Tolucombi 40mg/12.5mg Krka treat hypertension (4 blisters x 7 tablets)

ATC code: C09DA07.

Tolucombi is a combination of an Angiotensin II, Telmisartan and a diuretics thiazide, hydrochlorothiazide. The combination of these components has an anti -hypertension effect that reduces blood pressure at a larger level than using only single components.

Tolucombi used once a day, causing blood pressure loss effectively and mellow in the treatment limit.

telmisartan

Telmisartan is an Angiotensin II receptor antagonist (AT1 group) specific and effective when used orally. Telmisartan occupies Angiotensin II at the cohesion position with the AT1 receptor is the responsible position for the known activities of Angiotensin II.

Telmisartan does not show partial co -operations at the AT1 receptor. Telmisartan selectively mounted on the AT1 receptor. This cohesion lasts.

Telmisartan does not show craving with other receptors, including AT2 and less typical AT receptors. The function of these receptors is not clear, as well as excessive stimulation effects may be due to angiotensin II, which is a high concentration when using Telmisartan. Plasma Aldosterone levels decreased by Telmisartan.

Telmisartan does not inhibit human blood renin or ionic channels. Telmisartan does not inhibit the enzyme transferring angiotensin (Kininase II), this enzyme also has the effect of breaking Bradykinin. Therefore, it is not possible to increase the side effects through Bradykinin intermediaries.

On the human body, a dose of 80 mg Telmisartan has almost completely inhibited hypertension due to Angiotensin II. This inhibitory effect is maintained for 24 hours and can still be seen until 48 hours.

After the first Telmisartan dose, anti -hypertension activity gradually shows within 3 hours. The maximum level of hypotension is usually achieved after 4 weeks of treatment and is maintained throughout the long -term treatment.

The anti -hypertension effect is constantly sustainable for 24 hours after taking the drug, including 4 hours before the next dose.

This is confirmed by the base/vertex level curve that is always over 80% seen after the dose of 40 mg and 80 mg Telmisartan in control clinical studies with placebo.

In patients with hypertension, Telmisartan works to reduce both systolic and diastolic blood pressure without affecting the pulse. Telmisartan's anti -hypertension effect has been compared to other anti -hypertension drugs such as Amlodipine, Atenolone, Enalapril, Hydrochlorothiazid and Lisinopril.

If stopped with Telmisartan, the blood pressure will gradually return to the original value before treatment within a few days without the phenomenon of hypertension.

Through clinical studies directly compare two drugs for hypertension, the rate of dry cough is much less than in patients using Telmisartan compared to patients using angiotensin transferring enamel inhibitors.

Cardiovascular Protection

ontarget (ongoingtelmisartanalone and in combination with Ramipril Global Enfpoint Trial - Multinational research in single -treatment Telmisartan treatment and combined with RamIPril) compare the effective of Telmisartan, Ramipril and combine Telmisartan and Ramipril on 25.620 patients from 55 years old with a priority Coronary artery disease, stroke, peripheral blood vessel or diabetes with target organs (for example, retinopathy, left ventricular hypertrophy, microscopic albumin or general body), are typical signs of patients at high cardiovascular risk.

Patients are randomly selected in one of the following three treatment groups: Telmisartan 80mg (n = 8542), Ramipril 10mg (n = 8576), or the group combined Telmisartan 80mg and Ramipril 10mg (n = 8502) and is monitored on average of 4.5 years.

Telmisartan is similar to Ramipril, which reduces the evaluation criteria as a combination of cardiovascular death, myocardial infarction does not cause death, non -fatal stroke or hospitalized due to congestion.

The main criterion ratio is equivalent to Telmisartan (16.7%), Ramipril (16.5%) and Telmisartan combined with Ramipril (16.3%).

The risk rate in the Telmisartan group compared to the Ramipril group is 1.01 (97.5% Cl 0.93 -1,10, P (not inferior) - 0.0019 with a level of 1.13).

The mortality rate for all causes respectively is 11.6 % and 11.8 % in patients treated with telmisartan and ramipril.

The results show that Telmisartan is effective equivalent to RamIPril in the first secondary criterion, including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke [0.99 (97.5% CL 0.90-1.08), P (not inferior) = 0.0004], the main criterion in the Hope Reference Research is the effect of Ramipril SO effect Pharmacy.

Randomly organized a ACEI transcend arranged with other criteria similar to ontarget with telmisartan 80 mg (n = 2954) or placebo (n = 2972). The average time is up to 4 years and 8 months. There is no significant difference of the main coordination criteria (cardiovascular death, non -fatal myocardial infarction, non -fatal stroke, hospitalization due to congestive heart failure) shows [15.7% in the group using telmisartan and 17.0% in the placebo group with a dangerous ratio of 0.92 (95% Cl 0.81 -1,05, P = 0.22)]. There is evidence that the benefits of Telmisartan compared to the placebo in the secondary coordination criteria of cardiovascular death, myocardial infarction does not cause death and non -fatal stroke [0.87 (95% CL 0.76 -1,00, P = 0.048)]. There is no evidence of benefits on cardiovascular mortality rate (dangerous ratio of 1.03.95 % CL 0.85 -1.24).

Cough and angioedema are reported less in patients with Telmisartan treatment compared to RamIPril, while hypotension notice more often with Telmisartan.

Combining Telmisartan with RamIPril is not more beneficial when using each Ramipril or each Telmisartan. Cardiovascular deaths and death due to higher cause in terms of combination. In addition, increasing the rate of blood potassium, renal failure, hypotension and fainting in the combination group. Therefore, combining Telmisartan and Ramipril is not recommended in this population group.

In the research "Prevention Regimen for Effective Avoiding Seconded" for patients over 50 years old, having just experienced a stroke, increasing the rate of blood infections in patients using Telmisartan compared to placebo, 0.70% compared to 0.49% [RR 1.43 (95% trusted range 1.00-2,06)]; The proportion of deaths due to blood infections has increased in patients with Telmisartan (0.33 %) compared to patients with placebo (0.16 %) [RR 2.07 (95 %of reliable range of 1.14- 3.76)]. Observations that increase the occurrence of blood infections associated with the use of Telmisartan may be an opportunity or related to an unknown mechanism.

Two major random studies controlled ontarget and VA Nephrond-D have checked the use of ACE transfer inhibitors and Angiotensin II receptor inhibitors.

Ontarget research in patients with a history of cardiovascular and stroke or type 2 diabetes with diabetes.

and Nephrond study in type 2 diabetics and diabetes. These studies have shown that there is no serious effect on the kidneys and/or cardiovascular disease and the mortality rate, while observing increases the risk of hyperkalemia, acute kidney damage, calculation and/or hypotension.

With similar pharmacological properties, the results also indicate that there is a relevance to ACE inhibitors and Angiotensin II receptor inhibitors. ACE inhibitors and Angiotensine II receptor inhibitors should therefore not be used simultaneously in diabetes patients.

Altitude is a study designed to assess the benefits when taking Aliskiren with ACE inhibitors or Angiotensin II receptor inhibitors in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease or both.

This study was terminated early because of the increased risk of serious complications. Cardiovascular and stroke complications occur more often in the group using Aliskiren than the placebo group; And serious side effects (hyperkalemia, hypertension and kidney dysfunction) are more often informed in the group using Aliskiren compared to the placebo group.

Hydrochlorothiazide is a thiazide diuretic. The mechanism of hypotension is not known. Diuretics that affect the mechanism of reabsorption of electrolytes of electrolytes, directly increasing the excretion of sodium and chloride with equivalent approximation.

Hydrochlorothiazide diuretics reduce plasma volume, increase plasma renin activity, increase aldosterone secretion, with an increase in potassiumuria and loss of carbonate, and decrease in serum potassium.

Perhaps through the Renin-Anotensin-Aldosterone channel blocker system, Telmisartan's simultaneous indications tend to reverse potassium when combined with diuretics. With hydrochlorothiazide, the starting of the card occurs for 2 hours and the maximum effect occurs about 4 hours, while the impact lasts approximately 6 to 12 hours.

Epidemiological studies have shown long -term treatment with hydrochlorothiazide, which reduces the risk of cardiovascular death and disease.

The effects of the combination of fixed dose of Telmisartan/HCTZ on the rate of death and death on the heart are unknown.

pharmacokinetics

Simultaneous use Hydrochlorothiazide and Telmisartan does not affect the pharmacokinetics of each drug.

absorption

telmisartan

After taking the peak concentrations of Telmisartan achieved after 0.5-1.5 hours. The absolute bioavailability of Telmisartan 40 mg is 42% and 160 mg is 58%. Food mitigates Telmisartan's bioavailability with a reduction in the area under the plasma concentration curve over time (AUC) by about 6% for 40 mg tablets and about 19% for 160 mg dose. After 3 hours, plasma concentrations are equivalent to whether Telmisartan is used or not the same food.

The area under the concentration curve - The time is less reduced (AUC) does not reduce the effectiveness of treatment. The pharmacokinetics of Telmisartan are non -linear oral by doses of 20 - 160 mg, with an increase according to the concentration ratio in the acupuncture point (CMAX and AUC) when increasing the dose. Telmisartan accumulates negligible in plasma when taking the drug repeated many times.

hydrochlorothiazide

After taking Tolucombi the peak concentrations of hydrochlorothiazide achieved after 1.0-3.0 hours. Due to the excretion through the kidneys, absolute bioavailability is about 60%.

distribution

telmisartan

Telmisartan is strongly connected to plasma proteins (> 99.5%), mainly albumin and alpha-acid glycoprotein. The distribution of Telmisartan about 500 liters shows additional tissue cohesion.

hydrochlorothiazide

Hydrochlorothiazide is connected 68% to plasma proteins and the distribution integral is 0.83 -1.14 l/kg.

transformation

telmisartan

Metabolized by the combination of acylglucuronide formation without pharmacological activity. Glucuronide of the original compound is the only metabolic product determined in humans. After a dose of 14C Telmisartan, Glucuronide accounts for about 11% of radioactive activity measured in plasma. Cytochrome P450 Isoenzyme is not involved in Telmisartan metabolism.

hydrochlorothiazide

Not metabolized in the human body.

Elimination

telmisartan

After intravenous injection or toteral telmisartan attached 14C, most dose (> 97%) are eliminated into biliary tract. Only a small amount found in urine. Telmisartan elimination speed in total plasma after taking the drug is> 1500 ml/min. Telmisartan's ending time is> 20 hours.

hydrochlorothiazide

is excreted almost completely in the form of unchanged urine. About 60% of oral doses are eliminated in the form of unchanged within 48 hours. The speed of the kidney is about 250 - 300 ml/min. Hydrochlorothiazide waste time is 10 - 15 hours.

Special cases

Elderly patients

Gender

Telmisartan plasma concentrations are usually 2-3 times higher than in women. However, in clinical studies, there is no significant increase in blood pressure response or increasing the rate of hypotension standing in women. No need to adjust the dose. Tend to concentration of plasma hydrochlorothiazide in women than men. This is considered not clinically related.

Patients with renal failure

Elimination through the kidney does not contribute to the process of eliminating Telmisartan. According to experience in medium and mild renal impairment patients (Creatinine clearance rate of 30-60 ml/min, an average of about 50 ml/minute), do not need to adjust the dose.

Telmisartan is not excluded when dialysis. In patients with renal failure, the rate of elimination of hydrochlorothiazide is reduced. In a typical study in patients with an average creatinine clearance rate of 90 ml/min, the sale time of hydrochlorothiazide increases. In patients with kidney function no longer, the selling time cancel about 34 hours.

Patients with liver failure

studies in patients with hepatic impairment shows that there is an absolute bioavailability of nearly 100%. The half -life does not change in patients with liver failure.

rarely

2: Add a description, see the "Description of the selected side effects" more information on each component side.

Previous side effects were reported to one of the separate components that could be side effects with Tolucombi, even if not observed in clinical studies of this product.

telmisartan

Side reactions occur similarly to the place of placebo group and patients treated with Telmisartan.

The following side effects are listed synthesized from clinical trials in patients treated with Telmisartan due to high blood pressure or 50 -year -old patients or older at high risk of cardiovascular complications.

Not common

hydrochlorothiazide :

Hydrochlorothiazide can cause or seriously reduce blood volume that can lead to electrolyte imbalance.

Side effects of unknown frequency of hydrochlorothiazide include:

Unknown

Unusual liver/liver disorders.

Most cases of abnormal liver/liver function disorders due to Telmisartan have occurred in Japanese patients.

Blood infection

In Profess research, increasing the rate of blood infections observed in Telmisartan compared to placebo. This may be an accidental finding or related to an unknown mechanism.

Interstitial lung disease

Cases of interstitial lung disease have been reported from the use of telmisartan. However, the causal relationship has not been established.

Notice immediately to the doctor or pharmacist the harmful reactions encountered when using the drug.

Instructions on how to handle ADR

When experiencing side effects of the drug, it is necessary to stop using and notify the doctor or go to the nearest medical facility for timely treatment.

pregnancy

Do not start treating with Angiotensin II receptor antagonists during pregnancy. Patients who plan to get pregnant should switch to alternative hypertension treatments that have drug safety data proved to be used during pregnancy unless the continued use of angiotensin II receptor is considered to be really necessary. When women are diagnosed with pregnancy, immediately stop treating with Angiotensin II receptor antagonists and if necessary, start with an alternative therapy.

Hepatic failure

Do not use tolucombi for patients with bile stasis, bile congestion or severe liver failure because Telmisartan is largely excreted through bile. It can be seen that Telmisartan clearance through the liver decreases in these patients.

Tolucombi should be used with caution in patients with liver function or liver disease, because only minor changes in water and electrolytes can lead to liver coma. There is no clinical experience for Tolucombi in patients with liver failure.

Hypertension caused by kidney artery

Has the ability to increase the risk of severe hypotension and renal failure when the patient has narrowed kidney narrowing on both sides or the kidney stenosis to the only kidney is still functioning to be treated with drugs that affect the renin-angiotensin-alveone system.

kidney failure and kidney transplant

Do not use tolucombi in patients with severe renal impairment (creatinine clearance rate

Reducing internal volume

Symptomatic hypotension, especially after the first dose, can occur in patients with volume loss and/or sodium loss due to excessive diuretic therapy, too strict salt abstinence, diarrhea or vomiting. Such conditions should be overcome before using tolucombi.

Double Renin-Anotesin-Aldosterone System

There is evidence that simultaneously used with ACE enzyme inhibitors, Angiotensin II or Aliskiren receptor inhibitors increases sudden hypotension, hyperkalemia, functional renal failure (including acute renal failure). Therefore, the Dual System of the RAAS system through the use in combination with ACE enzyme inhibitors, Angiotensin II or Aliskiren receptor inhibitors are not recommended.

If double closed maple is necessary, it is necessary to have close monitoring and regular function of kidney, electrolyte and blood pressure.

ACE enzyme inhibitors and Angiotensin II receptor inhibitors are not used in combination with patients with diabetic kidney disease.

Other conditions have the stimulation of the renin-anidensin-aldosterone system

In patients with vascular tone and renal function depends largely on the activity of the renin-angiotensin-aldosterone system (for example, patients with severe congestive heart failure or basic kidney disease, including kidney artery stenosis), the treatment with other drugs affects the renin-anidensin-aldosterone system related to acute hypotension, increased blood urinary, rarely rarely impaired.

Increase primary Aldosterone

Patients with raw raw hyperplasia often do not respond to anti-hypertension drugs through inhibiting the Renin-Anotesin system. Therefore, it is not recommended to use Tolucombi.

Aortic valve stenosis and mitral valve, hypertrophic heart muscle disease

As well as for other vasodilators, special attention should be paid to patients with aortic valve stenosis or mitral valve, or hypertrophic cardiomyopathy.

Metabolic and endocrine effects

Thiazide therapy may reduce glucose tolerance. In patients with diabetes may need to adjust insulin dose or oral hypoglycemic drugs. Potential diabetes can become an entity during thiazide treatment.

Increase the concentration of cholesterol and triglyerids related to thiazide diuretic therapy, but very few or almost no such effects are reported at a dose of 12.5 mg contained in tolucombi.

Hyperglycemia can occur or gout may appear in some patients who are taking Thiazide therapy.

Electrolyte balance

For any patient who uses Thiazide therapy, the periodic test of electrolytes in serum must be performed according to the appropriate time.

Thiazide drugs, including hydrochlorothiazide, can cause water and electrolyte imbalance (hypotension, sodium hypoglycemia and alkaline infection due to hypoglycemia). The warning signs of electrolyte imbalance are dry mouth, thirst, weakness, sleep, drowsiness, restlessness, muscle pain or cramping, muscle weakness, reducing blood pressure, urinary decrease, tachycardia and gastrointestinal disorders such as nausea or vomiting.

Although hypokalemia may appear when using thiazide diuretics, simultaneous treatment with Telmisartan can reduce the ability to lower potassium potassium due to diuretics. The risk of hypokalemia will be the highest in patients with cirrhosis, on patients who are taking fast diuretics, in patients who are compensating for enough electrolytes through oral and on patients treated simultaneously with corticosteroids or ACTH. In contrast, due to the antagonistic mechanism of the Angiotensin II receptors (AT1) by Tolucombi's telmisartan component, the condition of hyperkalemia may occur.

Despite the clinical significant hyperkalemia that has not been recorded with Tolucombi, risk factors leading to hyperkalemia include kidney failure and/or heart failure and diabetes.

Potassium diuretic, potassium supplements or potassium salts should be used to be used carefully with tolucombi.

There is no evidence that tolucombi will reduce or prevent sodium hemorrhage due to diuretics. The deficiency of chlorine is usually mild and often does not need treatment.

Thiazide can reduce the excretion of calcium in the urinary tract and cause slight increase, temporary serum calcium in the condition that no other calcium metabolic disorders. Significant hypercalcemia may be evidence of hidden parathyroid gland. Thiazide should be stopped before performing the adjacent function tests.

Thiazide has shown to increase the elimination of magnesium through the urinary tract, which can lead to lower blood mages.

Sorbitol and Lactose Monohydrate

The drug contains lactose monohydrate and sorbitol. Patients with rare genetic diseases are intolerant to fructose and/or rare genetic diseases Glucose-Galactose should not use this drug.

Race difference

Like all Angiotensin II receptor antagonists, Telmisartan is less effective for African patients. Because in the body of black high blood pressure has a lower amount of renin.

Other notes

Like any other anti -hypertension, excessive hypotension in patients with ischemia or ischemia can lead to myocardial infarction or stroke.

Body

Hypersensitivity reactions with hydrochlorothiazide may occur in patients with or without a history of allergies or bronchial asthma, but there is more likely to occur for patients with such a history. The serious or activated condition of the system of lupus erythematosus has been reported for the use of thiazide diuretics, including hydrochlorothiazide.

Cases of reaction to light have been reported to thiazide diuretics. If a reaction to light occurs in treatment, treatment should be discontinued. If treatment is necessary, recommendation from sunlight or artificial UVA.

Acute myopia and glaucoma closed angle

Hydrochlorothiazide is a sulfonamide that can cause a separate reaction, leading to transient myopia and an increase in acute angle. Symptoms include an acute onset of vision or eye pain and typical within a few hours to a few weeks from the beginning of the drug. Increase angle of acute non -treatment angle can lead to permanent vision loss. Stop hydrochlorothiazide as quickly as possible. Medical treatment or surgery immediately can be considered immediately if the urban pressure is still uncontrolled. Risk factors for developing acute narrow -angle glaucoma leading to allergy history Sulfonamide or penicillin.

The ability to drive and operate machinery

There has been no research on the effect of the drug on the ability to drive and operate machinery. However, when driving or operating machinery, it should be noted that the feeling of dizziness or drowsiness can sometimes occur during anti -hypertension treatment.

Pregnancy

Do not use Angiotensin II receptor inhibitors during pregnancy.

There is no adequate data on the use of tolucombi in pregnant women, but shows that the effects of toxicity.

Epidemiological evidence related to the risk of teratogenicity after exposure to Angiotensin II receptor inhibitors during the first quarter of pregnancy is not concluded; However, increasing the risk of not being excluded. While there is no epidemiological data controlled for the risk of Angiotensin II receptor countertops, similar risks can exist in this drug group.

Women who are planning to get pregnant should switch to alternative hypertension therapies that have safe data proved to be used during pregnancy unless the continued use of angiotensin II receptor is considered to be really necessary. When diagnosed with pregnancy, Angiotensin II receptor is immediately diagnosed, and if appropriate, alternative treatment should be started.

Know how to use Angiotensin II receptor inhibitors for the last three months and the last three months toxic to the fetus (impaired renal function, amniotic fluid, skull slowly) and toxic to babies (kidney failure, low blood pressure, hyperboly). There has been an effect from the middle three months of pregnancy when using Angiotensin II receptor antagonists, recommending ultrasound to test kidney function and skull. Babies of mothers treated with Angiotensin II receptor antagonists should be monitored in a strict low blood pressure.

Thiazide passes through the placenta and appears in the umbilical cord blood. The drug can cause electrolyte disorders in the fetus and other reactions that have been met in adults. Cases of fetal or fetal or neonatal platelets have been reported for thiazide treatment during pregnancy. Hydrochlorothiazide is limited during pregnancy, especially in the first quarter. Lack of animal studies. Hydrochlorothiazide through the placenta. Based on the pharmacological mechanism of hydrochlorothiazide during the second quarter and the third quarter of pregnancy, it can reduce blood transfusion through the fetus leading to jaundice, electrolyte balance disorders and thrombocytopenia.

Hydrochlorothiazide should not be used for women during pregnancy, high blood pressure during pregnancy because of the risk of reducing plasma volume and reducing blood transfusion for the fetus, not beneficial for this disease. Hydrochlorothiazide is not used to treat high blood pressure in pregnant women except for rare cases that are not used.

Breastfeeding period

There is no relevant information on using tolucombi during breastfeeding, tolucombi is not recommended and replaced with better treatment for nursing patients, especially in newborn babies or premature babies.

Hydrochlorothiazide is small in breast milk. High -dose Thiazide has strong diuretic can limit milk secretion. Using tolucombi during breastfeeding is not recommended. If you use tolomombi during breastfeeding, you should lower the dose to the extent possible.

Drug interaction

lithium

Increased lithium and toxic lithium levels of lithium recovery have been reported during simultaneous use of lithium with enzyme inhibitors Angiotensin. In some cases, it has also been reported when used with Angiotensin II receptor antagonists including Telmisartan. Moreover, the lithium's kidney removal rate is reduced by thiazide so the risk of lithium poisoning can increase when using tolucombi. Lithium and tolucombi should only be used simultaneously under medical monitoring and need to monitor serum lithium concentration during simultaneous use.

Other drugs reduce potassium and hypotension

For example, diuretics loss of potassium, laxatives, corticosteroids, acth (hormone adrenocorticotropic), amphotericin, carbenoxolone, penicillin g sodium, salicylic acid and derivative.

If these drugs are prescribed with tolucombi, plasma potassium concentration should be monitored. These drugs may increase the effects of hydrochlorothiazide on blood potassium.

Other drugs increase potassium levels and hyperkalemia

For example, transferred inhibitors, potassium -saving diuretic, potassium supplements, replacement salt contains potassium, cyclosporine or other medicinal products such as sodium heparin.

If these drugs are prescribed with tolucombi, plasma potassium concentration should be monitored. Based on the experience of using other drugs that inhibit the Renin-Anotensin, simultaneous use of the above drugs can lead to increased serum potassium, so it is not recommended.

The drugs are affected by blood potassium disorders