Instructions for use Micardisplus tablets 80 mg + 12.5 mg No. 28
Composition
active ingredients: telmisartan, hydrochlorothiazide;
1 tablet contains telmisartan 40 mg or 80 mg and hydrochlorothiazide 12.5 mg;
Excipients: povidone (E 1201); meglumine; sodium hydroxide; sorbitol (E 420); magnesium stearate (E 470b); microcrystalline cellulose; red iron oxide (E 172); sodium starch glycolate; lactose, monohydrate; corn starch.
Dosage form
Pills.
Main physicochemical properties:
40 mg/12.5 mg tablets: oval, white-red biconvex, two-layer tablets with possible red inclusions in the white layer. The white side is imprinted with "H4" and the Boehringer Ingelheim company logo;
80 mg/12.5 mg tablets: oval, white-red biconvex, two-layer tablets with possible red inclusions in the white layer. The white side is imprinted with "H8" and the Boehringer Ingelheim company logo.
Pharmacotherapeutic group
Angiotensin II antagonists and diuretics. ATC code C09D A07.
Pharmacological properties
Pharmacodynamics.
MICARDIS PLUS is a combination of an angiotensin II receptor antagonist (telmisartan) and a thiazide diuretic (hydrochlorothiazide). The combination of these components has an additive antihypertensive effect, reducing blood pressure to a greater extent than either component alone. MICARDIS PLUS, tablets, when administered once daily within therapeutic doses, leads to an effective and slow reduction in blood pressure.
Telmisartan is an orally effective and specific angiotensin II receptor antagonist (AT1 subtype). With very high affinity for this receptor subtype, telmisartan displaces angiotensin II from its binding to AT1 receptors. It does not exhibit any partial agonist effect on AT1 receptors. Telmisartan binds selectively to AT1 receptors. The binding is long-lasting. Telmisartan shows no affinity for other receptors, including AT2 and other less characterized AT receptors. Telmisartan does not inhibit human plasma renin and does not block ion channels. Telmisartan does not inhibit angiotensin-converting enzyme (kinase II), an enzyme that also degrades bradykinin. Therefore, potentiation of bradykinin-associated side effects should not be expected.
The drug at a dose of 80 mg almost completely inhibits the hypertensive effect of angiotensin II in humans. The effect of the drug lasts for more than 24 hours and is observed up to 48 hours.
After the first dose of telmisartan, antihypertensive activity gradually manifests itself within 3 hours. The maximum reduction in blood pressure is observed 4-8 weeks after the start of treatment and is maintained during long-term therapy. The hypotensive effect is maintained continuously for 24 hours after taking the drug, including the last 4 hours before taking the next dose. This is confirmed by blood pressure measurements at the point of maximum effect and immediately before taking the next dose (the ratio of the lowest to the highest values is above 80% after taking doses of 40 and 80 mg of telmisartan in placebo-controlled clinical trials).
In patients with arterial hypertension, telmisartan reduces both systolic and diastolic blood pressure without affecting pulse rate. The antihypertensive efficacy of telmisartan is comparable to that of other classes of antihypertensive drugs (demonstrated in clinical trials comparing telmisartan with amlodipine, atenolol, enalapril, hydrochlorothiazide, losartan and lisinopril).
If treatment with telmisartan is abruptly discontinued, blood pressure gradually returns to pre-treatment values within a few days, without the likelihood of withdrawal syndrome.
In clinical trials comparing two antihypertensive regimens, the incidence of dry cough was significantly lower in patients taking telmisartan than in those taking angiotensin-converting enzyme inhibitors.
In the Preventive Treatment to Effectively Prevent Re-Stroke (PRoFESS) study, in patients aged 50 years and older who had recently had a stroke, sepsis was more common with telmisartan compared to placebo, 0.70% and
0.49% respectively [RR 1.43 (95% confidence interval 1.00-2.06)]; the incidence of fatal sepsis was higher among patients taking telmisartan (0.33%) compared with patients taking placebo (0.16%) [RR 2.07 (95% confidence interval 1.14-3.76)].
Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive action of thiazide diuretics is still not fully understood. Thiazide diuretics affect the mechanisms of electrolyte reabsorption in the renal tubules, thereby directly increasing the excretion of sodium and chloride in approximately equivalent volumes. Due to the diuretic effect of hydrochlorothiazide, plasma volume decreases, plasma renin activity increases, aldosterone secretion increases with a corresponding increase in urinary potassium and bicarbonate excretion and a decrease in serum potassium. Perhaps through blockade of the renin-angiotensin-aldosterone system, the concomitant administration of telmisartan helps to reverse the potassium loss associated with these diuretics. When using hydrochlorothiazide, the onset of diuresis occurs after 2 hours, the maximum effect is achieved after approximately 4 hours, while the action lasts for approximately
6-12 hours. Epidemiological trials have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular morbidity and mortality.
The effect of the fixed combination of telmisartan/hydrochlorothiazide on mortality and cardiovascular disease is unknown.
Pharmacokinetics.
Concomitant use of hydrochlorothiazide and telmisartan does not affect the pharmacokinetics of either drug in healthy subjects.
Absorption.
Telmisartan. After oral administration, the peak concentration of telmisartan is reached after 0.5-1.5 hours. The absolute bioavailability of telmisartan at a dose of 40 mg and 160 mg is 42% and 58%, respectively. Food slightly reduces the bioavailability of telmisartan, the decrease in the area under the concentration-time curve (AUC) for telmisartan varies from approximately 6% (40 mg dose) to approximately 19% (160 mg dose). 3 hours after administration, the plasma concentration is the same and does not depend on how telmisartan is taken - on an empty stomach or with food. It is believed that a small decrease in AUC does not cause a decrease in therapeutic efficacy. The pharmacokinetics of oral telmisartan are non-linear with dose increases from 20 to 160 mg, with plasma concentrations (Cmax and AUC) increasing more than proportionally. Telmisartan does not accumulate in plasma to any significant extent with repeated administration.
Hydrochlorothiazide: After oral administration of MICARDIS PLUS, peak hydrochlorothiazide concentrations are reached within 1–3 hours. Due to the cumulative renal excretion of hydrochlorothiazide, absolute bioavailability is approximately 60%.
Distribution.
Telmisartan: Telmisartan is highly bound to plasma proteins (> 99.5%), mainly to albumin and alpha-1-acid glycoprotein. The volume of distribution is approximately 500 l, indicating extensive tissue binding.
Hydrochlorothiazide: Hydrochlorothiazide is 68% bound to plasma proteins, with a volume of distribution of 0.83–1.14 L/kg.
Biotransformation.
Telmisartan is metabolized by conjugation to form a pharmacologically inactive acylglucuronide. The glucuronide of the parent compound is the only metabolite that has been identified in humans. After a single dose of 14C-labeled telmisartan, the glucuronide represents approximately 11% of the measured radioactivity in plasma. Cytochrome P450 isoenzymes are not involved in the metabolism of telmisartan.
Hydrochlorothiazide: Not metabolized in humans.
Breeding.
Telmisartan. After intravenous or oral administration of 14C-labeled telmisartan, the majority of the dose (> 97%) is excreted in the faeces via biliary excretion. Only a small amount was recovered in the urine. The total plasma clearance of telmisartan after oral administration is > 1500 ml/min. The terminal half-life is more than 20 hours.
Hydrochlorothiazide is excreted almost entirely unchanged in the urine. Approximately 60% of an oral dose is excreted unchanged within 48 hours. Renal clearance is approximately 250-300 ml/min. The terminal half-life is 10-15 hours.
Special categories of patients.
Elderly patients: The pharmacokinetics of telmisartan do not differ between elderly patients and patients under 65 years of age.
Gender. Plasma concentrations of telmisartan in women are generally 2-3 times higher than in men. However, according to clinical studies, the level of blood pressure reduction in women is not significantly increased, as is the number of cases of orthostatic hypotension. There is no need to adjust the dose. Women tend to have higher concentrations of hydrochlorothiazide than men, but this is of no clinical significance.
Patients with renal impairment. Renal excretion does not affect the elimination of telmisartan. Based on limited experience in patients with mild to moderate renal impairment (creatinine clearance 30-60 ml/min, mean almost 50 ml/min), no dose adjustment is necessary for these patients. Telmisartan is not removed by haemodialysis. In patients with renal insufficiency, the elimination rate of hydrochlorothiazide is reduced. In typical studies, in patients with a mean creatinine clearance of 90 ml/min, the half-life of hydrochlorothiazide is increased. In patients with a removed or absent kidney, the half-life is approximately 34 hours.
Patients with hepatic impairment: Pharmacokinetic studies in patients with hepatic impairment have shown an increase in absolute bioavailability to almost 100%. The elimination half-life is not altered in these patients.
Indication
Arterial hypertension.
MICARDIS PLUS, tablets, fixed dose combination (40 mg or 80 mg telmisartan/12.5 mg hydrochlorothiazide) is indicated for use in adult patients when telmisartan alone does not provide adequate blood pressure control.
Contraindication
· Hypersensitivity to the active substance or to any of the components of the drug.
Hypersensitivity to other sulfonamide derivatives (hydrochlorothiazide is a sulfonamide derivative).
· pregnant women or women planning to become pregnant (see sections "Special instructions" and "Use during pregnancy or breastfeeding").
· Cholestatic and biliary obstructive disorders.
Severe liver dysfunction.
Anuria, severe renal impairment (creatinine clearance < 30 ml/min).
· Refractory hypokalemia/hyponatremia, hypercalcemia.
Breastfeeding.
Symptomatic hyperuricemia (gout).
· Children's age (up to 18 years).
The concomitant use of MICARDIS PLUS and aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal insufficiency (GFR < 60 ml/min/1.73 m2) (see sections “Interaction with other medicinal products and other types of interactions” and “Pharmacological properties”).
Interaction with other medicinal products and other types of interactions
Lithium.
Reversible increases in serum lithium concentrations and toxicity have been reported with concomitant use of lithium with angiotensin-converting factor inhibitors. Such interactions have been reported with angiotensin II receptor antagonists (including MICARDIS PLUS). Concomitant use of lithium and MICARDIS PLUS is not recommended (see section 4.3). If the combination is proven to be effective, close monitoring of serum lithium levels is recommended.
Drugs associated with potassium loss and hypokalemia
(e.g. other potassium-sparing diuretics, laxatives, corticosteroids, ACTH, amphotericins, carbenoxolones, penicillin G sodium, salicylic acid and derivatives). When these medicinal products are used together with the combination of hydrochlorothiazide-telmisartan, monitoring of plasma potassium levels is recommended. These medicinal products may potentiate the effect of hydrochlorothiazide on plasma potassium levels (see section "Special precautions for use").
Medications that can increase sodium levels and cause hyperkalemia
(e.g. medicinal products that inhibit the renin-angiotensin system, potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, ciclosporin or other medicinal products such as heparin sodium). When these medicinal products are used together with the combination of hydrochlorothiazide and telmisartan, monitoring of plasma potassium levels is recommended. Based on experience with other medicinal products that inhibit the renin-angiotensin system, the concomitant use of these medicinal products may lead to increases in serum potassium and is therefore not recommended (see section 4.4).
Medicinal products that cause serum potassium disturbances. Periodic monitoring of serum potassium and ECG is recommended when MICARDIS PLUS is used with the following medicinal products that cause serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics) and medicinal products that induce ventricular fibrillation (including some antiarrhythmics), hypokalaemia being a precipitating factor for ventricular fibrillation:
- Class Ia antiarrhythmic drugs (e.g. quinidine, hydroquinidine, disopyramide);
- class III antiarrhythmic drugs (e.g. amiodarone, sotalol, dofetelide,
ibutelide);
- some antipsychotics (e.g. thioridazine, chlorpromazine, levopromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidolol);
- others (e.g. bepridil, cisapride, diphemanil, erythromycin IV, halofantrine, mizolastine, pentamidine, sparfloxacin, terfenadine, vincamine IV).
Digitalis glycosides.
Thiazide-induced hypokalemia or hypomagnesemia may contribute to digitalis-induced cardiac arrhythmias (see section 4.4).
Digoxin: When telmisartan was co-administered with digoxin, an increase in mean peak (49%) and trough (20%) digoxin plasma concentrations was observed. Digoxin levels should be monitored at the start of therapy, during dose adjustments, and when telmisartan is discontinued to maintain levels within the therapeutic range.
Clinical data have 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 incidence of adverse events such as hypotension, hyperkalemia and decreased renal function (including acute renal failure) compared with the use of a single RAAS-acting agent (see sections 4.4, 4.3 and 5.1).
Antidiabetic medications (oral agents and insulin).
The dose of the antidiabetic agent may need to be adjusted (see section "Special warnings and precautions for use").
Metformin: Metformin should be used with caution due to the risk of lactic acidosis when used concomitantly with hydrochlorothiazide.
Cholestyramine and colestipol resins: The absorption of hydrochlorothiazide is reduced in the presence of anion exchange resins.
Non-steroidal anti-inflammatory drugs. NSAIDs (i.e. acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, non-selective NSAIDs) may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics and the antihypertensive effect of angiotensin II receptor antagonists. In some patients with impaired renal function (in dehydrated patients or elderly patients with impaired renal function), the concomitant use of angiotensin II receptor antagonists and agents that inhibit cyclooxygenase may lead to worsening of renal function, including possible acute renal failure, which is usually reversible. Therefore, the combination should be used with caution, especially in elderly patients. After initiation of therapy with the combination of drugs and periodically thereafter, patients should be adequately hydrated and renal function should be closely monitored.
In one study, concomitant administration of telmisartan and ramipril resulted in a 2.5-fold increase in the area under the concentration-time curve (AUC0-24) and maximum plasma concentrations (Cmax) of ramipril and ramiprilat. The clinical significance of this observation remains unknown.
Vasopressor amines (e.g. noradrenaline). The effect of vasopressor amines may be reduced.
Non-depolarizing skeletal muscle relaxants (e.g. tubocurarine). The effects of non-depolarizing skeletal muscle relaxants may be potentiated by hydrochlorothiazide.
Medicines used to treat gout (e.g. probenecid, sulfinpyrazone and allopurinol). The dose of medicines that promote the excretion of uric acid may need to be adjusted, as hydrochlorothiazide may increase serum uric acid levels. It may be necessary to increase the dose of probenecid or sulfinpyrazone. Concomitant use of thiazides may increase the incidence of hypersensitivity reactions to allopurinol.
Calcium salts: Thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium supplements are required, serum calcium levels should be monitored and the dose adjusted accordingly.
Beta-blockers and diazoxide: The hyperglycemic effects of beta-blockers and diazoxide may be potentiated by thiazides.
Anticholinergic drugs (e.g. atropine, biperiden) may increase the bioavailability of thiazide diuretics by increasing gastrointestinal motility and the rate of gastric emptying.
Amantadine: Thiazides may increase the risk of side effects caused by amantadine.
Cytotoxic drugs (e.g. cyclophosphamide, methotrexate). Thiazides may reduce the renal excretion of cytotoxic drugs and enhance their myelosuppressive effect.
Based on their pharmacological properties, baclofen and amifostine are expected to potentiate the hypotensive effects of all antihypertensive drugs, including telmisartan. In addition, orthostatic hypotension may be potentiated by the use of alcohol, barbiturates, narcotics or antidepressants.
Salicylates: When using high doses of salicylates, hydrochlorothiazide may enhance their toxic effects on the central nervous system.
Methyldopa: Isolated cases of hemolytic anemia have been reported with concomitant use of hydrochlorothiazide and methyldopa.
Cyclosporine: Concomitant use of cyclosporine may increase hyperuricemia and increase the risk of complications such as gout.
The effect of drugs on laboratory test results.
Due to their effect on calcium metabolism, thiazides may interfere with the results of parathyroid function tests (see section 4.4).
Carbamazepine: Clinical and biological monitoring is necessary due to the risk of symptomatic hyponatremia.
Iodinated contrast media: In the case of diuretic-induced dehydration, the risk of acute renal failure is increased, especially with high doses of iodinated contrast media. Patients should be rehydrated before administration of iodinated contrast media.
Amphotericin B (for parenteral administration), corticosteroids, ACTH and stimulant laxatives. Hydrochlorothiazide increases electrolyte imbalance, mainly hypokalemia.
Application features
Angiotensin II receptor antagonists should not be initiated during pregnancy. Until treatment with angiotensin II receptor antagonists 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, angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.8).
Liver dysfunction.
MICARDIS PLUS should not be administered to patients with cholestasis, biliary obstructive disorders or severe hepatic insufficiency (see section "Contraindications"), since telmisartan is excreted mainly with bile. In these patients, a decrease in the hepatic clearance of telmisartan is expected. MICARDIS PLUS should be used with caution in patients with impaired hepatic function or progressive liver disease, since these drugs can cause intrahepatic cholestasis, and even minor changes in water-salt balance can lead to hepatic coma. There is no clinical experience with the use of MICARDIS PLUS in patients with hepatic insufficiency.
Renal hypertension: There is an increased risk of severe hypotension and renal failure when patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system.
Kidney failure and kidney transplantation.
MICARDIS PLUS should not be administered to patients with severe renal impairment (creatinine clearance < 30 ml/min) (see section 4.3). There is no experience with MICARDIS PLUS in patients with severe renal impairment or with a recent kidney transplant. There is limited experience in patients with mild to moderate renal impairment, therefore periodic monitoring of serum potassium, creatinine and uric acid levels is recommended. Thiazide diuretic-associated azotemia may occur in patients with impaired renal function.
Intravascular volume depletion. Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by diuretic therapy, dietary salt restriction, diarrhea, or vomiting. These conditions should be corrected before administration of MICARDIS PLUS.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS).
There is evidence that concomitant use of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalemia and decreased renal function (including acute renal failure).
Therefore, dual blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is not recommended (see sections “Interaction with other medicinal products and other types of interactions” and “Pharmacological properties”).
If dual blockade is considered absolutely necessary, it should only be performed under specialist supervision and with continuous 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 requiring 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 congestive heart failure or severe renal disease, including renal artery stenosis), treatment with other medicinal products that affect the renin-angiotensin-aldosterone system may be associated with acute hypotension, hyperazotemia, oliguria or, rarely, acute renal failure (see section 4.8).
Primary aldosteronism: Patients with primary aldosteronism generally do not respond to antihypertensive drugs that act through blockade of the renin-angiotensin system. Therefore, the use of MICARDIS PLUS is not recommended.
Metabolic and endocrine effects. Thiazide therapy may impair glucose tolerance, while hypoglycemia may occur in diabetic patients receiving insulin or antidiabetic therapy and telmisartan therapy. Therefore, blood glucose levels should be monitored in these patients; dose adjustment of insulin or hypoglycemic agents may be necessary. Latent diabetes mellitus may be revealed during thiazide therapy. Elevations in cholesterol and triglycerides have been associated with thiazide diuretic therapy; however, minimal or no elevations in cholesterol and triglycerides have been observed with a preparation containing 12.5 mg of hydrochlorothiazide. Hyperuricemia or overt gout may occur in some patients receiving thiazide therapy.
Electrolyte imbalance. All patients receiving diuretic therapy should have their serum electrolytes measured periodically. Thiazides, including hydrochlorothiazide, may cause electrolyte imbalance (hypokalemia, hyponatremia, and hypochloraemic alkalosis), which may develop in the presence of concomitant diarrhea or vomiting. Symptoms of electrolyte imbalance include dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting (see section 4.8).
- Hypokalaemia. Although thiazide diuretics may cause hypokalaemia, concomitant treatment with telmisartan may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is highest in patients with cirrhosis of the liver, in patients with significant diuresis, in patients receiving inadequate oral electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH (see section 4.5).
- Hyperkalaemia. Conversely, hyperkalaemia may occur due to antagonism of angiotensin II (AT1) receptors by telmisartan, a component of MICARDIS PLUS. However, clinically significant hyperkalaemia due to MICARDIS PLUS has not been documented, and risk factors for hyperkalaemia include renal insufficiency and/or heart failure and diabetes mellitus. Potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes should be administered with caution with MICARDIS PLUS (see section 4.5).
- Hyponatremia and hypochloraemic alkalosis. There is no evidence that MICARDIS PLUS will reduce or prevent diuretic-induced hyponatremia. Chloride deficiency is generally mild and usually does not require treatment. In warm weather, hyponatremia may occur in patients with oedema due to blood thinning.
- Hypercalcemia. Thiazides may reduce urinary calcium excretion and cause a transient and slight increase in serum calcium levels in the absence of known disorders of calcium metabolism. Significant hypercalcemia may be a sign of latent hyperparathyroidism. Thiazides should be discontinued before parathyroid function tests are performed.
- Hypomagnesemia. Thiazides have been shown to increase urinary magnesium excretion, which may lead to hypomagnesemia (see section "Interaction with other medicinal products and other forms of interaction").
Sorbitol and lactose monohydrate. The medicinal product contains lactose monohydrate and sorbitol. Therefore, patients with rare hereditary problems of fructose intolerance and/or galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Race: As with other angiotensin II receptor antagonists, telmisartan is likely to be less effective in lowering blood pressure in black patients, presumably because of the greater prevalence of low-renin states in this hypertensive population.
Others: As with any antihypertensive drug, a significant decrease in blood pressure in patients with ischemic cardiopathy or in patients with myocardial ischemia may lead to myocardial infarction or stroke.
General: Hypersensitivity reactions to hydrochlorothiazide are more likely to occur in patients with allergies or bronchial asthma, but this is more likely in patients with a history of such diseases. Exacerbation or activation of systemic lupus erythematosus has been observed with the use of thiazide diuretics, including hydrochlorothiazide.
Photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If photosensitivity reactions occur during treatment, discontinuation of the drug is recommended. If repeated use of diuretics is considered necessary, it is recommended to protect exposed areas from sunlight or artificial ultraviolet radiation.
Symptoms include an abrupt onset of decreased visual acuity or eye pain and usually occur within hours to weeks of starting treatment. Untreated acute angle-closure glaucoma may lead to irreversible vision loss. Hydrochlorothiazide should be discontinued as soon as possible. Urgent medical or surgical treatment may be required if intraocular pressure remains uncontrolled. Risk factors for the development of acute angle-closure glaucoma may include a history of sulphonamide or penicillin allergy.
The drug may affect the results of the following laboratory tests:
− the drug may reduce the level of protein-bound iodine in blood plasma;
− treatment with the drug should be discontinued before conducting a laboratory examination to assess the function of the parathyroid glands;
The drug is capable of increasing the concentration of free bilirubin in the blood serum.
Use during pregnancy or breastfeeding
Pregnancy
The drug is contraindicated for use in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this drug, its use should be discontinued and replaced with another drug approved for use (see sections "Contraindications" and "Special Instructions for Use").
There are no data on the use of MICARDISPLUS in pregnant women.
Epidemiological evidence of a risk of teratogenicity following use of inhibitors during the first trimester of pregnancy is inconclusive; however, a small increase in risk cannot be excluded.
Until continued therapy with angiotensin II receptor antagonists 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, angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.
Treatment with angiotensin II receptor antagonists during the second and third trimesters of pregnancy is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalemia). If angiotensin II receptor antagonists are used from the second trimester of pregnancy, ultrasound monitoring of renal function and skull is recommended. Infants whose mothers have taken angiotensin II receptor antagonists should be closely observed for hypotension (see sections 4.3 and 4.4). There is limited experience with the use of hydrochlorothiazide during pregnancy, especially during the first trimester.
Hydrochlorothiazide crosses the placental barrier. Given the pharmacological mechanism of action of hydrochlorothiazide, use of the drug during the II and III trimesters may impair fetal-placental perfusion and lead to intrauterine and neonatal effects such as jaundice, fetal electrolyte imbalance, and thrombocytopenia.
Hydrochlorothiazide should not be used in edema, pregnancy-induced hypertension, or late toxicosis due to the risk of plasma volume depletion and placental hypoperfusion without a positive effect on the course of the disease.
Hydrochlorothiazide should not be used in severe hypertension in pregnant women, except in rare cases where other treatment is not possible.
Breast-feeding
Because no information is available regarding the use of MICARDIS PLUS during breastfeeding, it is not recommended during breastfeeding; alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.
Hydrochlorothiazide is excreted in small amounts in breast milk. Thiazides in high doses, causing intense diuresis, may suppress the formation of breast milk. If MICARDIS PLUS is used during breastfeeding, the lowest possible dose should be used.
Fertility
Preclinical studies have not shown any effect of telmisartan and hydrochlorothiazide on male and female fertility.
Ability to influence reaction speed when driving vehicles or other mechanisms
When driving a car or operating machinery, it should be taken into account that dizziness or drowsiness may occur during antihypertensive therapy with MICARDISPLUS.
Method of administration and doses
Dosage
MICARDIS PLUS is indicated in patients whose blood pressure is not adequately controlled with telmisartan alone. The dose of each component should be determined before switching to MICARDIS PLUS. Direct change from monotherapy to fixed combinations may be considered.
MICARDIS PLUS 40 mg/12.5 mg can be administered alone
