Amlodipine, Telmisartan

Brand Cipla Ltd

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Available since: 2019-09-19

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Clinical Pharmacology

Tvinsta drug is a combined drug containing two antihypertensive substances with a complementary effect, which allows to control blood pressure in patients with arterial (essential) hypertension: angiotensin II receptor antagonist, telmisartan, and the slower 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 individual component. The drug, taken 1 time per day, leads to an effective and sustained lowering of blood pressure within 24 hours.

Telmisartan - A specific angiotensin II receptor antagonist (type AT1), effective when taken orally. It has a high affinity for the AT1 subtype of angiotensin II receptors, through which the action of angiotensin II is realized. Displaces angiotensin II from its association with the receptor, not having the action of an agonist on this receptor. Telmisartan binds only to the AT1 subtype of angiotensin II receptors. Communication is long lasting. It has no affinity for other receptors, including the AT2 receptor. Reduces the concentration of aldosterone in the blood, does not inhibit renin in the blood plasma and does not block the ion channels. Telmisartan does not inhibit angiotensin-converting enzyme (kininase I) (an enzyme that also destroys bradykinin). Therefore, the enhancement of bradykinin-induced side effects is not expected. In patients with telmisartan in a dose of 80 mg completely blocks the hypertensive effect of angiotensin II.

The onset of hypotensive action is noted within 3 hours after the first dose of telmisartan. The effect of the drug lasts 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 the heart rate (HR). In the case of abrupt cancellation of telmisartan, blood pressure gradually returns to its original level without the development of the "cancellation" syndrome.

Amlodipine - a derivative of dihydropyridine, belongs to the class of blockers of "slow" calcium channels. It inhibits transmembrane entry of calcium ions into cardiomyocytes and vascular smooth muscle cells. The mechanism of antihypertensive action of amlodipine is associated with a direct relaxing effect on vascular smooth muscle cells, which leads to a decrease in peripheral vascular resistance and a decrease in blood pressure. In patients with arterial hypertension, the use of amlodipine 1 time per day provides a clinically significant reduction in blood pressure for 24 hours. Orthostatic hypotension is not typical during the use of amlodipine due to the slow onset of the drug.

In patients with arterial hypertension and normal kidney function, amlodipine at therapeutic doses reduced kidney vascular resistance, increased glomerular filtration rate and effective plasma blood flow in the kidney without changing filtration or proteinuria. Amlodipine does not cause any metabolic adverse effects or changes in plasma lipid levels and is therefore suitable for use in patients with asthma, diabetes mellitus and gout. The use of amlodipine in patients with heart failure is not accompanied by a negative inotropic effect (exercise tolerance does not decrease, the left ventricular ejection fraction does not decrease). Pharmacokinetics. Pharmacokinetics of fixed dose combinations. The rate and extent of absorption of the drug are equivalent to the bioavailability of telmisartan and amlodipine when used as separate pills.

Pharmacokinetics

Fixed-dose combination pharmacokinetics

The speed and extent of absorption of the drug Tvinsta equivalent to the bioavailability of telmisartan and amlodipine when used as separate pills.

Pharmacokinetics of individual components

Telmisartan

Suction

When ingestion is rapidly absorbed from the gastrointestinal tract. Bioavailability - 50%. When taken simultaneously with food, the decrease in AUC ranges from 6% (at a dose of 40 mg) to 19% (at a dose of 160 mg). Three hours after ingestion, plasma concentration levels out, regardless of the meal.

Distribution

Plasma protein binding is 99.5%, mainly with albumin and alpha-1 glycoprotein. Visible average V_dat an equilibrium concentration of 500 liters.

Metabolism

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

Removal

T_1/2 - more than 20 hours. C_maxin blood plasma and, to a lesser extent, AUC increase disproportionately to the dose. There is no data on clinically significant accumulation of telmisartan. Excreted through the intestine unchanged, kidney excretion of less than 2%. Total plasma clearance is high (900 ml / min) compared with hepatic blood flow (about 1500 ml / min).

Amlodipine

Suction

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

Distribution

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.

Metabolism

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

Removal

Removal of amlodipine from blood plasma occurs in two phases. T_1/2is approximately 30-50 hours. Sustained plasma levels are reached after continuous administration of the drug for 7-8 days. Amlodipine is excreted by the kidneys both unchanged (10%) and as metabolites (60%).

Pharmacokinetics in special clinical situations:

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

The pharmacokinetics of telmisartan in elderly patients is not different from younger patients. Dose adjustment is not required. In elderly patients, there is a tendency to a decrease in the clearance of amlodipine, which leads to an increase in AUC and T_1/2.

Changing the dose of telmisartan in patients with renal insufficiency is not required, including patients on hemodialysis. Telmisartan is not removed by hemodialysis.

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

Pharmacokinetic studies conducted in patients with impaired liver function have shown that the absolute bioavailability of telmisartan increases to almost 100% .T_1/2in patients with impaired liver function is not changed. In patients with hepatic insufficiency, amlodipine clearance decreased, leading to an increase in the AUC value of about 40-60%.

Indications

arterial hypertension (for patients whose BP is not well controlled by telmisartan or amlodipine in monotherapy);
arterial hypertension (for patients for whom combination therapy is indicated);
patients with arterial hypertension receiving telmisartan and amlodipine as separate pills as a substitute for this therapy.

Composition

1 tablet contains:
active substances: Amlodipine besylate 6.935 mg, which corresponds to the content of amlodipine 5 mg, telmisartan 40 and 80 mg;
Excipients: sodium hydroxide, povidone K25, meglumine, sorbitol, magnesium stearate, microcrystalline cellulose, pregelled starch, corn starch, colloidal silicon dioxide, dye mixture *.
The composition of the mixture of dyes: ferric oxide black (E172) - 76%, ferric oxide yellow (E172) - 4%, FD & C blue No. 1 (diamond blue FCF aluminum varnish), aluminum pigment (E133) - 20%

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Dosage and Administration

Tvinsta drug must be taken 1 time / day, inside, regardless of the meal.
Twynsta may be administered to patients receiving the same doses of telmisartan and amlodipine as separate pills for ease of therapy and increased adherence to treatment.

Twynsta may be prescribed to patients in whom the use of amlodipine alone or one telmisartan does not lead to adequate blood pressure control. Patients taking amlodipine at a dose of 10 mg, in which there are adverse reactions limiting the drug, for example, peripheral edema, can switch to taking the drug Twist at a dose of 40/5 mg 1 time / day, which will reduce the dose of amlodipine, but not reduce overall expected antihypertensive effect.

Treatment of arterial hypertension in a patient may begin with the use of the drug Twynsta in the case when it is assumed that the achievement of BP control with the help of any one drug is unlikely. The usual initial dose of Twynsta is 40/5 mg 1 time per day. Patients who need a more significant reduction in blood pressure can start taking Twinst at a dose of 80/5 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 dose of 80/10 mg 1 time / day.
Twynsta can be used with other antihypertensive drugs.

Renal dysfunction
In patients with impaired renal function, including patients on hemodialysis, no changes in the dosage of the drug are required. Amlodipine and telmisartan are not removed from the body during hemodialysis.

Liver function disorders
In patients with mild or moderate hepatic impairment, Tvinsta should be used with caution. The dose of telmisartan should not exceed 40 mg 1 time / day.

Elderly patients
Dosing regimen does not require changes.

Peculiarities of the drug action at the first dose or when it is canceled
After the first dose of telmisartan, the hypotensive effect gradually develops during the first 3 hours and the effect of the drug lasts for 24 hours and remains significant until 48 hours.
In the case of abrupt withdrawal of telmisartan, blood pressure gradually returns to its original level without the development of withdrawal syndrome.

Adverse reactions

For oral use. the systemic organ classes, the following categories are used by the frequency of occurrence of side effects: very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10,000, <1/1000); very rarely (frequency unknown (cannot be calculated from available data).

System organ class	By-effect	Frequency of occurrence
Infections and invasions	Cystitis³⁾	Seldom
	Urinary tract infections¹⁾	Infrequently
	Upper respiratory tract infections¹⁾	Infrequently
	Sepsis, incl. fatal¹⁾	Seldom
Psychotic disorders	Depression³⁾, anxiety³⁾insomnia³⁾	Seldom
Psychotic disorders	Mood lability²⁾confused consciousness²⁾	Frequency unknown
Nervous system disorders	Dizziness³⁾	Often
	Drowsiness³⁾migraine³⁾, headache³⁾, paresthesias³⁾	Infrequently
	Decreased sensitivity or resistance to external factors³⁾taste disturbance³⁾faint³⁾tremor³⁾peripheral neuropathy³⁾	Seldom
Immune system disorders	Anaphylactic reaction¹⁾	Seldom
Immune system disorders	Hypersensitivity^1),2)	Seldom¹⁾, Frequency unknown¹⁾
Violations of the organs of sight	Blurred vision³⁾	Seldom
Hearing impairment	Vertigo³⁾	Infrequently
Hearing impairment	Noise in ears²⁾	Frequency unknown
Violations by cardiovascular systems	Bradycardia³⁾feeling of heartbeat³⁾	Infrequently
	Tachycardia¹⁾	Infrequently
	Myocardial infarction²⁾	Seldom
	Arrhythmia²⁾ventricular tachycardia²⁾atrial fibrillation²⁾	Frequency unknown
	A pronounced decrease in blood pressure³⁾orthostatic hypotension³⁾	Infrequently
Respiratory disorders	Cough³⁾	Infrequently
	Dyspnea^1),2)	Infrequently¹⁾ Frequency unknown²⁾
	Rhinitis²⁾	Frequency unknown
Violations by gastrointestinal tract	Abdominal pain³⁾diarrhea³⁾nausea³⁾flatulence¹⁾	Infrequently
	Vomiting³⁾dyspepsia³⁾stomach discomfort¹⁾	Seldom
	Defecation rhythm changes²⁾, pancreatitis²⁾gastritis²⁾	Frequency unknown
	Liver function disorders¹⁾	Seldom
	Hepatitis²⁾jaundice²⁾	Frequency unknown
	Increased liver transaminase activity (mainly reflecting cholestasis)²⁾	Frequency unknown
	Increased liver enzymes³⁾	Seldom
Violations of the skin and subcutaneous tissue	Eczema³⁾erythema³⁾rash^1),3)medicinal rash¹⁾toxic rash¹⁾	Seldom
	Pruritus³⁾	Infrequently
	Angioedema^1),2)	Seldom¹⁾, frequency unknown²⁾
	Hyperhidrosis^1),2)	Infrequently¹⁾, frequency unknown²⁾
	Hives^1),2)	Seldom¹⁾, frequency unknown²⁾
	Alopecia²⁾purple²⁾skin discoloration²⁾erythema multiforme²⁾exfoliative dermatitis²⁾Stevens-Johnson Syndrome²⁾photosensitization reaction²⁾vasculitis²⁾	Frequency unknown
Violations of the musculoskeletal system	Arthralgia³⁾, backache³⁾, muscle spasms (calf muscle cramps)³⁾myalgia³⁾	Infrequently
Violations of the musculoskeletal system	Pain in lower limbs³⁾, pain in tendons (tendonitis-like symptoms)¹⁾	Seldom
Violations of the genitourinary system	Nocturia³⁾	Seldom
	Impaired renal function, including acute renal failure¹⁾urination disorders²⁾frequent urination²⁾	Frequency unknown
	erectile disfunction³⁾	Infrequently
General violations	Peripheral edema³⁾	Often
	Asthenia (weakness)³⁾chest pain³⁾fatigue³⁾, swelling³⁾	Infrequently
	Malaise³⁾flu-like syndrome¹⁾feeling a rush of blood³⁾gingival hypertrophy³⁾dryness of the oral mucosa³⁾	Seldom
	Pain²⁾weight gain²⁾weight loss²⁾, gynecomastia²⁾	Frequency unknown
Reactions identified by special research	Increasing the concentration of uric acid in the blood³⁾, increased blood creatinine¹⁾ and creatine phosphokinase (CPK)¹⁾, hemoglobin reduction¹⁾ (anemia, weakness), hypoglycemia (in patients with diabetes)¹⁾, eosinophilia¹⁾	Seldom
	Leukopenia²⁾hyperglycemia²⁾	Frequency unknown
	Hyperkalemia¹⁾	Infrequently
	Thrombocytopenia^1),2)	Seldom¹⁾, frequency unknown ²⁾

Additional information regarding individual components

Side effects previously reported with one of the components of the drug (amlodipine or telmisartan) may increase with the use of Twint, even if they were not observed in clinical studies or during the post-marketing period.

Additional information regarding the combination of components

Peripheral edema, a dose-dependent side effect of amlodipine, was observed in patients who received the combination of telmisartan and amlodipine, less frequently than in patients who received only amlodipine.

Twynsta should be prescribed with caution patients with:

obstructive biliary tract diseases or liver failure;
bilateral renal artery stenosis or single kidney artery stenosis;
condition after kidney transplantation;
reduced bcc and / or hyponatremia;
a double blockade of the renin-angiotensin-aldosterone system (RAAS);
other conditions characterized by RAAS activation;
primary aldosteronism;
stenosis of the aortic and mitral valve, obstructive hypertrophic cardiomyopathy;
heart failure;
hyperkalemia;
diabetes mellitus with additional cardiovascular risk (i.e., concomitant coronary artery disease (IHD) /);
after 1 month after acute myocardial infarction and unstable angina.

Drug interactions

There were no interactions between the two active components that are included in fixed doses of this drug in clinical studies.
Special studies of drug interactions drug Twynsta with other drugs have been conducted.

The combination of active ingredients
With the simultaneous use of the drug Twynsta with the following drugs should be taken into account the following information.
Other antihypertensive drugs
With simultaneous use with other antihypertensive drugs, the hypotensive effect of the drug Twynsta may increase.
Drugs that can reduce blood pressure
It can be expected that some drugs, such as baclofen and amifostine, due to their pharmacological properties, will enhance the hypotensive effect of all antihypertensive drugs, including the drug Twynsta. In addition, orthostatic hypotension may be enhanced by ethanol, barbiturates, narcotic drugs or antidepressants.
Corticosteroids (systemic use)
Perhaps a decrease in the hypotensive effect.

Telmisartan
With simultaneous use of telmisartan with:

other antihypertensives: may increase the hypotensive effect. In one study, the combined use of telmisartan and ramipril showed an increase in AUC0-24 and Cmax of ramipril and ramiprilat by a factor of 2.5. The clinical significance of this interaction has not been established.
digoxin, warfarin, hydrochlorothiazide, glibenclamide, simvastatin and amlodipine: no clinically significant interaction was found. An increase in the average concentration of digoxin in the blood plasma was noted on average by 20% (in one case by 39%). With the simultaneous appointment of telmisartan and digoxin, it is advisable to periodically determine the concentration of digoxin in the blood.
lithium preparations: there was a reversible increase in the concentration of lithium in the blood, accompanied by toxic effects when taking ACE inhibitors. In rare cases, such changes have been reported with the appointment of angiotensin II receptor antagonists, in particular, telmisartan. With the simultaneous appointment of lithium preparations 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 agent, cyclooxygenase-2 inhibitors (COX-2) and non-selective NSAIDs can cause the development of acute renal failure in patients with reduced BCC. Preparations affecting the activity of the renin-angiotensin system, incl. telmisartan may have a synergistic effect. In patients receiving NSAIDs and telmisartan, at the beginning of treatment, BCC should be compensated and renal function should be monitored.

With the simultaneous use of NSAIDs and antihypertensive drugs like telmisartan, a decrease in the hypotensive effect was reported through inhibition of the vasodilator effect of prostaglandins.

Amlodipine
With simultaneous use of amlodipine with:

grapefruit and grapefruit juice: the simultaneous use of the drug with grapefruit or grapefruit juice is not recommended, because In some patients, as a result of the increased bioavailability of amlodipine, its antihypertinsive effects may be enhanced.
CYP3A4 isoenzyme inhibitors: In a study in elderly patients, diltiazem was shown to inhibit amlodipine metabolism, probably affecting CYP3A4 (amlodipine plasma concentrations increase by about 50% and the effect of amlodipine increases). It is possible that more active inhibitors of CYP3A4 (such as ketoconazole, itraconazole, ritonavir) may increase plasma concentrations of amlodipine to a greater extent than diltiazem.
CYP3A4 isoenzyme inducers - anticonvulsant drugs (for example, carbamazepine, phenobarbital, phenytoin, phosphenytoin, primidone), rifampicin, St. John's wort (Hypericum perforatum): combined use may lead to a decrease in the concentration of amlodipine in blood plasma. Regular medical surveillance is shown. When using CYP3A4 inducers, as well as after their cancellation, it is recommended (if possible) to change the dose of amlodipine.
The combined use of simvastatin in a dose of 80 mg with amlodipine, regardless of the dose, contributes to an increase in the exposure of simvastatin to 77% compared with simvastatin monotherapy.Therefore, the dose of simvastatin should not exceed 40 mg / day.

With the simultaneous use of the following drugs should take into account the following information
The safety of combined use of amlodipine with thiazide diuretics, beta-blockers, ACE inhibitors, long-acting nitrates, nitroglycerin (used sublingually), NSAIDs, antibiotics and hypoglycemic agents for oral administration has been established.
With simultaneous use of amlodipine and sildenafil, it was shown that each drug had an independent hypotensive effect.
Additional Information
The simultaneous use of 20 ml of grapefruit juice with a single dose of amlodipine 10 mg taken orally in 20 healthy volunteers did not lead to a significant effect on the pharmacokinetic properties of amlodipine.
The simultaneous use of amlodipine with cimetidine had no significant effect on the pharmacokinetics of amlodipine.
The simultaneous use of amlodipine with atorvastatin, digoxin, warfarin or cyclosporin did not significantly affect the pharmacokinetics or pharmacodynamics of these drugs.
Based on the experience of using other drugs that affect the RAAS, the simultaneous use of Twynsta and potassium-sparing diuretics, potassium-containing additives, potassium-containing dietary salt, and other drugs that increase the content of potassium in the blood (for example, heparin) can lead to hyperkalemia, therefore, this indicator should in patients. In this regard, their simultaneous use with telmisartan requires caution.

Pregnancy and Lactation

Special studies of the drug Twynsta during pregnancy and during lactation have not been conducted. The effects associated with the individual components of the drug are described below.

Pregnancy
Telmisartan
The use of angiotensin II receptor antagonists (ARA II) is contraindicated during pregnancy. When diagnosing pregnancy, the drug should be stopped immediately. If necessary, alternative therapy should be prescribed.
It is known that the use of APA II during the II and III trimesters of pregnancy has a fetotoxic effect (reduced kidney function, oligohydramnios, delayed ossification of the fetal skull), and there is neonatal toxicity (renal failure, arterial hypotension and hyperkalemia).
Amlodipine
The limited data available on the effects of amlodipine or other calcium receptor antagonists do not indicate the presence of negative effects on the fetus. However, there is a risk of slowing down the process of delivery

Breastfeeding period
Special studies on the allocation of telmisartan and / or amlodipine with breast milk in women have not been conducted. Animal studies have shown that telmisartan is excreted in milk from lactating animals. Given the possible adverse reactions, the decision to continue breastfeeding or to cancel therapy should be made taking into account its significance for the mother. Studies on the effect on human fertility were not conducted.

Special instructions

The drug should be administered with caution if the patient has the following conditions:

abnormal liver function;
bilateral renal artery stenosis or arterial stenosis of a single kidney, severe renal dysfunction. In some patients, due to the suppression of the RAAS, especially when using a combination of agents acting on this system, renal function is impaired (including acute renal failure). Therefore, therapy, accompanied by a similar double blockade of the RAAS, should be carried out strictly individually and with careful monitoring of renal function (including periodic monitoring of the content of potassium and creatinine in blood serum).In cases of dependence of the vascular tone and kidney function, mainly on the activity of the RAAS (for example, in patients with chronic heart failure or kidney diseases, including stenosis of the renal arteries, or stenosis of the artery of a single kidney), the administration of drugs affecting this system, may be accompanied by the development of acute arterial hypotension, hyperasotemia, oliguria, and, in rare cases, acute renal failure;
condition after kidney transplantation (no experience);
reduction of bcc and / or hyponatremia due to previous diuretic therapy, restriction of salt, diarrhea or vomiting;
double blockade of RAAS;
other conditions characterized by RAAS activation;
primary aldosteronism;
aortic and mitral stenosis, idiopathic hypertrophic subaortic stenosis;
heart failure;
hyperkalemia;
hereditary intolerance to fructose;
in patients with diabetes mellitus and additional cardiovascular risk, i.e. Patients with diabetes mellitus and concomitant coronary artery disease (IHD), the risk of fatal myocardial infarction and sudden cardiovascular death may be increased when treated with antihypertensive drugs such as angiotensin II receptor antagonists and ACE inhibitors. In patients with diabetes, IHD may be asymptomatic, as a result of which it may not be diagnosed. Patients with diabetes should undergo an appropriate diagnosis, for example, an exercise test, for the diagnosis and treatment of coronary artery disease, respectively, before starting treatment with Twist.

Other indications
Twynsta is less effective in treating patients of the Negroid race (renin activity in the blood is usually reduced in this population).
There are no data on the use of the drug Twynsta in patients with unstable angina, with acute myocardial infarction and during one month after the development of myocardial infarction.

Influence on ability to drive motor transport and control mechanisms
Studies of the impact on the ability to drive vehicles and control mechanisms were not conducted. However, it should be taken into account that during treatment such undesirable effects as syncope, drowsiness or dizziness may occur. Therefore, when driving a vehicle or machinery, care should be taken. If patients experience these sensations, they should avoid performing such potentially dangerous activities as driving a car or operating machinery.

Overdosage

Symptoms
No overdose cases have been identified. Possible symptoms of overdose consist of symptoms from the individual components of the drug.
Telmisartan - a pronounced decrease in blood pressure, tachycardia, possibly bradycardia, dizziness, increased serum creatinine levels, acute renal failure.
Amlodipine - excessive peripheral vasodilation and, possibly, reflex tachycardia. There may be severe and probably prolonged systemic hypotension, up to the development of a fatal shock.

Treatment
Hemodialysis is not effective. Monitoring the patient's condition, therapy should be symptomatic and supportive.
In order to counteract the blockade of calcium channels, intravenous administration of calcium gluconate may be useful.
Overdose treatment methods can be used, such as induction of vomiting, gastric lavage, the use of activated carbon, transferring the patient to the "supine-lying position" and the introduction of plasma substituting solutions in the case of a pronounced decrease in blood pressure.