Telzap AM, tablets 5 mg+80 mg 28 pcs

Telzap® AM contains two hypotensive agents with complementary mechanisms of action that provide blood pressure (BP) control in patients with essential 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 substances 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 of BMCC class and 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 amlodipine use due to slow onset of drug action.

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

There have been no adverse metabolic effects or changes in plasma lipid concentrations when taking amlodipine. Amlodipine can be taken by patients with bronchial asthma, diabetes mellitus and gout. Amlodipine usage in patients with cardiac insufficiency is not accompanied with negative inotropic action (does not decrease exercise tolerance and left ventricular ejection fraction).

Telmisartan

The 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 angiotensin II receptor subtype AT1. 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-term.

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 will almost completely stop the increase in BP under the influence of angiotensin II.

The 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 h. A pronounced antihypertensive effect usually develops 4-8 weeks after regular use. The action lasts for 24 h after telmisartan administration and remains significant up to 48 h.

In patients with arterial hypertension telmisartan provides reduction of BP and BP with no effect on HR.
After abrupt withdrawal of telmisartan treatment there is a gradual (over several days) return of BP values to their values before the start of the drug 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 drug amlodipine and telmisartan, administered once daily, results in effective and sustained BP reduction within 24 hours.

Pharmacokinetics

Amlodipine

Intake

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

Distribution

The apparent volume of distribution (Vd) is approximately 21 l/kg. In vitro studies have shown that approximately 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 T1/2 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 hepatic function

There is very limited clinical data on the use of amlodipine in patients with impaired hepatic function. In patients with hepatic impairment, decreased clearance of amlodipine has been observed, resulting in a prolonged T1/2 and increased AUC of approximately 40-60%.

Elderly patients

The time of reaching maximum plasma concentration (tmax) of amlodipine 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 t1/2.

Telmisartan

Intake

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, there is a decrease in the area under the curve “concentration-time” (AUC) of approximately 6% (when telmisartan is taken at a dose of 40 mg per day) to 19% (at a dose of 160 mg per day). Three hours after drug administration, telmisartan plasma concentrations level off, regardless of food intake.

Distribution

Telmisartan is highly bound to plasma proteins (> 99.5%), primarily to albumin and to alpha-1-acid glycoprotein. The average apparent volume of distribution in the equilibrium state (Vdss) 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.

The elimination half-life (T1/2) is more than 20 hours. Maximum plasma concentration (Cmax) 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. Cmax and, to a lesser extent, AUC increase disproportionately with doses above 40 mg per day.

Particular patient populations

Patient gender

There were differences in plasma concentrations of the drug in men and women: Cmax and AUC values were approximately 3 and 2 times higher in women than in men, respectively.

Patients in the elderly

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 concentrations was observed. However, in patients with renal impairment who are on hemodialysis, plasma concentrations of the drug were lower. Telmisartan is highly bound to plasma proteins and is not excreted by hemodialysis. The T1/2 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. The T1/2 in patients with impaired liver function was not altered.

Indications

Hypertension (high blood pressure)

• 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 + 80 mg contains:

Active ingredients:

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

telmisartan – 80,000 mg;

Excipients:

sorbitol,

sodium hydroxide,

povidon K25,

microcrystalline cellulose,

How to take, the dosage

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

• 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 drug administration, such as peripheral edema, may switch to Telzap® AM at 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 begin with Telzap® AM when it is believed that achieving BP control with any one drug is unlikely.
  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 may be gradually increased to a maximum of 10 mg + 80 mg, not earlier than 2 weeks after starting therapy.

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

Patients of advanced age (over 65 years): no dose adjustment is required.

Patients with impaired renal function

Dose adjustment is not required in patients with mild to moderate impaired renal function. The experience of using the drug in patients with severe renal impairment or who are on hemodialysis is limited. Treatment with Telzap® AM should be performed with caution in these patients since amlodipine and telmisartan are not excreted by hemodialysis.

Patients with hepatic impairment

Dose selection of Telzap® AM in patients with mild to 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.

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

. Effect 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 exposure to amlodipine. resulting in an increased risk of a sharp decrease in BP.

The clinical manifestations of these concomitant use variants may be more pronounced in elderly patients, and physician monitoring is necessary for possible dose adjustments.

CYP3A4 isoenzyme inducers

The concentration of amlodipine may vary with concomitant use of CYP3A4 isoenzyme inducers. BP should be monitored, and consideration should be given to adjusting the dose of amlodipine during and after concomitant use, especially with strong inducers of CYP3A4 isoenzyme (e.g., rifampicin and St. John’s Wort preparations).

Grapefruit and grapefruit juice

The 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 (as 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 who are prone to develop malignant hyperthermia and to treat this condition.

The effect 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

Cyclosporine and amlodipine interaction studies have not been performed in healthy volunteers or in any other populations except kidney transplant patients.

In these patients, increased residual plasma concentrations of cyclosporine were found (0-40% on average).

In patients receiving amlodipine in combination with cyclosporine after undergoing kidney transplantation, it is recommended to monitor cyclosporine concentrations and reduce the dose if necessary.

Simvastatin

In concomitant use of multiple doses of amlodipine 10 mg and simvastatin 80 mg once daily, the rate of systemic exposure to simvastatin was 77% higher than against 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 concentrations of tacrolimus. Patients taking amlodipine should have their plasma tacrolimus concentrations monitored and, if necessary, the dose should be adjusted to avoid toxic effects of tacrolimus.

Other drugs

The safety of co-administration of amlodipine with thiazide diuretics, beta-adrenoblockers, ACE inhibitors. Nitroglycerin (used sublingually), nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics and oral hypoglycemic agents. When amlodipine and sildenafil were used concomitantly, each drug was shown to have an independent hypotensive effect.

Interaction with telmisartan

Digoxin

Concomitant use of telmisartan and digoxin showed a 49% increase in median Cmax of digoxin and a 20% increase in residual concentration. In the initial stages of digoxin administration as well as when adjusting the dose and cancelling treatment, 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

PARA II agents such as telmisartan decrease potassium loss associated with diuretics. Potassium-saving diuretics, particularly spironolactone, eplerenone, triamterene, and amiloride. and potassium-containing supplements or salt substitutes may cause significant increases in plasma potassium.

When concomitant use of these drugs with telmisartan is required to eliminate confirmed hypokalemia, treatment should be given 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 increases 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 whose concomitant use requires caution

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 (particularly in patients with dehydration or elderly patients with decreased renal function) concomitant administration of APA II and COX-2 inhibitors may lead to worsening of renal function impairment and in some cases to acute renal failure, which is usually reversible.

Because of this, treatment with these drug combinations 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 and also regularly during treatment.

Ramipril

In a clinical study with concomitant use of telmisartan and ramipril, there was an increase in AUC0-24 and Cmax of ramipril and ramiprilate up to 2.5-fold. The clinical significance of this observation is unclear.
Diuretics (thiazide and petrous)

. 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 therapy with telmisartan.

Drugs whose concomitant use requires extra attention

Other hypotensive drugs

The effects of telmisartan may be enhanced by concomitant use of other hypotensive drugs.
Double blockade of renin-angiotensin-aldosterone system (RAAS)

The clinical studies showed that achievement of double blockade of RAAS against combined use of ACE inhibitors, ARA II or aliskiren was associated with increased incidence of adverse events such as BP decrease. hyperkalemia and impaired renal function (including acute renal failure), compared with monotherapy with an RAAS agent.

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

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

Based on the pharmacological properties of some drugs (particularly baclofen and amifostine), it is predictable that they will potentiate the effects of all hypotensive drugs, including telmisartan.

Alcohol, barbiturates, narcotics, and antidepressants

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

Glucocorticoids (for systemic use)

Weakening of the antihypertensive effect of telmisartan.

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, amlodipine use was associated with increased reports of pulmonary edema, despite no significant difference in the rate of heart failure progression compared to placebo.

The use of PBMCs, including amlodipine, should be used with caution in patients with CHF because of the possible risk of other cardiovascular complications and mortality.

Hepatic disorders

As with other BMCCs, the T1/2 of amlodipine is prolonged in patients with hepatic impairment. Therefore, Telzap® AM should be used with caution in such patients and the dose of telmisartan should not exceed 40 mg once daily. Telzap® AM is contraindicated in patients with severe hepatic impairment.

Renal 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

Telzap® AM dose adjustment is not required in elderly patients. Increasing the dose should be done with 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). The use of Telzap® AM is contraindicated in patients with rare hereditary fructose intolerance.

Telmisartan

Hepatic impairment

The use of the combination amlodipine + telmisartan is contraindicated in patients with cholestasis, biliary obstruction and/or severe hepatic impairment because telmisartan is mostly excreted with bile. There is reason to believe that hepatic clearance of telmisartan is reduced in these patients. Caution should be exercised in patients with mild to moderate hepatic dysfunction.

Renovascular hypertension

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

Kidney dysfunction 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.

Decreased circulating blood volume (CBC)

Decreased BP, especially after the first administration of Telzap® AM, may occur in patients with decreased CBC and/or low plasma sodium on the background of previous diuretic treatment, restricted intake of table salt, diarrhea or vomiting. Such conditions (fluid and/or sodium deficiency) should be eliminated before starting 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 to 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 blood pressure parameters 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.

In this regard, dual RAAS blockade (particularly when 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.

Other conditions associated with 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), use of medications 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.

Primary hyperaldosteronism

In patients with primary hyperaldosteronism, treatment with hypotensive drugs that act 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 require special caution.

Patients with diabetes mellitus receiving insulin or other hypoglycemic drugs

In patients with diabetes mellitus receiving insulin or other hypoglycemic drugs, telmisartan may lead to 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, or in patients who are concomitantly treated 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:

– diabetes mellitus, impaired renal function, older age (patients over 70 years);

– concomitant use with drugs acting on the RAAS and/or supplements containing potassium.

Drugs that may cause hyperkalemia. are potassium-containing salt substitutes, potassium-saving diuretics, ACE inhibitors, ARA II, NSAIDs, including selective COX-2 inhibitors, heparin, immunosuppressants (cyclosporine and tacrolimus) and trimethoprim.

– comorbidities, especially dehydration, acute heart failure, metabolic acidosis, acute renal failure (e.g., in infectious diseases), cytolysis syndrome (e.g., acute limb ischemia, rhabdomyolysis, extensive trauma).

Patients at risk are advised to carefully monitor plasma potassium.
Ethnic differences

Like all other ARA II, telmisartan reduces BP less effectively 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 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. Because of possible dizziness, headache, increased fatigability, nausea when taking the drug, caution should be exercised while driving vehicles and engaging in other activities requiring concentration and quick psychomotor functions.

In case of the described adverse reactions, the following activities should be avoided.

Contraindications

• High sensitivity to the active ingredients, excipients and other dihydropyridine derivatives
• pregnancy;
• breastfeeding period;
• obstructive biliary tract disease;
• severe arterial hypotension;
• left ventricular outflow tract obstruction (including high degree of aortic stenosis);
• Hemodynamically unstable heart failure after acute myocardial infarction;
• severe liver dysfunction;
• Shock (including cardiogenic shock);
• current use with aliskiren or drugs containing aliskiren in patients with diabetes and/or moderate to severe renal function impairment (glomerular filtration rate (GFR) less than 60 ml/min/1.73 m² body surface area);
• Simultaneous use with ACE inhibitors in patients with diabetic nephropathy;
• fructose intolerance and glucose/galactose malabsorption syndrome or sugar/isomaltase deficiency;
• age under 18 years (effectiveness and safety not established).

Cautions

• Bilateral renal artery stenosis or artery stenosis of the only functioning kidney;
• Kidney function impairment and condition after kidney transplantation;
• disorders of liver function; there are no dosing recommendations for patients with impaired liver function, so caution should be exercised in such clinical cases;
• decreased circulating blood volume (CBC) due to previous diuretics, restricted intake of table salt, diarrhea, or vomiting;
• hyponatremia;
• hyperkalemia;
• aortic or mitral valve stenosis;
• primary hyperaldosteronism (efficacy and safety not established);
• age above 70 years of age;
• ischemic heart disease and/or clinically significant cerebral vascular atherosclerosis (with excessive BP reduction there is a risk of worsening ischemic disorders, up to and including acute myocardial infarction and/or stroke);
• syndrome of weak sinus node (marked bradycardia, tachycardia);
• chronic heart failure (CHF) of non-ischemic etiology of NYHA functional class III-IV;
• hypertrophic obstructive cardiomyopathy.

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Side effects

The incidence of adverse reactions was determined according to the World Health Organization (WHO) classification: Very common (≥1/10); common (≥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 from available data).

Potential adverse reactions during treatment with Telzap® AM include all adverse reactions 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.

The 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: infrequent anemia; rare eosinophilia and thrombocytopenia.

Intrinsic system disorders: rarely – anaphylactic reactions and hypersensitivity reactions.

Disorders of metabolism and nutrition: infrequent hyperkalemia: rare – hypoglycemia (in patients with diabetes).

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

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

Visual system disorders: rare – visual disturbances.

Hearing and labyrinth disorders: infrequent – vertigo.

Chronic disorders: infrequent – bradycardia; rarely – tachycardia.

Vascular disorders: infrequent – decreased BP, orthostatic hypotension.

Respiratory system, thoracic and mediastinal disorders: infrequent – dyspnea, cough; very rare – interstitial lung disease.

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

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

Skin and subcutaneous tissue disorders: infrequent – skin itching, increased sweating, skin rash; rarely – angioedema (including lethal), eczema, erythema, urticaria, drug rash, toxidermia.
Musculoskeletal and connective tissue disorders: infrequent – back pain (e.g., ischialgia), muscle cramps, myalgia; rare – arthralgia, pain in extremities, tendon pain (symptoms resembling tendonitis).

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

General disorders and disorders at the site of administration: infrequent – pain in the chest, 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 creatine phosphokinase concentration.

Description of individual adverse reactions

Sepsis

In a clinical study, 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.

Pressure decrease

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 of this ethnic group are susceptible to developing adverse reactions of this type.

Interstitial lung disease

In the post-registration period, there were reports of cases of interstitial lung disease that had a temporal association with telmisartan administration. 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 with amlodipine include drowsiness, dizziness, headache, palpitations, feeling of “rush” to the skin, abdominal pain, nausea, edema of the ankles and other localizations, fatigue.

Blood and lymphatic system disorders: very rarely – leukopenia, thrombocytopenia.

Immune system disorders: very rare – allergic reactions.

Metabolism and nutrition disorders: infrequent – weight loss, weight gain; very rare – hyperglycemia.

Psychiatric disorders: infrequent – insomnia, mood changes (including anxiety), depression: rare – confusion.

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

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

Hearing and labyrinth disorders: infrequent – tinnitus.

Chronic disorders: often – 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 – decrease of BP; very rare – vasculitis.

Respiratory system, thoracic and mediastinal disorders: frequently – shortness of breath; infrequently – cough, rhinitis.

Gastro-intestinal 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.

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

Skin and subcutaneous tissue disorders: frequent – 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 rare – angioedema, erythema multiforme, exfoliative dermatitis, Stevens Johnson syndrome, photosensitivity; frequency unknown – toxic epidermal necrolysis.

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

Kidney and urinary tract disorders: infrequent – frequent frequent urination, dysuria, nycturia.

Gender 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 – pain in the chest, pain, general malaise.

Unwanted reactions expected on the basis of experience with amlodipine and telmisartan

Infectious and parasitic diseases: rarely – cystitis.

Mental disorders: rarely – anxiety, insomnia, depression.

Nervous system disorders: frequent – dizziness, infrequent – somnolence, migraine, headache, paresthesia; rare – syncope, peripheral neuropathy, hypoesthesia, dysgeusia, tremor.

Hearing and labyrinth disorders: infrequent – vertigo.

Chronic disorders: infrequent – bradycardia, palpitations.

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

Respiratory system disorders of the thorax and mediastinum: infrequent – cough; very rare – interstitial lung disease.

Gastrointestinal 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 cramps (cramps of the calf muscles), myalgia; rarely – back pain, pain in the lower extremities (legs).

Urinary tract disorders: rarely – nycturia.

Gender and mammary gland disorders: infrequent – erectile dysfunction.

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

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

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

Overdose

Symptoms

No cases of overdose of amlodipine + telmisartan combination have been reported. Possible symptoms of overdose consist of symptoms of individual drug components.

Amlodipine overdose may lead to excessive peripheral vasodilation and reflex tachycardia. Significant and persistent decrease in BP has been reported, including with the development of shock and lethal outcome. The most pronounced symptoms of telmisartan overdose were decreased BP and tachycardia. Clinical manifestations such as bradycardia, dizziness, increased plasma creatinine concentration 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 therapeutic 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.

Regular monitoring of plasma electrolyte and creatinine concentrations should be performed. 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 that 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 practically not excreted from the body by hemodialysis.

Similarities

Twinsta, Telmista