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

Active ingredient

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 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 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 Cmax 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 AUC0-24 and Cmax 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

Special Instructions

Amlodipine

Patients with Chronic Heart Failure

. In a long-term placebo-controlled study (PRAISE-2) in patients with CHF of functional class III-IV (NYHA classification) nonischemic etiology, use of amlodipine was associated with increased reports of pulmonary edema, despite no significant difference in the rate of heart failure progression compared with placebo. Caution should be exercised when using BMCCs, including amlodipine, in patients with CHF because of the possible risk of other cardiovascular complications and mortality.

Hepatic disorders

As with other BMCCs, the T½ of amlodipine is increased in patients with hepatic dysfunction. Therefore, Telzap® AM should be used with caution in such patients (see section “Caution”) and the dose of telmisartan should not exceed 40 mg once daily. In patients with severe hepatic impairment, Telzap® AM is contraindicated (see sections “Contraindications”).

Kidney function disorders

In patients with impaired renal function amlodipine may be used in normal doses. Changes in amlodipine plasma concentrations did not correlate with the severity of renal function impairment. Amlodipine is not excreted during dialysis.

Elderly patients

Dose adjustment of Telzap® AM in elderly patients is not necessary. Increasing the dose should be done with caution (see section “Caution”).

Children

The safety and effectiveness of Telzap® AM in children has not been established at this time.

Sorbitol

This drug contains sorbitol (E 420). In patients with rare hereditary fructose intolerance the use of Telzap® AM is contraindicated (see section “Contraindications”).

Telmisartan

Hepatic dysfunction

The use of amlodipine + telmisartan combination is contraindicated in patients with cholestasis, biliary obstruction and/or severe hepatic impairment because telmisartan is mostly excreted with bile (see See section “Contraindications”). There is reason to believe that hepatic clearance of telmisartan is reduced in these patients. Caution should be exercised when using the drug in patients with mild to moderate hepatic dysfunction.

Renovascular Hypertension

Patients with bilateral renal artery stenosis or artery stenosis of the only functioning kidney have an increased risk of significant BP reduction and acute renal failure when treated with drugs acting on the RAAS.

Disordersof renal function and renal transplantation

When using telmisartan in patients with impaired renal function, periodic monitoring of plasma potassium, creatinine is recommended. There is no experience of using the drug in patients who have undergone kidney transplantation shortly before use. Telmisartan is not excreted by dialysis.

Decrease in circulating blood volume (CBC)

A decrease in BP, especially after the first administration of Telzap® AM, may occur in patients with decreased RBC and/or low plasma sodium levels on the background of prior diuretic treatment, restricted intake of table salt, diarrhea or vomiting. Such conditions (fluid and/or sodium deficiency) should be eliminated prior to initiation of Telzap® AM.

Double RAAS blockade

The data on concomitant use of ACE inhibitors with ARA II or with drugs containing aliskiren confirm the increased risk of severe BP decrease, development of hyperkalemia and decreased renal function (including acute renal failure).

The concomitant use of ARA II with drugs containing aliskiren is contraindicated in patients with diabetes and/or with moderate or severe renal impairment (FFR less than 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients. If dual RAAS blockade is necessary, each case should be considered individually and renal function, water-electrolyte balance and BP values should be carefully monitored.

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

There have been cases of arterial hypotension, syncope, hyperkalemia, and renal dysfunction (including development of acute renal failure) in prone patients against the background of RAAS blockade, especially when concomitant use of drugs acting on RAAS. Therefore, dual RAAS blockade (in particular, concomitant use of telmisartan with other RAAS blockers) is not recommended. If simultaneous use of several RAAS blockers is necessary, renal function should be monitored carefully.

Otherconditionsrelated to RAAS stimulation

. In patients whose vascular tone and renal function are predominantly dependent on RAAS activity (e.g., patients with severe chronic heart failure or existing renal disease, including renal artery stenosis), the use of drugs acting on this system, such as telmisartan, is associated with the occurrence of acute BP decrease, hyperazotemia, oliguria, or rarely with the development of acute renal failure (see section “Caution”).

Primary hyperaldosteronism

In patients with primary hyperaldosteronism, treatment with hypotensive drugs whose action is performed by inhibiting the RAAS is usually ineffective. Due to this reason the use of Telzap>® AM is not recommended.

Aortic or mitral valve stenosis, obstructive hypertrophic cardiomyopathy

. As with other vasodilators, patients with aortic or mitral stenosis and hypertrophic obstructive cardiomyopathy should exercise special caution (see section “Caution”).

Patients with diabetes mellitus receiving insulin or other hypoglycemic drugs

. In patients with diabetes mellitus receiving insulin or other hypoglycemic preparations, the use of telmisartan may result in hypoglycemia and should be accompanied by monitoring of blood glucose levels. If necessary, the dose of insulin or other hypoglycemic drugs should be adjusted.

Hyperkalemia

Like other drugs acting on the RAAS, telmisartan may contribute to hyperkalemia.

In elderly patients, patients with renal insufficiency or diabetes mellitus, as well as in patients who simultaneously receive treatment with other drugs that increase plasma potassium levels or have concomitant pathological conditions, hyperkalemia may be the cause of death.

When concomitant use of drugs acting on the RAAS, the benefit-risk ratio should be carefully evaluated.

The main risk factors for hyperkalemia include:

Patients at risk should have their plasma potassium closely monitored.

Ethnic differences

Like all other ARAs II, telmisartan is less effective in reducing BP in patients of the Negro race than in other races, possibly due to a greater predisposition for decreased renin activity in this patient population.

Ischemic Heart Disease and Cerebrovascular Disease

As with any other hypotensive medication, excessive BP reduction in patients with ischemic heart disease or cerebrovascular disease can lead to myocardial infarction or stroke.

Influence on driving and operating machinery

The drug Telzap® AM has a moderate effect on the ability to drive vehicles and operate moving mechanisms. Due to possible dizziness, headache, increased fatigability, nausea during the drug administration one should be cautious while driving vehicles and performing other activities requiring concentration and quick psychomotor functions. In case of the occurrence of the described adverse reactions, the above activities should be avoided.

Synopsis

Tablets 5 mg + 40 mg: long biconvex tablets from white or almost white to yellowish or yellow, with “5” and “40” engraved and a rib on one side. The rim is not designed to break the tablet.

Tablets 10 mg + 40 mg: Long biconvex tablets from white or nearly white to yellowish or yellowish, with “10” and “40” engraved on one side.

Tablets 5 mg + 80 mg: long biconvex tablets from white or nearly white to yellowish or yellowish, with engravings “5” and “80” and a ridge on one side. The rim is not designed to break the tablet.

Tablets 10 mg + 80 mg: long biconvex tablets white or nearly white to yellowish or yellowish, with “10” and “80” engraved on one side.

Contraindications

With caution

Side effects

The incidence of adverse reactions was determined according to the World Health Organization (WHO) classification: very
frequent (≥ 1/10); frequent (≥ 1/100 and < 1/10); infrequent (≥ 1/1000 and < 1/100);
rare (≥ 1/10000 and < 1/1000); very rare (< 1/10000), frequency unknown (cannot be calculated based on available data).

Potential adverse reactions during treatment with Telzap® AM include all adverse reactions that have been previously reported with individual drug components.

Unwanted reactions expected based on experience with telmisartan

Serious adverse reactions include anaphylactic reactions and angioedema (frequency of occurrence “rare”), and acute renal failure.

In controlled clinical trials in patients with arterial hypertension, the overall incidence of adverse reactions in the telmisartan group was generally similar to that in the placebo group (41.4% and 43.9%, respectively). The incidence of adverse reactions was independent of the drug dose, as well as the gender, age, or race of patients. The safety profile of telmisartan in patients receiving the drug to reduce cardiovascular morbidity was similar to that of patients with arterial hypertension.

The adverse reactions listed below have been reported in controlled clinical trials in patients with arterial hypertension or identified in post-registration review reports. This list also included serious and non-serious adverse reactions that were reasons for treatment withdrawal in three long-term clinical trials involving 21,642 patients taking telmisartan to reduce cardiovascular morbidity over a period of up to 6 years.

Infectious and parasitic diseases: infrequent urinary tract infections (including cystitis), upper respiratory tract infections (including pharyngitis and sinusitis); rarely sepsis (including fatal).

Disorders of the blood and lymphatic system: infrequently – anemia; rarely – eosinophilia, thrombocytopenia.

Disorders of the immune system: seldom – anaphylactic reactions, hypersensitivity reactions.

Metabolic and nutritional disorders:frequent – hyperkalemia; rarely – hypoglycemia (in patients with diabetes).

Mental disorders: infrequent – insomnia, depression; rarely – anxiety.

Nervous system disorders: infrequent – fainting; rarely – drowsiness.

Visual system disorders: rarely – visual disturbances.

Hearing organ disorders and labyrinth disorders: infrequently – vertigo.

Chronic disorders: infrequent – bradycardia; rarely – tachycardia.

vascular disorders:infrequent – decreased BP, orthostatic hypotension.

Disorders of the respiratory system, chest and mediastinum organs: infrequently – shortness of breath, cough; very rarely – interstitial lung disease.

Gastrointestinal disorders: infrequent – abdominal pain, diarrhea, dyspepsia, bloating, vomiting; rarely – dry mouth, discomfort in the stomach.

Liver and biliary tract disorders: rarely – liver dysfunction/liver damage.

Skin and subcutaneous tissue disorders: infrequent – skin itching, increased sweating, skin rash; rarely – angioedema (including fatal), eczema, erythema, urticaria, drug rash, toxidermia.

Musculoskeletal and connective tissue disorders: infrequently – back pain (such as ischialgia), muscle spasms, myalgia; rarely – arthralgia, pain in the extremities, tendon pain (symptoms resembling tendinitis).

Renal and urinary tract disorders: infrequently – renal dysfunction, including acute renal failure.

General disorders and disorders at the site of administration: infrequent – chest pain, asthenic syndrome (general weakness); rarely – flu-like syndrome.

Laboratory and instrumental data: infrequent – increased plasma creatinine concentration; rare – decreased plasma hemoglobin concentration, increased plasma uric acid concentration, increased “liver” enzymes activity, increased plasma creatinphosphokinase concentration.

Description of individual adverse reactions

Sepsis

In a clinical trial, the incidence of sepsis was higher in the telmisartan group than in the placebo group. This may be regarded as an incidental finding or as the development of a phenomenon related to a currently unknown mechanism.

Decrease in BP

This adverse reaction has often been reported in patients with controlled BP on telmisartan in combination with standard therapy to reduce cardiovascular morbidity.

Hepatic dysfunction/liver damage

The highest incidence of hepatic dysfunction or liver damage was found when analyzing post-registration clinical case reports in patients of the Japanese ethnic group. Patients in this ethnic group are susceptible to developing adverse reactions of this type.

Interstitial lung disease

Cases of interstitial lung disease with a temporal relationship to telmisartan administration have been reported during the post-registration period. However, a causal relationship between telmisartan use and the development of this disease has not been established.

Unwanted reactions expected based on experience with amlodipine

The most common adverse reactions to amlodipine use include drowsiness, dizziness, headache, palpitations, feeling of “rush” of blood to the skin, abdominal pain, nausea, swelling of ankles and other localizations, and fatigue.

Disorders of the blood and lymphatic system: very rarely – leukopenia, thrombocytopenia.

Disorders of the immune system:very rare – allergic reactions.

Disorders of metabolism and nutrition: infrequent – weight loss, weight gain; very rare – hyperglycemia.

Mental disorders: infrequent – insomnia, mood changes (including anxiety), depression; rarely – confusion.

Nervous system disorders: frequent – somnolence, dizziness, headache (especially at the beginning of treatment); infrequent – tremor, dysgeusia, syncope, hypoesthesia, paresthesia; very rare – hypertonicity, peripheral neuropathy; frequency unknown – extrapyramidal disorders.

Visual disorders:often – visual disturbances (including diplopia).

Hearing organ disorders and labyrinth disorders: infrequent – tinnitus.

Chronic disorders: frequent – sensation of palpitation; infrequent – arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation); very rare – myocardial infarction.

Vascular disorders:often – feeling of “rush” of blood to the skin; infrequently – decreased BP; very rarely – vasculitis.

Disorders of the respiratory system, chest and mediastinum organs:often – shortness of breath; infrequently – cough, rhinitis.

Gastrointestinal disorders: frequently – abdominal pain, nausea, disorders of the rhythm of bowel emptying (including diarrhea and constipation); infrequently – vomiting, dry mouth; very rarely – pancreatitis, gastritis, gum hyperplasia.

Hepatic and biliary tract disorders:very rarely – hepatitis, jaundice, increased activity of “liver” enzymes (in most cases combined with cholestasis).

Skin and subcutaneous tissue disorders: often – swelling of ankles and feet; infrequent – alopecia, purpura, changes in skin pigmentation (appearance of discolored areas of skin), increased sweating, skin itching, skin rash, exanthema, urticaria; very rarely – angioedema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, photosensitivity; frequency unknown – toxic epidermal necrolysis.

Muscular and connective tissue disorders:often – muscle cramps; infrequently – arthralgia, myalgia, back pain.

Recreational and urinary tract disorders:infrequent – rapid urination, dysuria, nicturia.

Renital and mammary gland disorders: infrequent – erectile dysfunction, gynecomastia.

General disorders and disorders at the site of administration:very often – edema; often – increased fatigue, asthenic syndrome; infrequently – chest pain, pain, general malaise.

Unwanted reactions expected based on experience with amlodipine and telmisartan

Infectious and parasitic diseases: not infrequently, cystitis.

Mental disorders: rarely – anxiety, insomnia, depression.

Nervous system disorders: frequently – dizziness, infrequently – somnolence, migraine, headache, paresthesias; rarely – syncope, peripheral neuropathy, hypoesthesia, dysgeusia, tremor.

Hearing and labyrinth disorders: infrequent – vertigo.

Cardiac disorders: infrequent – bradycardia, palpitations.

Vascular disorders: infrequent – hypotension, orthostatic hypotension, “hot flashes”.

Disorders of the respiratory system, chest and mediastinum organs: infrequently – cough; very rarely – interstitial lung disease.

Gastrointestinal tract disorders: infrequent – abdominal pain, diarrhea, nausea; rarely – vomiting, gum hypertrophy, shortness of breath, dry mouth.

Skin and subcutaneous tissue disorders: infrequent – skin itching; rarely – eczema, erythema.

Muscular and connective tissue disorders: infrequent – arthralgia, muscle spasms (cramps of the calf muscles), myalgia; rarely – back pain, pain in the lower extremities (legs).

Urinary tract disorders: rarely – nycturia.

Renital and breast disorders: infrequent – erectile dysfunction.

General disorders and disorders at the site of administration:often – peripheral edema; infrequently – asthenia, chest pain, fatigue, edema.

Laboratory and instrumental data: infrequent – increased concentration of “hepatic” transaminases; rarely – increased concentration of uric acid in the blood.

Additional information regarding the combination of amlodipine and telmisartan: Peripheral edema, a dose-dependent side effect of amlodipine, was observed less frequently in patients who received the combination of amlodipine and telmisartan than in patients receiving amlodipine alone.

Overdose

Symptoms

Cases of overdose of the combination amlodipine + telmisartan have not been reported. Possible symptoms of overdose are composed of symptoms from the individual components of the drug.

Amlodipine overdose may lead to excessive peripheral vasodilation and reflex tachycardia. Severe and persistent decrease of BP has been reported, including development of shock and lethal outcome. The most pronounced symptoms of telmisartan overdose were decreased BP and tachycardia. Such clinical manifestations as bradycardia, dizziness, increased concentration of creatinine in plasma and acute renal failure were also recorded.

Treatment

The patient should be under close clinical observation. Treatment should include symptomatic and supportive therapy. The set of treatment measures depends on the length of time since taking the drug and the severity of the symptoms. Recommended measures include stimulation of vomiting and/or gastric lavage, intake of activated charcoal.

The plasma electrolyte and creatinine concentrations should be monitored regularly. In case of BP decrease, the patient should be placed in the supine position with the lower extremities elevated, and the administration of saline and other plasma substitute solutions to replenish the blood pressure should be started immediately. Restoration of vascular tone and normalization of BP can be achieved by administration of vasoconstrictors, provided there are no contraindications for their use. Intravenous administration of calcium gluconate may provide relief of symptoms associated with calcium channel blockade.

Amlodipine and telmisartan are not practically eliminated from the body by hemodialysis.

Pregnancy use

Pregnancy

The use of Telzap® AM during pregnancy is contraindicated. There have been no specific studies on the use of amlodipine + telmisartan combination during pregnancy and during breastfeeding. The effects associated with the individual active ingredients are described below.

Amlodipine

The safety of amlodipine in pregnant women has not been studied.

In studies in laboratory animals, use of the drug at high doses was accompanied by signs of reproductive toxicity.

The use of amlodipine during pregnancy is allowed only when there is no safer alternative and when the risk to the mother and child associated with the disease overweighs the risk associated with the use of the drug.

Telmisartan

The epidemiologic evidence for the risk of teratogenic effects of ACE inhibitors during the first trimester of pregnancy is not strong enough, but does not rule out a small increased risk of adverse effects on the fetus. Although controlled epidemiological studies of the teratogenic effects associated with ARA II administration have not been conducted, there may be a similar risk associated with the use of this group of drugs. Except in cases of extreme need for continuous ARA II treatment, patients planning to become pregnant should switch to alternative antihypertensive drugs with a studied safety profile during pregnancy. If pregnancy is confirmed, treatment with Telzap® AM should be discontinued immediately and alternative therapy initiated if necessary.

There is evidence that exposure to APA II during the second and third trimesters of pregnancy may be accompanied by fetal (decreased renal function, oligohydramnios, delayed cranial ossification) and neonatal (renal failure, decreased BP, hyperkalemia) toxicity events. In case of taking Telzap® AM starting from the second trimester of pregnancy, ultrasound examination of renal function and fetal cranial bones should be performed.

Infants born to women who have taken Telzap® AM during pregnancy should be closely monitored clinically for the timely detection of arterial hypotension.

Breastfeeding

The use of amlodipine and telmisartan during breastfeeding is not known. Therefore, the use of Telzap® AM during breastfeeding is contraindicated.

Amlodipine penetrates into breast milk in an amount 3-7% of the maternal dose (maximum up to 15%). The effect of amlodipine on newborns is unknown. When treating breastfeeding women, preference should be given to alternative drugs with a better studied safety profile during breastfeeding, especially when nursing a newborn or premature infant. A decision should be made to discontinue breastfeeding or to discontinue the drug, taking into account the need for the drug for the mother.

Fertility

Amlodipine

. Clinical data regarding the potential effects of amlodipine on fertility are scarce. One study in rats found adverse effects on male fertility.

In some patients, biochemical changes in the sperm head have been observed with the use of BMCC. There is insufficient clinical data on the potential effect of amlodipine on fertility.

Telmisartan

In preclinical studies, telmisartan had no effect on male or female fertility.

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