Amson-TE

Amson-TE

Amlodipine, Telmisartan

Arterial hypertension (for patients whose blood pressure is insufficiently controlled by telmisartan or amlodipine in monotherapy).

Arterial hypertension (for patients who are indicated for combination therapy).

Patients with arterial hypertension receiving telmisartan and amlodipine in the form of separate tablets (as a replacement for this therapy).

Inside, regardless of the meal, 1 time per day.

The drug Amson-TE^® it can be prescribed to patients receiving the same doses of telmisartan and amlodipine in the form of separate tablets, for the convenience of therapy and to increase adherence to treatment.

The drug Amson-TE^® it can be prescribed to patients in whom the use of one amlodipine or one telmisartan does not lead to adequate control of blood pressure.

Patients taking amlodipine at a dose of 10 mg, who have adverse reactions that limit the use of the drug, such as peripheral edema, can switch to taking the drug Amson-TE^® at a dose of 5 40 mg 1 time per day, which will reduce the dose of amlodipine, but will not reduce the overall expected hypotensive effect.

Treatment of arterial hypertension in a patient can begin with the use of the drug Amson-TE^® in the case when it is assumed that achieving control of blood pressure with any one drug is unlikely. The usual initial dose of Amson-TE^® - 5 40 mg 1 time per day. Patients who need a more significant reduction in blood pressure can start taking Amson-TE^® in a dose of 5 80 mg 1 time per day.

If at least 2 weeks of treatment require an additional reduction in blood pressure, the dose of the drug can be gradually increased to a maximum of 10 80 mg once a day.

The drug Amson-TE^® it can be used together with other antihypertensive drugs.

Special patient groups

Impaired renal function. In patients with impaired renal function, including patients on hemodialysis, changes in the dosage regimen of the drug are not required. Amlodipine and telmisartan are not removed from the body during hemodialysis.

Liver function disorders. In patients with mild to moderate hepatic insufficiency, the drug Amson-TE^® should be used with caution. The dose of telmisartan should not exceed 40 mg once a day.

Elderly patients. The dosage regimen does not require correction.

Children and adolescents under the age of 18. Data on the efficacy and safety of the amlodipine/telmisartan combination in children and adolescents under 18 years of age are not available.

hypersensitivity to telmisartan or amlodipine, dihydropyridine derivatives, or any of the excipients of the drug,

obstructive diseases of the biliary tract,

severe arterial hypotension (sBP less than 90 mmHg).),

left ventricular outflow tract obstruction (including severe aortic stenosis),

hemodynamically unstable heart failure after acute myocardial infarction,

severe hepatic insufficiency (class C on the Child-Pugh scale),

shock (including cardiogenic shock),

concomitant use with aliskiren in patients with diabetes mellitus or renal insufficiency (GFR <60 ml / min/1.73 m²),

fructose intolerance (due to the presence of sorbitol in the composition of the drug),

pregnancy,

breastfeeding period,

age under 18 (efficacy and safety not established).

With caution

The use of the drug requires careful medical supervision in the presence of the following conditions/diseases/risk factors:

chronic heart failure of non-ischemic etiology (III-IV functional class according to the classification NYHA),

coronary heart disease with severe obstructive coronary artery disease,

acute myocardial infarction (and the period within 1 month after it),

unstable angina,

aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy,

arterial hypotension,

sinus node weakness syndrome (pronounced tachycardia, bradycardia),

concomitant use with inhibitors or inducers of the CYP3A4 isoenzyme,

bilateral renal artery stenosis or stenosis of the artery to a solitary kidney,

mild to moderate renal or hepatic insufficiency,

conditions after kidney transplantation (due to lack of experience with the use of),

reduced BCC due to previous diuretic therapy, restricted salt intake, diarrhea, or vomiting,

hyponatremia, hyperkalemia.

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

Adverse reactions previously described when using one of the components (telmisartan or amlodipine) may also be potential side reactions when using the drug Amson-TE^®, even if they were not observed during clinical trials or during the post-registration period.

Within the system-organ classes, the following categories are used for the frequency of adverse reactions: very common (≥1/10), common (≥1/100, </10), infrequent (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), frequency unknown (cannot be calculated from available data).

Table

¹ Expected based on experience with telmisartan.

² Anticipated based on the experience with the use of amlodipine.

³ Expected with the simultaneous use of telmisartan and amlodipine.

Additional information on individual components. Adverse reactions previously reported with the use of one of the components of the drug (amlodipine or telmisartan) may increase with the use of Amson-TE^®, even if they were not observed in clinical trials or during the post-marketing period.

Additional information regarding the combination of components. Peripheral edema, a dose-dependent adverse reaction to amlodipine was observed in patients who received a combination of telmisartan and amlodipine, less often than in patients who received only amlodipine.

Symptoms: no cases of overdose have been identified. Possible symptoms of overdose consist of symptoms from the individual components of the drug.

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

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

Treatment: hemodialysis is ineffective. Monitoring of the patient's condition, therapy should be symptomatic and supportive.

In order to stop the blockage of the calcium channels, it is possible to inject calcium gluconate into/into the jet.

Methods of treating overdose can be used, such as induction of vomiting, gastric lavage, the use of activated charcoal, the transfer of the patient to a position with raised legs and the introduction of plasma-substituting solutions in the case of a pronounced decrease in blood pressure.

Amson-TE^® it is a combined drug containing 2 antihypertensive substances with a complementary effect that allows you to control blood pressure in patients with arterial (essential) hypertension: ARA II, telmisartan, and slow calcium channel blocker (BMCC), dihydropyridine derivative, amlodipine.

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

The drug Amson-TE^® Taken once a day, it leads to an effective and sustained reduction in blood pressure for 24 hours.

Telmisartan

Telmisartan-specific ARA II (type AT₁), effective when taken orally. It has a high affinity for the AT subtype₁- angiotensin II receptors, through which the action of angiotensin II is realized. Displaces angiotensin II from binding to the receptor, without having an agonist effect on this receptor. Telmisartan binds only to the AT subtype₁- angiotensin II receptors. The relationship is long-lasting. It has no affinity for other receptors, including AT₂- the receptor. Reduces the concentration of aldosterone in the blood, does not inhibit renin in the blood plasma and does not block ion channels. Telmisartan does not inhibit ACE (kininase II, an enzyme that also breaks down bradykinin). Therefore, an increase in the undesirable effects caused by bradykinin is not expected.

In patients, telmisartan at a dose of 80 mg completely blocks the hypertensive effect of angiotensin II. The onset of hypotensive action is noted within 3 hours after the first intake of telmisartan. The effect of the drug persists for 24 hours and remains significant up to 48 hours. Pronounced hypotensive effect usually develops in 4-8 weeks after regular administration.

In patients with arterial hypertension, telmisartan reduces the sAD and dBP, without affecting the heart rate.

In the 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 treated with telmisartan, compared with the use of ACE inhibitors.

In two large randomized controlled trials ONTARGET (Study of global endpoints when using telmisartan as part of monotherapy and in combination with ramipril) and VA NEPHRON-D (The Veterans Affairs Nephropathy in diabetes - a study of nephropathy in diabetes conducted by the U.S. Department of Veterans Affairs) studied the use of a combination of an ACE inhibitor in combination with ARA II.

Study ONTARGET The study was conducted in patients with a history of cardiovascular or cerebrovascular diseases or type 2 diabetes mellitus with confirmed target organ damage. Study VA NEPHRON-D This study was conducted in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies did not show a significant positive effect on renal and/or cardiovascular outcomes and mortality, while there was an increased risk of hyperkalemia, acute renal failure, and/or arterial hypotension compared to monotherapy. Given the similar pharmacodynamic properties, these results are also relevant for other ACE and ARA II inhibitors.

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

Study ALTITUDE (The aliskiren Use Study in patients with type 2 diabetes mellitus with assessment of cardiovascular and renal endpoints) was a study designed to test the benefits of adding aliskiren to standard treatment with an ACE inhibitor or ARA II in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated prematurely 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 and serious adverse events (hyperkalemia, hypotension, and impaired renal function) were more frequently reported in the aliskiren group than in the placebo group.

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

Amlodipine

Amlodipine is a dihydropyridine derivative and belongs to the BMCC class. It inhibits the transmembrane entry of calcium ions into cardiomyocytes and vascular smooth muscle cells.

The mechanism of antihypertensive action of amlodipine is associated with a direct relaxing effect on vascular smooth muscle cells, which leads to a decrease in peripheral vascular resistance and a decrease in blood pressure.

In patients with arterial hypertension, the use of amlodipine once a day provides a clinically significant reduction in blood pressure for 24 hours. Orthostatic hypotension is not typical during the use of amlodipine due to the slow onset of the drug.

In patients with arterial hypertension and normal renal function, amlodipine at therapeutic doses led to a decrease in renal vascular resistance, an increase in GFR, and an effective blood flow of plasma in the kidneys without changing filtration or proteinuria.

Amlodipine does not lead to any metabolic adverse effects or changes in the concentration of lipids in the blood plasma and is therefore 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 the ejection fraction of the left ventricle).

The pharmacokinetics of fixed-dose combination

The rate and degree of absorption of the drug Amson-TE^® they are equivalent to the bioavailability of telmisartan and amlodipine when used as separate tablets.

The pharmacokinetics of the individual components

Telmisartan

Suction. When taken orally, it is rapidly absorbed from the gastrointestinal tract. The absolute bioavailability of telmisartan is about 50%. When taken simultaneously with food, the decrease in AUC ranges from 6% (at a dose of 40 mg) to 19% (at a dose of 160 mg). After 3 hours after oral administration, the concentration in the blood plasma becomes similar to the concentration when taking telmisartan on an empty stomach.

Distribution. Communication with proteins of a blood plasma >99,5%, mainly to albumin and alpha₁ glycoprotein.

Average value of the visible V_ss - 500 l.

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

Output. T_1/2 is more than 20 h. C._max and to a lesser extent, the AUC increases disproportionately to the dose. There is no evidence of clinically significant accumulation of telmisartan when used at the recommended doses.

It is excreted through the intestine in an unchanged form, by the kidneys-less than 1%. Total plasma clearance is high (approximately 1000 ml/min) compared to hepatic blood flow (approximately 1500 ml/min).

Amlodipine

Suction. After taking amlodipine orally in therapeutic doses C_max in the blood plasma, they are reached after 6-12 hours. The absolute bioavailability ranges from 64 to 80%. Food intake does not affect the bioavailability of amlodipine.

Distribution. V_d amlodipine is approximately 21 l/kg. In research in vitro In patients with hypertension, approximately 97.5% of the circulating amlodipine is bound to plasma proteins.

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

Output. The elimination of amlodipine from the blood plasma occurs in two phases, T_1/2 it is approximately 30-50 hours. A stable concentration in the blood plasma is achieved after constant administration of the drug for 7-8 days. Amlodipine is excreted by the kidneys both in unchanged form (10%) and in the form of metabolites (60%).

Special patient groups

Old age. The pharmacokinetics of telmisartan in elderly patients does not differ from young patients. In elderly patients, there is a tendency to decrease the clearance of amlodipine, which leads to an increase in AUC and T_1/2.

Kidney failure. Telmisartan binds to plasma proteins and is not removed during hemodialysis in patients with renal insufficiency. In patients with renal insufficiency, the concentration of telmisartan in the blood plasma is doubled. However, patients on hemodialysis have lower concentrations of telmisartan, T_1/2 does not change. The pharmacokinetics of amlodipine in patients with impaired renal function does not significantly change.

Liver failure. Pharmacokinetic studies conducted in patients with impaired liver function have shown that the absolute bioavailability of telmisartan increases to almost 100%. T_1/2 in patients with impaired liver function, it does not change.

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

• Antihypertensive agent combined (blocker of" slow " calcium channels of angiotensin II receptors antagonist) [Angiotensin II receptor antagonists (AT₁- subtype) in combinations]

No interactions between amlodipine and telmisartan were found in clinical studies.

Special studies of drug interactions of the drug Amson-TE^® it was not carried out with other drugs.

Combination of active ingredients

Other antihypertensive agents. When used concomitantly with other antihypertensive drugs, the antihypertensive effect of Amson-TE^® it may increase.

Drugs that can reduce blood pressure. It can be expected that some drugs, such as baclofen, amifostin, neuroleptics and antidepressants, due to their pharmacological properties, will enhance the antihypertensive effect of all antihypertensive agents, including the drug Amson-TE^®. In addition, orthostatic hypotension may be enhanced by ethanol.

Corticosteroids (systemic use). It is possible to reduce the hypotensive effect.

Telmisartan

Joint use is not recommended

Potassium-sparing diuretics or potassium preparations. ARA II, such as telmisartan, reduces the loss of potassium caused by the use of diuretics. The use of potassium-sparing diuretics, such as spirinolactone, eplerenone, triamterene or amiloride, potassium preparations or potassium-containing salt can lead to a significant increase in the concentration of potassium in the blood serum. If concomitant use is indicated in connection with documented hypokalemia, these medications should be used with caution and frequent monitoring of serum potassium levels.

Lithium preparations. There was a reversible increase in the concentration of lithium in the blood, accompanied by toxic phenomena, when taking ACE inhibitors. In rare cases, such changes are registered when prescribing ARA II, in particular telmisartan. With the simultaneous administration of lithium and ARA II drugs, it is recommended to determine the content of lithium in the blood.

Other antihypertensive agents. It is possible to increase the hypotensive effect. In one study, the combined use of telmisartan and ramipril showed an increase in AUC_0–24 and C_max ramipril and ramiprilat 2.5 times. The clinical significance of this interaction has not been established.

Double blockade of RAAS (for example, co-administration of ACE inhibitors or aliskiren, a direct renin inhibitor with ARA II) it is not recommended due to possible renal impairment (including acute renal failure).

Joint use requiring precautionary measures

NSAIDs Including acetylsalicylic acid (in doses used as an anti-inflammatory agent), COX-2 inhibitors and non-selective NSAIDs, may reduce the severity of the antihypertensive effect of ARA II. In some patients with renal insufficiency (for example, patients with dehydration or elderly patients with renal insufficiency), the combined use of ARA II and drugs that inhibit the activity of COX can lead to 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 the elderly. Patients should be adequately hydrated, and kidney function should be monitored after the start of co-administration of these drugs and periodically thereafter.

Ramipril. In one study, the combined use of telmisartan and ramipril resulted in an increase in AUC values_0–24 and C_max ramipril and ramiprilat 2.5 times. The clinical significance of this observation is unknown.

Co-use that should be taken into account

Digoxin. When telmisartan was co-administered with digoxin, an increase in the median C was observed_max digoxin in the blood plasma (49%) and the residual concentration of digoxin (20%). During initiation, dose adjustment, and withdrawal of telmisartan, plasma digoxin concentrations should be monitored to maintain them within the therapeutic range.

Amlodipine

Joint use requiring precautionary measures

Inhibitors of the CYP3A4 isoenzyme. When combined with the CYP3A4 inhibitor erythromycin in young patients and diltiazem in elderly patients, the concentration of amlodipine in 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 the concentration of amlodipine in the blood plasma to a greater extent than diltiazem. Amlodipine should be used with caution in combination with inhibitors of the CYP3A4 isoenzyme. However, no adverse effects associated with this interaction were observed.

Inducers of the CYP3A4 isoenzyme. With the combined use of known inducers of CYP3A4, the concentration of amlodipine in the plasma may vary. Thus, it is necessary to control blood pressure and adjust the dose during and after concomitant treatment, especially with strong inducers of CYP3A4 (for example, rifampicin, preparations of St. John's wort (Hypericum perforatum).

Grapefruit and grapefruit juice. Concomitant administration of 240 ml of grapefruit juice in 20 healthy volunteers with a single dose of 10 mg of amlodipine taken orally did not significantly affect the pharmacokinetic properties of amlodipine.

Concomitant use of Amson-TE^® with grapefruit or grapefruit juice is not recommended, because in some patients, as a result of increased bioavailability of amlodipine, the antihypertensive effect may increase.

Co-use that should be taken into account

Tacrolimus. There is a risk of increased concentrations of tacrolimus when it is co-administered 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 dose of tacrolimus when necessary.

Cyclosporine. No studies of drug interactions between cyclosporine and amlodipine have been conducted in healthy volunteers or in other populations, with the exception of patients who underwent kidney transplantation, who had a variable increase in the residual concentration of cyclosporine (on average, 0-40%). The control of cyclosporine concentrations in amlodipine-treated kidney transplant patients should be considered, and the dose of cyclosporine should be reduced if necessary.

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

Other drugs. The safety of the combined use of amlodipine with digoxin, warfarin, atorvastatin, sildenafil, antacid drugs (aluminum hydroxide, magnesium hydroxide, simetikon), 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.

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