Telzap AM, tablets 5 mg+40 mg 28 pcs

Pharmacotherapeutic group: combined hypotensive agent (slow calcium channel blocker + angiotensin II receptor antagonist).

ATX code: C09DB04.

Pharmacological properties

.strong>Pharmacodynamics

The drug Telzap^® AM has two hypotensive agents with complementary mechanisms of action that provide blood pressure (BP) control in patients with essential arterial hypertension; amlodipine belongs to the pharmacological group of “slow” calcium channel blockers (SCBs), and telmisartan belongs to the group of angiotensin II receptor antagonists (ARA II). The combination of these agents shows additive antihypertensive effect, causing a more pronounced BP reduction than each of the components of the drug individually.

Amlodipine

. Amlodipine is a dihydropyridine derivative, belongs to the class of BMCC, inhibits transmembrane entry of calcium ions into cardiomyocytes and smooth muscle cells of blood vessels. The mechanism of antihypertensive action of amlodipine is associated with vasodilatory action on vascular smooth muscle. The exact mechanism by which amlodipine reduces the frequency and severity of angina attacks is not fully established, but amlodipine may reduce myocardial ischemia through the following two effects:

1. amlodipine dilates peripheral arterioles and thereby reduces total peripheral vascular resistance (PPR), the so-called afterload. As heart rate (HR) when taking amlodipine practically does not increase, this reduction of heart muscle load reduces myocardial energy expenditure and myocardial oxygen demand.
2. the mechanism of antianginal action of amlodipine also seems to be related to the dilation of the main coronary arteries and arterioles, both in areas of myocardium with normal blood flow and in the ischemic areas. This dilation increases myocardial oxygen delivery in patients with coronary artery spasm (in Prinzmetal or variant angina).

In patients with arterial hypertension, taking amlodipine once daily provides clinically significant reduction of BP in “lying” and “standing” position for 24 h. Orthostatic arterial hypotension is not typical during the use of amlodipine due to the slow onset of action of the drug.

In patients with arterial hypertension and normal renal function, amlodipine at therapeutic doses leads to decreased renal vascular resistance and increased glomerular filtration rate and effective renal plasma blood flow without changing filtration or proterinuria.

No adverse metabolic effects or changes in plasma lipid concentrations have been observed when taking amlodipine. Amlodipine can be taken by patients with bronchial asthma, diabetes mellitus and gout. Amlodipine use in patients with heart failure is not accompanied with negative inotropic effect (does not decrease exercise tolerance and left ventricular ejection fraction).

Telmisartan

Mechanism of action

Telmisartan is a specific ARA II (type AT₁) that is effective when taken orally. Having a very high affinity for the binding center of the subtype AT₁ receptor to angiotensin II, telmisartan displaces angiotensin II from binding to the receptor without having an agonist effect against this receptor. Telmisartan does not exhibit the properties of a partial agonist for the AT₁ receptor. Telmisartan selectively binds to the AT₁ receptor. Binding to the receptor is long-lasting. Telmisartan shows no affinity for other receptors, including AT₂ receptors and other less studied angiotensin receptors. Telmisartan reduces plasma aldosterone concentrations and does not inhibit renin or block ion channels. Telmisartan does not inhibit the activity of angiotensin-converting enzyme (ACE) (kininase II), an enzyme that also destroys bradykinin. This leads to the conclusion that the drug will not increase adverse events associated with the action of bradykinin.

The dose of telmisartan 80 mg daily almost completely stops the increase in BP under the influence of angiotensin II. Antihypertensive effect persists for 24 h and remains significant for 48 h.

After the first dose of telmisartan, the antihypertensive effect develops gradually over 3 hours. A pronounced antihypertensive effect usually develops 4-8 weeks after regular use. The effect persists for 24 h after telmisartan administration and remains significant up to 48 h.

In patients with arterial hypertension, telmisartan provides a decrease in BP and BP with no effect on HR.

After abrupt withdrawal of telmisartan treatment, there is a gradual (over several days) return of BP to its pre-treatment values without development of “withdrawal” syndrome.

The incidence of dry cough was significantly lower in patients taking telmisartan than in patients receiving ACE inhibitors. These data were obtained in clinical studies directly comparing these two types of antihypertensive therapy.

The combination of amlodipine and telmisartan, administered once daily, results in an effective and sustained reduction of BP within 24 hours.

Pharmacokinetics

Amlodipine

Absorption

.p> After oral administration of amlodipine at therapeutic doses, maximum plasma concentrations are reached after 6-12 h. Absolute bioavailability of the drug is 64-80%. Food intake has no effect on bioavailability of amlodipine.

Distribution

The apparent volume of distribution (V_d) is approximately 21 l/kg. Studies in vitro have shown that about 97.5% of amlodipine circulating in the blood is bound to plasma proteins.

Biotransformation

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

Elimation

The T_½ of amlodipine from blood plasma is approximately 35-50 h, which confirms the possibility of its use once daily. The drug is excreted by the kidneys: 10% of the administered dose of the drug is eliminated as the parent compound and 60% as metabolites. Excretion of amlodipine from blood plasma is biphasic.

Particular patient populations

Patients with impaired liver function

There is very limited clinical data on the use of amlodipine in patients with impaired hepatic function. Decreased clearance of amlodipine has been observed in patients with hepatic impairment, resulting in a prolongation of T_½ and an increase in AUC of approximately 40-60%.

Elderly patients

The time to maximum plasma concentration (t_max) of amlodipine is comparable in elderly patients and in younger patients. In elderly patients the clearance rate of amlodipine tends to decrease with a corresponding increase in AUC and prolongation of T_½.

Telmisartan

absorption

Telmisartan is rapidly absorbed, but the amount absorbed may vary. The average absolute bioavailability of telmisartan is approximately 50%. When telmisartan is taken with food, the area under the “concentration-time” curve (AUC) decreases from approximately 6% (when telmisartan is taken at a dose of 40 mg per day) to 19% (at a dose of 160 mg per day). In
3 h after drug administration, telmisartan plasma concentrations level off, regardless of food intake.

Distribution

Telmisartan has a high degree of binding to plasma proteins
(> 99.5%), mainly to albumin and to alpha-1-acid glycoprotein. The average apparent volume of distribution in the equilibrium state (V_dss) is approximately 500 liters.

Biotransformation

The metabolism of telmisartan consists of conjugation of the parent compound with glucuronic acid. The resulting conjugate has no pharmacological activity.

Elimation

The elimination half-life (T_½) is more than 20 hours. Maximum plasma concentrations (C_max) and, to a lesser extent, AUC increase disproportionately with increasing dose. There are no data on clinically significant accumulation of telmisartan taken at recommended doses. It is excreted unchanged in the intestine, renal excretion is less than 1%. Total plasma clearance is high (about 1000 ml/min) compared to “hepatic” blood flow (about 1500 ml/min).

Linearity/nonlinearity of pharmacokinetics

A linear relationship between the drug dose and its plasma concentration was not observed. C_max and, to a lesser extent, AUC increase disproportionately when doses above 40 mg daily are used.

Special patient populations

Patient gender

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There were differences in plasma drug concentrations between males and females: C_max and AUC values were approximately 3 and 2 times higher in women than in men, respectively.

Elderly patients

The pharmacokinetics of telmisartan did not differ between elderly patients and patients younger than 65 years of age.

Patients with renal impairment

In patients with mild, moderate and severe renal impairment, a 2-fold increase in plasma telmisartan concentration was observed. However, in patients with renal impairment on hemodialysis, plasma concentrations of the drug were lower. Telmisartan is highly bound to plasma proteins and is not excreted by hemodialysis. T_½ was not altered in patients with impaired renal function.

Patients with impaired hepatic function

The results of pharmacokinetic studies have shown increased absolute bioavailability of telmisartan to almost 100% in patients with impaired hepatic function. T_½ was not altered in patients with impaired liver function.

Indications

• Arterial hypertension (in patients whose BP is not sufficiently controlled with telmisartan or amlodipine as monotherapy);
• Arterial hypertension in patients receiving telmisartan and amlodipine as separate monotherapies as a substitute for this therapy.

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Active ingredient

Amlodipine, Telmisartan

Composition

1 tablet 5 mg + 40 mg contains:

the active ingredients:

amlodipine – 5,000 mg (in the form of amlodipine besylate – 6.935 mg),

telmisartan – 40,000 mg;

excipients: sorbitol, sodium hydroxide, povidone K25, microcrystalline cellulose, calcium hydrophosphate dihydrate, meglumine, magnesium stearate.

How to take, the dosage

Ingestion, once daily, regardless of meals, with a small amount of liquid.

• Patients receiving amlodipine and telmisartan as separate tablets may be switched to Telzap® AM containing the same doses of active ingredients.
• Telzap^® AM may be used in patients in whom amlodipine alone or telmisartan alone does not adequately control BP.

Patients taking amlodipine at a dose of 10 mg who experience adverse reactions that limit the drug, such as peripheral edema, may switch to Telzap^® AM at a dose of 5 mg + 40 mg once daily, which will reduce the amlodipine dose but will not reduce the overall expected hypotensive effect.

• The treatment of arterial hypertension in a patient may be initiated with Telzap^® AM when it is believed that achieving BP control with any one drug is unlikely.

The starting dose of Telzap^® AM: 5 mg + 40 mg once daily.

Patients who require a greater reduction in blood pressure may start Telzap^® AM at a dose of 5 mg + 80 mg once daily.

If additional BP reduction is required, the dose of the drug may be gradually increased to a maximum of 10 mg + 80 mg, no earlier than 2 weeks after initiation of therapy.

The maximum daily dose: 10 mg amlodipine + 80 mg telmisartan.

Elderly patients (over 65 years): Dose adjustment is not necessary.

Patients with impaired renal function

Dose adjustment is not required in patients with mild to moderate renal impairment. There is limited experience with the drug in patients with severe renal impairment or who are on hemodialysis. In these patients, treatment with Telzap® AM should be performed with caution since amlodipine and telmisartan are not excreted by hemodialysis (see section “Caution”).

Patients with hepatic impairment

The dosage of Telzap® AM in patients with mild to moderate hepatic impairment requires caution (see section “Caution”). The daily dose of telmisartan should not exceed 40 mg. Telzap>® AM is contraindicated in patients with severe hepatic impairment (see sections “Contraindications”).

Children and adolescents

The use of Telzap^® AM in patients younger than 18 years is contraindicated due to insufficient data on safety and effectiveness of the drug in this age group.

Interaction

There have been no interactions between the two active ingredients of this drug in fixed doses in clinical studies.

There have been no studies of drug interactions of Telzap® AM with other drugs.

Interaction with amlodipine

TheEffect of other drugs on the pharmacological properties of amlodipine

CYP3A4 isoenzyme inhibitors

Concomitant use of amlodipine with potent or moderate CYP3A4 isoenzyme inhibitors (HIV protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, and verapamil or diltiazem) may be accompanied by a significant increase in systemic amlodipine exposure, thereby increasing the risk of severe BP reduction. Clinical manifestations of these concomitant use variants may be more pronounced in elderly patients, and medical supervision is required for possible correction of doses of the drugs.

Inductors of CYP3A4 isoenzyme

The concentration of amlodipine may vary with concomitant use of CYP3A4 isoenzyme inducers. BP should be monitored, the possibility of adjusting the dose of amlodipine during and after concomitant use should be considered, especially with strong inducers of CYP3A4 isoenzyme (such as rifampicin and preparations of St. John’s Wort).

Grapefruit and grapefruit juice

. Use of amlodipine with consumption of grapefruit or grapefruit juice is not recommended because in some patients this may increase the bioavailability of the drug and therefore increase the antihypertensive effect.

Dantrolene (by infusion)

The development of fatal ventricular fibrillation and cardiovascular collapse associated with hyperkalemia has been observed in animals receiving verapamil in combination with intravenous administration of dantrolene. Because of the risk of hyperkalemia, it is recommended to avoid the use of DMICs such as amlodipine concomitantly with dantrolene in patients susceptible to the development of malignant hyperthermia and for the treatment of this condition.

Influence of amlodipine on the pharmacological properties of other drugs

Amlodipine increases the effect of other hypotensive drugs.

Atorvastatin, digoxin and warfarin

In clinical studies of drug interactions, amlodipine had no effect on the pharmacokinetics of atorvastatin, digoxin and warfarin.

Cyclosporine

There have been no interaction studies of cyclosporine and amlodipine in healthy volunteers or in any other populations, except kidney transplant patients. In these patients, an increase in residual plasma concentrations of cyclosporine (by 0-40% on average) has been detected. In patients receiving amlodipine in combination with cyclosporine after kidney transplantation, it is recommended to monitor cyclosporine concentrations and reduce the dose if necessary.

Simvastatin

When multiple doses of amlodipine 10 mg and simvastatin 80 mg once daily were used simultaneously, the rate of systemic exposure to simvastatin was 77% higher than on simvastatin monotherapy. In patients taking amlodipine, the dose of simvastatin should not exceed 20 mg per day.

Tacrolimus

The co-administration of tacrolimus with amlodipine is characterized by the risk of increased plasma concentration of tacrolimus. Patients taking amlodipine should have their plasma tacrolimus concentrations monitored and, if necessary, the dose should be adjusted to avoid the toxic effects of tacrolimus.

Other drugs

. The safety of concomitant use of amlodipine with thiazide diuretics, beta-adrenoblockers, ACE inhibitors, long-acting nitrates, nitroglycerin (used sublingually), nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics and oral hypoglycemic agents has been established. When amlodipine and sildenafil were used concomitantly, each drug was shown to have an independent hypotensive effect.

Interaction with telmisartan

Digoxin

When telmisartan and digoxin were used concomitantly, there was a 49% increase in median C_max of digoxin and a 20% increase in its residual concentration. In the initial stages of digoxin administration, as well as during dose adjustments and treatment withdrawal, the drug concentrations in the body should be monitored to maintain them within the therapeutic range.

Drugs not recommended for concomitant use

Potassium-saving diuretics and potassium-containing supplements

ARA II, such as telmisartan, reduces diuretic-induced potassium loss. Potassium-saving diuretics, particularly spironolactone, eplerenone, triamterene, and amiloride, as well as potassium-containing supplements or salt substitutes, may cause significant increases in plasma potassium. In those cases where concomitant use of these drugs with telmisartan is required to eliminate confirmed hypokalemia, treatment should be undertaken with caution and with regular monitoring of plasma potassium.

Lithium preparations

The concomitant use of lithium preparations and ACE inhibitors or ARA II, including telmisartan, has been associated with cases of reversible increase in plasma lithium concentration and symptoms of toxicity. If concomitant use of telmisartan with lithium is necessary, increased monitoring of plasma lithium concentrations is recommended.

Drugs that should be used with caution./u>

Non-steroidal anti-inflammatory drugs (NSAIDs)

NSAIDs (acetylsalicylic acid in doses that provide anti-inflammatory effects, cyclooxygenase-2 (COX-2) inhibitors and non-selective NSAIDs) may impair the antihypertensive effect of APA II. In some patients with impaired renal function (in particular, in patients with dehydration or elderly patients with reduced renal function), concomitant use of APA II and COX-2 inhibitor drugs may lead to worsening of renal impairment, and in some cases, to acute renal failure, which is usually reversible. Therefore, treatment with these combinations of drugs requires caution, especially in elderly patients. The patient should have an adequate degree of hydration. Renal function monitoring is recommended before starting the drug combination, as well as regularly during treatment.

Ramipril

In a clinical study with concomitant use of telmisartan and ramipril, increased AUC_0-24 and C_max of ramipril and ramiprilat up to 2.5-fold. The clinical significance of this observation is unclear.

Diuretics (thiazide and loop drugs)

. Prior treatment with high doses of diuretics such as furosemide (loop diuretic) and hydrochlorothiazide (thiazide diuretic), as well as restriction of table salt intake, diarrhea, or vomiting may decrease BOD and increase the risk of excessive BP reduction during initial telmisartan therapy.

Drugs whose concomitant use requires increased attention

The effects of telmisartan may be enhanced by concomitant use of other hypotensive drugs.

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

. Clinical studies have demonstrated that dual RAAS blockade with combined ACE inhibitors, ARA II, or aliskiren has been associated with an increased incidence of adverse events such as decreased BP, hyperkalemia, and impaired renal function (including acute renal failure) when compared to monotherapy with an RAAS agent.

The concomitant use of the combination of amlodipine and telmisartan 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 (see section “Contraindications”).

The concomitant use of a combination of amlodipine and telmisartan with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Baclofen and amifostine

Given the pharmacological properties of some drugs (particularly baclofen and amifostine), they can be predicted to potentiate the effects of all hypotensive drugs, including telmisartan.

Alcohol, barbiturates, narcotics, and antidepressants

The risk of orthostatic hypotension may increase with alcohol use, as well as use of barbiturates, narcotics, or antidepressants.

Glucocorticoids (for systemic use)

The antihypertensive effect of telmisartan is impaired.