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Concomitant sustanon 250 for sale use of these components leads to a greater antihypertensive effect than the use of each of them individually. Admission MikardisPlyus ® once daily, results in a significant gradual reduction in blood pressure (BP).

Telmisartan
Telmisartan – a specific antagonist of the angiotensin II receptor (type AT1). It has a high affinity for the AT1 subtype angiotensin II receptor antagonist, which is realized through the action of angiotensin II. Telmisartan displaces angiotensin II from binding with the receptor, having no agonist action against this receptor.Telmisartan forms a bond with just AT1 subtype angiotensin II receptor. The binding is long-term in nature. Telmisartan has no affinity for other receptors, including AT2 receptor and other less-studied receptors of angiotensin. The functional significance of these receptors, as well as their possible effect of over-stimulation by angiotensin II, whose concentration increases with telmisartan not studied. Telmisartan reduces aldosterone levels. Telmisartan is not blocking the renin in the blood and ion channels without blocking angiotensin converting enzyme does not inactivate bradykinin.

In humans telmisartan 80 mg completely block the hypertensive effects of angiotensin II. The drug lasts more than 24 hours, including the last 4 hours before taking another dose.

Home hypotensive effect observed for 3 hours after the first dose of telmisartan. The maximum reduction in blood pressure (BP) is usually observed after 4 weeks of treatment.

In patients with hypertension telmisartan reduces systolic and diastolic blood pressure without affecting heart rate (HR).

In the case of abrupt withdrawal of telmisartan, blood pressure gradually returned to baseline without the development of “cancellation” syndrome.

Hydrochlorothiazide
Hydrochlorothiazide is a thiazide diuretic. Thiazide diuretics affect electrolyte reabsorption in the renal tubules, directly increasing the excretion of sodium and chloride (approximately equivalent amounts).The diuretic action of hydrochlorothiazide reduces blood volume, an increase in plasma renin activity, aldosterone secretion and increase accompanied by an increase in the content of urinary potassium and bicarbonate, and hypokalemia. At the same time taking telmisartan tendency to stop the loss of potassium induced by these diuretics, presumably due to blockade of the renin-angiotensin-aldosterone system.

Upon receiving hydrochlorothiazide diuresis amplified by 2 hours, and the maximum effect is observed after about 4 h. The diuretic effect of the drug persists for approximately 6-12 hours.
Prolonged use of hydrochlorothiazide reduces the risk of complications of cardiovascular disease and mortality.
The maximum antihypertensive effect MikardisPlyus ® is usually achieved within 4 weeks after starting treatment.

Pharmacokinetics
The combined use of telmisartan gidrohlorotiazida and has no effect on the pharmacokinetics of each component of the drug.

Telmisartan:
The ingestion maximum concentrations of telmisartan are reached within 0.5 -1.5 hour after application. The absolute bioavailability of telmisartan in doses ranging from 40 mg to 160 was 42% and 58%, respectively. When taken with food while slightly decreases with decreased bioavailability of telmisartan area under the curve of concentration vs. time (AUC) is 6% at a dose of 40 mg and about 19% at a dose of 160 mg. After 3 hours after ingestion plasma concentration equalized regardless of whether the drug is taken with a meal or empty stomach. Pharmacokinetics of telmisartan the oral route at doses of 20 nonlinear – 160 mg with the more than proportional increase in plasma concentrations (Cmax and AUC) with increasing doses.

Hydrochlorothiazide: after ingestion MikardisPlyus, maximum concentrations of hydrochlorothiazide are reached within 1-3 hours. Absolute bioavailability is estimated on the cumulative renal excretion of hydrochlorothiazide and is about 60%.

Telmisartan: connection to plasma proteins is significant (> 99.5%) mainly albumin and alpha-1-glycoprotein. The volume of distribution for telmisartan approximately 500 liters.

Hydrochlorothiazide: 64% of hydrochlorothiazide is bound to plasma proteins and volume of distribution is 0.8 ± 0.3 L / kg. Telmisartan: The majority of the administered dose (> 97%) excreted in the bile and then in the feces. In small quantities drug excreted by the kidneys. Telmisartan is metabolized by conjugation with glucuronic acid. Metabolite (atsilglyukuronid) pharmacologically inactive. Glucuronide – the main metabolite, which is defined only by the people. The total plasma clearance is 1500 ml / min. The half-life (T 1/2) is more than 20 hours.

Gidrohlorotiazid not metabolized in the human body and excreted by the kidneys virtually unchanged. About 60% of an oral dose is eliminated within 48 hours. Renal clearance of about 250 – 300 ml / min. T ½ gidrohlorotiazida 10-15 hours.
There is a difference in plasma concentrations in men and women. In women, the plasma concentrations of telmisartan is 2-3 times higher than in men, as in women tend to increase the plasma concentrations of hydrochlorothiazide. Nevertheless, the gain in this hypertensive effect is not observed in women.

Elderly patients
Pharmacokinetic performance of telmisartan do not differ significantly in young and elderly patients.

Patients with renal impairment
Renal excretion does not affect the clearance of telmisartan. Based on the level excretion in patients with mild to moderate renal impairment (creatinine clearance of 30-60 ml / min, mean of 50 ml / min), a correction mode is not required.
Telmisartan is not removed by dialysis. Patients with impaired renal excretion rate decreased function of hydrochlorothiazide.
Studies sustanon 250 for sale involving patients with a creatinine clearance of 90 ml / minute, have shown that increased T ½ hydrochlorothiazide. In patients with reduced renal function, the T ½ of about 34 hours.

Patients with hepatic insufficiency
pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute bioavailability up to nearly 100%. In hepatic insufficiency the half-life is not changed.
The drug crosses the placental barrier and is determined in the blood of the umbilical cord.

Indications
Hypertension (in the case of the ineffectiveness of telmisartan or hydrochlorothiazide monotherapy).

Contraindications

  • Increased sensitivity to the drug or other derivatives of the sulfonamides;
  • Pregnancy (II and III trimester) and lactation;
  • Cholestasis and obstructive biliary tract disease;
  • Severe hepatic dysfunction;
  • Severe renal impairment (creatinine clearance less than 30 mL / min);
  • Hypokalemia, hyponatremia, hypercalcemia;
  • Hereditary fructose intolerance (contains sorbitol);
  • Age 18 years (effectiveness and safety have been established)

Precautions: impaired hepatic function or progressive liver disease; bilateral renal artery stenosis or stenosis of the artery to a solitary kidney; impairment of renal function; condition after kidney transplantation; reduction in circulating blood volume as a result of previous diuretic therapy, salt restriction reception, diarrhea or vomiting; Chronic heart nedotatochnost; stenosis of the aortic and mitral valve; obstructive hypertrophic cardiomyopathy; diabetes; cardiac ischemia; systemic lupus erythematosus; gout.

Pregnancy and lactation
Telmisartan is not teratogenic, but has a foetotoxic effect. Therefore, as a precaution, MikardisPlyus ® should not be used during the I trimester of pregnancy. When planning a pregnancy should be replaced MikardisPlyus ® drugs permitted for use during pregnancy. If pregnancy is established, you should immediately stop taking the drug.

In II and III trimester use of the drug can cause electrolyte abnormalities in the fetus, as well as possibly other disorders that are known in adults. It reported on the development of neonatal thrombocytopenia, jaundice (in the fetus or newborn) in the case of the mother receiving thiazide diuretics. Therefore, the drug is contraindicated in the II and III trimester of pregnancy.

It is not known whether telmisartan passes into breast milk, thiazide diuretics penetrates into breast milk and may inhibit lactation. MikardisPlyus therefore contraindicated during lactation.

Dosing and Administration
Inside, regardless of meals. MikardisPlyus ® should be taken once a day 1.

  • MikardisPlyus ® 40 / 12.5 mg may be administered to patients who use Mikardisa ® at a dose of 40 mg or hydrochlorothiazide does not lead to adequate control of blood pressure.
  • MikardisPlyus ® 80 / 12.5 mg may be administered to patients who use Mikardisa ® at a dose of 80 mg or MikardisPlyus ® 40 / 12.5 mg does not lead to adequate control of blood pressure.

Renal function
with limited experience of application MikardisPlyus ® in patients with minor or moderate impaired renal function does not require changes in the dose of the drug in these cases. In such patients, renal function should be controlled.

Impaired liver function.
In patients with low or moderate impaired hepatic function MikardisPlyus ® should not be used in a dose of 40 / 12.5 mg per day.

Elderly
Changes dosing regimen is required.

Side effect

  1. Expected based on experience with telmisartan
  2. Expected based on experience with hydrochlorothiazide

The respiratory system
Upper respiratory tract infection (including bronchitis, pharyngitis, sinusitis), shortness of breath 1 , dyspnea, respiratory distress (including pneumonitis and pulmonary edema) 2

Cardio-vascular system
Bradycardia 1 , tachycardia 1 , arrhythmias 2 , marked reduction of blood pressure 1 , orthostatic hypotension 2 , necrotizing angiitis (vasculitis) 2 , chest pain 1

On the part of the central nervous system
excitability, anxiety, depression, 1.2 , anxiety 2 , dizziness, syncope 1 , insomnia 1 , staggering when walking 2 , paresthesia 2 ,

Digestive system
Abdominal pain, diarrhea, dyspepsia, gastritis, anorexia2, loss of appetite2) sialadenitis2), xerostomia1, flatulence 1 , vomiting 1 , latch 2 , pancreatitis 2 , jaundice (hepatocellular or cholestatic) 2

From endocrine system
loss level of control hypoglycemia in diabetes

Metabolic disorders
Hypercholesterolemia, hyperuricemia, hypokalemia, hyponatremia 2 , reduction of circulating blood volume 2 , violation of electrolyte metabolism 2 , hyperglycemia 2 , hypercalcemia 1

From the side of hematopoiesis system
Eosinophilia 1 , aplastic anemia 2 , hemolytic anemia 2 , inhibition of bone marrow hematopoiesis 2 , leukopenia 2 , neutropenia / agranulocytosis 2 , thrombocytopenia 1.2

From the urinary system
infections of urinary tract, interstitial nephritis 2 , renal dysfunction 2 , glycosuria 2

On the part of the musculoskeletal system
Arthralgia, osteoarthritis, back pain, pain in the legs, myalgia, jerking the calf muscles (cramps) 1 , symptoms similar tendonitis 1 , weakness 1.2 , muscle spasm 2

Allergic reactions
Anaphylactic reactions 2, eczema, erythema 1, pruritus 1, cutaneous lupus reaction 2, cutaneous vasculitis 2, reactions of photosensitivity 2 rash 2, reactivation of cutaneous lupus erythematosus 2, toxic epidermal necrolysis 2
angioedema, urticaria, and other such reactions (as and in the case of other angiotensin II antagonist).

From the senses
Violations of visual acuity 1 , transient blurred vision 2 , xanthopsia 2 , vertigo.

Violations of the reproductive potency Reduction

Laboratory findings
Reduced hemoglobin 1 , increased uric acid levels 1 , creatinine 1 , liver enzymes 1 , triglycerides 2

Other
flu-like symptoms, fever 2 , increased sweating 1
The use of thiazide diuretics may interfere with glucose tolerance.

Overdose

The most likely symptoms of telmisartan overdose may be a marked reduction in blood pressure, tachycardia and / or bradycardia.

Overdose with hydrochlorothiazide is accompanied by loss of electrolytes (hypokalemia, chloropenia) and dehydration arising as a result of massive diuresis. The most common signs and symptoms of hydrochlorothiazide overdose are nausea and somnolence. Hypokalemia may result in muscle spasms and / or exacerbate cardiac arrhythmia caused by the simultaneous application of cardiac glycosides or certain anti-arrhythmic drugs.

Treatment: symptomatic and supportive therapy, the nature of which depends on the time elapsed since ingestion, and the degree of severity of the symptoms. It is recommended to induce vomiting, and / or carry out gastric lavage, activated charcoal to appoint. Requires frequent monitoring of electrolytes and creatinine in serum. In the case of arterial hypotension, the patient should be put on his back and quickly conduct therapy aimed at replacing electrolytes and blood volume.

Telmisartan is not removed by hemodialysis. Hydrochlorothiazide removal rate during hemodialysis is not installed.

Interactions with other drugs

With simultaneous use of lithium and angiotensin II receptor antagonists in rare cases was an increase in the concentration of lithium in blood serum and increased toxic effects. Furthermore, the use of lithium thiazides reduces clearance. Therefore, the simultaneous use of drugs lithium and MikardisPlyus ® is permitted only with careful medical supervision; recommended monitoring of lithium levels in blood serum.

Hypokalemic effect of hydrochlorothiazide kaliysberegayuschii offset by the effect of telmisartan. However, hypokalemic effect of hydrochlorothiazide may be enhanced by other medicines that cause potassium excretion and hypokalaemia (eg other diuretics, leading out potassium, laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G (sodium salt), salicylic acid and its derivatives).

Simultaneous use of potassium-sparing diuretics, potassium preparations, other means can increase the serum potassium (eg heparin sodium), or a salt substitute potassium salts, may, on the contrary, lead to hyperkalemia.

In cases where MikardisPlyus ® is used together with drugs, the effect of which varies with a decrease in the potassium content of the blood (for example, cardiac glycosides, antiarrhythmic drugs and drugs capable of causing arrhythmias such as “pirouette” the heart), it is recommended periodic monitoring the level of potassium in the plasma blood.

Telmisartan may increase the hypotensive effect of other antihypertensive drugs.

In pharmacokinetic studies have been studied drugs such as digoxin, warfarin, hydrochlorothiazide, glibenclamide, ibuprofen, paracetamol, simvastatin and amlodipine. As revealed 20% increase in digoxin median basal concentration (in one case the increase in the concentration reached 39%), it should be borne in mind that it can take control of digoxin concentration in the blood plasma.

Interact following drugs (in case of simultaneous application) can with thiazide diuretics:

  • alcohol, barbiturates or narcotics (risk of orthostatic hypotension);
  • hypoglycemic agents (such as oral hypoglycemic or insulin) may need to change the doses of antidiabetic drugs;
  • Metformin: while the use of hydrochlorothiazide There is the risk of lactic acidosis;
  • cholestyramine and colestipol: in the presence of anionic exchange resins is disturbed absorption of hydrochlorothiazide;
  • cardiac glycosides: hypokalemia or hypomagnesemia caused by thiazide diuretics, promotes the development of “digitalis” arrhythmias;
  • nonsteroidal anti-inflammatory drugs: reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some patients;
  • pressor amines (eg, norepinephrine) may weaken the effect of pressor amines;
  • non-depolarizing muscle relaxants (eg tubocurarine): hydrochlorothiazide may enhance the effect of non-depolarizing muscle relaxants muscle;
  • drugs used to treat gout: may need to change the dosage of drugs urikozuricheskih as hydrochlorothiazide can increase uric acid levels in the blood serum. The use of thiazide diuretics may increase the incidence of hypersensitivity reactions to allopurinol;
  • Calcium salts: thiazide diuretics may increase the level of calcium in blood serum as a result of decrease in its excretion.

Thiazide diuretics may increase the hyperglycemia caused by beta-blockers and diazoxide. Antiholi nergicheskie drugs (eg, atropine, biperidin) may reduce the motility of the stomach and intestines, increase the bioavailability of thiazide diuretics.

The drug can increase the risk of adverse effects caused by amantadine, reduce the renal excretion of cytotoxic drugs (eg cyclophosphamide, methotrexate) and enhance their myelosuppressive effects.

Application with MikardisPlyus ® potassium-sparing diuretics, potassium preparations or replacing salt potassium salts should be administered with caution.

special instructions

Disturbances of liver function

In patients with impaired hepatic function or progressive liver disease MikardisPlyus ® should be used with caution, because even small changes in fluid and electrolyte balance may contribute to the development of hepatic coma.

renovascular hypertension

In patients with bilateral renal artery stenosis or stenosis of the artery only functioning kidney using drugs that affect the renin-angiotensin-aldosterone system, increases the risk of severe hypotension and renal insufficiency.

Impaired renal function and condition after kidney transplantation

Experience of application MikardisPlyus ® in patients with severely impaired renal function or in patients after kidney transplantation is not available. As the experience of MikardisPlyus ® in patients with slight and moderate renal impairment is small, in such cases, periodic determination of levels of potassium, creatinine in serum. The use of thiazide diuretics in patients with impaired renal function may lead to azotemia. Recommended periodic monitoring of renal function.

Reduced blood volume

In patients with decreased blood volume and / or hyponatremia, arising as a result of massive diuretic therapy, limiting admission of salt, diarrhea or vomiting may develop symptomatic hypotension, especially after the first dose of the drug. Before starting the application MikardisPlyus ® requires correction of these violations.

Other conditions that enhance activity of the renin-angiotensin-aldosterone system

In cases where vascular tone and renal function largely depend on the activity of the renin-angiotensin-aldosterone system (e.g., in patients with severe chronic heart failure or concomitant diseases kidney, including renal artery stenosis), Use of drugs which It affects the state of the system may be accompanied by the development of acute hypotension, hyperasotemia, oliguria or, rarely, acute renal failure.

Primary aldosteronism

Patients with primary aldosteronism antihypertensive drugs, which the mechanism of action is inhibition of the activity of the renin-angiotensin-aldosterone system, usually ineffective. In such cases, the appointment of MikardisPlyus ® is not recommended.

Stenosis of the aortic and mitral valves, obstructive hypertrophic cardiomyopathy

In patients with aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy application MikardisPlyus ® (as well as other vasodilators) requires special care.

Effect on the metabolism and endocrine function

Patients with diabetes mellitus may require changes in insulin dosage or oral hypoglycemic agents. During thiazide therapy may manifest the latent form of diabetes.

In some cases, the use of thiazide diuretics may develop hyperuricemia and gout.

Electrolyte disturbances

When using MikardisPlyus ® , as in the case of each of diuretic therapy, need periodic determination of electrolytes in serum.

Thiazide diuretics, including hydrochlorothiazide may cause electrolyte imbalance and ksilotno-base balance (hypokalaemia, hyponatraemia and gipohloremichesky alkalosis). Signs, guards against these disturbances are dry mouth, thirst, weakness, lethargy, drowsiness, anxiety, myalgia, or jerking of the calf muscles (cramps), muscle weakness, hypotension, oliguria, tachycardia, and such gastrointestinal disorders nausea or vomiting.

If you are using thiazide diuretics may develop hypokalemia, but at the same time apply the telmisartan, it is able to reduce this disorder. The sustanon 250 for sale risk of hypokalemia is greatest in patients with cirrhosis of the liver, increased diuresis, with inadequate oral electrolyte compensation, as well as in the case of simultaneous use of corticosteroids or ACTH. Telmisartan, part of MikardisPlyus ® , on the contrary, can cause hyperkalemia due to the antagonism of angiotensin II (subtype AT1). Although using MikardisPlyus ® , clinically significant hyperkalaemia has not been registered, it is necessary to take into account that its risk factors include renal and / or heart failure, and diabetes mellitus.

Data that MikardisPlyus ® may reduce or prevent hyponatremia caused by diuretics, there is. Chloride deficit is generally low and does not require treatment.

Thiazide diuretics may decrease the excretion of calcium and cause (in the absence of known disorders of metabolism of this ion) transient and slight increase in the level of calcium in the blood serum. More significant hypercalcaemia may be a sign of hidden hyperparathyroidism. Before defining the function of the parathyroid glands thiazide diuretics should be lifted.

It is shown that the thiazide diuretics increase urinary excretion of magnesium, which can lead to hypomagnesemia.

Other warnings

In patients with ischemic cardiomyopathy or ischemic heart disease of any antihypertensive medication in case of an excessive reduction in blood pressure can lead to heart attack or stroke.

The recommended daily dose MikardisPlyus 40 / 12.5 or 80 / 12.5 contains 169 or 338 mg of sorbitol, respectively. Therefore, the drug is contraindicated in patients with hereditary fructose intolerance (see. “Contraindications”).

Warnings of a general nature

There may be hypersensitivity reactions to hydrochlorothiazide, especially in patients with allergy or bronchial asthma in history.

There are posts on the development of systemic lupus erythematosus using thiazide diuretics.

MikardisPlyus ® may, if necessary, be used together with another antihypertensive agent.

In a joint application with MikardisPlyus ® potassium-containing diuretics, laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G (sodium salt), salicylic acid and its derivatives, we recommend regular monitoring of potassium in the blood plasma.

In a joint application MikardisPlyus ® and potassium-sparing diuretics, potassium preparations, other means can increase the serum potassium (eg heparin sodium), or replacing salt potassium salt, it is recommended to regularly monitor potassium levels in the blood plasma.

If you want to use calcium supplements, should regularly monitor the blood calcium concentration and, if necessary, change the dose of these drugs.

Effects on ability to drive and use machinery

Special study of the effect of the drug on the ability to drive and use machinery have not been conducted. However, when driving and mechanical equipment should be aware of the possibility of dizziness and drowsiness with the use of drugs used to treat hypertension.