Twinsta, tablets 5 mg+80 mg 28 pcs

combined hypotensive agent (slow calcium channel blocker + angiotensin II receptor antagonist) ATX code: C09DB04 Pharmacological properties Pharmacodynamics
Twinsta is a combination drug containing two hypotensive agents with complementary actions to control blood pressure in patients with arterial (essential) hypertension: The angiotensin II receptor antagonist (ARA II), telmisartan, and the “slow” calcium channel blocker (CMCB) dihydropyridine derivative, amlodipine.

The combination of these agents has additive hypotensive effects, lowering blood pressure to a greater extent than each individual component.

The drug Twinsta, taken once daily, results in an effective and sustained decrease in blood pressure within 24 hours.

Telmisartan
Telmisartan is a specific ARA II (type AT 1) that is effective when taken orally. It has high affinity for the AT 1 subtype of angiotensin II receptors, through which angiotensin II action is realized. It displaces angiotensin II from binding to the receptor, having no agonist effect against this receptor. Telmisartan binds only to the AT 1 subtype of angiotensin II receptor. The binding is long-lasting. It has no affinity for other receptors, including AT 2 receptor. Reduces blood aldosterone concentration, does not inhibit plasma renin and does not block ion channels. Telmisartan does not inhibit angiotensin-converting enzyme (kinininase II, an enzyme that also degrades bradykinin). Therefore, an increase in bradykinin-induced adverse effects is not expected.

In patients, telmisartan at a dose of 80 mg completely blocks the hypertensive effects of angiotensin II. The onset of hypotensive action is noted within 3 hours after the first telmisartan administration. The action of the drug persists for 24 hours and remains significant up to 48 hours. A pronounced hypotensive effect usually develops 4-8 weeks after regular use.

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

In case of abrupt telmisartan withdrawal, BP gradually returns to baseline levels without development of “withdrawal” syndrome.

The incidence of dry cough was significantly lower in patients receiving telmisartan compared with the use of angiotensin-converting enzyme inhibitors (ACEs).

Two large randomized controlled trials, ONTARGET (Global Endpoints in Telmisartan Monotherapy and Ramipril) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes Study, conducted by the US Department of Veterans Affairs), examined the use of a combination ACE inhibitor in combination with an angiotensin II receptor antagonist. The ONTARGET study was a study conducted in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with confirmed target organ damage. The VA NEPHRON-D study was a study in patients with type 2 diabetes and diabetic nephropathy.

These studies showed no significant beneficial effects on renal and/or cardiovascular outcomes and mortality, whereas an increased risk of hyperkalemia, acute renal failure and/or arterial hypotension was observed compared to monotherapy. Given similar pharmacodynamic properties, these results are also relevant for other ACE inhibitors and angiotensin II receptor antagonists.

Therefore, ACE inhibitors and angiotensin II receptor antagonists should not be used together in patients with diabetic nephropathy.

The ALTITUDE (Aliskiren Use in Patients with Type 2 Diabetes with Assessment of Cardiovascular and Renal Endpoints) was a study designed to test the benefit of adding aliskiren to standard treatment with an ACE inhibitor or angiotensin II receptor antagonist in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease or both. The study was terminated early due to an increased risk of adverse outcomes. Cardiovascular death and stroke were more frequently reported in the aliskiren group than in the placebo group, and adverse events and serious adverse events (hyperkalemia, arterial hypotension, and impaired renal function) were more frequently reported in the aliskiren group than in the placebo group.

There was a difference in plasma concentrations of telmisartan in men and women. Cmax and AUC were approximately 3 and 2 times higher in women compared to men, respectively, with no significant effect on efficacy.

Amlodipine
Amlodipine is a dihydropyridine derivative and belongs to the BMCC class. It inhibits transmembrane entry of calcium ions into cardiomyocytes and vascular smooth muscle cells.

The mechanism of hypotensive action of amlodipine is associated with a direct relaxant effect on vascular smooth muscle cells, resulting in reduction of peripheral vascular resistance and BP decrease.

In patients with arterial hypertension, use of amlodipine once daily provides clinically significant BP reduction for 24 hours. Orthostatic arterial hypotension is not common 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 resulted in decreased renal vascular resistance and increased glomerular filtration rate and effective renal plasma blood flow without changes in filtration or proteinuria.

Amlodipine does not cause any metabolic adverse effects or changes in plasma lipid concentrations and is therefore suitable for use in patients with bronchial asthma, diabetes and gout.

The use of amlodipine in patients with heart failure is not associated with negative inotropic effects (does not decrease exercise tolerance and left ventricular ejection fraction).

Pharmacokinetics
Pharmacokinetics of fixed-dose combination
The rate and degree of absorption of Twinsta are equivalent to the bioavailability of telmisartan and amlodipine when used as separate tablets.

Pharmacokinetics of individual components:
Telmisartan
Absorption
When taken orally, it is rapidly absorbed from the gastrointestinal tract. Absolute bioavailability of telmisartan is about 50%. When taken concomitantly with food, the decrease in area under the curve “concentration-time” (AUC) ranges from 6% (at a dose of 40 mg) to 19% (at a dose of 160 mg). Three hours after oral administration, plasma concentrations become similar to those of telmisartan on an empty stomach.

Distribution
Binding to plasma proteins > 99.5%, mainly to albumin and alpha-1 glycoprotein. Average apparent volume of distribution at equilibrium concentration is 500L.

Metabolism
Telmisartan is metabolized by conjugation with glucuronic acid. Metabolites are pharmacologically inactive.

Elimation
The elimination half-life (T V) is more than 20 hours. Maximum plasma concentration (Cmax) and, to a lesser extent, AUC increase disproportionately to the dose. There are no data on clinically significant accumulation of telmisartan, when used in recommended doses.

Extracted through the intestine unchanged, excretion by the kidneys is less than 1%. Total plasma clearance is high (approximately 1000 ml/min) compared to “hepatic” blood flow (about 1500 ml/min).

Amlodipine
Absorption
After oral administration of amlodipine at therapeutic doses the maximum plasma concentrations are reached after 6-12 hours. The absolute bioavailability ranges from 64% to 80%. Food intake does not affect the bioavailability of amlodipine.

Distribution
The volume of distribution of amlodipine is approximately 21 l/kg. In in vitro studies it has been shown that in patients with arterial hypertension approximately 97.5% of circulating amlodipine is bound to plasma proteins.

Metabolism
Amlodipine is largely (approximately 90%) metabolized in the liver to form inactive metabolites.

Elimation
Blood plasma excretion of amlodipine is biphasic with a TA of approximately 30-50 hours. Stable concentration in blood plasma is reached after continuous drug administration for 7-8 days. Amlodipine is excreted by the kidneys both unchanged (10%) and as metabolites (60%).

Pharmacokinetics in special clinical cases:
In elderly patients
The pharmacokinetics of telmisartan in elderly patients does not differ from younger patients. Amlodipine clearance tends to decrease in elderly patients, resulting in increased AUC and TA.

Patients with renal impairment
Telmisartan is bound to plasma proteins and is not eliminated by hemodialysis in patients with renal impairment. In patients with renal impairment, plasma concentrations of telmisartan are doubled. However, telmisartan concentrations are lower in patients on hemodialysis and the T1/2 is unchanged. Pharmacokinetics of amlodipine in patients with impaired renal function is not significantly changed.

Patients with hepatic impairment
Pharmacokinetics studies performed in patients with hepatic impairment have shown that the absolute bioavailability of telmisartan is increased to almost 100%. TA in patients with hepatic impairment does not change. In patients with hepatic impairment, the clearance of amlodipine was decreased, resulting in an increase in AUC of approximately 40-60%.

Indications

Arterial hypertension (for patients who are indicated for combination therapy).

Patients with arterial hypertension receiving telmisartan and amlodipine as separate tablets as a substitute for this therapy.

Active ingredient

Composition

How to take, the dosage

Intentionally, regardless of meals.

If, after at least 2 weeks of treatment, additional blood pressure reduction is needed, the dose of the drug may be gradually increased to a maximum dose of 10 mg + 80 mg once daily.

The drug Twinsta may be used together with other hypotensive drugs.

The use of the drug in special clinical groups of patients
Renal disorders
In patients with impaired renal function, including patients on hemodialysis, no changes in the dosing regimen of the drug are required. Amlodipine and telmisartan are not eliminated from the body during hemodialysis.

Hepatic disorders
In patients with mild to moderate hepatic impairment, Twinsta should be used with caution. The dose of telmisartan should not exceed 40 mg once daily.

Elderly patients
The dosing regimen does not require adjustment.

Children and adolescents under 18 years of age
There are no data on the efficacy and safety of the amlodipine/telmisartan combination in children and adolescents under 18 years of age.

Interaction

Special studies of drug interactions of the drug Twinsta with other drugs have not been conducted.

Combinations of active ingredients
Other hypotensive agents
The hypotensive effect of Twinsta may be increased when used concomitantly with other hypotensive drugs.

Drugs that can decrease blood pressure
Some drugs, such as baclofen, amifostine, neuroleptics, and antidepressants can be expected due to their pharmacological properties to increase the hypotensive effects of all hypotensive drugs, including Twinsta. In addition, orthostatic arterial hypotension may be enhanced by ethanol.

Corticosteroids (systemic use)
Possible decrease in hypotensive effect.

Telmisartan
Co-use is not recommended
Potassium-saving diuretics or potassium preparations
Angiotensin II receptor antagonists, such as telmisartan, reduce potassium loss caused by diuretics. Use of potassium-saving diuretics such as spirinolactone, eplerenone, triamterene, or amiloride, potassium preparations, or potassium-containing salt may result in a significant increase in serum potassium concentration. If concomitant use is indicated due to documented hypokalemia, these medications should be used with caution and with frequent monitoring of serum potassium.

Lithium preparations
Reversible increases in blood lithium concentrations with toxic effects have been reported with ACE inhibitors. In rare cases, such changes have been reported when prescribing angiotensin II receptor antagonists, particularly telmisartan. When concomitant administration of lithium preparations and angiotensin II receptor antagonists, it is recommended to determine lithium content in blood.

Other hypotensive agents
It is possible to increase the hypotensive effect. In one study when telmisartan and ramipril were combined, there was a 2.5-fold increase in AUC0-24 and C mah of ramipril and ramiprilat. The clinical significance of this interaction has not been established.

Double RAAS blockade (e.g. co-administration of iAPP or aliskiren, direct renin inhibitor with APA II) is not recommended because of possible renal dysfunction (including acute renal failure).

Mixed use requiring precautions
Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid (in doses used as an anti-inflammatory agent), cyclooxygenase-2 (COX-2) inhibitors and non-selective NSAIDs may reduce the severity of the hypotensive effect of angiotensin II receptor antagonists.

In some patients with renal impairment (e.g., patients with dehydration or elderly patients with renal impairment) the combined use of angiotensin II receptor antagonists and drugs that inhibit COX activity may lead to additional impairment of renal function, including possible development of acute renal failure; these effects are generally reversible. Therefore, this combination should be used with caution, especially in the elderly. Patients should be adequately hydrated, and renal function should be monitored after initiation of co-administration of these drugs and periodically thereafter.

Ramipril
In one study, co-administration of telmisartan and ramipril resulted in a 2.5-fold increase in AUC0-24 and Cmax values of ramipril and ramiprilat. The clinical significance of this observation is unknown.

Co-use to consider
Digoxin
When telmisartan was co-administered with digoxin, there was an increase in median maximum plasma digoxin concentration (49%) and residual digoxin concentration (20%). When initiating, adjusting doses, and withdrawing telmisartan, plasma digoxin concentrations should be monitored to maintain them within the therapeutic range.

Amlodipine
Co-use requiring precautions
CYP3A4 isoenzyme inhibitors
When co-administered with the CYP3A4 inhibitor erythromycin in younger patients and with diltiazem in older patients, plasma concentrations of amlodipine increased by 22% and 50%, respectively. However, the clinical significance of this observation is unclear.

It cannot be excluded that more active CYP3A4 isoenzyme inhibitors (such as ketoconazole, itraconazole, ritonavir) may increase plasma concentrations of amlodipine more than diltiazem. Amlodipine should be used with caution together with CYP3A4 isoenzyme inhibitors. However, no adverse effects associated with such interaction have been noted.

CYP3A4 isoenzyme inducers
When co-administering known CYP3A4 inducers, plasma concentrations of amlodipine may vary. Thus, it is necessary to monitor blood pressure and adjust the dose during and after concomitant treatment, especially with strong CYP3A4 inducers (e.g., rifampicin, preparations of Hypericum perforatum).

Grapefruit and grapefruit juice
Simultaneous administration in 20 healthy volunteers of 240 mL grapefruit juice with a single oral dose of amlodipine 10 mg had no significant effect on the pharmacokinetic properties of amlodipine. Concomitant use of Twinsta with grapefruit or grapefruit juice is not recommended, because in some patients the increased bioavailability of amlodipine may increase the antihypertensive effect.

Co-use to consider
Tacrolimus
There is a risk of increased concentrations of tacrolimus when co-administered with amlodipine, but the pharmacokinetic mechanism of this interaction is not fully understood. To avoid tacrolimus toxicity, the use of amlodipine in patients receiving tacrolimus requires monitoring of tacrolimus concentrations and adjusting the tacrolimus dose when necessary.

Cyclosporine
There have been no studies of drug interactions between cyclosporine and amlodipine in healthy volunteers or in other populations, except in renal transplant patients who have had variable increases in residual cyclosporine concentrations (average 0 – 40%). Consideration should be given to controlling cyclosporine concentrations in renal transplant patients receiving amlodipine, and reducing cyclosporine doses if necessary.

Simvastatin
Co-administration of amlodipine with simvastatin at a dose of 80 mg resulted in an increase in simvastatin exposure of up to 77% compared with simvastatin monotherapy. Therefore, the dose of simvastatin should not exceed 20 mg per day.

Other drugs
The safety of concomitant use of amlodipine with digoxin, warfarin, atorvastatin, sildenafil, antacid drugs (aluminum hydroxide, magnesium hydroxide, simethicone), cimetidine, antibiotics and oral hypoglycemic drugs has been established. When amlodipine and sildenafil were used concomitantly, each drug was shown to have an independent hypotensive effect.

The concomitant use of amlodipine with cimetidine had no significant effect on the pharmacokinetics of amlodipine. Concomitant use of amlodipine with atorvastatin, digoxin, warfarin or cyclosporine had no significant effect on the pharmacokinetics or pharmacodynamics of these drugs.

Special Instructions

Hepatic impairment
Telmisartan is excreted predominantly with bile. In patients with biliary obstruction or hepatic insufficiency, drug clearance is expected to be decreased. In addition, as with all calcium antagonists, the half-life of amlodipine in patients with impaired liver function is prolonged, and dosing recommendations for this drug have not been established. Therefore, the telmisartan/amlodipine combination should be used with caution in such patients.

Renovascular Arterial Hypertension
Patients with bilateral renal artery stenosis or artery stenosis of a single functioning kidney taking drugs that affect the renin-angiotensin-aldosterone system (RAAS) are at increased risk of developing severe hypotension and renal failure.

Kidney function abnormalities and conditions after kidney transplantation
There is no experience with Twinsta in patients who have recently undergone a kidney transplant. Amlodipine and telmisartan are not eliminated by hemodialysis. Periodic monitoring of serum potassium and creatinine is recommended in patients with impaired renal function.

Decreased circulating blood volume (CBC) and/or hyponatremia
Symptomatic arterial hypotension may develop due to restriction of table salt intake, intensive diuretic therapy, diarrhea or vomiting, especially after the first dose of the drug. Such conditions require correction before using the drug Twinsta. If arterial hypotension occurs against the background of using Twinste, the patient should be laid on his back and, if necessary, intravenous administration of saline solution should be administered. Treatment may be continued after the blood pressure has stabilized.

Double blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that simultaneous use of iAPP, angiotensin II receptor antagonists or aliskiren increases the risk of hypotension, hyperkalemia and reduced renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combined use of iAPP, angiotensin II receptor antagonists, or aliskiren is not recommended.

If treatment with dual RAAS blockade is considered necessary, it should only be performed under the supervision of a specialist and with close monitoring of renal function, electrolyte concentrations and blood pressure.

The ACE inhibitors and angiotensin II receptor antagonists should not be used simultaneously in patients with diabetic nephropathy.

Other conditions characterized by activation of the RAAS
. In cases of dependence of vascular tone and renal function mainly on the activity of RAAS (for example, in patients with chronic heart failure or renal diseases, including renal artery stenosis) prescription of drugs affecting this system may be accompanied by development of acute arterial hypotension, hyperazotemia, oliguria, and, in rare cases, acute renal failure.

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

Diabetes mellitus
In patients with diabetes mellitus (DM) with additional cardiovascular risk (i.e. with concomitant coronary heart disease), the risk of fatal myocardial infarction and sudden cardiovascular death may be increased by treatment with hypotensive agents such as APA II and angiotensin-converting enzyme inhibitors (ACEIs).

Aortic and mitral valve stenosis, hypertrophic obstructive cardiomyopathy
In patients with aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy, the use of Twinst, as well as other vasodilators, requires special caution.

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

Heart failure
In a clinical study it was found that amlodipine use in patients with heart failure of non-ischemic etiology of NYHA functional class III and IV was accompanied by a higher incidence of pulmonary edema (despite no significant difference in the frequency of worsening of heart failure compared to placebo).

Patients with diabetes mellitus receiving insulin or other antidiabetic drugs
In these patients hypoglycemia may occur with telmisartan treatment. Therefore, proper monitoring of blood glucose concentrations should be considered in these patients; adjustments to the dose of insulin or antidiabetic drugs may be necessary, if necessary.

Hyperkalemia
During treatment with drugs that affect the RAAS, especially in the presence of renal dysfunction and/or heart failure, hyperkalemia may occur. Hyperkalemia can be fatal in elderly patients, in patients with renal insufficiency, in patients with diabetes mellitus, in patients who simultaneously receive other medications that can increase the concentration of potassium in the serum, and/or in patients with intercurrent events.

Before considering coadministration of drugs that affect the RAAS, the benefit-risk ratio should be evaluated.

The main risk factors for hyperkalemia are:

Serum potassium concentration should be monitored carefully in these patients.

Sorbitol
Each tablet of Twinsta contains 168.64 mg of sorbitol.

Other
Excessive lowering of blood pressure in patients with ischemic cardiomyopathy or ischemic cardiovascular disease can lead to myocardial infarction or stroke.

The drug Twinsta is effective in treating patients of the Negro race (blood renin activity is generally decreased in this population).

Contraindications

Side effects

Unwanted reactions previously described with one of the components (telmisartan or amlodipine) may also be potential adverse reactions with Twinsta, even if they were not observed in clinical studies or during the post-registration period.

The following categories are used within the system-organ classes for the frequency of adverse reactions: Very common (≥ 1/10); common (≥ 1/100, < 1/10); infrequent (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); frequency unknown (cannot be calculated from available data).

1) expected based on experience with telmisartan
2) expected based on experience with amlodipine
3) expected with concurrent use of telmisartan and amlodipine

Additional information regarding individual components

Adverse reactions previously reported with one component of the drug (amlodipine or telmisartan) may be increased with Twinst, even if they were not observed in clinical trials or during the postmarketing period.

Additional information regarding the combination of components
Peripheral edema, a dose-dependent adverse reaction to amlodipine, has been observed less frequently in patients who received a combination of telmisartan and amlodipine than in patients who received amlodipine alone.

Overdose

Treatment

Hemodialysis is not effective. Control of the patient’s condition; therapy should be symptomatic and supportive.

In order to relieve calcium channel blockade intravenous calcium gluconate may be given.
Overdose treatment methods such as induction of vomiting, gastric lavage, activated charcoal, moving the patient into the “elevated legs” position and administration of plasma exchange solutions in case of marked BP decrease may be used.

Pregnancy use

Pregnancy
Telmisartan
The use of ARA II is contraindicated during pregnancy. If pregnancy is diagnosed, the drug should be stopped immediately. Alternative therapy should be prescribed if necessary.

Preclinical studies of telmisartan showed no teratogenic properties, but found the presence of fetotoxicity.

The use of APA II during the second and third trimesters of pregnancy is known to have fetotoxic effects (decreased renal function, oligohydramnios, delayed fetal skull ossification) and neonatal toxicity (renal failure, arterial hypotension and hyperkalemia) has been observed.

In patients planning pregnancy, APA II should be replaced with other hypotensive agents that have an established safety profile for use during pregnancy (unless continued treatment with APA II is deemed necessary).

If APA II is used during pregnancy, ultrasound monitoring of renal function and cranial condition is recommended beginning in the second trimester of pregnancy. Newborns whose mothers have received APA II should be closely monitored with respect to the development of arterial hypotension.

Amlodipine
The limited data available regarding the effects of amlodipine or other DMARDs do not indicate any adverse effects on the fetus. However, there may be a risk of delayed labor.

Breastfeeding
Amlodipine is excreted into breast milk. The fraction of the dose received by the infant has been estimated to range from 3% to 7%, with a maximum of 15%. The effect of amlodipine on breastfed infants is unknown.

There have been no specific studies on the excretion of telmisartan with breast milk in women. Animal studies have found that telmisartan is excreted with the milk of lactating animals. Given the possible adverse reactions, the decision to continue breastfeeding or to discontinue therapy should be made on the basis of its relevance to the mother. Studies of the effect on human fertility have not been conducted.

Similarities