Instructions Valodip film-coated tablets 10 mg + 160 mg blister No. 30
Composition
active ingredient: amlodipine in the form of amlodipine besylate, valsartan;
1 film-coated tablet contains 5 mg of amlodipine as amlodipine besylate and 80 mg of valsartan or 5 mg of amlodipine as amlodipine besylate and 160 mg of valsartan, or 10 mg of amlodipine as amlodipine besylate and 160 mg of valsartan;
excipients: microcrystalline cellulose, mannitol (E 421), magnesium stearate, croscarmellose sodium, povidone, colloidal anhydrous silicon dioxide, sodium lauryl sulfate;
film coating: polyvinyl alcohol (partially hydrolyzed), titanium dioxide (E 171), macrogol 3000, talc, iron oxide yellow (E 172).
Dosage form
Film-coated tablets.
Main physicochemical properties:
Valodip, film-coated tablets, 5 mg/80 mg: round biconvex tablets with beveled edges, film-coated brownish-yellow, dark inclusions possible;
Valodip, film-coated tablets, 5 mg/160 mg: oval biconvex tablets, film-coated, brownish-yellow in color, dark inclusions possible;
Valodip, film-coated tablets, 10 mg/160 mg: oval, biconvex, film-coated tablets of brownish-yellow color.
Pharmacotherapeutic group
Angiotensin II inhibitors and calcium channel blockers. ATC code C09D B01.
Pharmacological properties
Pharmacodynamics
Valodip contains two antihypertensive components with additional mechanisms of blood pressure control in 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 has an additive antihypertensive effect, lowering blood pressure to a greater extent than either component alone.
Amlodipine
Amlodipine inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle. The mechanism of antihypertensive action of amlodipine is due to a direct relaxing effect on vascular smooth muscle, which leads to a decrease in peripheral vascular resistance and a decrease in blood pressure. Experimental data confirm that amlodipine binds to dihydropyridine and nonhydropyridine binding sites. Contractility of cardiac muscle and vascular smooth muscle depends on the passage of extracellular calcium into these cells through specific ion channels.
After administration of therapeutic doses to patients with essential 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 concentrations 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.
Measurements of cardiac hemodynamics at rest and during exercise in patients with normal ventricular function treated with amlodipine generally showed a small increase in cardiac index without significant effects on dP/dt and on left ventricular and diastolic pressure or volume. In hemodynamic studies, amlodipine did not exhibit a negative inotropic effect at therapeutic doses in intact animals and humans, even when coadministered with beta-blockers.
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 in patients with essential hypertension or angina, no changes in electrocardiogram parameters were noted.
Positive clinical effects of amlodipine have been observed in patients with chronic stable angina, vasospastic angina, and angiographically confirmed coronary artery disease.
Valsartan
Valsartan does not inhibit angiotensin-converting enzyme (ACE), also known as kininase II, which converts angiotensin I to angiotensin II and destroys bradykinin. No bradykinin-related side effects have been observed. 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% versus 7.9%, respectively). Patients previously treated with an ACE inhibitor developed a dry cough, with valsartan treatment occurring in 19.5% of cases and thiazide diuretic treatment in 19% of cases, while cough was observed in 68.5% of patients in the ACE inhibitor group (P < 0.05). Valsartan does not interact with or block receptors for other hormones or ion channels known to play an important role in the regulation of cardiovascular function.
The use of the drug in 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 the need for hospitalization in patients with New York Heart Association (NYHA) class II-IV chronic heart failure. 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.
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 amlodipine/valsartan once daily in two placebo-controlled studies.
The use of amlodipine besylate/valsartan was studied in two placebo-controlled studies in patients with uncomplicated essential hypertension of mild to moderate severity (mean sitting diastolic blood pressure ≥ 95 and < 110 mm Hg).
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 that occurred within one year.
In a multicenter, randomized, double-blind, active-controlled, parallel-group study, blood pressure normalization (to diastolic pressure <90 mmHg at the end of the trial) was observed in 75% of patients receiving 10 mg/160 mg amlodipine/valsartan, 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 an additional reduction in systolic/diastolic pressure of 6/4.8 mmHg and 3.9/2.9 mmHg, respectively, compared with patients receiving 160 mg valsartan alone.
In a multicenter, randomized, double-blind, active-controlled, parallel-group study, blood pressure normalization (to diastolic blood pressure <90 mmHg at the end of the trial) was observed 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 mmHg compared with patients receiving 10 mg amlodipine alone.
Amlodipine/valsartan was studied in an active-controlled trial in 130 patients with essential hypertension with diastolic blood pressure ≥ 110 mmHg and < 120 mmHg. In this trial (baseline blood pressure 171/113 mmHg), amlodipine/valsartan 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 amlodipine/valsartan is maintained for more than one year. Abrupt withdrawal of the drug does not lead to a rapid increase in blood pressure.
In patients whose blood pressure is adequately controlled with amlodipine but who have unacceptable edema, combination therapy may provide similar blood pressure control while reducing edema.
Pharmacokinetics
Linearity
Valsartan and amlodipine exhibit linear pharmacokinetics.
Absorption. After oral administration of therapeutic doses of amlodipine, peak plasma concentrations (Cmax) are reached within 6–12 hours. The estimated absolute bioavailability is 64% to 80%. Food significantly affects 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: 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 unchanged amlodipine and 60% of amlodipine metabolites are excreted in the urine.
Valsartan.
Absorption. After oral administration of the drug, Cmax of valsartan in plasma is reached within 2-4 hours. The average absolute bioavailability of the drug is 23%. Food reduces the exposure of valsartan in terms of AUC (plasma concentration - time) by approximately 40%, and Cmax - by 50%, although 8 hours after administration, the concentration of valsartan in plasma was the same in the group that took the drug on an empty stomach and in the group of patients that took the drug after a meal. The 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. The pharmacokinetic curve of valsartan has a descending multiexponential nature (half-life T1/2a less than 1 hour and T1/2b 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 the amlodipine/valsartan combination, plasma Cmax of valsartan and amlodipine is achieved in 3 and 6-8 hours, respectively. The rate and extent of absorption of the amlodipine/valsartan combination are equivalent to the bioavailability of valsartan and amlodipine.
Pharmacokinetics in different patient groups.
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 dysfunction
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%. In patients with mild to moderate chronic liver disease, valsartan exposure (determined by AUC values) is on average twice that of healthy volunteers (selected for age, sex and body weight). Patients with liver disease should be careful 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 medicinal product;
Severe liver dysfunction, biliary cirrhosis or cholestasis.
Concomitant use of angiotensin receptor antagonists (ARBs), including valsartan, or angiotensin-converting enzyme (ACE) inhibitors with aliskiren in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) < 60 mg/min/1.73 m2).
Contraindicated in pregnant women and women planning to become pregnant (see section "Use during pregnancy or breastfeeding").
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
Studies of drug interactions with other drugs have not been conducted.
Should be considered 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.
Caution is required with concomitant use
CYP3A4 inhibitors
Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may result in 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 CYP3A4 inducers, the plasma concentration of amlodipine may change. Therefore, blood pressure should be monitored and the dose adjusted during and after concomitant administration of the drug, especially with strong CYP3A4 inducers (e.g. rifampicin, Hypericum perforatum).
Simvastatin
Multiple doses of 10 mg amlodipine with 80 mg simvastatin resulted 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 in association with 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.
Should be considered when used concomitantly
Tacrolimus.
There is a risk of increased blood levels of tacrolimus when co-administered with amlodipine, but the pharmacokinetic mechanism of this interaction is not fully established. To avoid tacrolimus toxicity, patients taking tacrolimus should have their blood levels monitored regularly and their dose adjusted if necessary when amlodipine is co-administered with amlodipine.
mTOR inhibitors (mammalian target of rapamycin).
mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are substrates of CYP3A. Amlodipine is a weak inhibitor of CYP3A. When amlodipine is used concomitantly with mTOR inhibitors, it may potentiate their effects.
Sildenafil
A single dose of 100 mg of sildenafil in patients with essential hypertension did not affect the pharmacokinetics of amlodipine. When amlodipine and sildenafil were used simultaneously as combination therapy, each drug exhibited an independent hypotensive effect.
Others
Amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, 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 Valdoxan 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 plasma potassium should be considered.
Caution is required with concomitant use
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 increases the risk of worsening of 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.
In vitro studies of 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.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with ARBs, ACE inhibitors, or aliskiren
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 < 60 mg/min/1.73 m2).
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 a deficiency in the body of sodium and/or circulating blood volume
Excessive hypotension has been observed in patients with uncomplicated hypertension. Symptomatic hypotension may occur in patients with an activated renin-angiotensin system (with reduced sodium and/or volume, receiving high doses of diuretics) who are taking angiotensin receptor blockers. Correction of this condition before the use of Valodip or close medical supervision at the beginning of therapy is recommended.
If hypotension occurs during the use of Valodip, the patient should be placed on his back and, if necessary, an intravenous infusion of saline should be performed. After stabilization of blood pressure, treatment can be continued.
Hyperkalemia
Concomitant treatment with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other drugs that may increase potassium levels (heparin, etc.) should be carried out with caution, and frequent monitoring of potassium levels should be planned.
Renal artery stenosis
It 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 no experience with the safe use of Valodip 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 (plasma concentration-time) is higher in patients with impaired liver function; dosage recommendations have not been established. Special caution is required when using Valodip in patients with mild to moderate liver dysfunction 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 to 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 < 60 mg/min/1.73 m2).
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 occurred in patients taking valsartan. Some of these patients had a history of angioedema while taking other drugs, including ACE inhibitors. The drug should be discontinued immediately if angioedema occurs. Re-administration is not recommended.
Heart failure/previous myocardial infarction
When amlodipine is used in patients with non-ischemic heart failure of NYHA class III and IV, the incidence of pulmonary edema may increase. Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they increase the risk of cardiovascular events and mortality.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
As with other vasodilators, special caution should be exercised in patients with known aortic or 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 the drug has not been studied in patients with diseases other than arterial hypertension.
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 treatment with this drug, its use should be discontinued immediately and replaced with another drug approved for use in pregnant women.
Epidemiological data on the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy have not been conclusive; however, 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 ARA II 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, arterial hypotension, hyperkalemia).
If ARBs have been used from the second trimester of pregnancy, ultrasound examination of renal function and fetal skull is recommended.
Infants whose mothers have taken ARA II should be closely observed for the development of arterial hypotension.
Breastfeeding period
Amlodipine is excreted in breast milk. The proportion of the dose received by the infant during breastfeeding is determined by the range of 3–7%, maximum – 15%. The effect of amlodipine on infants is unknown. Therefore, the use of Valodip is not recommended during breastfeeding; alternative drugs with a studied safety profile are preferable, especially in the case of breastfeeding newborns or premature infants.
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 a 60 kg patient).
Amlodipine
Reversible biochemical changes in the heads of spermatozoa 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
Patients using Valodip may experience dizziness or a feeling of weakness after taking the drug, so this should be taken into account when driving vehicles and other mechanisms.
Amlodipine may have minor or moderate influence on the ability to drive or use machines. If patients experience dizziness, headache, fatigue or nausea while taking amlodipine, their reactions may be impaired.
Method of administration and doses
Patients whose blood pressure is not adequately controlled with amlodipine or valsartan monotherapy may benefit from combination therapy with Valodip. The recommended dose is 1 tablet per day. Valodip tablets can be taken regardless of meals, with a small amount of water.
Patients taking valsartan and amlodipine separately can be prescribed Valodip, which contains the same doses of the components.
The maximum daily dose is 1 tablet of Valodip 5 mg/80 mg or 1 tablet of Valodip 5 mg/160 mg, or 1 tablet of Valodip 10 mg/160 mg (maximum permissible doses of the drug components are 10 mg of amlodipine, 320 mg of valsartan).
Dosage in special patient groups
Kidney dysfunction
There are no clinical data available on the use in patients with severe renal impairment.
No dose adjustment is required in patients with mild or moderate renal impairment. In patients with moderate renal impairment, it is recommended to monitor potassium and creatinine levels in the blood.
Concomitant use of Valodip with aliskiren is contraindicated in patients with renal impairment (GFR < 60 mg/min/1.73 m2).
Diabetes mellitus
Concomitant use of Valodip with aliskiren is contraindicated in patients with diabetes mellitus.
Liver dysfunction
The drug is contraindicated in patients with severe liver dysfunction.
Caution should be exercised in patients with mild or moderate hepatic impairment or obstructive biliary tract disease. For patients with mild or moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg of valsartan. Dosage recommendations for amlodipine in patients with mild or moderate hepatic impairment have not been developed. When transferring such patients with arterial hypertension and hepatic impairment to amlodipine or Valodip, the lowest recommended dose of amlodipine should be administered in monotherapy or as part of combination therapy.
Elderly patients (65 years and older)
For elderly patients, the usual dosage regimens are recommended.
Caution should be exercised when increasing the dose of the drug in elderly patients. When transferring such patients with arterial hypertension and impaired liver function to amlodipine or Valodip, the lowest recommended dose of amlodipine should be prescribed in monotherapy or as part of combination therapy.
Children
The safety and efficacy of Valodip in children (under 18 years of age) have not been studied. Data are lacking. Therefore, Valodip is not recommended for use in children until more complete information is available.
Overdose
Symptoms
There is currently no experience of overdose with the drug. The main symptom of valsartan overdose is likely to be severe hypotension with dizziness. Overdose of amlodipine may lead to increasing peripheral vasodilation and possibly reflex tachycardia. Significant prolonged systemic hypotension, up to shock and death, has been reported.
Non-cardiogenic pulmonary edema has been reported rarely following amlodipine overdose, which may have a delayed onset (24-48 hours after ingestion) and may require mechanical ventilation. Early resuscitation measures (including fluid overload) to maintain perfusion and cardiac output may be precipitating factors.
Treatment
If the drug has been used recently, vomiting should be induced or the stomach should be lavaged. The absorption of amlodipine is significantly reduced by the use of activated charcoal immediately or within two hours after taking amlodipine.
Clinically significant hypotension caused by Valodip overdose requires active cardiovascular support, including frequent monitoring of cardiac and respiratory function, elevation of extremities, attention to circulating fluid volume, and urination. A vasoconstrictor may be used to restore vascular tone and blood pressure if there are no contraindications to its use. In cases of persistent hypotension resulting from calcium channel blockade, intravenous calcium gluconate may be appropriate.
Removal of valsartan and amlodipine by hemodialysis is unlikely.
Adverse reactions
The most frequently observed or significant or severe adverse reactions
