Amlodipine + Telmisartan - instructions for use, dose, side effects, contraindications

Clinical and pharmacological group: & nbsp

Angiotensin II receptor antagonists (AT1 subtype)

Calcium channel blockers

Included in the formulation

Twinsta®

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Boehringer Ingelheim International GmbH Germany

Telsartan® AM

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Dr. Reddy's Laboratories Ltd. India

Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

VED

АТХ:

C.08.C.A.01 Amlodipine

C.09.C.A.07 Telmisartan

Pharmacodynamics:

Combined antihypertensive drug containing two active components with a complementary effect, allowing control of blood pressure in patients with arterial (essential) hypertension: angiotensin II receptor antagonist (telmisartan) and a slow calcium channel blocker, a dihydropyridine derivative (amlodipine). The combination of these substances has an additive antihypertensive effect, reducing blood pressure to a greater extent than each component separately. The drug, taken 1 time / day, leads to an effective and steady decrease in blood pressure within 24 hours.

Pharmacokinetics:

Telmisartan

When ingested quickly absorbed from the digestive tract. Bioavailability - 50%. When taken concomitantly with food, the decrease in AUC ranges from 6% (when administered at a dose of 40 mg) to 19% (when administered at a dose of 160 mg).After 3 hours after ingestion, the concentration in the blood plasma levels out, regardless of food intake.

Binding to blood plasma proteins - 99.5%, mainly with albumin and alpha₁glycoprotein. The average value of the visible V_din an equilibrium concentration of 500 liters.

Metabolized telmisartan by conjugation with glucuronic acid. Metabolites are pharmacologically inactive.

T_1/2 is more than 20 hours. C_maxin blood plasma and, to a lesser extent, AUC increase disproportionately to the magnitude of the dose. There are no data on the clinically significant accumulation of telmisartan.

Output unchanged with feces, excretion in the urine - less than 2%. The total plasma clearance is high (900 ml / min) compared with hepatic blood flow (about 1500 ml / min).

There is a difference in plasma concentrations of telmisartan in men and women. C_max and AUC were approximately 3 and 2 times, respectively, higher in women than in men without significant effect on efficacy.

The pharmacokinetics of telmisartan in elderly patients does not differ from pharmacokinetics in young patients.

Telmisartan binds to blood plasma proteins and is not removed during hemodialysis in patients with renal insufficiency.Also lower concentrations of telmisartan in the blood plasma, T_1/2 does not change.

Studies of pharmacokinetics performed in patients with impaired hepatic function showed that the absolute bioavailability of telmisartan increases almost to 100%. T_1/2in patients with impaired liver function does not change.

Amlodipine

After taking amlodipine inside at therapeutic doses of C_maxin blood plasma is achieved in 6-12 hours. The absolute bioavailability is from 64% to 80%. Eating food does not affect the bioavailability of amlodipine.

V_dAmlodipine is approximately 21 l / kg. In vitro studies have shown that in patients with arterial hypertension, approximately 97.5% of circulating amlodipine binds to plasma proteins. Stable concentrations in the blood plasma are achieved after a constant use of the drug for 7-8 days.

Amlodipine is metabolized to a significant extent (approximately 90%) in the liver with the formation of inactive metabolites.

Removal of amlodipine from the blood plasma occurs biphasic. T_1/2is about 30-50 hours. Amlodipine is excreted in the urine both in unchanged form (10%) and in the form of metabolites (60%).

In elderly patients there is a tendency to decrease the clearance of amlodipine, which leads to an increase in AUC and T_1/2.

The pharmacokinetics of amlodipine in patients with impaired renal function does not change significantly.

In patients with hepatic insufficiency, clearance of amlodipine decreased, which led to an increase in the AUC value by approximately 40-60%.

Indications:

For the treatment of hypertension:

in patients whose blood pressure is not adequately controlled by telmisartan or amlodipine, used as monotherapy; in patients who are shown combined therapy; in patients receiving telmisartan and amlodipine in the form of separate dosage forms, as a substitute for this therapy.

ICD-10

IX.I10-I15.I10 Essential [primary] hypertension

Contraindications:

Obstructive diseases of the biliary tract; severe arterial hypotension; obstruction of the left ventricular outflow tract (including a high degree of aortic stenosis); hemodynamically unstable heart failure after acute myocardial infarction; hepatic failure of severe degree; shock; simultaneous use with aliskiren in patients with diabetes mellitus or renal dysfunction (GFR less than 60 ml / min / 1.73 m²); fructose intolerance and glucose / galactose absorption disorder or sugarase / isomaltase deficiency; pregnancy; lactation period; age under 18 years (effectiveness and safety not established); hypersensitivity to active components or excipients;

Caution should be given to the drug with a violation of liver function, renovascular hypertension, primary aldosteronism, stenosis of aortic and mitral valves, hypertrophic obstructive cardiomyopathy, heart failure, diabetes mellitus, unstable angina, acute myocardial infarction, renal dysfunction, condition after kidney transplantation, reduced Bcc and / or hyponatremia, hyperkalemia, other conditions characterized by activation of RAAS.

Carefully:

Carefully should prescribe the drug in violation of liver function, renovascular arterial hypertension, primary aldosteronism, stenosis of aortic and mitral valves, hypertrophic obstructive cardiomyopathy, heart failure, diabetes mellitus, unstable angina, acute myocardial infarction,renal dysfunction, condition after kidney transplantation, reduced BCC and / or hyponatremia, hyperkalemia, other conditions characterized by activation of RAAS.

Pregnancy and lactation:

Special studies on the use of the drug during pregnancy and lactation were not conducted. Pregnancy

Telmisartan

The use of angiotensin II receptor antagonists is contraindicated in pregnancy. When pregnancy occurs, the drug should be discontinued immediately. If necessary, an alternative therapy should be prescribed.

It is known that the use of angiotensin II receptor antagonists in the II and III trimesters of pregnancy has a fetotoxic effect (decreased kidney function, oligohydramnion, slowing ossification of the fetal skull), and neonatal toxicity (kidney failure, arterial hypotension and hyperkalemia) is observed.

Patients planning a pregnancy should replace angiotensin II receptor antagonists with other antihypertensive drugs that have an established safety profile when used in pregnant women (unless continued treatment with angiotensin II receptor antagonists is considered necessary).

If angiotensin II receptor antagonists are used in pregnancy, then starting with the second trimester of pregnancy, it is recommended to perform ultrasound of the kidneys and bones of the fetal skull. Newborns whose mothers received angiotensin II receptor antagonists should be carefully monitored for the development of arterial hypotension.

Amlodipine

Available limited data on the effects of amlodipine or other calcium channel blockers do not indicate a negative effect on the fetus. However, there is a risk of slowing the delivery process.

Breastfeeding period

Special studies on the isolation of telmisartan and / or amlodipine in breast milk have not been conducted in women. In experimental animal studies, it was found that telmisartan is excreted with the milk of lactating animals. Taking into account possible adverse reactions, the decision to continue breastfeeding or to abolish therapy should be made taking into account its importance for the mother.

Dosing and Administration:

The drug is taken orally 1 time / day, regardless of food intake.

The drug can be administered to patients in whom the use of amlodipine or telmisartan as monotherapy does not lead to adequate control of blood pressure. Patients receiving amlodipine in a dose of 10 mg, which have adverse reactions limiting the use of the drug (eg, peripheral edema), can be switched to 40 mg / 5 mg once a day, which will reduce the dose of amlodipine, but not reduce the overall expected antihypertensive Effect.

The treatment of arterial hypertension in a patient can begin with the use of the drug in the event that it is unlikely that it is possible to achieve BP control with the help of any one drug. The recommended initial dose of the drug is 40 mg / 5 mg 1 time / day. In patients who need a more significant reduction in blood pressure, the initial dose of the drug can be increased to 80 mg / 5 mg 1 time / day.

If, at least after 2 weeks of treatment, an additional reduction in blood pressure is required, the dose of the drug can be gradually increased to a maximum - 80 mg / 10 mg 1 time / day.

The drug can be used together with other antihypertensive drugs.

In patients with impaired renal function, incl. in patients on hemodialysis, dose adjustment is not required. Amlodipine and telmisartan Do not remove from the body during hemodialysis.

In patients with impaired hepatic and mild liver function the drug should be used with caution. The dose of telmisartan should not exceed 40 mg 1 time / day.

Side effects:

Urinary tract infections, upper respiratory tract infections. Depression, anxiety, insomnia. Lability of mood, confusion. Dizziness. Drowsiness, migraine, headache, paresthesia. Decreased sensitivity or resistance to external factors, a taste disorder, syncope, tremor, peripheral neuropathy. Anaphylactic reaction. Hypersensitivity, angioedema, hives. Visual disturbances, decreased vision, tinnitus. Bradycardia, palpitations, marked decrease in blood pressure, orthostatic hypotension, tachycardia, myocardial infarction, arrhythmia, ventricular tachycardia, atrial fibrillation. Cough, shortness of breath, rhinitis. Abdominal pain, diarrhea, nausea, flatulence, increased activity of hepatic enzymes. Vomiting, indigestion, discomfort in the stomach, violations of the liver. Hepatitis, jaundice, change in the rhythm of defecation, pancreatitis, gastritis, increased activity of hepatic transaminases. Skin itching, eczema, erythema, rash, drug rash, toxic rash.Alopecia, purpura, discoloration, erythema multiforme, exfoliative dermatitis, photosensitization reaction, vasculitis. Arthralgia, muscle spasms (calf muscle cramps), myalgia. Nocturia, cystitis. Violations of kidney function, including acute renal failure, urination disorders, frequent urination. Erectile dysfunction, gynecomastia. Peripheral edema, weakness, pain in the chest, increased fatigue, swelling, a sensation of a flush of blood to the face. Hyperkalemia, anemia, increased concentration of creatinine in the blood

Overdose:

Cases of overdose have not been identified. Possible symptoms consist of symptoms of overdose of individual components of the drug.

Symptoms of an overdose of telmisartan: tachycardia, possibly bradycardia, dizziness, increased serum creatinine concentration, acute renal failure.

Symptoms of an overdose of amlodipine: excessive decrease in blood pressure with the possible development of reflex tachycardia and symptoms of excessive peripheral vasodilation (risk of development of severe and persistent arterial hypotension, including with the development of shock and death).

Treatment: conducting symptomatic and maintenance therapy, monitoring the patient's condition. Such methods of treatment as induction of emesis, gastric lavage, the use of activated carbon can be used. In the case of a marked decrease in blood pressure, the patient should be placed in a horizontal position with a low headboard; recommended the introduction of plasma-substituting solutions. In order to counter blockade of calcium channels, intravenous calcium gluconate is shown. Hemodialysis is ineffective.

Interaction:

The interaction between the two active components that are included in fixed doses in the composition of this drug has not been observed in clinical studies.

Special studies of drug drug interaction with other drugs have not been conducted.

Combination of active components

With simultaneous use with other antihypertensive drugs, the antihypertensive effect of the drug may be intensified.

It can be expected that some drugs (for example, baclofen and amifostine), due to their pharmacological properties, will enhance the antihypertensive effect of all anygipertenzive funds, including the drug.In addition, orthostatic hypotension can be enhanced by ethanol, barbiturates, narcotics or antidepressants.

When used simultaneously with corticosteroids (for systemic use), a reduction in the antihypertensive effect is possible.

Based on the experience of using other drugs that affect RAAS, the simultaneous use of the drug and potassium-sparing diuretics, potassium-containing supplements, potassium-containing edible salt, other potassium-increasing agents (eg, heparin), can lead to hyperkalemia. Therefore, the use of such combinations requires caution and control of potassium in the blood.

Telmisartan

When used simultaneously with other antihypertensive drugs, the hypotensive effect may increase. In one study, combined use of telmisartan and ramipril showed an increase in AUC_0-24 and C_maxramipril and ramiprilata 2.5 times. The clinical significance of this interaction is not established.

Double blockade of RAAS (eg, simultaneous use of an ACE inhibitor or aliskiren,direct inhibitor of renin with angiotensin II receptor antagonists) is not recommended because of possible renal dysfunction (including acute renal failure).

There was a reversible increase in the concentration of lithium in the blood, accompanied by toxic phenomena when applied simultaneously with ACE inhibitors. In rare cases, such changes were registered with the appointment of angiotensin II receptor antagonists, in particular telmisartan. When concomitantly using lithium drugs and angiotensin II receptor antagonists, it is recommended to determine the content of lithium in the blood.

NSAIDs, including acetylsalicylic acid (in doses used as an anti-inflammatory drug), COX-2 inhibitors and nonselective NSAIDs can cause the development of acute renal failure in patients with reduced BCC. Drugs affecting the activity of the RAAS system, incl. telmisartan, may have a synergistic effect. In patients receiving NSAIDs and telmisartan, at the beginning of treatment should compensate for BCC and conduct a study of kidney function.

With the simultaneous use of NSAIDs and antihypertensive drugs,like telmisartan, a decrease in the antihypertensive effect was reported by inhibiting the vasodilating effect of prostaglandins.

There was no clinically significant interaction with digoxin, warfarin, hydrochlorothiazide, glibenclamide, simvastatin, ibuprofen, paracetamol and amlodipine. An increase in the average concentration of digoxin in the blood plasma was observed on average by 20% (in one case by 39%). With the simultaneous use of telmisartan and digoxin, it is advisable to periodically determine the concentration of digoxin in the blood.

Amlodipine

Simultaneous use of the drug with grapefruit or grapefruit juice is not recommended, tk. In some patients, as a result of increasing the bioavailability of amlodipine, its antihypertensive effect may increase.

In a study in elderly patients, it was shown that diltiazem inhibits the metabolism of amlodipine, probably influencing CYP3A4 (amlodipine concentrations in the blood plasma increase by about 50% and amplify the effect of amlodipine). It can not be ruled out that the more active inhibitors of CYP3A4 (such as ketoconazole, itraconazole, ritonavir) can increase the concentration of amlodipine in the blood plasma to a greater extent than diltiazem.

Simultaneous use with inductors of the isoenzyme CYP3A4 (anticonvulsants (for example, carbamazepine, phenobarbital, phenytoin, phosphenytoin, primidon), rifampicin, Hypericum perforatum (Hypericum perforatum)) can lead to a decrease in the concentration of amlodipine in the blood plasma. Regular medical supervision is shown. During the application of inducers CYP3A4, and also after their cancellation, it is recommended (if possible) a change in the dose of amlodipine.

Simvastatin simultaneous application in a dose of 80 mg with amlodipine, regardless of dose, promotes an increase in the exposure of simvastatin up to 77% compared with simvastatin monotherapy. Therefore, the dose of simvastatin should not exceed 40 mg / day.

The safety of simultaneous use of amlodipine with thiazide diuretics, beta-adrenoblockers, ACE inhibitors, long-acting nitrates, nitroglycerin (used sublingually), NSAIDs, antibiotics and hypoglycemic drugs for oral administration has been established.

With the simultaneous use of amlodipine and sildenafil, it was shown that each drug had an independent antihypertensive effect.

Special instructions:

During treatment with drugs that affect RAAS, especially if there are abnormalities in kidney function and / or heart failure, hyperkalemia may occur. These patients are recommended regular monitoring of potassium in the blood serum. Patients with impaired renal function are also encouraged to periodically monitor serum creatinine concentrations. In some patients, due to inhibition of RAAS, especially with the use of a combination of agents acting on this system (for example, the addition of an ACE inhibitor or aliskiren, a direct inhibitor of renin, to angiotensin II receptor antagonists), kidney function (including acute kidney failure) is impaired. Therapy, accompanied by such a double blockade of RAAS, is not recommended and therefore should be limited and carried out strictly individually with careful monitoring of kidney function.

In cases of vascular tone and kidney function, mainly from RAAS activity (for example, in patients with chronic heart failure or kidney disease, including renal artery stenosis), the administration of drugs that affect this system,may be accompanied by the development of acute arterial hypotension, hyperaemia, oliguria, and, in rare cases, acute renal failure.

In patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney taking medications that affect RAAS, there is an increased risk of developing severe arterial hypotension and renal failure.

In patients with primary aldosteronism, antihypertensive drugs, whose mechanism of action is inhibition of RAAS, are usually not effective. Thus, the use of telmisartan in such cases is not recommended.

In patients with aortic or mitral stenosis, or with obstructive hypertrophic cardiomyopathy, the use of the drug, as well as of other vasodilators, requires extreme caution.

The clinical study found that the use of amlodipine in patients with non-ischemic heart failure of non-ischemic etiology of NYHA class III and IV was associated with a more frequent development of pulmonary edema (despite the absence of significant differences in the incidence of worsening heart failure compared with placebo).

In patients with diabetes mellitus, IHD can be asymptomatic, so it can be undiagnosed. Patients with diabetes need to pass the corresponding examination for diagnosis and treatment of coronary heart disease (e.g., exercise tests) before drug treatment. In patients with diabetes coronary artery disease with concomitant likelihood of fatal myocardial infarction and sudden cardiovascular death can be increased by the treatment such as the antihypertensive agents of angiotensin II receptor antagonists and ACE inhibitors.

There is no data on the use of the drug in patients with unstable angina, in the acute period and within one month after myocardial infarction.

Limiting consumption of salt, intensive diuretic therapy, diarrhea or vomiting can lead to a decrease in the BCC and / or hyponatremia, thus may develop symptomatic hypotension, especially after the first dose. Before applying the drug, such conditions require correction.

The experience of using the drug in patients who have recently undergone kidney transplantation is not available. Amlodipine and telmisartan not removed during hemodialysis. Patients with impaired renal function are encouraged to periodically monitor potassium and creatinine levels in the blood serum.

Studies of the impact on the ability to drive vehicles and control mechanisms have not been conducted. However, it should be appreciated that during treatment, undesirable effects such as syncope, drowsiness, or dizziness may be noted. Therefore, care should be taken or avoidance of such potentially dangerous actions as driving vehicles or controlling mechanisms.

Instructions

Amlodipine + Telmisartan (Amlodipinum + Telmisartanum)