Instructions for Diforce XL film-coated tablets 10 mg + 160 mg blister No. 30
Composition
active ingredients: amlodipine besylate and valsartan;
1 tablet contains 6.94 mg of amlodipine besylate equivalent to 5 mg of amlodipine and 80 mg of valsartan or 6.94 mg of amlodipine besylate equivalent to 5 mg of amlodipine and 160 mg of valsartan, or 13.88 mg of amlodipine besylate equivalent to 10 mg of amlodipine and 160 mg of valsartan;
excipients: calcium hydrogen phosphate, dihydrate; microcrystalline cellulose; croscarmellose sodium; hydroxypropylcellulose; colloidal anhydrous silica; talc; magnesium stearate; coating for applying the shell Opadry II White (polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide (E 171)).
Dosage form
Film-coated tablets.
Main physicochemical properties: round, biconvex tablets, coated with a white film coating.
Pharmacotherapeutic group
Combination drugs of angiotensin II inhibitors.
ATX code C09D B01.
Pharmacological properties
Pharmacodynamics
Diforce contains two antihypertensive components with additional mechanisms 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 has an additive antihypertensive effect, lowering blood pressure to a greater extent 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 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.
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 the function of the sinoatrial node or atrioventricular conduction in healthy animals or humans. It is known that in clinical studies when amlodipine was used in combination with beta-blockers in patients with arterial 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.
Use in patients with arterial hypertension
A randomized, double-blind, morbidity and mortality study 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 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.
The primary endpoint was fatal coronary heart disease or nonfatal myocardial infarction. There were no significant differences in the primary endpoint when comparing amlodipine and chlorthalidone. Among the secondary endpoints, the number of cases of heart failure was significantly higher in the amlodipine group compared with the placebo group. However, there were no significant differences in all-cause mortality between the amlodipine and chlorthalidone groups.
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 angiotensin-converting enzyme (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% versus 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). A more significant effect was achieved 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).
It is known that two large randomized controlled trials have studied the use of a combination of an ACE inhibitor and an ARB. In these trials, no significant positive differences were found in terms of 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 similarity of 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.
It is known that a study was conducted 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. Mortality from cardiovascular disease and strokes were numerically more frequent in the aliskiren group than in the placebo group, while the development of adverse events and serious adverse events of special importance (hyperkalemia, hypotension, and renal dysfunction) were also reported more frequently in the aliskiren group compared to the placebo group.
Valsartan/amlodipine.
The combination of amlodipine/valsartan in patients with arterial hypertension produces an antihypertensive effect for approximately 24 hours. 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 and who have unacceptable edema, combination therapy may provide similar blood pressure control while reducing edema.
Pharmacokinetics
Linearity: Valsartan and amlodipine exhibit linear pharmacokinetics.
Amlodipine.
Absorption. After oral administration of therapeutic doses of amlodipine alone, the maximum concentration (Cmax) in the blood plasma is reached within 6-12 hours. The calculated absolute bioavailability is from 64 to 80%. Food significantly affects the bioavailability of amlodipine.
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 metabolites of amlodipine are excreted in the urine.
Valsartan.
Absorption. After oral administration, the peak plasma concentration (Cmax) of valsartan is reached within 2-4 hours. The mean absolute bioavailability of the drug is 23%. Food reduces the exposure of valsartan, as shown by AUC (plasma concentration - time), by approximately 40%, and the peak plasma concentration (Cmax) by 50%, although 8 hours after administration, the plasma concentration of valsartan 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. 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: Valsartan exhibits multi-exponential elimination kinetics (half-life T1/2a < 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 elimination half-life of valsartan is 6 hours.
Valsartan/amlodipine.
After oral administration of Diforce, peak plasma concentrations (Cmax) of valsartan and amlodipine are achieved in 3 and 6-8 hours, respectively. The rate and extent of absorption of Diforce are equivalent to the bioavailability of valsartan and amlodipine when administered separately.
Special populations.
Children.
There are no data on the pharmacokinetics of the drug in children.
Elderly patients (aged 65 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 exposure (determined by AUC values) of valsartan 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 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 components of the drug.
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 mL/min/1.73 m2).
Pregnant women or 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
Drug interactions.
Studies of drug interactions between Diforce and other drugs have not been conducted.
Medicines that require caution when used concomitantly.
Commonly used antihypertensive drugs (e.g. alpha-blockers, diuretics) and other drugs that may 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 is 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).
Plasma concentrations of amlodipine may be altered when co-administered with CYP3A4 inducers. Therefore, blood pressure should be monitored and the dosage adjusted during and after co-administration, 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 reported 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 associated with valsartan.
Concomitant use is 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 Difors with diuretics.
Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, and other drugs that can increase potassium levels.
If drugs that affect potassium channels are prescribed in combination with valsartan, frequent monitoring of plasma potassium should be considered.
Medicines that require caution when used concomitantly.
Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective 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 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.
Dual blockade of the 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 was observed in patients with uncomplicated hypertension (0.4%).
In patients with an activated renin-angiotensin system (with reduced sodium and/or volume depletion, receiving high doses of diuretics) taking angiotensin receptor blockers, symptomatic hypotension may occur. Correction of this condition before the use of Diforce or close medical supervision at the beginning of therapy is recommended.
If hypotension occurs during the use of Diforce, the patient should be placed on his back and, if necessary, an intravenous infusion of saline should be administered. 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 and others) should be carried out with caution, and frequent monitoring of potassium levels in the blood plasma is necessary.
Renal artery stenosis.
Diforce should be used with caution for the treatment of hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis of a single kidney, as serum urea and creatinine levels may increase.
Kidney transplantation.
There is no experience with the safe use of Diforce 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 Diforce in patients with mild to moderate liver dysfunction or obstructive gallbladder disease. The maximum recommended dose for patients with mild to moderate liver dysfunction 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 patients with moderate renal impairment, monitoring of potassium and creatinine levels in the blood is recommended.
Concomitant use of angiotensin receptor antagonists, including valsartan, or angiotensin-converting enzyme inhibitors with aliskiren is contraindicated in patients with renal impairment (GFR < 60 mg/min/1.73 m2).
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. Diforce should be discontinued immediately if angioedema occurs, and re-administration is not recommended.
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.
Heart failure/post-myocardial infarction.
As a result of inhibition of the renin-angiotensin-aldosterone system, renal function may be impaired in susceptible patients. In patients with severe heart failure, in whom renal function may depend on the activity of the renin-angiotensin-aldosterone system, the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with the development of oliguria and/or progressive azotemia, and (in rare cases) acute renal failure and/or fatal outcome. Similar results have been observed with valsartan. Patients with heart failure or after myocardial infarction should have their renal function assessed. It is known that in a long-term placebo-controlled study of amlodipine in patients with non-ischemic heart failure of NYHA class III and IV, the incidence of pulmonary edema was higher with amlodipine compared to 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 as they may increase the risk of cardiovascular events and mortality. Aortic and mitral valve stenosis.
As with other vasodilators, particular caution should be exercised in patients with mild aortic stenosis or mitral valve stenosis.
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 be carried out only under specialist supervision with frequent and careful 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 Diforce has not been studied in patients with diseases other than arterial hypertension.
Use during pregnancy or breastfeeding
Pregnancy.
Diforce is contraindicated for use by pregnant women or women planning to become pregnant.
If pregnancy is detected during therapy, Diforce should be discontinued immediately and, if necessary, replaced with another drug with an established safety profile 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, some increased risk cannot be excluded. Although there are no data from controlled epidemiological studies of angiotensin II receptor antagonists (ARBs), a similar risk may arise with the use of drugs of this class. It is known that the use of ARA II during the second and third trimesters of pregnancy 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 the condition of the fetal skull bones 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 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 there is no information on the use of Diforce during breastfeeding, the drug is not recommended for use during breastfeeding; alternative drugs with a better established safety profile are preferable, especially while breastfeeding a newborn or premature infant.
Fertility.
Clinical studies on the effect on fertility have not been conducted.
Valsartan.
Valsartan has been shown to cause no 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 (calculated using a dose of 320 mg/day for 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 effect of amlodipine on fertility are insufficient. It is known that in one study in rats, adverse reactions were found on the part of male fertility.
Ability to influence reaction speed when driving vehicles or other mechanisms
Patients using Diforce may experience dizziness or a feeling of weakness after taking the drug, so they should take this into account when driving vehicles and working with potentially dangerous 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 controlled by monotherapy with amlodipine or valsartan may be switched to combination therapy with Diforce. The recommended dose is 1 tablet per day. Diforce should be taken regardless of meals, with a small amount of water.
Patients taking valsartan and amlodipine separately can be switched to Diforce, which contains the same doses of the components. Individual dose titration of the individual components (i.e. amlodipine and valsartan) is recommended before switching to the fixed-dose combination. If clinically appropriate, direct change from monotherapy to the fixed-dose combination may be considered.
The maximum daily dose is 1 tablet of Diforce 80 or 1 tablet of Diforce 160, or 1 tablet of Diforce XL (maximum permissible doses of the drug components are 10 mg of amlodipine, 320 mg of valsartan).
Dosage in certain patient groups.
Kidney dysfunction.
There are no clinical data available on the use in patients with severe renal impairment.
For patients with mild and moderate renal impairment, there is no need to adjust the dose of Diforce.
Concomitant use of Diforce with aliskiren is contraindicated in patients with renal impairment (GFR < 60 mg/min/1.73 m2).
Diabetes.
Concomitant use of Diforce with aliskiren is contraindicated in patients with diabetes mellitus.
Liver dysfunction.
The drug Diforce is contraindicated in patients with severe liver dysfunction.
Diforce should be used with caution in patients with impaired liver function or obstructive biliary tract diseases.
The maximum recommended dose for patients with mild or moderate hepatic impairment without cholestasis 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 (see section "Indications") and hepatic impairment to amlodipine or Diforce, the lowest recommended dose of amlodipine should be prescribed in monotherapy or as part of combination therapy.
Elderly patients (65 years and older).
For elderly patients, the usual dosage regimens are recommended, but caution should be exercised when increasing the dose of the drug. When transferring such patients with arterial hypertension (see section "Indications") and impaired liver function to amlodipine or Diforce, the lowest recommended doses of amlodipine should be prescribed in monotherapy or as part of combination therapy.
Pediatric population.
The safety and efficacy of Diforce in children (under 18 years of age) have not been studied. Data are lacking.
Children
Studies of the treatment of children (under 18 years of age) with this drug have not been conducted. Therefore, until more complete information is available, the drug Diforce is not recommended for the treatment of children.
Overdose
Symptoms.
There is no experience of overdose with Diforce. The main symptom of valsartan overdose is likely to be marked hypotension with dizziness. Overdose of amlodipine may lead to increasing peripheral vasodilation and possibly reflex tachycardia. Significant and potentially prolonged systemic hypotension, up to shock and death, has been reported.
Non-cardiogenic pulmonary edema has been reported rarely following amlodipine overdose, the onset of which may be delayed (24-48 hours after administration) 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 taken 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 2 hours after taking amlodipine.
Clinically significant hypotension caused by overdose with Diforce requires active cardiovascular support, including frequent monitoring of cardiac and respiratory function, elevation of the lower 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.
Side effects
The safety of the amlodipine/valsartan combination has been evaluated in 5 controlled clinical trials involving 5,175 patients, 2,613 of whom received valsartan in combination with amlodipine. The most frequently observed or significant or severe adverse reactions were: nasopharyngitis, influenza,
