Vamloset®
The drug Vamloset®
Common drug interactions for Vamloset® (amlodipine/valsartan)
Concomitant use requiring attention
Other antihypertensive drugs (eg, alpha-blockers, diuretics) and drugs that have a hypotensive effect (eg, tricyclic antidepressants, alpha-blockers for the treatment of benign prostatic hyperplasia) may enhance the antihypertensive effect.
Drug interactions for amlodipine
Undesirable simultaneous use
Grapefruit or grapefruit juice
Concomitant use is not recommended due to the possibility of increased bioavailability in some patients and enhanced antihypertensive effects.
Concomitant use requiring caution
CYP3A4 isoenzyme inhibitors
Concomitant use with strong or moderate inhibitors of the CYP3A4 isoenzyme (protease inhibitors, verapamil or diltiazem, azole antifungals, macrolides such as erythromycin or clarithromycin) may lead to a significant increase in the systemic exposure of amlodipine. In elderly patients, these changes are of clinical significance, so medical supervision and dosage adjustment are necessary.
Inducers of the CYP3A4 isoenzyme (anticonvulsants (for example, carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone), rifampicin, herbal preparations containing St. John's wort)
With simultaneous use of inducers of the CYP3A4 isoenzyme, the concentration of amlodipine in the blood plasma may vary. Therefore, blood pressure control and dose adjustment of amlodipine are indicated both during treatment with inducers of the CYP3A4 isoenzyme and after their withdrawal, especially when using strong inducers of the CYP3A4 isoenzyme (for example, rifampicin, drugs containing St. John's wort).
Simvastatin
Simultaneous repeated use of amlodipine at a dose of 10 mg/day and simvastatin at a dose of 80 mg/day increases the exposure of simvastatin by 77% compared with that of simvastatin monotherapy. For patients receiving amlodipine, it is recommended to use simvastatin at a dose of no more than 20 mg/day.
Dantrolene (intravenous administration)
In animal experiments, cases of fatal ventricular fibrillation and cardiovascular failure associated with hyperkalemia were observed after oral administration of verapamil and intravenous administration of dantrolene. Given the risk of developing hyperkalemia, simultaneous use of slow calcium channel blockers, including amlodipine, should be avoided in patients prone to developing malignant hyperthermia.
Tacrolimus
When used concomitantly with amlodipine, there is a risk of increasing the concentration of tacrolimus in the blood plasma, but the pharmacokinetic mechanism of this interaction has not been fully studied. To prevent the toxic effect of tacrolimus when used concomitantly with amlodipine, the concentration of tacrolimus in the blood plasma should be monitored and the dose of tacrolimus should be adjusted if necessary.
Cyclosporine
Drug interaction studies have not been conducted with cyclosporine and amlodipine in healthy volunteers or other patient populations, except for renal transplant patients in whom variable trough concentrations (mean: 0%-40%) of cyclosporine were observed. With the simultaneous use of amlodipine in patients who have undergone kidney transplantation, the concentration of cyclosporine in the blood plasma should be monitored and, if necessary, its dose should be reduced.
Clarithromycin
Clarithromycin is an inhibitor of the CYP3A4 isoenzyme. With simultaneous use of amlodipine and clarithromycin, the risk of developing arterial hypotension is increased. Close medical monitoring of patients receiving amlodipine concomitantly with clarithromycin is recommended.
Mammalian target of rapamycin (mTOR) inhibitors
mTOR inhibitors such as sirolimus, temsirolimus and everolimus are substrates of the CYP3A isoenzyme. Amlodipine is a weak inhibitor of the CYP3A isoenzyme. When used concomitantly with mTOR inhibitors, amlodipine may increase their exposure.
Concomitant use requiring attention
Other
In clinical studies of amlodipine, there was no significant interaction with thiazide diuretics, alpha-blockers, beta-blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, atorvastatin, sildenafil, Maalox (aluminum- or magnesium-containing antacids, simethicone) , cimetidine, non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics and oral hypoglycemic agents.
Simultaneous use of amlodipine and ethanol
does not affect the pharmacokinetics of the latter.
Calcium preparations
may reduce the effect of BMCC.
With simultaneous use of BMCC with lithium preparations
(no data available for amlodipine) their neurotoxicity may increase (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus).
Glucocorticosteroids
Decreased antihypertensive effect (retention of fluid and sodium ions as a result of action (retention of fluid and sodium ions as a result of the action of corticosteroids).
Drug interactions for valsartan
Concomitant use is contraindicated
Concomitant use of ARB II, including valsartan, with aliskiren and drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients.
Concomitant use of ARB II with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.
Undesirable simultaneous use
Lithium
Simultaneous use with lithium preparations is not recommended, since a reversible increase in the concentration of lithium in the blood plasma and the development of intoxication are possible. If simultaneous use with lithium preparations is necessary, the concentration of lithium in the blood plasma should be carefully monitored. The risk of toxic effects associated with the use of lithium preparations may further increase when used simultaneously with Vamloset® and diuretics.
Potassium-sparing diuretics, potassium supplements, potassium-containing dietary supplements, and other drugs and substances that may increase serum potassium levels (eg, heparin)
If simultaneous use with drugs that affect potassium levels is necessary, it is recommended to monitor the potassium content in the blood plasma.
Concomitant use requiring caution
NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, acetylsalicylic acid in a dose of more than 3 g/day and non-selective NSAIDs
With simultaneous use, it is possible to weaken the antihypertensive effect, increase the risk of developing renal dysfunction and increase the potassium content in the blood plasma. At the beginning of therapy, it is recommended to assess renal function, as well as correct water and electrolyte imbalances.
Transport protein inhibitors
in vitro study results
valsartan is a substrate for the transporter proteins OATP1B1 and MRP2. Concomitant use of valsartan with OATP1B1 transporter protein inhibitors (eg, rifampicin, cyclosporine) and an MRP2 transporter protein inhibitor (eg, ritonavir) may increase the systemic exposure of valsartan (Cmax and AUC). This should be taken into account at the beginning and at the end of concomitant therapy.
Double blockade of the RAAS when using ARA II, ACE inhibitors or aliskiren
The simultaneous use of ARA II with other drugs that affect the RAAS leads to an increase in the incidence of cases of arterial hypotension, hyperkalemia, and renal dysfunction. It is necessary to monitor blood pressure, renal function, and the content of blood plasma electrolytes when using Vamloset® with other drugs that affect the RAAS.
Other
When monotherapy with valsargan, no clinically significant interactions were identified with the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine and glibenclamide.
Vamloset
A combined antihypertensive drug containing active substances with a complementary mechanism for blood pressure control. Amlodipine, a dihydropyridine derivative, belongs to the class of slow calcium channel blockers (SCBCs), valsartan belongs to the class of angiotensin II receptor antagonists. The combination of these components has a mutually complementary antihypertensive effect, which leads to a more pronounced reduction in blood pressure than when they are used separately.
Amlodipine/Valsartan
The combination of amlodipine and valsartan reduces blood pressure in an additive dose-dependent manner over the therapeutic dose range. When taking the amlodipine/valsartan combination in a single dose, the hypotensive effect persists for 24 hours.
The clinical effectiveness of the amlodipine/valsartan combination has been proven in patients with mild and moderate arterial hypertension (mean diastolic blood pressure ≥95 mm Hg and <110 mm Hg) without complications in comparison with placebo. The level of blood pressure reduction in the sitting position in arterial hypertension with diastolic blood pressure ≥110 mmHg. Art. and <120 mm Hg. Art. comparable to the use of a combination of an ACE inhibitor and a thiazide diuretic.
The antihypertensive effect lasts for a long time. Sudden cessation of drug use is not accompanied by a sharp increase in blood pressure (there is no withdrawal syndrome).
Therapeutic effectiveness does not depend on the patient's age, gender, race and body mass index.
When using combination therapy with amlodipine/valsartan, comparable blood pressure control is achieved with a lower likelihood of developing peripheral edema in patients with previously achieved blood pressure control and severe peripheral edema during amlodipine therapy.
Amlodipine
Amlodipine is a dihydropyridine derivative, a slow calcium channel blocker, and has antianginal and antihypertensive effects. Inhibits the transmembrane entry of calcium ions into cardiomyocytes and vascular smooth muscle cells. The mechanism of the antihypertensive effect of amlodipine is due to a direct relaxing effect on vascular smooth muscle, which leads to a decrease in peripheral vascular resistance and blood pressure.
Amlodipine in therapeutic doses in patients with arterial hypertension causes dilation of blood vessels, which leads to a decrease in blood pressure (in the supine and standing position). A decrease in blood pressure with long-term use of amlodipine is not accompanied by a significant change in heart rate and the concentration of catecholamines in the blood plasma.
Plasma concentrations of amlodipine correlate with the clinical effect in both young and elderly patients.
In arterial hypertension in patients with normal renal function, amlodipine in therapeutic doses leads to a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal blood flow without changing the filtration fraction or proteinuria.
Amlodipine, like other BMCCs, in patients with normal left ventricular function causes changes in hemodynamic parameters of cardiac function at rest and during exercise (or stimulation): a slight increase in cardiac index, without a significant effect on the maximum rate of increase in pressure in the left ventricle (dP/ dt) or end-diastolic pressure and end-diastolic volume of the left ventricle. The use of amlodipine in the therapeutic dose range does not cause a negative inotropic effect, even when used simultaneously with beta-blockers.
Amlodipine does not alter sinoatrial node function or AV conduction in intact animals or humans. The use of amlodipine in combination with beta-blockers in patients with arterial hypertension or angina pectoris was not accompanied by undesirable changes on the ECG.
The clinical effectiveness of amlodipine has been proven in patients with stable angina pectoris, vasospastic angina and angiographically confirmed lesions of the coronary arteries.
Valsartan
Valsartan is a selective angiotensin II receptor antagonist (AT1 type) for oral administration, of a non-protein nature.
Selectively blocks receptors of the AT1 subtype, which are responsible for the effects of angiotensin II. An increase in plasma concentrations of angiotensin II due to blockade of AT1 receptors by valsartan may stimulate unblocked AT2 receptors, which counteract the effects of AT1 receptor stimulation. Valsartan does not have agonist activity against AT1 receptors. The affinity of valsartan for receptors of the AT1 subtype is approximately 20,000 times higher than for receptors of the AT2 subtype.
Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin II and destroys bradykinin. Due to the lack of influence on ACE, the effects of bradykinin or substance P are not potentiated, therefore, when using angiotensin II receptor antagonists, the development of a dry cough is unlikely. It has been proven that the incidence of dry cough during treatment with valsartan is significantly lower than when using ACE inhibitors. Valsartan does not interact with or block receptors of other hormones or ion channels involved in the regulation of the functions of the cardiovascular system.
In the treatment of arterial hypertension, valsartan reduces blood pressure without affecting heart rate.
After oral administration of valsartan in a single dose, the hypotensive effect develops within 2 hours, and the maximum reduction in blood pressure is achieved within 4-6 hours. The antihypertensive effect of valsartan persists for 24 hours after its administration. With repeated use of valsartan, the maximum reduction in blood pressure, regardless of the dose, is achieved after 2-4 weeks and is maintained at the achieved level during long-term therapy. Sudden cessation of valsartan use is not accompanied by a significant increase in blood pressure or other adverse effects (withdrawal syndrome).
Pharmacokinetics
The pharmacokinetics of amlodipine and valsartan are linear.
Amlodipine/Valsartan
After oral administration of the amlodipine/valsartan combination, Cmax of valsartan and amlodipine in blood plasma is achieved after 3 hours and 6-8 hours, respectively. The rate and extent of absorption are equivalent to the bioavailability of valsartan and amlodipine when taken individually.
Amlodipine
Suction
After oral administration, amlodipine is slowly absorbed from the gastrointestinal tract. Cmax is reached within 6-12 hours. Absolute bioavailability is 64-80%. Bioavailability is independent of food intake.
Distribution
Vd is approximately 21 l/kg. According to in vitro data, binding to blood plasma proteins is 97.5%.
Css in blood plasma are achieved after prolonged oral use for 7-8 days.
Metabolism
Amlodipine is intensively (about 90%) metabolized in the liver with the formation of inactive metabolites.
Removal
Amlodipine is eliminated from blood plasma in a biphasic manner, with terminal T1/2 from 30 to 50 hours. 10% of unchanged amlodipine and 60% of amlodipine in the form of metabolites are excreted in the urine.
Valsartan
Suction
After taking valsartan orally, Cmax is achieved within 2-3 hours. The average absolute bioavailability is 23%. When taking valsartan with food, there is a decrease in bioavailability (according to AUC value) by approximately 40%, and Cmax by approximately 50%. Approximately 8 hours after oral administration, plasma concentrations of valsartan in the group of patients taking the drug with food and in the group taking the drug on an empty stomach level out. The decrease in AUC is not clinically significant, so valsartan can be taken without regard to meals.
Distribution
Vd of valsartan during the steady state period after intravenous administration is about 17 l, which indicates the absence of extensive distribution of valsartan in tissues. Valsartan is highly bound to serum proteins (94-97%), mainly to serum albumin.
Metabolism
Valsartan is not subject to significant metabolism. Only about 20% of the dose taken is determined in the blood plasma in the form of metabolites. The hydroxyl metabolite is detected in blood plasma in low concentrations (less than 10% of the AUC of valsartan). This metabolite is pharmacologically inactive.
Removal
Valsartan is excreted in two phases: α-phase with T1/2α less than 1 hour and β-phase with T1/2β - about 9 hours. Valsartan is excreted mainly unchanged with bile through the intestines (about 83%) and in urine (about 13%). ). After intravenous administration, the plasma clearance of valsartan is about 2 l/h and its renal clearance is 0.62 l/h (about 30% of the total clearance). T1/2 of valsartan is 6 hours.
Pharmacokinetics in special groups of patients
There are no pharmacokinetic data on the use of the drug in children and adolescents under 18 years of age.
The time to reach Cmax of amlodipine in the blood plasma is the same in young patients and elderly patients. In elderly patients, the clearance of amlodipine tends to decrease, which leads to an increase in AUC and T1/2. In elderly patients, the mean systemic exposure (AUC) of valsartan is slightly higher than in younger patients. However, this was not clinically significant. Given the good tolerability of amlodipine and valsartan in elderly and younger patients, it is recommended to use the usual dosage regimens.
In patients with renal failure, pharmacokinetic parameters do not change. The renal clearance of valsartan is only approximately 30% of the total clearance from plasma, so there is no correlation between renal function and systemic exposure (as measured by AUC) of valsartan. No changes to the initial dose are required in patients with mild to moderate renal failure (creatinine clearance 30-50 ml/min).
Experience with the drug in patients with impaired liver function is limited. Patients with impaired liver function have reduced clearance of amlodipine, resulting in an increase in AUC of approximately 40-60%. On average, in patients with mild (5-6 Child-Pugh scores) and moderate (7-9 Child-Pugh scores) liver dysfunction, the bioavailability (AUC value) of valsartan is doubled compared to age-matched healthy volunteers , gender and body weight.
Vamloset, 30 pcs., 10 mg+160 mg, film-coated tablets
WHO classification of the incidence of side effects: very often - ≥1/10; often - from ≥1/100 to <1/10; uncommon - from ≥1/1000 to <1/100; rarely - from ≥1/10000 to <1/1000; very rarely - <1/10000; frequency unknown—cannot be estimated from available data.
Vamloset
Infectious and parasitic diseases:
often - nasopharyngitis, influenza.
From the immune system:
rarely - hypersensitivity.
Metabolism and nutrition:
often - hypokalemia; uncommon - anorexia, hypercalcemia, hyperlipidemia, hyperuricemia, hyponatremia.
Mental disorders:
rarely - anxiety.
From the nervous system:
often - headache; uncommon - loss of coordination, dizziness, postural dizziness, paresthesia, drowsiness.
From the side of the organ of vision:
infrequently - visual impairment; rarely - visual impairment.
Hearing and labyrinth disorders:
infrequently - vertigo; rarely - tinnitus.
From the heart:
infrequently - palpitations, tachycardia; rarely - fainting.
From the side of blood vessels:
infrequently - orthostatic hypotension; rarely - a pronounced decrease in blood pressure.
From the respiratory system, chest and mediastinal organs:
infrequently - cough, pain in the pharynx and larynx.
From the digestive system:
uncommon - diarrhea, nausea, abdominal discomfort, pain in the upper abdomen, constipation, dry oral mucosa.
For the skin and subcutaneous tissues:
infrequently - erythema, skin rash; rarely - exanthema, hyperhidrosis, itching.
From the musculoskeletal and connective tissue side:
infrequently - arthralgia, back pain, swelling of the joints; rarely - muscle spasms, a feeling of heaviness throughout the body.
From the kidneys and urinary tract:
rarely - pollakiuria, polyuria.
From the genital organs and breast:
rarely - erectile dysfunction.
General disorders and disorders at the injection site:
often - asthenia, increased fatigue, swelling of the face, a feeling of a rush of blood to the skin of the face, edema, peripheral edema, pastiness.
Additional Information
In patients receiving the amlodipine/valsartan combination, peripheral edema was less common (5.8%) than in patients receiving amlodipine therapy alone (9%).
Amlodipine
From the blood and lymphatic system:
very rarely - leukopenia, thrombocytopenia, sometimes with purpura.
From the immune system:
very rarely - hypersensitivity.
Metabolism and nutrition:
very rarely - hyperglycemia.
Mental disorders:
uncommon - depression, insomnia/sleep disorders, mood lability; rarely - confusion.
From the nervous system:
often - dizziness, headache, drowsiness; uncommon - taste disturbance, paresthesia, fainting, tremor, hypoesthesia; very rarely - muscle hypertonicity, peripheral neuropathy, neuropathy; frequency unknown - extrapyramidal disorders.
From the side of the organ of vision:
Uncommon: blurred vision, blurred vision.
Hearing and labyrinth disorders:
infrequently - tinnitus.
From the heart:
often - a feeling of palpitations; very rarely - arrhythmias (including bradycardia, ventricular tachycardia and atrial fibrillation), myocardial infarction.
From the side of blood vessels:
often - a feeling of a rush of blood to the skin of the face, a pronounced decrease in blood pressure; very rarely - vasculitis.
From the respiratory system, chest and mediastinal organs:
infrequently - shortness of breath, rhinitis; very rarely - cough.
From the digestive system:
often - nausea, abdominal discomfort, pain in the upper abdomen; uncommon - changes in stool, diarrhea, dry oral mucosa, dyspepsia, vomiting; rarely - gastritis, gingival hyperplasia, pancreatitis.
From the liver and biliary tract:
very rarely - increased activity of liver enzymes (usually with symptoms of cholestasis), increased concentration of bilirubin in the blood plasma, hepatitis, intrahepatic cholestasis, jaundice.
For the skin and subcutaneous tissues:
uncommon - alopecia, exanthema, erythema, photosensitivity reactions, itching, hyperhidrosis, purpura, skin rash, skin discoloration; very rarely - erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, angioedema.
From the musculoskeletal and connective tissue side:
often - swelling of the ankles; uncommon - arthralgia, back pain, muscle spasms, myalgia.
From the kidneys and urinary tract:
infrequently - urinary disturbances, nocturia, pollakiuria.
From the genital organs and breast:
infrequently - erectile dysfunction, gynecomastia.
General disorders and disorders at the injection site:
often - increased fatigue, peripheral edema; uncommon - asthenia, discomfort, malaise, non-cardiogenic heart pain, pain.
Laboratory and instrumental data:
infrequently - decrease/increase in body weight.
Valsartan
From the blood and lymphatic system:
frequency unknown - decreased hemoglobin and hematocrit, leukopenia, neutropenia, thrombocytopenia, sometimes with purpura.
From the immune system:
very rarely - hypersensitivity.
Hearing and labyrinth disorders:
infrequently - vertigo.
From the side of blood vessels:
frequency unknown - vasculitis.
From the respiratory system, chest and mediastinal organs:
infrequently - cough.
From the digestive system:
infrequently - a feeling of discomfort in the abdomen, pain in the upper abdomen.
From the liver and biliary tract:
frequency unknown - increased activity of liver enzymes, increased concentration of bilirubin in the blood plasma.
For the skin and subcutaneous tissues:
frequency unknown - skin itching, skin rash, angioedema.
From the musculoskeletal and connective tissue side:
frequency unknown - myalgia.
From the kidneys and urinary tract:
frequency unknown - increased plasma creatinine concentration, impaired renal function, including acute renal failure.
General disorders and disorders at the injection site:
infrequently - increased fatigue.
Laboratory and instrumental data:
frequency unknown - increased potassium levels in the blood serum.
Additional information about the components of the drug
Adverse events previously reported with each of the components may occur with Vamloset, even if they were not observed in clinical studies.
Amlodipine
Often - drowsiness, dizziness, palpitations, abdominal pain, nausea, swelling of the ankles.
Uncommon: insomnia, mood lability (including anxiety), depression, tremor, taste disturbance, fainting, hypoesthesia, visual impairment (including diplopia), tinnitus, marked decrease in blood pressure, shortness of breath, rhinitis, vomiting , dyspepsia, alopecia, purpura, skin discoloration, hyperhidrosis, itching, exanthema, myalgia, muscle cramps, pain, urinary disturbance, increased frequency of urination, impotence, gynecomastia, chest pain, malaise, weight gain, weight loss.
Rarely - confusion.
Very rarely - leukopenia, thrombocytopenia, allergic reactions, hyperglycemia, muscle hypertonicity, peripheral neuropathy, myocardial infarction, arrhythmias (including bradycardia, ventricular tachycardia and atrial fibrillation), vasculitis, pancreatitis, gastritis, gingival hyperplasia, hepatitis, jaundice, increased activity of liver enzymes (most often due to cholestasis), angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, photosensitivity.
Isolated cases of extrapyramidal syndrome have been described.
Valsartan
Frequency unknown - decreased hemoglobin and hematocrit, neutropenia, thrombocytopenia, increased serum potassium, increased liver enzyme activity, increased plasma bilirubin concentration, increased plasma creatinine concentration, impaired renal function, including renal failure, angioedema, myalgia , vasculitis, hypersensitivity, including serum sickness.
