Demerkon
UkraineTable of Contents
INSTRUCTION for medical use of the medicinal product Demerkon (Demerkon)
Composition:
Active substances: amlodipine, valsartan, hydrochlorothiazide;
One film-coated tablet of 5 mg/160 mg/12.5 mg contains: amlodipine (as amlodipine besilate) 5 mg, valsartan 160 mg, hydrochlorothiazide 12.5 mg;
Excipients: microcrystalline cellulose, crospovidone (type A), colloidal anhydrous silicon dioxide, magnesium stearate; film coating (OpadryWhite 03F280024): hypromellose (E 464), titanium dioxide (E 171), macrogol 4000/polyethylene glycol (E 1521), talc (E 553b).
One film-coated tablet of 5 mg/160 mg/25 mg contains: amlodipine (as amlodipine besilate) 5 mg, valsartan 160 mg, hydrochlorothiazide 25 mg;
Excipients: microcrystalline cellulose, crospovidone (type A), colloidal anhydrous silicon dioxide, magnesium stearate; film coating (OpadryYellow 03F220081): hypromellose (E 464), titanium dioxide (E 171), macrogol 4000/polyethylene glycol (E 1521), iron oxide yellow (E 172), talc (E 553b).
One film-coated tablet of 10 mg/160 mg/12.5 mg contains: amlodipine (as amlodipine besilate) 10 mg, valsartan 160 mg, hydrochlorothiazide 12.5 mg;
Excipients: microcrystalline cellulose, crospovidone (type A), colloidal anhydrous silicon dioxide, magnesium stearate; film coating (OpadryYellow 03F220083): hypromellose (E 464), titanium dioxide (E 171), macrogol 4000/polyethylene glycol (E 1521), talc (E 553b), iron oxide yellow (E 172), iron oxide red (E 172).
One film-coated tablet of 10 mg/160 mg/25 mg contains: amlodipine (as amlodipine besilate) 10 mg, valsartan 160 mg, hydrochlorothiazide 25 mg;
Excipients: microcrystalline cellulose, crospovidone (type A), colloidal anhydrous silicon dioxide, magnesium stearate; film coating (OpadryYellow 03F220082): hypromellose (E 464), titanium dioxide (E 171), macrogol 4000/polyethylene glycol (E 1521), talc (E 553b), iron oxide yellow (E 172).
One film-coated tablet of 10 mg/320 mg/25 mg contains: amlodipine (as amlodipine besilate) 10 mg, valsartan 320 mg, hydrochlorothiazide 25 mg;
Excipients: microcrystalline cellulose, crospovidone (type A), colloidal anhydrous silicon dioxide, magnesium stearate; film coating (OpadryYellow 03F220080): hypromellose (E 464), titanium dioxide (E 171), macrogol 4000/polyethylene glycol (E 1521), talc (E 553b), iron oxide yellow (E 172).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
Tablets 5 mg/160 mg/12.5 mg: white, oval, biconvex film-coated tablets with "LLL" imprint on one side and smooth on the other side, length 15.3 ± 0.3 mm, width 6.2 ± 0.3 mm;
Tablets 5 mg/160 mg/25 mg: yellow, oval, biconvex film-coated tablets with "LLH" imprint on one side and smooth on the other side, length 15.3 ± 0.3 mm, width 6.2 ± 0.3 mm;
Tablets 10 mg/160 mg/12.5 mg: pale yellow, oval, biconvex film-coated tablets with "HLL" imprint on one side and smooth on the other side, length 15.3 ± 0.3 mm, width 6.2 ± 0.3 mm;
Tablets 10 mg/160 mg/25 mg: brown-yellow, oval, biconvex film-coated tablets with "HLH" imprint on one side and smooth on the other side, length 15.3 ± 0.3 mm, width 6.2 ± 0.3 mm;
Tablets 10 mg/320 mg/25 mg: brown-yellow, oval, biconvex film-coated tablets with "HHH" imprint on one side and smooth on the other side, length 19.1 ± 0.3 mm, width 8.3 ± 0.3 mm.
Pharmacotherapeutic group. Angiotensin II antagonists, other combinations. Valsartan, amlodipine and hydrochlorothiazide. ATC code C09D X01.
Pharmacological Properties
Pharmacodynamics
Amlodipine/valsartan/hydrochlorothiazide
Mechanism of action
The medicinal product combines three antihypertensive compounds with complementary mechanisms of blood pressure control in patients with essential hypertension: amlodipine belongs to the class of calcium channel antagonists, valsartan to the class of angiotensin II receptor blockers, and hydrochlorothiazide to the class of thiazide diuretics. The combination of these three components demonstrates complementary antihypertensive effects.
Clinical efficacy and safety
Amlodipine/valsartan/hydrochlorothiazide was studied in a double-blind, active-controlled trial involving patients with arterial hypertension. Overall, 2271 patients with moderate to severe hypertension (mean baseline systolic/diastolic blood pressure was 170/107 mm Hg) received treatment with amlodipine/valsartan/hydrochlorothiazide 10 mg/320 mg/25 mg, valsartan/hydrochlorothiazide 320 mg/25 mg, amlodipine/valsartan 10 mg/320 mg, or hydrochlorothiazide/amlodipine 25 mg/10 mg. At the beginning of the study, patients were initiated on lower doses of their combination and titrated up to full treatment dose by week 2.
At week 8, mean reduction in systolic/diastolic blood pressure was 39.7/24.7 mm Hg with amlodipine/valsartan/hydrochlorothiazide, 32.0/19.7 mm Hg with valsartan/hydrochlorothiazide, 33.5/21.5 mm Hg with amlodipine/valsartan, and 31.5/19.5 mm Hg with amlodipine/hydrochlorothiazide. Triple combination therapy statistically surpassed each of the three dual combination treatments in reducing both diastolic and systolic blood pressure. Reduction in systolic/diastolic blood pressure with amlodipine/valsartan/hydrochlorothiazide was 7.6/5.0 mm Hg greater than with valsartan/hydrochlorothiazide, 6.2/3.3 mm Hg greater than with amlodipine/valsartan, and 8.2/5.3 mm Hg greater than with amlodipine/hydrochlorothiazide. Full blood pressure-lowering effect was achieved within 2 weeks after administration of the maximum dose of amlodipine/valsartan/hydrochlorothiazide. A statistically greater proportion of patients achieved blood pressure control (< 140/90 mm Hg) with the amlodipine/valsartan/hydrochlorothiazide combination (71%) compared to each of the three two-component combinations (45–54%) (p < 0.0001).
In a subgroup of 283 patients undergoing ambulatory blood pressure monitoring, clinically and statistically more effective reduction in 24-hour systolic and diastolic blood pressure was observed with the triple combination compared to valsartan/hydrochlorothiazide, amlodipine/valsartan, and hydrochlorothiazide/amlodipine.
Amlodipine
Mechanism of action
Amlodipine, included in the medicinal product, inhibits transmembrane influx of calcium ions into cardiac muscle and vascular smooth muscle. The antihypertensive effect of amlodipine occurs via direct vasorelaxant action on vascular smooth muscle, leading to reduced peripheral vascular resistance and blood pressure.
Pharmacodynamic effects
Experimental data indicate that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. Contractile processes in cardiac and vascular smooth muscle depend on the movement of extracellular calcium ions into these cells through specific ion channels.
At therapeutic doses in patients with arterial hypertension, amlodipine causes vasodilation, resulting in reduced blood pressure in both supine and standing positions. This blood pressure reduction is not accompanied by pronounced changes in heart rate or plasma catecholamine levels during long-term use.
Plasma concentrations correlate with effect in both young and elderly patients.
In patients with arterial hypertension and normal renal function, amlodipine at therapeutic doses reduces renal vascular resistance and increases glomerular filtration rate and effective renal plasma flow without altering filtration fraction or proteinuria.
As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or cardiac pacing) in patients with normal ventricular function receiving amlodipine generally showed a slight increase in cardiac index without significant effect on dP/dt or left ventricular end-diastolic pressure or volume. Hemodynamic studies have shown that amlodipine does not produce a negative inotropic effect when administered within the therapeutic dose range in intact animals and humans, even when co-administered with beta-blockers.
Amlodipine does not alter sinoatrial node function or atrioventricular conduction in intact animals or humans. In clinical trials where amlodipine was administered in combination with beta-blockers to patients with arterial hypertension or angina, no negative effects on electrocardiographic parameters were observed.
Amlodipine has been studied in patients with chronic stable angina, vasospastic angina, and angiographically documented coronary artery disease.
Clinical efficacy and safety
The randomized, double-blind ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) trial on morbidity and mortality was conducted to compare new treatment approaches. Patients were assigned amlodipine 2.5–10 mg/day (a calcium channel blocker) or lisinopril 10–40 mg/day (an angiotensin-converting enzyme [ACE] inhibitor) as first-line therapy, combined with the thiazide diuretic chlorthalidone 12.5–25 mg/day, 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, including: prior myocardial infarction or stroke (>6 months before enrollment) or other atherosclerotic cardiovascular diseases (51.5% overall), type 2 diabetes (36.1%), high-density lipoprotein cholesterol level <35 mg/dL or <0.906 mmol/L (11.6%), left ventricular hypertrophy diagnosed by electrocardiography or echocardiography (20.9%), or smoking (21.9%).
The primary endpoint was fatal ischemic heart disease or non-fatal myocardial infarction. There was no significant difference in the primary endpoint between amlodipine-based therapy and chlorthalidone-based therapy: risk ratio (RR) 0.98, 95% CI (0.90–1.07), p = 0.65. Among secondary endpoints, the incidence of heart failure (a component of the combined cardiovascular endpoint) was significantly higher in the amlodipine group compared to the chlorthalidone group (10.2% vs. 7.7%, RR 1.38, 95% CI (1.25–1.52), p < 0.001). However, there was no significant difference in all-cause mortality between amlodipine-based and chlorthalidone-based therapy: RR 0.96, 95% CI (0.89–1.02), p = 0.20.
Valsartan
Mechanism of action
Valsartan is an orally active, potent, and specific antagonist of angiotensin II receptors. Valsartan acts selectively on the AT1 receptor subtype, which mediates the known effects of angiotensin II.
Clinical efficacy and safety
In patients with arterial hypertension, administration of valsartan reduces blood pressure without affecting pulse rate.
In most patients, after a single oral dose, the onset of the antihypertensive effect occurs within 2 hours, and maximum blood pressure reduction is achieved within 4–6 hours. The antihypertensive effect lasts for 24 hours after dosing. With repeated administration, maximum blood pressure reduction (at all dosage regimens) is typically achieved within 2–4 weeks.
Hydrochlorothiazide
Mechanism of action
The primary site of action of thiazide diuretics is the distal convoluted tubules of the kidneys. High-affinity receptors in the renal cortex have been identified as the main binding site for thiazide diuretics and for inhibition of NaCl transport in the distal convoluted tubules. The mechanism of action of thiazides involves inhibition of the Na+Cl– transporter, possibly by competing for Cl– sites, thereby affecting electrolyte reabsorption: directly enhancing excretion of sodium and chloride to approximately equivalent degrees, and indirectly, via diuresis, reducing plasma volume, which subsequently increases plasma renin activity, aldosterone secretion, and urinary potassium excretion, as well as lowering serum potassium levels.
Non-melanoma skin cancer. Epidemiological data indicate a cumulative, dose-dependent association between hydrochlorothiazide exposure and the development of non-melanoma skin cancer (NMSC). In one study, 71,533 cases of basal cell carcinoma (among 1,430,833 individuals in the control group) and 8,629 cases of squamous cell carcinoma (among 172,462 individuals in the control group) were recorded. High cumulative exposure to hydrochlorothiazide (≥50,000 mg) was associated with an adjusted risk ratio (RR) 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 cumulative dose-response relationship was observed for both basal cell and squamous cell carcinomas. Another study indicated a possible association between lip cancer and hydrochlorothiazide use: 633 cases of lip cancer were identified among 63,067 individuals in the control group. A cumulative dose-response relationship was demonstrated with an adjusted RR of 2.1 (95% CI: 1.7–2.6), increasing to RR 3.9 (3.0–4.9) for high dose (~25,000 mg) and RR 7.7 (5.7–10.5) for the highest dose (~100,000 mg) (see section "Special precautions").
Paediatric population. The European Medicines Agency has waived the obligation to submit results of studies with the reference medicinal product containing amlodipine/valsartan/hydrochlorothiazide in all subgroups of the paediatric population with essential hypertension (see section "Dosage and administration" regarding use in paediatrics).
Dual blockade of the renin-angiotensin-aldosterone system. Two large randomized controlled trials, ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (Veterans Affairs Nephropathy in Diabetes trial), investigated the concomitant use of an ACE inhibitor with an angiotensin II receptor antagonist.
The ONTARGET trial included patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. The VA NEPHRON-D trial included patients with type 2 diabetes and diabetic nephropathy.
These trials did not demonstrate significant beneficial effects on renal and/or cardiovascular function or mortality; however, an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was observed compared to monotherapy. Given the similar pharmacodynamic properties, these findings are also relevant to other ACE inhibitors and angiotensin II receptor antagonists.
Therefore, concomitant use of ACE inhibitors and angiotensin II receptor antagonists is not recommended in patients with diabetic nephropathy (see section "Special precautions").
Additionally, the ALTITUDE trial (Aliskiren Trial in Type 2 Diabetes with Cardiovascular and Renal Disease) evaluated the benefits of adding aliskiren to standard therapy (an ACE inhibitor or angiotensin II receptor antagonist) in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. The trial was prematurely terminated due to an increased risk of adverse outcomes. Cardiovascular death and stroke occurred more frequently in the aliskiren group than in the placebo group; furthermore, adverse events and serious adverse events (hyperkalemia, hypotension, and renal function impairment) occurred more frequently in the aliskiren group than in the placebo group.
Pharmacokinetics
Amlodipine/valsartan/hydrochlorothiazide
Amlodipine, valsartan, and hydrochlorothiazide exhibit linear pharmacokinetics.
After oral administration of the fixed combination amlodipine/valsartan/hydrochlorothiazide to healthy adult volunteers, maximum plasma concentrations of amlodipine, valsartan, and hydrochlorothiazide were reached within 6–8 hours, 3 hours, and 2 hours, respectively. The rate and extent of absorption of amlodipine, valsartan, and hydrochlorothiazide when administered in combination are similar to those observed when each drug is administered alone.
Amlodipine
Absorption. After oral administration of amlodipine alone at therapeutic doses, maximum plasma concentration is reached within 6–12 hours. Absolute bioavailability ranges from 64% to 80%. Food intake does not affect the bioavailability of amlodipine.
Distribution. The volume of distribution is approximately 21 L/kg. In vitro studies with amlodipine show that approximately 97.5% of the drug in circulation is bound to plasma proteins.
Metabolism. Amlodipine is extensively metabolized (approximately 90%) in the liver to inactive metabolites.
Elimination. Amlodipine is eliminated from plasma in a biphasic manner, with a terminal half-life of approximately 30–50 hours. Steady-state plasma concentrations are achieved after 7–8 days of continuous administration. About 10% of unchanged amlodipine and 60% of its metabolites are excreted in urine.
Valsartan
Absorption. After oral administration of valsartan alone, maximum concentrations are reached within 2–4 hours. Mean absolute bioavailability is 23%. Food intake reduces valsartan exposure (as defined by AUC) by approximately 40% and maximum plasma concentration (Cmax) by approximately 50%, although about 8 hours after dosing, plasma concentrations of valsartan are similar in fasting and postprandial groups. However, this reduction in AUC does not result in clinically significant reduction in therapeutic effect; therefore, valsartan can be administered independently of food intake.
Distribution. The volume of distribution of valsartan at steady state after intravenous administration is approximately 17 liters, indicating limited distribution of valsartan. Valsartan is highly bound to serum proteins (94–97%), primarily to serum albumin.
Metabolism. Valsartan undergoes minimal biotransformation, as only about 20% of the dose is excreted as metabolites. A hydroxymetabolite has been identified in plasma at low concentrations (less than 10% of the AUC of valsartan). This metabolite is pharmacologically inactive.
Elimination. Valsartan exhibits multiphasic elimination kinetics (t½α < 1 hour and t½ß approximately 9 hours). Valsartan is primarily excreted in feces (approximately 83% of the dose) and urine (approximately 13% of the dose), mainly as unchanged drug. After intravenous administration, the plasma clearance of valsartan is about 2 L/h, and renal clearance is 0.62 L/h (approximately 30% of total clearance). The elimination half-life of valsartan is 6 hours.
Hydrochlorothiazide
Absorption. Hydrochlorothiazide is rapidly absorbed after oral administration (Tmax approximately 2 hours). The increase in mean AUC is linear and proportional to dose within the therapeutic dose range.
The effect of food on hydrochlorothiazide absorption, if any, is not clinically significant. Absolute bioavailability of hydrochlorothiazide after oral administration is 70%.
Distribution. The apparent volume of distribution is 4–8 L/kg. Circulating hydrochlorothiazide is bound to plasma proteins (40–70%), primarily to serum albumin. Hydrochlorothiazide also accumulates in erythrocytes at concentrations three times higher than in plasma.
Metabolism. Hydrochlorothiazide is excreted unchanged.
Elimination. Hydrochlorothiazide is eliminated from plasma with a terminal half-life averaging 6 to 15 hours. The pharmacokinetics of hydrochlorothiazide do not change with repeated dosing, and accumulation is minimal with once-daily administration. More than 95% of the absorbed dose is excreted unchanged in urine. Renal clearance involves passive filtration and active tubular secretion.
Special patient groups
Children (under 18 years). No pharmacokinetic data are available in children.
Elderly patients (65 years and older). Time to reach Cmax for amlodipine is similar in young and elderly patients. In elderly patients, clearance of amlodipine tends to be reduced, leading to increased AUC and elimination half-life. Mean systemic AUC of valsartan is 70% higher in elderly patients than in younger patients; therefore, dose escalation should be cautious in these patients.
Systemic exposure to valsartan is slightly higher in elderly patients compared to younger patients, but this is not clinically significant.
Some data indicate that systemic clearance of hydrochlorothiazide is reduced in both healthy elderly volunteers and elderly patients with arterial hypertension compared to younger healthy volunteers.
Since all three active components of the medicinal product are similarly well tolerated in young and elderly patients, the recommended dosing regimen is the same (see section "Dosage and administration").
Patients with renal impairment. Renal impairment does not significantly affect the pharmacokinetics of amlodipine. As expected for a drug with only 30% of total plasma clearance being renal clearance, no correlation was observed between renal function and systemic exposure to valsartan.
Therefore, patients with mild to moderate renal impairment can receive the medicinal product at the usual initial dose (see sections "Dosage and administration" and "Special precautions").
In renal insufficiency, peak plasma levels and AUC values of hydrochlorothiazide increase, and urinary excretion rate decreases. In patients with mild to moderate renal impairment, a 3-fold increase in AUC of hydrochlorothiazide was observed. In patients with severe renal impairment, an 8-fold increase in AUC was observed. The medicinal product is contraindicated in patients with severe renal impairment, anuria, and in patients on dialysis (see section "Paediatric population").
Patients with hepatic impairment. Clinical data on the use of amlodipine in patients with hepatic impairment are very limited.
In patients with hepatic impairment, clearance of amlodipine is reduced, resulting in an increase in AUC by approximately 40–60%. On average, exposure (as measured by AUC) to valsartan is twice as high in patients with mild to moderate chronic liver disease compared to healthy adult volunteers (matched for age, sex, and body weight). The medicinal product should be used with caution in patients with liver disease (see sections "Dosage and administration" and "Contraindications").
Clinical characteristics
Indications. For the treatment of essential hypertension in adult patients whose blood pressure is adequately controlled with a combination of amlodipine, valsartan, and hydrochlorothiazide either as three separate medications or as two medications, one of which is a combination product.
Contraindications
- Hypersensitivity to the active substances, other sulfonamides, dihydropyridine derivatives, or to any excipient.
- Pregnancy or planned pregnancy.
- Impaired liver function, biliary cirrhosis, or cholestasis.
- Severe renal impairment (glomerular filtration rate (GFR) < 30 mL/min/1.73 m²), anuria, or patients on dialysis.
- Concomitant use of the medicinal product with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics").
- Refractory hypokalemia, hyponatremia, hypercalcemia, symptomatic hyperuricemia.
- Severe hypotension.
- Shock (including cardiogenic shock).
- Obstruction of the left ventricular outflow tract (e.g., hypertrophic obstructive cardiomyopathy and severe aortic stenosis).
- Hemodynamically unstable heart failure following acute myocardial infarction.
Interaction with other medicinal products and other forms of interaction
Interaction studies between the medicinal product Demercon and other medicinal products have not been conducted. This section provides information only on interactions of individual active substances with other medicinal agents.
However, it is important to consider that the medicinal product may enhance the hypotensive effect of other antihypertensive agents.
Table 1
| Concomitant use not recommended |
||
| Individual components of the medicinal product Demercon |
Known interactions with the following medicinal products |
Effect of interaction with other medicinal products |
| Valsartan and hydrochlorothiazide |
Lithium |
Reversible increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of lithium and ACE inhibitors, angiotensin II receptor antagonists (including valsartan), or thiazide diuretics such as hydrochlorothiazide. Since thiazides reduce renal clearance of lithium, the risk of lithium toxicity may increase when used with this medicinal product. Therefore, careful monitoring of serum lithium levels is recommended during concomitant therapy. |
| Valsartan |
Potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, and other agents that may increase potassium levels |
If concomitant use of a medicinal product affecting potassium levels with valsartan is required, frequent monitoring of plasma potassium levels is recommended. |
| Amlodipine |
Grapefruit or grapefruit juice |
Concomitant use of amlodipine with grapefruit or grapefruit juice is not recommended, as bioavailability may increase in some patients, thereby enhancing the blood pressure-lowering effect. |
| Concomitant use requires caution |
||
| Individual components of the medicinal product Demercon |
Known interactions with the following medicinal products |
Effect of interaction with other medicinal products |
| Amlodipine |
CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir) |
Studies in elderly patients have shown that diltiazem inhibits the metabolism of amlodipine, possibly via CYP3A4 (plasma concentration increases by approximately 50%, and the effect of amlodipine is enhanced). Stronger CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir) may increase plasma concentrations of amlodipine more markedly than diltiazem. 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. These pharmacokinetic changes may be more pronounced in elderly patients. Therefore, clinical monitoring and dose adjustment may be necessary. |
| CYP3A4 inducers (anticonvulsants [e.g., carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone], rifampicin, Hypericum perforatum [St. John's wort]) |
There are no data on the effect of CYP3A4 inducers on amlodipine. Concomitant use of CYP3A4 inducers (e.g., rifampicin, St. John's wort) may reduce plasma concentrations of amlodipine. Clinical monitoring with possible dose adjustment of amlodipine during and after treatment with such inducers is recommended. Amlodipine should be used with caution together with CYP3A4 inducers (e.g., rifampicin, Hypericum perforatum [St. John's wort]). |
|
| Simvastatin |
Repeated doses of 10 mg amlodipine with 80 mg simvastatin increase simvastatin exposure by 77% compared to simvastatin alone. It is recommended to reduce the daily dose of simvastatin to 20 mg in patients taking amlodipine. |
|
| Dantrolene (infusions) |
In animals, fatal ventricular fibrillations and cardiovascular collapse due to hyperkalemia have been observed after intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalemia, concomitant use of calcium channel blockers such as amlodipine should be avoided in patients prone to malignant hyperthermia and during treatment of malignant hyperthermia. |
|
| Valsartan and hydrochlorothiazide |
Non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day), and non-selective NSAIDs |
NSAIDs may attenuate the antihypertensive effect of both angiotensin II antagonists and hydrochlorothiazide when used concomitantly. Additionally, concomitant use of this medicinal product with NSAIDs may lead to worsening renal function and increased serum potassium levels. Therefore, monitoring of renal function at the start of treatment and adequate hydration of the patient are recommended. |
| Valsartan |
Inhibitors of uptake transporters (rifampicin, cyclosporine) or efflux transporters (ritonavir) |
In vitro studies using human liver tissue have shown that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Concomitant use of inhibitors of uptake transporters (rifampicin, cyclosporine) or efflux transporters (ritonavir) may increase systemic exposure to valsartan. |
| Hydrochlorothiazide |
Alcohol, barbiturates, or narcotic agents |
Concomitant administration of thiazide diuretics with substances that also lower blood pressure (e.g., those reducing central sympathetic activity or causing direct vasodilation) may potentiate orthostatic hypotension. |
| Amantadine |
Thiazides, including hydrochlorothiazide, may increase the risk of adverse reactions caused by amantadine. |
|
| Anticholinergic agents and other medicinal products affecting gastrointestinal motility |
Anticholinergic agents (e.g., atropine, biperiden) may increase the bioavailability of thiazide diuretics, likely due to reduced gastrointestinal motility and delayed gastric emptying. Conversely, prokinetic agents such as cisapride may reduce the bioavailability of thiazide diuretics. |
|
| Antidiabetic agents (e.g., insulin and oral antidiabetics) Metformin |
Thiazides may alter glucose tolerance. Dose adjustments of insulin and oral hypoglycemic agents may be required. Metformin should be used with caution due to the risk of lactic acidosis associated with potential functional renal impairment caused by hydrochlorothiazide. |
|
| Beta-blockers and diazoxide |
Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta-blockers increases the risk of hyperglycemia. Thiazide diuretics, particularly hydrochlorothiazide, may enhance the hyperglycemic effect of diazoxide. |
|
| Carbamazepine |
Hyponatremia may develop in patients receiving hydrochlorothiazide concomitantly with carbamazepine. Patients should be warned about the possibility of hyponatremic reactions and monitored accordingly. |
|
| Cyclosporine |
Concomitant therapy with cyclosporine increases the risk of hyperuricemia and complications of gout-like type. |
|
| Cytotoxic agents (e.g., cyclophosphamide, methotrexate) |
Thiazides, including hydrochlorothiazide, may reduce renal excretion of cytotoxic agents (e.g., cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects. |
|
| Cardiac glycosides |
Hypokalemia or hypomagnesemia induced by thiazides may predispose to digitalis-induced cardiac arrhythmias. |
|
| Iodine-containing contrast agents |
There is an increased risk of acute renal failure due to diuretic-induced dehydration, especially with high doses of iodine-containing agents. Rehydration should be performed prior to administration. |
|
| Ion-exchange resins |
Cholestyramine and colestipol reduce the absorption of thiazide diuretics, including hydrochlorothiazide, potentially diminishing their therapeutic effects. However, administration of hydrochlorothiazide at least 4 hours before or 4–6 hours after the resin may minimize this interaction. |
|
| Medicinal products affecting potassium levels (potassium-sparing diuretics, corticosteroids, laxatives, ACTH, amphotericin, carbenoxolone, penicillin G, salicylate derivatives) and antiarrhythmic agents |
The hypokalemic effect of hydrochlorothiazide may be enhanced by potassium-wasting diuretics, corticosteroids, laxatives, adrenocorticotropic hormone (ACTH), amphotericin, carbenoxolone, penicillin G, salicylate derivatives, and antiarrhythmic agents. If such agents are prescribed concomitantly with amlodipine/valsartan/hydrochlorothiazide, monitoring of plasma potassium levels is recommended. |
|
| Medicinal products affecting sodium levels |
The hyponatremic effect of diuretics may be enhanced by concomitant use of antidepressants, antipsychotics, antiepileptics, etc. Caution is required during prolonged use of these medicinal products. |
|
| Medicinal products that may cause torsades de pointes |
Due to the risk of hypokalemia, hydrochlorothiazide should be used with caution with medicinal products that may induce torsades de pointes, including class Ia and class III antiarrhythmics, and certain antipsychotics. |
|
| Medicinal products used to treat gout (probenecid, sulfinpyrazone, allopurinol) |
Dose adjustment of uricosuric agents may be necessary, as hydrochlorothiazide may increase serum uric acid levels. Higher doses of probenecid or sulfinpyrazone may be required. Concomitant use of thiazide diuretics, including hydrochlorothiazide, may increase the frequency of hypersensitivity reactions to allopurinol. |
|
| Methyldopa |
Isolated reports of hemolytic anemia have been observed with concomitant use of hydrochlorothiazide and methyldopa. |
|
| Non-depolarizing skeletal muscle relaxants (e.g., tubocurarine) |
Thiazides, including hydrochlorothiazide, potentiate the action of curare derivatives. |
|
| Other antihypertensive agents |
Thiazides potentiate the antihypertensive effect of other antihypertensive agents (e.g., guanethidine, methyldopa, beta-blockers, vasodilators, calcium channel blockers, ACE inhibitors, angiotensin receptor blockers, and direct renin inhibitors). |
|
| Pressor amines (e.g., noradrenaline, adrenaline) |
Hydrochlorothiazide may reduce the response to pressor amines such as noradrenaline. The clinical significance of this effect is insufficient to warrant discontinuation of their use. |
|
| Vitamin D and calcium salts |
Concomitant use of thiazide diuretics, including hydrochlorothiazide, with vitamin D or calcium salts may potentiate increases in serum calcium levels. Concomitant use may lead to hypercalcemia in susceptible patients (e.g., those with hyperparathyroidism, malignancies, or vitamin D-mediated conditions) due to increased tubular reabsorption of calcium. |
|
Double blockade of the RAAS with angiotensin II receptor antagonists, ACE inhibitors, or aliskiren
Clinical data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is associated with an increased risk of adverse reactions, such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to monotherapy with a drug acting on the RAAS (see sections "Contraindications", "Special precautions", and "Pharmacodynamics").
Special precautions for use
The safety and efficacy of amlodipine in hypertensive crisis have not been studied.
Patients with sodium depletion and dehydration
Excessive hypotension, including orthostatic hypotension, was observed in 1.7% of patients receiving the maximum dose of the medicinal product (10 mg/320 mg/25 mg), compared to 1.8% of patients receiving valsartan/hydrochlorothiazide (320 mg/25 mg), 0.4% of patients receiving amlodipine/valsartan (10 mg/320 mg), and 0.2% of patients receiving hydrochlorothiazide/amlodipine (25 mg/10 mg) in a controlled study involving patients with moderate or severe uncomplicated hypertension.
Symptomatic arterial hypotension may occur in patients with salt depletion and/or dehydration who are receiving high-dose diuretics upon initiation of treatment with the medicinal product. It is recommended to correct such conditions prior to administration of the medicinal product or to closely monitor the patient at the beginning of treatment.
If marked arterial hypotension occurs during treatment with the medicinal product, the patient should be placed in a supine position with the legs elevated, and, if necessary, receive intravenous infusion of physiological saline. Treatment may be continued after stabilization of blood pressure.
Changes in serum electrolyte levels
Amlodipine/valsartan/hydrochlorothiazide
In a controlled study of the combination amlodipine/valsartan/hydrochlorothiazide, the opposing effects of valsartan 320 mg and hydrochlorothiazide 25 mg on serum potassium levels approximately balanced each other in many patients. In some patients, one or the other effect may predominate.
Serum electrolyte and potassium levels should be monitored periodically to prevent electrolyte imbalance, especially in patients with risk factors such as impaired renal function, treatment with other medications, or a history of electrolyte imbalance.
Valsartan
Concomitant use with potassium-containing supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other agents that may increase potassium levels (e.g., heparin) is not recommended. If necessary, potassium levels should be monitored.
Hydrochlorothiazide
Initiation of treatment with the medicinal product should only occur after correction of hypokalemia and any concomitant hypomagnesemia. Thiazide diuretics may cause hypokalemia or exacerbate existing hypokalemia. Thiazide diuretics should be used with caution in patients with conditions involving potassium loss, such as salt-wasting nephropathy and prerenal (cardiogenic) renal dysfunction. If hypokalemia develops during hydrochlorothiazide therapy, the medicinal product should be discontinued until potassium balance is stably corrected.
Treatment with thiazide diuretics, including hydrochlorothiazide, is associated with the development of hyponatremia and hypochloremic alkalosis or may exacerbate existing hyponatremia. Hyponatremia accompanied by neurological symptoms (nausea, progressive disorientation, apathy) has been observed. Treatment with hydrochlorothiazide should only be initiated after correction of hyponatremia. If severe or rapidly progressing hyponatremia occurs during treatment, the medicinal product should be discontinued until parameters normalize.
Thiazides, including hydrochlorothiazide, enhance urinary excretion of magnesium, which may lead to hypomagnesemia.
All patients receiving thiazide diuretics require monitoring of electrolyte levels, particularly potassium, sodium, and magnesium.
Renal impairment
Thiazide diuretics may accelerate azotemia in patients with chronic kidney disease.
During treatment with the medicinal product, periodic monitoring of serum potassium, creatinine, and uric acid levels is recommended in patients with renal impairment.
The medicinal product is contraindicated in patients with severe renal impairment, anuria, and patients on dialysis (see section "Contraindications").
No dose adjustment of the medicinal product is required in patients with mild to moderate renal impairment (eGFR ≥ 30 mL/min/1.73 m²).
Renal artery stenosis
The medicinal product should be used with caution in the treatment of hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis of a solitary kidney, as serum urea and creatinine levels may increase.
Kidney transplantation
There is currently no information on the safety of using the medicinal product in patients who have recently undergone kidney transplantation.
Hepatic impairment
Valsartan is primarily excreted unchanged in bile. The elimination half-life of amlodipine is prolonged and the AUC (plasma concentration-time) is higher in patients with hepatic impairment; dosage recommendations are not available. For patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose of valsartan is 80 mg. However, the medicinal product is not indicated for this patient group (see sections "Dosage and administration", "Contraindications", and "Pharmacokinetics").
Angioedema
Angioedema, including laryngeal and glottal edema that may lead to airway obstruction, and/or facial, lip, pharyngeal, and/or tongue swelling, has been observed in patients taking valsartan. Some of these patients had a history of angioedema with other medications, including angiotensin-converting enzyme (ACE) inhibitors. If angioedema occurs, the medicinal product should be discontinued immediately; re-administration is not recommended.
Intestinal angioedema
Intestinal angioedema has been reported in patients receiving angiotensin II receptor antagonists, including valsartan (see section "Adverse reactions"). These patients experienced abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, valsartan should be discontinued and appropriate monitoring initiated until complete symptom resolution.
Heart failure and coronary artery disease / post-myocardial infarction state
Due to inhibition of the renin-angiotensin-aldosterone system, renal dysfunction may be expected in susceptible patients. In patients with severe heart failure, in whom renal function may depend on renin-angiotensin-aldosterone system activity, treatment with ACE inhibitors and angiotensin receptor antagonists may lead to oliguria and/or progressive azotemia (rarely) with acute renal failure and/or fatal outcomes. Similar outcomes have been observed with valsartan use. Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renal function.
In a long-term placebo-controlled study of amlodipine (PRAISE-2) in patients with NYHA (New York Heart Association) class III and IV non-ischemic heart failure, the incidence of pulmonary edema was higher with amlodipine compared to placebo, despite minimal differences in the development or worsening of heart failure.
Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of cardiovascular complications and mortality.
The medicinal product should be prescribed with caution to patients with heart failure and coronary artery disease, particularly at the maximum dose of 10 mg/320 mg/25 mg, as data on use in this patient group are limited.
Aortic and mitral valve stenosis
As with other vasodilators, the medicinal product should be prescribed with particular caution in patients with mild aortic and mitral valve stenosis.
Pregnancy
Treatment with angiotensin II receptor antagonists (ARBs) should not be initiated during pregnancy. If ARB therapy is considered necessary for a woman planning pregnancy, she should switch to alternative antihypertensive agents with established safety profiles in pregnancy. If pregnancy occurs, ARB therapy should be discontinued immediately and, if necessary, alternative therapy initiated (see sections "Contraindications" and "Use in pregnancy and lactation").
Primary hyperaldosteronism
Patients with primary hyperaldosteronism should not be treated with the angiotensin II antagonist valsartan, as the renin-angiotensin system is not activated in these patients. Therefore, the medicinal product is not recommended for this patient group.
Systemic lupus erythematosus
Thiazide diuretics, including hydrochlorothiazide, are known to exacerbate or activate systemic lupus erythematosus.
Other metabolic disturbances
Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance and increase serum cholesterol, triglycerides, and uric acid levels. Dose adjustments of insulin or oral hypoglycemic agents may be required in patients with diabetes mellitus.
Since the medicinal product contains hydrochlorothiazide, it is contraindicated in systemic hyperuricemia. Hydrochlorothiazide may increase serum uric acid levels due to reduced uric acid clearance and may precipitate hyperuricemia and acute gout attacks in susceptible patients.
Thiazides may reduce calcium excretion in urine and cause occasional slight increases in serum calcium levels in the absence of calcium metabolism disorders. The medicinal product should be discontinued if hypercalcemia develops during treatment. Serum calcium levels should be monitored periodically during thiazide therapy. Marked hypercalcemia may indicate occult hyperparathyroidism. Thiazide use should be discontinued before parathyroid function tests are performed.
Photosensitivity
Cases of photosensitivity reactions have been reported with thiazide diuretics. If photosensitivity reactions occur during treatment with the medicinal product, therapy should be discontinued. If resumption of diuretic therapy is considered necessary, protection of exposed skin from sunlight or artificial UV radiation is recommended.
Choroidal effusion, acute myopia, and secondary angle-closure glaucoma
Hydrochlorothiazide, a sulfonamide, has been associated with allergic reactions leading to choroidal effusion with visual field defects, acute transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours or the first week after starting treatment.
Untreated angle-closure glaucoma may lead to irreversible vision loss.
Hydrochlorothiazide should be discontinued as soon as possible. If intraocular pressure remains uncontrolled, immediate medical or surgical treatment should be considered. Risk factors for developing angle-closure glaucoma include a history of allergic reactions to sulfonamides or penicillin.
Hypersensitivity
The medicinal product should be prescribed with caution in patients who have experienced hypersensitivity to other angiotensin II receptor antagonists. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergies or asthma.
Elderly patients (aged 65 years and older)
The medicinal product should be prescribed with caution, particularly with frequent monitoring of blood pressure, in elderly patients, especially at maximum doses of 10 mg/320 mg/25 mg, as data on use in this patient group are limited.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of hypotension, hyperkalemia, and renal dysfunction (including acute renal failure).
Therefore, dual blockade of the RAAS by concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is not recommended (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics").
If dual blockade is required, it should be performed under close specialist supervision with regular monitoring of renal function, electrolyte levels, and blood pressure. Concomitant use of ACE inhibitors and angiotensin II receptor antagonists is not recommended in patients with diabetic nephropathy.
Non-melanoma skin cancer (NMSC)
An increased risk of non-melanoma skin cancer (NMSC) (basal cell carcinoma and squamous cell carcinoma) with increasing cumulative dose of hydrochlorothiazide was observed in two epidemiological studies based on data from the Danish National Cancer Registry. The photosensitizing effect of hydrochlorothiazide is a potential mechanism for NMSC development.
Patients taking hydrochlorothiazide should be informed about the risk of NMSC. These patients should be advised to regularly check their skin for new lesions and promptly report any suspicious skin changes. Preventive measures to minimize skin cancer risk, such as limiting exposure to sunlight and ultraviolet radiation and using adequate protection when exposed to sunlight, may be appropriate. Suspicious skin lesions should be promptly evaluated, including histological examination. The use of hydrochlorothiazide should also be reconsidered in patients with a history of NMSC (see section "Adverse reactions").
Acute respiratory toxicity
Very rare 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, worsening lung condition, and hypotension. If ARDS is suspected, the medicinal product should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be administered to patients who previously experienced ARDS after hydrochlorothiazide intake.
Use during pregnancy or breastfeeding
Pregnancy
Amlodipine
Studies on the safety of amlodipine use during pregnancy have not been conducted. Reproductive toxicity was observed in animal studies with high doses. Use during pregnancy is recommended only if no safer alternative medicinal product is available and if the disease poses a greater risk to the pregnant woman and fetus.
Valsartan
The medicinal product is contraindicated in pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment with this medicinal product, its use should be discontinued immediately and, if necessary, replaced with another medicinal product approved for use during pregnancy.
Hydrochlorothiazide
Experience with hydrochlorothiazide use during pregnancy, especially in the first trimester, is limited. Data from animal studies are insufficient.
Hydrochlorothiazide crosses the placenta. The pharmacological mechanism of action of hydrochlorothiazide suggests that its use during the second and third trimesters of pregnancy may impair fetoplacental perfusion and cause fetal and neonatal adverse effects such as jaundice, electrolyte imbalance, and thrombocytopenia, and may also be associated with other adverse reactions observed in adults.
Amlodipine/valsartan/hydrochlorothiazide
There is no experience with the use of the medicinal product in pregnant women. Due to the effects of individual components during pregnancy, the use of the medicinal product is contraindicated.
Period of breastfeeding
Amlodipine is excreted in breast milk. The fraction of maternal dose received by the infant was estimated at an interquartile range of 3–7%, with a maximum of 15%. The effect of amlodipine on the infant is unknown. Information on the use of valsartan in breastfeeding mothers is lacking. Hydrochlorothiazide is present in breast milk in small amounts. High-dose thiazides causing strong diuresis may interfere with breast milk production.
The use of the medicinal product is contraindicated in women during the breastfeeding period.
Fertility
There are no clinical studies on the effect of the medicinal product on fertility.
Valsartan
Valsartan had no adverse effect on reproductive function in male or female rats at oral doses up to 200 mg/kg/day, which is 6 times the maximum recommended human dose based on mg/m² (oral dose of 320 mg/day for a 60 kg patient).
Amlodipine
Reversible biochemical changes in sperm heads have been reported in some patients receiving calcium channel blockers. Clinical data on the potential effect of amlodipine on fertility are insufficient. Unfavorable effects on male fertility were observed in one rat study.
Ability to influence reaction speed when driving or operating machinery
Dizziness or weakness may occur in patients after taking the medicinal product; therefore, patients should take this into account when driving or operating potentially hazardous machinery.
Amlodipine may slightly or moderately affect the ability to drive or operate machinery. If patients experience dizziness, headache, fatigue, or nausea during amlodipine treatment, their reaction time may be impaired.
Dosage and Administration
The recommended dose of the medicinal product is 1 tablet per day, preferably in the morning.
Before switching to this medicinal product, the patient's arterial pressure should be controlled with unchanged doses of the individual monotherapy components currently being taken. The dose of the medicinal product should correspond to the doses of the individual components of the combination being used at the time of the switch.
The maximum recommended dose of the medicinal product is 10 mg/320 mg/25 mg.
Special Patient Groups
Renal Impairment
Since hydrochlorothiazide is a component of the medicinal product, it is contraindicated in patients with anuria and severe renal impairment (glomerular filtration rate (GFR) < 30 mL/min/1.73 m²) (see sections "Contraindications", "Special Warnings and Precautions for Use", and "Pharmacokinetics").
Dose adjustment is not required in patients with mild or moderate renal impairment (see sections "Contraindications" and "Pharmacokinetics").
Hepatic Impairment
Since valsartan is a component of the medicinal product, it is contraindicated in patients with severe hepatic impairment (see section "Contraindications"). In patients with mild to moderate hepatic impairment not associated with cholestasis, the maximum recommended dose of valsartan is 80 mg; therefore, this medicinal product is not recommended for this patient group (see sections "Contraindications", "Special Warnings and Precautions for Use", and "Pharmacokinetics"). Dosing recommendations for amlodipine in patients with mild to moderate hepatic impairment have not been established. When switching hypertensive patients (see section "Indications") with hepatic impairment to this medicinal product, the lowest available dose of amlodipine should be used.
Heart Failure and Coronary Artery Disease
Experience with the use of this medicinal product, particularly at maximum doses, in patients with heart failure and coronary artery disease is limited. Caution is recommended when administering the product to such patients, especially the maximum dose of 10 mg/320 mg/25 mg.
Elderly Patients (aged 65 years and older)
Caution, including frequent monitoring of arterial pressure, is recommended when administering this medicinal product to elderly patients, particularly the maximum dose of 10 mg/320 mg/25 mg, due to limited data in this patient population. When switching elderly patients to this medicinal product, the lowest available dose of amlodipine should be used.
Administration
The medicinal product is administered orally. It can be taken independently of food intake. Tablets should be swallowed whole with water at the same time each day, preferably in the morning.
Children
There are no adequate data on the use of this medicinal product in the paediatric population (under 18 years of age) for the indication of arterial hypertension.
Overdose
Symptoms
There are no data on overdose with this medicinal product. The main potential symptom of overdose is marked arterial hypotension with dizziness. Overdose of amlodipine may lead to pronounced peripheral vasodilation and reflex tachycardia. Marked and potentially prolonged systemic hypotension has been reported, including shock with fatal outcome.
Rare cases of non-cardiogenic pulmonary oedema following amlodipine overdose have been reported, which may manifest 24–48 hours after ingestion and may require mechanical ventilation. Contributing factors to the development of non-cardiogenic pulmonary oedema may include early resuscitation measures (including fluid overload) aimed at maintaining perfusion and cardiac output.
Treatment
Amlodipine/Valsartan/Hydrochlorothiazide
Clinically significant arterial hypotension due to overdose requires active cardiovascular support, including careful monitoring of cardiac and respiratory function, placing the patient in a supine position with elevation of the lower limbs, monitoring of circulating blood volume and diuresis. Vasoconstrictors may be useful in restoring vascular tone and arterial pressure, provided there are no contraindications to their use. Intravenous calcium gluconate may be effective in reducing the effects of calcium channel blockade.
Amlodipine
If only a short time has passed since ingestion, induction of emesis or gastric lavage may be considered. Administration of activated charcoal within 2 hours of amlodipine intake significantly reduces amlodipine absorption in healthy volunteers.
Amlodipine is unlikely to be removed by hemodialysis.
Valsartan
Valsartan is unlikely to be removed by hemodialysis.
Hydrochlorothiazide
Hydrochlorothiazide overdose is associated with electrolyte depletion (hypokalemia, hypochloremia) and hypovolemia due to excessive diuresis. The most common symptoms of overdose are nausea and drowsiness. Hypokalemia may lead to muscle cramps and/or exacerbation of arrhythmias, particularly in patients receiving concomitant digitalis glycosides or certain antiarrhythmic drugs.
The extent to which hydrochlorothiazide is removed by hemodialysis has not been established.
Adverse Reactions
The safety profile presented below is based on results from clinical studies and safety data for the individual components: amlodipine, valsartan, and hydrochlorothiazide.
Summary of safety profile
The safety of the medicinal product was evaluated at the maximum dose of 10 mg/320 mg/25 mg in a controlled short-term (8-week) clinical study involving 2,271 patients, of whom 582 received valsartan in combination with amlodipine and hydrochlorothiazide. Adverse reactions were generally mild and transient and rarely required discontinuation of therapy. In this actively controlled clinical study, the most common reasons for treatment discontinuation were dizziness and hypotension (0.7%).
In the 8-week controlled clinical study, no significant new or unexpected adverse effects were observed with triple therapy compared to the known effects of monotherapy or dual therapy with the active substances of the medicinal product.
In the 8-week controlled clinical study, laboratory test changes observed during treatment with the medicinal product were minor and consistent with the pharmacological mechanisms of action of the individual monotherapeutic agents. The presence of valsartan in the triple combination attenuated the hypokalemic effect of hydrochlorothiazide.
List of adverse reactions
Below is a list of adverse reactions of the amlodipine/valsartan/hydrochlorothiazide combination, as well as those of amlodipine, valsartan, and hydrochlorothiazide individually, by organ system (according to MedDRA [Medical Dictionary for Regulatory Activities]).
Frequency is defined as: very common — ≥ 1/10; common — ≥ 1/100 to < 1/10; uncommon — ≥ 1/1000 to < 1/100; rare — ≥ 1/10,000 to < 1/1000; very rare — < 1/10,000; not known — cannot be estimated from available data.
Table 2
| Organ systems |
Adverse reactions |
Frequency |
|||
| Demerkon |
Amlodipine |
Valsartan |
Hydrochlorothiazide |
||
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) |
-- |
-- |
-- |
Unknown |
| Blood and lymphatic system |
Agranulocytosis, bone marrow failure |
-- |
-- |
-- |
Very rare |
| Decreased hemoglobin and hematocrit levels |
-- |
-- |
Unknown |
-- |
|
| Hemolytic anemia |
-- |
-- |
-- |
Very rare |
|
| Leukopenia |
-- |
Very rare |
-- |
Very rare |
|
| Neutropenia |
-- |
-- |
Unknown |
-- |
|
| Thrombocytopenia, sometimes with purpura |
-- |
Very rare |
Unknown |
Rare |
|
| Aplastic anemia |
-- |
-- |
-- |
Unknown |
|
| Immune system |
Hypersensitivity |
-- |
Very rare |
Unknown |
Very rare |
| Metabolism and nutrition |
Anorexia |
Uncommon |
-- |
-- |
-- |
| Hypercalcemia |
Uncommon |
-- |
-- |
Rare |
|
| Hyperglycemia |
-- |
Very rare |
-- |
Rare |
|
| Hyperlipidemia |
Uncommon |
-- |
-- |
-- |
|
| Hyperuricemia |
Uncommon |
-- |
-- |
Common |
|
| Hyperchloremic alkalosis |
-- |
-- |
-- |
Very rare |
|
| Hypokalemia |
Common |
-- |
-- |
Very common |
|
| Hypomagnesemia |
-- |
-- |
-- |
Common |
|
| Hyponatremia |
Uncommon |
-- |
-- |
Common |
|
| Worsening of metabolic signs of diabetes |
-- |
-- |
-- |
Rare |
|
| Psychiatric disorders |
Depression |
-- |
Uncommon |
-- |
Rare |
| Insomnia / sleep disturbances |
Uncommon |
Uncommon |
-- |
Rare |
|
| Mood changes |
-- |
Uncommon |
-- |
||
| Apathy |
-- |
Rare |
-- |
-- |
|
| Nervous system |
Coordination disorders |
Uncommon |
-- |
-- |
-- |
| Dizziness |
Common |
Common |
-- |
Rare |
|
| Postural dizziness, effort-induced dizziness |
Uncommon |
-- |
-- |
-- |
|
| Dysgeusia |
Uncommon |
Uncommon |
-- |
-- |
|
| Extrapyramidal syndrome |
-- |
Unknown |
-- |
-- |
|
| Headache |
Common |
Common |
-- |
Rare |
|
| Hypertonia |
-- |
Very rare |
-- |
-- |
|
| Lethargy |
Uncommon |
-- |
-- |
-- |
|
| Paresthesia |
Uncommon |
Uncommon |
-- |
Rare |
|
| Peripheral neuropathy, neuropathy |
Uncommon |
Very rare |
-- |
-- |
|
| Somnolence |
Uncommon |
Common |
-- |
-- |
|
| Syncope |
Uncommon |
Uncommon |
-- |
-- |
|
| Tremor |
-- |
Uncommon |
-- |
-- |
|
| Hypoesthesia |
-- |
Uncommon |
-- |
-- |
|
| Eye disorders |
Visual disturbances |
Uncommon |
Uncommon |
-- |
Rare |
| Visual disorders |
-- |
Uncommon |
-- |
-- |
|
| Acute angle-closure glaucoma |
-- |
-- |
-- |
Unknown |
|
| Choroidal effusion |
-- |
-- |
-- |
Unknown |
|
| Ear and labyrinth disorders |
Tinnitus |
-- |
Uncommon |
-- |
-- |
| Vertigo |
Uncommon |
-- |
Uncommon |
-- |
|
| Cardiac disorders |
Palpitations |
-- |
Common |
-- |
-- |
| Tachycardia |
Uncommon |
-- |
-- |
-- |
|
| Arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation) |
-- |
Very rare |
-- |
Rare |
|
| Myocardial infarction |
-- |
Very rare |
-- |
-- |
|
| Vascular disorders |
Flushing |
-- |
Common |
-- |
-- |
| Arterial hypotension |
Common |
Uncommon |
-- |
-- |
|
| Orthostatic hypotension |
Uncommon |
-- |
-- |
Common |
|
| Phlebitis, thrombophlebitis |
Uncommon |
-- |
-- |
-- |
|
| Vasculitis |
-- |
Very rare |
Unknown |
-- |
|
| Respiratory, thoracic and mediastinal disorders |
Cough |
Uncommon |
Very rare |
Uncommon |
|
| Dyspnea |
Uncommon |
Uncommon |
-- |
-- |
|
| Acute respiratory distress syndrome (ARDS) (see section "Special precautions"), pulmonary edema, pneumonitis |
-- |
-- |
-- |
Very rare |
|
| Rhinitis |
-- |
Uncommon |
-- |
-- |
|
| Throat irritation |
Uncommon |
-- |
-- |
-- |
|
| Gastrointestinal disorders |
Abdominal discomfort, upper abdominal pain |
Uncommon |
Common |
Uncommon |
Rare |
| Intestinal angioedema |
-- |
-- |
Very rare |
-- |
|
| Unpleasant breath odor |
Uncommon |
-- |
-- |
-- |
|
| Change in defecation frequency |
-- |
Uncommon |
-- |
-- |
|
| Constipation |
-- |
-- |
-- |
Rare |
|
| Decreased appetite |
-- |
-- |
-- |
Common |
|
| Diarrhea |
Uncommon |
Uncommon |
-- |
Rare |
|
| Dry mouth |
Uncommon |
Uncommon |
-- |
-- |
|
| Dyspepsia |
Common |
Uncommon |
-- |
-- |
|
| Gastritis |
-- |
Very rare |
-- |
-- |
|
| Gingival hyperplasia |
-- |
Very rare |
-- |
-- |
|
| Nausea |
Uncommon |
Common |
-- |
Common |
|
| Pancreatitis |
-- |
Very rare |
-- |
Very rare |
|
| Vomiting |
Uncommon |
Uncommon |
-- |
Common |
|
| Hepatobiliary disorders |
Elevated liver enzymes, including elevated serum bilirubin levels |
-- |
Very rare** |
Unknown |
-- |
| Hepatitis |
-- |
Very rare |
-- |
-- |
|
| Intrahepatic cholestasis, jaundice |
-- |
Very rare |
-- |
Rare |
|
| Skin and subcutaneous tissue disorders |
Alopecia |
-- |
Uncommon |
-- |
-- |
| Angioedema |
-- |
Very rare |
Unknown |
-- |
|
| Bullous dermatitis |
-- |
-- |
Unknown |
-- |
|
| Skin reactions resembling lupus erythematosus, reactivation of cutaneous lupus erythematosus |
-- |
-- |
-- |
Very rare |
|
| Multiform erythema |
-- |
Very rare |
-- |
Unknown |
|
| Exanthema |
-- |
Uncommon |
-- |
-- |
|
| Hyperhidrosis |
Uncommon |
Uncommon |
-- |
-- |
|
| Photosensitivity reactions* |
-- |
Very rare |
-- |
Rare |
|
| Pruritus |
Uncommon |
Uncommon |
Unknown |
-- |
|
| Purpura |
-- |
Uncommon |
-- |
Rare |
|
| Rash |
-- |
Uncommon |
Unknown |
Common |
|
| Skin color changes |
-- |
Uncommon |
-- |
-- |
|
| Urticaria and other forms of rash |
-- |
Very rare |
-- |
Common |
|
| Necrotic vasculitis and toxic epidermal necrolysis |
-- |
Unknown |
-- |
Very rare |
|
| Exfoliative dermatitis |
-- |
Very rare |
-- |
-- |
|
| Stevens-Johnson syndrome |
-- |
Very rare |
-- |
-- |
|
| Quincke's edema |
-- |
Very rare |
-- |
-- |
|
| Musculoskeletal and connective tissue disorders |
Arthralgia |
-- |
Uncommon |
-- |
-- |
| Back pain |
Uncommon |
Uncommon |
-- |
-- |
|
| Joint swelling |
Uncommon |
-- |
-- |
-- |
|
| Muscle cramps |
Uncommon |
Uncommon |
-- |
Unknown |
|
| Muscle weakness |
Uncommon |
-- |
-- |
-- |
|
| Myalgia |
Uncommon |
Uncommon |
Unknown |
-- |
|
| Limb pain |
Uncommon |
-- |
-- |
-- |
|
| Ankle swelling |
-- |
Common |
-- |
-- |
|
| Renal and urinary system disorders |
Elevated serum creatinine levels |
Uncommon |
-- |
Unknown |
-- |
| Urination disorders |
Uncommon |
||||
| Nocturia |
-- |
Uncommon |
-- |
-- |
|
| Polyuria |
Common |
Uncommon |
-- |
-- |
|
| Renal dysfunction |
-- |
-- |
-- |
Unknown |
|
| Acute renal failure |
Uncommon |
-- |
-- |
Unknown |
|
| Renal failure and impaired kidney function |
-- |
-- |
Unknown |
Rare |
|
| Reproductive system and breast disorders |
Impotence |
Uncommon |
Uncommon |
-- |
Common |
| Gynecomastia |
-- |
Uncommon |
-- |
-- |
|
| General disorders and administration site conditions |
Akinesia, gait disturbance |
Uncommon |
-- |
-- |
-- |
| Asthenia |
Uncommon |
Uncommon |
-- |
Unknown |
|
| Discomfort, malaise |
Uncommon |
Uncommon |
-- |
-- |
|
| Weakness |
Common |
Common |
Uncommon |
-- |
|
| Non-cardiac chest pain |
Uncommon |
Uncommon |
-- |
-- |
|
| Edema |
Common |
Common |
-- |
-- |
|
| Pyrexia |
-- |
-- |
-- |
Unknown |
|
| Pain |
-- |
Uncommon |
-- |
-- |
|
| Investigations |
Elevated lipid levels |
-- |
Very common |
||
| Elevated blood urea nitrogen |
Uncommon |
-- |
-- |
-- |
|
| Elevated blood uric acid levels |
Uncommon |
-- |
-- |
-- |
|
| Glucosuria |
Rare |
||||
| Decreased blood potassium levels |
Uncommon |
-- |
-- |
-- |
|
| Elevated blood potassium levels |
-- |
-- |
Unknown |
-- |
|
| Increased body weight |
Uncommon |
Uncommon |
-- |
-- |
|
| Decreased body weight |
-- |
Uncommon |
-- |
-- |
|
*See section "Special precautions. Photosensitivity".
**More associated with cholestasis.
Description of individual adverse reactions
Non-melanoma skin cancer: according to available epidemiological data, there is a cumulative dose-response relationship between the use of hydrochlorothiazide and the development of NMSC.
Reporting of adverse reactions after marketing authorization 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 of the medicinal product through the Automated Pharmacovigilance Information System at the following link: http://aisf.dec.gov.ua/.
Shelf life. 2 years.
Storage conditions.
Store at temperatures not exceeding 30 °C, in a light-resistant and moisture-protected place.
Keep out of reach of children.
Packaging. 14 tablets in a blister pack, 2 blisters in a cardboard box.
Prescription status. Prescription only.
Manufacturer.
ALKALOID AD Skopje.
ALKALOID AD Skopje.
Manufacturer's address and site of operations.
Boulevard Aleksandar Makedonski 12, Skopje, 1000, Republic of North Macedonia.