Telsartan^® AM (Tablets) Instructions for Use

Marketing Authorization Holder

Dr. Reddy’s Laboratories Ltd. (India)

ATC Code

C09DB04 (Amlodipine and Telmisartan)

Active Substances

Telmisartan (Rec.INN registered by WHO)

Amlodipine (Rec.INN registered by WHO)

Dosage Forms

	Telsartan® AM	Tablets 5 mg+40 mg: 10, 14 or 28 pcs.
		Tablets 5 mg+80 mg: 10, 14 or 28 pcs.
		Tablets 10 mg+40 mg: 10, 14 or 28 pcs.
		Tablets 10 mg+80 mg: 10, 14 or 28 pcs.

Dosage Form, Packaging, and Composition

Tablets of oblong shape, biconvex, two-layer, one layer – from light pink to pink in color, with inclusions of white color, the second layer – white or almost white.

Excipients: sodium hydroxide – 3.36 mg, meglumine – 12 mg, povidone K30 – 15.5 mg, polysorbate 80 – 0.5 mg, mannitol – 351.605 mg, magnesium stearate – 9.8 mg, iron oxide red dye (E172) – 0.3 mg.

5 pcs. – blisters (2) – cardboard packs.
7 pcs. – blisters (2) – cardboard packs.
7 pcs. – blisters (4) – cardboard packs.

Tablets of oblong shape, biconvex, two-layer, one layer – from light pink to pink in color, with inclusions of white color, the second layer – white or almost white.

Excipients: sodium hydroxide – 6.72 mg, meglumine – 24 mg, povidone K30 – 26.5 mg, polysorbate 80 – 1 mg, mannitol – 519.945 mg, magnesium stearate – 14.6 mg, iron oxide red dye (E172) – 0.3 mg.

2 pcs. – blisters (5) – cardboard packs.
7 pcs. – blisters (2) – cardboard packs.
7 pcs. – blisters (4) – cardboard packs.

Tablets of oblong shape, biconvex, two-layer,: one layer – from light yellow to yellow in color, the second layer – white or almost white.

Excipients: sodium hydroxide – 3.36 mg, meglumine – 12 mg, povidone K30 – 15.5 mg, polysorbate 80 – 0.5 mg, mannitol – 344.67 mg, magnesium stearate – 9.8 mg, iron oxide red dye (E172) – 0.3 mg.

5 pcs. – blisters (2) – cardboard packs.
7 pcs. – blisters (2) – cardboard packs.
7 pcs. – blisters (4) – cardboard packs.

Tablets of oblong shape, biconvex, two-layer, one layer – from light yellow to yellow in color, the second layer – white or almost white.

Excipients: sodium hydroxide – 6.72 mg, meglumine – 24 mg, povidone K30 – 26.5 mg, polysorbate 80 – 1 mg, mannitol – 513.01 mg, magnesium stearate – 14.6 mg, iron oxide red dye (E172) – 0.3 mg.

2 pcs. – blisters (5) – cardboard packs.
7 pcs. – blisters (2) – cardboard packs.
7 pcs. – blisters (4) – cardboard packs.

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Agents acting on the renin-angiotensin system; angiotensin II receptor antagonists, combinations; angiotensin II receptor antagonists and calcium channel blockers

Pharmacological Action

A combined antihypertensive drug containing active components with complementary antihypertensive action: amlodipine (a calcium channel blocker) and Telmisartan (an angiotensin II receptor antagonist). The combination of these substances has an additive antihypertensive effect, reducing blood pressure to a greater extent than each component separately.

Amlodipine is a calcium channel blocker, a dihydropyridine derivative. It has antianginal and antihypertensive action. Amlodipine inhibits the transmembrane transition of calcium ions into cardiomyocytes and smooth muscle cells of the vascular wall. The antihypertensive effect of amlodipine is due to a direct relaxing effect on the smooth muscle cells of the vascular wall. The mechanism of the antianginal action of amlodipine is not fully understood; it is presumably associated with the following effects: it causes dilation of peripheral arterioles, reducing total peripheral resistance – afterload, which leads to a decrease in myocardial oxygen demand; it causes dilation of coronary arteries and arterioles both in intact and ischemic areas of the myocardium, which increases oxygen supply to the myocardium, including in patients with Prinzmetal’s angina. Amlodipine reduces the severity of left ventricular hypertrophy. It does not affect myocardial contractility and conductivity, does not cause a reflex increase in heart rate, inhibits platelet aggregation, increases glomerular filtration rate, and has a weak natriuretic effect.

In patients with arterial hypertension, taking amlodipine once a day provides a clinically significant reduction in blood pressure (in supine and standing positions) over 24 hours. The antihypertensive effect develops slowly, so the development of acute arterial hypotension is not typical. In patients with angina, taking amlodipine once a day increases exercise tolerance, time to onset of angina attack and to ischemic ST-segment depression, reduces the frequency of angina attacks and the need for nitroglycerin intake (short-acting forms). Amlodipine does not have an undesirable effect on lipid metabolism and does not cause changes in the plasma lipid profile. Amlodipine can be used in patients with bronchial asthma, diabetes mellitus, and gout.

After a single oral dose, the effect of amlodipine begins within 2-4 hours and lasts for 24 hours. The maximum antihypertensive effect is achieved no earlier than 4 weeks from the start of taking the drug. The hemodynamic effects of the drug remain unchanged with long-term use.

Telmisartan is a specific angiotensin II receptor antagonist (type AT₁), effective when taken orally. It has a high affinity for the AT₁ receptor subtype of angiotensin II, through which the action of angiotensin II is realized. It displaces angiotensin II from binding to the receptor, having no agonist action on this receptor. Telmisartan binds only to the AT₁ receptor subtype of angiotensin II. The binding is long-lasting. It has no affinity for other receptors, including the AT₂ receptor. It reduces the concentration of aldosterone in the blood, does not inhibit plasma renin and does not block ion channels. Telmisartan does not inhibit ACE (kininase II), an enzyme that also breaks down bradykinin, so an increase in bradykinin-mediated side effects is not expected.

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

In patients with arterial hypertension, Telmisartan reduces systolic and diastolic blood pressure without affecting heart rate. In case of abrupt withdrawal of telmisartan, blood pressure gradually returns to the initial level without the development of withdrawal syndrome.

Pharmacokinetics

The rate and extent of absorption of the drug are equivalent to the bioavailability of telmisartan and amlodipine when used as separate tablets.

Amlodipine

After oral administration, amlodipine is slowly and almost completely absorbed from the gastrointestinal tract. Simultaneous food intake does not affect the absorption of amlodipine. C_max in plasma is reached 6-12 hours after administration. The mean absolute bioavailability is 64-80%. The mean V_d is 21 L/kg of body weight, indicating that most of the amlodipine is in the tissues, and a smaller part is in the blood. Most of the amlodipine in the blood (97.5%) is bound to plasma proteins. C_ss in plasma are reached after 7-8 days of constant amlodipine use. Amlodipine penetrates the blood-brain barrier and the placental barrier.

Amlodipine undergoes slow but active metabolism in the liver in the absence of a significant first-pass effect through the liver. Metabolites do not have significant pharmacological activity.

After a single dose of amlodipine, T_1/2 ranges from 35 to 50 hours; with repeated use, it is approximately 45 hours. About 60% of the orally administered dose is excreted by the kidneys mainly in the form of metabolites, 10% – unchanged, 20-25% – through the intestine with bile. The total clearance of amlodipine is 0.116 ml/s/kg (7 ml/min/kg, 0.42 L/h/kg). Amlodipine is not removed by hemodialysis.

Prolongation of T_1/2 in patients with hepatic insufficiency suggests that with long-term use, the accumulation of amlodipine in the body will be higher (increases to 60 hours).

Telmisartan

When taken orally, it is rapidly absorbed from the gastrointestinal tract. Bioavailability is 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). After 3 hours of oral administration, the concentration in plasma levels off, regardless of food intake. C_max in plasma and, to a lesser extent, AUC increase disproportionately to the dose size. Binding to plasma proteins is 99.5%, mainly to albumin and alpha-1-glycoprotein. The mean apparent V_d at steady state is 500 L.

It is metabolized by conjugation with glucuronic acid. Metabolites are pharmacologically inactive. T_1/2 is more than 20 hours. It is excreted through the intestine unchanged; renal excretion is less than 2%. Total plasma clearance is high (900 ml/min) compared to hepatic blood flow (about 1500 ml/min).

Indications

• Arterial hypertension in patients whose blood pressure is insufficiently controlled by telmisartan or amlodipine in monotherapy;
• Arterial hypertension in patients for whom combination therapy is indicated;
• For patients with arterial hypertension receiving Telmisartan and amlodipine as separate tablets, as a replacement for this therapy.

ICD codes

Dosage Regimen

The drug is taken orally, once a day, regardless of meals.

This combination can be prescribed to patients receiving Telmisartan and amlodipine in the same doses as separate tablets, for the convenience of therapy and to increase treatment adherence.

The drug can be prescribed to patients in whom the use of amlodipine alone or telmisartan alone does not lead to adequate blood pressure control. Patients taking amlodipine at a dose of 10 mg, who experience side effects limiting drug intake, such as peripheral edema, can switch to taking this combination at a dose of 40/5 mg once a day, which will reduce the dose of amlodipine but will not reduce the overall expected antihypertensive effect.

Treatment of arterial hypertension in a patient can be started with the use of this combination in cases where it is assumed that achieving blood pressure control with any single drug is unlikely. The usual initial dose of the drug is 40/5 mg once a day. Patients who require a more significant reduction in blood pressure can start taking the drug at a dose of 80/5 mg once a day.

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

The drug can be used together with other antihypertensive drugs.

In patients with impaired renal function, including patients on hemodialysis, dose adjustment is not required. Amlodipine and Telmisartan are not removed from the body during hemodialysis.

In patients with mild or moderate hepatic impairment, the drug should be used with caution. The dose of telmisartan should not exceed 40 mg once a day.

In elderly patients, no dose adjustment is required.

Adverse Reactions

The frequency of side effects is defined as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10 000, <1/1000); very rare (<1/10 000); frequency unknown (cannot be estimated from the available data).

Infections and infestations uncommon – urinary tract infections, upper respiratory tract infections; rare – sepsis, including fatal.

From the immune system rare – hypersensitivity reactions.

Mental disorders rare – depression, anxiety, insomnia; frequency unknown – mood lability, confusion.

From the nervous system common – dizziness; uncommon – drowsiness, migraine, headache, paresthesia; rare – decreased sensitivity or resistance to external factors, taste disturbance, syncope, tremor, peripheral neuropathy.

From the organ of vision rare – visual impairment.

From the organ of hearing and balance uncommon – vertigo; frequency unknown – tinnitus.

From the cardiovascular system uncommon – bradycardia, palpitations, tachycardia, pronounced decrease in blood pressure, orthostatic hypotension; rare – myocardial infarction; frequency unknown – arrhythmia, ventricular tachycardia, atrial fibrillation.

From the respiratory system uncommon – cough, dyspnea; frequency unknown – rhinitis.

From the digestive system uncommon – abdominal pain, diarrhea, nausea, flatulence; rare – vomiting, dyspepsia, stomach discomfort, liver function disorders, increased activity of liver enzymes; frequency unknown – changes in bowel rhythm, pancreatitis, gastritis, hepatitis, jaundice, increased activity of liver transaminases (mainly reflecting cholestasis).

From the skin and subcutaneous tissue uncommon – skin itching, hyperhidrosis; frequency unknown – alopecia, purpura, skin discoloration, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, photosensitivity reaction, vasculitis.

From the musculoskeletal system uncommon – arthralgia, muscle cramps (calf cramps), myalgia; rare – tendon pain (symptoms resembling tendinitis).

From the urinary system rare – nocturia; frequency unknown – renal function disorders, including acute renal failure, urination disorders, frequent urination.

From the reproductive system and mammary gland uncommon – erectile dysfunction.

Allergic reactions rare – urticaria, angioedema.

Laboratory and instrumental findings uncommon – hyperkalemia; rare – increased blood uric acid concentration, increased blood creatinine and CPK levels), decreased hemoglobin (anemia, weakness), hypoglycemia (in patients with diabetes mellitus), eosinophilia, thrombocytopenia; frequency unknown – leukopenia, hyperglycemia.

General disorders common – peripheral edema; uncommon – asthenia (weakness), chest pain, back pain, increased fatigue, edema; rare – malaise, flu-like syndrome, feeling of facial flushing, gingival hypertrophy, dry mouth, pain in the lower extremities; frequency unknown – pain, weight gain, weight loss, gynecomastia.

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

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

Contraindications

• Obstructive biliary tract diseases;
• Severe arterial hypotension;
• Obstruction of the left ventricular outflow tract (including severe aortic stenosis);
• Hemodynamically unstable heart failure after acute myocardial infarction;
• Severe hepatic insufficiency;
• Shock;
• Fructose intolerance and glucose/galactose malabsorption syndrome or sucrase/isomaltase deficiency;
• Pregnancy;
• Breastfeeding period;
• Age under 18 years (efficacy and safety not established);
• Hypersensitivity to the active components or excipients;
• Hypersensitivity to other dihydropyridine derivatives.

With caution the drug should be prescribed to patients with hepatic insufficiency (less than 9 points on the Child-Pugh scale); bilateral renal artery stenosis or stenosis of the artery of a single kidney; condition after kidney transplantation; reduced circulating blood volume and/or hyponatremia; dual blockade of the RAAS; other conditions characterized by activation of the RAAS; 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 /CAD/); within 1 month after acute myocardial infarction and unstable angina.

Use in Pregnancy and Lactation

The use of the drug is contraindicated during pregnancy and lactation.

Use in Hepatic Impairment

The use of the drug is contraindicated in severe hepatic insufficiency, obstructive biliary tract diseases.

In patients with mild or moderate hepatic impairment, the drug should be used with caution.

Use in Renal Impairment

In patients with renal impairment, including patients on hemodialysis, dose adjustment is not required.

The drug should be prescribed with caution to patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney; condition after kidney transplantation.

Pediatric Use

The use of the drug is contraindicated under the age of 18 years (efficacy and safety have not been established).

Geriatric Use

In elderly patients, dose adjustment is not required.

Special Precautions

The drug is less effective in treating patients of Black race (this population usually has reduced blood renin activity).

In some patients, due to suppression of the RAAS, especially when using a combination of agents acting on this system, renal function may be impaired (including acute renal failure). Therefore, therapy accompanied by such dual blockade of the RAAS should be carried out strictly individually and with careful monitoring of renal function (including periodic monitoring of serum potassium and creatinine levels). In cases where vascular tone and renal function are predominantly dependent on RAAS activity (for example, in patients with chronic heart failure, or kidney diseases, including renal artery stenosis or stenosis of the artery of a solitary kidney), the administration of drugs affecting this system may be accompanied by the development of acute arterial hypotension, hyperazotemia, oliguria, and, in rare cases, acute renal failure.

In patients with diabetes mellitus and additional cardiovascular risk (coronary artery disease), the risk of fatal myocardial infarction and sudden cardiovascular death may be increased when treated with antihypertensive agents such as angiotensin II receptor antagonists and ACE inhibitors. In patients with diabetes mellitus, coronary artery disease may be asymptomatic, and therefore may be undiagnosed. Before starting treatment with the drug, patients with diabetes mellitus should undergo appropriate diagnostic tests (for example, an exercise test) to diagnose and treat coronary artery disease.

Effect on the ability to drive vehicles and machinery

It should be taken into account that adverse effects such as fainting, drowsiness, or dizziness may occur during treatment. Therefore, caution should be exercised when driving vehicles or operating machinery.

Drug Interactions

With simultaneous use with other antihypertensive drugs, the hypotensive effect of this combination may be enhanced.

Some drugs, for example, baclofen and amifostine, due to their pharmacological properties, may enhance the hypotensive effect of this combination. In addition, orthostatic hypotension may be enhanced with simultaneous use of ethanol, barbiturates, narcotics, or antidepressants.

With simultaneous use with corticosteroids (for systemic use), a reduction in the hypotensive effect is possible.

Based on the experience with other agents affecting the RAAS, simultaneous use of this combination and potassium-sparing diuretics, potassium-containing supplements, potassium-containing dietary salt, other agents that increase blood potassium levels (for example, heparin), may lead to hyperkalemia, therefore, potassium concentration should be monitored in patients.

Amlodipine

Simultaneous use of the drug with grapefruit or grapefruit juice is not recommended, as in some patients the antihypertensive effect of amlodipine may be enhanced due to increased bioavailability.

A study in elderly patients showed that diltiazem inhibits the metabolism of amlodipine, probably affecting CYP3A4 (amlodipine plasma concentration increases by approximately 50% and the effect of amlodipine is enhanced). It cannot be excluded that more potent CYP3A4 inhibitors (such as ketoconazole, itraconazole, ritonavir) may increase amlodipine plasma concentration to a greater extent than diltiazem.

Concomitant use with inducers of the CYP3A4 isoenzyme (anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone), rifampicin, St. John’s wort (Hypericum perforatum)) may lead to a decrease in amlodipine plasma concentration. Regular medical supervision is indicated. During the use of CYP3A4 inducers, as well as after their discontinuation, a dose adjustment of amlodipine is recommended (if possible).

Concomitant use of simvastatin at a dose of 80 mg with amlodipine, regardless of the dose, contributes to an increase in simvastatin exposure by up to 77% compared with simvastatin monotherapy. Therefore, the dose of simvastatin should not exceed 40 mg/day.

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

Telmisartan

With simultaneous use of telmisartan with other antihypertensive agents, an enhancement of the hypotensive effect is possible. In one study, with combined use of telmisartan and ramipril, an increase in AUC_0-24 and C_max of ramipril and ramiprilat by 2.5 times was observed.

With simultaneous use of telmisartan with digoxin, an average increase in digoxin plasma concentration by 20% (in one case by 39%) was noted. With simultaneous administration of telmisartan and digoxin, it is advisable to periodically determine the concentration of digoxin in the blood.

With simultaneous use of telmisartan with lithium preparations, a reversible increase in blood lithium concentration was observed, accompanied by toxic phenomena when taking ACE inhibitors. In rare cases, similar changes have been reported with the administration of angiotensin II receptor antagonists, in particular, telmisartan. With simultaneous administration of lithium preparations and angiotensin II receptor antagonists, it is recommended to determine the lithium content in the blood.

Simultaneous use of telmisartan with NSAIDs, including acetylsalicylic acid in high doses (≥3 mg/day), COX-2 inhibitors and non-selective NSAIDs, may cause the development of acute renal failure in patients with reduced circulating blood volume. Drugs affecting RAAS activity, including Telmisartan, may have a synergistic effect. In patients receiving NSAIDs and Telmisartan, fluid loss should be compensated and renal function should be carefully monitored, both at the beginning and during treatment.

With simultaneous use of NSAIDs and antihypertensive drugs similar to telmisartan, a reduction in the hypotensive effect has been reported due to inhibition of the vasodilatory effect of prostaglandins.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.