function, oligohydramnios, delayed ossification of the fetal skull), and neonatal toxicity (renal failure, arterial hypotension and hyperkalemia) is also observed.

When planning pregnancy, ARA II should be replaced with other antihypertensive drugs with an established safety profile during pregnancy (unless continued use of ARA II is considered necessary).

If ARA II is used during pregnancy, then, starting from the second trimester of pregnancy, an ultrasound scan is recommended to monitor kidney function and the condition of the fetal skull.

Newborns whose mothers received ARA II should be carefully monitored for the development of arterial hypotension.

Breastfeeding period

Amlodipine

Amlodipine is excreted into human breast milk. In women with pregnancy-associated hypertension receiving amlodipine at an initial dosage of 5 mg per day, the mean milk/plasma ratio for amlodipine concentration was 0.85 among 31 lactating women. The dosage of the drug was adjusted if necessary (the average daily dose of amlodipine and the dose depending on body weight were 6 mg and 98.7 mcg/kg, respectively). The estimated daily dose of amlodipine received by an infant through breast milk is 4.17 mcg/kg.

The use of amlodipine during breastfeeding is contraindicated. If it is necessary to use Telmista® AM during lactation, breastfeeding should be stopped.

Telmisartan

No special studies have been conducted on the excretion of telmisartan in breast milk in women. Animal studies have shown that telmisartan is excreted in the milk of lactating animals. Given the potential for adverse reactions, the decision to continue breastfeeding or discontinue therapy should be made taking into account its significance for the mother.

Effect on fertility

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

In some patients receiving BMCC, biochemical changes were detected in the head of the sperm. However, there is currently insufficient clinical data regarding the potential effect of amlodipine on fertility. A study in rats found undesirable effects on male fertility.

Contraindications

Hypersensitivity to amlodipine and/or telmisartan, as well as to any of the excipients (see section “Composition”),
Hypersensitivity to other dihydropyridine derivatives.
Fructose intolerance, galactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.
Pregnancy.
Breastfeeding period.
Age up to 18 years (efficacy and safety have not been established).
Obstructive diseases of the biliary tract.
Severe arterial hypotension (systolic blood pressure less than 90 mm Hg).
Left ventricular outflow tract obstruction (including severe aortic stenosis).
Hemodynamically unstable heart failure after acute myocardial infarction.
Shock (including cardiogenic shock).
Severe liver dysfunction (class C according to the Child-Pugh classification).
Concomitant use with aliskiren and drugs containing aliskiren in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area).
Concomitant use with ACE inhibitors in patients with diabetic nephropathy.
With caution

Chronic heart failure (CHF) of non-ischemic etiology of functional class III-IV according to the NYHA classification, coronary heart disease (CHD) with severe obstructive lesions of the coronary arteries, acute myocardial infarction (and within 1 month after it), unstable angina, aortic stenosis, mitral stenosis, idiopathic hypertrophic obstructive cardiomyopathy (HOCM), arterial hypotension, sick sinus syndrome (severe tachycardia, bradycardia), simultaneous use with inhibitors or inducers of the CYP3A4 isoenzyme (see section “Interaction with other drugs”), bilateral renal artery stenosis or stenosis of the artery of the only functioning kidney, mild to moderate renal dysfunction, condition after kidney transplantation (no experience with use), decreased circulating blood volume (CBV) by background of previous use of diuretics, restriction of salt intake, diarrhea or vomiting, hyponatremia, hyperkalemia, mild to moderate liver dysfunction.

Side Effects

The most common HPs include dizziness and peripheral edema. Serious syncope may occur in rare cases (less than 1 in 1000 patients).

HP registered based on experience with amlodipine and telmisartan used as monotherapy and when used simultaneously are presented in accordance with the World Health Organization (WHO) HP classification: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, < 1/1000), very rare (<1/10000), including isolated reports, frequency unknown (frequency cannot be estimated from available data).

HP are distributed among organs and systems in accordance with the MedDRA classification.

System-organ class
Junk
reaction
Amlodipine + telmisartan
Amlodipine
Telmisartan
Infectious and parasitic diseases
Urinary tract infections (including cystitis)
–
–
Uncommon
Upper respiratory tract infections, including pharyngitis and sinusitis
–
–
Uncommon
Sepsis, including death
–
–
Rarely
Cystitis
Rarely
–
–
Blood and lymphatic system disorders
Anemia
–
–
Uncommon
Eosinophilia
–
–
Rarely
Leukopenia
–
Very rarely
–
Thrombocytopenia
–
Very rarely
Rarely
Immune system disorders
Increased sensitivity
–
Very rarely
Rarely
Anaphylactic reaction
–
–
Rarely
Metabolic and nutritional disorders
Hyperkalemia
–
–
Uncommon
Hypoglycemia (in patients with diabetes).
–
–
Rarely
Hyperglycemia
–
Very rarely
–
Mental disorders
Mood lability
–
Uncommon
–
Confusion of knowledge
–
Rarely
–
Depression
Rarely
–
–
Anxiety
Rarely
–
–
Insomnia
Rarely
–
–
Nervous system disorders
Dizziness
Often
–
–
Drowsiness
Uncommon
–
–
Migraine
Uncommon
–
–
Headache
Uncommon
–
–
Paresthesia
Uncommon
–
–
Fainting
Rarely
–
–
Peripheral neuropathy
Rarely
–
–
Hypesthesia
Rarely
–
–
Dysgeusia
Rarely
–
–
Tremor
Rarely
–
–
Extrapyramidal syndrome
–
Very rarely
–
Visual disorders
Visual impairment
–
Uncommon
Rarely
Hearing and labyrinth disorders
Tinnitus
–
Uncommon
–
Vertigo
Uncommon
–
–
Heart disorders
Bradycardia
Uncommon
–
–
Feeling of heartbeat
Uncommon
–
–
Tachycardia
–
–
Rarely
Myocardial infarction
–
Very rarely
–
Heart rhythm disturbances
–
Very rarely
–
Ventricular tachycardia
–
Very rarely
–
Atrial fibrillation
–
Very rarely
–
Vascular disorders
Arterial hypotension
Uncommon
–
–
Orthostatic hypotension
Uncommon
–
–
Feeling of “hot flashes”
Uncommon
–
–
Vasculitis
–
Very rarely
–
Respiratory, thoracic and mediastinal disorders
Dyspnea
Rarely
Uncommon
Uncommon
Rhinitis
–
Uncommon
–
Cough
Uncommon
–
–
Interstitial lung disease
Very rarely
–
–
Digestive system disorders
Changing the rhythm of bowel movements
–
Uncommon
–
Flatulence
–
–
Uncommon
Abdominal pain
Uncommon
–
–
Diarrhea
Uncommon
–
–
Nausea
Uncommon
–
–
Vomit
Rarely
–
–
Gum hypertrophy
Rarely
–
–
Dryness of the oral mucosa
Rarely
–
–
Discomfort in the stomach area
–
–
Rarely
Pancreatitis
–
Very rarely
–
Gastritis
–
Very rarely
–
Disorders of the liver and biliary tract
Liver dysfunction
–
–
Rarely
Liver pathology
–
–
Rarely
Hepatitis
–
Very rarely
–
Jaundice
–
Very rarely
–
Increased activity of “liver” transaminases (mainly reflecting cholestasis)
–
Very rarely
–
Skin and subcutaneous tissue disorders
Hyperhidrosis
–
Uncommon
Uncommon
Alopecia
–
Uncommon
–
Purpura
–
Uncommon
–
Change in skin color
–
Uncommon
–
Itchy skin
Uncommon
–
–
Angioedema (fatal)
–
–
Rarely
Drug rash
–
–
Rarely
Toxic rash
–
–
Rarely
Eczema
Rarely
–
–
Erythema
Rarely
–
–
Angioedema
–
Very rarely
–
Hives
–
Very rarely
Rarely
Photosensitivity reactions
–
Very rarely
–
Erythema multiforme
–
Very rarely
–
Stevens-Johnson syndrome
–
Very rarely
–
Exfoliative dermatitis
–
Very rarely
–
Toxic epidermal necrolysis
–
Frequency
unknown
–
Musculoskeletal and connective tissue disorders
Arthralgia
Uncommon
–
–
Muscle spasms (calf cramps)
Uncommon
–
–
Myalgia
Uncommon
–
–
Pain in lower extremities
Rarely
–
–
Back pain
Rarely
–
–
Tendon pain (tendonitis-like symptoms)
–
–
Rarely
Renal and urinary tract disorders
Urinary dysfunction
–
Uncommon
–
Pollakiuria (frequent urination).
–
Uncommon
–
Renal dysfunction, including acute renal failure
–
–
Uncommon
Nocturia
Rarely
–
–
Disorders of the genital organs and breast
Gynecomastia
–
Uncommon
–
Erectile dysfunction
Uncommon
–
–
General and administration site disorders
Peripheral edema
Often
–
–
Pain
–
Uncommon
–
Asthenia
Uncommon
–
–
Chest pain
Uncommon
–
–
Fatigue
Uncommon
–
–
Edema
Uncommon
–
–
Malaise
–
Rarely
–
Flu-like syndrome
–
–
Rarely
Laboratory and instrumental data
Weight gain
–
Uncommon
–
Weight loss
–
Uncommon
–
Increased plasma creatinine concentration
–
–
Uncommon
Increased activity of “liver” enzymes in blood plasma
Uncommon
–
–
Increased activity of creatine phosphokinase (CPK) in blood plasma
–
–
Rarely
Decreased hemoglobin
–
–
Rarely
Increased concentration of uric acid in blood plasma
Rarely
–
–

Additional information regarding individual components

HP previously reported with the use of one of the components of the drug (amlodipine or telmisartan) may be increased when using their combination, even if they were not observed in clinical studies or in the post-marketing period.

Additional information about component combinations

Peripheral edema, a dose-dependent response to amlodipine, was observed less frequently in patients receiving the combination of amlodipine and telmisartan than in patients receiving amlodipine alone.

Interaction

There were no interactions between amlodipine and telmisartan in clinical studies. There have been no specific studies of drug interactions between the combination of amlodipine and telmisartan and other drugs.

Combination of active ingredients

Other antihypertensive drugs

When used simultaneously with other antihypertensive drugs, the antihypertensive effect of Telmista® AM may be enhanced.

Drugs that can lower blood pressure

Some drugs, for example, baclofen, amifostine, antipsychotics and antidepressants, due to their pharmacological properties, can be expected to enhance the antihypertensive effect of all antihypertensive drugs, including the combination drug Telmista® AM. In addition, orthostatic hypotension may be exacerbated by ethanol use.

Corticosteroids (systemic use)

The antihypertensive effect may be reduced.

Amlodipine

Concomitant use requiring precautions

CYP3A4 isoenzyme inhibitors

When used simultaneously with an inhibitor of the CYP3A4 isoenzyme (erythromycin) in young patients and with diltiazem in elderly patients, the concentration of amlodipine in the blood plasma increased by 22% and 50%, respectively. However, the clinical significance of this observation is unclear.

It cannot be excluded that more active inhibitors of the CYP3A4 isoenzyme (such as ketoconazole, itraconazole, ritonavir) may increase plasma concentrations of amlodipine to a greater extent than diltiazem. Amlodipine should be used with caution concomitantly with inhibitors of the CYP3A4 isoenzyme. However, no adverse effects associated with this interaction were noted.

Inducers of the CYP3A4 isoenzyme

With simultaneous use of known inducers of the CYP3A4 isoenzyme, the concentration of amlodipine in the blood plasma may vary. Therefore, it is necessary to monitor blood pressure and adjust the dose during and after concomitant treatment, especially with strong inducers of the CYP3A4 isoenzyme (for example, rifampicin, St. John’s wort preparations).

Grapefruit and grapefruit juice

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

The simultaneous use of Telmista® AM with grapefruit or grapefruit juice is not recommended, since in some patients the antihypertensive effect may be enhanced as a result of increased bioavailability of amlodipine.

Amiodarone and quinidine

Although negative inotropic effects have not generally been observed in amlodipine studies, some BMCCs may enhance the negative inotropic effects of antiarrhythmic drugs that prolong the QT interval.

Concomitant use to consider

Tacrolimus

There is a risk of increased tacrolimus concentrations when used concomitantly with amlodipine, but the pharmacokinetic mechanism of this interaction is not fully understood. To avoid tacrolimus toxicity, the use of amlodipine in patients receiving tacrolimus requires monitoring tacrolimus concentrations and adjusting the tacrolimus dose when necessary.

Cyclosporine

There have been no drug interaction studies of cyclosporine and amlodipine in healthy volunteers or other populations except renal transplant patients, in whom variable increases in cyclosporine trough concentrations were observed (average 0-40%). Consider monitoring cyclosporine concentrations in renal transplant patients receiving amlodipine, and reduce the dose of cyclosporine if necessary.

Simvastatin

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

Calcium preparations

Calcium supplements can reduce the effect of BMCC.

Lithium preparations

With the simultaneous use of BMCC (no data for amlodipine) with lithium preparations, it is possible to increase the manifestation of their neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus).

Other drugs

The safety of simultaneous use of amlodipine with digoxin, warfarin, atorvastatin, sildenafil, antacid drugs (aluminum hydroxide, magnesium hydroxide, simethicone), cimetidine, antibiotics and oral hypoglycemic drugs has been established.

With the simultaneous use of amlodipine and sildenafil, it was shown that each drug had an independent antihypertensive effect.

The simultaneous use of amlodipine with cimetidine did not have a significant effect on 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.

Mammalian target of rapamycin (mTOR) inhibitors

mTOR inhibitors such as sirolimus, temsirolimus and everolimus are substrates of the CYP3A isoenzyme. Amlodipine is a weak inhibitor of the CYP3A4 isoenzyme. When used concomitantly with mTOR inhibitors, amlodipine may increase their exposure.

Telmisartan

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

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

The simultaneous use of ARA II with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients.

The simultaneous use of ACE inhibitors and ARB II is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Concomitant use is not recommended

Potassium-sparing diuretics and salt substitutes containing potassium

II ARBs, such as telmisartan, reduce potassium losses caused by diuretics. The use of potassium-sparing diuretics, such as spironolactone, eplerenone, triamterene or amiloride, potassium supplements or potassium-containing salt substitutes, can lead to a significant increase in serum potassium levels. If their simultaneous use is necessary due to the presence of documented hypokalemia, then treatment should be carried out with caution and with frequent monitoring of serum potassium levels. If concomitant use is indicated due to documented hypokalemia, these drugs should be used with caution and serum potassium levels monitored regularly.

Lithium preparations

There was a reversible increase in the concentration of lithium in the blood plasma, accompanied by toxic effects, when taking ACE inhibitors. In rare cases, such changes have been reported with the administration of ARA II, in particular telmisartan. When prescribing lithium drugs and ARA II simultaneously, it is recommended to determine the concentration of lithium in the blood plasma.

Other antihypertensive drugs

The antihypertensive effect may be enhanced. In one study, with the combined use of telmisartan and ramipril, an increase in AUC0-24 and Cmax of ramipril and ramiprilat was observed by 2.5 times. The clinical significance of this interaction has not been established.

Concomitant use requiring precautions

Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid (at doses used as an anti-inflammatory drug), cyclooxygenase-2 (COE-2) inhibitors and non-selective NSAIDs may reduce the antihypertensive effect of ARB II.

In some patients with renal insufficiency (for example, dehydrated patients or elderly patients with renal insufficiency), concomitant use of ARB II and drugs that inhibit COX activity may lead to an additional deterioration of renal function, including the possible development of acute renal failure; these effects are usually reversible. Therefore, this combination should be used with caution, especially in elderly patients. Ensure that patients are adequately hydrated and renal function monitored after initiating concomitant use of these drugs and periodically thereafter.

Concomitant use to consider

Digoxin

With simultaneous use of telmisartan with digoxin, an increase in the median digoxin Cmax (49%) and residual digoxin concentration (20%) was observed. When initiating, adjusting doses and discontinuing telmisartan, the concentration of digoxin in the blood plasma should be monitored.

Overdose

Symptoms

No cases of overdose have been identified. Possible symptoms of overdose are listed from the symptoms of overdose of individual components of the drug.

Amlodipine – a pronounced decrease in blood pressure with the possible development of reflex tachycardia and symptoms of excessive peripheral vasodilation (risk of developing severe and persistent arterial hypotension, including the development of shock and death).

Telmisartan – tachycardia, possibly bradycardia, dizziness, increased serum creatinine concentration, acute renal failure.

Treatment

Hemodialysis is ineffective; amlodipine and telmisartan are not removed from the body during it.

Monitoring of the patient’s condition is required, therapy should be symptomatic and supportive.

Intravenous administration of calcium gluconate may be useful to relieve calcium channel blockade.

Treatment methods for overdose may include induction of vomiting, gastric lavage, use of activated charcoal, transferring the patient to the “lying with legs elevated” position and administration of plasma replacement solutions in case of a pronounced decrease in blood pressure.

Storage conditions

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

Keep out of the reach of children.

Shelf life

3 years.

Do not use the drug after the expiration date.

Manufacturer

KRKA dd Novo Mesto, Slovenia