Instructions for Valmisar A 160/5 tablets 160 mg/5 mg No. 30
Composition
1 tablet of 80 mg/5 mg contains:
active ingredients: valsartan 80 mg; amlodipine besylate equivalent to amlodipine 5 mg;
excipients: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;
Instacoat Universal Yellow A05G11327 coating: hypromellose, polyethylene glycol, talc, titanium dioxide (E 171), iron oxide yellow (E 172).
1 tablet of 160 mg/5 mg contains:
active ingredients: valsartan 160 mg; amlodipine besylate equivalent to amlodipine 5 mg; excipients: microcrystalline cellulose, crospovidone, colloidal anhydrous silica, magnesium stearate;
Instacoat Universal Yellow A05G11327 coating: hypromellose, polyethylene glycol, talc, titanium dioxide (E 171), iron oxide yellow (E 172).
1 tablet of 160 mg/10 mg contains:
active ingredients: valsartan 160 mg; amlodipine besylate equivalent to amlodipine 10 mg; excipients: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;
Instacoat Universal Yellow A05G11323 coating: hypromellose, polyethylene glycol, talc, titanium dioxide (E 171), iron oxide yellow (E 172), iron oxide red (E 172).
Dosage form
Film-coated tablets.
Main physicochemical properties:
80 mg/5 mg tablets – biconvex, film-coated tablets, round, dark yellow in color with engraving “T28” on one side and smooth on the other side;
160 mg/5 mg tablets – biconvex, film-coated tablets, oval-shaped, dark yellow in color with engraving “C94” on one side and smooth on the other side;
160 mg/10 mg tablets – biconvex, film-coated, oval-shaped, pale yellow tablets engraved with “C95” on one side and plain on the other side.
Pharmacotherapeutic group
Combination drugs of angiotensin II inhibitors.
ATX code C09D B01.
Pharmacological properties
Pharmacodynamics
Valmisar A contains two antihypertensive components with an additional mechanism of blood pressure control in patients with essential hypertension: amlodipine belongs to the class of calcium antagonists, and valsartan belongs to the class of angiotensin II antagonists. The combination of these ingredients exhibits an additive antihypertensive effect, lowering blood pressure more than either component alone.
Amlodipine
Amlodipine inhibits the transmembrane penetration of calcium ions into the smooth muscles of the heart and blood vessels. The mechanism of antihypertensive action of amlodipine is due to a direct relaxing effect on vascular smooth muscle, which causes a decrease in peripheral vascular resistance and leads to a decrease in blood pressure. Experimental data confirm that amlodipine binds to dihydropyridine and nonhydropyridine binding sites. Contractile processes of the heart muscle and vascular smooth muscle depend on the passage of extracellular calcium into these cells through specific ion channels.
After administration of therapeutic doses to patients with arterial hypertension, amlodipine causes vasodilation, resulting in a decrease in blood pressure in the supine and standing positions. This decrease in blood pressure is not accompanied by a significant change in heart rate or plasma catecholamine levels with prolonged use.
The effect correlates with plasma concentration in young and elderly patients.
In patients with arterial hypertension and normal renal function, therapeutic doses of amlodipine lead to a decrease in renal vascular resistance and an increase in glomerular filtration rate, as well as effective renal plasma flow without changes in the filtered fraction or proteinuria.
As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or walking) in patients with normal ventricular function treated with amlodipine generally showed a small increase in cardiac index without a significant effect on dP/dt or end-diastolic pressure or left ventricular volume. In hemodynamic studies, amlodipine did not produce a negative inotropic effect at therapeutic doses in intact animals and humans, even when co-administered with beta-blockers in humans.
Amlodipine does not alter sinoatrial node function or atrioventricular conduction in healthy animals or humans. In clinical studies in which amlodipine was used in combination with beta-blockers, no changes in electrocardiogram parameters were observed in patients with arterial hypertension or angina pectoris.
A positive clinical effect of amlodipine was observed in patients with chronic stable angina, vasospastic angina, and angiographically confirmed coronary artery disease.
A randomized, double-blind, morbidity and mortality study – the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) – was conducted to compare new therapies: the use of amlodipine at a dose of 2.5–10 mg per day (a calcium channel blocker) or lisinopril at a dose of 10–40 mg per day (an angiotensin-converting enzyme (ACE) inhibitor) as first-line therapy compared with the thiazide diuretic chlorthalidone at a dose of 12.5–25 mg per day in mild to moderate hypertension.
A total of 33,357 hypertensive patients aged 55 years or older were randomized and followed for a median of 4.9 years. Each patient had at least one additional risk factor for coronary heart disease, including a history of myocardial infarction or stroke (> 6 months before study entry) or documented other cardiovascular disease with evidence of atherosclerosis (overall 51.5%), type 2 diabetes mellitus (36.1%), high-density lipoprotein cholesterol concentration mg/dL or mmol/L (11.6%), left ventricular hypertrophy diagnosed by electrocardiography or echocardiography (20.9%), and smoking at study entry (21.9%).
The primary endpoint was fatal coronary heart disease or nonfatal myocardial infarction. There was no significant difference in the primary endpoint when comparing amlodipine and chlorthalidone: the hazard ratio (HR) was 0.98, 95% CI (0.90–1.07), p=0.65. Among the secondary endpoints, the incidence of heart failure (a component of the composite cardiovascular endpoint) was significantly higher in the amlodipine group compared with the chlorthalidone group (10.2% vs. 7.7%, HR=1.38, 95% CI (1.25–1.52), p=0.20).
Valsartan
Valsartan is an active, potent and specific angiotensin II receptor antagonist for oral administration. It acts selectively on the AT1 receptor subtype, which is rare and responsible for the effects of angiotensin II. Increased levels of angiotensin II due to blockade of AT1 receptors by valsartan may stimulate free AT2 receptors, which balances the effect of AT1 receptors. Valsartan does not have any partial agonist activity at AT1 receptors and has a much higher (approximately 20,000-fold) affinity for AT1 receptors than for AT2 receptors.
Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin II and destroys bradykinin. Because of the lack of effect on ACE and the lack of potentiation of bradykinin or substance P activity, angiotensin II receptor antagonists are not usually associated with cough. In clinical trials comparing valsartan with an ACE inhibitor, the incidence of dry cough was significantly lower (P < 0.05) in patients treated with valsartan than in patients treated with an ACE inhibitor (2.6% vs. 7.9%, respectively). Patients previously treated with an ACE inhibitor developed dry cough. This complication was observed in 19.5% of patients treated with valsartan and 19% of patients treated with thiazide diuretics, while in the group of patients treated with ACE inhibitors, cough was observed in 68.5% of cases (P 0.05). Valsartan does not interact with or block receptors for other hormones or ion channels, which are known to play an important role in the regulation of cardiovascular function.
Prescribing the drug to patients with arterial hypertension leads to a decrease in blood pressure without affecting the pulse rate.
In most patients, after a single oral dose of the drug, the onset of antihypertensive activity is noted within 2 hours, and the maximum reduction in blood pressure is achieved within 4–6 hours.
The antihypertensive effect persists for more than 24 hours after a single dose. With regular use of the drug, the maximum therapeutic effect is usually achieved within 2-4 weeks and is maintained at the achieved level during long-term therapy. Abrupt withdrawal of valsartan does not lead to the resumption of arterial hypertension or other adverse clinical events.
Valsartan has been shown to significantly reduce hospitalization rates in patients with chronic heart failure (NYHA class II–IY). The effect was more significant in patients not receiving ACE inhibitors or beta-blockers. Valsartan has also been shown to reduce cardiovascular mortality in clinically stable patients with left ventricular disease or left ventricular dysfunction after myocardial infarction.
Other studies: dual blockade of the renin-angiotensin-aldosterone system (RAAS)
The ONTARGET study was conducted in patients with cardiovascular or cerebrovascular disease or type 2 diabetes mellitus with a history of proven target organ damage. The VA NEPHRON-D study was conducted in patients with type 2 diabetes mellitus and diabetic nephropathy.
In these studies, no significant positive differences were found in renal and/or cardiovascular effects and mortality compared with monotherapy, while an increased risk of hyperkalemia, acute kidney injury and/or hypotension was found. Given the similar pharmacokinetic properties, these results are also relevant for other ACE inhibitors and ARBs.
Therefore, ACE inhibitors and ARBs should not be used concomitantly in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) is a study that aimed to determine the benefit of adding aliskiren to standard therapy with an ACE inhibitor or an ARB in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or a combination of the two. The study was stopped early due to an increased risk of complications of therapy. Death from cardiovascular pathologies and stroke were observed more often in the aliskiren group than in the placebo group, while the development of adverse reactions and serious adverse reactions of special importance (hyperkalemia, hypotension, and renal dysfunction) was also observed more often in the aliskiren group compared to the placebo group.
Valsartan/amlodipine
The combination of amlodipine and valsartan provides a dose-dependent additive reduction in blood pressure across the therapeutic dose range. The hypotensive effect after a single dose of the combination is maintained for 24 hours.
More than 1400 patients with hypertension received valsartan/amlodipine once daily in two placebo-controlled studies.
Valsartan/amlodipine was studied in two placebo-controlled trials in patients with uncomplicated mild to moderate essential hypertension (mean sitting diastolic blood pressure ≥ 95 and 110 mmHg).
Patients with high risk of cardiovascular disorders were excluded: heart failure, type I diabetes mellitus and poorly controlled type II diabetes mellitus, history of myocardial infarction or stroke within one year.
In a multicenter, randomized, double-blind, active-controlled, parallel-group study, blood pressure normalization (to a diastolic pressure of 90 mm Hg at the end of the trial) was demonstrated in patients whose blood pressure was not adequately controlled with valsartan monotherapy at a dose of 160 mg. Blood pressure normalization was achieved in 75% of patients receiving 10 mg/160 mg amlodipine/valsartan, in 62% of patients receiving 5 mg/160 mg amlodipine/valsartan, compared with 53% of patients receiving 160 mg valsartan. The addition of 10 mg and 5 mg amlodipine resulted in additional reductions in systolic/diastolic blood pressure of 6/4.8 mm Hg and 3.9/2.9 mm Hg, respectively. respectively compared to those when using only 160 mg of valsartan.
In a multicenter, randomized, double-blind, active-controlled, parallel-group study, blood pressure normalization (to a diastolic pressure of 90 mm Hg at the end of the trial) was demonstrated in patients whose blood pressure was not adequately controlled with amlodipine 10 mg monotherapy. Blood pressure normalization was achieved in 78% of patients receiving 10 mg/160 mg amlodipine/valsartan compared with 67% of patients who continued to receive 10 mg amlodipine alone. The addition of 160 mg valsartan resulted in an additional reduction in systolic/diastolic blood pressure of 2.9/2.1 mm Hg compared with those receiving 10 mg amlodipine alone.
Valsartan/amlodipine was studied in an active-controlled trial in 130 patients with essential hypertension and a mean sitting diastolic blood pressure ≥ 110 mmHg and 120 mmHg. In this trial (baseline blood pressure 171/113 mmHg), valsartan/amlodipine 5 mg/160 mg to 10 mg/160 mg reduced standing blood pressure by 36/29 mmHg compared with 32/28 mmHg with lisinopril/hydrochlorothiazide 10 mg/12.5 mg to 20 mg/12.5 mg.
Two long-term studies have shown that the effect of valsartan/amlodipine was maintained for more than one year. Abrupt withdrawal of the drug did not lead to a rapid increase in blood pressure.
In patients whose blood pressure is adequately controlled with amlodipine and who have unacceptable edema, combination therapy may provide similar blood pressure control with a reduction in edema.
There have been no studies of valsartan/amlodipine in populations other than hypertensive patients. There are studies of valsartan in patients with heart failure and in the post-infarction period. Amlodipine has been studied in patients with chronic stable angina, vasospastic angina, and angiographically confirmed ischemic heart disease.
Pharmacokinetics
Linearity
Valsartan and amlodipine exhibit linear pharmacokinetics.
Amlodipine
Absorption. After oral administration of therapeutic doses of amlodipine alone, peak plasma concentrations (Cmax) are reached within 6–12 hours. The estimated absolute bioavailability is 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 of amlodipine have shown that approximately 97.5% of the circulating drug is bound to plasma proteins in patients with essential hypertension.
Biotransformation: Amlodipine is extensively (approximately 90%) metabolized in the liver to inactive metabolites.
Elimination: The elimination of amlodipine from plasma is biphasic, with a half-life of approximately 30–50 hours. Steady-state plasma levels are reached after continuous administration for 7–8 days. 10% of the parent amlodipine and 60% of the amlodipine metabolites are excreted in the urine.
Valsartan
Absorption. After oral administration of the drug, Cmax of valsartan in blood plasma is reached within 2–4 hours. The average absolute bioavailability of the drug is 23%. Food reduces the area under the pharmacokinetic curve "concentration-time" (AUC) of valsartan by approximately 40%, and Cmax - by 50%, although 8 hours after administration, the concentration of valsartan in blood plasma is the same for the group that took the drug on an empty stomach and the group of patients that took the drug after a meal. A decrease in AUC is not accompanied by a clinically significant decrease in the therapeutic effect, so valsartan can be taken regardless of food intake.
Distribution: The steady-state volume of distribution of valsartan after intravenous administration is approximately 17 L, indicating that valsartan is not extensively distributed into tissues. Valsartan is highly bound to plasma proteins (94–97%), mainly to serum albumin.
Biotransformation: Valsartan is not significantly transformed, with only 20% of the dose converted to metabolites. A hydroxymetabolite, which is pharmacologically inactive, has been identified in plasma at low concentrations (less than 10% of the AUC of valsartan).
Elimination: Valsartan exhibits multi-exponential elimination kinetics (half-life T1/2a of 1 hour and T1/2b of approximately 9 hours). Valsartan is excreted mainly unchanged in the feces (approximately 83% of the dose) and urine (approximately 13% of the dose). After intravenous administration, the plasma clearance of valsartan is approximately 2 l/h, and its renal clearance is approximately 0.62 l/h (approximately 30% of the total clearance). The half-life of valsartan is 6 hours.
Valsartan/amlodipine
After oral administration of Valmisar A, Cmax of valsartan and amlodipine in blood plasma is achieved in 3 and 6–8 hours, respectively. The rate and extent of absorption of Valmisar A are equivalent to the bioavailability of valsartan and amlodipine when administered as monodrugs.
Special populations
Children
There are no data on the pharmacokinetics of the drug in children.
Elderly patients (aged 65 years and over)
The time to reach Cmax of amlodipine in plasma is approximately the same in young and elderly patients. In elderly patients, the clearance of amlodipine tends to decrease, which leads to an increase in AUC and a prolongation of the half-life. The average systemic AUC of valsartan in elderly patients is 70% higher than in younger patients, so caution should be exercised when increasing the dose.
Kidney failure
Renal impairment does not significantly affect the pharmacokinetics of amlodipine. As expected for a compound whose renal clearance accounts for only 30% of total plasma clearance, there was no correlation between renal function status and systemic exposure to valsartan.
Liver dysfunction
In patients with hepatic impairment, the clearance of amlodipine is reduced, resulting in an increase in AUC by approximately 40–60%. On average, in patients with mild to moderate chronic liver disease, the AUC exposure to valsartan is on average twice that of healthy volunteers (selected for age, sex, and body weight). Patients with liver disease should be cautious when using the drug.
Indication
Essential hypertension in adult patients whose blood pressure is not controlled with amlodipine or valsartan monotherapy.
Contraindication
· Hypersensitivity to the active substance, dihydropyridine derivatives or to any of the excipients of the drug.
Severe liver dysfunction, biliary cirrhosis or cholestasis.
Concomitant use of angiotensin receptor antagonists (ARBs), including valsartan, or ACE inhibitors with aliskiren in patients with diabetes mellitus or renal impairment (GFR 2).
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 after acute myocardial infarction.
Interaction with other medicinal products and other types of interactions
Inter-physician interactions
Drug-drug interactions of Valmisar A with other drugs have not been studied.
Medicines that require caution when used concomitantly
Other antihypertensive drugs
Commonly used antihypertensive drugs (e.g. alpha-blockers, diuretics) and other drugs that can cause hypotensive adverse events (e.g. tricyclic antidepressants, alpha-blockers used to treat benign prostatic hyperplasia) may enhance the hypotensive effect of the combination. Interactions related to amlodipine
Concomitant use not recommended
Grapefruit or grapefruit juice
The use of amlodipine with grapefruit juice or grapefruit is not recommended, as bioavailability may be increased in some patients, leading to increased hypotensive effect of the drug.
Medicines that require caution when used concomitantly
CYP3A4 inhibitors
Concomitant use of amlodipine with more or less potent CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may lead to a significant increase in systemic exposure to amlodipine. The clinical manifestations of such pharmacokinetic changes may be enhanced in elderly patients. Clinical monitoring and dose adjustment may be necessary.
CYP3A4 inducers (anticonvulsants (e.g. carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone), rifampicin, St. John's wort (Hypericum perforatum))
When used concomitantly with known CYP3A4 inducers, amlodipine plasma concentrations may be altered. Therefore, blood pressure should be monitored and dosage adjusted during and after concomitant use, especially in the case of strong CYP3A4 inducers (e.g. rifampicin, Hypericum perforatum).
Simvastatin
Multiple administration of 10 mg amlodipine with 80 mg simvastatin results in a 77% increase in simvastatin exposure compared to simvastatin alone. It is recommended that the daily dose of simvastatin be reduced to 20 mg for patients taking amlodipine.
Dantrolene (infusion)
Fatal cases of 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 predisposed to malignant hyperthermia and in the treatment of malignant hyperthermia.
Medicines that require caution when used concomitantly
Others
In clinical studies, amlodipine did not affect the pharmacokinetics of atorvastatin, dioxin, warfarin, or cyclosporine.
Interactions related to valsartan
Concomitant use not recommended
Lithium
Reversible increases in serum lithium concentrations and toxicity have been reported with concomitant use of lithium with ACE inhibitors or angiotensin II receptor antagonists, including valsartan. Concomitant use of valsartan and lithium is not recommended. If the combination proves necessary, serum lithium levels should be closely monitored. The risk of lithium toxicity may be further increased by concomitant use of Valsartan and diuretics.
Potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other drugs that may increase potassium levels
If drugs that affect potassium channels are prescribed in combination with valsartan, frequent monitoring of potassium plasma levels should be considered.
Medicines that require caution when used concomitantly
Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, acetylsalicylic acid (>3 g/day), and nonselective NSAIDs
With the simultaneous use of angiotensin II antagonists and NSAIDs, a weakening of the hypotensive effect is possible. Also, the simultaneous use of angiotensin II antagonists and NSAIDs may increase the risk of impaired renal function and an increase in serum potassium. Therefore, at the beginning of treatment, it is recommended to monitor the state of renal function, as well as ensure adequate fluid intake in the patient.
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.
Clinical trials have shown that dual blockade of the RAAS with the combined use of ACE inhibitors, ARBs or aliskiren leads to an increased incidence of adverse events such as hypotension, hyperkalemia and decreased renal function (including acute renal failure) compared with treatment with a single drug that affects the RAAS. Therefore, the concomitant use of ARBs (including valsartan) or ACE inhibitors with aliskiren is contraindicated in patients with diabetes mellitus or impaired renal function (GFR 2).
Others
With valsartan monotherapy, no clinically significant drug interactions have been established with the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide.
Application features
The safety and efficacy of amlodipine in the treatment of hypertensive crisis have not been established.
Patients with sodium and/or circulating blood volume (CV) deficiency
In patients with uncomplicated hypertension (0.4%) excessive hypotension was observed during treatment with valsartan/amlodipine in placebo-controlled studies. In patients with an activated renin-angiotensin system (with reduced sodium and/or volume depletion and in the case of receiving high doses of diuretics) taking angiotensin receptor blockers, symptomatic hypotension may occur. Correction of this condition before the use of valsartan/amlodipine or close medical supervision at the beginning of therapy is recommended.
If hypotension occurs during treatment with valsartan/amlodipine, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of saline. Treatment may be continued once blood pressure has stabilized.
Hyperkalemia
Concomitant treatment with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other drugs that may increase potassium levels (e.g. heparin) should be undertaken with caution and frequent monitoring of potassium levels is necessary.
Renal artery stenosis
Valsartan/amlodipine should be used with caution in 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 no experience with the safe use of valsartan/amlodipine in patients with a recent kidney transplant.
Liver dysfunction
Valsartan is excreted mainly unchanged in the bile. The half-life of amlodipine is prolonged and the AUC is increased in patients with impaired hepatic function; dosage recommendations have not been established. Special caution is required when using valsartan/amlodipine in patients with mild to moderate hepatic impairment or obstructive gallbladder disease.
The maximum recommended dose for patients with mild or moderate hepatic impairment without cholestasis is 80 mg of valsartan.
Kidney dysfunction
No dose adjustment is required in patients with mild or moderate renal impairment (GFR > 30 ml/min/1.73 m2). In moderate renal impairment, monitoring of potassium and creatinine levels is recommended.
Concomitant use of angiotensin receptor antagonists, including valsartan, or ACE inhibitors with aliskiren is contraindicated in patients with renal impairment (GFR 2).
Primary hyperaldosteronism
Patients with primary hyperaldosteronism should not take the angiotensin II antagonist valsartan because their renin-angiotensin system is impaired due to the underlying disease.
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 ACE inhibitors. This medicinal product should be discontinued immediately if angioedema occurs; re-administration is not recommended.
Heart failure/post-myocardial infarction
In a long-term placebo-controlled study (PRAISE-2) of amlodipine in patients with non-ischemic heart failure of NYHA class III and IV, the incidence of pulmonary edema was higher with amlodipine than with placebo, but there was no significant difference in the occurrence or worsening of heart failure. Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure because they may increase the risk of cardiovascular events and death.
Aortic and mitral valve stenosis
As with other vasodilators, particular caution should be exercised in patients with known mitral valve stenosis or severe low-grade aortic stenosis.
Dual blockade of RAAS
There is evidence that the combined use of ACE inhibitors, ARBs or aliskiren increases the risk of hypotension, hyperkalemia and decreased renal function (including acute renal failure). Therefore, dual blockade of the RAAS by the combined use of ACE inhibitors, ARBs or aliskiren is not recommended.
If dual blockade is absolutely necessary, it should only be carried out under specialist supervision with frequent close monitoring of renal function, electrolyte concentrations and blood pressure. ACE inhibitors and ARBs should not be used concomitantly in patients with diabetic nephropathy.
The use of Valmisar A in patients with diseases other than arterial hypertension has not been studied.
Use during pregnancy or breastfeeding
Pregnancy
The drug is contraindicated for use in pregnant women or women planning to become pregnant. If pregnancy is confirmed during the use of this drug, its use should be immediately discontinued and replaced with another drug approved for use in pregnant women.
Epidemiological evidence on the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive, but a small increased risk cannot be excluded. Although there are no controlled epidemiological studies with angiotensin II receptor antagonists (ARBs), a similar risk may exist with this class of drugs.
Exposure to ARAII in the second and third trimesters is known to have toxic effects on the human fetus (decreased renal function, oligohydramnios, delayed ossification of the skull bones) and the newborn (renal failure, hypotension, hyperkalemia).
If AIIRAs have been used from the second trimester of pregnancy, ultrasound examination of renal function and fetal skull is recommended.
Infants whose mothers have taken ARAII should be closely observed for the development of arterial hypotension.
Breastfeeding period
Amlodipine is excreted in breast milk. The proportion of the maternal dose received by the infant is estimated with an interquartile range of 3–7%, with a maximum of 15%. The effects of amlodipine on the infant are unknown.
Since no information is available on the use of Valmisar A during breastfeeding, the drug is not recommended for use during breastfeeding; alternative treatments with better established safety profiles are preferable, especially while breastfeeding a newborn or premature infant.
Fertility
Clinical studies on the effect on fertility have not been conducted.
Valsartan
Valsartan did not cause adverse reproductive effects in male and female rats when administered orally at doses up to 200 mg/kg/day, which is 6 times the maximum recommended human dose on a mg/m2 basis (calculations using a dose of 320 mg/day for oral administration to a 60 kg patient).
Amlodipine
Reversible biochemical changes in the heads of sperm have been reported in some patients treated with calcium channel blockers. Clinical data on the effects of amlodipine on fertility are insufficient. In one study in rats, adverse effects on male fertility were observed.
Ability to influence reaction speed when driving vehicles or other mechanisms
In patients taking Valmisar A, you may
