Difors xl
UkraineTable of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIFORS 80 DIFORS 160 DIFORS XL (DIFORS 80) (DIFORS 160) (DIFORS XL)
Composition:
Active substances: amlodipine besylate and valsartan;
One 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; sodium croscarmellose; hydroxypropylcellulose; colloidal anhydrous silicon dioxide; talc; magnesium stearate; film-coating Opadry II White (polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide (E 171)).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties: white, round, biconvex film-coated tablets.
Pharmacotherapeutic group. Combined angiotensin II inhibitors.
ATC code C09D B01.
Pharmacological Properties.
Pharmacodynamics.
Diforce contains two antihypertensive components with complementary mechanisms of blood pressure control in patients with essential hypertension: amlodipine, which belongs to the class of calcium channel blockers, and valsartan, which belongs to the class of angiotensin II antagonists. The combination of these ingredients provides an additive antihypertensive effect, reducing blood pressure to a greater extent than either component alone.
Amlodipine.
Amlodipine inhibits transmembrane influx of calcium ions into vascular and cardiac smooth muscle cells. The antihypertensive mechanism of amlodipine is due to direct relaxation of vascular smooth muscle, resulting in reduced peripheral vascular resistance and consequent lowering of arterial blood pressure. Experimental data confirm that amlodipine binds at both dihydropyridine and non-dihydropyridine binding sites. Contraction of cardiac and vascular smooth muscle depends on the influx of extracellular calcium into these cells through specific ion channels.
After administration of therapeutic doses to patients with hypertension, amlodipine causes vasodilation, leading to reduction in arterial blood pressure in both supine and standing positions. This reduction in blood pressure is not accompanied by significant changes in heart rate or plasma catecholamine levels during long-term treatment.
The effect correlates with plasma concentrations in both young and elderly patients.
In patients with arterial hypertension and normal renal function, therapeutic doses of amlodipine reduce renal vascular resistance and increase glomerular filtration rate and effective renal plasma flow, without changes in filtration fraction or proteinuria.
As with other calcium channel blockers, hemodynamic studies of cardiac function at rest and during exercise (or walking) in patients with normal ventricular function treated with amlodipine have generally shown a slight increase in cardiac index without significant effects on dP/dt, end-diastolic pressure, or left ventricular volume. Hemodynamic studies have shown that amlodipine has no negative inotropic effect at therapeutic doses in intact animals and humans, even when co-administered with beta-blockers.
Amlodipine does not alter sinus node function or atrioventricular conduction in healthy animals or humans. Clinical studies have shown no changes in electrocardiographic parameters when amlodipine is used in combination with beta-blockers in patients with hypertension or angina.
Positive clinical effects of amlodipine have been observed in patients with chronic stable angina, vasospastic angina, and angiographically confirmed ischemic heart disease.
Use in Patients with Hypertension
A randomized, double-blind morbidity and mortality trial was conducted to compare new treatment approaches: amlodipine at doses of 2.5–10 mg daily (a calcium channel blocker) or lisinopril at doses of 10–40 mg daily (an ACE inhibitor) as first-line therapy, compared to the use of the thiazide diuretic chlorthalidone at doses of 12.5–25 mg daily in patients with mild to moderate hypertension.
The primary endpoint was fatal or non-fatal myocardial infarction due to ischemic heart disease. No significant differences in the primary endpoint were observed between amlodipine and chlorthalidone treatment groups. Among secondary endpoints, the incidence of heart failure was significantly higher in the amlodipine group compared to the chlorthalidone group. However, there were no significant differences in all-cause mortality between the amlodipine and chlorthalidone groups.
Valsartan.
Valsartan is a potent, specific, orally active antagonist of angiotensin II receptors. It selectively blocks AT1 receptors, which mediate the effects of angiotensin II. Increased levels of angiotensin II due to AT1 receptor blockade by valsartan may stimulate unopposed AT2 receptors, counterbalancing the effects of AT1 receptor activation. Valsartan has no partial agonist activity at AT1 receptors and has approximately 20,000-fold greater 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 degrades bradykinin. Because of its lack of effect on ACE and absence of potentiation of bradykinin or substance P activity, angiotensin II receptor antagonists are generally not associated with cough. In clinical trials comparing valsartan with ACE inhibitors, the incidence of dry cough was significantly lower (P < 0.05) in patients treated with valsartan than in those receiving an ACE inhibitor (2.6% vs. 7.9%, respectively). In patients previously treated with an ACE inhibitor who developed dry cough, this adverse effect occurred in 19.5% of cases with valsartan treatment and in 19% of cases with thiazide diuretic treatment, whereas cough was observed in 68.5% of patients in the ACE inhibitor group (P < 0.05). Valsartan does not interact with or block receptors of other hormones or ion channels known to play important roles in cardiovascular regulation.
Administration of the drug to patients with hypertension results in blood pressure reduction without affecting pulse rate.
In most patients, after a single oral dose, onset of antihypertensive activity occurs within 2 hours, and maximal blood pressure reduction is achieved within 4–6 hours.
The antihypertensive effect persists for more than 24 hours after a single dose. With regular administration, the maximum therapeutic effect is usually achieved within 2–4 weeks and is maintained at that level during long-term therapy. Abrupt discontinuation of valsartan does not lead to rebound hypertension or other adverse clinical effects.
It has been established that valsartan significantly reduces hospitalization rates in patients with chronic heart failure (NYHA class II–IV). A more pronounced effect was observed in patients not receiving ACE inhibitors or beta-blockers. It has also been shown that valsartan reduces cardiovascular mortality in clinically stable patients with left ventricular dysfunction or pathology following myocardial infarction.
Other studies: dual blockade of the renin-angiotensin-aldosterone system (RAAS).
It is known that two large randomized controlled trials evaluated the use of a combination of an ACE inhibitor and an angiotensin receptor antagonist (ARA). In these studies, no significant benefits on kidney and/or cardiovascular outcomes or mortality were observed compared to monotherapy, while an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was established. Given the similarity of pharmacokinetic properties, these findings are also relevant to other ACE inhibitors and ARAs. Therefore, concomitant use of ACE inhibitors and ARAs is not recommended in patients with diabetic nephropathy.
It is known that a study was conducted to evaluate the benefit of adding aliskiren to standard therapy with an ACE inhibitor or ARA in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or a combination thereof. The study was terminated early due to an increased risk of adverse events. Cardiovascular mortality and stroke occurred numerically more frequently in the aliskiren group than in the placebo group, and the aliskiren group also reported more frequent adverse events and serious adverse events of special interest (hyperkalemia, hypotension, and renal function impairment) compared to the placebo group.
Valsartan/Amlodipine.
The combination of amlodipine/valsartan in patients with hypertension produces an antihypertensive effect lasting approximately 24 hours. Abrupt discontinuation of the drug does not lead to rapid rebound increase in blood pressure.
In patients whose blood pressure is adequately controlled with amlodipine but who experience unacceptable edema, combination therapy may provide similar blood pressure control with reduced edema.
Pharmacokinetics.
Linearity. Valsartan and amlodipine exhibit linear pharmacokinetics.
Amlodipine.
Absorption. After oral administration of therapeutic doses of amlodipine alone, maximum plasma concentration (Cmax) is reached within 6–12 hours. The calculated absolute bioavailability ranges from 64% to 80%. Food significantly affects amlodipine bioavailability.
Distribution. The volume of distribution is approximately 21 L/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins in patients with essential hypertension.
Metabolism. Amlodipine is extensively metabolized (approximately 90%) in the liver to inactive metabolites.
Elimination. Plasma elimination of amlodipine is biphasic, with an elimination half-life of approximately 30–50 hours. Steady-state plasma levels are achieved after 7–8 days of continuous dosing. About 10% of the original amlodipine and 60% of its metabolites are excreted in urine.
Valsartan.
Absorption. After oral administration, peak plasma concentration (Cmax) of valsartan is reached within 2–4 hours. The mean absolute bioavailability of the drug is 23%. Food reduces valsartan exposure, as measured by AUC (area under the plasma concentration-time curve), by approximately 40%, and peak plasma concentration (Cmax) by 50%. However, plasma valsartan concentrations 8 hours after administration are similar between fasting and postprandial groups. The reduction in AUC does not result in clinically significant reduction in therapeutic effect; therefore, valsartan can be administered with or without food.
Distribution. The steady-state volume of distribution of valsartan after intravenous administration is approximately 17 L, indicating limited tissue distribution. Valsartan is highly bound to plasma proteins (94–97%), primarily to serum albumin.
Metabolism. Valsartan undergoes minimal biotransformation, with only about 20% of the dose converted to metabolites. A hydroxymetabolite has been identified in plasma at low concentrations (<10% of valsartan AUC) and is pharmacologically inactive.
Elimination. Valsartan exhibits multi-exponential elimination kinetics (elimination half-life T1/2α < 1 hour and T1/2β approximately 9 hours). Valsartan is primarily excreted unchanged in feces (approximately 83% of dose) and urine (approximately 13% of dose). After intravenous administration, plasma clearance of valsartan is approximately 2 L/h, and renal clearance is approximately 0.62 L/h (about 30% of 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 reached at 3 and 6–8 hours, respectively. The rate and extent of absorption of Diforce are bioequivalent to valsartan and amlodipine administered separately.
Special Populations.
Children.
Pharmacokinetic data in pediatric patients are lacking.
Elderly Patients (aged 65 years and older).
Time to reach Cmax of amlodipine in plasma is similar in younger and elderly patients. In elderly patients, clearance of amlodipine tends to be reduced, leading to increased AUC and prolonged elimination half-life. Mean systemic AUC of valsartan is 70% higher in elderly individuals than in younger patients; therefore, caution is advised when increasing the dose.
Renal Impairment.
Renal dysfunction does not significantly affect the pharmacokinetics of amlodipine. As expected for a compound with renal clearance accounting for only 30% of total plasma clearance, no correlation was observed between renal function and systemic exposure to valsartan.
Hepatic Impairment.
In patients with hepatic impairment, 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, exposure to valsartan (as measured by AUC) is approximately twice that observed in healthy, age-, sex-, and weight-matched volunteers. Patients with liver disease should use the drug with caution.
Clinical characteristics.
Indications.
Essential hypertension in patients whose blood pressure is not controlled by monotherapy with amlodipine or valsartan.
Contraindications.
- Hypersensitivity to the active substance, dihydropyridine derivatives, or to any component of the medicinal product.
- Severe hepatic impairment, biliary cirrhosis, or cholestasis.
- Concomitant use of angiotensin receptor antagonists (ARAs), 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).
- Pregnancy or women planning to become pregnant (see section "Use in 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 following acute myocardial infarction.
Interaction with other medicinal products and other forms of interaction.
Pharmacological interactions.
Studies on drug interactions of Difors with other medicinal products have not been conducted.
Medicinal products requiring caution during concomitant use.
Other antihypertensive agents.
Commonly used antihypertensive agents (e.g., alpha-blockers, diuretics) and other medicinal products that may cause hypotensive adverse effects (e.g., tricyclic antidepressants, alpha-blockers used for treatment of 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 in some patients bioavailability may be increased, leading to an enhanced hypotensive effect of the drug.
Medicinal products requiring caution during concomitant use.
Inhibitors of CYP3A4.
Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem) may lead to a significant increase in systemic exposure to amlodipine. Clinical manifestations of such pharmacokinetic changes may be more pronounced in elderly patients. Clinical monitoring and dose adjustment may be necessary.
Inducers of CYP3A4 (antiepileptic drugs (e.g., carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone), rifampicin, St. John’s wort (Hypericum perforatum)).
Concomitant use of CYP3A4 inducers may alter plasma concentrations of amlodipine. Therefore, blood pressure should be monitored and dosage adjusted during and after concomitant use, especially with potent CYP3A4 inducers (e.g., rifampicin, Hypericum perforatum).
Simvastatin.
Repeated administration of 10 mg amlodipine with 80 mg simvastatin results in a 77% increase in simvastatin exposure compared to simvastatin alone. It is recommended to reduce the daily dose of simvastatin to 20 mg in patients receiving amlodipine.
Dantrolene (infusions).
In animals, fatal cases of ventricular fibrillation and cardiovascular collapse associated with hyperkalemia have been observed following intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalemia, concomitant use of calcium channel blockers such as amlodipine should be avoided in patients predisposed to malignant hyperthermia or during treatment of malignant hyperthermia.
Other medicinal products requiring caution during concomitant use.
Other.
In clinical studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, warfarin, or cyclosporine.
Interactions related to valsartan.
Concomitant use not recommended.
Lithium.
When lithium is used concomitantly with ACE inhibitors or angiotensin II receptor antagonists, including valsartan, reversible increases in serum lithium concentrations and lithium toxicity have been reported. Concomitant use of valsartan and lithium is not recommended. If such combination therapy is necessary, serum lithium levels should be closely monitored. The risk of increased lithium toxicity may be further elevated when Difors is used concomitantly with diuretics.
Potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, and other agents that may increase potassium levels.
When agents affecting potassium channels are prescribed in combination with valsartan, frequent monitoring of plasma potassium levels should be anticipated.
Medicinal products requiring caution during concomitant use.
Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid (>3 g/day), and nonselective NSAIDs.
Concomitant use of angiotensin II antagonists and NSAIDs may result in reduced antihypertensive effect. Additionally, concomitant use of angiotensin II antagonists and NSAIDs increases the risk of worsening renal function and elevated serum potassium levels. Therefore, at the start of treatment, monitoring of renal function and ensuring adequate hydration are recommended.
Inhibitors of uptake transporters (rifampicin, cyclosporine) or efflux transporters (ritonavir).
In vitro studies using human liver tissue have shown that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Concomitant use of inhibitors of uptake transporters (rifampicin, cyclosporine) or efflux transporters (ritonavir) may increase systemic exposure to valsartan.
Dual blockade of the RAAS with ARAs, ACE inhibitors, or aliskiren.
Clinical studies have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, ARAs, or aliskiren leads to an increased incidence of adverse events such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to treatment with a single RAAS-acting agent. Therefore, concomitant use of ARAs—including valsartan—or ACE inhibitors with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²).
Other.
During monotherapy with valsartan, no clinically significant drug interactions have been observed with the following medicinal products: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, or glyburide.
Special precautions for use.
The safety and efficacy of amlodipine in the treatment of hypertensive crisis have not been established.
Patients with sodium and/or circulating blood volume deficiency.
Excessive hypotension has been observed in patients with uncomplicated arterial hypertension (0.4%).
Symptomatic hypotension may occur in patients with activated renin-angiotensin system (with reduced sodium and/or circulating blood volume, such as those receiving high doses of diuretics) who are taking angiotensin receptor blockers. Correction of this condition prior to initiation of Diforce or careful medical monitoring at the beginning of therapy is recommended.
If arterial hypotension occurs during treatment with Diforce, the patient should be placed in a supine position and, if necessary, receive intravenous infusion of physiological saline. Treatment may be continued after stabilization of blood pressure.
Hyperkalemia.
Concomitant use of potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other drugs that may increase potassium levels (e.g., heparin, etc.) should be administered with caution, and frequent monitoring of plasma potassium levels is required.
Renal artery stenosis.
Diforce should be used with caution in the treatment of hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis of a solitary kidney, as serum urea and creatinine levels may increase.
Kidney transplantation.
There is no experience with the safe use of Diforce in patients who have recently undergone kidney transplantation.
Hepatic impairment.
Valsartan is primarily excreted unchanged in bile. The elimination half-life of amlodipine is prolonged and the AUC (plasma concentration–time) is higher in patients with hepatic impairment; dosage recommendations have not been established. Particular caution is required when administering Diforce to patients with mild to moderate hepatic impairment or obstructive biliary disorders. The maximum recommended dose for patients with mild or moderate hepatic impairment without cholestasis is 80 mg of valsartan.
Renal impairment.
Dose adjustment is not required in patients with mild or moderate renal impairment (eGFR > 30 mL/min/1.73 m²). In patients with moderate renal impairment, monitoring of blood potassium and creatinine levels is recommended.
Concomitant use of angiotensin receptor antagonists, including valsartan, or angiotensin-converting enzyme (ACE) inhibitors with aliskiren is contraindicated in patients with renal impairment (eGFR < 60 mL/min/1.73 m²).
Angioedema.
Angioedema, including laryngeal and glottal edema that 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 with other drugs, including angiotensin-converting enzyme (ACE) inhibitors. Diforce should be discontinued immediately if angioedema occurs, and re-administration is not recommended.
Intestinal angioedema. Intestinal angioedema has been reported in patients treated with angiotensin II receptor antagonists, including valsartan (see section "Adverse reactions"). These patients experienced abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, valsartan should be discontinued and appropriate patient monitoring initiated until complete resolution of symptoms.
Primary hyperaldosteronism.
Patients with primary hyperaldosteronism should not receive the angiotensin II antagonist valsartan, as their renin-angiotensin system is already impaired due to the underlying disease.
Heart failure/post-myocardial infarction.
Due to suppression of the renin-angiotensin-aldosterone system, renal function disturbances may occur in susceptible patients. In patients with severe heart failure, in whom renal function may depend on the activity of the renin-angiotensin-aldosterone system, use of ACE inhibitors and angiotensin receptor antagonists has led to oliguria and/or progressive azotemia, and in rare cases, acute renal failure and/or death. Similar outcomes have been observed with valsartan. Renal function should be assessed in patients with heart failure or post-myocardial infarction. It is known that in a long-term placebo-controlled study of amlodipine in patients with NYHA (New York Heart Association) class III and IV non-ischemic heart failure, the incidence of pulmonary edema was higher with amlodipine than with placebo, although 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 is required in patients with severe aortic stenosis or mitral valve stenosis.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS).
Data indicate that combined use of ACE inhibitors, ARBs, or aliskiren increases the risk of hypotension, hyperkalemia, and reduced renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors, ARBs, or aliskiren is not recommended.
If dual blockade is absolutely necessary, it should be performed only under specialist supervision with frequent and careful monitoring of renal function, electrolyte concentrations, and blood pressure. Concomitant use of ACE inhibitors and ARBs is not recommended in patients with diabetic nephropathy.
The use of Diforce has not been studied in patients with conditions other than arterial hypertension.
Use during pregnancy or breastfeeding.
Pregnancy.
Diforce is contraindicated in pregnant women or women who may become pregnant.
If pregnancy is detected during treatment, Diforce should be discontinued immediately and replaced, if necessary, with another medicinal product with an established safety profile in pregnancy.
Epidemiological data on teratogenic risk following exposure to ACE inhibitors during the first trimester of pregnancy are inconclusive; however, a certain risk cannot be excluded. Although controlled epidemiological data on angiotensin II receptor antagonists (ARBs) are lacking, a similar risk may exist with drugs of this class. It is known that use of ARBs during the second and third trimesters of pregnancy has toxic effects on the human fetus (impaired renal function, oligohydramnios, delayed skull ossification) and on the newborn (renal failure, arterial hypotension, hyperkalemia).
If ARBs have been used from the second trimester of pregnancy, ultrasound monitoring of fetal renal function and skull ossification is recommended.
Newborns of mothers who received ARBs should be closely monitored for the development of arterial hypotension.
Breastfeeding period.
Amlodipine is excreted in breast milk. The fraction of the maternal dose received by the infant is estimated at an interquartile range of 3–7%, with a maximum of 15%. The effect of amlodipine on infants is unknown.
Since information on the use of Diforce during breastfeeding is lacking, the drug is not recommended during breastfeeding; alternative drugs with a well-established safety profile should be preferred, especially when breastfeeding newborns or preterm infants.
Fertility.
Clinical studies on the effect on fertility have not been conducted.
Valsartan.
It is known that valsartan did not cause adverse effects on the reproductive system in male and female rats following oral administration at doses up to 200 mg/kg/day. This dose is 6 times higher than the maximum recommended human dose on a mg/m² basis (based on a 320 mg daily dose for a 60 kg patient).
Amlodipine.
In some patients treated with calcium channel blockers, reversible biochemical changes in sperm heads have been reported. Clinical data on the effect of amlodipine on fertility are insufficient. It is known that in one study in rats, adverse effects on male fertility were observed.
Ability to affect reaction speed when driving or operating machinery.
Patients taking Diforce may experience dizziness or weakness after taking the medication and should therefore take this into account when driving or operating potentially hazardous machinery.
Amlodipine may have a slight or moderate effect on the ability to drive or operate machinery. If patients experience dizziness, headache, fatigue, or nausea while taking amlodipine, their reaction time may be impaired.
Method of Administration and Dosage
Patients whose arterial blood pressure is not controlled by monotherapy with amlodipine or valsartan may be switched to combination therapy with the drug Difors. The recommended dose is 1 tablet per day. Difors should be taken independently of food intake, swallowed with a small amount of water.
Patients currently taking valsartan and amlodipine separately may be switched to Difors containing the same doses of the components. Prior to switching to fixed-dose combination therapy, individual dose titration of each component (i.e., amlodipine and valsartan) is recommended. In cases of clinical necessity, direct substitution of monotherapy with fixed-dose combination therapy may be considered.
Maximum daily dose – 1 tablet of Difors 80 or 1 tablet of Difors 160, or 1 tablet of Difors XL (maximum permitted doses of the components: 10 mg amlodipine and 320 mg valsartan).
Dosage in Specific Patient Groups
Renal Impairment
There are no available clinical data on the use of Difors in patients with severe renal impairment.
For patients with mild to moderate renal impairment, no dose adjustment of Difors is required.
In patients with moderate renal impairment, monitoring of serum potassium and creatinine levels is recommended.
Concomitant use of Difors with aliskiren is contraindicated in patients with renal impairment (eGFR < 60 mL/min/1.73 m²).
Diabetes Mellitus
Concomitant use of Difors with aliskiren is contraindicated in patients with diabetes mellitus.
Hepatic Impairment
Difors is contraindicated in patients with severe hepatic impairment.
Difors should be used with caution in patients with hepatic impairment or obstructive biliary disorders.
The maximum recommended dose of valsartan in patients with mild or moderate hepatic impairment without cholestasis is 80 mg.
Dosage recommendations for amlodipine in patients with mild or moderate hepatic impairment have not been established. When switching such patients with arterial hypertension (see section "Indications") and hepatic impairment to amlodipine or Difors, the lowest recommended dose of amlodipine, either as monotherapy or in combination therapy, should be initiated.
Elderly Patients (aged 65 years and older)
Standard dosing regimens are recommended for elderly patients; however, caution should be exercised when increasing the dose. When switching elderly patients with arterial hypertension (see section "Indications") and hepatic impairment to amlodipine or Difors, the lowest recommended dose of amlodipine, either as monotherapy or in combination therapy, should be initiated.
Pediatric Population
The safety and efficacy of Difors in children (under 18 years of age) have not been studied. Data are lacking.
Children
Studies on the treatment of children (under 18 years of age) with this drug have not been conducted. Therefore, until more complete information is available, Difors is not recommended for use in children.
Overdose
Symptoms
There is currently no experience with overdose of Difors. The main symptom of valsartan overdose is likely to be pronounced arterial hypotension with dizziness. Overdose with amlodipine may lead to progressive peripheral vasodilation and, possibly, reflex tachycardia. Cases of severe and potentially prolonged systemic hypotension, up to shock and fatal outcome, have been reported.
Rare cases of non-cardiogenic pulmonary edema have been reported following amlodipine overdose, with onset possibly delayed (24–48 hours after ingestion), requiring mechanical ventilation. Early resuscitation measures (including fluid loading) to support perfusion and cardiac output may act as triggering factors.
Treatment
If the drug has been recently ingested, induce vomiting or perform gastric lavage. The absorption of amlodipine is significantly reduced by administration of activated charcoal given immediately or within 2 hours after amlodipine intake.
Clinically significant arterial hypotension caused by Difors overdose requires active cardiovascular support, including frequent monitoring of cardiac and respiratory function, elevation of the lower extremities, and attention to circulating fluid volume and urinary output. Vasoconstrictor agents may be used to restore vascular tone and blood pressure, provided there are no contraindications to their use. In cases of persistent hypotension due to calcium channel blockade, intravenous administration of calcium gluconate may be beneficial.
Hemodialysis is unlikely to remove valsartan or amlodipine effectively.
Adverse Reactions
It is known that the safety of the amlodipine/valsartan combination has been evaluated in five controlled clinical studies involving 5175 patients, of whom 2613 received valsartan in combination with amlodipine. The most commonly observed or significant and severe adverse reactions were nasopharyngitis, influenza, hypersensitivity, headache, syncope, orthostatic hypotension, edema, soft tissue edema, facial edema, peripheral edema, increased fatigue, flushing, asthenia, and hot flushes.
The adverse reactions listed below are classified by system organ class and frequency of occurrence. The frequency of adverse reactions was assessed according to the following criteria:
very common (> 1/10); common (> 1/100 – ≤ 1/10); uncommon (> 1/1000 – ≤ 1/100); rare (> 1/10000 – ≤ 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from the available data).
| MedDRA system organ class |
Adverse reaction |
Frequency |
||
| Difors |
Amlodipine |
Vallosartan |
||
| Infections and infestations |
Nasopharyngitis |
Common |
-- |
-- |
| Influenza |
Common |
-- |
-- |
|
| Blood and lymphatic system disorders |
Decreased hemoglobin and hematocrit levels |
-- |
-- |
Unknown |
| Leukopenia |
-- |
Very rare |
-- |
|
| Neutropenia |
-- |
-- |
Unknown |
|
| Thrombocytopenia, sometimes with purpura |
-- |
Very rare |
Unknown |
|
| Immune system disorders |
Hypersensitivity |
Uncommon |
Very rare |
Unknown |
| Nutritional and metabolism disorders |
Anorexia |
Uncommon |
-- |
-- |
| Hypercalcemia |
Uncommon |
-- |
-- |
|
| Hyperglycemia |
-- |
Very rare |
-- |
|
| Hyperlipidemia |
Uncommon |
-- |
-- |
|
| Hyperuricemia |
Uncommon |
-- |
-- |
|
| Hypokalemia |
Common |
-- |
-- |
|
| Hyponatremia |
Uncommon |
-- |
-- |
|
| Psychiatric disorders |
Depression |
-- |
Uncommon |
-- |
| Anxiety |
Uncommon |
-- |
-- |
|
| Insomnia/sleep disorders |
-- |
Uncommon |
-- |
|
| Mood swings |
-- |
Uncommon |
-- |
|
| Confusion |
-- |
Uncommon |
-- |
|
| Nervous system disorders |
Coordination disorder |
Uncommon |
-- |
-- |
| Dizziness |
Uncommon |
Common |
-- |
|
| Postural dizziness |
Uncommon |
-- |
-- |
|
| Dysgeusia |
-- |
Uncommon |
-- |
|
| Extrapyramidal syndrome |
-- |
Unknown |
-- |
|
| Headache |
Common |
Common |
-- |
|
| Hypertension |
-- |
Very rare |
-- |
|
| Paresthesia |
Uncommon |
Uncommon |
-- |
|
| Peripheral neuropathy, neuropathy |
-- |
Very rare |
-- |
|
| Somnolence |
Uncommon |
Common |
-- |
|
| Syncope |
-- |
Uncommon |
-- |
|
| Tremor |
-- |
Uncommon |
-- |
|
| Hypoesthesia |
-- |
Uncommon |
-- |
|
| Eye disorders |
Visual disturbance |
Uncommon |
Uncommon |
-- |
| Blurred vision |
Uncommon |
Uncommon |
-- |
|
| Ear and labyrinth disorders |
Tinnitus |
Uncommon |
Uncommon |
-- |
| Dizziness |
Uncommon |
-- |
Uncommon |
|
| Cardiac disorders |
Palpitations |
Uncommon |
Common |
-- |
| Syncope |
Uncommon |
-- |
-- |
|
| Tachycardia |
Uncommon |
-- |
-- |
|
| Arrhythmias (including bradycardia, ventricular tachycardia, atrial fibrillation) |
-- |
Very rare |
-- |
|
| Myocardial infarction |
-- |
Very rare |
-- |
|
| Vascular disorders |
Hyperemia |
-- |
Common |
-- |
| Hypotension |
Uncommon |
Uncommon |
-- |
|
| Orthostatic hypotension |
Uncommon |
-- |
-- |
|
| Vasculitis |
-- |
Very rare |
Unknown |
|
| Respiratory, thoracic and mediastinal disorders |
Cough |
Uncommon |
Very rare |
Very rare |
| Dyspnea |
-- |
Uncommon |
-- |
|
| Pharyngolaryngeal pain |
Uncommon |
-- |
-- |
|
| Rhinitis |
-- |
Uncommon |
-- |
|
| Gastrointestinal disorders |
Abdominal discomfort and upper abdominal pain |
Uncommon |
Common |
Uncommon |
| Change in defecation rhythm |
-- |
Uncommon |
-- |
|
| Constipation |
Uncommon |
-- |
-- |
|
| Diarrhea |
Uncommon |
Uncommon |
-- |
|
| Dry mouth |
Uncommon |
Uncommon |
-- |
|
| Dyspepsia |
-- |
Uncommon |
-- |
|
| Gastritis |
-- |
Very rare |
-- |
|
| Gingival hyperplasia |
-- |
Very rare |
-- |
|
| Nausea |
Uncommon |
Common |
-- |
|
| Pancreatitis |
-- |
Very rare |
-- |
|
| Vomiting |
-- |
Uncommon |
-- |
|
| Angioedema of the intestine |
-- |
-- |
Very rare |
|
| Hepatobiliary disorders |
Abnormal liver function tests, including increased blood bilirubin levels |
-- |
Very rare* |
Unknown |
| Hepatitis |
-- |
Very rare |
-- |
|
| Intrahepatic cholestasis, jaundice |
-- |
Very rare |
-- |
|
| Skin and subcutaneous tissue disorders |
Alopecia |
-- |
Uncommon |
-- |
| Angioedema |
-- |
Very rare |
Unknown |
|
| Bullous dermatitis |
-- |
-- |
Unknown |
|
| Erythema |
Uncommon |
-- |
-- |
|
| Multiform erythema |
-- |
Very rare |
-- |
|
| Exanthema |
Uncommon |
Uncommon |
-- |
|
| Hyperhidrosis |
Uncommon |
Uncommon |
-- |
|
| Photosensitivity |
-- |
Uncommon |
-- |
|
| Pruritus |
Uncommon |
Uncommon |
Unknown |
|
| Purpura |
-- |
Uncommon |
-- |
|
| Rash |
Uncommon |
Uncommon |
Unknown |
|
| Skin discoloration |
-- |
Uncommon |
-- |
|
| Urticaria and other forms of rash |
-- |
Very rare |
-- |
|
| Exfoliative dermatitis |
-- |
Very rare |
-- |
|
| Stevens-Johnson syndrome |
-- |
Very rare |
-- |
|
| Quincke's edema |
-- |
Very rare |
-- |
|
| Toxic epidermal necrolysis |
-- |
Unknown |
-- |
|
| Musculoskeletal and connective tissue disorders |
Arthralgia |
Uncommon |
Uncommon |
-- |
| Back pain |
Uncommon |
Uncommon |
-- |
|
| Joint swelling |
Uncommon |
-- |
-- |
|
| Muscle cramps |
Uncommon |
Uncommon |
-- |
|
| Muscle pain |
-- |
Uncommon |
Unknown |
|
| Ankle swelling |
-- |
Common |
-- |
|
| Heaviness sensation |
Uncommon |
-- |
-- |
|
| Renal and urinary disorders |
Increased blood creatinine levels |
-- |
-- |
Unknown |
| Urinary disorder |
-- |
Uncommon |
-- |
|
| Nocturia |
-- |
Uncommon |
-- |
|
| Polyakiuria |
Uncommon |
Uncommon |
-- |
|
| Polyuria |
Uncommon |
-- |
-- |
|
| Renal failure and renal function impairment |
-- |
-- |
Unknown |
|
| Reproductive system disorders |
Impotence |
-- |
Uncommon |
-- |
| Erectile dysfunction |
Uncommon |
-- |
-- |
|
| Gynecomastia |
-- |
Uncommon |
-- |
|
| General disorders |
Asthenia |
Common |
Uncommon |
-- |
| Discomfort, malaise |
-- |
Uncommon |
-- |
|
| Increased fatigue |
Common |
Common |
Uncommon |
|
| Facial swelling |
Common |
-- |
-- |
|
| Hyperemia, flushing |
Common |
-- |
-- |
|
| Chest pain, non-cardiac |
-- |
Uncommon |
-- |
|
| Edema |
Common |
Common |
-- |
|
| Peripheral edema |
Common |
-- |
-- |
|
| Pain |
-- |
Uncommon |
-- |
|
| Soft tissue swelling |
Common |
-- |
-- |
|
| Investigations |
Increased blood potassium levels |
-- |
-- |
Unknown |
| Increased body weight |
-- |
Uncommon |
-- |
|
| Decreased body weight |
-- |
Uncommon |
-- |
|
* Mainly associated with cholestasis.
Additional information on the components of the medicinal product.
Adverse reactions previously observed with one of the components of the medicinal product (amlodipine or valsartan) may also occur with the use of Difors, even if they were not reported during clinical trials or in the post-marketing period.
Additional information on the combination.
Peripheral edema, a known side effect of amlodipine, occurred generally less frequently in patients receiving the amlodipine/valsartan combination than with amlodipine alone. In double-blind, controlled clinical trials, the average incidence of peripheral edema, uniformly distributed across the entire dose range, was 5.1% for the amlodipine/valsartan combination.
Amlodipine.
Common: somnolence, dizziness, palpitations, abdominal pain, nausea, ankle swelling.
Uncommon: insomnia, mood changes (including anxiety), depression, tremor, dysgeusia, syncope, hypoesthesia, visual disturbances (including diplopia), tinnitus, hypotension, dyspnea, rhinitis, vomiting, dyspepsia, alopecia, purpura, skin discoloration, hyperhidrosis, pruritus, exanthema, myalgia, muscle cramps, pain, urinary disorders, increased frequency of urination, impotence, gynecomastia, chest pain, malaise, weight gain or loss.
Rare: confusion.
Very rare: leukopenia, thrombocytopenia, allergic reactions, hyperglycemia, hypertension, peripheral neuropathy, myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia, and atrial fibrillation), vasculitis, pancreatitis, gastritis, gingival hyperplasia, hepatitis, jaundice, increased liver enzyme levels, usually associated with cholestasis, angioneurotic edema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke's edema, photosensitivity.
Frequency not known: toxic epidermal necrolysis.
Isolated cases of extrapyramidal syndrome have been reported.
Valsartan.
The following additional adverse events were observed during clinical trials of valsartan monotherapy, regardless of causal relationship to the investigational medicinal product.
Frequency not known: decreased hemoglobin levels, decreased hematocrit, neutropenia, thrombocytopenia, increased serum potassium levels, elevated liver function tests, including serum bilirubin concentration, renal failure and impaired renal function, increased serum creatinine levels, angioneurotic edema, myalgia, vasculitis, hypersensitivity reactions, including serum sickness.
Shelf life. 2 years.
Storage conditions. Store in a place inaccessible to children, in the original packaging, at a temperature not exceeding 25 °C.
Packaging. 10 tablets per blister; 1 or 3 blisters per cardboard pack.
Prescription status. Prescription only.
Manufacturer: LLC "Pharma Start".
Manufacturer's address and location of its business operations.
8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.
If adverse effects occur or if you have questions regarding the safety of this medicinal product, please contact the Pharmacovigilance Department of LLC "ASINO UKRAINE" at 8 Vatslava Havela Boulevard, Kyiv, 03124, Tel/Fax: +38 044 281 2333