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 BP is not sufficiently controlled by amlodipine or telmisartan in monotherapy).

Arterial hypertension (for patients who are indicated for combination therapy). Patients with arterial hypertension receiving amlodipine and telmisartan as separate tablets as a substitute for this therapy.

Active ingredient

Amlodipine, Telmisartan

Composition

Per 1 tablet:

First layer

The active ingredient: telmisartan 40.00 mg

The excipients: Meglumine, sodium hydroxide, povidone K30, lactose monohydrate, sorbitol, iron oxide yellow dye (E172), magnesium stearate, sodium stearylfumarate

Second layer

Active substance: Amlodipine besylate 6.94 mg, equivalent to amlodipine 5.00 mg

Excipients: mannitol, colloidal silicon dioxide, stearic acid

How to take, the dosage

Ingestion, once daily, regardless of the time of meals.

The drug Telmist® AM may be administered:

• patients receiving the same doses of amlodipine and telmisartan as separate tablets for convenience of therapy and increased adherence;
• patients in whom use of amlodipine alone or telmisartan alone does not result in adequate BP control. Patients taking amlodipine at a dose of 10 mg who have HP that limits drug administration, such as peripheral edema, may be switched to Telmist® AM at a dose of 5 mg + 40 mg once daily, which will reduce the amlodipine dose but will not reduce the overall expected antihypertensive effect.
• for the treatment of arterial hypertension: therapy may be initiated with Telmist® AM when it is believed that achieving BP control with any single drug is unlikely. The usual starting dose of Telmist® AM is 5 mg + 40 mg once daily. Patients who require a more significant decrease in BP may start Telmist® AM at a dose of 5 mg + 80 mg once daily.

If, after at least 2 weeks of treatment, additional BP reduction is required, the dose of Telmist® AM may be gradually increased to a maximum dose of 10 mg + 80 mg once daily.

Telmista® AM may be used together with other hypotensive drugs.

Particular groups of patients

In patients with impaired renal function, including those on hemodialysis, no changes in dosing regimen are required. Amlodipine and telmisartan are not eliminated from the body by hemodialysis.

Hepatic disorders

In patients with mild to moderate hepatic impairment (Child-Pugh grades A and B), Telmist® AM should be used with caution. The dose of telmisartan should not exceed 40 mg once daily.

Elderly patients

Telmista® AM does not require dose adjustment when used in elderly patients.

Children and adolescents less than 18 years of age

Telmista® AM should not be indicated in children and adolescents less than 18 years of age because there are no data on efficacy and safety of amlodipine and telmisartan in these patient groups either in monotherapy or in combination therapy.

Interaction

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

Combination of active ingredients

Other hypotensive drugs

The antihypertensive effect of Telmist® AM may be enhanced when used concomitantly with other hypotensive drugs.

Drugs capable of lowering BP

Some drugs, such as baclofen, amifostine, neuroleptics, and antidepressants may be expected to increase the antihypertensive effects of all hypotensive agents, including the combination drug Telmista® AM, due to their pharmacological properties. In addition, orthostatic hypotension may be increased by the use of ethanol.

Corticosteroids (systemic use)

The antihypertensive effect may be reduced.

Amlodipine

Concurrent use requiring precautions

CYP3A4 isoenzyme inhibitors

Concomitant use with a CYP3A4 isoenzyme inhibitor (erythromycin) in young patients and with diltiazem in elderly patients increased plasma concentrations of amlodipine by 22% and 50%, respectively. However, the clinical significance of this observation is unclear.

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

CYP3A4 isoenzyme inducers

When concomitant use of known CYP3A4 isoenzyme inducers, plasma concentrations of amlodipine may vary. Thus, it is necessary to monitor BP and adjust the dose during and after concomitant treatment, especially with potent inducers of CYP3A4 isoenzyme (e.g., rifampicin, St. John’s Wort preparations).

Grapefruit and grapefruit juice

Concomitant administration in 20 healthy volunteers of 240 mL grapefruit juice with a single oral dose of amlodipine 10 mg had no significant effect on the pharmacokinetic properties of amlodipine.

The concomitant use of Telmist® AM with grapefruit or grapefruit juice is not recommended because the antihypertensive effect may be enhanced in some patients due to increased bioavailability of amlodipine.

Amiodarone and quinidine

While negative inotropic effects have not generally been observed in studies of amlodipine, however, some PBMCs may increase the severity of negative inotropic effects of antiarrhythmic agents that cause QT interval prolongation.

Simultaneous 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 studies of drug interactions between cyclosporine and amlodipine in healthy volunteers or in other populations, except in renal transplant patients who have had variable increases in residual cyclosporine concentrations (mean 0-40%). Consideration should be given to controlling cyclosporine concentrations in renal transplant patients receiving amlodipine, and to reducing cyclosporine doses if necessary.

Simvastatin

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

Calcium preparations

Calcium preparations may reduce the effect of BMCC.

Lithium preparations

The concomitant use of BMCC (no data for amlodipine) with lithium preparations may increase their neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus).

Other drugs

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

When amlodipine and sildenafil were used concomitantly, each drug was shown to have an independent antihypertensive effect.

The concomitant use of amlodipine with cimetidine had no significant effect on the pharmacokinetics of amlodipine. Concomitant use of amlodipine with atorvastatin, digoxin, warfarin or cyclosporine had no significant effect on the pharmacokinetics or pharmacodynamics of these drugs.

Inhibitors of mammalian mechanistic targeting of rapamycin (mTOR)

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

Telmisartan

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

p> Dual RAAS blockade (e.g., concomitant use of ACE inhibitors or aliskiren, a direct renin inhibitor with APA II) is not recommended because of possible renal dysfunction (including ARF).

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

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

Simultaneous use is not recommended

Caliberating diuretics and salt substitutes containing potassium

ARA II, such as telmisartan, reduces potassium loss caused by diuretic use. Use of potassium-saving diuretics such as spironolactone, eplerenone, triamterene, or amiloride, potassium preparations, or potassium-containing salt substitutes may result in a significant increase in serum potassium. If their concomitant use is necessary due to the presence of reported hypokalemia, treatment should be given with caution and with frequent monitoring of serum potassium. If concomitant use is indicated due to documented hypokalemia, these drugs should be used with caution and serum potassium should be monitored regularly.

Lithium preparations

There have been reversible increases in plasma lithium concentrations accompanied by toxic effects when using ACE inhibitors. In rare cases, similar changes have been registered when prescribing ARA II, in particular, telmisartan. When concomitant administration of lithium and ARA II it is recommended to determine plasma lithium concentration.

Other hypotensive agents

It is possible to increase the antihypertensive effect. In one study when telmisartan and ramipril were combined, there was a 2.5-fold increase in AUC0-24 and Cmax of ramipril and ramiprilat. The clinical significance of this interaction has not been established.

Concomitant use requiring precautionary measures

. Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid (in doses used as an anti-inflammatory agent), cyclooxygenase-2 inhibitors (COE-2) and non-selective NSAIDs may reduce the severity of ARA II antihypertensive effect.

In some patients with renal impairment (e.g., patients with dehydration or elderly patients with renal impairment) the simultaneous use of APA II and drugs that inhibit COX activity may lead to additional impairment of renal function, including possible development of ARF; these effects are generally reversible. Therefore, this combination should be used with caution, especially in elderly patients. Patients should be adequately hydrated, and renal function should be monitored after initiation of concomitant use of these drugs and periodically thereafter.

Simultaneous use to consider

Digoxin

Concomitant use of telmisartan with digoxin has shown an increase in median Cmax of digoxin (49%) and residual concentration of digoxin (20%). Plasma digoxin concentrations should be monitored when initiating, adjusting doses, and withdrawing telmisartan.

Special Instructions

Amlodipine

Cardiovascular disease

The efficacy and safety of amlodipine in hypertensive crisis have not been established.

In acute myocardial infarction, amlodipine may be used only after hemodynamic stabilization.

In rare cases in patients with CHD (especially with severe obstructive coronary artery disease) an increase in frequency, duration and/or severity of angina attacks has been noted after initiation of BMCC or after increasing their dosage.

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

Aortic stenosis, mitral stenosis, GOCMP

Like all drugs with vasodilator effect, amlodipine should be used with caution in patients with aortic stenosis, mitral stenosis or GOCMP. In patients with left ventricular outflow tract obstruction (including severe aortic stenosis) the use of the drug is contraindicated.

While there is no withdrawal syndrome with BMCC, it is advisable to discontinue amlodipine treatment by gradually reducing the dose of the drug. Amlodipine does not prevent abrupt withdrawal from beta-adrenoblockers.

Peripheral edema

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

Hepatic impairment

There have been no controlled studies in patients with hepatic impairment. In a small number of patients with mild to moderate hepatic impairment, an increased T1/2 of amlodipine has been observed. Patients with hepatic insufficiency should be under medical supervision if amlodipine should be used. In some cases (e.g., in moderate hepatic insufficiency) a lower initial dose of amlodipine (2.5 mg per day) is recommended.

Elderly patients

In elderly patients the T1/2 may increase and the clearance of amlodipine may decrease. In clinical trials, the incidence of NS in patients aged >65 years was approximately 6% higher than in younger patients. No change in amlodipine doses is required, but closer monitoring of patients in this category is necessary.

Other

At the time of amlodipine therapy, body weight and table salt intake should be controlled and an appropriate diet should be prescribed.

Tooth hygiene and dental care should be monitored (to prevent soreness, bleeding, and gum hyperplasia).

Telmisartan

Pregnancy

The use of APA II should not be started during pregnancy. Unless continued treatment is deemed unnecessary, in patients planning to become pregnant, these medications should be replaced with alternative antihypertensive medications that have a studied safety profile for use during pregnancy. If pregnancy is diagnosed, treatment with ARA II should be discontinued immediately and, if necessary, alternative treatment should be initiated.

Renovascular arterial hypertension

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

Double RAAS blockade

There is evidence that concomitant use of ACE inhibitors, ARA II or aliskiren increases the risk of arterial hypotension, hyperkalemia and decreased renal function (including ARF). Therefore, dual RAAS blockade by combined use of ACE inhibitors, ARA II or aliskiren is not recommended.

If dual RAAS blockade is considered necessary, it should only be performed under the supervision of a specialist and with close monitoring of renal function, electrolyte concentrations and BP.

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

The concomitant use of ACE inhibitors and ARA 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 of dependence of vascular tone and renal function mainly on the activity of RAAS (for example, in patients with CHF or renal diseases, including renal artery stenosis) administration of drugs affecting it can be accompanied by development of acute arterial hypotension, hyperazotemia, oliguria, and, in rare cases, ARF.

Hepatic failure

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

Primary hyperaldosteronism

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

Diabetes

In patients with diabetes mellitus with additional cardiovascular risk (i.e., with concomitant CHD), the risks of fatal myocardial infarction and sudden cardiovascular death may be increased by treatment with hypotensive agents such as ARA II and ACE inhibitors.

Hypoglycemia may occur in patients with diabetes mellitus receiving insulin or other hypoglycemic drugs when telmisartan is used. Therefore, proper monitoring of blood glucose concentrations should be considered in such patients; adjustments to the dose of insulin or hypoglycemic medications may be required if necessary.

Hyperkalemia

Hyperkalemia may occur during treatment with drugs that affect the RAAS, especially in the presence of renal dysfunction and/or heart failure. Hyperkalemia can be fatal in elderly patients, in patients with renal insufficiency, in patients with diabetes mellitus, in patients simultaneously receiving other medicinal products which can increase potassium content in serum, and/or in patients with intercurrent events.

Before considering concomitant use of medications that affect the RAAS, the benefit-risk ratio should be evaluated. The main risk factors for hyperkalemia are:

• diabetes mellitus, impaired renal function, age (>70 years);
• combination with one or more other drugs that affect the RAAS and/or dietary supplements containing potassium. Drugs or therapeutic classes of drugs that may provoke hyperkalemia include salts containing potassium, potassium-saving diuretics, ACE inhibitors, ARA II, NSAIDs (including selective COX-2 inhibitors), heparin, immunosuppressants (cyclosporine or tacrolimus), and trimethoprim;
• intercurrent events, particularly dehydration, acute cardiac decompensation, metabolic acidosis, impaired renal function, sudden renal deterioration (eg, infectious diseases), cellular lysis (eg, limb ischemia, rhabdomyolysis, extensive trauma).

Serum potassium should be carefully monitored in these patients.

Amlodipine + telmisartan

Hepatic impairment

Telmista® AM should be used with caution in patients with hepatic impairment.

Kidney function impairment and conditions after renal transplantation

There is no experience with the combined drug containing amlodipine and telmisartan in patients who have recently undergone renal transplantation. Amlodipine and telmisartan are not excreted by hemodialysis. Periodic monitoring of potassium and serum creatinine concentrations is recommended in patients with impaired renal function.

Decreased RBC and/or hyponatremia

Symptomatic arterial hypotension may develop due to restriction of table salt intake, intensive diuretic therapy, diarrhea or vomiting, especially after the first dose of the drug. Such conditions require correction before using the drug Telmist® AM. If arterial hypotension occurs during the use of the drug Telmist® AM, the patient should be laid on his back and, if necessary, intravenous administration of saline solution should be administered. The treatment may be continued after BP stabilization.

Aortic and mitral valve stenosis, GOCMP

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

Instable angina, acute myocardial infarction

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

Other

A pronounced decrease in BP in patients with ischemic cardiomyopathy or CHD may lead to myocardial infarction or stroke.

The drug Telmist® AM is effective in treating patients of the Negro race (plasma renin activity is generally reduced in this population).

Special information about excipients

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

Influence on the ability to drive vehicles, mechanisms

Studies on the effect on the ability to drive vehicles, mechanisms have not been conducted. However, it should be taken into account that HP such as fainting, drowsiness or dizziness may be noted during treatment. Therefore, caution should be exercised while driving vehicles or operating mechanisms. If patients experience these sensations, they should avoid performing potentially dangerous activities such as driving vehicles, mechanisms.

Contraindications

• High sensitivity to amlodipine and/or telmisartan as well as to any of the excipients (see Composition).
• High sensitivity to other dihydropyridine derivatives.
• Fructose intolerance, galactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.
• Pregnancy.
• Breastfeeding period.
• Age under 18 years of age (effectiveness and safety not established).
• Biliary obstructive disease.
• Severe arterial hypotension (systolic BP less than 90 mmHg. Left ventricular outflow tract obstruction (including severe aortic stenosis).
• Hemodynamically unstable heart failure after acute myocardial infarction.
• Shock (including cardiogenic shock).
• Severe hepatic dysfunction (Child-Pugh class C).
• Simultaneous use with aliskiren and drugs containing aliskiren in patients with diabetes and/or moderate to severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area).
• Simultaneous use with ACE inhibitors in patients with diabetic nephropathy.

Cautions

Chronic heart failure (CHF) of non-ischemic etiology of NYHA functional class III-IV, coronary heart disease (CHD) with severe obstructive coronary artery disease, acute myocardial infarction (and within 1 month after it), unstable angina aortic stenosis, mitral stenosis, idiopathic hypertrophic obstructive cardiomyopathy (HICMP), arterial hypotension, sinus node weakness syndrome (significant tachycardia, bradycardia), concomitant use with CYP3A4 inhibitors or inducers (see sect. section “Interaction with other medicinal products”), bilateral renal artery stenosis or artery stenosis of the only functioning kidney, mild to moderate renal function impairment, conditions after renal transplantation (no experience of use), reduction of circulating blood volume (CBC) with previous diuretic use, restricted intake of table salt, diarrhea or vomiting, hyponatremia, hyperkalemia, mild to moderate liver function impairment.

Side effects

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

The HP reported based on experience with amlodipine and telmisartan used as monotherapy and with their concomitant use are presented according to the World Health Organization (WHO) HP classification: Very common (≥1/10), common (≥1/100, < 1/10), infrequent (≥1/1000, < 1/100), rare (≥1/10000, < 1/1000), very rare (< 1/10000), including individual reports, frequency unknown (frequency cannot be estimated from available data).

The HPs are distributed among organs and systems according to the MedDRA classification.

Additional information regarding individual components

HP previously reported with one component of the drug (amlodipine or telmisartan) may be enhanced with their combination, even if not observed in clinical trials or in the post-registration period.

Further information on the combination of the components

Peripheral edema, a dose-dependent HP on amlodipine use, was observed less frequently in patients who received a combination of amlodipine and telmisartan than in patients who received amlodipine alone.

Overdose

Symptoms

There have been no identified cases of overdose. Possible symptoms of overdose are given from the symptoms of overdose of individual components of the drug.

Amlodipine – marked BP decrease with possible development of reflex tachycardia and symptoms of excessive peripheral vasodilation (risk of severe and persistent arterial hypotension, including development of shock and death).

Telmisartan – tachycardia, possible bradycardia, dizziness, increased serum creatinine concentration, ARF.

Treatment

Hemodialysis is ineffective; amlodipine and telmisartan are not eliminated from the body when it is performed.

Control of the patient’s condition is required; therapy must be symptomatic and supportive.

In order to stop calcium channel blockade, intravenous administration of calcium gluconate may be useful.

Induction of vomiting, gastric lavage, activated charcoal, elevated position, and plasma exchange solutions if there is a significant decrease in BP may be indicated.

Pregnancy use

Telmista® AM is contraindicated in pregnancy and during breastfeeding.

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

Pregnancy

Amlodipine

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

Telmisartan

The use of APA II is contraindicated in pregnancy. If pregnancy is diagnosed, telmisartan should be discontinued immediately. Alternative therapy should be used if necessary.

Preclinical studies of telmisartan showed no teratogenic properties, but found fetotoxicity. The use of APA II during the second and third trimesters of pregnancy is known to have fetotoxic effects (decreased renal function, oligohydramnios, delayed fetal skull ossification) and neonatal toxicity (renal failure, arterial hypotension and hyperkalemia) has been observed.

ARA II should be replaced with other hypotensive agents with an established safety profile in pregnancy if pregnancy is planned (unless continued use of ARA II is deemed necessary).

If APA II is used during pregnancy, an ultrasound scan is recommended beginning in the second trimester of pregnancy to monitor renal function and the fetal skull.

Newborns whose mothers have received APA II should be closely monitored with respect to the development of arterial hypotension.

The period of breastfeeding

Amlodipine

Amlodipine is excreted in women’s breast milk. In women with pregnancy-related arterial hypertension receiving amlodipine at an initial dose of 5 mg daily, the mean milk/plasma ratio for amlodipine concentration was 0.85 among 31 breastfeeding women. The dosage of the drug was adjusted as necessary (the mean daily dose of amlodipine and the weight-dependent dose were 6 mg and 98.7 mcg/kg, respectively). The estimated daily dose of amlodipine received by the infant via breast milk is 4.17 mcg/kg.

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

Telmisartan

There have been no specific studies on excretion of telmisartan with breast milk in women. Animal studies have found that telmisartan is excreted with 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 relevance to the mother.

Influence on fertility

There have been no studies of the effect on human fertility.

Biochemical changes in the sperm head have been found in some patients receiving BMCC. However, there is currently insufficient clinical data regarding the potential effect of amlodipine on fertility. In a study in rats, adverse effects on fertility in males were found.

Similarities

Twinsta, Telzap