Olme stad trio
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT OLMESTAD TRIO (OLMESTAD TRIO)
Composition:
Active substances: olmesartan medoxomil/amlodipine besylate/hydrochlorothiazide;
One film-coated tablet contains olmesartan medoxomil 20 mg, amlodipine besylate 6.935 mg, equivalent to amlodipine 5 mg and hydrochlorothiazide 12.5 mg; or olmesartan medoxomil 40 mg, amlodipine besylate 13.87 mg, equivalent to amlodipine 10 mg and hydrochlorothiazide 12.5 mg;
Excipients: microcrystalline cellulose, crospovidone (type A), colloidal silicon dioxide anhydrous, magnesium stearate, lactose monohydrate;
Coating: Opadry II pink 31F270001 or Opadry II pink 31F240019, purified water. Opadry II pink 31F270001 or Opadry II pink 31F240019 consists of: hypromellose, lactose monohydrate, macrogol, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172), black iron oxide (E 172).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
for the 20 mg/5 mg/12.5 mg dosage: light orange, round, biconvex, film-coated tablets;
for the 40 mg/10 mg/12.5 mg dosage: greyish-red, round, biconvex, film-coated tablets.
Pharmacotherapeutic group.
Cardiovascular system. Medicinal products affecting the renin-angiotensin system. Angiotensin II antagonists in combination with other agents. Olmesartan medoxomil, amlodipine and hydrochlorothiazide. ATC code C09DX03.
Pharmacological properties.
Pharmacodynamics.
Olmesartan Trio is a combination medicinal product containing olmesartan medoxomil – an angiotensin II receptor antagonist, amlodipine besylate – a calcium channel blocker, and the thiazide diuretic hydrochlorothiazide. The combination of these components provides an additional antihypertensive effect, reducing arterial pressure to a greater extent than each active ingredient alone.
Olmesartan medoxomil
Olmesartan medoxomil is an oral active, selective antagonist of angiotensin II receptors (type AT1). Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system (RAAS) and plays a key role in the pathophysiology of arterial hypertension. The effects of angiotensin II include vasoconstriction, stimulation of aldosterone synthesis and release, cardiac stimulation, and renal sodium reabsorption. Olmesartan blocks the vasoconstrictive and aldosterone-secreting effects of angiotensin II by inhibiting its binding to AT1 receptors in tissues, including vascular smooth muscle and adrenal glands. The action of olmesartan is independent of the source or pathway of angiotensin II synthesis. Selective antagonism of angiotensin II receptors (AT1) by olmesartan leads to increased plasma renin levels and concentrations of angiotensin I and II, as well as a slight reduction in plasma aldosterone concentration.
In patients with arterial hypertension, olmesartan medoxomil provides sustained reduction in blood pressure, the degree of which is dose-dependent. No signs of arterial hypotension after the first dose (first-dose effect), tachyphylaxis during prolonged use, or rebound hypertension after abrupt discontinuation have been observed.
When administered once daily to patients with arterial hypertension, olmesartan medoxomil produces effective and gradual reduction in blood pressure over the 24-hour dosing interval. When administered once daily, its antihypertensive effect was approximately equivalent to that achieved with twice-daily administration at the same total daily dose.
With continuous treatment, maximum blood pressure reduction is achieved within 8 weeks of initiating therapy, while a significant antihypertensive effect is observed as early as 2 weeks after starting treatment.
The effect of olmesartan medoxomil on mortality and the incidence of complications has not been established.
The Randomized Olmesartan for the Prevention of Diabetic Microalbuminuria (ROADMAP) trial, involving 4447 patients with type 2 diabetes, normal albuminuria levels, and at least one additional cardiovascular risk factor, was conducted to determine whether olmesartan therapy could delay the onset of microalbuminuria. During a mean follow-up period of 3.2 years, patients received olmesartan or placebo in addition to other antihypertensive agents, excluding angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs).
In the primary endpoint of the study, a significant reduction in the risk of time to onset of microalbuminuria was demonstrated with olmesartan use. After adjusting for differences in blood pressure levels, this risk reduction was no longer statistically significant. Microalbuminuria developed in 8.2% (178 out of 2160) of patients in the olmesartan group and in 9.8% (210 out of 2139) of patients in the placebo group.
In the secondary endpoint, cardiovascular events occurred in 96 patients (4.3%) receiving olmesartan and in 94 patients (4.2%) receiving placebo. Cardiovascular mortality was higher in the olmesartan group compared to the placebo group (15 patients (0.7%) vs. 3 patients (0.1%)), despite similar rates of non-fatal stroke (14 patients (0.6%) vs. 8 patients (0.4%)), non-fatal myocardial infarction (17 patients (0.8%) vs. 26 patients (1.2%)), and non-cardiovascular mortality (11 patients (0.5%) vs. 12 patients (0.5%)). Overall mortality was higher in the olmesartan group (26 patients (1.2%) vs. 15 patients (0.7%)), primarily due to higher cardiovascular mortality.
The ORIENT trial (Olmesartan Reducing Incidence of End-stage Renal Disease in Diabetic Nephropathy) evaluated the effect of olmesartan on renal and cardiovascular outcomes in 577 randomized patients in Japan and China with type 2 diabetes and overt nephropathy. During a mean follow-up period of 3.1 years, patients received olmesartan or placebo in addition to other antihypertensive agents, including ACE inhibitors.
The primary composite endpoint (time to first occurrence of doubling of serum creatinine, end-stage renal disease, or death from any cause) was reached in 116 patients (41.1%) in the olmesartan group and in 129 patients (45.4%) in the placebo group (HR 0.97 (95% confidence interval (CI) 0.75–1.24); p = 0.791). The secondary composite cardiovascular endpoint occurred in 40 patients receiving olmesartan (14.2%) and in 53 patients receiving placebo (18.7%). This composite cardiovascular endpoint included cardiovascular mortality in 10 (3.5%) patients receiving olmesartan and 3 (1.1%) receiving placebo; overall mortality was 19 (6.7%) and 20 (7.0%), non-fatal stroke was 8 (2.8%) and 11 (3.9%), and non-fatal myocardial infarction was 3 (1.1%) and 7 (2.5%), respectively.
Amlodipine
Amlodipine, included in the formulation, is a calcium channel blocker that inhibits transmembrane calcium ion influx through voltage-dependent L-type channels in the heart and vascular smooth muscle. Experimental data indicate that amlodipine interacts with both dihydropyridine binding sites and other regions. Amlodipine has relative vasoselectivity and exerts a greater effect on vascular smooth muscle cells than on cardiomyocytes. The antihypertensive effect of amlodipine is due to its direct relaxing action on arterial smooth muscle cells, leading to reduced peripheral vascular resistance and, consequently, reduced arterial pressure.
In arterial hypertension, amlodipine produces a dose-dependent, prolonged reduction in blood pressure. No arterial hypotension after the first dose, signs of tachyphylaxis during long-term treatment, or rebound hypertension after discontinuation have been observed.
After oral administration at therapeutic doses, amlodipine effectively reduces blood pressure in patients with arterial hypertension in supine, sitting, and standing positions. Long-term use of amlodipine is not associated with significant changes in heart rate or plasma catecholamine levels. In patients with arterial hypertension and normal renal function, therapeutic doses of amlodipine reduce renal vascular resistance and increase glomerular filtration rate (GFR) and effective renal plasma flow, without altering filtration fraction or causing proteinuria.
Hemodynamic studies in patients with heart failure, as well as clinical exercise testing studies in patients with heart failure (NYHA classes II–IV), showed that amlodipine did not worsen patient status as assessed by exercise tolerance, left ventricular ejection fraction, or clinical signs and symptoms.
In a placebo-controlled trial (PRAISE) involving patients with heart failure (NYHA classes III–IV) receiving digoxin, diuretics, and ACE inhibitors, amlodipine did not increase the risk of mortality or the combined risk of mortality and morbidity in patients with heart failure.
In a subsequent long-term placebo-controlled trial (PRAISE-2) involving patients with heart failure (NYHA III and IV) without clinical symptoms or objective evidence of ischemic heart disease, treated with ACE inhibitors, digitalis, and diuretics at stable doses, amlodipine did not affect overall mortality or cardiovascular mortality specifically. In this patient group, an increased incidence of pulmonary edema was observed with amlodipine use, but no statistically significant differences in the frequency of worsening heart failure compared to the placebo group were noted.
To compare therapies of new medicinal products, a double-blind randomized trial of morbidity and mortality titled "Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial" (ALLHAT) was conducted: amlodipine at 2.5–10 mg daily (calcium channel blocker) or lisinopril at 10–40 mg daily (ACE inhibitor) as first-line therapy, and the thiazide diuretic chlorthalidone at 12.5–25 mg daily for mild to moderate arterial hypertension.
A total of 33,357 hypertensive patients aged 55 years or older were randomized and followed for a mean of 4.9 years. Patients had at least one additional risk factor for ischemic heart disease (IHD), such as prior myocardial infarction or stroke (more than 6 months before enrollment) or other atherosclerotic cardiovascular diseases (51.5% total), type 2 diabetes (36.1%), high-density lipoprotein cholesterol (HDL-C) level < 35 mg/dL (11.6%), left ventricular hypertrophy diagnosed by electrocardiography or echocardiography (20.9%), or current smoking (21.9%).
The primary endpoint was a composite of fatal IHD or non-fatal myocardial infarction. No significant differences were observed between amlodipine and chlorthalidone therapy regarding the primary endpoint: OR 0.98 (95% CI 0.90–1.07; p = 0.65). Regarding secondary endpoints, the incidence of heart failure (a component of the composite cardiovascular endpoint) was significantly higher in the amlodipine group compared to the chlorthalidone group (10.2% vs. 7.7%; OR 1.38, 95% CI 1.25–1.52; p < 0.001). However, no significant differences in all-cause mortality between amlodipine and chlorthalidone therapy were observed (OR 0.96, 95% CI 0.89–1.02; p = 0.20).
Hydrochlorothiazide
Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive action of thiazide diuretics is not fully understood. Thiazides affect electrolyte reabsorption in renal tubules, thereby enhancing the excretion of sodium and chloride (approximately to a similar extent). Acting as a diuretic, hydrochlorothiazide reduces plasma volume, leading to increased plasma renin activity and aldosterone secretion, increased urinary excretion of potassium and bicarbonate, and decreased serum concentrations of these electrolytes. Since the relationship between renin levels and aldosterone secretion is mediated by angiotensin II, potassium losses induced by thiazide diuretics may be reduced when hydrochlorothiazide is used in combination with an angiotensin II receptor blocker. Diuresis begins approximately 2 hours after administration, peak effect occurs around 4 hours, and the effect lasts for 6–12 hours.
According to epidemiological data, long-term use of hydrochlorothiazide as monotherapy reduces the risk of cardiovascular complications and mortality from them.
Clinical efficacy and safety
In a 12-week double-blind, randomized, parallel-group study involving 2492 patients (67% Caucasian), treatment with Olmesartan Trio resulted in greater reductions in diastolic and systolic blood pressure compared to treatment with any of the following dual combinations: olmesartan medoxomil 40 mg plus amlodipine 10 mg, olmesartan medoxomil 40 mg plus hydrochlorothiazide 25 mg, and amlodipine 10 mg plus hydrochlorothiazide 25 mg.
The additional blood pressure-lowering effect of Olmesartan Trio compared to these dual combinations was -3.8 to -6.7 mm Hg for seated diastolic blood pressure and -7.1 to -9.6 mm Hg for seated systolic blood pressure, occurring within the first 2 weeks.
The proportion of patients achieving blood pressure targets (< 140/90 mm Hg for non-diabetic patients and < 130/80 mm Hg for diabetic patients) at week 12 ranged from 34.9% to 46.6% in the dual combination groups compared to 64.3% in the Olmesartan Trio group.
In a second double-blind, randomized, parallel-group study involving 2690 patients (99.9% Caucasian), treatment with Olmesartan Trio showed significant reductions in diastolic and systolic blood pressure compared to the following dual combinations: olmesartan medoxomil 20 mg plus amlodipine 5 mg, olmesartan medoxomil 40 mg plus amlodipine 5 mg, and olmesartan medoxomil 40 mg plus amlodipine 10 mg, after 10 weeks of treatment.
The additional blood pressure-lowering effect of Olmesartan Trio compared to these dual combinations was -1.3 to -1.9 mm Hg for seated diastolic blood pressure and -2.7 to -4.9 mm Hg for seated systolic blood pressure.
The proportion of patients achieving blood pressure targets (< 140/90 mm Hg for non-diabetic patients and < 130/80 mm Hg for diabetic patients) at week 10 ranged from 42.7% to 49.6% in the combination therapy groups compared to 52.4% to 58.8% in the Olmesartan Trio group.
In a randomized, double-blind study involving 808 patients (99.9% Caucasian) with uncontrolled blood pressure after 8 weeks of dual therapy with olmesartan medoxomil 40 mg and amlodipine 10 mg, treatment with Olmesartan Trio showed significant additional blood pressure reduction in the seated position (-1.8/-1.0 mm Hg) with Olmesartan Trio 40 mg/10 mg/12.5 mg, and statistically significant blood pressure reduction in the seated position (-3.6/-2.8 mm Hg) compared to dual therapy with olmesartan medoxomil 40 mg and amlodipine 10 mg.
Triple combination therapy with Olmesartan Trio resulted in a statistically significant higher percentage of patients achieving blood pressure targets compared to dual combination therapy with olmesartan medoxomil 40 mg and amlodipine 10 mg (41.3% vs. 24.2%); treatment with Olmesartan Trio 40 mg/10 mg/12.5 mg in triple combination therapy resulted in a numerically higher percentage of patients achieving blood pressure targets compared to dual combination therapy with olmesartan medoxomil 40 mg and amlodipine 10 mg (29.5% vs. 24.2%) in patients inadequately controlled with dual combination therapy.
The antihypertensive effect of Olmesartan Trio was similar regardless of patient age and sex and was comparable in patients with and without diabetes.
Other information
The combined use of ACE inhibitors and ARBs was investigated in two large-scale randomized controlled trials (ONTARGET (ONgoing Telmisartan Alone in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)).
ONTARGET was a trial involving patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with target organ damage. VA NEPHRON-D was a trial involving patients with type 2 diabetes and diabetic nephropathy. The studies did not demonstrate a significant beneficial effect on renal and/or cardiovascular outcomes or mortality, while the risk of hyperkalemia, acute kidney injury, and/or hypotension was increased compared to monotherapy. Given the similar pharmacodynamic properties, these results are also applicable to other ACE inhibitors and ARBs. Therefore, the combined use of ACE inhibitors and ARBs is contraindicated in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a trial designed to evaluate the positive effect of adding aliskiren to standard therapy with ACE inhibitors or ARBs in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. The trial was terminated early due to an increased risk of adverse outcomes. Cardiovascular mortality and stroke incidence were higher in the aliskiren group compared to the placebo group, and reports of adverse reactions, including serious ones (hyperkalemia, arterial hypotension, and renal function impairment), were more frequent in the aliskiren group than in the placebo group.
Pharmacokinetics.
Concomitant administration of olmesartan medoxomil, amlodipine, and hydrochlorothiazide had no clinically significant effect on the pharmacokinetics of any component in healthy volunteers.
After oral administration of Olmesartan Trio in healthy adult volunteers, maximum plasma concentrations (Cmax) of olmesartan, amlodipine, and hydrochlorothiazide are reached at approximately 1.5–3 hours, 6–8 hours, and 1.5–2 hours, respectively. The rate and extent of absorption of olmesartan medoxomil, amlodipine, and hydrochlorothiazide are equivalent to those observed with the administration of a fixed dual combination of olmesartan medoxomil and amlodipine together with a single-component hydrochlorothiazide tablet, or with a fixed dual combination of olmesartan medoxomil and hydrochlorothiazide together with a single-component amlodipine tablet at the same doses. Food intake does not affect the bioavailability of the drug.
Olmesartan medoxomil
Absorption and distribution
Olmesartan medoxomil is a prodrug. It is rapidly converted to the pharmacologically active metabolite olmesartan by esterases in the intestinal mucosa and portal blood during absorption in the gastrointestinal tract. Unconverted olmesartan medoxomil or the medoxomil side chain are not detected in plasma or excreted products. The average absolute bioavailability of olmesartan in tablet form is 25.6%.
The average Cmax of olmesartan in plasma is reached approximately 2 hours after oral administration. Plasma olmesartan concentration increases approximately linearly with increasing single doses up to 80 mg.
Food has minimal effect on the bioavailability of olmesartan; therefore, olmesartan medoxomil can be administered independently of food intake. No clinically significant differences in olmesartan pharmacokinetics between genders have been observed.
Olmesartan is highly bound to plasma proteins (99.7%), but the risk of clinically significant interactions with other drugs that are highly protein-bound is low, as confirmed by the absence of interaction between olmesartan medoxomil and warfarin. Olmesartan is minimally bound to blood cells. The mean volume of distribution after intravenous administration is low (16–29 L).
Metabolism and elimination
Total plasma clearance of olmesartan is typically 1.3 L/hour (coefficient of variation 19%) and is relatively low compared to hepatic blood flow (approximately 90 L/hour). After oral administration of 14C-labeled olmesartan medoxomil, 10–16% of radioactivity is excreted in urine (mostly within 24 hours after administration), with the remainder excreted in feces. Based on systemic availability (25.6%), it can be calculated that approximately 40% of olmesartan is excreted renally and 60% via the hepatobiliary system. All recovered radioactivity was attributed to olmesartan. No other significant metabolites have been identified. Enterohepatic recirculation of olmesartan is minimal. Since most olmesartan is excreted in bile, its use is contraindicated in patients with biliary obstruction (see section "Contraindications").
The terminal elimination half-life of olmesartan after multiple oral doses ranges from 10 to 15 hours. Steady-state is achieved after the first few doses, and no further accumulation is observed after 14 days of multiple dosing. Renal clearance is approximately 0.5–0.7 L/hour, independent of dose.
Interaction with other medicinal products
Cholestyramine, a bile acid-binding medicinal product
Concomitant administration of 40 mg olmesartan medoxomil and 3750 mg cholestyramine hydrochloride in healthy volunteers resulted in a 28% reduction in Cmax and a 39% reduction in the area under the plasma concentration-time curve (AUC) for olmesartan. A smaller effect, with 4% and 15% reductions in Cmax and AUC, respectively, was observed when olmesartan medoxomil was administered 4 hours before cholestyramine hydrochloride. The elimination half-life of olmesartan was reduced by 50–52%, regardless of whether the drugs were administered together or olmesartan was administered 4 hours before cholestyramine hydrochloride (see section "Interaction with other medicinal products and other forms of interaction").
Amlodipine
Absorption and distribution
After oral administration of therapeutic doses, amlodipine is well absorbed, with Cmax in blood reached within 6–12 hours after administration. Absolute bioavailability is estimated at 64–80%. The volume of distribution is approximately 21 L/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.
Amlodipine absorption is not affected by concomitant food intake.
Metabolism and elimination
The terminal elimination half-life from plasma is approximately 35–50 hours, corresponding to once-daily dosing.
Amlodipine is rapidly metabolized by the liver into inactive metabolites, with 10% of the parent compound and 60% of metabolites excreted in urine.
Hydrochlorothiazide
Absorption and distribution
After oral administration of olmesartan medoxomil and hydrochlorothiazide in combination, the mean time to reach Cmax of hydrochlorothiazide is 1.5–2 hours. Hydrochlorothiazide is 68% protein-bound in plasma, and its apparent volume of distribution is 0.83–1.14 L/kg.
Metabolism and elimination
Hydrochlorothiazide is not metabolized in the human body and is almost entirely excreted unchanged in urine. After oral administration, approximately 60% of the dose is excreted unchanged within 48 hours. Renal clearance is approximately 250–300 mL/min. The terminal elimination half-life is approximately 10–15 hours.
Pharmacokinetics in specific patient populations
Elderly patients (aged 65 years and older)
It has been demonstrated that in patients with arterial hypertension, the steady-state AUC of olmesartan in elderly (65–75 years) and very elderly (≥75 years) patients is increased by approximately 35% and 44%, respectively, compared to younger patients (see section "Dosage and administration").
This can be partly explained by the age-related decline in renal function in this patient group. However, the same dosing regimen is recommended for elderly patients as for other patients, although dose escalation should be done cautiously.
The time to reach Cmax of amlodipine in plasma is the same in elderly and younger patients. In elderly patients, there is a tendency toward reduced amlodipine clearance, leading to increased AUC and prolonged elimination half-life. The increases in AUC and elimination half-life in patients with congestive heart failure are consistent with predictions for this age group (see section "Special precautions for use").
Limited data suggest that systemic clearance of hydrochlorothiazide is reduced in elderly patients (including those with arterial hypertension) compared to young healthy volunteers.
Children
The European Medicines Agency has waived the obligation to submit results of studies with Olmesartan Trio in all pediatric subpopulations with essential hypertension.
Renal impairment
In patients with mild, moderate, and severe renal impairment, the steady-state AUC of olmesartan was 62%, 82%, and 179% higher, respectively, than in healthy volunteers. The elimination half-life of hydrochlorothiazide is prolonged in patients with renal impairment.
The pharmacokinetics of olmesartan medoxomil in patients undergoing hemodialysis has not been studied.
Amlodipine is extensively metabolized to inactive metabolites. 10% of the drug is excreted unchanged in urine. Changes in amlodipine plasma concentration do not correlate with the degree of renal impairment. Amlodipine can be administered at usual doses to these patients. Amlodipine is not removed by dialysis.
The elimination half-life of hydrochlorothiazide is prolonged in patients with renal impairment.
Hepatic impairment
After single oral administration, AUC values of olmesartan were 6% and 65% higher in patients with mild or moderate hepatic impairment, respectively, compared to healthy volunteers. The unbound fraction of olmesartan 2 hours after administration in healthy volunteers, and in patients with mild or moderate hepatic impairment, was 0.26%, 0.34%, and 0.41%, respectively.
After repeated administration, the mean AUC of olmesartan in patients with moderate hepatic impairment was 65% higher than in healthy volunteers. Mean Cmax values of olmesartan in patients with hepatic impairment and healthy volunteers were similar (see sections "Special precautions for use" and "Dosage and administration").
Clinical data on amlodipine use in patients with hepatic impairment are very limited. In patients with hepatic impairment, reduced amlodipine clearance and prolonged elimination half-life are observed, leading to an increase in AUC by approximately 40–60% (see sections "Special precautions for use" and "Dosage and administration").
Hepatic insufficiency does not significantly affect the pharmacokinetics of hydrochlorothiazide.
Non-clinical safety data
Repeated-dose toxicity studies in rats showed that combined administration of olmesartan medoxomil, amlodipine, and hydrochlorothiazide did not exacerbate any previously recorded or existing toxic effects of the individual components and did not cause any new toxicity. No synergistic toxicological effects were observed.
No additional studies on mutagenicity, carcinogenicity, or reproductive toxicity were conducted for Olmesartan Trio, given the well-understood safety profile of the individual active components.
Olmesartan medoxomil
In chronic toxicity studies in rats and dogs, the effects of olmesartan medoxomil were similar to those of other AT1 receptor antagonists and ACE inhibitors: increased blood urea nitrogen (BUN) and creatinine levels, reduced heart weight, decreased erythrocyte parameters (erythrocyte count, hemoglobin concentration, hematocrit), and histological signs of kidney damage (regenerative renal epithelial injury, thickening of the basement membrane, tubular dilation). These adverse effects, caused by the pharmacological action of olmesartan medoxomil, were also observed in preclinical studies with other AT1 receptor antagonists and ACE inhibitors and can be mitigated by adding sodium chloride orally.
Similar to other AT1 receptor antagonists, olmesartan medoxomil increases the frequency of chromosomal breaks in vitro. This effect was not observed in several in vivo studies where olmesartan medoxomil was administered orally at very high doses up to 2000 mg/kg. Overall, comprehensive genotoxicity testing data suggest that genotoxic effects of olmesartan are unlikely at clinical use.
No carcinogenic effects of olmesartan medoxomil were observed in rats or transgenic mice.
In reproductive toxicity studies in rats, olmesartan medoxomil did not affect fertility and had no teratogenic effects. As with other angiotensin II receptor antagonists, offspring survival was reduced after exposure to olmesartan medoxomil, and female rats receiving the drug in late pregnancy and during lactation showed renal pelvis dilation. No fetotoxic effects were observed in rabbits.
Amlodipine
Reproductive toxicity
Reproductive function studies in rats and mice showed delayed delivery, prolonged labor, and reduced offspring survival at doses approximately 50 times higher than the maximum recommended human dose based on body surface area (mg/m²).
Fertility impairment
No effects on fertility were observed in rats (males for 64 days, females for 14 days before mating) receiving amlodipine at doses up to 10 mg/kg/day (8 times the maximum recommended human dose of 10 mg based on mg/m², assuming a patient body weight of 50 kg). In another study, male rats receiving amlodipine besylate for 30 days at doses comparable to human doses based on mg/kg showed reduced plasma follicle-stimulating hormone and testosterone concentrations, reduced sperm density, and decreased numbers of mature spermatids and Sertoli cells.
Carcinogenesis, mutagenesis
Two-year carcinogenicity studies in rats and mice receiving amlodipine in feed at concentrations calculated to provide daily doses of 0.5 mg/kg/day, 1.25 mg/kg/day, and 2.5 mg/kg/day showed no evidence of carcinogenicity. The highest dose (equivalent to the maximum recommended human dose of 10 mg based on mg/m² in mice and twice the maximum recommended human dose in rats) was close to the maximum tolerated dose in mice but not in rats.
Mutagenicity studies showed no drug-related effects at the gene or chromosome level.
Hydrochlorothiazide
Non-melanoma skin cancer
Available epidemiological data indicate a cumulative dose-dependent association between hydrochlorothiazide use and the development of non-melanoma skin cancer. In a study involving 1,430,833 and 172,462 individuals, respectively, 71,533 cases of basal cell carcinoma and 8,629 cases of squamous cell carcinoma were recorded. High cumulative doses of hydrochlorothiazide (≥ 50,000 mg) were associated with an adjusted risk ratio of 1.29 (95% CI: 1.23–1.35) for basal cell carcinoma and 3.98 (95% CI: 3.68–4.31) for squamous cell carcinoma. A clear cumulative dose effect was observed for both basal cell and squamous cell carcinoma. Another study suggested a possible link between lip cancer (squamous cell carcinoma) and hydrochlorothiazide exposure: 633 cases of lip cancer in a study involving 63,067 individuals using a risk-set sampling strategy. A cumulative dose effect was demonstrated with an adjusted risk ratio of 2.1 (95% CI: 1.7–2.6), increasing to 3.9 (3.0–4.9) with high-dose use (~25,000 mg) and to 7.7 (5.7–10.5) with the highest cumulative dose (~100,000 mg) (see section "Special precautions for use").
Clinical characteristics.
Indications.
Treatment of essential hypertension.
Additional therapy
Olmesartad Trio is indicated for adult patients whose blood pressure is not adequately controlled with a combination of olmesartan medoxomil and amlodipine as a two-component medicinal product.
Substitution therapy
Olmesartad Trio is indicated as an alternative therapy for adult patients whose blood pressure is well controlled with a combination of olmesartan medoxomil, amlodipine, and hydrochlorothiazide as two-component medicinal products (olmesartan medoxomil and amlodipine or olmesartan medoxomil and hydrochlorothiazide) and single-component medicinal products (hydrochlorothiazide or amlodipine).
Contraindications.
- Hypersensitivity to the active substances, to dihydropyridine derivatives, or to sulfonamide derivatives (since hydrochlorothiazide is a sulfonamide agent), or to any of the excipients of the medicinal product.
- Severe renal impairment (see sections "Pharmacological properties" and "Special precautions").
- Persistent hypokalemia, hypercalcemia, hyponatremia, and clinically evident hyperuricemia.
- Severe hepatic impairment, cholestasis, and obstructive biliary disorders (see section "Pharmacological properties").
- Pregnancy or planned pregnancy. If pregnancy is confirmed during treatment with this medicinal product, its use must be discontinued immediately and replaced with another medicinal product approved for use during pregnancy (see sections "Special precautions" and "Use during pregnancy or lactation").
Concomitant use of Olmesartad Trio and drugs containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73 m²) (see sections "Pharmacological properties" and "Interaction with other medicinal products and other forms of interaction").
Due to the presence of amlodipine as an active ingredient, the medicinal product Olmesartad Trio is contraindicated in patients with:
- Shock (including cardiogenic shock);
- Severe arterial hypotension;
- Impaired left ventricular outflow (e.g., severe aortic stenosis);
- Hemodynamically unstable heart failure following acute myocardial infarction.
Interaction with other medicinal products and other forms of interaction.
Concomitant use not recommended
Lithium preparations
Concomitant use of lithium with ACE inhibitors and sometimes with angiotensin II receptor blockers has been associated with reversible increases in serum lithium concentration and lithium toxicity. In addition, thiazides reduce renal clearance of lithium, thereby increasing the risk of lithium toxicity when used with hydrochlorothiazide. Therefore, concomitant use of Olmesartad Trio with lithium is not recommended. In patients who require concomitant use of these drugs, serum lithium concentrations should be closely monitored during treatment.
Concomitant use with the following medicinal products requires caution
Baclofen
May enhance the antihypertensive effect.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
NSAIDs (e.g., acetylsalicylic acid (> 3 g/day), COX-2 inhibitors, and nonselective NSAIDs) may attenuate the antihypertensive effects of thiazide diuretics and angiotensin II receptor antagonists. In some patients with renal impairment (e.g., dehydrated patients or elderly patients with renal impairment), concomitant use of angiotensin II receptor antagonists and cyclooxygenase inhibitors 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, especially in elderly patients. Patients should be adequately hydrated. Renal function should be monitored after initiation of concomitant therapy and periodically during treatment.
Considerations for concomitant use
Amifostine
May enhance antihypertensive effect.
Other antihypertensive agents
The antihypertensive effect of Olmesartad Trio may be enhanced when used concomitantly with other drugs that lower blood pressure.
Ethanol, barbiturates, narcotic analgesics, and antidepressants
May increase the manifestations of orthostatic hypotension.
Potentially possible interactions with olmesartan medoxomil
Concomitant use not recommended
ACE inhibitors, angiotensin II receptor blockers, or aliskiren
Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse outcomes such as arterial hypotension, hyperkalemia, and reduced renal function (including acute renal failure), compared to use of a single RAAS-acting agent.
Medicinal products affecting serum potassium concentration
Concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medicinal products that may increase serum potassium levels (e.g., heparin, ACE inhibitors) may lead to increased potassium levels in blood (see section "Special precautions"). Monitoring of serum potassium levels is recommended when medicinal products affecting potassium levels are used concomitantly with Olmesartad Trio.
Additional information
Bile acid-binding medicinal product Colesevelam
Concomitant use of the bile acid-binding agent colesevelam hydrochloride reduces systemic exposure and Cmax of olmesartan in plasma and decreases its elimination half-life. Administration of olmesartan medoxomil at least 4 hours before colesevelam hydrochloride reduces the effect of this drug interaction. Administration of olmesartan medoxomil at least 4 hours before colesevelam hydrochloride should be considered (see section "Pharmacological properties").
A moderate reduction in olmesartan bioavailability has been observed after administration of antacids (aluminum hydroxide, magnesium hydroxide).
Olmesartan medoxomil has no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or on the pharmacokinetics of digoxin.
Concomitant administration of olmesartan medoxomil and pravastatin has no clinically significant effect on the pharmacokinetics of either component in healthy volunteers.
In vitro studies have shown no clinically significant inhibition by olmesartan of the activity of human cytochrome P450 isoenzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1, and 3A4; olmesartan either had minimal inducing effects or no effect at all on animal cytochrome P450 isoenzymes. Therefore, clinically significant interactions between olmesartan and medicinal products metabolized by the aforementioned cytochrome P450 isoenzymes are not expected.
Potentially possible interactions with amlodipine
Concomitant use of medicinal products requiring caution
Effect of other medicinal products on amlodipine
CYP3A4 inhibitors
Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem) may lead to a significant increase in amlodipine exposure. The clinical manifestation of these pharmacokinetic variations may be more pronounced in elderly patients. Therefore, clinical monitoring and dose adjustment may be required.
CYP3A4 inducers
Concomitant use with CYP3A4 inducers may reduce amlodipine plasma concentrations. Therefore, careful monitoring and dose adjustment are necessary during and after concomitant use of amlodipine with CYP3A4 inducers (rifampicin, St. John's wort).
Consumption of amlodipine with grapefruit or grapefruit juice is not recommended, as it may increase the bioavailability of the drug in some patients, resulting in enhanced hypotensive effects.
Dantrolene (infusion)
In laboratory animal studies, ventricular fibrillation and cardiovascular failure with fatal outcome were observed after verapamil administration and intravenous dantrolene. Due to the risk of hyperkalemia in patients predisposed to malignant hyperthermia or during treatment of malignant hyperthermia, concomitant use of calcium channel blockers such as amlodipine should be avoided.
Effect of amlodipine on other medicinal products
The antihypertensive effect of amlodipine is additive to the antihypertensive effect of other drugs that lower blood pressure.
In clinical drug interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.
Simvastatin
Concomitant administration of multiple doses of amlodipine (10 mg) and simvastatin (80 mg) results in a 77% increase in simvastatin exposure compared to simvastatin alone. The simvastatin dose for patients taking amlodipine should not exceed 20 mg daily.
Tacrolimus
There is a risk of increased blood levels of tacrolimus when used concomitantly with amlodipine. To avoid tacrolimus toxicity, regular monitoring of tacrolimus blood levels and dose adjustment if necessary are required when used concomitantly with amlodipine.
mTOR inhibitors (mammalian target of rapamycin)
mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are substrates of CYP3A. Amlodipine is a weak inhibitor of CYP3A. Concomitant use of mTOR inhibitors with amlodipine may increase their effects.
Cyclosporine
In a prospective study in kidney transplant patients, amlodipine increased cyclosporine levels by an average of 40%. Concomitant use of Olmesartad Trio and cyclosporine increases systemic exposure to the latter. Monitoring of cyclosporine levels and dose adjustment if necessary are required during such treatment.
Potentially possible interactions with hydrochlorothiazide
Concomitant use not recommended
Medicinal products affecting serum potassium concentration
The hypokalemic effect of hydrochlorothiazide may be enhanced when used concomitantly with other medicinal products causing potassium loss and hypokalemia (e.g., potassium-wasting diuretics, laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, sodium penicillin G, and salicylate derivatives). Therefore, concomitant use of hydrochlorothiazide with these drugs is not recommended.
Concomitant use requiring special attention
Calcium salts
By slowing calcium excretion, thiazide diuretics may increase serum calcium concentration. If calcium supplements are necessary, serum calcium levels should be monitored and the calcium dose adjusted accordingly.
Cholestyramine and colestipol resins
The presence of anion-exchange resins impairs the absorption of hydrochlorothiazide from the gastrointestinal tract.
Cardiac glycosides
Use of cardiac glycosides increases the risk of arrhythmias due to hypokalemia and hypomagnesemia caused by thiazides.
Medicinal products causing changes in serum potassium levels
Hypokalemia is a predisposing factor for the development of ventricular tachycardia of the torsades de pointes type. Periodic monitoring of serum potassium and ECG is recommended when Olmesartad Trio is used concomitantly with medicinal products causing disturbances in serum potassium levels (e.g., glycosides and antiarrhythmics) and medicinal products causing torsades de pointes (including certain antiarrhythmics):
- Class Ia antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide);
- Class III antiarrhythmics (e.g., amiodarone, sotalol, dofetilide, ibutilide);
- Certain antipsychotics (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, zuclopenthixol, sulpiride, sulthiade, amisulpride, tiapride, pimozide, haloperidol, droperidol);
- Other medicinal products (e.g., bepridil, cisapride, difemanil, IV erythromycin, halofantrine, mizolastine, pentamidine, sparfloxacin, terfenadine, IV vinpocetine).
Nondepolarizing skeletal muscle relaxants (e.g., tubocurarine)
Hydrochlorothiazide may potentiate the effect of nondepolarizing skeletal muscle relaxants.
Anticholinergic agents (e.g., atropine and biperiden)
By reducing gastrointestinal motility and gastric emptying rate, anticholinergic agents may increase the bioavailability of thiazide diuretics.
Antidiabetic medicinal products (oral agents and insulin)
Thiazide therapy may affect glucose tolerance. Dose adjustment of antidiabetic agents may be necessary (see section "Special precautions").
Metformin
Metformin should be used with caution due to the risk of lactic acidosis caused by functional renal impairment, which may occasionally occur with hydrochlorothiazide use.
Beta-blockers and diazoxide
The hyperglycemic effect of beta-adrenergic blockers and diazoxide may be enhanced by thiazides.
Pressor amines (e.g., noradrenaline)
The effectiveness of pressor amines may be reduced.
Medicinal products used for gout treatment (probenecid, sulfinpyrazone, and allopurinol)
Since hydrochlorothiazide may occasionally increase serum uric acid concentration, dose adjustment of uricosuric agents for gout treatment may be necessary. In addition, the dose of probenecid or sulfinpyrazone may sometimes need to be increased. When allopurinol is used concomitantly with thiazides, the frequency of allergic reactions to allopurinol may increase.
Amantadine
Thiazides may increase the risk of adverse reactions caused by amantadine.
Cytostatics (e.g., cyclophosphamide, methotrexate)
Thiazides may reduce renal excretion of antineoplastic agents and enhance their myelosuppressive effects.
Salicylates
When salicylates are taken in high doses, hydrochlorothiazide may potentiate their toxic effects on the central nervous system.
Metildopa
Published case reports describe isolated cases of hemolytic anemia following concomitant use of hydrochlorothiazide and methyldopa.
Cyclosporine
Concomitant use of thiazides with cyclosporine may increase the risk of hyperuricemia and complications similar to gout.
Tetracycline
Concomitant use of thiazides with tetracycline increases the risk of tetracycline-induced uremia. This effect likely does not apply to doxycycline.
Special precautions for use.
Patients with hypovolemia or sodium deficiency
In patients with reduced circulating blood volume and/or low sodium levels due to intensive diuretic therapy, low-salt diet, diarrhea, or vomiting, clinically significant arterial hypotension may occur, especially after the first dose of the drug. Before initiating treatment with Olmestad Trio, these conditions should be corrected.
Other conditions associated with RAAS activation
Patients in whom vascular tone and renal function are significantly dependent on the activity of the renin-angiotensin-aldosterone system (RAAS) (e.g., in severe congestive heart failure or renal disease, including renal artery stenosis) may develop acute arterial hypotension, azotemia, oliguria, and in rare cases, acute renal failure when treated with drugs affecting this system.
Renovascular hypertension
Administration of drugs affecting the RAAS to patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney is associated with an increased risk of severe arterial hypotension and renal failure.
Renal impairment and kidney transplantation
When Olmestad Trio is administered to patients with renal impairment, periodic monitoring of serum potassium and creatinine levels is recommended. Olmestad Trio is not recommended for patients with severe renal impairment (creatinine clearance < 30 mL/min) (see sections "Pharmacological properties", "Contraindications", and "Dosage and administration").
Diuretic-induced azotemia may occur in patients with impaired renal function.
If signs of worsening renal function occur, therapy should be reassessed and discontinuation of diuretic therapy should be considered.
There is no experience with the use of Olmestad Trio in patients who have recently undergone kidney transplantation or in patients with end-stage renal disease (creatinine clearance < 12 mL/min).
Dual blockade of the RAAS
Concomitant use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), or aliskiren increases the risk of arterial hypotension, hyperkalemia, and decreased renal function (including acute renal failure). Therefore, dual blockade of the RAAS by concomitant use of ACE inhibitors, ARBs, or aliskiren is not recommended (see sections "Pharmacological properties" and "Interaction with other medicinal products and other forms of interaction").
If dual blockade is considered absolutely necessary, it should be performed only under specialist supervision and with careful monitoring of renal function, electrolyte levels, and blood pressure.
Patients with diabetic nephropathy should not receive concomitant treatment with ACE inhibitors and ARBs.
Hepatic impairment
In patients with hepatic impairment, plasma concentrations of olmesartan medoxomil and amlodipine are increased (see section "Pharmacological properties"). Additionally, minor disturbances in water and electrolyte balance caused by thiazide therapy may precipitate hepatic coma in patients with hepatic impairment or progressive liver disease. Therefore, Olmestad Trio should be used with caution in patients with mild to moderate hepatic impairment. For patients with moderate hepatic impairment, the dose of olmesartan medoxomil should not exceed 20 mg (see section "Dosage and administration").
When treating patients with hepatic impairment, amlodipine therapy should be initiated at the lowest dose, with particular caution both at the beginning of treatment and during dose escalation.
Olmestad Trio is contraindicated in patients with severe hepatic insufficiency, cholestasis, or biliary obstruction (see section "Contraindications").
Aortic and mitral stenosis, hypertrophic obstructive cardiomyopathy
As with other vasodilators, olmesartan medoxomil should be administered with caution in patients with aortic stenosis or mitral stenosis, as well as in patients with obstructive hypertrophic cardiomyopathy.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism generally do not respond to antihypertensive agents that suppress the renin-angiotensin system. Therefore, Olmestad Trio is not recommended for these patients.
Metabolic and endocrine effects
Thiazide diuretics may impair glucose tolerance. Diabetic patients may require adjustment of insulin or oral hypoglycemic agents (see section "Interaction with other medicinal products and other forms of interaction"). Thiazide therapy may unmask latent diabetes mellitus.
Thiazide diuretics may cause adverse reactions such as increased cholesterol and triglyceride levels. In some cases, thiazide use may lead to hyperuricemia or gout.
Electrolyte disturbances
As with any diuretic, serum electrolyte concentrations should be monitored periodically during hydrochlorothiazide therapy. Thiazide diuretics, including hydrochlorothiazide, may cause disturbances in water and electrolyte balance (including hypokalemia, hyponatremia, and hypochloremic alkalosis). Signs of electrolyte and fluid imbalance include dry mouth, thirst, weakness, prolonged fatigue, drowsiness, restlessness, muscle pain or cramps, muscle weakness, arterial hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting (see section "Adverse reactions"). The risk of hypokalemia is highest in patients with liver cirrhosis, sudden increase in diuresis, inadequate oral electrolyte intake, and when corticosteroids or ACTH are used concomitantly (see section "Interaction with other medicinal products and other forms of interaction").
Conversely, due to blockade of angiotensin II receptors (AT1) by olmesartan medoxomil in Olmestad Trio, hyperkalemia may occur, particularly in patients with renal impairment and/or heart failure, as well as in patients with diabetes mellitus. Serum potassium levels should be appropriately monitored in these patients. Olmestad Trio should be used with caution when administered concomitantly with potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, and other drugs that may increase serum potassium levels (e.g., heparin). There are no data indicating that olmesartan medoxomil can prevent or reduce diuretic-induced hyponatremia. Chloride deficiency is usually mild and does not require specific treatment. Thiazides may reduce urinary calcium excretion and cause mild, transient increases in serum calcium concentration in the absence of calcium metabolism disorders. Hypercalcemia may indicate occult hyperparathyroidism. Thiazides should be discontinued before parathyroid function testing. Thiazides increase urinary magnesium excretion, which may lead to hypomagnesemia. Hyponatremia of dilution may occur in patients with edema during hot weather.
Hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH)
SIADH and subsequent hyponatremia have been observed in some patients treated with quinapril and other ACE inhibitors. Regular monitoring of serum sodium levels is recommended in elderly patients and other patients at risk of hyponatremia.
Lithium preparations
As with other medicinal products containing angiotensin II receptor blockers in combination with thiazides, Olmestad Trio is not recommended for concomitant use with lithium preparations (see section "Interaction with other medicinal products and other forms of interaction").
Heart failure
Due to RAAS inhibition, changes in renal function may occur in susceptible patients.
In patients with severe heart failure, in whom renal function may depend on RAAS activity, treatment with ACE inhibitors and angiotensin receptor antagonists may be associated with oliguria and/or progressive azotemia, and rarely, acute renal failure with potentially fatal outcomes.
Treatment of patients with heart failure requires special attention. In a long-term placebo-controlled study of amlodipine in patients with severe heart failure (NYHA III and IV), the number of reports of pulmonary edema was higher in the amlodipine group compared to placebo (see section "Pharmacological properties"). Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as these drugs may increase the risk of future cardiovascular complications and mortality.
Sprue-like enteropathy
In very rare cases, severe chronic diarrhea with significant weight loss has been reported, developing several months or years after initiation of treatment in patients taking olmesartan; the cause is likely a localized delayed hypersensitivity reaction. Intestinal biopsy findings in these patients often show villous atrophy. If these symptoms occur during olmesartan treatment and other possible causes are excluded, olmesartan therapy should be discontinued immediately and not resumed in the future. If diarrhea does not resolve within one week after discontinuation, patients should consult a specialist (e.g., a gastroenterologist).
Choroidal effusion, acute myopia, and secondary angle-closure glaucoma
Medicinal products containing sulfonamide or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours to weeks after starting treatment. Untreated acute angle-closure glaucoma may lead to permanent vision loss. The drug should be discontinued as soon as possible. If intraocular pressure cannot be controlled, immediate therapeutic or surgical intervention may be necessary. A history of allergy to sulfonamides or penicillin may be a risk factor for angle-closure glaucoma (see section "Adverse reactions").
Pregnancy
Angiotensin II receptor antagonists are contraindicated during pregnancy. If angiotensin II receptor antagonist therapy must be continued in a woman planning pregnancy, alternative antihypertensive agents with a well-established safety profile during pregnancy should be used. If pregnancy is confirmed during treatment with angiotensin II receptor antagonists, treatment should be discontinued immediately and, if necessary, replaced with another medicinal product (see sections "Contraindications" and "Use during pregnancy or lactation").
Children
Olmestad Trio is not indicated for use in children and adolescents (under 18 years of age).
Elderly patients
Dose escalation in elderly patients should be performed with caution (see section "Pharmacological properties").
Photosensitivity
Cases of photosensitivity have been reported during treatment with thiazide diuretics (see section "Adverse reactions"). If such a reaction occurs during treatment with Olmestad Trio, the drug should be discontinued. When thiazide diuretics are used again, exposure to direct sunlight and artificial UV radiation should be avoided.
Non-melanoma skin cancer
Results from two Danish pharmacoepidemiological studies showed an increased risk of non-melanoma skin cancer and lip cancer (basal cell carcinoma, squamous cell carcinoma) associated with cumulative hydrochlorothiazide dose. Photosensitization caused by hydrochlorothiazide may contribute to the development of non-melanoma skin cancer.
Patients taking hydrochlorothiazide should be informed about the risk of non-melanoma skin cancer or lip cancer and advised to regularly check their skin for new lesions or suspicious skin changes. Patients should be advised to limit exposure to sunlight and ultraviolet radiation and to use appropriate protection when exposed to sunlight or UV radiation to minimize skin cancer risk. Suspicious skin lesions should be evaluated, possibly with histological examination of biopsy material. Additionally, hydrochlorothiazide-containing products should be prescribed with caution in patients with a history of non-melanoma skin cancer (see section "Adverse reactions").
Acute respiratory toxicity
Very rare, severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after hydrochlorothiazide administration. Pulmonary edema usually develops within minutes or hours after hydrochlorothiazide intake. Initial symptoms include dyspnea, fever, pulmonary deterioration, and hypotension. If ARDS is suspected, Olmestad Trio should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be prescribed to patients who previously experienced ARDS after hydrochlorothiazide intake.
Other precautions
Excessive reduction in blood pressure in patients with generalized atherosclerosis, ischemic heart disease, or cerebral ischemia may lead to myocardial infarction or stroke.
The risk of allergic reactions to hydrochlorothiazide is higher in patients with a history of allergy or bronchial asthma, although such reactions may also occur in patients without such history.
According to scientific literature, thiazide diuretics may cause exacerbation or activation of systemic lupus erythematosus.
As with other angiotensin II antagonists, the antihypertensive effect of Olmestad Trio may be somewhat lower in patients of black race compared to others, although this effect was not observed in three clinical trials involving 30% black patients (see section "Pharmacological properties").
This medicinal product contains less than 1 mmol of sodium (23 mg) per film-coated tablet, i.e., it is considered sodium-free.
The medicinal product contains lactose and therefore should not be administered to patients with hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.
Use during pregnancy or breastfeeding.
Pregnancy
Olmestad Trio should not be used by pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this medicinal product, its use should be discontinued immediately and replaced with another medicinal product approved for use during pregnancy (see sections "Contraindications" and "Special precautions for use").
Olmesartan medoxomil
The use of angiotensin II receptor antagonists is not recommended during the first trimester of pregnancy. Angiotensin II receptor antagonists are contraindicated during the second and third trimesters of pregnancy.
Epidemiological data on teratogenic risk associated with ACE inhibitor exposure during the first trimester of pregnancy are inconclusive, although a small increased risk cannot be excluded. Although there is no epidemiological information on the risk of angiotensin II receptor antagonists, similar risks cannot be ruled out. If angiotensin receptor antagonist therapy must be continued in patients planning pregnancy, they should be switched to alternative antihypertensive agents with a well-established safety profile during pregnancy. Once pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be discontinued immediately, and alternative therapy initiated if necessary.
During the second and third trimesters of pregnancy, angiotensin II receptor antagonists have toxic effects on the fetus (impaired renal function, oligohydramnios, delayed skull ossification) and the newborn (renal failure, arterial hypotension, hyperkalemia).
If exposure to angiotensin II receptor antagonists occurs from the second trimester of pregnancy, ultrasound monitoring of fetal renal function and skull development is recommended.
Newborns whose mothers received angiotensin II receptor antagonists should be carefully monitored for hypotension (see sections "Contraindications" and "Special precautions for use").
Hydrochlorothiazide
Experience with hydrochlorothiazide use during pregnancy, especially in the first trimester, is limited. Animal experimental data are insufficient. Hydrochlorothiazide crosses the placental barrier. Due to its mechanism of action, hydrochlorothiazide use during the second and third trimesters of pregnancy may impair fetoplacental circulation and adversely affect the fetus and newborn, causing jaundice, electrolyte disturbances, and thrombocytopenia.
Hydrochlorothiazide is not indicated for the treatment of edema in pregnancy, pregnancy-induced hypertension, or preeclampsia, as it may reduce plasma volume and cause placental hypoperfusion without effectively treating the condition.
Hydrochlorothiazide is also not recommended for the treatment of essential hypertension in pregnancy, except in rare cases where other agents cannot be used.
Amlodipine
Data from a limited number of pregnant women do not indicate that amlodipine or other calcium channel antagonists have harmful effects on fetal health. However, there is a risk of prolonged labor.
Lactation
Due to lack of information on the use of Olmestad Trio during lactation, Olmestad Trio is not recommended for administration to breastfeeding women. Alternative treatments with a better-established safety profile during breastfeeding are recommended, especially when breastfeeding newborns or preterm infants.
Olmesartan passes into the milk of lactating rats. However, it is unknown whether olmesartan passes into human breast milk. It is unknown whether amlodipine passes into breast milk.
Amlodipine passes into human breast milk. The fraction of maternal dose received by the infant is estimated at 3–7% (interquartile range), with a maximum of 15%. The effect of amlodipine on infants is unknown.
Other calcium channel blockers of the dihydropyridine type are secreted into breast milk. Hydrochlorothiazide passes into breast milk in small amounts. High-dose thiazide therapy causing strong diuresis may interfere with breast milk production. The use of Olmestad Trio during breastfeeding is not recommended. If Olmestad Trio is used during breastfeeding, the dose should be kept as low as possible.
Fertility
Cases of reversible biochemical changes in the sperm head have been reported in some patients taking calcium channel blockers. Clinical data on the potential effect of amlodipine on fertility are insufficient. Adverse effects on male fertility were observed in rat studies (see section "Pharmacological properties").
Ability to influence reaction speed when driving or operating machinery
No studies have been conducted on the effect on reaction speed when driving or operating machinery. However, it should be noted that patients undergoing antihypertensive therapy may occasionally experience dizziness, headache, nausea, or fatigue, which may impair their reaction ability. Caution is recommended, especially at the beginning of treatment.
Method of Administration and Dosage
Adults
Olmesartad Trio tablets should be taken once daily, independently of food intake.
The tablet should be taken with sufficient fluid (e.g., a glass of water). The tablet must not be chewed. The medication should be taken every day at the same time.
Additional Therapy
Olmesartad Trio 20 mg/5 mg/12.5 mg may be used in patients whose blood pressure is not adequately controlled with olmesartan medoxomil 20 mg and amlodipine 5 mg as a two-component combination.
Olmesartad Trio 40 mg/10 mg/12.5 mg may be used in patients whose blood pressure is not adequately controlled with olmesartan medoxomil 40 mg and amlodipine 10 mg as a two-component combination.
Prior to switching to the three-component combination, gradual titration of individual component doses is recommended. If clinically appropriate, direct substitution of the two-component combination with the three-component combination may be considered.
Substitution Therapy
Patients currently receiving stable doses of olmesartan medoxomil, amlodipine, and hydrochlorothiazide as a two-component medicinal product (olmesartan medoxomil and amlodipine or olmesartan medoxomil and hydrochlorothiazide) and a single-component medicinal product (hydrochlorothiazide or amlodipine) may be switched to Olmesartad Trio containing equivalent doses of the components.
The maximum daily dose of Olmesartad Trio is 40 mg/10 mg/25 mg.
Elderly Patients (aged 65 years and older)
Elderly patients should be treated with caution, with more frequent monitoring of blood pressure, especially when receiving the maximum dose of Olmesartad Trio 40 mg/10 mg/12.5 mg once daily.
Dose escalation should be performed cautiously in elderly patients (see sections "Pharmacological Properties" and "Special Warnings and Precautions for Use").
Experience with Olmesartad Trio in patients aged 75 years and older is very limited. Extreme caution is required, including more frequent monitoring of blood pressure.
Renal Impairment
The maximum recommended dose for patients with mild to moderate renal impairment (creatinine clearance 30–60 mL/min) is 20 mg/5 mg/12.5 mg once daily, due to limited experience with 40 mg of olmesartan medoxomil in this patient group.
Patients with moderate renal impairment should be monitored for serum potassium and creatinine concentrations.
Olmesartad Trio is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see sections "Pharmacological Properties", "Contraindications", and "Special Warnings and Precautions for Use").
Hepatic Impairment
Olmesartad Trio should be used with caution in patients with mild hepatic impairment (see sections "Pharmacological Properties" and "Special Warnings and Precautions for Use").
For patients with moderate hepatic impairment, the maximum dose should not exceed 20 mg/5 mg/12.5 mg once daily. Careful monitoring of blood pressure and renal function is recommended in patients with hepatic impairment.
As with all calcium channel antagonists, the elimination half-life of amlodipine is prolonged in patients with hepatic dysfunction; dosage recommendations have not been established. Therefore, Olmesartad Trio should be administered with caution in such patients. The pharmacokinetics of amlodipine have not been studied in patients with severe hepatic impairment. Amlodipine therapy in patients with severe hepatic impairment should be initiated at the lowest dose with gradual dose escalation.
Olmesartad Trio is contraindicated in patients with severe hepatic impairment, cholestasis, or biliary obstruction (see section "Contraindications").
Children
Olmesartad Trio is not recommended for use in children and adolescents (under 18 years of age) due to insufficient data on safety and efficacy.
Overdose
Symptoms
The maximum recommended daily dose of Olmesartad Trio is 40 mg/10 mg/25 mg once daily. There is no clinical experience with overdose of Olmesartad Trio in humans. The most likely effect of overdose is arterial hypotension.
The most likely effect of olmesartan medoxomil overdose is arterial hypotension and tachycardia; bradycardia may occur if parasympathetic (vagal) stimulation takes place.
Overdose of amlodipine may lead to excessive peripheral vasodilation resulting in marked hypotension and possibly reflex tachycardia. Severe and potentially prolonged systemic hypotension, including shock with fatal outcome, has been reported.
Rare cases of non-cardiogenic pulmonary edema have been reported following amlodipine overdose, which may present with delayed onset (24–48 hours after ingestion) and may require mechanical ventilation. Early resuscitation measures (including fluid loading) to maintain perfusion and cardiac output may act as precipitating factors.
Hydrochlorothiazide overdose is associated with electrolyte imbalance (hypokalemia, hypochloremia) and dehydration due to excessive diuresis.
The most common symptoms of overdose include nausea and drowsiness. Hypokalemia may lead to muscle cramps and/or severe cardiac arrhythmias, particularly when concomitant therapy includes digitalis glycosides or certain antiarrhythmic drugs.
Treatment
In case of Olmesartad Trio overdose, treatment is symptomatic and supportive, and depends on the time elapsed since ingestion and the severity of symptoms.
If ingestion was recent, gastric lavage may be considered. In healthy volunteers, administration of activated charcoal immediately or within 2 hours after amlodipine intake significantly reduces amlodipine absorption.
Clinically significant hypotension caused by Olmesartad Trio overdose requires active cardiovascular support: careful monitoring of cardiac and respiratory function, positioning the patient in a supine position with elevated legs, monitoring circulating fluid volume and diuresis. A vasopressor may be beneficial to restore vascular tone and blood pressure, provided there are no contraindications to its use. Intravenous calcium gluconate may be helpful in reversing calcium channel blockade effects.
Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a supine position and administered saline replacement therapy.
Since amlodipine is highly protein-bound, dialysis is unlikely to be beneficial.
The extent of removal of olmesartan and hydrochlorothiazide by hemodialysis has not been established.
Adverse reactions
The safety of Olmestad Trio has been evaluated in clinical trials involving 7,826 patients who received olmesartan medoxomil in combination with amlodipine and hydrochlorothiazide.
Adverse reactions observed during clinical trials and post-marketing safety studies, as well as adverse reactions reported spontaneously, are presented in Table 1 below for Olmestad Trio, and also for its individual components—olmesartan medoxomil, amlodipine, and hydrochlorothiazide—based on the known safety profile of each individual component.
During treatment with Olmestad Trio, the most commonly reported adverse reactions are peripheral edema, headache, and dizziness.
The following classification was used to indicate the frequency of adverse reactions: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), and not known (cannot be estimated from available data).
Table 1
Description of adverse reactions for Olmestad Trio and its individual components
| MedDRA Organ systems |
Adverse reaction |
Frequency |
|||
| Olmesartan |
Olmesartan |
Amlodipine |
Hydrochlorothiazide |
||
| Infections and infestations |
Upper respiratory tract infections |
Common |
|||
| Nasopharyngitis |
Common |
||||
| Urinary tract infections |
Common |
Common |
|||
| Sialadenitis |
Uncommon |
||||
| Neoplasms benign, malignant and unspecified (including cysts and polyps) |
Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) |
Frequency unknown |
|||
| Blood and lymphatic system disorders |
Leukopenia |
Very rare |
Uncommon |
||
| Thrombocytopenia |
Uncommon |
Very rare |
Uncommon |
||
| Bone marrow suppression |
Uncommon |
||||
| Neutropenia/ Agranulocytosis |
Uncommon |
||||
| Hemolytic anemia |
Uncommon |
||||
| Aplastic anemia |
Uncommon |
||||
| Immune system disorders |
Anaphylactic reaction |
Uncommon |
|||
| Drug hypersensitivity |
Very rare |
||||
| Nutritional and metabolism disorders |
Hyperkalemia |
Uncommon |
Uncommon |
||
| Hypokalemia |
Uncommon |
Common |
|||
| Anorexia |
Uncommon |
||||
| Glucosuria |
Common |
||||
| Hypercalcemia |
Common |
||||
| Hyperglycemia |
Very rare |
Common |
|||
| Hypomagnesemia |
Common |
||||
| Hypnatremia |
Common |
||||
| Hypochloremia |
Common |
||||
| Hypertriglyceridemia |
Common |
Very common |
|||
| Hypercholesterolemia |
Very common |
||||
| Hyperuricemia |
Common |
Very common |
|||
| Hypochloremic alkalosis |
Very rare |
||||
| Hyperamylasemia |
Common |
||||
| Endocrine disorders |
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) |
Frequency unknown |
|||
| Psychiatric disorders |
Confusion |
Uncommon |
Common |
||
| Depression |
Uncommon |
Uncommon |
|||
| Apathy |
Uncommon |
||||
| Irritability |
Uncommon |
||||
| Agitation |
Uncommon |
||||
| Mood changes (including anxiety) |
Uncommon |
||||
| Sleep disorders (including insomnia) |
Uncommon |
Uncommon |
|||
| Nervous system disorders |
Dizziness |
Common |
Common |
Common |
Common |
| Headache |
Common |
Common |
Common |
Uncommon |
|
| Postural dizziness |
Uncommon |
||||
| Loss of consciousness |
Uncommon |
||||
| Dysgeusia |
Uncommon |
||||
| Hypertonia |
Very rare |
||||
| Hypoesthesia |
Uncommon |
||||
| Paraesthesia |
Uncommon |
Uncommon |
|||
| Peripheral neuropathy |
Very rare |
||||
| Somnolence |
Common |
||||
| Loss of consciousness |
Uncommon |
||||
| Seizures |
Uncommon |
||||
| Loss of appetite |
Uncommon |
||||
| Tremor |
Uncommon |
||||
| Extrapyramidal disorders |
Frequency unknown |
||||
| Eye disorders |
Visual disturbances (including diplopia, blurred vision) |
Common |
Uncommon |
||
| Decreased lacrimation |
Uncommon |
||||
| Myopia exacerbation |
Uncommon |
||||
| Xanthopsia |
Uncommon |
||||
| Acute myopia, acute angle-closure glaucoma (see section "Special warnings and precautions for use") |
Frequency unknown |
||||
| Choroidal effusion |
Frequency unknown |
||||
| Ear and labyrinth disorders |
Dizziness |
Uncommon |
Uncommon |
Uncommon |
|
| Tinnitus |
Uncommon |
||||
| Cardiac disorders |
Pounding heartbeat |
Common |
Common |
||
| Tachycardia |
Uncommon |
||||
| Myocardial infarction |
Very rare |
||||
| Arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation) |
Uncommon |
Uncommon |
|||
| Angina pectoris |
Uncommon |
Uncommon, including angina exacerbation |
|||
| Vascular disorders |
Arterial hypotension |
Common |
Uncommon |
Uncommon |
|
| Flushing |
Uncommon |
Common |
|||
| Orthostatic hypotension |
Uncommon |
||||
| Vasculitis (including necrotizing) |
Very rare |
Uncommon |
|||
| Thrombosis |
Uncommon |
||||
| Embolism |
Uncommon |
||||
| Respiratory, thoracic and mediastinal disorders |
Cough |
Uncommon |
Common |
Uncommon |
|
| Bronchitis |
Common |
||||
| Dyspnea |
Common |
Uncommon |
|||
| Pharyngitis |
Common |
||||
| Rhinitis |
Common |
Uncommon |
|||
| Acute interstitial pneumonia |
Uncommon |
||||
| Respiratory distress |
Uncommon |
||||
| Lung edema |
Uncommon |
||||
| Acute respiratory distress syndrome (ARDS) |
Very rare |
||||
| Gastrointestinal disorders |
Diarrhea |
Common |
Common |
Common |
|
| Nausea |
Common |
Common |
Common |
Common |
|
| Constipation |
Common |
Common |
|||
| Dry mouth |
Uncommon |
Uncommon |
|||
| Abdominal pain |
Common |
Common |
Common |
||
| Intestinal dysfunction (including constipation and diarrhea) |
Common |
||||
| Flatulence |
Common |
||||
| Dyspepsia |
Common |
Common |
|||
| Gastritis |
Very rare |
||||
| Gastric irritation |
Common |
||||
| Gastroenteritis |
Common |
||||
| Gingival hyperplasia |
Very rare |
||||
| Paralytic ileus |
Very rare |
||||
| Pancreatitis |
Very rare |
Uncommon |
|||
| Vomiting |
Uncommon |
Uncommon |
Common |
||
| Sprue-like enteropathy (see section "Special warnings and precautions for use") |
Very rare |
||||
| Hepatobiliary disorders |
Hepatitis |
Very rare |
|||
| Jaundice (cholestatic jaundice) |
Very rare |
Uncommon |
|||
| Acute cholecystitis |
Uncommon |
||||
| Autoimmune hepatitis* |
Frequency unknown |
||||
| Skin and subcutaneous tissue disorders |
Alopecia |
Uncommon |
|||
| Angioedema |
Uncommon |
Very rare |
|||
| Allergic dermatitis |
Uncommon |
||||
| Multiform erythema |
Very rare |
||||
| Erythema |
Uncommon |
||||
| Reactions resembling systemic lupus erythematosus skin manifestations |
Uncommon |
||||
| Exanthema |
Uncommon |
Uncommon |
|||
| Exfoliative dermatitis |
Very rare |
||||
| Increased sweating |
Uncommon |
||||
| Photosensitivity |
Very rare |
Uncommon |
|||
| Pruritus |
Uncommon |
Uncommon |
Uncommon |
||
| Purpura |
Uncommon |
Uncommon |
|||
| Quincke's edema |
Very rare |
||||
| Rash |
Uncommon |
Uncommon |
Uncommon |
||
| Exacerbation of cutaneous systemic lupus erythematosus |
Uncommon |
||||
| Toxic epidermal necrolysis |
Frequency unknown |
Uncommon |
|||
| Skin color changes |
Uncommon |
||||
| Stevens-Johnson syndrome |
Very rare |
||||
| Urticaria |
Uncommon |
Uncommon |
Uncommon |
||
| Musculoskeletal and connective tissue disorders |
Muscle cramps |
Common |
Uncommon |
Common |
|
| Joint swelling |
Common |
||||
| Muscle weakness |
Uncommon |
Uncommon |
|||
| Leg swelling |
Common |
||||
| Arthralgia |
Uncommon |
||||
| Arthritis |
Common |
||||
| Back pain |
Common |
Uncommon |
|||
| Paralysis |
Uncommon |
||||
| Myalgia |
Uncommon |
Uncommon |
|||
| Bone pain |
Common |
||||
| Renal and urinary disorders |
Frequency of urination |
Common |
|||
| Increased frequency of urination |
Uncommon |
||||
| Acute renal failure |
Uncommon |
||||
| Hematuria |
Common |
||||
| Urinary disorders |
Uncommon |
||||
| Nocturia |
Uncommon |
||||
| Interstitial nephritis |
Uncommon |
||||
| Renal failure |
Uncommon |
Uncommon |
|||
| Reproductive system and breast disorders |
Erectile dysfunction |
Uncommon |
Uncommon |
Uncommon |
|
| Gynecomastia |
Uncommon |
||||
| General disorders |
Asthenia |
Common |
Uncommon |
Common |
|
| Peripheral edema |
Common |
Common |
|||
| Fatigue |
Common |
Common |
Common |
||
| Chest pain |
Common |
Uncommon |
|||
| Fever |
Uncommon |
||||
| Influenza-like symptoms |
Common |
||||
| Somnolence |
Uncommon |
||||
| Anxiety |
Uncommon |
Uncommon |
|||
| Edema |
Very common |
||||
| Pain |
Common |
Uncommon |
|||
| Facial swelling |
Uncommon |
||||
| Investigations |
Increased blood creatinine levels |
Common |
Uncommon |
Common |
|
| Increased blood urea levels |
Common |
Common |
Common |
||
| Increased blood uric acid levels |
Common |
||||
| Decreased blood potassium levels |
Uncommon |
||||
| Increased blood gamma-glutamyltransferase levels |
Uncommon |
||||
| Increased alanine aminotransferase activity |
Uncommon |
||||
| Increased aspartate aminotransferase activity |
Uncommon |
||||
| Elevated liver enzymes |
Common |
Very rare (mostly in the context of cholestasis) |
|||
| Elevated blood creatine phosphokinase levels |
Common |
||||
| Decreased body weight |
Uncommon |
||||
| Increased body weight |
Uncommon |
||||
*During the post-marketing period, cases of autoimmune hepatitis with a latent period ranging from several months to years have been reported, which were reversible upon discontinuation of olmesartan.
Several cases of rhabdomyolysis, temporally associated with the use of angiotensin II receptor blockers, have been reported. Extrapyramidal syndrome has been reported in patients receiving amlodipine.
Non-melanoma skin cancer
Pharmacoepidemiological studies have shown an increased risk of non-melanoma skin cancer associated with cumulative dose of hydrochlorothiazide (see sections "Pharmacological properties" and "Special precautions").
Adverse reactions reported in clinical trials or known from post-marketing experience with the fixed combination of olmesartan medoxomil and amlodipine, but not reported with Olmestad Trio, monotherapy with olmesartan medoxomil or monotherapy with amlodipine, or reported more frequently with the dual combination, are presented in Table 2.
Description of selected adverse reactions
Cases of choroidal effusion with visual field defects have been reported following the use of thiazide and thiazide-like diuretics.
Table 2
Combination of olmesartan medoxomil and amlodipine
| Organs and systems |
Frequency |
Adverse reactions |
| Immune system disorders |
rare |
hypersensitivity to the drug |
| Gastrointestinal disorders |
uncommon |
upper abdominal pain |
| Reproductive system and breast disorders |
uncommon |
decreased libido |
| General disorders |
common |
soft tissue swelling |
| uncommon |
sleepiness |
|
| Musculoskeletal and connective tissue disorders |
uncommon |
limb pain |
The following adverse reactions relate to clinical studies and post-marketing use of fixed-dose combinations of olmesartan medoxomil and hydrochlorothiazide and do not pertain to the use of Olmestad Trio, monotherapy with olmesartan medoxomil or hydrochlorothiazide, or indicate a higher frequency of adverse reactions with the two-component combination (see Table 3).
Table 3
Combination of olmesartan medoxomil and hydrochlorothiazide
| Organs and systems |
Frequency |
Adverse reactions |
| Neurological disorders |
rare |
impaired consciousness (loss of consciousness) |
| Skin and subcutaneous tissue disorders |
uncommon |
eczema |
| Musculoskeletal and connective tissue disorders |
uncommon |
limb pain |
| Laboratory and instrumental data |
rare |
slight decrease in mean hemoglobin and hematocrit values |
Reporting of Adverse Reactions
Reporting adverse reactions following registration of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.
Shelf life. 3 years.
Storage conditions.
The medicinal product does not require special storage conditions. Keep out of reach of children. Store in the original packaging to protect from moisture.
Packaging.
10 tablets in a blister; 3 blisters in a cardboard box.
Prescription status. Prescription only.
Manufacturer.
STADA Arzneimittel AG (batch release).
Manufacturer's address and location of operations.
Stadastrasse 2-18, 61118 Bad Vilbel, Germany.