Sevikar hct
Ukraine
Table of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT SEVIKAR HCT
Composition:
Active substances: olmesartan medoxomil; amlodipine besylate; hydrochlorothiazide;
One film-coated tablet contains olmesartan medoxomil 20 mg, amlodipine besylate 6.944 mg, equivalent to amlodipine 5 mg, and hydrochlorothiazide 12.5 mg
or olmesartan medoxomil 40 mg, amlodipine besylate 13.888 mg, equivalent to amlodipine 10 mg, and hydrochlorothiazide 12.5 mg;
Excipients: maize pregelatinized starch, silicified microcrystalline cellulose (containing 98% microcrystalline cellulose (Ph. Eur.) and 2% colloidal anhydrous silicon dioxide (Ph. Eur.)), sodium croscarmellose, magnesium stearate (of plant origin);
film coating contains: Opadry II 85F24118 or Opadry II 85F32331, or Opadry II 85F25437 (polyvinyl alcohol, titanium dioxide (E 171), polyethylene glycol, talc, iron oxide yellow (E 172), iron oxide red (E 172), iron oxide black (E 172)).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
for the 20 mg/5 mg/12.5 mg dosage: light orange, round, film-coated tablets, 8 mm in size, with "C51" embossed on one side;
for the 40 mg/10 mg/12.5 mg dosage: grey-red, round, film-coated tablets, 9.5 mm in size, with "C55" embossed on one side.
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.
Sevikar HCT is a combination medicinal product containing olmesartan medoxomil – an angiotensin II receptor antagonist, amlodipine besylate – a calcium channel blocker, and hydrochlorothiazide – a thiazide diuretic. The combination of these components provides an additional antihypertensive effect, reducing blood pressure to a greater extent than each active ingredient alone.
Olmesartan medoxomil
Olmesartan medoxomil is an orally active, selective antagonist of angiotensin II receptors (type AT1). Angiotensin II is the main vasoactive hormone of the renin-angiotensin-aldosterone system and plays an important 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 decrease in plasma aldosterone concentration.
In patients with arterial hypertension, olmesartan medoxomil provides sustained reduction in blood pressure, the degree of which depends on the dose. No signs of arterial hypotension after the first dose (first-dose effect), tachyphylaxis during prolonged use, or rebound hypertension after abrupt discontinuation of the drug have been observed.
When administered once daily to patients with arterial hypertension, olmesartan medoxomil produces effective and smooth blood pressure reduction over the 24-hour dosing interval. When administered once daily, its antihypertensive effect was approximately the same as when administered twice daily at the same total daily dose.
With continuous treatment, maximum blood pressure reduction is achieved within 8 weeks of starting therapy; however, a significant antihypertensive effect is observed as early as 2 weeks of treatment.
The effect of olmesartan medoxomil on mortality and the incidence of complications has not been established.
The randomized trial of olmesartan use for prevention of diabetic microalbuminuria (ROADMAP), involving 4447 patients with type 2 diabetes with 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, except for ACE inhibitors or 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 (BP) values, 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.
In the ORIENT trial (The Olmesartan Reducing Incidence of End-stage Renal Disease in Diabetic Nephropathy Trial), the effect of olmesartan on renal and cardiovascular outcomes was studied 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 in the olmesartan group (41.1%) and in 129 patients receiving placebo (45.4%) (HR 0.97 (95% CI 0.75–1.24); p = 0.791). The secondary composite cardiovascular endpoint was reached in 40 patients receiving olmesartan (14.2%) and in 53 patients receiving placebo (18.7%). This composite cardiovascular endpoint included cardiovascular death in 10 (3.5%) patients receiving olmesartan and in 3 (1.1%) patients receiving placebo; overall mortality was 19 (6.7%) and 20 (7.0%), non-fatal stroke – 8 (2.8%) and 11 (3.9%), non-fatal myocardial infarction – 3 (1.1%) and 7 (2.5%), respectively.
Amlodipine
Amlodipine, included in the formulation, is a calcium channel blocker that inhibits transmembrane calcium ion transport through voltage-dependent L-type channels in the heart and smooth muscle. Experimental data indicate that amlodipine interacts with both dihydropyridine binding sites and other sites. Amlodipine has relative vasoselectivity and affects vascular smooth muscle cells more than 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 blood pressure.
In arterial hypertension, amlodipine causes a prolonged, dose-dependent reduction in blood pressure. No arterial hypotension after the first dose, signs of tachyphylaxis during prolonged treatment, or recurrence of arterial hypertension after discontinuation of treatment have been observed.
After administration in 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, amlodipine in therapeutic doses reduces renal vascular resistance and increases glomerular filtration rate and effective renal plasma flow, without altering filtration fraction or causing proteinuria.
In hemodynamic studies in patients with heart failure, as well as in clinical exercise testing studies in heart failure (NYHA classes II–IV), amlodipine did not worsen participants' condition as assessed by exercise tolerance, left ventricular ejection fraction, and 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 was shown not to increase the risk of fatal outcomes or the combined risk of mortality and morbidity in patients with heart failure.
In a subsequent long-term placebo-controlled trial (PRAISE-2) of amlodipine in patients with heart failure (NYHA III and IV) without clinical symptoms or objective evidence of ischemic heart disease, treated with ACE inhibitors, digitalis preparations, and diuretics at constant doses, amlodipine did not affect overall mortality or cardiovascular mortality specifically. In this patient group, an increase in cases of pulmonary edema associated with amlodipine intake was observed, but no statistically significant differences in the frequency of worsening heart failure compared to the placebo group were observed.
To compare modern therapeutic approaches, a double-blind randomized trial on the impact on morbidity and mortality named "Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial" (ALLHAT) was conducted: amlodipine at a dose of 2.5–10 mg/day (calcium channel blocker) or lisinopril at a dose of 10–40 mg/day (ACE inhibitor) as first-line therapy, and the thiazide diuretic chlorthalidone at a dose of 12.5–25 mg/day in mild to moderate hypertension.
A total of 33,357 patients with arterial hypertension aged 55 years and older were randomized and followed for a mean of 4.9 years. Patients had at least one additional risk factor for coronary heart disease, such as a previous myocardial infarction or stroke (more than 6 months prior to enrollment) or presence of other atherosclerotic cardiovascular diseases (51.5% total), type 2 diabetes (36.1%), LDL-cholesterol level < 35 mg/dL (11.6%), left ventricular hypertrophy diagnosed by electrocardiography or echocardiography (20.9%), current smoking (21.9%).
The primary endpoint of the study was a combination of fatal coronary heart disease or non-fatal myocardial infarction. No significant differences regarding the primary endpoint were observed between amlodipine and chlorthalidone therapy: OR 0.98, 95% CI (0.90–1.07), p = 0.65. Regarding secondary endpoints, the incidence of heart failure (a component of the combined cardiovascular disease 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 excretion of sodium and chloride (approximately at similar levels). Acting as a diuretic, hydrochlorothiazide reduces plasma volume, resulting in increased plasma renin activity and aldosterone secretion, increased urinary excretion of potassium and bicarbonate, and decreased serum concentrations. Since the relationship between renin levels and aldosterone secretion is mediated by angiotensin II, during hydrochlorothiazide use in combination with an angiotensin II receptor blocker, potassium losses in urine due to thiazide diuretics may be reduced. Diuresis after hydrochlorothiazide administration begins approximately 2 hours after intake, maximum effect is reached approximately 4 hours later, 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 death from them.
Clinical efficacy and safety
In a 12-week double-blind randomized parallel-group study involving 2492 patients (67% were Caucasian) it was shown that treatment with Sevikar HCT 40 mg/10 mg/25 mg leads to a greater reduction 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 Sevikar HCT 40 mg/10 mg/25 mg compared to the corresponding 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 levels < 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 therapy groups compared to 64.3% in the Sevikar HCT 40 mg/10 mg/25 mg group.
During a second double-blind randomized parallel-group study involving 2690 patients (99.9% were Caucasian), treatment with Sevikar HCT (20 mg/5 mg/12.5 mg, 40 mg/5 mg/12.5 mg, 40 mg/5 mg/25 mg, 40 mg/10 mg/12.5 mg, 40 mg/10 mg/25 mg) showed significant reduction 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 Sevikar HCT compared to the corresponding 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 levels < 140/90 mm Hg for non-diabetic patients and < 130/80 mm Hg for diabetic patients at week 10 was 42.7–49.6% in the dual combination therapy groups compared to 52.4–58.8% in the Sevikar HCT group.
In a randomized double-blind study involving 808 patients (99.9% were Caucasian) whose blood pressure was inadequately controlled after 8 weeks of dual therapy with olmesartan medoxomil 40 mg and amlodipine 10 mg, significant additional reduction in seated blood pressure (-1.8/-1.0 mm Hg) was demonstrated with Sevikar HCT 40 mg/10 mg/12.5 mg and statistically significant reduction in seated blood pressure (-3.6/-2.8 mm Hg) with Sevikar HCT 40 mg/10 mg/25 mg compared to dual combination therapy with olmesartan medoxomil 40 mg and amlodipine 10 mg.
Treatment with Sevikar HCT 40/10/25 using the triple combination of active ingredients led to a statistically significant increase in the percentage of patients achieving target blood pressure compared to dual combination therapy with olmesartan medoxomil (40 mg) and amlodipine (10 mg) (41.3% vs. 24.2%); conversely, use of the triple combination contained in Sevikar HCT 40/10/12.5 led to a numerically higher percentage of patients achieving target blood pressure compared to dual combination therapy with olmesartan medoxomil (40 mg) and amlodipine (10 mg) in patients who did not achieve adequate blood pressure control (29.5% vs. 24.2%).
The antihypertensive effect of Sevikar HCT was independent of patient age and sex, as well as presence or absence of diabetes.
Other information
The combined use of ACE inhibitors and angiotensin II receptor blockers was studied 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. These trials did not demonstrate a significant beneficial effect on renal and/or cardiovascular outcomes or mortality, while compared to monotherapy, there was an increased risk of hyperkalemia, acute kidney injury, and/or hypotension. Due to the similarity of pharmacodynamic properties, these results are also applicable to other ACE inhibitors and angiotensin II receptor blockers. Thus, the combined use of ACE inhibitors and angiotensin II receptor blockers is contraindicated in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a trial conducted to determine the positive effect of adding aliskiren to standard therapy with ACE inhibitors or angiotensin II receptor blockers in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. This trial was terminated prematurely due to an increased risk of adverse outcomes. Cardiovascular death and stroke were more frequent in the aliskiren group than in the placebo group, and reports of adverse events and serious adverse events (hyperkalemia, 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 Sevikar HCT in healthy adult volunteers, maximum plasma concentrations of olmesartan, amlodipine, and hydrochlorothiazide are reached approximately at 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 the same as when administered as a dual fixed combination of olmesartan medoxomil and amlodipine together with a single-component hydrochlorothiazide tablet or as a dual fixed combination of olmesartan medoxomil and hydrochlorothiazide together with a single-component amlodipine tablet at equivalent 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 group are not detected in plasma or excretory products. The mean absolute bioavailability of olmesartan in tablet form is 25.6%.
The mean maximum plasma concentration (Cmax) of olmesartan 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 olmesartan bioavailability; therefore, olmesartan medoxomil can be administered regardless 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 competitive interactions with other drugs that are highly protein-bound is low. This is confirmed by the absence of interaction between olmesartan medoxomil and warfarin. Olmesartan binds minimally 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 usually 1.3 L/hour (coefficient of variation 19%) and is relatively low compared to hepatic blood flow (approximately 90 L/hour). After a single oral dose of 14C-labeled olmesartan medoxomil, 10–16% of radioactivity was excreted in urine (mostly within 24 hours after administration), with the remainder of recovered radioactivity excreted in feces. Based on systemic availability (25.6%), it can be calculated that approximately 40% of olmesartan is excreted by the kidneys and 60% via the hepatobiliary system. All recovered radioactivity was attributed to olmesartan. No other significant metabolites were found. 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 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 drug dose.
Interaction with other medicinal products
The medicinal product colesevelam, a bile acid-binding agent.
Concomitant administration of 40 mg olmesartan medoxomil and 3750 mg colesevelam hydrochloride in healthy volunteers resulted in a 28% reduction in olmesartan Cmax and a 39% reduction in olmesartan AUC. A smaller effect, with reductions in Cmax and AUC of 4% and 15%, respectively, was observed when olmesartan medoxomil was administered 4 hours before colesevelam hydrochloride. The half-life of olmesartan was reduced by 50–52%, regardless of whether the drugs were administered together or olmesartan was administered 4 hours before colesevelam hydrochloride (see section "Interaction with other medicinal products and other forms of interaction").
Amlodipine
Absorption and distribution
After oral administration in therapeutic doses, amlodipine is well absorbed, with peak blood concentrations reached 6–12 hours after intake. Absolute bioavailability is approximately 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 plasma elimination half-life ranges from 35 to 50 hours and remains unchanged with daily single administration. Amlodipine is extensively metabolized to inactive metabolites. Approximately 60% of the administered dose is excreted in urine, of which 10% is unchanged.
Hydrochlorothiazide
Absorption and distribution
After oral administration of olmesartan medoxomil and hydrochlorothiazide in combination, the mean time to reach maximum hydrochlorothiazide concentration is 1.5–2 hours. Hydrochlorothiazide is 68% bound to plasma proteins, 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. 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.
Pharmacokinetics in specific patient populations
Elderly patients (aged 65 years and older)
It has been demonstrated that at steady state, AUC of olmesartan in elderly patients (aged 65–75 years) with arterial hypertension is approximately 35% higher, and in very elderly patients (≥ 75 years) approximately 44% higher, compared to younger patients (see section "Dosage and administration").
This can partly be explained by moderate age-related reduction 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 with caution.
The time to reach maximum plasma concentration of amlodipine is the same in older and younger patients. In elderly patients, there is a tendency toward decreased amlodipine clearance, leading to increased AUC and prolonged half-life. Increased AUC and prolonged half-life in patients with congestive heart failure were consistent with expectations for this age group (see section "Special precautions for use").
Limited data suggest that systemic clearance of hydrochlorothiazide is reduced in healthy elderly patients and in elderly patients with hypertension compared to younger healthy volunteers.
Children
The European Medicines Agency has waived the obligation to submit results of Sevikar HCT studies in all subgroups of pediatric patients with essential hypertension.
Renal impairment
In patients with mild, moderate, and severe renal impairment, steady-state AUC of olmesartan was 62%, 82%, and 179% higher, respectively, compared to healthy volunteers. The 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 in usual doses to such patients. Amlodipine is not removed by dialysis.
The half-life of hydrochlorothiazide is prolonged in patients with renal impairment.
Hepatic impairment
After a single oral dose, AUC values of olmesartan were 6% and 65% higher, respectively, in patients with mild or moderate hepatic impairment 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 dosing, 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 "Dosage and administration", "Special precautions for use").
Clinical data on amlodipine use in patients with hepatic impairment are very limited. In patients with hepatic impairment, decreased amlodipine clearance and prolonged half-life are observed, leading to increased AUC by approximately 40–60% (see sections "Dosage and administration", "Special precautions for use").
Hepatic insufficiency does not significantly affect the pharmacokinetics of hydrochlorothiazide.
Preclinical safety data
Repeat toxicity studies in rats showed that combined administration of olmesartan medoxomil, amlodipine, and hydrochlorothiazide did not enhance any previously recorded or existing toxic effects of individual components, nor did it cause any new toxicity. No toxicological synergistic effects were observed.
No additional studies on mutagenicity, carcinogenicity, or reproductive toxicity were conducted for Sevikar HCT due to the well-understood safety profile of individual active components.
Olmesartan medoxomil
In chronic toxicity studies in rats and dogs, effects of olmesartan medoxomil were similar to those of other AT1 receptor antagonists and ACE inhibitors: increased blood urea nitrogen (BUN) and creatinine levels, decreased heart weight, decreased erythrocyte parameters (erythrocyte count and hemoglobin concentration, hematocrit), histological signs of kidney damage (regenerative damage to renal epithelium, thickening of the basement membrane, tubular dilation). These adverse reactions, 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 in vitro cell cultures. 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 study results indicate that genotoxic effects of olmesartan in clinical use are unlikely.
No carcinogenic effect of olmesartan medoxomil was observed in rats and transgenic mice.
In reproductive toxicity studies in rats, olmesartan medoxomil did not affect fertility and had no teratogenic effect. As with exposure to other angiotensin II receptor antagonists, offspring survival was reduced after exposure to olmesartan medoxomil, and dilatation of renal pelvises was observed in females receiving the drug in late pregnancy and during lactation. No fetotoxic effect was observed in rabbits.
Amlodipine
Reproductive toxicity
Reproductive function studies in rats and mice revealed delayed onset of labor, prolonged labor duration, and reduced offspring survival at doses approximately 50 times higher than the maximum recommended human dose based on body weight (mg/kg).
Fertility impairment
No effect on fertility was 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, in which male rats received amlodipine besylate for 30 days at doses comparable to the human dose based on mg/kg, decreased plasma concentrations of follicle-stimulating hormone and testosterone, decreased sperm density, and reduced numbers of mature spermatids and Sertoli cells were observed.
Carcinogenesis, mutagenesis
Two-year carcinogenicity studies in rats and mice receiving amlodipine in the diet at concentrations calculated to reproduce daily doses of 0.5, 1.25, and 2.5 mg/kg/day did not reveal signs of carcinogenicity. The highest dose (equivalent to the maximum recommended dose of 10 mg based on mg/m² for mice and twice the maximum recommended dose for rats) was close to the maximum tolerated dose for mice but not for rats.
Mutagenicity studies did not reveal any 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, 71,533 cases of basal cell carcinoma and 8,629 cases of squamous cell carcinoma were recorded, respectively. 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 of the skin) 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) at high dose (~25,000 mg) and to 7.7 (5.7–10.5) at the highest cumulative dose (~100,000 mg) (see section "Special precautions for use").
Clinical characteristics.
Indications.
Treatment of essential hypertension.
Additional therapy.
Sevikar HCT is indicated for adult patients whose blood pressure is not adequately controlled with the combination of olmesartan medoxomil and amlodipine as a two-component medicinal product.
Substitution therapy.
Sevikar HCT is indicated as an alternative therapy for adult patients whose blood pressure is well controlled with the 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 compounds (since hydrochlorothiazide is a sulfonamide agent), or to any of the excipients.
- Severe renal impairment (see sections "Special precautions for use", "Pharmacological properties").
- Persistent hypokalemia, hypercalcemia, hyponatremia, and symptomatic hyperuricemia.
- Severe hepatic impairment, cholestasis, and obstructive biliary disorders (see section "Pharmacological properties").
- Pregnancy or planning pregnancy. If pregnancy is confirmed during treatment with this medicinal product, it must be discontinued immediately and replaced with another medicinal product approved for use during pregnancy (see sections "Special precautions for use", "Use during pregnancy or breastfeeding").
- Concomitant use of Sevikar HCT and drugs containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction", "Pharmacological properties").
Due to the presence of amlodipine as an active ingredient, Sevikar HCT is contraindicated in patients with:
- Shock (including cardiogenic shock);
- Severe hypotension;
- Obstruction of blood outflow from the left ventricle (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
Litium preparations
Concomitant use of lithium with angiotensin-converting enzyme (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, thus increasing the risk of lithium toxicity when used with hydrochlorothiazide. Therefore, concomitant use of Sevikar HCT with lithium is not recommended. In patients who require concomitant administration 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 effect of thiazide diuretics and angiotensin II receptor blockers. 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 combination therapy and periodically during treatment.
Should be considered during concomitant use
Amifostine
May enhance the antihypertensive effect.
Other antihypertensive agents
The antihypertensive effect of Sevikar HCT may be enhanced when used concomitantly with other drugs that lower blood pressure.
Ethanol, barbiturates, narcotic analgesics, and antidepressants
May enhance symptoms 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) using a combination of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse outcomes such as hypotension, hyperkalemia, and reduced renal function (including acute renal failure), compared to using a single RAAS-acting agent.
Medicinal products affecting blood 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 for use"). Monitoring of serum potassium levels is recommended when medicinal products affecting potassium levels are used in combination with Sevikar HCT.
Additional information
Bile acid-binding medicinal product colesevelam
Concomitant use of the bile acid-binding agent colesevelam hydrochloride reduces systemic exposure and peak plasma concentration of olmesartan, as well as shortens 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").
After treatment with an antacid (aluminum hydroxide, magnesium hydroxide), a moderate decrease in olmesartan bioavailability was observed.
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 drug in healthy volunteers.
In vitro studies revealed no clinically significant inhibition by olmesartan of the activity of human cytochrome P450 isoenzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1, and 3A4; regarding cytochrome P450 isoenzymes in animals, olmesartan either had negligible inducing effects or none at all. 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
Inhibitors of CYP3A4
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.
Inducers of CYP3A4
Concomitant use with CYP3A4 inducers may reduce plasma concentrations of amlodipine. Therefore, careful monitoring of the patient and dose adjustment are necessary during and after concomitant use of amlodipine with CYP3A4 inducers (such as 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 administration of verapamil and intravenous dantrolene, associated with the development of hyperkalemia. 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 dose of simvastatin in patients taking amlodipine should not exceed 20 mg per day.
Tacrolimus
There is a risk of increased blood levels of tacrolimus when used concomitantly with amlodipine. To avoid tacrolimus toxicity during concomitant use with amlodipine, regular monitoring of blood tacrolimus levels and, if necessary, dose adjustment are required.
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. When used concomitantly with mTOR inhibitors, amlodipine may increase their effects.
Cyclosporine
In a prospective study in patients with transplanted kidneys, amlodipine increased cyclosporine levels by an average of 40%. Concomitant use of Sevikar HCT and cyclosporine increases the systemic effect of the latter. During such treatment, cyclosporine levels must be monitored and its dose adjusted if necessary.
Potentially possible interactions with hydrochlorothiazide
Concomitant use not recommended
Medicinal products affecting blood 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 preparations are necessary, serum calcium levels should be monitored and the calcium dose adjusted accordingly.
Cholestyramine and colestipol resins
In the presence of anion-exchange resins, absorption of hydrochlorothiazide from the gastrointestinal tract is impaired.
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 torsades de pointes (ventricular tachycardia). Periodic monitoring of serum potassium levels and ECG is recommended when Sevikar HCT is used concomitantly with medicinal products causing disturbances in serum potassium levels (e.g., glycosides and antiarrhythmics) and with 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);
- Some antipsychotics (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, zuclopenthixol, sulpiride, sulthiade, amisulpride, tiapride, pimozide, haloperidol, droperidol);
- Other medicinal products (e.g., bepridil, cisapride, difemanil, erythromycin IV, halofantrine, mizolastine, pentamidine, sparfloxacin, terfenadine, vinpocetine IV).
Non-depolarizing skeletal muscle relaxants (e.g., tubocurarine)
Hydrochlorothiazide may enhance the efficacy of non-depolarizing 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. Adjustment of hypoglycemic agent dosage may be necessary (see section "Special precautions for use").
Metformin
Metformin should be used with caution due to the risk of lactic acidosis caused by functional renal impairment, which sometimes occurs as a result of hydrochlorothiazide use.
Beta-blockers and diazoxide
The hyperglycemic effect of beta-adrenergic blockers and diazoxide may be enhanced under the influence of thiazides.
Pressor amines (e.g., noradrenaline)
The effectiveness of pressor amines may be reduced.
Medicinal products used for the treatment of gout (probenecid, sulfinpyrazone, and allopurinol)
Since hydrochlorothiazide may occasionally increase serum uric acid concentration, dose adjustment of uricosuric agents used for the treatment of gout may be necessary. Additionally, the dose of probenecid or sulfinpyrazone may occasionally 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 enhance their toxic effects on the central nervous system.
Methyldopa
Published reports describe isolated cases of hemolytic anemia associated with the use of hydrochlorothiazide in combination with 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 uremia caused by tetracycline. 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. Prior to initiating treatment with Sevikar HCT, these conditions should be corrected.
Other conditions associated with activation of the renin-angiotensin-aldosterone system (RAAS)
Patients in whom vascular tone and renal function largely depend on RAAS activity (e.g., in severe congestive heart failure or renal pathology, including renal artery stenosis) may experience acute arterial hypotension, azotemia, oliguria, or, in rare cases, acute renal failure when treated with drugs affecting this system.
Renovascular hypertension
Use of drugs affecting the renin-angiotensin-aldosterone system in 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 using Sevikar HCT in patients with renal impairment, periodic monitoring of serum potassium and creatinine levels is recommended. Sevikar HCT is not recommended in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see sections "Dosage and administration", "Contraindications", "Pharmacological properties").
Diuretic-induced azotemia may occur in patients with renal dysfunction.
If signs of worsening renal function appear, therapy should be reassessed and discontinuation of diuretics considered.
There is no experience with the use of Sevikar HCT in patients who have recently undergone kidney transplantation or have end-stage renal disease (creatinine clearance < 12 mL/min).
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and reduced renal function (including acute renal failure). Therefore, dual blockade of RAAS by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see sections "Interaction with other medicinal products and other forms of interaction", "Pharmacological properties").
If dual RAAS blockade is absolutely necessary, it should be administered only under specialist supervision, with careful monitoring of renal function, electrolyte levels, and blood pressure.
Patients with diabetic nephropathy should not receive concomitant treatment with ACE inhibitors and angiotensin II receptor blockers.
Hepatic impairment
In patients with hepatic impairment, plasma levels of olmesartan medoxomil and amlodipine are increased (see section "Pharmacological properties"). Additionally, minor fluid and electrolyte imbalances caused by thiazide therapy may precipitate hepatic coma in patients with hepatic impairment or progressive liver disease. Therefore, Sevikar HCT should be used with caution in patients with mild to moderate hepatic impairment. In patients with moderate hepatic impairment, the dose of olmesartan medoxomil should not exceed 20 mg (see section "Dosage and administration").
Amlodipine therapy in patients with hepatic impairment should be initiated at the lowest dose, with careful monitoring of the patient's condition both at the beginning of treatment and during dose escalation.
Sevikar HCT 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 used with caution in patients with aortic or mitral stenosis, as well as in those with obstructive hypertrophic cardiomyopathy.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism usually do not respond to antihypertensive agents that suppress the renin-angiotensin system. Therefore, Sevikar HCT is not recommended for such patients.
Metabolic and endocrine effects
Thiazide-containing drugs may impair glucose tolerance. Diabetic patients may require adjustment of insulin or oral hypoglycemic agent doses (see section "Interaction with other medicinal products and other forms of interaction"). Thiazide use 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 fluid and electrolyte balance (including hypokalemia, hyponatremia, and hypochloremic alkalosis). Signs of fluid and electrolyte imbalance include: dry mouth, thirst, weakness, prolonged sleep, drowsiness, restlessness, muscle pain or cramps, muscle fatigue, 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, marked diuresis, inadequate oral electrolyte intake, or concomitant use of corticosteroids and ACTH (see section "Interaction with other medicinal products and other forms of interaction"). On the other hand, due to blockade of angiotensin II receptors (AT1) by olmesartan medoxomil in Sevikar HCT, 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 closely monitored in these patients. Sevikar HCT 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), and serum potassium levels should be frequently monitored (see section "Interaction with other medicinal products and other forms of interaction").
There are no data indicating that olmesartan medoxomil can mitigate or prevent diuretic-induced hyponatremia. Chloride deficiency is usually mild and does not require specific treatment. Thiazides may reduce urinary calcium excretion and cause mild and 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 enhance urinary excretion of magnesium, potentially leading to hypomagnesemia. In patients with edema, hyponatremia of dilution may occur in hot weather.
Lithium preparations
As with other medicinal products containing angiotensin II receptor blockers in combination with thiazides, Sevikar HCT 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 suppression of the renin-angiotensin-aldosterone system, 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 to years after starting treatment with olmesartan; the cause is likely a localized delayed hypersensitivity reaction. Intestinal mucosal biopsies in such patients often show villous atrophy. If such symptoms occur during olmesartan treatment and other likely etiologies are excluded, olmesartan therapy should be immediately discontinued and not resumed. If diarrhea does not resolve within one week after stopping the drug, a specialist (e.g., a gastroenterologist) should be consulted.
Intestinal angioedema
Cases of intestinal angioedema have been reported in patients taking angiotensin II receptor blockers, including olmesartan (see section "Adverse reactions"). These patients experienced abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor blockers. If intestinal angioedema is diagnosed, olmesartan should be discontinued and appropriate monitoring initiated until complete symptom resolution.
Choroidal effusion, acute myopia, and secondary angle-closure glaucoma
Hydrochlorothiazide is a sulfonamide and may cause idiosyncratic reactions leading to choroidal effusion with visual field defects, acute transient myopia, and acute angle-closure glaucoma. Symptoms include sudden onset of myopia or eye pain and usually occur within hours to weeks after starting treatment. Untreated acute angle-closure glaucoma may lead to permanent vision loss. Hydrochlorothiazide should be discontinued as soon as possible. If intraocular pressure cannot be controlled, urgent medical or surgical treatment may be required. 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 should not be initiated during pregnancy. If antihypertensive therapy is considered necessary, women planning pregnancy should switch from angiotensin II receptor antagonists to an alternative with a proven safety profile in pregnancy. Sevikar HCT should not be used in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this drug, its use should be immediately discontinued and replaced with another drug approved for use in pregnancy (see sections "Contraindications" and "Use during pregnancy or breastfeeding").
Children
Sevikar HCT is not administered to children (under 18 years of age).
Elderly patients
Dosage increase in elderly patients should be performed with caution (see section "Pharmacological properties").
Photosensitization
Cases of photosensitivity have been reported during thiazide diuretic use (see section "Adverse reactions"). If such a reaction occurs during Sevikar HCT therapy, the drug should be discontinued. When resuming diuretic therapy, exposure to direct sunlight and artificial UV radiation should be avoided.
Non-melanoma skin cancer
Results from two pharmacoepidemiological studies involving the Danish population showed an increased risk of non-melanoma skin cancer and lip cancer (basal cell carcinoma, squamous cell carcinoma) associated with cumulative hydrochlorothiazide (HCTZ) dose. Photosensitization during HCTZ use may contribute to the development of non-melanoma skin cancer.
Patients taking HCTZ 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 UV radiation and 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, HCTZ-containing drugs 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 intake. Pulmonary edema usually develops within minutes or hours after hydrochlorothiazide administration. Initial symptoms include dyspnea, fever, pulmonary deterioration, and hypotension. If ARDS is suspected, Sevikar HCT 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 ischemic cerebrovascular disease 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 exacerbate or activate systemic lupus erythematosus.
As with other angiotensin II antagonists, the antihypertensive effect of Sevikar HCT may be somewhat lower in patients of Black race compared to other races, although this effect was not observed in three studies including Black patients (30%) (see section "Pharmacological properties").
This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, i.e., it is considered sodium-free.
Use during pregnancy or breastfeeding
Pregnancy
Sevikar HCT should not be used in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this medicinal product, its use should be immediately discontinued and replaced with another medicinal product approved for use during pregnancy (see sections "Contraindications", "Special precautions for use").
Olmesartan medoxomil
Epidemiological data on teratogenic risk of ACE inhibitors in the first trimester of pregnancy do not allow definitive conclusions, although a small risk of such effects cannot be completely excluded. A similar risk may be assumed with angiotensin II receptor antagonists, although controlled epidemiological studies on these drugs have not been conducted. Women planning pregnancy should be advised to switch to antihypertensive drugs with a proven safety profile in pregnancy, unless there is an urgent need for angiotensin II receptor antagonists. If pregnancy is detected, angiotensin II receptor antagonists should be immediately discontinued and alternative treatment considered if necessary.
In the second and third trimesters, angiotensin II receptor antagonists have toxic effects on the fetus (impaired renal function, oligohydramnios, delayed skull ossification) and newborn (renal failure, arterial hypotension, hyperkalemia) (see section "Preclinical safety data").
If angiotensin II receptor antagonists are taken from the second trimester of pregnancy, renal function and skull ossification in the fetus should be monitored by ultrasound. Newborns whose mothers received angiotensin II receptor antagonists should be monitored for possible arterial hypotension (see sections "Contraindications" and "Special precautions for use").
Hydrochlorothiazide
Experience with hydrochlorothiazide use during pregnancy, especially in the first trimester, is limited. Experimental animal studies are insufficient. Hydrochlorothiazide crosses the placental barrier. Due to its mechanism of action, hydrochlorothiazide use in the second and third trimesters of pregnancy may impair fetoplacental blood flow and adversely affect the fetus and newborn, causing jaundice, electrolyte imbalances, 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 providing adequate therapeutic effect.
Hydrochlorothiazide is also not recommended for the treatment of essential hypertension in pregnant women, except in rare cases when other drugs cannot be used.
Amlodipine
Data from limited observations in pregnant women do not indicate that amlodipine or other calcium channel blockers have harmful effects on fetal health. However, there is a risk of prolonged labor.
Breastfeeding
Due to lack of information on the use of Sevikar HCT during breastfeeding, this medicinal product is not recommended for nursing mothers. Alternative treatments with a better-established safety profile during breastfeeding are recommended, especially for women breastfeeding newborns or preterm infants.
Olmesartan passes into the milk of lactating rats. However, it is unknown whether olmesartan passes into human breast milk.
Amlodipine passes into human breast milk. The fraction of maternal dose received by the infant is estimated at an interquartile range of 3–7%, with a maximum of 15%. The effect of amlodipine on infants is unknown.
Hydrochlorothiazide passes into breast milk in small amounts. Use of thiazides in high doses causing strong diuresis may interfere with breast milk production. Use of Sevikar HCT during breastfeeding is not recommended. If Sevikar HCT is used during breastfeeding, the dose should be kept as low as possible.
Fertility
Cases of reversible biochemical changes in sperm heads have been reported in some patients taking calcium channel blockers. Clinical data on the potential effect of amlodipine on fertility are insufficient. An adverse effect on male fertility was observed in rat studies (see section "Pharmacological properties").
Effects on ability to drive and use machines
No studies have been conducted on the effects on driving or operating machinery.
However, it should be noted that patients receiving antihypertensive therapy may occasionally experience dizziness, headache, nausea, or fatigue, which could impair their reaction ability. Caution is advised, especially at the beginning of treatment.
Method of Administration and Dosage.
Adults
Sevikar HCT tablets are taken once daily, regardless of food intake.
The tablet should be swallowed with sufficient liquid (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
Sevikar HCT 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.
Sevikar HCT 40 mg/10 mg/12.5 mg may be used in patients whose blood pressure is not adequately controlled with Sevikar HCT 20 mg/5 mg/12.5 mg.
Before 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 who are currently receiving stable doses of olmesartan medoxomil, amlodipine, and hydrochlorothiazide as a two-component (olmesartan medoxomil and amlodipine or olmesartan medoxomil and hydrochlorothiazide) and single-component (hydrochlorothiazide or amlodipine) medication may be switched to Sevikar HCT containing equivalent doses of the components.
The maximum daily dose of Sevikar HCT is 40 mg/10 mg/12.5 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 daily dose of Sevikar HCT 40 mg/10 mg/12.5 mg.
Dose escalation should be performed cautiously in elderly patients (see sections "Special Warnings and Precautions for Use", "Pharmacological Properties").
Experience with Sevikar HCT 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 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 olmesartan medoxomil in this patient group.
Patients with moderate renal impairment should be monitored for serum potassium and creatinine levels.
Sevikar HCT is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see sections "Contraindications", "Special Warnings and Precautions for Use", "Pharmacological Properties").
Hepatic Impairment
Sevikar HCT should be used with caution in patients with mild hepatic impairment (see sections "Special Warnings and Precautions for Use", "Pharmacological Properties").
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 antagonists, the elimination half-life of amlodipine is prolonged in patients with hepatic dysfunction; dosage recommendations have not been established. Therefore, Sevikar HCT should be prescribed with caution in such patients. The pharmacokinetics of amlodipine in patients with severe hepatic impairment have not been studied. Amlodipine administration in patients with severe hepatic impairment should begin with the lowest dose and be gradually increased.
Sevikar HCT is contraindicated in patients with severe hepatic impairment, cholestasis, or biliary obstruction (see section "Contraindications").
Children
Sevikar HCT is not recommended for use in children (under 18 years of age) due to insufficient data on safety and efficacy.
Overdose.
Symptoms
The maximum recommended dose of Sevikar HCT is 40 mg/10 mg/12.5 mg once daily. There is no information on Sevikar HCT overdose in humans. The most likely effect of overdose is hypotension.
The most likely effects of olmesartan medoxomil overdose are hypotension and tachycardia; bradycardia may occur if there is parasympathetic (vagal) stimulation.
Overdose with 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.
Rarely, non-cardiogenic pulmonary edema has been reported as a consequence of amlodipine overdose, which may have a 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 triggering factors.
Hydrochlorothiazide overdose is associated with electrolyte imbalances (hypokalemia, hypochloremia) and dehydration due to excessive diuresis.
The most common symptoms of overdose are nausea and drowsiness. Hypokalemia may lead to muscle cramps and/or severe cardiac arrhythmias, particularly when combined with digitalis glycosides or certain antiarrhythmic drugs.
Treatment
In case of Sevikar HCT 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 its absorption.
Clinically significant hypotension caused by Sevikar HCT overdose requires active cardiovascular support, including careful monitoring of cardiac and respiratory function, placing the patient in a supine position with legs elevated, and monitoring circulating fluid volume and diuresis. A vasopressor may be useful to restore vascular tone and blood pressure, provided there are no contraindications to its use. Intravenous calcium gluconate may be beneficial in reversing calcium channel blockade effects.
Serum electrolytes and creatinine levels should be monitored frequently. If hypotension occurs, the patient should be placed in a supine position and receive intravenous saline replacement therapy.
Since amlodipine is highly protein-bound, dialysis is unlikely to be beneficial.
The extent to which olmesartan and hydrochlorothiazide are removed by hemodialysis has not been established.
Adverse Reactions
The safety of Sevikar HCT was evaluated in clinical trials involving 7,826 patients who received olmesartan medoxomil in combination with amlodipine and hydrochlorothiazide.
Adverse events observed during clinical trials and post-marketing safety studies, as well as adverse reactions reported via spontaneous reports, are presented in Table 1 below for Sevikar HCT and for its individual components—olmesartan medoxomil, amlodipine, and hydrochlorothiazide—based on the known safety profiles of the individual components.
The most commonly reported adverse reactions during treatment with Sevikar HCT 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 (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), and frequency not known (cannot be estimated from the available data).
Table 1
Adverse reactions associated with the use of Sevikar HCT and its individual components
| MedDRA Organ system |
Adverse reaction |
Frequency |
|||
| Sevikar HCT |
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 |
||||
| Metabolism and nutrition disorders |
Hyperkalemia |
Uncommon |
Uncommon |
||
| Hypokalemia |
Uncommon |
Common |
|||
| Anorexia |
Uncommon |
||||
| Glucosuria |
Common |
||||
| Hypercalcemia |
Common |
||||
| Hypoglycemia |
Very rare |
Common |
|||
| Hypomagnesemia |
Common |
||||
| Hyponatremia |
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 |
||||
| Convulsions |
Uncommon |
||||
| Loss of appetite |
Uncommon |
||||
| Tremor |
Uncommon |
||||
| Extrapyramidal disorders |
Frequency unknown |
||||
| Eye disorders |
Visual disturbances (including diplopia, blurred vision) |
Common |
Uncommon |
||
| Decreased lacrimation |
Uncommon |
||||
| Acute myopia |
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 |
Vertigo |
Uncommon |
Uncommon |
Uncommon |
|
| Tinnitus |
Uncommon |
||||
| Cardiac disorders |
Pounding heartbeat |
Common |
Common |
||
| Tachycardia |
Uncommon |
||||
| Myocardial infarction |
Very rare |
||||
| Arrhythmias (including bradycardia, ventricular tachycardia, atrial fibrillation) |
Uncommon |
Uncommon |
|||
| Angina pectoris |
Uncommon |
Uncommon including worsening of angina |
|||
| Vascular disorders |
Arterial hypotension |
Common |
Uncommon |
Uncommon |
|
| Flushing |
Uncommon |
Common |
|||
| Orthostatic hypotension |
Uncommon |
||||
| Vasculitis (including necrotizing vasculitis) |
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) (see section "Special warnings and precautions for use") |
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 |
||||
| Stomach 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 |
||||
| Angioneurotic intestinal edema |
Uncommon |
||||
| Hepatobiliary disorders |
Hepatitis |
Very rare |
|||
| Jaundice (cholestatic jaundice) |
Very rare |
Uncommon |
|||
| Acute cholecystitis |
Uncommon |
||||
| Autoimmune hepatitis* |
Unknown |
||||
| Skin and subcutaneous tissue disorders |
Alopecia |
Uncommon |
|||
| Angioedema |
Uncommon |
Very rare |
|||
| Allergic dermatitis |
Uncommon |
||||
| Multiform erythema |
Very rare |
||||
| Erythema |
Uncommon |
||||
| Skin reactions resembling systemic lupus erythematosus |
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 form of systemic lupus erythematosus |
Uncommon |
||||
| Toxic epidermal necrolysis |
Frequency unknown |
Uncommon |
|||
| Skin color change |
Uncommon |
||||
| Stevens-Johnson syndrome |
Very rare |
||||
| Urticaria |
Uncommon |
Uncommon |
Uncommon |
||
| Musculoskeletal and connective tissue disorders |
Muscle spasms |
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 |
||||
| Nycturia |
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 edema |
Uncommon |
||||
| Investigations |
Increase in blood creatinine level |
Common |
Uncommon |
Common |
|
| Increase in blood urea level |
Common |
Common |
Common |
||
| Increase in blood uric acid level |
Common |
||||
| Decrease in blood potassium level |
Uncommon |
||||
| Increase in gamma-glutamyltransferase blood level |
Uncommon |
||||
| Increase in alanine aminotransferase activity |
Uncommon |
||||
| Increase in aspartate aminotransferase activity |
Uncommon |
||||
| Increase in liver enzymes |
Common |
Very rare (mostly in cholestasis) |
|||
| Increase in blood creatine phosphokinase level |
Common |
||||
| Decrease in body weight |
Uncommon |
||||
| Increase in 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 was reversible upon discontinuation of olmesartan.
Several cases of rhabdomyolysis, temporally associated with the use of angiotensin II receptor blockers, have been reported. Extrapyramidal disorder has been reported in several 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 (HCTZ) (see sections "Special warnings and precautions for use", "Pharmacological properties").
Adverse reactions reported in clinical trials or known from post-marketing experience with the fixed-dose combination of olmesartan medoxomil and amlodipine, but not reported with Sevikar HCT, monotherapy with olmesartan medoxomil or monotherapy with amlodipine, or reported more frequently with the dual combination, are listed in Table 2.
Table 2
Adverse reactions during treatment with the combination of olmesartan medoxomil and amlodipine
| Organs and systems |
Frequency |
Adverse reactions |
| Immune system |
Uncommon |
Hypersensitivity to the drug |
| Gastrointestinal system |
Uncommon |
Upper abdominal pain |
| Reproductive system and breast |
Uncommon |
Decreased libido |
| General disorders |
Common |
Soft tissue edema |
| Uncommon |
Somnolence |
|
| Musculoskeletal and connective tissue |
Uncommon |
Limb pain |
The adverse reactions listed in Table 3 refer to clinical studies and post-marketing use of fixed-dose combinations of olmesartan medoxomil and hydrochlorothiazide and do not pertain to the use of Sevikar HCT, monotherapy with olmesartan medoxomil or hydrochlorothiazide, or indicate a higher frequency of adverse reactions with the combination of the two components.
Table 3
Adverse reactions associated with the use of the combination of olmesartan medoxomil and hydrochlorothiazide
| Organs and systems |
Frequency |
Adverse reactions |
| Neurological disorders |
Uncommon |
Impaired consciousness (loss of consciousness) |
| Skin and subcutaneous tissue disorders |
Uncommon |
Atopic dermatitis |
| 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 after marketing authorization of a medicinal product is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to 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.
No special storage conditions required.
Keep out of reach of children.
Packaging.
14 film-coated tablets in a blister; 2 blisters per cardboard box.
Prescription status. Prescription only.
Manufacturer.
Daiichi Sankyo Europe GmbH.
Manufacturer's address and location of operations.
Luitpoldstraße 1, 85276 Pfaffenhofen a.d. Ilm, Germany.