Instructions for use Kombisart H tablets 5 mg / 160 mg / 12.5 mg No. 30
Composition
active ingredients: amlodipine, valsartan, hydrochlorothiazide;
1 tablet 5 mg/160 mg/12.5 mg contains: amlodipine besylate 6.94 mg, corresponding to 5 mg amlodipine; valsartan 160 mg; hydrochlorothiazide 12.5 mg;
excipients: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;
shell: film coating mixture Opadry II White 32F280008 (hypromellose (hydroxypropylmethylcellulose); lactose monohydrate; titanium dioxide (E 171); polyethylene glycol (macrogol));
or
active ingredients: amlodipine, valsartan, hydrochlorothiazide;
1 tablet 10 mg/160 mg/12.5 mg contains: amlodipine besylate 13.87 mg, corresponding to 10 mg amlodipine; valsartan 160 mg; hydrochlorothiazide 12.5 mg;
excipients: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;
shell: film-coating mixture Opadry II Orange 32F230000 (hypromellose (hydroxypropylmethylcellulose); lactose monohydrate; titanium dioxide (E 171); polyethylene glycol (macrogol); iron oxide yellow (E 172); iron oxide red (E 172)).
Dosage form
Film-coated tablets.
Main physicochemical properties:
5 mg/160 mg/12.5 mg tablets: oval-shaped tablets with a flat surface with beveled edges, coated with a white film coating;
10 mg/160 mg/12.5 mg tablets: oval-shaped tablets with a flat surface and beveled edges, coated with a light reddish-brown film coat.
Pharmacotherapeutic group
Angiotensin II antagonists, other combinations.
ATX code C09D X01.
Pharmacological properties
Pharmacodynamics
Kombisart H contains three antihypertensive agents with complementary mechanisms of blood pressure control in patients with essential hypertension: amlodipine belongs to the class of calcium antagonists, valsartan to the class of angiotensin II antagonists, and hydrochlorothiazide to the class of thiazide diuretics.
The combination of these three components is characterized by a complementary antihypertensive effect.
Amlodipine
Amlodipine, which is part of Kombisart H, inhibits the transmembrane entry of calcium ions into the heart muscle and vascular smooth muscle. The mechanism of antihypertensive action of amlodipine occurs through a direct relaxing effect on vascular smooth muscle, causing a decrease in peripheral vascular resistance and blood pressure.
Amlodipine at therapeutic doses in patients with hypertension causes vasodilation, resulting in a decrease in supine and standing blood pressure. This decrease in blood pressure is not accompanied by significant changes in heart rate or plasma catecholamine levels with prolonged use.
Plasma concentrations correlate with effect in both young and elderly patients.
In patients with arterial hypertension and normal renal function, amlodipine in therapeutic doses leads to a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without changing the filtration fraction or proteinuria.
Valsartan
Valsartan is an orally active, potent and specific angiotensin II receptor antagonist. Valsartan acts selectively on the AT1 receptor subtype, which is responsible for the known effects of angiotensin II.
Taking valsartan by patients with arterial hypertension helps reduce blood pressure without affecting pulse rate.
In most patients, after a single oral dose, the onset of the hypotensive effect occurs within 2 hours, and the maximum reduction in blood pressure is achieved within 4-6 hours. The antihypertensive effect lasts for 24 hours after administration of the drug. With repeated administration, the maximum reduction in blood pressure (with all dosage regimens) is usually achieved within 2-4 weeks.
Hydrochlorothiazide
The site of action of thiazide diuretics is mainly the distal convoluted tubules of the kidneys. It has been confirmed that there are high-affinity receptors in the renal cortex, which are the main binding site for thiazide diuretics and inhibit NaCl transport into the distal convoluted tubules. The mechanism of action of thiazides is to inhibit Na+Cl– transporters, possibly by competing for Cl– sites, which in turn affects the mechanisms of electrolyte reabsorption: directly increases the excretion of sodium and chlorine to an approximately equivalent extent and indirectly, due to the diuretic effect, reduces plasma volume with subsequent increases in plasma renin activity, aldosterone secretion and urinary potassium excretion, as well as a decrease in serum potassium.
Available epidemiological data suggest a cumulative dose-dependent association between hydrochlorothiazide exposure and the development of NSCLC. One study included 71,533 cases of basal cell carcinoma (including 1,430,833 controls) and 8,629 cases of squamous cell carcinoma (including 172,462 controls). High doses of hydrochlorothiazide (≥50,000 mg cumulative) were associated with an adjusted odds ratio (OR) 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 carcinoma and squamous cell carcinoma. Another study showed a possible association between lip cancer and hydrochlorothiazide use: 633 lip cancer cases were matched to 63,067 population controls using a risk selection strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR of 2.1 (95% CI: 1.7–2.6) increasing to an OR of 3.9 (3.0–4.9) for the high dose (25,000 mg) and an OR of 7.7 (5.7–10.5) for the highest dose (100,000 mg).
Other: dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Two large randomized controlled trials, ONTARGET (an ongoing trial of telmisartan alone and in combination with ramipril) and VA NEPHRON-D (a Veterans Affairs diabetic nephropathy trial), have examined the concomitant use of an ACE inhibitor with an angiotensin II receptor antagonist.
The ONTARGET study was conducted in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. The VA NEPHRON-D study was conducted in patients with type 2 diabetes and diabetic nephropathy.
These studies did not show any significant benefit on renal and/or cardiovascular function or mortality; however, there was an increased risk of hyperkalemia, acute kidney injury, and/or hypotension compared with monotherapy. Given their similar pharmacodynamic properties, these results are also relevant for other ACE inhibitors and angiotensin II receptor antagonists.
Therefore, the concomitant use of ACE inhibitors and angiotensin II receptor antagonists is not recommended in patients with diabetic nephropathy (see section "Special warnings and precautions for use").
In addition, the ALTITUDE trial (Aliskiren in Type 2 Diabetes with Cardiovascular and Renal Endpoints) tested the benefits of adding aliskiren to standard therapy (ACE inhibitor or angiotensin II receptor antagonist) in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. The trial was terminated early due to an increased risk of adverse outcomes. Cardiovascular death and stroke were significantly more common in the aliskiren add-on group than in the placebo group; in addition, adverse events and serious adverse events (hyperkalemia, hypotension, and renal dysfunction) were more common in the aliskiren group than in the placebo group.
Pharmacokinetics
Linearity
Amlodipine, valsartan and hydrochlorothiazide exhibit linear pharmacokinetics.
Amlodipine/valsartan/hydrochlorothiazide
After oral administration of Combisart H to healthy adult volunteers, peak plasma concentrations of amlodipine, valsartan and hydrochlorothiazide were achieved within 6–8 hours, 3 hours and 2 hours, respectively. The rate and extent of absorption of amlodipine, valsartan and hydrochlorothiazide from Combisart H are similar to those observed when the components are administered as separate drugs.
Amlodipine
Absorption: After oral administration of therapeutic doses of amlodipine alone, peak plasma concentrations were reached within 6–12 hours. Absolute bioavailability ranged from 64 to 80%. Food intake did not affect the bioavailability of amlodipine.
Distribution: The volume of distribution is approximately 21 L/kg. In vitro studies of amlodipine have shown that approximately 97.5% of the drug in circulating blood is bound to plasma proteins.
Biotransformation: Amlodipine is extensively (approximately 90%) metabolized in the liver to inactive metabolites.
Elimination: Amlodipine is eliminated from plasma in two phases, with a terminal half-life of approximately 30–50 hours. Steady-state plasma levels are reached after 7–8 days of continuous dosing. 10% of parent amlodipine and 60% of amlodipine metabolites are excreted in the urine.
Valsartan
Distribution: The volume of distribution of valsartan at steady state after intravenous administration is approximately 17 liters, indicating that valsartan is not extensively distributed. Valsartan is extensively bound to serum proteins (94–97%), mainly to serum albumin.
Biotransformation: Valsartan is not significantly transformed, with only approximately 20% of the dose 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 is excreted primarily in the feces (approximately 83% of the dose) and urine (approximately 13% of the dose), mainly as unchanged drug. After intravenous administration, 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 dose-proportional over the therapeutic dose range. There is no change in the kinetics of hydrochlorothiazide with repeated administration, and accumulation was minimal with once-daily dosing. Both increases and decreases in systemic availability of hydrochlorothiazide were observed when taken with food compared with fasting conditions. The magnitude of these effects is small and of little clinical significance. The absolute bioavailability of hydrochlorothiazide is 60–80% after oral administration.
Distribution: The apparent volume of distribution is 4–8 L/kg. Hydrochlorothiazide in the circulating blood is bound to plasma proteins (40–70%), mainly serum albumin. Hydrochlorothiazide also accumulates in erythrocytes at levels 1.8 times higher than in plasma.
Biotransformation: Hydrochlorothiazide is excreted unchanged.
Excretion: More than 95% of the absorbed dose is excreted unchanged in the urine. Renal clearance consists of passive filtration and active secretion in the renal tubules. The half-life is 6–15 hours.
Certain patient groups
Children (under 18 years of age)
There are no pharmacokinetic data in children.
Elderly patients (aged 65 years and over)
The time to reach Cmax of amlodipine is similar in young and elderly patients. In elderly patients, the clearance of amlodipine tends to decrease, resulting in an increase in the area under the curve (AUC) and half-life. The mean systemic AUC of valsartan is 70% higher in elderly patients than in younger patients, so caution is advised when increasing the dose in such patients.
Systemic exposure to valsartan is slightly higher in elderly patients compared to younger patients, but this is not clinically relevant.
Limited data indicate that the systemic clearance of hydrochlorothiazide is reduced in both healthy elderly volunteers and elderly patients with hypertension compared to younger healthy volunteers.
Since the three components of the drug are equally well tolerated by young and elderly patients, the usual dosage regimen is recommended.
Kidney dysfunction
Renal impairment does not significantly affect the pharmacokinetics of amlodipine. As expected, for a drug whose renal clearance accounts for only 30% of total plasma clearance, there was no relationship between renal function and systemic exposure to valsartan. Therefore, patients with mild to moderate renal impairment can use the drug at the usual starting dose.
Liver dysfunction
In patients with impaired liver function, the clearance of amlodipine is reduced, resulting in an increase in AUC by approximately 40-60%. On average, in patients with chronic diseases of mild to moderate severity, the exposure (determined by AUC) of valsartan is 2 times higher than in adult volunteers (grouped by age, gender and body weight). The drug should be prescribed with caution to patients with liver disease.
The combination of amlodipine/valsartan/hydrochlorothiazide has not been tested for genotoxicity and carcinogenicity, as there is no evidence of interaction between these drugs, which have been on the market for a long time. However, amlodipine, valsartan and hydrochlorothiazide have been tested individually for genotoxicity and carcinogenicity; negative results were obtained.
Indication
Treatment of essential hypertension in adult patients whose blood pressure is adequately controlled with a combination of amlodipine, valsartan and hydrochlorothiazide, given as three separate drugs or as two drugs, one of which is a combination.
Contraindication
Hypersensitivity to the active substances, other sulfonamides, dihydropyridine derivatives or to any of the excipients.
Pregnancy or planning pregnancy (see "Use during pregnancy or breastfeeding").
Liver dysfunction, biliary cirrhosis or cholestasis.
Concomitant use of Combisart H with aliskiren-containing drugs in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2).
Refractory hypokalemia, hyponatremia, hypercalcemia, symptomatic hyperuricemia.
Severe hypotension.
Shock (including cardiogenic shock).
Left ventricular outflow tract obstruction (e.g. hypertrophic obstructive cardiomyopathy and severe aortic stenosis).
Hemodynamically unstable heart failure after acute myocardial infarction.
Interaction with other medicinal products and other types of interactions
Interaction studies with other medicinal products have not been conducted. Table 1 only presents information on interactions with other medicinal products known for each individual active substance.
However, it is important to consider that the drug Kombisart H may enhance the hypotensive effect of other antihypertensive drugs.
Table 1
| Concomitant use is not recommended. |
| Components of Kombisart N | Drugs and substances with which interactions exist | Effect upon interaction |
| Valsartan and hydrochlorothiazide | Lithium | Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant use of lithium with ACE inhibitors, angiotensin II receptor antagonists including valsartan, or thiazides such as hydrochlorothiazide. Since renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity is likely to increase with the use of Combisart N. In this regard, careful monitoring of serum lithium levels is recommended during concomitant use of the drugs. |
| Valsartan | Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, and other agents that may increase potassium levels | If a medicinal product that affects potassium levels is required in combination with valsartan, frequent monitoring of plasma potassium levels is recommended. |
| Amlodipine | Grapefruit or grapefruit juice | The use of amlodipine with grapefruit or grapefruit juice is not recommended, as bioequivalence may be increased in some patients, leading to an increased blood pressure-lowering effect. |
| Concomitant use requires caution |
| Components of Kombisart N | Drugs and substances with which interactions exist | Effect upon interaction |
| Amlodipine | CYP3A4 inhibitors (such as ketoconazole, itraconazole, ritonavir) | Studies in elderly patients have shown that diltiazem inhibits the metabolism of amlodipine, possibly with the participation of CYP3A4 (plasma concentration increases by approximately 50% and the effect of amlodipine is enhanced). It cannot be excluded that more potent CYP3A4 inhibitors (such as ketoconazole, itraconazole, ritonavir) may increase the plasma concentration of amlodipine to a greater extent 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 result in a significant increase in amlodipine exposure. The clinical manifestations of these pharmacokinetic changes may be more pronounced in elderly patients. Therefore, clinical monitoring and dose adjustment may be required. |
| CYP3A4 inducers (anticonvulsants [such as carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone], rifampicin, 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 lead to decreased plasma concentrations of amlodipine. Clinical monitoring with possible dose adjustment of amlodipine is indicated during treatment with the inducer and after its withdrawal. Amlodipine should be used with caution with CYP3A4 inducers. | - |
| Simvastatin | Administration of multiple doses of 10 mg amlodipine with 80 mg simvastatin resulted in a 77% increase in simvastatin exposure compared to administration of simvastatin alone. It is recommended that the daily dose of simvastatin be reduced to 20 mg in patients taking amlodipine. | - |
| Dantrolene (infusion) | Fatalities due to ventricular fibrillation and cardiovascular collapse have been observed in animals due to hyperkalemia following intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalemia, it is recommended that concomitant use of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the treatment of malignant hyperthermia. | - |
| Valsartan and hydrochlorothiazide | NSAIDs may reduce the antihypertensive effect of both angiotensin II antagonists and hydrochlorothiazide when used concomitantly. In addition, concomitant use of Combisart H and NSAIDs may lead to deterioration of renal function and an increase in serum potassium. Therefore, monitoring of renal function at the beginning of treatment and appropriate hydration of the patient are recommended. |
| Valsartan | Inhibitors of the accumulation transporter (rifampicin, cyclosporine) or efflux transporter (ritonavir) | In vitro studies with 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 the uptake transporter (rifampicin, cyclosporine) or efflux transporter (ritonavir) may increase systemic exposure to valsartan. |
| Hydrochlorothiazide | Alcohol, barbiturates, or narcotics | Concomitant administration of thiazide diuretics with substances that also have a blood pressure-lowering effect (e.g. those that reduce sympathetic activity of the central nervous system or direct vasodilation) may increase orthostatic hypotension. |
| Amantadine | Thiazides, including hydrochlorothiazide, may increase the risk of adverse reactions caused by amantadine. | - |
| Anticholinergic drugs and other drugs that affect gastric motility | The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g. atropine, biperiden), apparently by reducing gastrointestinal motility and gastric emptying rate. Conversely, it is thought that prokinetic agents such as cisapride may reduce the bioavailability of thiazide diuretics. | - |
Antidiabetic medications (e.g. insulin and oral antidiabetic agents) Metformin | Thiazides may alter glucose tolerance. Insulin and oral hypoglycemic agents may need to be re-adjusted. Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure associated with the use of hydrochlorothiazide. | - |
| Beta-blockers and diazoxide | Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta-blockers may increase the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may enhance the hyperglycemic effect of diazoxide. | - |
| Carbamazepine | Hyponatremia may develop in patients receiving hydrochlorothiazide concomitantly with carbamazepine. Therefore, patients should be warned about the possibility of hyponatremic reactions and monitored. | - |
| Cyclosporine | Concomitant treatment with cyclosporine may increase the risk of hyperuricemia and gout-like complications. | - |
| Cytotoxic drugs (e.g. cyclophosphamide, methotrexate) | Thiazides, including hydrochlorothiazide, may reduce the renal excretion of cytotoxic drugs (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effect. | - |
| Digitalis glycosides | Thiazide-induced hypokalemia or hypomagnesemia may occur as adverse effects, contributing to the development of digitalis-induced cardiac arrhythmias. | - |
| Iodine-containing contrast agents | In case of diuretic-induced dehydration, there is an increased risk of developing acute renal failure, especially with high doses of iodine preparations. Rehydration should be performed before use. | - |
| Ion exchange resins | The absorption of thiazide diuretics, including hydrochlorothiazide, is reduced by cholestyramine or colestipol. This may result in subtherapeutic effects of the thiazide diuretics. However, the effective dose of hydrochlorothiazide and the resin is such that hydrochlorothiazide should be administered at least 4 hours before or 4 to 6 hours after the resin, potentially minimizing the interaction. | - |
| Drugs that affect potassium levels (kaliuretic diuretics, corticosteroids, laxatives, ACTH, amphotericin, carbenoxolone, penicillin G, salicylic acid derivatives) and antiarrhythmics | The hypokalemic effect of hydrochlorothiazide may be enhanced by kaliuretic diuretics, corticosteroids, laxatives, adrenocorticotropic hormone (ACTH), amphotericin, carbenoxolone, penicillin G, salicylic acid derivatives and antiarrhythmics. If such drugs are prescribed with the combination of amlodipine/valsartan/hydrochlorothiazide, monitoring of plasma potassium levels is recommended. | - |
| Medications that affect sodium levels | The hyponatremic effect of diuretics may be enhanced by antidepressants, antipsychotics, antiepileptic drugs, etc. Caution is required with prolonged use of these drugs. | - |
| Due to the risk of hypokalemia, hydrochlorothiazide should be used with caution with drugs that can induce torsades de pointes, in particular with class Ia and class III antiarrhythmic drugs, as well as with some antipsychotics. | - |
| Medications used to treat gout (probenecid, sulfinpyrazone, and allopurinol) | Dose adjustment of uricosuric medicinal products may be necessary as hydrochlorothiazide may increase serum uric acid levels. Dose increase of probenecid or sulfinpyrazone may be necessary. Concomitant administration of thiazide diuretics, including hydrochlorothiazide, may increase the incidence of hypersensitivity reactions to allopurinol. | - |
| Methyldopa | There have been isolated reports of the development of hemolytic anemia with the simultaneous use of hydrochlorothiazide and methyldopa. | - |
| Non-depolarizing skeletal muscle relaxants (e.g. tubocurarine) | Thiazides, including hydrochlorothiazide, potentiate the action of curare derivatives. | - |
| Other antihypertensive drugs | Thiazides potentiate the antihypertensive effect of other antihypertensive drugs (such as guanethidine, methyldopa, beta-blockers, vasodilators, calcium channel blockers, ACE inhibitors, angiotensin II receptor blockers and direct renin inhibitors). | - |
| Pressor amines (e.g., noradrenaline, adrenaline) | Hydrochlorothiazide may reduce the response to pressor amines such as norepinephrine. The clinical significance of this effect is uncertain and insufficient to warrant discontinuation of their use. | - |
| Vitamin D and calcium salts | The use of thiazide diuretics, including hydrochlorothiazide, with vitamin D or calcium salts may potentiate the increase in serum calcium levels. Concomitant use of thiazide diuretics may lead to hypercalcemia in predisposed patients (e.g., hyperparathyroidism, malignancy, or vitamin D-mediated conditions) by increasing tubular calcium reabsorption. | - |
Dual blockade of the RAAS with angiotensin II receptor antagonists, ACE inhibitors, or aliskiren
Clinical data have demonstrated that dual blockade of the RAAS through the 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 renal impairment (including acute renal failure) compared with monotherapy with a substance affecting the RAAS.
Application features
The safety and efficacy of amlodipine in hypertensive crisis have not been studied.
Patients with sodium deficiency and dehydration
In patients with salt depletion and/or dehydration receiving high doses of diuretics, symptomatic hypotension may occur after initiation of treatment. It is recommended to correct this condition before starting treatment with Combisart H or to closely monitor the patient at the beginning of treatment.
If severe hypotension occurs during the use of Combisart H, the patient should be placed in a horizontal position with the lower extremities elevated and, if necessary, intravenous saline infusion should be administered. Treatment can be continued after blood pressure has stabilized.
Changes in serum electrolyte levels
Amlodipine/valsartan/hydrochlorothiazide
Serum electrolyte levels should be checked periodically to identify possible electrolyte imbalance.
Periodic determination of serum electrolytes and potassium levels should be performed at appropriate intervals to prevent possible electrolyte imbalance, especially in patients with risk factors such as renal impairment, treatment with other drugs and a history of electrolyte imbalance.
Valsartan
Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other drugs that may increase potassium levels (e.g. heparin) is not recommended. Potassium levels should be monitored if necessary.
Hydrochlorothiazide
Hypokalemia has been reported with thiazide diuretics, including hydrochlorothiazide.
Treatment with thiazide diuretics, including hydrochlorothiazide, is associated with the development of hyponatremia and hypochloremic alkalosis or with exacerbation of existing hyponatremia. Hyponatremia is observed, accompanied by neurological symptoms (nausea, progressive disorientation, apathy). Treatment with hydrochlorothiazide should be started only after correction of existing hyponatremia. In case of severe or rapid hyponatremia during treatment with Kombisart H, the drug should be discontinued until normalization of sodium. Thiazides, including hydrochlorothiazide, increase the excretion of magnesium in the urine, which can lead to hypomagnesemia. When using thiazide diuretics, calcium excretion is reduced, which can lead to hypercalcemia.
All patients receiving thiazide diuretics should have periodic monitoring of electrolyte levels, especially potassium, sodium, and magnesium.
Kidney dysfunction
Thiazide diuretics may precipitate azotemia in patients with chronic kidney disease.
When using the drug Combisart H, it is recommended to periodically monitor the level of potassium, creatinine and uric acid in the blood serum of patients with impaired renal function.
Kombisart H is contraindicated in patients with severe renal insufficiency, anuria, or patients on dialysis.
There is no need to adjust the dose of Combisart H in patients with mild to moderate renal impairment (GFR ≥ 30 ml/min/1.73 m2).
Renal artery stenosis
Kombisart H should be used with caution for the treatment of hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, as serum urea and creatinine levels may increase.
Kidney transplantation
There is currently no information on the safety of using Combisart H in patients who have recently undergone a kidney transplant.
Liver dysfunction
Valsartan is mainly excreted unchanged in the bile. The half-life of amlodipine is prolonged and the AUC (plasma concentration-time) is higher in patients with impaired liver function; no dosage recommendations are available. For patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose of valsartan is 80 mg. For this reason, Combisart H is not indicated in this group of patients.
Angioedema.
Angioedema, including swelling of the larynx and glottis, which may lead to airway obstruction, and/or swelling of the face, lips, pharynx and/or tongue, has been reported in patients taking valsartan. Some of these patients had a history of angioedema while taking other drugs, including angiotensin-converting enzyme (ACE) inhibitors. Use of Combisart H should be discontinued immediately if angioedema occurs; re-administration is not recommended.
Heart failure and coronary artery disease/post-myocardial infarction
Due to inhibition of the renin-angiotensin-aldosterone system, renal dysfunction may be expected in susceptible patients. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has resulted in oliguria and/or progressive azotemia (rarely) with acute renal failure and/or fatal outcome. Similar results have been reported with valsartan. Evaluation of patients with heart failure or after myocardial infarction should always include assessment of renal function.
In a long-term placebo-controlled study of amlodipine (PRAISE-2) in patients with non-ischemic heart failure of NYHA class III and IV, the incidence of pulmonary edema was higher with amlodipine, despite a small difference in the occurrence or worsening of heart failure compared with placebo.
In patients with congestive heart failure, calcium channel blockers, including amlodipine, should be used with caution.
