Composition
1 tablet 5 mg + 40 mg contains:
active ingredients:
amlodipine-5,000 mg (as amlodipine bezylate-6,935 mg),
telmisartan-40,000 mg;
excipients: Â sorbitol, sodium hydroxide, povidone K 25, microcrystalline cellulose, calcium hydrophosphate dihydrate, meglumine, magnesium stearate.
Pharmacological action
Pharmacotherapeutic group: combined antihypertensive agent (slow calcium channel blocker + angiotensin II receptor antagonist).
ATX code: C09DB04.
Pharmacological properties
Pharmacodynamics
The drug Telzap ® AM contains two antihypertensive substances with complementary mechanisms of action that provide control of blood pressure (BP) in patients with essential arterial hypertension; amlodipine belongs to the pharmacological group of slow calcium channel blockers (BMCC), and telmisartan belongs to the group of angiotensin II receptor antagonists (ARA II). The combination of these substances exhibits an additive antihypertensive effect, causing a more pronounced decrease in blood pressure than each of the components of the drug separately.
Amlodipine
Amlodipine-a dihydropyridine derivative, belongs to the BMCC class, inhibits the transmembrane supply of calcium ions to cardiomyocytes and smooth muscle cells of blood vessels. The mechanism of antihypertensive action of amlodipine is associated with the vasodilating effect on vascular smooth muscles. The exact mechanism by which amlodipine reduces the frequency and severity of angina attacks is not fully understood, but amlodipine can reduce myocardial ischemia due to the following two effects: :
In patients with arterial hypertension, taking amlodipine once a day provides a clinically significant reduction in blood pressure in the “lying” and “standing” positions for 24 hours. Orthostatic 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 at therapeutic doses leads to a decrease in renal vascular resistance, an increase in glomerular filtration rate and effective plasma flow in the kidneys without changing filtration or proterinuria.
No adverse metabolic effects or changes in plasma lipid concentrations were observed when taking amlodipine. Amlodipine can be taken in patients with asthma, diabetes, and gout. The use of amlodipine in patients with heart failure is not accompanied by a negative inotropic effect (exercise tolerance does not decrease, the left ventricular ejection fraction does not decrease).
Telmisartan
Mechanism of action
Telmisartan is a specific ARA II (type AT1) that is effective when taken orally. Telmisartan has a very high affinity for the binding site of the AT1 receptor subtype to angiotensin II, and it displaces angiotensin II from binding to the receptor without having an agonist effect on this receptor. Telmisartan does not exhibit the properties of a partial agonist of the AT1 receptor. Telmisartan selectively binds to the AT1 receptor. Communication with the receptor is long-term. Telmisartan does not show affinity for other receptors, including AT2-type receptors and other less well-studied angiotensin receptors. Telmisartan reduces the concentration of aldosterone in blood plasma, does not inhibit renin and does not block ion channels. Telmisartan does not inhibit the activity of angiotensin-converting enzyme (ACE) (kininase II), an enzyme that also destroys bradykinin. This suggests that the drug will not increase the adverse events associated with the action of bradykinin.
A dose of telmisartan 80 mg per day almost completely stops the increase in blood pressure under the influence of angiotensin II. The antihypertensive effect persists for 24 hours and remains significant for 48 hours.
After taking 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 hours after taking telmisartan and remains significant for up to 48 hours.
In patients with arterial hypertension, telmisartan reduces SBP and DBP without affecting heart rate.
After abrupt discontinuation of treatment with telmisartan, there is a gradual (over several days) return of blood pressure indicators to their values before starting the drug without the development of “withdrawal”syndrome.
In patients treated with telmisartan, the incidence of dry cough was significantly lower than in patients treated with ACE inhibitors. These data were obtained in clinical trials with a direct comparison of these two types of antihypertensive therapy.
The combined preparation of amlodipine and telmisartan, used once a day, leads to an effective and sustained decrease in blood pressure for 24 hours
. Pharmacokinetics
Amlodipine
Suction
After oral use of amlodipine in therapeutic doses, the maximum plasma concentrations are reached in 6-12 hours. The absolute bioavailability of the drug is 64-80%. Food intake does not affect the bioavailability of amlodipine.
Distribution
The apparent volume of distribution(vd) 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.
Biotransformation
Amlodipine is largely (approximately 90%) metabolized in the liver to form inactive metabolites.
The elimination
half-life of amlodipine from the blood 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 of the drug is eliminated in the form of the initial compound and 60% in the form of metabolites. The elimination of amlodipine from the blood plasma occurs in two phases.
Special patient populations
Patients with impaired liver function
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 clearance of amlodipine was observed, which led to an elongation ofthe half-life and an increase in AUC by approximately 40-60%.
Elderly patients
The time to reach the maximum concentration (tmax) of amlodipine in blood plasma 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 ofHalf-life.
Telmisartan
Suction
Telmisartan is rapidly absorbed, but the amount of drug absorbed may vary. The average absolute bioavailability of telmisartan is approximately 50%. When taking telmisartan with food, there is a decrease in the area under the concentration-time curve (AUC) from approximately 6% (when taking telmisartan at a dose of 40 mg per day) to 19% (at a dose of 160 mg per day).3 hours after taking the drug, the concentration of telmisartan in the blood plasma is leveled, regardless of food intake.
Distribution
Telmisartan is characterized by a high degree of binding to plasma proteins (> 99.5%), mainly to albumin and alpha-1-acid glycoprotein. The average apparent volume of distribution at steady state (vdss) is approximately 500 liters.
Biotransformation
The metabolism of telmisartan consists in conjugation of the parent compound with glucuronic acid. The resulting conjugate has no pharmacological activity.
Deduction
The half-life (half-life) is more than 20 hours. The maximum plasma concentration (cmax) and, to a lesser extent, AUC increase disproportionately to the dose increase. There are no data on clinically significant accumulation of telmisartan taken at the recommended doses. It is excreted through the intestines in unchanged form, excretion by the kidneys-less than 1%. Total plasma clearance is high (about 1000 ml / min) compared to “hepatic” blood flow (about 1500 ml / min).
Linearity / non-linearity of pharmacokinetics
There was no linear relationship between the dose of the drug and its plasma concentration. Cmax and, to a lesser extent, AUC increase disproportionately at doses higher than 40 mg per day.
Special patient populations
Gender of patients
Differences in the concentration of the drug in blood plasma in men and women were revealed: cmax valuesand AUC in women were approximately 3 and 2 times higher than in men, respectively.
Elderly patients
The pharmacokinetics of telmisartan did not differ between elderly patients and patients under 65 years of age.
Patients with impaired renal function
In patients with mild, moderate and severe renal impairment, a 2-fold increase in the concentration of telmisartan in blood plasma was observed. However, in patients with renal insufficiency undergoing 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. Thehalf-life did not change in patients with impaired renal function.
Patients with impaired liver function
The results of pharmacokinetic studies showed an increase in the absolute bioavailability of telmisartan to almost 100% in patients with impaired liver function. Thehalf-life 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);
- arterial hypertension (in patients who are indicated for combination therapy);
- arterial hypertension in patients receiving telmisartan and amlodipine as separate monopreparations, as a substitute for this therapy.
Use during pregnancy and lactation
Pregnancy
The use of Telzap ® AM during pregnancy is contraindicated. Special studies on the use of the combination amlodipine + telmisartan during pregnancy and lactation have not been conducted. The effects associated with individual active substances are described below.
Amlodipine
The safety of amlodipine 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 prevails over the risk associated with the use of the drug.
Telmisartan
Epidemiological evidence for the risk of teratogenic effects of ACE inhibitors during the first trimester of pregnancy is not sufficiently convincing, but it does not allow us to exclude a slight increase in the risk of negative effects on the fetus. Although controlled epidemiological studies of the teratogenic effect associated with ARA II have not been conducted, the use of drugs in this group may be associated with a similar risk. Except in cases of extreme need for continuous treatment of ARA II, patients planning pregnancy should switch to alternative antihypertensive drugs with a studied safety profile during pregnancy. If pregnancy is confirmed, treatment with Telzap ® AM should be stopped immediately and, if necessary, alternative therapy should be initiated.
It has been reported that exposure to ARA II during the second and third trimesters of pregnancy may be accompanied by fetal toxicity (decreased renal function, oligohydramnion, delayed cranial ossification) and neonatal toxicity (renal failure, decreased blood pressure, hyperkalemia). If you are taking Telzap® AM starting in the second trimester of pregnancy, an ultrasound examination of the fetal kidney function and cranial bones should be performed.
children born to women who have taken Telzap ® AM during pregnancy should be closely monitored for the timely detection of hypotension.
Breast-feeding period
There are no data on the use of amlodipine and telmisartan during breastfeeding. In this regard, the use of Telzap® AM during breastfeeding is contraindicated.
Amlodipine passes into breast milk in an amount of 3-7% of the maternal dose (up to a maximum of 15%). The effect of amlodipine on newborns is unknown. In the case of nursing women, preference should be given to alternative medications with a more studied safety profile during breastfeeding, especially when feeding a newborn or premature baby. A decision should be made to stop breastfeeding or discontinue the drug, taking into account the need for its use for the mother.
Fertility
Amlodipine
Clinical data regarding the potential effect of amlodipine on fertility are insufficient. In one rat study, adverse effects on male fertility were found.
When using BMCC, biochemical changes in the sperm head were observed in some patients. The amount of clinical data on the potential effect of amlodipine on fertility is insufficient.
Telmisartan
In preclinical studies, telmisartan had no effect on male and female fertility.
Contraindications
- Hypersensitivity to the active, auxiliary substances and other derivatives of dihydropyridine;
- pregnancy;
- breastfeeding;
- obstructive disease of the biliary tract;
- severe arterial hypotension;
- obstruction of the output tract of the left ventricle (including a high degree of aortic stenosis);
- hemodynamically unstable heart failure after acute myocardial infarction;
- severe hepatic impairment;
- shock (including cardiogenic);
- concurrent use with aliskiren or drugs containing aliskiren, in patients with diabetes and/or moderate to severe renal impairment (glomerular filtration rate (GFR) less than 60 ml/min/1.73 m 2 of the body surface area);
- concurrent use of ACE inhibitors in patients with diabetic nephropathy;
- fructose intolerance and malabsorption syndrome glucose/galactose or sucrase deficiency/isomaltase;
- age to 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 (data on the use in the acute period and within one month after myocardial infarction);
- the impairment of renal function and condition after kidney transplantation;
- the liver; recommendations on dosage in patients with hepatic impairment has not been developed, therefore, in such clinical cases, use caution;
- decline in the volume of circulating blood (BCC) on the background of the preceding use of diuretics, limit the consumption of salt, diarrhoea or vomiting;
- diabetes mellitus;
- hypernatremia;
- hyperkalemia;
- stenosis of the aortic or mitral valve;
- primary hyperaldosteronism (efficacy and safety not established);
- age over 70 years;
- ischemic heart disease and/or clinically significant atherosclerosis of the brain (at excessive decrease in blood pressure have a risk of developing ischemic disorders, until the development of acute myocardial infarction and/or stroke);
- syndrome of weakness of the sinus node (bradycardia, tachycardia);
- congestive heart failure (CHF) in non-ischemic etiology of III-IV functional class NYHA classification;
- hypertrophic obstructive cardiomyopathy.
Side effects
The frequency of adverse reactions was determined according to the World Health Organization (WHO) classification: very rare (≥ 1/10); common (≥ 1/100 and < 1/10);infrequent (≥ 1/1000 and < 1/100); rare (≥ 1/10000 and < 1/1000); very rare (
Potential adverse reactions during treatment with Telzap ® AM include all adverse reactions that have previously been reported with the use of individual components of the drug.
Adverse reactions expected based on experience with telmisartan
Serious adverse reactions include anaphylactic reactions and angioedema (the frequency of occurrence is “rare”), and acute renal failure.
In controlled clinical trials in patients with 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 frequency of adverse reactions did not depend on the dose of the drug, as well as on the gender, age or race of the patients. The safety profile of telmisartan in patients treated with the drug to reduce cardiovascular morbidity was similar to that in patients with arterial hypertension.
The adverse reactions listed below have been reported in controlled clinical trials in patients with arterial hypertension or identified in the analysis of reports received in the post-marketing period. This list also includes serious and non-serious adverse reactions that led to treatment discontinuation in three long-term clinical trials involving 21,642 patients who took telmisartan to reduce cardiovascular morbidity for a period of up to 6 years.
Infectious and parasitic diseases: infrequently-urinary tract infections (including cystitis), upper respiratory tract infections (including pharyngitis and sinusitis); rarely – sepsis (including fatal outcome).
Disorders of the blood and lymphatic system: infrequently-anemia; rarely-eosinophilia, thrombocytopenia.
Immune system disorders: rarely – anaphylactic reactions, hypersensitivity reactions.
Metabolic and nutritional disorders:infrequently-hyperkalemia; rarely-hypoglycemia (in patients with diabetes mellitus).
Mental disorders: infrequently – insomnia, depression; rarely-anxiety.
Nervous system disorders: infrequently-fainting; rarely-drowsiness.
Visual disturbances: rarely-visual disorders.
Hearing disorders and labyrinth disorders: infrequently-vertigo.
Cardiac disorders: infrequently-bradycardia; rarely-tachycardia.
Vascular disorders: infrequently-decreased blood pressure, orthostatic hypotension.
Respiratory, thoracic and mediastinal disorders: infrequently-shortness of breath, cough; very rarely – interstitial lung disease.
Disorders of the gastrointestinal tract: infrequently – abdominal pain, diarrhea, dyspepsia, bloating, vomiting; rarely-dry mouth, stomach discomfort.
Liver and biliary tract disorders: rarely-impaired liver function/liver damage.
Skin and subcutaneous tissue disorders: infrequently – skin pruritus, increased sweating, skin rash; rarely-angioedema (including fatal ones), eczema, erythema, urticaria, drug rash, toxicoderma.
Musculoskeletal and connective tissue disorders: infrequently-back pain (for example, sciatica), muscle spasms, myalgia; rarely-arthralgia, pain in the extremities, pain in the tendons (symptoms similar to tendinitis).
Kidney and urinary tract disorders: infrequently-impaired renal function, including acute renal failure.
General disorders and disorders at the injection site: infrequently-chest pain, asthenic syndrome (general weakness); rarely-flu-like syndrome.
Laboratory and instrumental data: infrequently-an increase in the concentration of creatinine in blood plasma; rarely-a decrease in the concentration of hemoglobin in blood plasma, an increase in the concentration of uric acid in blood plasma, an increase in the activity of “liver” enzymes, an increase in the concentration of creatine phosphokinase in blood plasma.
Description of individual adverse reactions
Sepsis
In a clinical study, the incidence of sepsis in the telmisartan group was higher than in the placebo group. This can be regarded as an accidental discovery or as the development of a phenomenon associated with a currently unknown mechanism.
Lowering blood pressure
This adverse reaction has often been reported in patients with controlled blood pressure while using telmisartan in combination with standard therapy to reduce cardiovascular morbidity.
Impaired liver function/liver damage
The greatest number of cases of liver dysfunction or liver damage was detected in the analysis of post-marketing reports of clinical cases in patients of the Japanese ethnic group. Patients of this ethnic group are susceptible to the development of adverse reactions of this type.
Interstitial lung disease
During the post-marketing period, cases of interstitial lung disease that were temporarily associated with telmisartan were reported. However, a causal relationship between the use of telmisartan and the development of this disease has not been established.
Adverse reactions expected based on experience with amlodipine
The most common adverse reactions associated with the use of amlodipine include drowsiness, dizziness, headache, palpitations, a feeling of “rush” of blood to the skin, abdominal pain, nausea, swelling of the ankles and other localization, fatigue.
Disorders of the blood and lymphatic system: very rarely – leukopenia, thrombocytopenia.
Immune system disorders: very rarely – allergic reactions.
Metabolic and nutritional disorders: infrequently-weight loss, weight gain; very rarely-hyperglycemia.
Mental disorders: infrequently – insomnia, mood swings (including anxiety), depression; rarely-confusion.
Nervous system disorders: often-drowsiness, dizziness, headache (especially at the beginning of treatment); infrequently-tremor, dysgeusia, syncope, hypesthesia, paresthesia; very rarely – hypertonus, peripheral neuropathy; frequency unknown – extrapyramidal disorders.
Visual disturbances: often – visual disorders (including diplopia).
Hearing disorders and labyrinth disorders: infrequently-tinnitus.
Cardiac disorders: often-palpitation sensation; infrequently-arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation); very rarely – myocardial infarction.
Vascular disorders: often – a feeling of “rush” of blood to the skin; infrequently-a decrease in blood pressure; very rarely-vasculitis.
Respiratory, thoracic and mediastinal disorders: often-shortness of breath; infrequently-cough, rhinitis.
Gastrointestinal disorders: often-abdominal pain, nausea, irregular bowel movements (including diarrhea and constipation); infrequently – vomiting, dry oral mucosa; 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: often swelling of the ankles and feet; rarely, alopecia, purpura, pigmentation changes of the skin (the appearance of discolored skin areas), increased sweating, pruritus, skin rash, exanthema, urticaria; very rarely – angioedema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, photosensitivity; frequency unknown – toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders: often-muscle spasms; infrequently-arthralgia, myalgia, back pain.
Kidney and urinary tract disorders: infrequently – frequent urination, dysuria, nocturia.
Genital and breast disorders: infrequently-erectile dysfunction, gynecomastia.
General disorders and disorders at the injection site: very often-edema; often-increased fatigue, asthenic syndrome; infrequently-chest pain, pain, general malaise.
Adverse reactions expected based on experience with amlodipine and telmisartan
Infectious and parasitic diseases: rarely – cystitis.
Mental disorders: rarely-anxiety, insomnia, depression.
Nervous system disorders: often – dizziness, infrequently-drowsiness, migraine, headache, paresthesia; rarely-fainting, peripheral neuropathy, hypesthesia, dysgeusia, tremor.
Hearing disorders and labyrinth disorders: infrequently-vertigo.
Cardiac disorders: infrequently-bradycardia, palpitation sensation.
Vascular disorders: infrequently-hypotension, orthostatic hypotension, hot flashes.
Respiratory, thoracic and mediastinal disorders: infrequently-cough; very rarely – interstitial lung disease.
Gastrointestinal disorders: infrequently-abdominal pain, diarrhea, nausea; rarely-vomiting, gum hypertrophy, shortness of breath, dry mouth.
Skin and subcutaneous tissue disorders: infrequently-pruritus of the skin; rarely-eczema, erythema.
Musculoskeletal and connective tissue disorders: infrequently-arthralgia, muscle spasms (calf muscle spasms), myalgia; rarely-back pain, pain in the lower extremities (legs).
Urinary tract disorders: rarely-nocturia.
Disorders of the genitals and breast: infrequently-erectile dysfunction.
General disorders and disorders at the injection site: often-peripheral edema; infrequently-asthenia, chest pain, fatigue, edema.
Laboratory and instrumental data: infrequently-an increase in the concentration of “hepatic” transaminases; rarely-an increase in the 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 in patients who received the combination of amlodipine and telmisartan less often than in patients receiving amlodipine alone.
Interaction
Interactions between the two active substances that make up this drug in fixed doses were not detected in clinical studies.
Studies on the drug interactions of Telzap ® AM with other drugs have not 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 potent or moderate inhibitors of the CYP3A4 isoenzyme (HIV protease inhibitors, azole antifungal drugs, macrolides, for example, erythromycin or clarithromycin, as well as with 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 blood pressure. Clinical manifestations of these variants of simultaneous use may be more pronounced in elderly patients, and medical supervision is necessary in order to possibly adjust the doses of drugs.
Inducers of the CYP3A4 isoenzyme
With simultaneous use of inducers of the CYP3A4 isoenzyme, the concentration of amlodipine may vary. Blood pressure should be monitored, and dose adjustment of amlodipine should be considered during and after concomitant use, especially with strong inducers of the CYP3A4 isoenzyme (for example, rifampicin and St. John’s wort preparations).
Grapefruits and grapefruit juice
The use of amlodipine against the background of eating grapefruit or grapefruit juice is not recommended, since in some patients this may lead to an increase in the bioavailability of the drug and, accordingly, to an increased antihypertensive effect.
Dantrolene (in the form of infusions)
Fatal ventricular fibrillation and cardiovascular collapse associated with hyperkalemia were observed in animals treated with verapamil in combination with intravenous dantrolene. Due to the risk of developing hyperkalemia, it is recommended to avoid the use of BMCs, such as amlodipine, simultaneously with dantrolen in patients who are susceptible to developing 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 had no effect on the pharmacokinetics of atorvastatin, digoxin, and warfarin.
Cyclosporine
Studies of the interaction of cyclosporine and amlodipine have not been conducted either in healthy volunteers or in any other population, with the exception of patients who have undergone kidney transplantation. These patients showed an increase in the residual concentrations of cyclosporine in blood plasma (on average by 0-40%). In patients receiving amlodipine in combination with cyclosporine after a kidney transplant, it is recommended to monitor the concentrations of cyclosporine and, if necessary, reduce its dose.
Simvastatin
When multiple doses of 10 mg amlodipine and 80 mg simvastatin were administered once a day, the systemic exposure of simvastatin was 77% higher than with simvastatin monotherapy. In patients taking amlodipine, the dose of simvastatin should not exceed 20 mg per day.
Tacrolimus
Concomitant use of tacrolimus with amlodipine is characterized by the risk of increasing the concentration of tacrolimus in blood plasma. Patients taking amlodipine should monitor the concentration of tacrolimus in the blood plasma, as well as, if necessary, adjust the dose to avoid toxic effects of tacrolimus.
Other medications
The safety of co-use of amlodipine with thiazide diuretics, beta-blockers, ACE inhibitors, long-acting nitrates, nitroglycerin (used sublingually), nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics and oral hypoglycemic agents has been established. Concomitant use of amlodipine and sildenafil showed that each of the drugs had an independent antihypertensive effect.
Interaction with telmisartan
Digoxin
With simultaneous use of telmisartan and digoxin, an increase in the mediancmax of digoxin by 49% and its residual concentration by 20% was observed. At the initial stages of taking digoxin, as well as when adjusting its dose and discontinuing treatment, it is necessary to monitor the concentration of the drug in the body to maintain them within the therapeutic range.
Medications that are not recommended for concomitant use
Potassium-sparing diuretics and potassium-containing dietary supplements
ARA II drugs, such as telmisartan, reduce the potassium loss caused by diuretics. Potassium-sparing diuretics, such as spironolactone, eplerenone, triamterene, and amiloride, as well as potassium-containing dietary supplements or salt substitutes, can cause a significant increase in blood potassium levels. In cases where the 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 the potassium content in the blood plasma.
Lithium preparations
Concomitant use of lithium preparations with ACE inhibitors or ARA II inhibitors, including telmisartan, was accompanied by cases of reversible increase in the concentration of lithium in blood plasma and symptoms of toxicity. If the concomitant use of telmisartan with a lithium preparation is necessary, it is recommended to conduct enhanced monitoring of the concentration of lithium in the blood plasma.
Medications that require caution when used concomitantly
Nonsteroidal anti-inflammatory drugs (NSAIDs)
NSAIDs (acetylsalicylic acid in doses that provide anti-inflammatory effects, cyclooxygenase-2 (COX-2) inhibitors and non-selective NSAIDs) may weaken the antihypertensive effect of ARA II. In some patients with impaired renal function (in particular, in patients with dehydration or in elderly patients with reduced renal function), the simultaneous use of ARA II and drugs that suppress COX-2 may lead to an aggravation of impaired renal function, and in some cases to acute renal failure, which is usually reversible. In this regard, treatment with these drug combinations requires caution, especially in elderly patients. The patient should have a sufficient degree of hydration. Monitoring of renal function is recommended before starting a combination of medications, as well as regularly during treatment.
Ramipril
In a clinical study with the simultaneous use of telmisartan and ramipril, an increase in the AUCof 0-24 andcmax of ramipril and ramiprilat up to 2.5 times was observed. The clinical significance of this observation is unclear.
Diuretics (thiazide and loop)
Previous 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 lead to a decrease in BCC and increase the risk of excessive blood pressure reduction at the initial stage of telmisartan therapy.
Medications that require special attention when used simultaneously
Other antihypertensive drugs
The effect of telmisartan may be enhanced with the simultaneous use of other antihypertensive drugs.
Double blockade of the renin-angiotensin-aldosterone system (RAAS)
Clinical studies have shown that achieving double blockade of the RAAS with the combined use of ACE inhibitors, ARA II or aliskiren was associated with an increased incidence of adverse events such as decreased blood pressure, hyperkalemia and impaired renal function (including acute renal failure), compared with monotherapy with a drug acting on the RAAS.
Concomitant use of the combination of amlodipine and telmisartan with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or moderate or severe renal insufficiency (GFR less than 60 ml/min / 1.73 m%^%2 of body surface area) and is not recommended in other patients (see section “Contraindications”).
Concomitant use of the combination of amlodipine and telmisartan with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.
Baclofen and amifostin
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.
Alcohol, barbiturates, narcotic drugs and antidepressants
The risk of developing orthostatic hypotension may increase with alcohol consumption, as well as the use of barbiturates, narcotic drugs or antidepressants.
Glucocorticoids (for systemic use)
Attenuation of the antihypertensive effect of telmisartan.
How to take it, course of use and dosage
Inside, once a day, regardless of food intake, with a small amount of liquid.
- Patients receiving amlodipine and telmisartan as separate tablets may be transferred to Telzap® AM therapy, which contains the same doses of active substances.
- 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 have observed adverse reactions that limit the use of the drug, for example, peripheral edema, can switch to taking Telzap® AM at a dose of 5 mg + 40 mg 1 time per day, which will reduce the dose of amlodipine, but will not reduce the overall expected hypotensive effect.
- Treatment of arterial hypertension in a patient may begin with the use of Telzap® AM in cases where it is assumed that achieving blood pressure control with any one drug is unlikely.
The initial dose of Telzap® AM is 5 mg + 40 mg once a day.
Patients who need a more significant reduction in blood pressure can start taking Telzap® AM at a dose of 5 mg + 80 mg once a day.
If an additional reduction in blood pressure 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.
Maximum daily dose: 10 mg of amlodipine + 80 mg of telmisartan.
Elderly patients (over 65 years of age): no dose adjustment is required.
Patients with impaired renal function
No dose adjustment is required in patients with mild to moderate renal impairment. Experience with the drug in patients with severe renal impairment or undergoing hemodialysis is limited. In this category of patients, treatment with Telzap ® AM should be carried out with caution, since amlodipine and telmisartan are not eliminated from the body by hemodialysis (see the section “With caution”).
Patients with impaired liver function
Selecting the dose of Telzap ® AM in patients with mild or moderate hepatic impairment requires caution (see section “With 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 teenagers
The use of Telzap® AM in patients under 18 years of age is contraindicated due to the lack of sufficient data on the safety and efficacy of the drug in this age group.
Overdose
Symptoms
No cases of overdose of the amlodipine + telmisartan combination have been reported. Possible symptoms of overdose consist of symptoms from the individual components of the drug.
Overdose of amlodipine can lead to excessive peripheral vasodilation and reflex tachycardia. A marked and persistent decrease in blood pressure, including shock and death, has been reported. The most pronounced symptoms of telmisartan overdose were a decrease in blood pressure and tachycardia. Clinical manifestations such as bradycardia, dizziness, increased plasma creatinine, and acute renal failure were also reported.
Treatment
The patient should be under close clinical supervision. 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 symptoms. Recommended measures include inducing vomiting and / or gastric lavage, and taking activated charcoal.
Regular monitoring of the concentration of electrolytes and creatinine in the blood plasma should be carried out. If blood pressure decreases, the patient should be placed in a supine position with the lower extremities raised, and immediately begin the use of saline and other plasma-substituting solutions to replenish the BCC. Restoration of vascular tone and normalization of blood pressure can be achieved by introducing vasoconstrictors, provided that there are no contraindications to their use. Intravenous use of calcium gluconate may provide relief from symptoms associated with calcium channel blockage.
Amlodipine and telmisartan are practically not eliminated from the body by hemodialysis.
Description
Tablets 5 mg + 40 mg: oblong biconvex tablets from white or almost white to yellowish or yellow in color, with engravings “5” and “40” and a risk on one side. It is not intended for breaking the tablet.
Tablets 10 mg + 40 mg: oblong biconvex tablets from white or almost white to yellowish or yellow in color, with the engravings “10” and “40” on one side.
Tablets 5 mg + 80 mg: oblong biconvex tablets from white or almost white to yellowish or yellow in color, with engravings “5” and “80” and a risk on one side. It is not intended for breaking the tablet.
Tablets 10 mg + 80 mg: oblong biconvex tablets from white or almost white to yellowish or yellow in color, with the engravings “10” and “80” on one side.
Special instructions
Amlodipine
Patients with chronic heart failure
In a long-term placebo-controlled trial (PRAISE-2) in patients with NYHA functional class III-IV CHF of non-ischemic etiology, the use of amlodipine was associated with an increase in reports of pulmonary edema, despite the absence of a significant difference in the incidence of heart failure progression compared to placebo. BMCC, including amlodipine, should be used with caution in patients with CHF due to the possible risk of other cardiovascular complications and mortality.
Liver function disorders
As with other BMCs, thehalf-life of amlodipine is increased in patients with impaired liver function. Therefore, Telzap ® AM should be used with caution in such patients (see section “With caution”), and the dose of telmisartan should not exceed 40 mg once a day. Telzap ® AM is contraindicated in patients with severe hepatic impairment (see sections “Contraindications”).
Impaired renal function
In patients with impaired renal function, amlodipine can be used in normal doses. Changes in amlodipine plasma concentrations did not correlate with the severity of renal impairment. Amlodipine is not eliminated from the body during dialysis.
Elderly patients
No dose adjustment of Telzap ® AM is required in elderly patients. Increasing the dose should be carried out with caution (see the section “With caution”).
Children
The safety and efficacy of Telzap® AM in children have not yet been established.
Sorbitol
This medicinal product contains sorbitol (E 420). In patients with rare hereditary problems of fructose intolerance, the use of Telzap® AM is contraindicated (see section “Contraindications”).
Telmisartan
Impaired liver function
The use of the combination of amlodipine + telmisartan is contraindicated in patients with cholestasis, biliary tract obstruction and / or severe hepatic impairment, since telmisartan is mainly excreted in the bile (see section “Contraindications”). There is reason to believe that these patients have reduced hepatic clearance of telmisartan. The drug should be used with caution in patients with mild to moderate hepatic impairment.
Renovascular hypertension
Patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are at increased risk of significantly lowering blood pressure and developing acute renal failure when treated with drugs acting on the RAAS.
Impairedkidney function and kidney transplantation
When using telmisartan in patients with impaired renal function, it is recommended to periodically monitor the content of potassium and creatinine in blood plasma. There is no experience of using the drug in patients who underwent kidney transplantation shortly before use. Telmisartan is not eliminated by dialysis.
Decreased circulating blood volume (BCC)
A decrease in blood pressure, especially after the first use of Telzap® AM, may occur in patients with a reduced BCC and / or low blood sodium content against the background of previous treatment with diuretics, restriction of salt intake, diarrhea or vomiting. Such conditions (fluid and/or sodium deficiency) should be corrected before starting Telzap AM.
Double blockade of the RAAS
Data on the concomitant use of ACE inhibitors with ARA II or with drugs containing aliskiren confirm an increased risk of a sharp decrease in blood pressure, hyperkalemia, and decreased renal function (including acute renal failure).
Concomitant use of ARA II with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or moderate or severe renal insufficiency (GFR less than 60 ml/min / 1.73 m%^%2 of body surface area) and is not recommended in other patients. If it is necessary to implement a double blockade of the RAAS, each case should be considered individually and renal function, water-electrolyte balance and blood pressure indicators should be carefully monitored.
Concomitant use of ARA II with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.
Hypotension, syncope, hyperkalemia, and impaired renal function (including acute renal failure) have been reported with RAAS blockade in predisposed patients, especially with concomitant use of medications acting on the RAAS. In this regard, double blockade of the RAAS (in particular, with the simultaneous use of telmisartan with other RAAS blockers) is not recommended. Renal function should be carefully monitored if multiple RAAS blockers are required at the same time.
Other conditionsassociated with RAAS stimulation
In patients whose vascular tone and renal function depend primarily on the activity of the RAAS (for example, patients with severe chronic heart failure or existing kidney disease, including renal artery stenosis), the use of drugs acting on this system, such as telmisartan, is associated with the occurrence of acute blood pressure reduction, hyperazotemia, oliguria, or rarely with the development of acute renal failure (see the section “With caution”).
Primary hyperaldosteronism
In patients with primary hyperaldosteronism, treatment with antihypertensive drugs, the effect of which is carried out by inhibiting the RAAS, is usually ineffective. Therefore, the use of Telzap® AM is not recommended.
Aortic or mitral valve stenosis, obstructive hypertrophic cardiomyopathy
As with other vasodilators, special care should be taken in patients with aortic or mitral stenosis, as well as hypertrophic obstructive cardiomyopathy (see section “With caution”).
Patients with diabetes mellitus receiving insulin or other hypoglycemic medications
In patients with diabetes mellitus who are taking insulin or other hypoglycemic preparations, the use of 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
As with 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 the content of potassium in the blood plasma, or have concomitant pathological conditions, hyperkalemia can be a cause of death.
When concomitant use of drugs acting on the RAAS should carefully evaluate the benefit-risk ratio.
The main risk factors for hyperkalemia include:
- diabetes mellitus, impaired renal function, elderly (patients over 70 years of age);
- concomitant use with drugs acting on the RAAS, and/or supplements containing potassium. Medications that may cause hyperkalemia include potassium-containing salt substitutes, potassium-sparing diuretics, ACE inhibitors, ARA II, 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 advised to carefully monitor the potassium content in the blood plasma.
Ethnic differences
Like all other ARA II drugs, telmisartan is less effective in reducing blood pressure in black patients than in other races, possibly due to a greater predisposition to a decrease in renin activity in the population of these patients.
Coronary heart disease and cerebrovascular disease
As with any other antihypertensive medication, excessive lowering of blood pressure in patients with coronary heart disease or cerebrovascular disease can lead to the development of myocardial infarction or stroke.
Influence on the ability to drive vehicles and mechanisms
Telzap ® AM has a moderate effect on the ability to drive vehicles and control moving mechanisms. Due to the possible development of dizziness, headache, fatigue, nausea when taking the drug, care should be taken when driving vehicles and engaging in other activities that require concentration of attention and speed of psychomotor functions. If the described adverse reactions occur, you should refrain from performing these activities.
Form of production
Tablets,5 mg + 40 mg; 10 mg +40 mg; 5 mg + 80 mg; 10 mg + 80 mg.
7,10 or 14 tablets in a blister of OPA / Alu / PVC/The Alu. By 1,2,3,4,7,8 or 9 blisters together with the instructions for use in a cardboard box.
Storage conditions
At a temperature not exceeding 25 °C in the original packaging (blister in a cardboard box). Keep out of reach of children.
Shelf
life is 2 years. Do not use after the expiration date.
Active ingredient
Amlodipine, Telmisartan
Conditions of release from pharmacies
By prescription
Dosage form
Tablets
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