Telmilax

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TELMILAX (Telmilax)

Composition:

Active substance: telmisartan;

1 tablet contains 20 mg, or 40 mg, or 80 mg of telmisartan;

Excipients: sodium hydroxide, povidone (K 25), meglumine, mannitol (E 421), magnesium stearate, crospovidone.

Dosage form. Film-coated tablets.

Main physicochemical properties:

20 mg tablets: round-shaped, white tablets with bevelled edges and embossing “LC” on one side.

40 mg tablets: oval-shaped, white tablets with embossing “LC” on one side.

80 mg tablets: oval-shaped, white tablets with embossing “LC” on one side.

Pharmacotherapeutic group.

Simple preparations of angiotensin II antagonists. Telmisartan.

ATC code C09CA07.

Pharmacological Properties

Pharmacodynamics.

Mechanism of action.

Telmisartan is a specific and effective oral angiotensin II receptor (type AT1) antagonist. Telmisartan competitively displaces angiotensin II from its binding sites on AT1 receptor subtypes responsible for the actions of angiotensin II, with very high affinity. Telmisartan exhibits no partial agonist activity at the AT1 receptor. It selectively binds to the AT1 receptor, and this binding is long-lasting. Telmisartan has no affinity for other receptors, including AT2 and other less-characterized AT receptors. The functional role of these receptors is not fully understood, nor is the effect of their potential stimulation by angiotensin II, the levels of which are increased by telmisartan. Telmisartan reduces plasma aldosterone levels. It does not reduce plasma renin levels and does not block ion channels. Telmisartan does not inhibit angiotensin-converting enzyme (kininase II), the enzyme responsible for bradykinin breakdown. Therefore, potentiation of bradykinin-mediated adverse effects is not expected.

In humans, telmisartan at a dose of 80 mg almost completely inhibits the increase in arterial pressure induced by angiotensin II. The blocking effect persists for 24 hours and remains detectable up to 48 hours.

Pharmacokinetics.

Absorption. Telmisartan is rapidly absorbed, but the amount absorbed varies. The mean absolute bioavailability of telmisartan is approximately 50%. When Telmilax is administered with food, the area under the concentration-time curve (AUC) for telmisartan decreases by approximately 6% (40 mg) to 19% (160 mg). However, after 3 hours, plasma concentrations are similar to those observed when telmisartan is taken without food.

Linearity/non-linearity. The slight reduction in AUC is not considered to reduce therapeutic efficacy. There is no linear relationship between dose and plasma levels. Cmax and, to a lesser extent, AUC increase disproportionately at doses above 40 mg.

Distribution. Telmisartan is highly bound to plasma proteins (>99.5%), primarily to albumin and alpha-1 acid glycoprotein. The mean volume of distribution at steady state (Vss) is approximately 500 L.

Metabolism. Telmisartan is metabolized via conjugation of the parent compound to glucuronide. The pharmacological activity of the conjugate has not been established.

Elimination. Telmisartan exhibits biexponential pharmacokinetic elimination with a terminal half-life of >20 hours. Maximum plasma concentration (Cmax) and, to a lesser extent, AUC increase disproportionately with dose. There is no evidence of clinically significant accumulation of telmisartan with repeated administration at recommended doses. Plasma concentrations were higher in women than in men, without a corresponding impact on efficacy.

After oral (and intravenous) administration, telmisartan is almost exclusively eliminated in feces, mainly as unchanged compound. Cumulative renal excretion accounts for <1% of the dose. Total plasma clearance (Cltot) is high (approximately 1000 mL/min), compared to hepatic blood flow (about 1500 mL/min).

Special patient populations.

Gender. Plasma concentrations (Cmax) and AUC in women are approximately 3 and 2 times higher, respectively, than in men.

Elderly patients. The pharmacokinetics of telmisartan do not differ between elderly patients and those under 65 years of age.

Patients with renal impairment. In patients with moderate to severe renal impairment, plasma concentrations were doubled. However, in patients with renal failure undergoing dialysis, low plasma concentrations were observed. Telmisartan has high plasma protein binding in patients with renal impairment and is not dialyzable. The elimination half-life of telmisartan is not altered in patients with renal impairment.

Patients with hepatic impairment. Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute bioavailability to approximately 100%. The elimination half-life of telmisartan is not altered in patients with hepatic impairment.

Clinical characteristics.

Indications.

Hypertension.

Treatment of essential hypertension in adults.

Prevention of cardiovascular diseases.

Reduction of cardiovascular morbidity in patients with:

• Manifest atherothrombotic cardiovascular disease (ischemic heart disease, stroke, or peripheral arterial disease in medical history);
• Type 2 diabetes mellitus with documented target organ damage.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product;
• Pregnancy or women planning pregnancy (see sections "Special precautions for use", "Use during pregnancy or breastfeeding");
• Obstructive biliary tract disorders;
• Severe hepatic impairment.

Concomitant use of telmisartan and aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²) (see sections "Dosage and administration", "Special precautions for use", "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Double blockade of the renin-angiotensin-aldosterone system (RAAS)

Combination of telmisartan and aliskiren is contraindicated in patients with diabetes mellitus and renal impairment (GFR < 60 mL/min/1.73 m²) and is not recommended for other patients (see sections "Contraindications", "Special precautions for use").

Clinical data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse effects such as arterial hypotension, hyperkalemia, and decreased renal function (including acute renal failure), compared to using a single RAAS-acting agent.

Digoxin

When telmisartan and digoxin are used concomitantly, mean increases in digoxin plasma peak concentrations (by 49%) and trough concentrations (by 20%) have been observed. Monitoring of digoxin levels should be performed at the start of treatment, during dose adjustments, and upon discontinuation of telmisartan to maintain levels within the therapeutic range.

Like other drugs that inhibit the renin-angiotensin-aldosterone system, telmisartan may provoke hyperkalemia (see section "Special precautions for use"). The risk may increase when used in combination with other medicinal products that may also cause hyperkalemia (potassium-containing salt substitutes, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs, including selective COX-2 inhibitors), heparin, immunosuppressants (cyclosporine or tacrolimus), and trimethoprim).

Cases of hyperkalemia depend on associated risk factors. The risk increases with the above-mentioned therapeutic combinations. The risk is particularly high when combined with potassium-sparing diuretics or potassium-containing salt substitutes. Combination with ACE inhibitors or NSAIDs is less risky provided that the relevant precautions are strictly observed.

Concomitant use is not recommended.

Potassium-sparing diuretics or potassium supplements. Angiotensin II receptor antagonists, such as telmisartan, reduce potassium loss caused by diuretics. Potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, or potassium-containing salt substitutes may lead to a significant increase in serum potassium concentration. If concomitant use is indicated due to documented hypokalemia, they should be used with caution and serum potassium levels should be monitored frequently.

Lithium. When lithium is used concomitantly with ACE inhibitors or angiotensin II receptor antagonists, including telmisartan, reversible increases in serum lithium concentrations and lithium toxicity have been reported. If use of this combination is necessary, careful monitoring of serum lithium levels is recommended.

Concomitant use requires caution.

Nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs (i.e., acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, and non-selective NSAIDs) may reduce the antihypertensive effect of angiotensin II receptor antagonists.

In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with renal impairment), combined use of angiotensin II receptor antagonists and agents that inhibit cyclooxygenase may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, such combination should be used with caution, especially in elderly patients. Patients should receive adequate hydration. Consideration should be given to monitoring renal function after initiation of concomitant therapy and periodically thereafter.

In one study, concomitant administration of telmisartan and ramipril resulted in a 2.5-fold increase in AUC0–24 and Cmax for ramipril and ramiprilat. The clinical significance of this phenomenon is unknown.

Diuretics (thiazide or loop diuretics). Prior treatment with high doses of diuretics such as furosemide (a loop diuretic) and hydrochlorothiazide (a thiazide diuretic) may lead to dehydration and risk of developing arterial hypotension at the beginning of telmisartan therapy.

Should be considered when used concomitantly.

Other antihypertensive agents. The ability of telmisartan to lower blood pressure may be enhanced by concomitant use of other antihypertensive agents.

Due to the pharmacological properties of baclofen and amifostine, it can be expected that these medicinal products may enhance the hypotensive effect of all antihypertensive agents, including telmisartan. In addition, orthostatic hypotension may be exacerbated by alcohol consumption, barbiturates, narcotics, and antidepressants.

Corticosteroids (systemic use). Reduction of antihypertensive effect.

Special precautions for use.

Angiotensin II receptor antagonists are contraindicated during pregnancy. Female patients who are planning pregnancy should switch to an alternative antihypertensive therapy with an established safety profile for use in pregnancy. Angiotensin II receptor antagonists must be discontinued immediately upon confirmation of pregnancy, and alternative treatment should be initiated if necessary (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Angioedema of the intestine. Cases of intestinal angioedema have been reported in patients receiving angiotensin II receptor blockers (see section "Adverse reactions"). These patients presented with abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor blockers. If intestinal angioedema is diagnosed, telmisartan should be discontinued and appropriate monitoring initiated until complete symptom resolution.

Hepatic impairment. Telmilax must not be administered to patients with cholestasis, obstructive biliary disorders, or severe hepatic impairment (see section "Contraindications"), as telmisartan is primarily excreted via bile. In patients with these conditions, hepatic clearance of telmisartan is reduced.

Telmilax should be used with caution in patients with mild to moderate hepatic impairment.

Renovascular hypertension. There is an increased risk of severe hypotension and renal impairment in patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney when treated with drugs affecting the renin-angiotensin-aldosterone system.

Renal impairment and kidney transplantation. Periodic monitoring of serum potassium and creatinine levels is recommended in patients with renal dysfunction receiving Telmilax. There is no experience with the use of Telmilax in patients who have recently undergone kidney transplantation.

Reduced intravascular fluid volume. Symptomatic hypotension, particularly after the first dose of Telmilax, may occur in patients with reduced intravascular volume and/or sodium levels resulting from intensive diuretic therapy, a low-salt diet, or diarrhea and vomiting. These conditions should be corrected prior to initiating Telmilax. Sodium levels and/or intravascular fluid volume should be normalized before starting treatment with Telmilax.

Dual blockade of the renin-angiotensin-aldosterone system.

Evidence indicates that concomitant use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, and impaired renal function (up to acute renal failure).

Therefore, dual blockade by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics").

If dual blockade is considered absolutely necessary, it should be performed only under specialist supervision and with continuous careful monitoring of renal function, electrolyte levels, and blood pressure.

ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Other conditions requiring renin-angiotensin-aldosterone system activity.

In patients whose vascular tone and renal function primarily depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure or significant renal disease, including renal artery stenosis), treatment with Telmilax and other drugs affecting this system may lead to acute hypotension, hyperazotemia, oliguria, and rarely, acute renal failure (see section "Adverse reactions").

Primary hyperaldosteronism. Patients with primary hyperaldosteronism usually do not respond to antihypertensive drugs acting via blockade of the renin-angiotensin system. Therefore, telmisartan is not recommended for these patients.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy. As with other vasodilators, Telmilax should be administered with caution in patients with diagnosed aortic or mitral stenosis or obstructive hypertrophic cardiomyopathy.

Patients treated with insulin or antidiabetic medicinal products.

Hypoglycemia may occur during telmisartan treatment in such patients. Blood glucose levels should be monitored in these patients, and this should be taken into account when adjusting the dose of insulin or antidiabetic drugs.

In patients with diabetes and cardiovascular risk (diabetic patients with concomitant coronary artery disease), the risk of fatal myocardial infarction and sudden cardiovascular death may be higher when treated with antihypertensive drugs such as angiotensin II receptor antagonists and ACE inhibitors. Coronary artery disease may be asymptomatic in diabetic patients and therefore may remain undiagnosed. Diabetic patients should be carefully evaluated, for example by stress testing, to detect and treat concomitant coronary artery disease before initiating treatment with this medicinal product.

Hyperkalemia. Medicinal products affecting the renin-angiotensin-aldosterone system may cause hyperkalemia.

In elderly patients, patients with renal impairment, patients with diabetes, patients receiving other medicinal products that may increase potassium levels, and/or patients with concomitant diseases, hyperkalemia may lead to fatal outcomes.

Before considering concomitant use of medicinal products that inhibit the renin-angiotensin system, the benefit-risk ratio should be carefully evaluated.

Key risk factors for hyperkalemia to consider:

• diabetes, renal impairment, age over 70 years;
• combination therapy with one or more other drugs affecting the renin-angiotensin-aldosterone system and/or potassium-containing dietary supplements. Medicinal products or therapeutic groups that may provoke hyperkalemia include potassium-containing salt substitutes, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, non-steroidal anti-inflammatory drugs (NSAIDs, including selective COX-2 inhibitors), heparin, immunosuppressants (cyclosporine or tacrolimus), and trimethoprim;
• intercurrent events, particularly dehydration, acute heart failure, metabolic acidosis, worsening renal function, sudden deterioration of kidney function (e.g., due to infections), and cellular lysis (e.g., acute limb ischemia, rhabdomyolysis, extensive trauma).

Patients at risk require careful monitoring of serum potassium concentration (see section "Interaction with other medicinal products and other forms of interaction").

Ethnic differences. Like all other angiotensin II receptor antagonists, telmisartan is less effective in reducing blood pressure in black patients compared to patients of other races. This may be explained by the higher prevalence of low-renin states in black patients with arterial hypertension.

Other. As with other antihypertensive agents, excessive reduction of blood pressure in patients with ischemic heart disease or ischemic cardiomyopathy may lead to myocardial infarction or stroke.

Use during pregnancy or breastfeeding.

Pregnancy.

This medicinal product is contraindicated in pregnant women or women who are planning to become pregnant. If pregnancy is confirmed during treatment with this product, therapy must be discontinued immediately, and if necessary, replaced with another medicinal product approved for use during pregnancy.

It is known that angiotensin II receptor antagonists cause fetotoxicity in humans during the second and third trimesters of pregnancy (renal dysfunction, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia). If angiotensin II receptor antagonists are used from the second trimester of pregnancy, ultrasound monitoring of fetal renal and skull bone development is recommended. Newborns whose mothers received angiotensin II receptor antagonists should be closely monitored for arterial hypotension (see sections "Contraindications" and "Special precautions for use").

Breastfeeding.

Due to lack of information on the use of Telmilax during breastfeeding, this medicinal product is not recommended for use in breastfeeding women. Alternative treatment with a better-established safety profile is preferred, especially when breastfeeding a newborn or preterm infant.

Fertility.

Preclinical studies did not reveal any effect of Telmilax on male or female fertility.

Effects on ability to drive and use machines.

Dizziness or hypersomnia may occur; therefore, caution should be exercised when driving or operating machinery.

Dosage and Administration

Arterial Hypertension Treatment

The usual effective dose of telmisartan is 40 mg once daily. Some patients may achieve adequate blood pressure control with a daily dose of 20 mg telmisartan. If blood pressure is not adequately controlled, the dose of telmisartan may be increased to 80 mg once daily. Alternatively, telmisartan may be combined with thiazide diuretics such as hydrochlorothiazide, which provide an additional blood pressure-lowering effect when used in combination with telmisartan. When considering dose escalation, it should be noted that the maximum antihypertensive effect is achieved within 4–8 weeks after initiation of treatment.

Cardiovascular Disease Prevention

The recommended dose is 80 mg once daily. The efficacy of telmisartan at doses lower than 80 mg for the prevention of cardiovascular disease is unknown.

When initiating telmisartan therapy to reduce cardiovascular risk, careful monitoring of blood pressure is recommended, with dose adjustment of concomitant antihypertensive medications as needed.

Special Patient Groups

Renal Impairment. Experience in patients with renal insufficiency or those undergoing hemodialysis is limited. Such patients should be started on the lowest initial dose of telmisartan, 20 mg (see section "Special Warnings and Precautions for Use"). Dose adjustment is not required in patients with mild to moderate renal impairment.

Concomitant use of telmisartan and aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²) (see section "Contraindications").

Hepatic Impairment. Telmilax is contraindicated in patients with severe hepatic impairment.

In patients with mild to moderate hepatic impairment, the daily dose of telmisartan should not exceed 40 mg once daily (see section "Special Warnings and Precautions for Use").

Elderly Patients. Dose adjustment is not required.

Administration

Telmilax should be taken orally once daily with sufficient fluid, independent of food intake.

Tablets should be stored in the sealed blister pack to protect from moisture. Tablets should be removed from the blister immediately before administration.

Children

The safety and efficacy of Telmilax in children (under 18 years of age) have not been established.

Overdose

Information regarding overdose is limited.

Symptoms. The most prominent symptoms of telmisartan overdose were hypotension and tachycardia. Bradycardia, dizziness, increased serum creatinine concentration, and acute renal failure have also been reported.

Treatment. Telmisartan is not removed from the body by hemodialysis. Patients should be closely monitored and receive symptomatic and supportive treatment. Management depends on the time elapsed since overdose and the severity of symptoms. Induction of emesis and/or gastric lavage may be considered. Activated charcoal may be used in the management of overdose. Serum electrolytes and creatinine levels should be monitored frequently. In cases of arterial hypotension, the patient should be placed in a supine position and treated with rapid volume and salt repletion.

Side effects

Serious adverse reactions including anaphylactic reaction and angioedema may occur in isolated cases (from ≥ 1/10,000 to <1/1,000), and acute renal failure has also been observed.

The overall incidence of adverse reactions in patients with arterial hypertension during controlled clinical trials receiving telmisartan was generally comparable to that with placebo (41.4% vs. 43.9%). The incidence of adverse reactions was dose-independent and not related to patient sex, age, or race. The safety profile of telmisartan in patients receiving the drug for cardiovascular disease prevention was consistent with the safety profile observed in patients with arterial hypertension.

The adverse reactions listed below are based on results from controlled clinical studies in hypertensive patients and post-marketing reports. This list also includes serious adverse reactions and those leading to discontinuation of the drug during three long-term clinical trials involving 21,642 patients who received telmisartan for cardiovascular disease prevention over six years.

Adverse reactions are listed according to frequency: very common (≥1/10); common (from 1/100 to <1/10); uncommon (from 1/1,000 to <1/100); rare (from 1/10,000 to <1/1,000); very rare (<1/10,000).

Within each category, adverse reactions are presented in order of decreasing severity.

Infections and infestations:

uncommon – urinary tract infections (including cystitis), upper respiratory tract infections (including pharyngitis and sinusitis);

rare – sepsis, including fatal cases¹.

Blood and lymphatic system disorders:

uncommon – anaemia;

rare – eosinophilia, thrombocytopenia.

Immune system disorders:

rare – anaphylactic reaction, hypersensitivity.

Metabolism and nutrition disorders:

uncommon – hyperkalaemia;

rare – hypoglycaemia (in patients with diabetes mellitus).

Psychiatric disorders:

uncommon – insomnia, depression;

rare – anxiety.

Nervous system disorders:

uncommon – syncope;

rare – somnolence.

Eye disorders:

rare – visual disturbance.

Ear and labyrinth disorders:

uncommon – vertigo.

Cardiac disorders:

uncommon – bradycardia;

rare – tachycardia.

Vascular disorders:

uncommon – arterial hypotension², orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders:

uncommon – dyspnoea, cough;

very rare – interstitial lung disease⁴.

Gastrointestinal disorders:

uncommon – abdominal pain, diarrhoea, dyspepsia, flatulence, vomiting;

rare – dry mouth, gastric discomfort, dysgeusia.

Hepatobiliary disorders:

rare – liver function abnormalities/liver disorders³.

Skin and subcutaneous tissue disorders:

uncommon – pruritus, increased sweating, rash;

rare – angioedema (including fatal cases), eczema, erythema, urticaria, drug dermatitis, toxic dermatitis.

Musculoskeletal and connective tissue disorders:

uncommon – back pain (e.g. sciatica), muscle cramps, myalgia;

rare – arthralgia, limb pain, tendon pain (symptoms similar to tendinitis).

Renal and urinary disorders:

uncommon – renal dysfunction, including acute renal failure.

General disorders:

uncommon – chest pain, asthenia (weakness);

rare – influenza-like symptoms.

Investigations:

uncommon – increased blood creatinine;

rare – decreased haemoglobin, increased blood uric acid, increased liver enzymes, increased blood creatine phosphokinase.

^{1, 2, 3, 4} See section "Side effects. Description of selected adverse reactions".

Description of selected adverse reactions

Sepsis. In the PRoFESS study, a higher incidence of sepsis was observed in patients receiving telmisartan compared to those receiving placebo. This may be due to chance or reflect an as yet unknown underlying process.

Hypotension. This adverse reaction was commonly observed in patients with controlled blood pressure who were receiving telmisartan for reduction of cardiovascular disease risk in addition to standard therapy.

Liver function abnormalities/liver disorders. According to post-marketing data, most cases of liver function abnormalities/liver disorders were observed in patients of Japanese nationality. Patients of Japanese nationality appear to be more susceptible to these adverse reactions.

Interstitial lung disease. Cases of interstitial lung disease have been reported during the post-marketing period in temporal association with telmisartan use. However, a causal relationship has not been established.

Intestinal angioedema. Cases of intestinal angioedema have been reported following use of angiotensin II receptor blockers (see section "Special precautions").

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

14 tablets in a blister, 2 blisters in a cardboard carton.

Prescription category. Prescription only.

Manufacturer.

LABORATORIOS LICONSA, S.A.

Manufacturer's address.

Avda. Miralcampo, 7, Pol. Ind. Miralcampo, Azuqueca de Henares, 19200, Guadalajara, Spain

Marketing Authorisation Holder.

M. BIOTECH LIMITED

Address of Marketing Authorisation Holder.

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom