Telzap^® AM (Tablets) Instructions for Use

Marketing Authorization Holder

Sanofi Russia JSC (Russia)

Manufactured By

Zentiva, k.s. (Czech Republic)

Contact Information

SANOFI

ATC Code

C09DB04 (Amlodipine and Telmisartan)

Active Substances

Telmisartan (Rec.INN registered by WHO)

Amlodipine (Rec.INN registered by WHO)

Dosage Forms

	Telzap® AM	Tablets 5 mg+40 mg: 28 or 56 pcs.
		Tablets 5 mg+80 mg: 28 or 56 pcs.
		Tablets 10 mg+40 mg: 28 or 56 pcs.
		Tablets 10 mg+80 mg: 28 or 56 pcs.

Dosage Form, Packaging, and Composition

Tablets from white or almost white to yellowish or yellow, oblong, biconvex, with engravings “5” and “40” and a score on one side; the score is not intended for breaking the tablet.

Excipients: sorbitol, sodium hydroxide, povidone K25, microcrystalline cellulose, calcium hydrogen phosphate dihydrate, meglumine, magnesium stearate.

7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.

Tablets from white or almost white to yellowish or yellow, oblong, biconvex, with engravings “10” and “40” on one side.

Excipients: sorbitol, sodium hydroxide, povidone K25, microcrystalline cellulose, calcium hydrogen phosphate dihydrate, meglumine, magnesium stearate.

7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.

Tablets from white or almost white to yellowish or yellow, oblong, biconvex, with engravings “5” and “80” and a score on one side; the score is not intended for breaking the tablet.

Excipients: sorbitol, sodium hydroxide, povidone K25, microcrystalline cellulose, calcium hydrogen phosphate dihydrate, meglumine, magnesium stearate.

7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.

Tablets from white or almost white to yellowish or yellow, oblong, biconvex, with engravings “10” and “80” on one side.

Excipients: sorbitol, sodium hydroxide, povidone K25, microcrystalline cellulose, calcium hydrogen phosphate dihydrate, meglumine, magnesium stearate.

7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.

Clinical-Pharmacological Group

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

Pharmacotherapeutic Group

Combined antihypertensive agent (slow calcium channel blocker + angiotensin II receptor antagonist)

Pharmacological Action

The drug Telzap^® AM contains two antihypertensive substances with complementary mechanisms of action that provide control of blood pressure in patients with essential arterial hypertension; Amlodipine belongs to the pharmacological group of slow calcium channel blockers (CCBs), and Telmisartan belongs to the group of angiotensin II receptor antagonists (ARBs). The combination of these substances exhibits an additive antihypertensive effect, causing a more pronounced decrease in blood pressure than each of the drug components separately.

Amlodipine

Amlodipine is a dihydropyridine derivative, belongs to the class of CCBs, inhibits the transmembrane influx of calcium ions into cardiomyocytes and vascular smooth muscle cells. The mechanism of the antihypertensive action of amlodipine is associated with its vasodilatory effect on vascular smooth muscles. The exact mechanism by which Amlodipine reduces the frequency and severity of angina attacks has not been fully established, but Amlodipine may reduce myocardial ischemia through the two effects described below.

• Amlodipine dilates peripheral arterioles and thereby reduces total peripheral resistance, the so-called afterload. Since the heart rate during amlodipine intake practically does not increase, this reduction in the load on the heart muscle reduces the energy expenditure of the myocardium and its oxygen demand;
• The mechanism of the antianginal action of amlodipine also appears to be associated with the dilation of the main coronary arteries and arterioles, both in areas of the myocardium with normal blood flow and in ischemic areas. This dilation increases oxygen delivery to the myocardium in patients with coronary artery spasm (Prinzmetal’s angina or variant angina).

In patients with arterial hypertension, taking amlodipine once a day provides a clinically significant reduction in blood pressure in the supine and standing positions for 24 hours. Orthostatic arterial hypotension is not characteristic 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 in therapeutic doses leads to a decrease in renal vascular resistance, an increase in GFR and effective renal plasma flow without changes in filtration fraction or proteinuria.

No adverse metabolic effects or changes in plasma lipid concentrations were observed during amlodipine intake. Amlodipine can be taken by 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 (exercise tolerance is not reduced, left ventricular ejection fraction is not reduced).

Telmisartan

Telmisartan is a specific angiotensin II receptor antagonist (type AT₁), effective when taken orally. Possessing a very high affinity for the angiotensin II subtype AT₁ receptor binding site, Telmisartan displaces angiotensin II from binding to the receptor, without having an agonist action on this receptor. Telmisartan does not exhibit partial agonist properties for the AT₁ receptor. Telmisartan selectively binds to the AT₁ receptor. The binding to the receptor is long-lasting. Telmisartan does not exhibit affinity for other receptors, including AT₂ receptors and other less studied angiotensin receptors. Telmisartan reduces plasma aldosterone concentration, does not inhibit renin, and does not block ion channels. Telmisartan does not inhibit the activity of angiotensin-converting enzyme (kininase II) – an enzyme that also breaks down bradykinin. This suggests that the drug will not enhance adverse effects associated with the action of bradykinin.

A telmisartan dose of 80 mg/day almost completely blocks the increase in blood pressure under the influence of angiotensin II. The antihypertensive effect persists for 24 hours and remains significant for up to 48 hours.

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

In patients with arterial hypertension, Telmisartan provides a reduction in systolic and diastolic blood pressure without affecting heart rate.

After abrupt discontinuation of telmisartan treatment, a gradual (over several days) return of blood pressure values to their pre-treatment levels is observed without the development of withdrawal syndrome.

In patients taking Telmisartan, the incidence of dry cough was significantly lower than in patients receiving ACE inhibitors. These data were obtained in clinical studies with direct comparison of these two types of antihypertensive therapy.

The combined drug (Amlodipine+Telmisartan), used once a day, leads to effective and sustained reduction of blood pressure over 24 hours.

Pharmacokinetics

Amlodipine

Absorption

After oral administration of amlodipine in therapeutic doses, C_max in plasma is reached within 6-12 hours. The absolute bioavailability of the drug is 64-80%. Food intake does not affect the bioavailability of amlodipine.

Distribution

The apparent V_d is approximately 21 L/kg. In vitro studies have shown that about 97.5% of amlodipine circulating in the blood is bound to plasma proteins.

Metabolism

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

Excretion

The T_1/2 of amlodipine from plasma is approximately 35-50 hours, which confirms the possibility of its use once a day. The drug is excreted by the kidneys: 10% of the administered dose is eliminated as the parent compound and 60% as metabolites. The elimination of amlodipine from plasma is biphasic.

Pharmacokinetics in special patient groups

There is very limited clinical data on the use of amlodipine in patients with impaired liver function. In patients with hepatic insufficiency, a decrease in the clearance of amlodipine was observed, leading to a prolongation of T_1/2 and an increase in AUC by approximately 40-60%.

T_max of amlodipine in plasma is comparable in elderly patients and in younger patients. In elderly patients, the clearance of amlodipine tends to decrease with a corresponding increase in AUC and prolongation of T_1/2.

Telmisartan

Absorption

Telmisartan is rapidly absorbed, but the amount of the drug absorbed may vary. The average absolute bioavailability of telmisartan is approximately 50%. When telmisartan is taken with food, there is a decrease in the AUC value from approximately 6% (when taking telmisartan at a dose of 40 mg/day) to 19% (at a dose of 160 mg/day). Three hours after taking the drug, the concentration of telmisartan in plasma levels out, regardless of food intake.

No linear relationship between the drug dose and its plasma concentration was noted. C_max and to a lesser extent AUC increase disproportionately when used in doses above 40 mg/day.

Distribution

Telmisartan is characterized by a high degree of binding to plasma proteins (>99.5%), mainly to albumin and alpha-1-acid glycoprotein. The mean apparent volume of distribution at steady state (V_d^ss) is approximately 500 L.

There are no data on clinically significant accumulation of telmisartan taken at recommended doses.

Metabolism

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

Excretion

The T_1/2 is more than 20 hours. It is excreted through the intestine unchanged, renal excretion is less than 1%. The total plasma clearance is high (about 1000 ml/min) compared to hepatic blood flow (about 1500 ml/min).

Pharmacokinetics in special patient groups

Differences in drug plasma concentration parameters were identified in men and women: C_max and AUC values in women were approximately 3 and 2 times higher than in men, respectively.

The pharmacokinetic parameters of telmisartan did not differ between elderly patients and patients under 65 years of age.

In patients with mild, moderate, and severe renal impairment, a 2-fold increase in telmisartan plasma concentration was observed. However, in patients with renal failure on hemodialysis, plasma concentrations of the drug were lower. Telmisartan is characterized by a high degree of binding to plasma proteins and is not eliminated from the body by hemodialysis. T_1/2 did not change in patients with impaired renal function.

The results of pharmacokinetic studies showed an increase in the absolute bioavailability of telmisartan to almost 100% in patients with impaired liver function. T_1/2 in patients with impaired liver function did not change.

Indications

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

ICD codes

Dosage Regimen

The drug is taken orally, once a day, regardless of meals, with a small amount of liquid.

Patients receiving therapy with amlodipine and telmisartan as separate tablets can be switched to therapy with Telzap^® AM, containing the same doses of active substances.

The drug Telzap^® AM can be used in patients in whom the use of amlodipine alone or telmisartan alone does not lead to adequate blood pressure control.

Patients taking Amlodipine at a dose of 10 mg, who experience adverse reactions limiting the intake of the drug, for example, peripheral edema, can switch to taking Telzap^® AM at a dose of 5 mg + 40 mg once a day, which will reduce the dose of amlodipine but will not reduce the overall expected antihypertensive effect.

Treatment of arterial hypertension in a patient can be started with the use of Telzap^® AM in cases where it is assumed that achieving blood pressure control with any single drug is unlikely.

The initial dose of Telzap^® AM is 5 mg + 40 mg once a day.

Patients who require a more significant reduction in blood pressure can start taking Telzap^® AM at a dose of 5 mg + 80 mg once a day.

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

The maximum daily dose is 10 mg of amlodipine + 80 mg of telmisartan.

For elderly patients (over 65 years old) no dose adjustment is required.

In patients with mild or moderate renal impairment no dose adjustment is required. Experience with the drug in patients with severe renal impairment or on hemodialysis is limited. In patients of this category, treatment with Telzap^® AM should be carried out with caution, since Amlodipine and Telmisartan are not eliminated from the body by hemodialysis.

Dose selection of Telzap^® AM in patients with mild or moderate hepatic impairment requires caution. The daily dose of telmisartan should not exceed 40 mg. Telzap^® AM is contraindicated in patients with severe hepatic impairment.

If the patient forgot to take the tablet on time, then this dose should be skipped. The next dose should be taken at the usual time. In case of a missed dose, the patient should not take a double dose.

The patient should not stop taking the drug on their own due to the possible risk of worsening the condition.

Adverse Reactions

The frequency of adverse reactions was determined in accordance with the WHO classification: very common (≥1/10); common (≥1/100 and <1/10); uncommon (≥1/1000 and <1/100); rare (≥1/10,000 and <1/1000); very rare (<1/10,000), frequency not known (cannot be estimated from the available data).

Potential adverse reactions during treatment with Telzap^® AM include all adverse reactions that were previously reported during the use of the individual components of the drug.

Adverse reactions expected based on experience with amlodipine

The most common adverse reactions during the use of amlodipine include drowsiness, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle and other localized edema, fatigue.

From the hematopoietic system very rare – leukopenia, thrombocytopenia.

From the immune system very rare – allergic reactions.

From the metabolism uncommon – weight decrease, weight increase; very rare – hyperglycemia.

Mental disorders uncommon – insomnia, mood changes (including anxiety), depression; rare – confusion.

From the nervous system common – drowsiness, dizziness, headache (especially at the beginning of treatment); uncommon – tremor, dysgeusia, syncope, hypoesthesia, paresthesia; very rare – hypertonia, peripheral neuropathy; frequency not known – extrapyramidal disorders.

From the organ of vision common – visual disturbances (including diplopia).

From the organ of hearing and labyrinthine disorders uncommon – tinnitus.

From the cardiovascular system common – palpitations, flushing; uncommon – arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), decreased blood pressure; very rare – myocardial infarction, vasculitis.

From the respiratory system common – dyspnea; uncommon – cough, rhinitis.

From the digestive system common – abdominal pain, nausea, bowel habit disorders (including diarrhea and constipation); uncommon – vomiting, dry mouth; very rare – pancreatitis, gastritis, gingival hyperplasia.

From the liver and biliary tract very rare – hepatitis, jaundice, increased activity of liver enzymes (mostly in combination with cholestasis).

From the skin and subcutaneous tissues common – ankle and foot edema; uncommon – alopecia, purpura, skin discoloration (appearance of discolored skin areas), hyperhidrosis, pruritus, skin rash, exanthema, urticaria; very rare – angioedema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, photosensitivity; frequency not known – toxic epidermal necrolysis.

Musculoskeletal system disorders Common – muscle spasms; Uncommon – arthralgia, myalgia, back pain.

Urinary system disorders Uncommon – frequent urination, dysuria, nocturia.

Reproductive system and breast disorders Uncommon – erectile dysfunction, gynecomastia.

General disorders and administration site conditions Very common – edema; Common – increased fatigue, asthenic syndrome; Uncommon – chest pain, pain, general malaise.

Adverse reactions expected based on experience with telmisartan

Serious adverse reactions include anaphylactic reactions and angioedema (frequency “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 did not depend on the drug dose, nor on the patient’s sex, age, or race. The safety profile of telmisartan in patients receiving the drug to reduce cardiovascular morbidity was similar to that in patients with arterial hypertension.

The adverse reactions listed below were recorded in controlled clinical trials in patients with arterial hypertension or identified from post-marketing reports. This list also includes serious and non-serious adverse reactions that led to treatment discontinuation during three long-term clinical trials involving 21,642 patients taking Telmisartan to reduce cardiovascular morbidity for up to 6 years.

Infections and infestations Uncommon – urinary tract infections (including cystitis), upper respiratory tract infections (including pharyngitis and sinusitis); Rare – sepsis (including fatal cases).

Blood and lymphatic system disorders Uncommon – anemia; Rare – eosinophilia, thrombocytopenia.

Immune system disorders Rare – anaphylactic reactions, hypersensitivity reactions.

Metabolism and nutrition disorders Uncommon – hyperkalemia; Rare – hypoglycemia (in patients with diabetes mellitus).

Psychiatric disorders Uncommon – insomnia, depression; Rare – anxiety.

Nervous system disorders Uncommon – syncope; Rare – somnolence.

Eye disorders Rare – visual disturbances.

Ear and labyrinth disorders Uncommon – vertigo.

Cardiac disorders Uncommon – bradycardia, decreased blood pressure, orthostatic hypotension; Rare – tachycardia.

Respiratory, thoracic and mediastinal disorders Uncommon – dyspnea, cough; Very rare – interstitial lung disease.

Gastrointestinal disorders Uncommon – abdominal pain, diarrhea, dyspepsia, abdominal distension, vomiting; Rare – dry mouth, gastric discomfort.

Hepatobiliary disorders Rare – impaired liver function/liver injury.

Skin and subcutaneous tissue disorders Uncommon – pruritus, hyperhidrosis, skin rash; Rare – angioedema (including fatal cases), eczema, erythema, urticaria, drug eruption, toxicoderma.

Musculoskeletal and connective tissue disorders Uncommon – back pain (e.g., sciatica), muscle spasms, myalgia; Rare – arthralgia, pain in extremity, tendon pain (symptoms resembling tendinitis).

Renal and urinary disorders Uncommon – impaired renal function, including acute renal failure.

General disorders and administration site conditions Uncommon – chest pain, asthenic syndrome (general weakness); Rare – flu-like syndrome.

Investigations Uncommon – increased blood creatinine; Rare – decreased blood hemoglobin, increased blood uric acid, increased hepatic enzyme levels, increased blood creatine phosphokinase.

Description of selected adverse reactions

Sepsis

In a clinical trial, the incidence of sepsis in the telmisartan group was higher than in the placebo group. This may be considered a chance finding or the development of a phenomenon associated with a currently unknown mechanism.

Decreased blood pressure

This adverse reaction was frequently reported in patients with controlled blood pressure while using telmisartan in combination with standard therapy to reduce cardiovascular morbidity.

Impaired liver function/liver injury

The largest number of cases of impaired liver function or liver injury were identified from post-marketing clinical case reports in patients of Japanese ethnicity. Patients of this ethnic group are susceptible to developing this type of adverse reaction.

Interstitial lung disease

During the post-marketing period, reports of interstitial lung disease cases temporally associated with telmisartan intake were received. However, a causal relationship between telmisartan use and the development of this disease has not been established.

Adverse reactions expected based on experience with amlodipine and telmisartan

The most common adverse reactions associated with amlodipine use include somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle and other localized edema, fatigue.

Infections and infestations Rare – cystitis.

Psychiatric disorders Rare – anxiety, insomnia, depression.

Nervous system disorders Common – dizziness; Uncommon – somnolence, migraine, headache, paresthesia; Rare – syncope, peripheral neuropathy, hypoesthesia, dysgeusia, tremor.

Ear and labyrinth disorders Uncommon – vertigo.

Cardiac disorders Uncommon – bradycardia, palpitations, arterial hypotension, orthostatic hypotension, flushing.

Respiratory, thoracic and mediastinal disorders Uncommon – cough; Very rare – interstitial lung disease.

Gastrointestinal disorders Uncommon – abdominal pain, diarrhea, nausea; Rare – vomiting, gingival hyperplasia, dyspnea, dry mouth.

Skin and subcutaneous tissue disorders Uncommon – pruritus; Rare – eczema, erythema.

Musculoskeletal and connective tissue disorders Uncommon – arthralgia, muscle cramps (calf cramps), myalgia; Rare – back pain, pain in lower limb (legs).

Renal and urinary disorders Rare – nocturia.

Reproductive system and breast disorders Uncommon – erectile dysfunction.

General disorders and administration site conditions Common – peripheral edema; Uncommon – asthenia, chest pain, fatigue, edema.

Investigations Uncommon – increased hepatic transaminases; Rare – increased blood uric acid.

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

Contraindications

• Hypersensitivity to the active substances, excipients, and other dihydropyridine derivatives;
• Obstructive biliary tract diseases;
• Severe arterial hypotension;
• Left ventricular outflow tract obstruction (including significant aortic stenosis);
• Hemodynamically unstable heart failure after acute myocardial infarction;
• Severe hepatic impairment;
• Shock (including cardiogenic);
• Concomitant use with aliskiren or drugs containing aliskiren in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area);
• Concomitant use with ACE inhibitors in patients with diabetic nephropathy;
• Fructose intolerance and glucose/galactose malabsorption syndrome or sucrase/isomaltase deficiency;
• Pregnancy;
• Breastfeeding period;
• Age under 18 years (efficacy and safety not established).

With caution

• Bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney;
• Unstable angina, acute myocardial infarction (no data on use in the acute period and within one month after myocardial infarction);
• Renal impairment and status after kidney transplantation;
• Hepatic impairment (dosing recommendations for patients with hepatic impairment have not been established, therefore caution should be exercised in such clinical cases);
• Reduced blood volume due to prior diuretic use, salt restriction, diarrhea, or vomiting;
• Diabetes mellitus;
• Hyponatremia;
• Hyperkalemia;
• Aortic or mitral valve stenosis;
• Primary hyperaldosteronism (efficacy and safety not established);
• Age over 70 years when dose increase is necessary;
• Coronary artery disease and/or clinically significant cerebral atherosclerosis (with excessive blood pressure reduction, there is a risk of increased ischemic disorders, up to the development of acute myocardial infarction and/or stroke);
• Sick sinus syndrome (severe bradycardia, tachycardia);
• Chronic heart failure (CHF) of non-ischemic etiology, NYHA functional class III-IV;
• Hypertrophic obstructive cardiomyopathy.

Use in Pregnancy and Lactation

Pregnancy

The use of the drug Telzap^® AM during pregnancy is contraindicated. No specific studies on the use of the Amlodipine+Telmisartan combination during pregnancy and breastfeeding have been conducted. The effects associated with the individual active substances are described below.

Amlodipine

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

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

The use of amlodipine during pregnancy is allowed only in the absence of a safer alternative and in cases where the risk to the mother and child associated with the disease outweighs the risk associated with the use of the drug.

Telmisartan

Epidemiological evidence regarding the risk of teratogenic effects of ACE inhibitors during the first trimester of pregnancy is not entirely conclusive but does not rule out a small increase in the risk of adverse effects on the fetus. Although controlled epidemiological studies on the teratogenic effect associated with the use of ARBs have not been conducted, the use of drugs in this group may be associated with a similar risk. Unless continuous treatment with ARBs is absolutely necessary, women planning pregnancy should switch to alternative antihypertensive drugs with a known safety profile during pregnancy. If pregnancy is confirmed, treatment with Telzap^® AM must be discontinued immediately and alternative therapy initiated if necessary.

It is known that exposure to ARBs during the second and third trimesters of pregnancy can lead to fetal toxicity (decreased renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia). If Telzap^® AM is taken starting from the second trimester of pregnancy, an ultrasound examination of fetal renal function and skull bones should be performed.

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

Breastfeeding period

Information on the use of amlodipine and telmisartan during breastfeeding is not available. Therefore, the use of Telzap^® AM during breastfeeding is contraindicated.

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

Fertility

Amlodipine

Clinical data on the potential effect of amlodipine on fertility are insufficient. In one study in rats, adverse events on male fertility were found.

When using CCBs, biochemical changes in the sperm head were observed in some patients. The volume of clinical data on the potential effect of amlodipine on fertility is insufficient.

Telmisartan

In preclinical studies, Telmisartan did not affect fertility in males or females.

Use in Hepatic Impairment

The use of the drug is contraindicated in severe hepatic impairment.

Caution is required in patients with mild or moderate hepatic impairment.

Use in Renal Impairment

The drug should be prescribed with caution in cases of renal impairment and status after kidney transplantation.

Pediatric Use

Use is contraindicated under the age of 18 years (efficacy and safety not established).

Geriatric Use

No dose adjustment is required for elderly patients (over 65 years).

The drug should be prescribed with caution in patients over 70 years of age.

Special Precautions

Amlodipine

Patients with chronic heart failure

In a long-term placebo-controlled study (PRAISE-2) in patients with CHF NYHA functional class III-IV of non-ischemic etiology, the use of amlodipine was associated with an increased reporting of pulmonary edema, despite no significant difference in the frequency of heart failure progression compared to placebo. CCBs, including Amlodipine, should be used with caution in patients with CHF due to the possible risk of other cardiovascular complications and mortality.

Hepatic impairment

As with other CCBs, the T_1/2 of amlodipine is prolonged in patients with hepatic impairment. Therefore, the drug Telzap^® AM should be used with caution in such patients, and the dose of telmisartan should not exceed 40 mg once daily. The drug Telzap^® AM is contraindicated in patients with severe hepatic impairment.

Renal impairment

Amlodipine can be used in usual doses in patients with renal impairment. Changes in amlodipine plasma concentration did not correlate with the degree of renal impairment. Amlodipine is not removed from the body by dialysis.

Telmisartan

Hepatic impairment

The use of the Amlodipine + Telmisartan combination is contraindicated in patients with cholestasis, biliary obstruction, and/or severe hepatic impairment, since Telmisartan is mainly excreted in the bile. There is reason to believe that hepatic clearance of telmisartan is reduced in these patients. The drug should be used with caution in patients with mild to moderate hepatic impairment.

Renovascular hypertension

When treating with drugs affecting the RAAS in patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney, there is an increased risk of a significant decrease in blood pressure and the development of acute renal failure.

Renal impairment and kidney transplantation

When using telmisartan in patients with renal impairment, periodic monitoring of plasma potassium and creatinine levels is recommended. There is no experience with the drug in patients who have recently undergone kidney transplantation. Telmisartan is not removed by dialysis.

Reduced blood volume

A decrease in blood pressure, especially after the first dose of Telzap^® AM, may occur in patients with reduced blood volume and/or low plasma sodium levels due to prior treatment with diuretics, salt restriction, diarrhea, or vomiting. Such conditions (fluid and/or sodium deficiency) should be corrected before starting Telzap^® AM.

Dual blockade of the RAAS

Data on the concomitant use of ACE inhibitors with ARBs or with drugs containing aliskiren confirm an increased risk of a sharp decrease in blood pressure, hyperkalemia, and impaired renal function (including acute renal failure).

Concomitant use of ARBs with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients. If dual blockade of the RAAS is necessary, each case should be considered individually and renal function, water-electrolyte balance, and blood pressure parameters should be carefully monitored. Concomitant use of ARBs with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Cases of arterial hypotension, syncope, hyperkalemia, and impaired renal function (including the development of acute renal failure) have been observed in predisposed patients during RAAS blockade, especially with the concomitant use of drugs affecting the RAAS. Therefore, dual blockade of the RAAS (in particular, with the simultaneous use of telmisartan with other RAAS blockers) is not recommended. If simultaneous use of several RAAS blockers is necessary, renal function should be carefully monitored.

Other conditions associated with RAAS stimulation

In patients whose vascular tone and renal function depend predominantly on the activity of the RAAS (e.g., patients with severe chronic heart failure or existing kidney disease, including renal artery stenosis), the use of drugs affecting this system, such as Telmisartan, is associated with the occurrence of an acute decrease in blood pressure, hyperazotemia, oliguria, or rarely, the development of acute renal failure.

Primary hyperaldosteronism

In patients with primary hyperaldosteronism, treatment with antihypertensive drugs that act by inhibiting the RAAS is generally ineffective. Therefore, the use of the drug Telzap^® AM is not recommended.

Aortic or mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with other vasodilators, patients with aortic or mitral stenosis, as well as hypertrophic obstructive cardiomyopathy, must exercise particular caution.

Patients with diabetes mellitus receiving insulin or other hypoglycemic drugs

In patients with diabetes mellitus taking insulin or other hypoglycemic drugs, the use of telmisartan may lead to the development of hypoglycemia and should be accompanied by monitoring of blood glucose concentration. If necessary, the dose of insulin or other hypoglycemic drugs should be adjusted.

Hyperkalemia

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

In elderly patients, patients with renal insufficiency or diabetes mellitus, as well as in patients who are simultaneously receiving treatment with other drugs that increase plasma potassium levels, or have concomitant pathological conditions, hyperkalemia can be fatal.

When drugs acting on the RAAS are used concomitantly, the benefit-risk ratio should be carefully assessed.

The main risk factors for the development of hyperkalemia include

• Diabetes mellitus, impaired renal function, old age (patients over 70 years);
• Concomitant use with drugs acting on the RAAS, and/or potassium-containing supplements. Drugs that can cause hyperkalemia are potassium-containing salt substitutes, potassium-sparing diuretics, ACE inhibitors, ARBs, NSAIDs, including selective COX-2 inhibitors, heparin, immunosuppressants (cyclosporine and tacrolimus), and trimethoprim;
• Concomitant diseases, especially dehydration, acute heart failure, metabolic acidosis, acute renal failure (for example, in infectious diseases), cytolysis syndrome (for example, acute limb ischemia, rhabdomyolysis, extensive trauma).

Patients at risk are recommended to carefully monitor plasma potassium levels.

Coronary artery disease and cerebrovascular disease

As with the use of any other antihypertensive drugs, an excessive decrease in blood pressure in patients with coronary artery disease or cerebrovascular disease may lead to the development of myocardial infarction or stroke.

Ethnic differences

Like all other ARBs, Telmisartan reduces blood pressure less effectively in Black patients than in patients of other races, possibly due to a greater predisposition to reduced renin activity in this patient population.

Elderly patients

Dose adjustment of the drug Telzap^® AM in elderly patients is not required. Dose escalation should be performed with caution.

Use in pediatrics

The safety and efficacy of the drug Telzap^® AM in children have not been established to date.

Sorbitol

The drug contains sorbitol (E420). In patients with rare hereditary fructose intolerance, the use of the drug Telzap^® AM is contraindicated.

Effect on the ability to drive vehicles and operate machinery

The drug Telzap^® AM has a moderate effect on the ability to drive vehicles and operate moving machinery. Due to the possible development of dizziness, headache, increased fatigue, nausea when taking the drug, caution should be exercised when driving vehicles and engaging in other activities that require concentration and speed of psychomotor reactions. If the described adverse reactions occur, one should refrain from performing these activities.

Overdose

Symptoms

No cases of overdose of the Amlodipine + Telmisartan combination have been reported. Possible overdose symptoms are composed of symptoms from the individual components of the drug.

Overdose of amlodipine can lead to excessive peripheral vasodilation and reflex tachycardia. Severe and persistent decrease in blood pressure, including with the development of shock and fatal outcome, has been reported. The most pronounced symptoms of telmisartan overdose were decreased blood pressure and tachycardia. Clinical manifestations such as bradycardia, dizziness, increased plasma creatinine concentration, and acute renal failure have also been recorded.

Treatment

The patient should be under close clinical supervision. Treatment should include symptomatic and supportive therapy. The set of therapeutic measures depends on the time elapsed since drug intake and the severity of symptoms. Recommended measures include induction of vomiting and/or gastric lavage, intake of activated charcoal.

Regular monitoring of plasma electrolyte and creatinine concentrations should be performed. In case of decreased blood pressure, the patient should be placed in a supine position with legs elevated, and intravenous infusion of saline and other plasma-substituting solutions should be started immediately to restore circulating blood volume. Restoration of vascular tone and normalization of blood pressure can be achieved by administering vasoconstrictor drugs, provided there are no contraindications to their use. Intravenous administration of calcium gluconate may alleviate symptoms associated with calcium channel blockade.

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

Drug Interactions

No interaction between the two active substances included in this fixed-dose combination drug was identified in clinical studies. No studies on the drug interaction of Telzap^® AM with other drugs have been conducted.

Interaction with amlodipine

Effect of other drugs on the pharmacological properties of amlodipine

Inhibitors of the CYP3A4 isoenzyme. Concomitant use of amlodipine with strong or moderate inhibitors of the CYP3A4 isoenzyme (HIV protease inhibitors, antifungal drugs from the azole group, macrolides, such as erythromycin or clarithromycin, as well as with verapamil or diltiazem) may be accompanied by a significant increase in systemic exposure parameters of amlodipine, resulting in an increased risk of a sharp decrease in blood pressure. The clinical manifestations of these concomitant use options may be more pronounced in elderly patients; medical supervision is necessary for possible dose adjustment of the drugs.

Inducers of the CYP3A4 isoenzyme. When used concomitantly with inducers of the CYP3A4 isoenzyme, the concentration of amlodipine may vary. Blood pressure should be monitored; the possibility of adjusting the dose of amlodipine during and after concomitant administration, especially with strong inducers of the CYP3A4 isoenzyme (e.g., rifampicin and preparations of St. John’s wort), should be considered.

Grapefruit and grapefruit juice. The use of amlodipine while consuming grapefruit or grapefruit juice is not recommended, as in some patients this may lead to an increase in the bioavailability of the drug and, accordingly, to an enhancement of the antihypertensive effect.

Dantrolene (infusion). In animals receiving verapamil in combination with intravenous dantrolene, the development of lethal ventricular fibrillation and cardiovascular collapse associated with hyperkalemia was observed. Due to the risk of hyperkalemia, it is recommended to avoid the use of calcium channel blockers, such as Amlodipine, concomitantly with dantrolene in patients prone to malignant hyperthermia, as well as for the treatment of this condition.

Effect of amlodipine on the pharmacological properties of other drugs

Amlodipine enhances the effect of other antihypertensive drugs.

Atorvastatin, digoxin and warfarin. In clinical drug interaction studies, Amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin and warfarin.

Cyclosporine. Interaction studies of cyclosporine and amlodipine have not been conducted in healthy volunteers or in any other populations, except for patients who have undergone kidney transplantation. In these patients, an increase in residual plasma concentrations of cyclosporine was detected (on average by 0-40%). In patients receiving Amlodipine in combination with cyclosporine after kidney transplantation, it is recommended to monitor cyclosporine concentrations and, if necessary, reduce its dose.

Simvastatin. With multiple concomitant use of amlodipine at a dose of 10 mg and simvastatin at a dose of 80 mg once daily, the systemic exposure parameter of simvastatin was 77% higher than with simvastatin monotherapy. In patients taking Amlodipine, the dose of simvastatin should not exceed 20 mg/day.

Tacrolimus. Concomitant use of tacrolimus with amlodipine is characterized by a risk of increased plasma concentration of tacrolimus. Patients taking Amlodipine should have their plasma tacrolimus concentration monitored, and dose adjustment should be made if necessary to avoid the toxic effects of tacrolimus.

Other drugs. The safety of concomitant use of amlodipine with thiazide diuretics, beta-blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, NSAIDs, antibiotics, and oral hypoglycemic agents has been established. When amlodipine and sildenafil were used concomitantly, it was shown that each of the drugs had an independent hypotensive effect.

Interaction with telmisartan

Digoxin

When telmisartan and digoxin were used concomitantly, an increase in the median C_max of digoxin by 49% and its residual concentration by 20% was observed. At the initial stages of digoxin use, as well as during dose adjustment and treatment discontinuation, it is necessary to monitor the drug concentration parameters in the body to maintain them within the therapeutic range.

Drugs for which concomitant use is not recommended

Potassium-sparing diuretics and potassium-containing dietary supplements. ARBs, such as Telmisartan, reduce potassium losses caused by the action of diuretics. Potassium-sparing diuretics, in particular spironolactone, eplerenone, triamterene and amiloride, as well as potassium-containing dietary supplements or salt substitutes can cause a significant increase in plasma potassium levels. In cases where concomitant use of these drugs with telmisartan is required to eliminate confirmed hypokalemia, treatment should be carried out with caution and subject to regular monitoring of plasma potassium levels.

Lithium preparations. Concomitant use of lithium preparations and ACE inhibitors or ARBs, including Telmisartan, has been accompanied by cases of reversible increase in plasma lithium concentration and symptoms of toxicity. If concomitant use of telmisartan with a lithium preparation is necessary, enhanced monitoring of plasma lithium concentration is recommended.

Drugs for which concomitant use requires caution

NSAIDs (acetylsalicylic acid in doses providing an anti-inflammatory effect, COX-2 inhibitors and non-selective NSAIDs) may weaken the antihypertensive effect of ARBs. In some patients with impaired renal function (in particular, in dehydrated patients or elderly patients with reduced renal function), concomitant use of ARBs and drugs that suppress COX-2 may lead to worsening of renal function impairment, and in some cases to acute renal failure, which is usually reversible. Therefore, treatment with these drug combinations requires caution, especially in elderly patients. The patient must be adequately hydrated. Monitoring of renal function 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, an increase in the AUC_0-24 and C_max parameters of ramipril and ramiprilat up to 2.5 times was observed. The clinical significance of this observation is unclear.

Diuretics (thiazide and loop). Prior treatment with high doses of diuretics, such as furosemide (loop diuretic) and hydrochlorothiazide (thiazide diuretic), as well as salt restriction, diarrhea or vomiting can lead to a decrease in circulating blood volume and increase the risk of excessive decrease in blood pressure at the initial stage of telmisartan therapy.

Drugs for which concomitant use requires increased attention

Other antihypertensive drugs. The effect of telmisartan may be enhanced when used concomitantly with other antihypertensive drugs.

Dual blockade of the RAAS. Clinical studies have shown that achieving dual blockade of the RAAS during combined use of ACE inhibitors, ARBs or aliskiren was associated with an increased frequency of adverse events such as hypotension, hyperkalemia and impaired renal function (including acute renal failure), compared with monotherapy with a drug acting on the RAAS. Concomitant use of the amlodipine and telmisartan combination with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients.

Concomitant use of the amlodipine and telmisartan combination 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 (in particular, baclofen and amifostine), it can be predicted that they will potentiate the effect of all antihypertensive drugs, including Telmisartan.

Ethanol, barbiturates, narcotic drugs and antidepressants. The risk of orthostatic hypotension may increase with alcohol consumption, as well as with the use of barbiturates, narcotic drugs or antidepressants.

Glucocorticoids (for systemic use). Weakening of the antihypertensive effect of telmisartan.

Storage Conditions

The drug should be stored in the original packaging (blister in a cardboard carton), in a place inaccessible to children, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.