Telmisartan-NAN

Telmisartan

Tablets

White or off-white oval biconvex tablets scored on one side; marbling is acceptable.

Each tablet contains:
Active substance: telmisartan 40 mg or 80 mg;
Auxiliary substances: meglumine, sodium hydroxide, povidone, microcrystalline cellulose, mannitol, magnesium stearate.

Agents acting on the renin-angiotensin system. Angiotensin II antagonists.

C09CA07

Telmisartan is an orally active and specific angiotensin II receptor (type AT₁) antagonist. Telmisartan displaces angiotensin II with very high affinity from its binding site at the AT₁ receptor subtype, which is responsible for the known actions of angiotensin II. Telmisartan does not exhibit any partial agonist activity at the AT₁ receptor. Telmisartan selectively and durably binds the AT₁ receptor. Telmisartan does not show affinity for other receptors, including AT₂ and other less characterized AT receptors. The functional role of these receptors is not known, nor is the effect of their possible overstimulation by angiotensin II, whose levels are increased by telmisartan. Plasma aldosterone levels are decreased by telmisartan. Telmisartan does not inhibit human plasma renin or block ion channels. Telmisartan does not inhibit angiotensin converting enzyme (kininase II), the enzyme which also degrades bradykinin. Therefore, it is not expected to potentiate bradykinin-mediated adverse effects.

In human, an 80 mg dose of telmisartan almost completely inhibits the angiotensin II evoked blood pressure increase. The inhibitory effect is maintained over 24 hours and still measurable up to 48 hours.

Clinical efficacy and safety

Treatment of essential hypertension
After the first dose of telmisartan, the antihypertensive activity gradually becomes evident within 3 hours. The maximum reduction in blood pressure is generally attained 4 to 8 weeks after the start of treatment and is sustained during long-term therapy.

The antihypertensive effect persists constantly over 24 hours after dosing and includes the last 4 hours before the next dose as shown by ambulatory blood pressure measurements. This is confirmed by trough to peak ratios consistently above 80% seen after doses of 40 and 80 mg of telmisartan in placebo controlled clinical studies. There is an apparent trend to a dose relationship to a time to recovery of baseline systolic blood pressure (SBP). In this respect data concerning diastolic blood pressure (DBP) are inconsistent.

In patients with hypertension telmisartan reduces both systolic and diastolic blood pressure without affecting pulse rate. The contribution of Telmisartan-NAN’s diuretic and natriuretic effect to its hypotensive activity has still to be defined. The antihypertensive efficacy of telmisartan is comparable to that of agents representative of other classes of antihypertensive medicinal products (demonstrated in clinical trials comparing telmisartan to amlodipine, atenolol, enalapril, hydrochlorothiazide, and lisinopril).

Upon abrupt cessation of treatment with telmisartan, blood pressure gradually returns to pre-treatment values over a period of several days without evidence of rebound hypertension.
The incidence of dry cough was significantly lower in patients treated with telmisartan than in those given angiotensin converting enzyme inhibitors in clinical trials directly comparing the two antihypertensive treatments.

Cardiovascular prevention
A clinical trial compared the effects of telmisartan, ramipril and their combination on cardiovascular events in patients over 55 years of age at risk for cardiovascular events. Telmisartan showed a similar effect to ramipril in reducing the primary composite endpoint of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for congestive heart failure. Telmisartan was found to be similarly effective to ramipril in the pre-specified secondary endpoint of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke.

Cough and angioedema were less frequently reported in patients treated with telmisartan than in patients treated with ramipril. Combining telmisartan with ramipril did not add further benefit over ramipril or telmisartan alone. CV mortality and all-cause mortality were numerically higher with the combination. In addition, there was a significantly higher incidence of hyperkalaemia, renal failure, hypotension and syncope in the combination arm. Therefore, the use of a combination of telmisartan and ramipril is not recommended in this population.

Hypertension
Treatment of essential hypertension in adults.

Cardiovascular prevention
Reduction of cardiovascular morbidity in adults with:

• manifest atherothrombotic cardiovascular disease (history of coronary heart disease, stroke, or peripheral arterial disease)
• type 2 diabetes mellitus with documented target organ damage.

Tablets should be taken orally once daily with a sufficient amount of chilled boiled water, with or without food.

Warnings and precautions
Telmisartan-NAN should be kept in the sealed blister due to the hygroscopic property of the tablets. Tablets should be taken out of the blister shortly before administration.

Treatment of hypertension
The usually effective dose is 40 mg once daily. Some patients may already benefit at a daily dose of 20 mg. The tablet can be divided into two equal parts. In cases where the target blood pressure is not achieved, the dose of telmisartan can be increased to a maximum of 80 mg once daily.
Alternatively, telmisartan may be used in combination with thiazide-type diuretics such as hydrochlorothiazide, which has been shown to have an additive blood pressure lowering effect with telmisartan. When considering raising the dose, it must be borne in mind that the maximum antihypertensive effect is generally attained four to eight weeks after the start of treatment.

Cardiovascular prevention
The recommended dose is 80 mg once daily. It is not known whether doses lower than 80 mg of telmisartan are effective in reducing cardiovascular morbidity. When initiating telmisartan therapy for the reduction of cardiovascular morbidity, close monitoring of blood pressure is recommended, and if appropriate adjustment of medications that lower blood pressure may be necessary.

Special populations

Patients with renal impairment
Limited experience is available in patients with severe renal impairment or haemodialysis. A lower starting dose of 20 mg is recommended in these patients. Dose adjustments are not required in patients with mild to moderate renal impairment.

Patients with hepatic impairment
Telmisartan-NAN is contraindicated in patients with severe hepatic impairment.
In patients with mild to moderate hepatic impairment, the posology should not exceed 40 mg once daily.

Elderly patients
No dose adjustment is necessary for elderly patients.

Children and adolescents
The use of telmisartan in children and adolescents aged below 18 years is not recommended as the safety and efficacy of the medication have not been established.

Skipping a subsequent intake
If you forget to take Telmisartan-NAN do not take double dose to make up for a forgotten tablet, take your next dose at its usual time.

Stopping the current medication
Do not stop taking Telmisartan-NAN without consulting your healthcare provider. When you stop taking Telmisartan-NAN, your blood pressure may rise again. You should continue taking Telmisartan-NAN, even if you feel well.

Serious adverse reactions include anaphylactic reaction and angioedema which may occur rarely (≥ 1/10,000 to < 1/1,000), and acute renal failure. The overall incidence of adverse reactions reported with telmisartan was usually comparable to placebo (41.4% vs 43.9%) in placebo-controlled trials in patients treated for hypertension. The incidence of adverse reactions was not dose related and showed no correlation with gender, age or race of the patients. The safety profile of telmisartan in patients treated for the reduction of cardiovascular morbidity was consistent with that obtained in hypertensive patients. The adverse reactions listed below have been accumulated from controlled clinical trials in patients treated for hypertension and from post-marketing reports. The listing also takes into account serious adverse reactions and adverse reactions leading to discontinuation reported in three clinical long-term studies including 21,642 patients treated with telmisartan for the reduction of cardiovascular morbidity for up to six years. The incidence of adverse events: very common (≥ 1/10); common (≥ 1/100, but < 1/10); uncommon (≥ 1/1000, but < 1/100); rare (≥ 1/10,000, but < 1/1000); very rare (< 1/10,000). Based on data from clinical studies and post-marketing experience, the following side effects have been reported. The incidence of adverse events is presented in descending order of severity. Infections and infestations
Uncommon: urinary tract infection including cystitis, upper respiratory tract infection including pharyngitis and sinusitis;
Rare: sepsis including fatal outcome.

Blood and lymphatic system disorders
Uncommon: anaemia;
Rare: eosinophilia, thrombocytopenia.

Immune system disorders
Rare: anaphylactic reaction, hypersensitivity.

Metabolic and nutrition disorders
Uncommon: hyperkalemia;
Rare: hypoglycaemia (in diabetic patients).

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: hypotension, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders
Uncommon: dysponoea, cough;
Rare: interstitial lung disease.

Gastrointestinal disorders
Uncommon: abdominal pain, diarrhoea, dyspepsia, flatulence, vomiting;
Rare: dry mouth, stomach discomfort, dysgeusia.

Hepato-biliary disorders
Rare: hepatic impairment.

Skin and subcutaneous tissue disorders
Uncommon: pruritus, hyperhidrosis, rash;
Rare: angioedema (also with fatal outcome), eczema, erythema, urticaria, drug eruption, toxic skin eruption.

Musculoskeletal and connective tissue disorders
Uncommon: back pain (e.g. sciatica), muscle spasms, myalgia;
Rare: arthralgia, pain in extremity, tendon pain (tendinitis like symptoms).

Renal and urinary disorders
Uncommon: renal impairment including acute renal failure.

General disorders and administration site conditions
Uncommon: chest pain, asthenia (weakness);
Rare: influenza-like illness.

Investigations
Uncommon: blood creatinine increased;
Rare: haemoglobin decreased, blood uric acid increased, hepatic enzyme increased, blood creatine phosphokinase increased.

Description of selected adverse reactions

Sepsis
In one study in telmisartan arm an increased incidence of sepsis was observed with telmisartan compared with placebo. The event may be a chance finding or related to a mechanism currently not known.

Hypotension
This adverse reaction was reported as common in patients with controlled blood pressure who were treated with telmisartan for the reduction of cardiovascular morbidity on top of standard care.

Hepatic impairment
Most cases of hepatic impairment from post-marketing experience occurred in Japanese patients. Japanese patients are more likely to experience these adverse reactions.

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

In case of any adverse reactions, including those not specified in this patient’s leaflet, consult your healthcare provider.

• Hypersensitivity to the active substance or to any of the auxiliary substances.
• Second and third trimesters of pregnancy (see Sections Warnings and precautions and Administration during pregnancy or lactation).
• Biliary obstructive disorders.
• Severe hepatic impairment.
• The concomitant use of telmisartan with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2).
• Children and adolescents under 18 years of age (safety and administration efficiency in children under 18 years is not established).

If taking a larger dose than prescribed by your doctor, immediately contact specialists to provide timely medical care!

There is limited information available with regard to overdose in humans.

Symptoms: the most prominent manifestations of telmisartan overdose were hypotension and tachycardia; bradycardia dizziness, increase in serum creatinine, and acute renal failure have also been reported.

Management: telmisartan is not removed by haemodialysis. The patient should be closely monitored, and the treatment should be symptomatic and supportive. Management depends on the time since ingestion and the severity of the symptoms. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful. Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a supine position, with salt and volume replacement given quickly.

Digoxin: When telmisartan was co-administered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed. When initiating, adjusting, and discontinuing telmisartan, monitor digoxin levels in order to maintain levels within the therapeutic range.

As with other medicinal products acting on the renin-angiotensin-aldosterone system, telmisartan may provoke hyperkalaemia. The risk may increase in case of treatment combination with other medicinal products that may also provoke hyperkalaemia (salt substitutes containing potassium, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, non-steroidal anti-inflammatory medicinal products (NSAIDs, including selective COX-2 inhibitors), heparin, immunosuppressives (cyclosporin or tacrolimus), and trimethoprim).

The occurrence of hyperkalaemia depends on associated risk factors. The risk is increased in case of the above-mentioned treatment combinations. The risk is particularly high in combination with potassium sparing-diuretics, and when combined with salt substitutes containing potassium. A combination with ACE inhibitors or NSAIDs, for example, presents a lesser risk provided that precautions for use are strictly followed.

Concomitant use not recommended
Potassium sparing diuretics or potassium supplements: angiotensin II receptor antagonists such as telmisartan, attenuate diuretic induced potassium loss. Potassium sparing diuretics e.g., spirinolactone, eplerenone, triamterene, or amiloride, potassium supplements, or potassium-containing salt substitutes may lead to a significant increase in serum potassium. If concomitant use is indicated because of documented hypokalaemia, they should be used with caution and with frequent monitoring of serum potassium.

Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors, and with angiotensin II receptor antagonists, including telmisartan. If use of the combination proves necessary, careful monitoring of serum lithium levels is recommended.

Concomitant use requiring caution
Non-steroidal anti-inflammatory drugs (NSAID): NSAIDs (i.e., acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs) may reduce the antihypertensive effect of angiotensin II receptor antagonists.

In some patients with compromised renal function (e.g., dehydrated patients or elderly patients with compromised renal function), the co-administration of angiotensin II receptor antagonists and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically thereafter.

The co-administration of telmisartan and ramipril led to an increase of up to 2.5-fold in the AUC_0-24 and C_max of ramipril and ramiprilat. The clinical relevance of this observation is not known.

Diuretics (thiazide or loop diuretics): prior treatment with high dose diuretics such as furosemide (loop diuretic) and hydrochlorothiazide (thiazide diuretic) may result in volume depletion, and in a risk of hypotension when initiating therapy with telmisartan.

To be taken into account with concomitant use
Other antihypertensive agents: the blood pressure lowering effect of telmisartan can be increased by concomitant use of other antihypertensive medicinal products.

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to monotherapy.

Based on their pharmacological properties it can be expected that the following medicinal products may potentiate the hypotensive effects of all antihypertensives including telmisartan: baclofen, amifostine. Furthermore, orthostatic hypotension may be aggravated by alcohol, barbiturates, narcotics, or antidepressants.

Corticosteroids (systemic route): reduction of the antihypertensive effect.

Inform your healthcare provider about all medications you are taking. Consult your healthcare provider before you start taking any medication during treatment with Telmisartan-NAN.

Pregnancy
Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.

Hepatic impairment
Telmisartan-NAN is not to be given to patients with cholestasis, biliary obstructive disorders or severe hepatic impairment since telmisartan is mostly eliminated with the bile. These patients can be expected to have reduced hepatic clearance for telmisartan. Telmisartan-NAN should be used only with caution in patients with mild to moderate hepatic impairment.

Renovascular hypertension
There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system.

Renal impairment and kidney transplantation
When Telmisartan-NAN is used in patients with impaired renal function, periodic monitoring of potassium and creatinine serum levels is recommended. There is no experience regarding the administration of Telmisartan-NAN in patients with recent kidney transplantation.

Intravascular hypovolaemia
Symptomatic hypotension, especially after the first dose of Telmisartan-NAN, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea, or vomiting. Volume and/or sodium depletion should be corrected prior to administration of telmisartan.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended. If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

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

Other conditions with stimulation of the renin-angiotensin-aldosterone system
In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with medicinal products that affect this system such as telmisartan has been associated with acute hypotension, hyperazotaemia, oliguria, or rarely acute renal failure.

Primary hyperaldosteronism
Patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of Telmisartan-NAN is not recommended.

Aortic and mitral valve stenosis (obstructive hypertrophic cardiomyopathy)
As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Diabetic patients treated with insulin or antidiabetics
In these patients hypoglycaemia may occur under telmisartan treatment. Therefore, in these patients an appropriate blood glucose monitoring should be considered; a dose adjustment of insulin or antidiabetics may be required, when indicated.

Hyperkalaemia
The use of medicinal products that affect the renin-angiotensin-aldosterone system may cause hyperkalaemia.

In the elderly, in patients with renal insufficiency, in diabetic patients, in patients concomitantly treated with other medicinal products that may increase potassium levels, and/or in patients with intercurrent events, hyperkalaemia may be fatal.

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

The main risk factors for hyperkalaemia to be considered are:

• Diabetes mellitus, renal impairment, age (>70 years).
• Combination with one or more other medicinal products that affect the renin-angiotensin-aldosterone system and/or potassium supplements. Medicinal products or therapeutic classes of medicinal products that may provoke hyperkalaemia are salt substitutes containing potassium, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, non-steroidal anti-inflammatory medicinal products (NSAIDs, including selective COX-2 inhibitors), heparin, immunosuppressives (cyclosporin or tacrolimus), and trimethoprim.
• Intercurrent events, in particular dehydratation, acute cardiac decompensation, metabolic acidosis, worsening of renal function, sudden worsening of the renal condition (e.g., infectious diseases), cellular lysis (e.g., acute limb ischemia, rhabdomyolysis, extend trauma).
  Close monitoring of serum potassium in at risk patients is recommended.

Ethnic differences
As observed for angiotensin converting enzyme inhibitors, telmisartan and the other angiotensin II receptor antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population.

Other
As with any antihypertensive agent, excessive reduction of blood pressure in patients with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke.

If you have one of the diseases or conditions listed above, consult your healthcare provider before taking Telmisartan-NAN.

Pregnancy
The use of AIIRAs is not recommended during the first trimester of pregnancy and is contraindicated during the second and third trimesters of pregnancy.

There are no adequate data from the use of telmisartan in pregnant women. Studies in animals have shown reproductive toxicity.

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however, a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with angiotensin II receptor antagonists, similar risks may exist for this class of medications.
Unless continued telmisartan therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy.

When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists (including Telmisartan-NAN) should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to angiotensin II receptor antagonist therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).

Should exposure to angiotensin II receptor antagonists have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken angiotensin II receptor antagonists should be closely observed for hypotension.

Breast-feeding
Because no information is available regarding the use of telmisartan during breast-feeding, Telmisartan-NAN is not recommended. Alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

No studies on the effects of Telmisartan-NAN on the ability to drive and use machines have been performed. When driving vehicles or operating machinery it should be taken into account that dizziness or drowsiness may occasionally occur when taking antihypertensive therapy.

14 or 15 tablets in a blister pack. 2 blister packs (14 or 15 tablets) with a patient information leaflet, packed in a carton.

Protect from light and moisture, at a temperature not above 25°C.
Keep away from children.

2 years. Do not use after the expiration date indicated on the package.

State enterprise ACADEMPHARM
220141, 5/3 Kuprevicha Street, Minsk, Belarus
Phone / Fax +375 17 268 63 64
production@academpharm.by
To report adverse reactions use the electronic application form on the manufacturer’s website: https://academpharm.by/en