Instructions for Diforce 80 film-coated tablets 5 mg + 80 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 exhibits 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 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 dosing.
The effect correlates with plasma concentrations in young and elderly patients.
In patients with normal renal function, therapeutic doses of amlodipine lead to a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without changes in the filtered fraction or proteinuria.
Hemodynamic measurements of cardiac function at rest and during exercise 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 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 the function of the sinoatrial node and atrioventricular conduction in healthy animals or humans. When amlodipine was used in combination with beta-blockers in patients with essential hypertension or angina pectoris, 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 is a 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. No side effects due to bradykinin have been observed. 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.
Prescribing the drug to patients with arterial hypertension leads to a decrease in blood pressure without affecting the pulse rate.
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/amlodipine.
The combination of amlodipine besylate/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, peak plasma concentrations 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 patients with essential hypertension, approximately 97.5% of the circulating drug is bound to plasma proteins.
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 the parent amlodipine and 60% of the amlodipine metabolites are excreted in the urine.
Valsartan.
Absorption. After oral administration, peak plasma valsartan concentrations are reached within 2-4 hours. The mean absolute bioavailability of the drug is 23%. The pharmacokinetic curve of valsartan has a descending multiexponential nature (half-life T1/2a < 1 hour and T1/2b approximately 9 hours). Food reduces valsartan exposure, as shown by AUC (plasma concentration - time), by approximately 40%, and peak plasma concentration (Cmax) by 50%, although 8 hours after administration, the plasma valsartan concentration 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 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 total clearance). The half-life of valsartan is 6 hours.
Valsartan/amlodipine.
After oral administration of Diforce, peak plasma concentrations of valsartan and amlodipine are reached in 3 and 6-8 hours, respectively. The rate and extent of absorption of Diforce are equivalent to the bioavailability of valsartan and amlodipine.
Kidney failure.
Renal impairment does not significantly affect the pharmacokinetics of amlodipine.
There is no real correlation between renal function (as measured by creatinine clearance) and exposure (as determined by AUC) when valsartan is administered to patients with varying degrees of renal impairment. Therefore, patients with mild to moderate renal impairment should receive the usual starting dose.
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, the exposure (determined by AUC values) of valsartan is on average twice that of healthy volunteers. Patients with liver disease should be cautious when using the drug.
Indication
Essential hypertension in patients whose blood pressure is not controlled with amlodipine or valsartan monotherapy.
Contraindication
Hypersensitivity to any of the components of the drug.
Severe liver dysfunction, biliary cirrhosis or cholestasis.
Severe renal impairment (glomerular filtration rate (GFR) < 30 mL/min/1.73 m2).
Contraindicated in patients on dialysis.
The concomitant use of angiotensin receptor antagonists, including valsartan, or angiotensin-converting enzyme inhibitors with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) < 60 mL/min/1.73 m2).
Contraindicated for pregnant women and women planning to become pregnant.
- obstruction of the left ventricular outflow tract (for example, severe aortic stenosis);
- hemodynamically unstable heart failure after acute myocardial infarction.
Interaction with other medicinal products and other types of interactions
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.
Amlodipine.
In monotherapy with amlodipine, no clinically significant drug interactions have been established with the following drugs: thiazide diuretics, beta-blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, atorvastatin, sildenafil; combined antacids containing aluminum hydroxide gel, magnesium hydroxide, simethicone; cimetidine, nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, oral hypoglycemic agents.
CYP3A4 inhibitors.
A study in elderly patients showed that diltiazem inhibits the metabolism of amlodipine, probably via CYP3A4 (plasma concentrations increased by approximately 50% and the effect of amlodipine was enhanced). It is possible that more potent CYP3A4 inhibitors (such as ketoconazole, itraconazole, ritonavir) may increase plasma concentrations of amlodipine to a greater extent than diltiazem.
CYP3A4 inducers.
Concomitant use of anticonvulsants (e.g. carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone), rifampicin, St. John's wort (Hypericum perforatum) may lead to a decrease in plasma concentrations of amlodipine. Clinical monitoring is recommended; amlodipine dose adjustment may also be necessary during and after the induction agent is discontinued.
Valsartan.
With valsartan monotherapy, no clinically significant drug interactions have been established with the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide.
Caution should be exercised when using angiotensin receptor antagonists (ARBs), including valsartan, with other drugs that block the renin-angiotensin system (RAS), such as angiotensin-converting enzyme inhibitors (ACEIs) or aliskiren.
The concomitant use of ARBs, including Diforce, or ACE inhibitors with aliskiren in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m2) is contraindicated.
Lithium.
Reversible increases in serum lithium concentrations and toxicity have been reported with concomitant use of ACE inhibitors. Although there is no experience with the concomitant use of valsartan and lithium, this combination is not recommended. If the combination proves necessary, serum lithium levels should be closely monitored.
Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, and other drugs that can increase potassium levels.
The simultaneous use of the drug with these substances requires caution (see the section "Special instructions for use").
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 an adequate level of water in the patient's body.
Transporters.
In vitro studies have shown that valsartan is a substrate for the hepatic uptake transporter OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical significance of these findings is unknown. Concomitant use of inhibitors of the uptake transporter (e.g. rifampicin, cyclosporine) or efflux transporter (e.g. ritonavir) may increase systemic exposure to valsartan. Appropriate precautions should be taken when initiating and terminating concomitant use of these medicinal products.
Application features
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.
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 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. Treatment should be continued until blood pressure stabilizes.
Caution should be exercised when concomitant treatment with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other drugs that may increase potassium levels (heparin, etc.). If the use of a drug that affects potassium levels is considered necessary in combination with valsartan, monitoring of potassium levels in the blood plasma is recommended.
Withdrawal of beta-blockers.
Amlodipine is not a beta-blocker and therefore does not protect against the dangers of abrupt withdrawal of beta-blockers, so the dose of the beta-blocker should be reduced gradually.
Renal artery stenosis.
There are no data on the use of Diforce in patients with unilateral or bilateral renal artery stenosis. Since other medicinal products that affect the renin-angiotensin-aldosterone system (RAAS) may increase blood urea and serum creatinine in patients with unilateral renal artery stenosis, monitoring of renal function is recommended as a safety measure during treatment with valsartan.
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, while amlodipine is extensively metabolized in the liver. Particular caution is required when using Difors in patients with mild to moderate hepatic impairment or obstructive gallbladder disease.
Kidney dysfunction.
Regarding the use of Diforce in patients with impaired renal function, see the sections "Contraindications" and "Method of administration and dosage".
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 treated with valsartan. Some of these patients had a history of angioedema while taking other drugs, including angiotensin-converting enzyme (ACE) inhibitors. Difors 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.
In patients with severe heart failure whose 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 oliguria and/or progressive azotemia, and (in rare cases) acute renal failure and/or death. Similar results have been reported with valsartan, therefore caution should be exercised in patients with heart failure and renal function should always be assessed.
Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure as they increase the risk of cardiovascular events, pulmonary edema, and death.
Patients with acute myocardial infarction.
Worsening of angina pectoris and acute myocardial infarction may occur after initiation or dose increase of amlodipine, especially in patients with severe aortic stenosis.
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 obstructive hypertrophic cardiomyopathy.
The drug should be used with caution in unstable angina.
Use during pregnancy or breastfeeding
Diforce is contraindicated for use in pregnant women and women planning to become pregnant. Physicians should warn women planning to become pregnant of the potential risk to the unborn child when taking the drug and prescribe such women alternative antihypertensive therapy with an established safety profile for use during pregnancy. 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 pregnancy.
Epidemiological studies on the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy have not been conclusive; however, some increase in risk cannot be excluded. The use of ARA II during the second and third trimesters of pregnancy is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, 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.
It is not known whether valsartan or amlodipine is excreted in human milk, therefore, the use of the drug during breastfeeding is not recommended; alternative treatments with better established safety profiles are preferable, especially while breastfeeding a newborn or preterm infant. If therapy with the drug is necessary for the mother, breastfeeding should be discontinued.
Fertility.
Clinical studies on the effect on fertility have not been conducted.
Ability to influence reaction speed when driving vehicles or other mechanisms
Studies on the effect of the drug on the ability to drive and use potentially dangerous mechanisms have not been conducted. However, patients who experience dizziness or weakness after taking the drug should refrain from driving and using potentially dangerous mechanisms.
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 is taken regardless of meals, with water.
Patients taking valsartan and amlodipine separately can be switched to Diforce, which contains the same doses of the components. Before switching to the fixed-dose combination, individual dose titration of the individual components (i.e. amlodipine and valsartan) is recommended.
Daily dose – 1 tablet of Diforce 80 or 1 tablet of Diforce 160, or 1 tablet of Diforce XL (maximum permissible doses of the drug components – 10 mg of amlodipine content, 320 mg of valsartan content).
Dosage in certain patient groups.
Kidney dysfunction.
For patients with mild and moderate renal impairment (GFR < 30 ml/min/1.73 m2), there is no need to adjust the dose of Diforce.
In patients with moderate renal impairment, it is recommended to monitor blood potassium and creatinine levels.
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.
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.
Children
The drug is not recommended for use in children due to lack of data on safety and efficacy.
Overdose
There is no experience of studying overdose with Diforce. The following is information regarding the active ingredients of the drug.
Symptoms.
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 with amlodipine overdose.
Treatment: If the drug has been taken recently, induce vomiting or perform gastric lavage. 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 an overdose of Diforce requires active support of the cardiovascular system, including frequent monitoring of cardiac and respiratory function, elevation of the lower extremities, attention to the volume of circulating fluid and urination. To restore vascular tone and blood pressure, a vasoconstrictor can be used in the absence of contraindications to its use. In case of persistent decrease in blood pressure, which is a consequence of calcium channel blockade, intravenous administration of calcium gluconate may be appropriate.
Removal of valsartan and amlodipine by hemodialysis is unlikely.
Adverse reactions
The following adverse reactions are classified by system organ class and frequency. The frequency of adverse reactions was assessed using the following criteria:
very common (≥ 1/10); common (> 1/100 - ≤ 1/10); uncommon (> 1/1000 - ≤ 1/100); rare (> 1/10,000 - ≤ 1/1000); very rare (< 1/10,000); frequency unknown (cannot be estimated from the available data).
Infections: common: nasopharyngitis, flu-like symptoms.
On the part of the immune system: rarely - hypersensitivity.
On the part of the organs of vision: rarely - visual impairment.
Mental disorders: rarely - agitation.
From the nervous system: often - headache; infrequently - dizziness, drowsiness, postural dizziness, paresthesia.
From the side of the organs of hearing and labyrinth: often - vertigo; rarely - tinnitus.
On the part of the heart: infrequently - tachycardia, palpitations; rarely - fainting.
Vascular disorders: infrequently - orthostatic hypotension; rarely - arterial hypotension.
From the respiratory system: infrequently - cough, pain in the throat and larynx.
On the part of the digestive tract: infrequently - abdominal pain, constipation, diarrhea, nausea, dry mouth.
Musculoskeletal system: infrequently - joint swelling, back pain, arthralgia; rarely - muscle cramps, feeling of heaviness in the muscles.
On the part of the kidneys and urinary system: rarely - increased urination, polyuria, increased blood urea nitrogen.
Reproductive system disorders: rarely - erectile dysfunction.
General disorders: rarely - edema, facial edema, peripheral edema, increased fatigue, hot flashes, asthenia, hyperemia.
Additional information about the combination.
Peripheral edema, a known side effect of amlodipine, was generally reported less frequently in patients taking the amlodipine/valsartan combination than in patients taking amlodipine alone.
Additional information about the components of the drug.
Diforce may cause adverse reactions that were previously observed when using one of the components of the drug (amlodipine or valsartan), even if they were not observed when used in this combination.
Amlodipine.
Common: vomiting.
Uncommon: alopecia, intestinal dysrhythmia, dyspepsia, dyspnoea, rhinitis, gastritis, gingival hyperplasia, gynecomastia, hyperglycaemia, impotence, leukopenia, malaise, mood changes, myalgia, peripheral neuropathy, pancreatitis, hepatitis, thrombocytopenia, vasculitis, angioedema, pulmonary oedema, erythema multiforme, insomnia, depression, confusion, tremor, dysgeusia, hypoesthesia, hypertonicity, skin discolouration, exfoliative dermatitis, Stevens-Johnson syndrome, photosensitivity, nocturia, weight gain or loss.
Rare: bradycardia. Occasionally, in patients, especially with severe obstructive atherosclerotic heart disease, the frequency, duration or severity of angina pectoris or acute myocardial infarction has increased when calcium channel blockers are started or when their dose is increased. Cases of arrhythmia (including ventricular tachycardia and atrial fibrillation) have also been reported. It is not possible to determine whether these adverse reactions are caused by the effects of amlodipine or are a manifestation of the underlying disease.
Very rare: cholestatic jaundice, increased AST and ALT levels, purpura. Isolated cases of extrapyramidal syndrome have been reported.
Valsartan.
Frequency unknown: viral infections, upper respiratory tract infections, sinusitis, rhinitis, neutropenia, insomnia, increased blood creatinine, decreased hemoglobin, decreased hematocrit, thrombocytopenia, increased serum potassium, increased liver function tests, including serum bilirubin concentrations, renal failure and renal dysfunction, hyponatremia, heart failure, angioedema, myalgia, vasculitis, hypersensitivity reactions, including serum sickness.
Expiration date
2 years.
Storage conditions
Store out of the reach of children, in the original packaging, at a temperature not exceeding 25 °C.
Packaging
10 tablets in a blister; 1 or 3 blisters in a cardboard pack.
Vacation category
According to the recipe.
Producer
Pharma Start LLC, Ukraine.
Location of the manufacturer and its business address
Ukraine, 03124, Kyiv, I. Lepse Blvd., 8.
