Micardis®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MİCARDİS® (Micardis®)

Composition:

Active substance: telmisartan;

1 tablet contains 80 mg of telmisartan;

Excipients: sodium hydroxide, povidone (E 1201), meglumine, sorbitol (E 420), magnesium stearate (E 470b).

Pharmaceutical form. Tablets.

Main physico-chemical properties: oval tablets, white or almost white, with imprint “52H” on one side and the company symbol on the other.

Pharmacotherapeutic group. Angiotensin II receptor blockers (ARBs), plain preparations.

ATC code C09CA07.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Telmisartan is a specific and effective oral angiotensin II receptor (type AT1) blocker. Telmisartan competitively displaces angiotensin II from its binding sites at AT1 receptor subtypes responsible for the actions of angiotensin II. Telmisartan exhibits no partial agonist activity at the AT1 receptor. Telmisartan 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 angiotensin 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 increase due to telmisartan. Telmisartan reduces plasma aldosterone levels. Telmisartan does not reduce plasma renin levels and does not block ion channels. Telmisartan does not inhibit angiotensin-converting enzyme (kininase II), an enzyme that also degrades bradykinin. 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 blood 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 extent of absorption varies. The mean absolute bioavailability of telmisartan is approximately 50%. When telmisartan is administered with food, the area under the concentration-time curve (AUC0–∞) decreases by approximately 6% (40 mg) to 19% (160 mg). However, plasma concentrations 3 hours after dosing 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 concentration. 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 a biexponential pharmacokinetic profile with a terminal elimination half-life >20 hours. Maximum plasma concentration (Cmax) and, to a lesser extent, the area under the plasma concentration-time curve (AUC) increase disproportionately with dose. There are no data indicating clinically relevant accumulation of telmisartan with recommended dosing. Plasma concentrations were higher in women than in men, without a corresponding impact on efficacy.

After oral (and intravenous) administration, telmisartan is almost entirely eliminated via feces, primarily 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.

Children. The pharmacokinetics of two doses of telmisartan were evaluated as a secondary objective in hypertensive patients (n = 57) aged 6 to <18 years, after receiving telmisartan at 1 mg/kg or 2 mg/kg for 4 weeks of treatment. Pharmacokinetic objectives included determining telmisartan levels at steady state in children and adolescents and investigating age-related differences. Although the study was too small to reliably assess pharmacokinetics in children under 12 years of age, the results overall are consistent with those obtained in adults and confirm the nonlinearity of telmisartan, particularly for Cmax.

Gender. Plasma Cmax and AUC concentrations 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 patients under 65 years of age.

Patients with renal impairment. In patients with mild to moderate and severe renal impairment, plasma concentrations were approximately doubled. However, in patients with renal impairment undergoing dialysis, lower plasma concentrations were observed. Telmisartan is highly protein-bound in patients with renal impairment and cannot be removed by dialysis. 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 disease.

Reduction of cardiovascular morbidity in adult patients with:

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

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients (see section "Composition");
• pregnancy or planned pregnancy (see sections "Special precautions for use", "Use in pregnancy or breastfeeding");
• biliary obstruction;
• severe hepatic impairment;
• pediatric use (under 18 years of age).

Concomitant use of MICARDIS and aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacological properties").

Interaction with other medicinal products and other forms of interaction.

Digoxin

When telmisartan and digoxin are used concomitantly, median increases in peak plasma concentrations of digoxin (by 49%) and trough concentrations (by 20%) have been observed. Monitoring of digoxin levels is recommended at the initiation 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 (RAAS), telmisartan may cause hyperkalemia (see section "Special precautions for use"). The risk may be increased when telmisartan is used in combination with other agents that can also induce hyperkalemia (potassium-containing salt substitutes, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor blockers, 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 induced 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, these agents should be used with caution and serum potassium levels should be monitored frequently.

Lithium. Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of lithium and ACE inhibitors or angiotensin II receptor antagonists, including telmisartan. These effects are usually reversible upon discontinuation of lithium. If concomitant use is necessary, careful monitoring of serum lithium levels is recommended.

Concomitant use requiring caution.

Nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs (i.e., acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, and nonselective 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), concomitant use of angiotensin II receptor antagonists and drugs that inhibit cyclooxygenase may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, this combination should be used with caution, particularly in elderly patients. Adequate hydration should be ensured; consideration should be given to monitoring renal function after initiation and periodically after discontinuation of concomitant therapy.

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

Diuretics (thiazide or loop diuretics). Prior treatment with high doses of diuretics such as furosemide (a loop diuretic) or hydrochlorothiazide (a thiazide diuretic) may result in volume depletion and an increased risk of hypotension at the start of telmisartan therapy.

Concomitant use requiring attention.

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

Clinical data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse effects such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to monotherapy with a single RAAS-acting agent (see sections "Special precautions for use", "Contraindications", and "Pharmacodynamics").

Due to the pharmacological properties of baclofen and amifostine, an enhanced hypotensive effect may be expected when these medicinal products are used concomitantly with antihypertensive agents, including telmisartan. Additionally, orthostatic hypotension may be exacerbated by alcohol consumption, barbiturates, narcotics, and antidepressants.

Corticosteroids (systemic use). Reduction of antihypertensive effect.

Special precautions for use.

Pregnancy. Angiotensin II receptor blockers must not be initiated during pregnancy. If continuation of therapy with an angiotensin II receptor blocker is considered essential in a woman planning pregnancy, she should switch to an alternative antihypertensive treatment with an established safety profile during pregnancy. Angiotensin II receptor blockers must be discontinued as soon as pregnancy is confirmed, and alternative therapy should be initiated if necessary (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

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

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

Renovascular hypertension. There is an increased risk of severe arterial 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. In patients with impaired renal function treated with MICARDIS, periodic monitoring of serum potassium and creatinine levels is recommended. There is no experience with the use of MICARDIS in patients who have recently undergone kidney transplantation.

Telmisartan is not removed from blood by hemofiltration or dialysis.

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

Dual blockade of the renin-angiotensin-aldosterone system (RAAS).

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 of the RAAS by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

If dual blockade is considered absolutely necessary, it should only be performed under specialist supervision and with continuous, careful 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 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 drugs affecting this system, such as telmisartan, 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 in these patients.

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

Diabetic patients treated with insulin or antidiabetic medicinal products.

Hypoglycemia may occur in such patients during treatment with telmisartan. Blood glucose levels should be monitored in these patients, and dose adjustments of insulin or antidiabetic drugs may be necessary.

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

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

The benefit-risk ratio should be carefully considered before combining medicinal products that suppress the renin-angiotensin system.

Key risk factors for hyperkalemia to consider include:

• Diabetes mellitus, renal impairment, age over 70 years;
• Combination therapy with one or more other agents 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 blockers, non-steroidal anti-inflammatory drugs (NSAIDs, including selective COX-2 inhibitors), heparin, immunosuppressants (cyclosporine or tacrolimus), and trimethoprim;
• Intercurrent events such as dehydration, acute heart decompensation, metabolic acidosis, worsening of renal function, sudden deterioration of kidney function (e.g., due to infections), and cellular lysis (e.g., acute limb ischemia, acute skeletal muscle necrosis, extensive trauma).

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

Ethnic differences. As observed with ACE inhibitors, telmisartan and other angiotensin II receptor blockers appear to be 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 among black patients with arterial hypertension.

Ischemic heart disease.

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.

Intestinal angioedema.

Cases of intestinal angioedema have been reported in patients taking angiotensin II receptor blockers (see section "Adverse reactions"). These patients experienced 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 symptoms completely resolve.

Sorbitol.

The medicinal product contains 337.28 mg of sorbitol per tablet. This medicinal product should not be used in patients with rare hereditary fructose intolerance.

Sodium.

Each tablet contains less than 1 mmol of sodium (23 mg), which is considered essentially "sodium-free."

Use during pregnancy or breastfeeding.

Pregnancy.

There are no adequate data on the use of MIKARDIS in pregnant women. Animal studies have shown toxic effects of this medicinal product on reproductive function.

Epidemiological evidence of teratogenic risk associated with the use of angiotensin-converting enzyme (ACE) inhibitors during the first trimester of pregnancy has not been convincing; however, a small increased risk cannot be excluded. Although there are no controlled epidemiological data on the teratogenic risk of angiotensin II receptor blockers, similar risks may exist for this class of medicinal products. If continued treatment with angiotensin II receptor blockers is necessary, the drug should be replaced in a timely manner with another antihypertensive agent that has an established safety profile during pregnancy when planning for pregnancy. Upon confirmation of pregnancy, treatment with angiotensin II receptor blockers must be discontinued immediately, and alternative therapy should be initiated if necessary.

It is known that the use of angiotensin II receptor blockers during the second and third trimesters of pregnancy causes fetotoxicity in humans (renal dysfunction, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia). If angiotensin II receptor blockers are initiated from the second trimester of pregnancy, ultrasound evaluation of fetal renal function and skull ossification is recommended. Infants born to mothers who have taken angiotensin II receptor blockers must be closely monitored for signs of arterial hypotension (see sections "Contraindications" and "Special precautions").

Breast-feeding.

Due to the lack of information on the use of MIKARDIS during breast-feeding, this medicinal product is not recommended for administration to women who are breast-feeding. An alternative treatment with a better-established safety profile is preferred, especially when breast-feeding a newborn or a preterm infant.

Fertility.

Preclinical studies have not shown any effect of MIKARDIS on male or female fertility.

Ability to influence reaction rate while driving or operating machinery.

When driving vehicles or operating machinery, one should consider the possibility of syncope or vertigo associated with antihypertensive therapy, including treatment with MIKARDIS.

Dosage and Administration

Arterial Hypertension Treatment

The usual effective dose of telmisartan is 40 mg once daily. Some patients may respond adequately to 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. When considering dose escalation, it should be noted that the maximum antihypertensive effect is achieved within 4–8 weeks of starting treatment (see section "Pharmacological Properties. Pharmacodynamics"). Alternatively, telmisartan may be administered in combination with thiazide diuretics such as hydrochlorothiazide, which provide additional blood pressure-lowering effects when used concomitantly with telmisartan.

Cardiovascular Disease Prevention

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

When initiating telmisartan treatment for cardiovascular risk reduction, careful monitoring of blood pressure is recommended, with dose adjustment of antihypertensive medications as needed.

Elderly Patients

Dose adjustment is not required for elderly patients.

Renal Impairment. Experience in patients with renal impairment 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"). No dose adjustment is necessary for patients with mild to moderate renal impairment. Telmisartan is not removed from blood by hemofiltration and is not dialyzable.

Hepatic Impairment. MICARDIS is contraindicated in patients with severe hepatic impairment (see section "Contraindications").

For 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").

Administration

Telmisartan tablets are taken orally once daily, independent of food intake. Tablets should be swallowed whole with sufficient liquid.

Storage and Handling Precautions

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

Pediatric Population

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

Current available data are presented in the sections "Pharmacokinetics" and "Pharmacodynamics," but no dosage recommendations can be made.

Overdose

Information on overdose in humans is limited.

Symptoms. The most prominent symptoms of telmisartan overdose are hypotension and tachycardia; bradycardia, dizziness, increased serum creatinine levels, and acute renal failure have also been reported.

Treatment. Telmisartan is not removed by hemofiltration and is not dialyzable. Patients should be closely monitored and receive symptomatic and supportive treatment. Management depends on the time 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 case of arterial hypotension, the patient should be placed in a supine position and treated with measures aimed at rapid restoration of fluid and salt volume.

Adverse Reactions

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 independent of dose, patient sex, age, or race. The safety profile of telmisartan in patients who received the drug for cardiovascular disease prevention was consistent with the safety profile observed in patients treated for arterial hypertension.

The adverse reactions listed below are based on results from controlled clinical studies involving 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 a period of up to 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 listed in order of decreasing severity.

Infections and infestations:

Uncommon – urinary tract infections (cystitis), upper respiratory tract infections (including pharyngitis and sinusitis);
Rare – sepsis, including fatal outcome¹.

Blood and lymphatic system disorders:

Uncommon – anemia;
Rare – eosinophilia, thrombocytopenia.

Immune system disorders:

Rare – anaphylactic reaction, hypersensitivity.

Metabolism and nutrition disorders:

Uncommon – hyperkalaemia;
Rare – hypoglycaemia (in patients with diabetes mellitus), hyponatraemia.

Psychiatric disorders:

Uncommon – insomnia, depression;
Rare – anxiety.

Nervous system disorders:

Uncommon – syncope;
Rare – somnolence.

Eye disorders:

Rare – visual disturbances.

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, abdominal discomfort, dysgeusia.

Hepatobiliary disorders:

Rare – liver function abnormalities/liver disorders³.

Skin and subcutaneous tissue disorders:

Uncommon – pruritus, increased sweating, rash;
Rare – angioedema (including fatal outcome), eczema, erythema, urticaria, drug eruption, toxic dermatitis.

Musculoskeletal and connective tissue disorders:

Uncommon – back pain (e.g., sciatica), muscle cramps, myalgia;
Rare – arthralgia, limb pain, tendon pain (symptoms resembling tendonitis).

Renal and urinary disorders:

Uncommon – renal dysfunction, including acute kidney injury.

General disorders:

Uncommon – chest pain, asthenia (weakness);
Rare – influenza-like symptoms.

Laboratory findings:

Uncommon – increased blood creatinine;
Rare – decreased haemoglobin, increased blood uric acid, increased liver enzymes, increased blood creatine phosphokinase.

^{1, 2, 3, 4} For detailed descriptions, see section "Adverse Reactions. Description of selected adverse reactions".

Description of selected adverse reactions

Sepsis. In the PRoFESS trial, a higher incidence of sepsis was observed in patients receiving telmisartan compared to those receiving placebo. This may be due to chance or may reflect an underlying process not yet understood.

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

Liver function abnormalities / liver disorders. According to post-marketing data, most cases of liver function abnormalities / liver disorders occurred 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 temporally associated with telmisartan use have been reported during the post-marketing period. However, a causal relationship has not been established.

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

Reporting of adverse reactions

Reporting of adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30°C. Keep out of reach of children.

Packaging.

7 tablets per blister; 2 or 4 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Boehringer Ingelheim Pharma GmbH & Co. KG
or
Boehringer Ingelheim Hellas Single Member S.A.

Manufacturer's address and place of business.

Binger Strasse 173, 55216 Ingelheim am Rhein, Germany
or
5th km Paiania-Markopoulo, Koropi Attiki, 19441, Greece.