Vamloset, 5 mg+160 mg 90 pcs.

Hypotensive combined agent (slow calcium channel blocker + angiotensin II receptor antagonist).

Indications

Arterial hypertension (patients who are indicated for combination therapy).

Active ingredient

Composition

for 1 tablet 5 mg + 80 mg

Core:

Active ingredients:

Amlodipine besylate (amlodipine besylate) 6.94 mg, equivalent to amlodipine 5.00 mg Valsartan A, 125.675 mg granule substance

[Active ingredient of the granule substance: Valsartan 80.00 mg

Auxiliary substances of the granule substance: microcrystalline cellulose, sodium croscarmellose, povidone K-25, sodium lauryl sulfate]

Excipients: mannitol, magnesium stearate, colloidal silicon dioxide

film sheath:

Opadray II white1, iron oxide yellow dye (E172)

for 1 tablet 5 mg + 160 mg

Core:

Active substances:

Amlodipine besylate (amlodipine besylate) 6.94 mg, equivalent to amlodipine 5.00 mg Valsartan A, substance-granules 251.35 mg

[Active ingredient of the granule substance: Valsartan 160.00 mg

Auxiliary substances of the granule substance: Microcrystalline cellulose, sodium croscarmellose, povidone K-25, sodium lauryl sulfate]

Auxiliary substances: mannitol, magnesium stearate, colloidal silicon dioxide

coating film:

Opadray II white1, iron oxide yellow dye (E172)

for 1 tablet 5 mg + 320 mg

Core:

Active ingredients:

Amlodipine besylate (amlodipine besylate) 6.94 mg, equivalent to amlodipine 5.00 mg

Valsartan A, substance-granules 502.70 mg

[Active ingredient of the granule substance: Valsartan 320.00 mg

Auxiliary substances of the granule substance: Microcrystalline cellulose, sodium croscarmellose, povidone K-25, sodium lauryl sulfate]

Auxiliary substances: mannitol, magnesium stearate, colloidal silicon dioxide

coating film:

Opadray II white1, iron oxide yellow dye (E172), iron oxide red dye (E172)

for 1 tablet 10 mg + 160 mg

Kernel:

Active substances:

Amlodipine besylate (amlodipine besylate) 13.88 mg, equivalent to amlodipine 10.00 mg

Valsartan A, substance-granules 251.35 mg

[Active ingredient of the granule substance: Valsartan 160.00 mg

Auxiliary substances of the granule substance: microcrystalline cellulose, croscarmellose sodium, povidone K-25, sodium lauryl sulfate]

Auxiliary substances: mannitol, magnesium stearate, colloidal silicon dioxide

Film shell:

Opadray II white1, iron oxide yellow dye (E172)

for 1 tablet 10 mg + 320 mg

Core:

Active ingredients:

Amlodipine besylate (amlodipine besylate) 13.88 mg, equivalent to amlodipine 10.00 mg

Valsartan A, substance-granules 502.70 mg

[Active ingredient of the granule substance: Valsartan 320.00 mg

Ancillary substances of the granule substance: microcrystalline cellulose, croscarmellose sodium, povidone K-25, sodium lauryl sulfate]

Auxiliary substances: mannitol, magnesium stearate, colloidal silicon dioxide

Shell film:

Opadray II white1, iron oxide yellow dye (E172)

1 Opadray II white: polyvinyl alcohol, titanium dioxide (E171), macrogol, talc.

How to take, the dosage

Overly with a small amount of water, once daily, regardless of the time of meals.

The recommended daily dose is 1 tablet of Vamloset ® containing amlodipine/valvasartan at a dose of 5/80 mg or 5/160 mg or 10/160 mg or 5/320 mg or 10/320 mg.

The maximum daily dose is 5/320 mg (in terms of valsartan) or 10/160 mg (in terms of amlodipine) or 10/320 mg.

The initiation of Vamloset® is recommended with a dose of 5/80 mg once daily. The dose can be increased 1-2 weeks after starting therapy.

Patient Special Groups

Elderly patients (>65 years)

Patients over 65 years of age do not need dose adjustments. In patients in this category, if necessary, reduction of the starting dose of Vamloset® to contain the lowest dose of amlodipine, i.e. 1 tablet containing amlodipine/valvasartan at a dose of 5/80 mg or 5/160 mg is possible.

Application in children and adolescents (under 18 years of age)

Because data on the safety and efficacy of Vamloset® in children and adolescents (under 18 years) are lacking, the drug is not recommended for use in this patient population.

Patients with impaired renal function

In patients with mild to moderate renal dysfunction (CK ³ 30 ml/min), no adjustment of the initial dose is required.

Patients with impaired liver function

Due to the presence of valsartan and amlodipine, Vamloset® should be used with caution in patients with hepatic dysfunction and obstructive biliary tract disease. In patients in this category, if necessary, it is possible to reduce the initial dose of Vamloset® to contain the lowest dose of amlodipine, i.e. 1 tablet containing amlodipine/valsartan at a dose of 5/80 mg or 5/160 mg.

Interaction

Drug Vamloset®

General drug interactions of the drug Vamloset®: justify;”> General drug interactions for the drug Vamloset®(amlodipine/valsartan)

Single use requiring attention

Other hypotensive drugs (e.g., alpha-adrenoblockers, diuretics) and drugs with hypotensive effects (e.g., tricyclic antidepressants, alpha-adrenoblockers to treat benign prostatic hyperplasia) may increase the antihypertensive effect.

Drug interactions for amlodipine

Unwanted concomitant use

Grapefruit or grapefruit juice

Simultaneous use is not recommended, given the possibility of increased bioavailability in some patients and increased antihypertensive effects.

Simultaneous use requiring caution

Inhibitors of isoenzyme CYP3A4

Concurrent use with strong or moderate isoenzyme inhibitorsCYP3A4 (protease inhibitors, verapamil or diltiazem, azole antifungal drugs, macrolides such as erythromycin or clarithromycin) may result in significantly increased systemic exposure to amlodipine. In elderly patients, these changes are clinically important, so medical monitoring and dose adjustments are necessary.

Isoenzyme inducers CYP3A4 (anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone), rifampicin, herbal preparations containing St. John’s Wort)

When CYP3A4 isoenzyme inducers are used concomitantly, plasma concentrations of amlodipine may vary. Therefore, blood pressure control and amlodipine dose adjustment are indicated both during treatment with CYP3A4 isoenzyme inducers and after their withdrawal, especially when strong CYP3A4 isoenzyme inducers (e.g., rifampicin, preparations containing St. John’s Wort) are used.

Simvastatin

The simultaneous repeated use of amlodipine at a dose of 10 mg/day and simvastatin at a dose 80 mg/day increases simvastatin exposure by 77% compared to that of simvastatin monotherapy. In patients receiving amlodipine it is recommended to use simvastatin in dose not more than 20 mg/day.

Dantrolene (intravenous administration)

In animal experiments, fatal ventricular fibrillation and cardiovascular failure associated with hyperkalemia have been observed after ingestion of verapamil and intravenous administration of dantrolene. Taking into account the risk of hyperkalemia development, concomitant use of “slow” calcium channel blockers, including amlodipine, in patients prone to the development of malignant hyperthermia should be avoided.

Tacrolimus

When used concomitantly with amlodipine, there is a risk of increased plasma concentrations of tacrolimus, but the pharmacokinetic mechanism of this interaction is not fully understood. To prevent the toxic effect of tacrolimus concomitantly used with amlodipine, the tacrolimus plasma concentration should be monitored and the tacrolimus dose should be adjusted if necessary.

Cyclosporine

Drug interaction studies using cyclosporine and amlodipine in healthy volunteers or other patient groups have not been performed, except in kidney transplant patients who have had variable minimum concentrations (mean values: 0 %-40 %) of cyclosporine. When concomitant use of amlodipine in patients undergoing renal transplantation, plasma concentrations of cyclosporine should be monitored, and if necessary, its dose should be reduced.

Clarithromycin

Clarithromycin is an inhibitor of the CYP3A4 isoenzyme. Concomitant use of amlodipine and clarithromycin increases the risk of arterial hypotension. Close medical monitoring of patients receiving amlodipine concomitantly with clarithromycin is recommended.

Inhibitors of the mechanistic target for rapamycin in mammals (tTOR)

MTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A isoenzyme substrates. Amlodipine is a weak inhibitor of CYP3A isoenzyme. When used concomitantly with mTOR inhibitors, amlodipine may increase their exposure.

Simultaneous use requiring attention

Other

In clinical trials of amlodipine, there are no significant interactions withwith thiazide diuretics, alpha-adrenoblockers, beta-adrenoblockers, ACE inhibitors, long-acting nitrates, nitroglycerin for sublingual use, digoxin, warfarin, atorvastatin, sildenafil, Maalox (aluminum- or magnesium-containing antacids, simethicone), cimetidine, nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, and oral hypoglycemic agents.

Simultaneous use of amlodipine and ethanol does not affect pharmacokinetics of the latter.

Calcium preparations may decrease the effect of BMCC.

The simultaneous use of BMCC with lithium preparations (no data for amlodipine) may increase the manifestation of their neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus).

Glucocorticosteroids

Decrease antihypertensive effect (fluid and sodium ion retention as a result of corticosteroid action).

Drug interactions for valsartan

Simultaneous use is contraindicated

The concomitant use of ARA II, including valsartan, with aliskiren and drugs containing aliskiren is contraindicated in patients with diabetes and/or moderate to severe renal function impairment (GFR less than 60 mL/min/1.73 m2 body surface area) and is not recommended in other patients.

The concomitant use of ARA II with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Undesirable concomitant use

Lithium

Simultaneous use with lithium preparations is not recommended because. concomitant use of lithium preparations is not recommended because of possible reversible increase of lithium concentration in blood plasma and development of intoxication. If concomitant use with lithium preparations is necessary, the lithium concentration in blood plasma should be carefully monitored. The risk of toxic effects associated with the use of lithium preparations may be additionally increased when concomitant use with Vamloset® and diuretics.

Kalium-saving diuretics, potassium supplements, and other drugs and substances that may increase serum potassium (e.g., heparin)

When concomitant use with drugs that affect potassium content is necessary, it is recommended to monitor the plasma potassium content.

Simultaneous use requiring caution

NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, acetylsalicylic acid at a dose greater than 3 g/day and non-selective NSAIDs

With concomitant use, it is possible to weaken the antihypertensive effect, increase the risk of renal dysfunction and increase the plasma potassium content. At the beginning of therapy, it is recommended to assess renal function and to correct the water-electrolyte balance disorders.

Inhibitors of carrier proteins

According to results of in vitro study, Valsartan is a substrate for carrier proteins OATP1B1 and MRP2. Concomitant use of valsartan with OATP1B1 transporter protein inhibitors (e.g., rifampicin, cyclosporine) and MRP2 transporter protein inhibitor (e.g., ritonavir) may increase systemic valsartan exposure (Cmax and AUC). This should be considered at the beginning and at the end of concomitant therapy.

Double RAAS blockade when using ARA II, ACE inhibitors, or aliskiren

The concomitant use of APA II with other drugs that affect the RAAS results in an increased incidence of arterial hypotension, hyperkalemia, and renal function impairment. Indexes of arterial pressure, renal function and plasma electrolytes values should be monitored when using Vamloset® with other drugs affecting the RAAS.

Other

No clinically significant interactions with the following medications have been identified during valsartan monotherapy Cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, and glibenclamide.

Directions for use

The drug should be taken orally, once daily, regardless of meals, with a small amount of water.

The recommended daily dose is 1 tablet of the drug containing the combination amlodipine/valsartan at a dose of 5 mg/80 mg, 5 mg/160 mg, 10 mg/160 mg, 5 mg/320 mg or 10 mg/320 mg.

The starting dose of the drug is 5 mg/80 mg once daily. The dose can be increased after 1-2 weeks of therapy.

The maximum daily dose is 5 mg/320 mg (in terms of valsartan) or 10 mg/160 mg (in terms of amlodipine) or 10 mg/320 mg.

In patients with impaired renal function (CK >30 ml/min), no adjustment of the initial dose of the drug is required.

Patients with impaired hepatic function should use the drug with caution. The maximum daily dose of valsartan in mild to moderate hepatic impairment is 80 mg. The drug is contraindicated in patients with severe hepatic impairment, biliary cirrhosis and cholestasis.

In elderly patients no dose adjustment is required.

Special Instructions

Mild (5-6 points on the Child-Pugh scale) and moderate (7-9 points on the Child-Pugh scale) hepatic impairment, as well as in obstructive biliary tract disease, unilateral or bilateral renal artery stenosis or stenosis of the artery of the single kidney Chronic heart failure (CHF) of III-IV functional class according to NYHA classification, acute coronary syndrome, after acute myocardial infarction, hyperkalemia, hyponatremia, diet with restriction of table salt intake, decreased circulating blood volume (DCV) (including diarrhea, vomiting).

As with other vasodilators, special caution should be used in patients with mild to moderate mitral or aortic stenosis and hypertrophic obstructive cardiomyopathy (HCMP).

Because data about safety and efficacy of Vamloset® in children and adolescents (younger than 18 years) are insufficient, the drug is not recommended for use in this category of patients.

Patients with impaired renal function

In patients with mild to moderate renal dysfunction (CK ³ 30 ml/min), no adjustment of the initial dose is required.

Patients with impaired liver function

Due to the presence of valsartan and amlodipine, Vamloset® should be used with caution in patients with hepatic dysfunction and obstructive biliary tract disease. In patients in this category, if necessary, it is possible to reduce the initial dose of Vamloset® to contain the lowest dose of amlodipine, i.e. 1 tablet containing amlodipine/valsartan at a dose of 5/80 mg or 5/160 mg.

Elderly patients (over 65 years)

In patients over 65 years of age, no adjustment of the drug dose is required. In patients in this category, if necessary, reduction of the starting dose of Vamloset® to contain the lowest dose of amlodipine, i.e. 1 tablet containing amlodipine/valvasartan at a dose of 5/80 mg or 5/160 mg is possible.

Patients with hyponatremia and/or decreased RBC

Patients with uncomplicated arterial hypertension receiving therapy with the amlodipine/valsartan combination experienced severe arterial hypotension in 0.4% of cases.

In patients with activated RAAS (for example, in patients with dehydration and/or hyponatremia taking high-dose diuretics) when taking ARA II symptomatic arterial hypotension may develop. Before the treatment it is recommended to restore the sodium content and/or make up the BOD, particularly by reducing the doses of diuretics or start the therapy under close medical supervision.

In case of pronounced BP decrease the patient should be laid horizontally with elevated legs and, if necessary, intravenous infusion of 0.9% sodium chloride solution should be performed. The therapy with Vamloset® can be continued after hemodynamic stabilization.

Hyperkalemia

Caution should be exercised when concomitantly using potassium-saving diuretics, potassium supplements, supplements containing potassium, or other drugs that can increase plasma potassium levels (e.g., heparin). Regular monitoring of plasma potassium content is necessary.

Renal artery stenosis

The drug Vamloset® should be used with caution in patients with arterial hypertension with unilateral or bilateral renal artery stenosis or renal artery stenosis of the sole kidney, given the possibility of increased serum concentrations of urea and creatinine.

Condition after kidney transplantation

The safety of amlodipine/valsartan combination in patients who have recently undergone a kidney transplant has not been established.

Liver function impairment

Valsartan is primarily excreted unchanged in bile. In patients, T1/2 is prolonged and AUC is increased. Caution should be exercised when using Vamloset® in patients with mild (5-6 points on the Child-Pugh scale) or moderate (7-9 points on the Child-Pugh scale) impaired liver function or obstructive biliary tract disease.

Kidney function disorder

Dose adjustment of Vamloset® is not required in patients with mild to moderate renal impairment. In patients with moderate renal dysfunction, it is recommended to monitor potassium and creatinine plasma concentrations. Concomitant use of ARA II, including valsartan, or ACE inhibitors with aliskiren is contraindicated in patients with impaired renal function (CK less than 60 ml/min).

Primary Hyperaldosteronism

Given the RAAS lesion in primary hyperaldosteronism, these patients should not be prescribed ARA II, including valsartan.

Angioneurotic edema

Among patients with angioedema (including laryngeal and vocal cord edema causing airway obstruction and/or edema of the face, lips, pharynx, and/or tongue) on therapy with Vamloset®, there have been cases of a history of developing angioedema, including on ACE inhibitors. In case of development of angioedema the drug should be immediately discontinued and the possibility of repeated use should be excluded.

Heart failure/previous myocardial infarction

In patients whose renal function may depend on RAAS activity (e.g., in severe CHF), therapy with ACE inhibitors and ARA II is accompanied by oliguria and/or an increase in azotemia and, in rare cases, acute renal failure and/or death. Similar outcomes have been described with valsartan. In patients with CHF or myocardial infarction, renal function should always be evaluated.

Synopsis

Tablets 5 mg + 80 mg:

Round, slightly biconvex, film-coated tablets, brownish-yellow with possible dark spots, beveled.

Tablets 5 mg + 160 mg:

Oval, biconvex, film-coated tablets in brownish-yellow color with possible dark spots.

Tablets 5 mg + 320 mg:

Capsule-shaped, biconvex, film-coated orange-brown tablets.

Tablets 10 mg + 160 mg:

Oval, biconvex, film-coated, brownish-yellow tablets.

Tablets 10 mg + 320 mg:

Capsule-shaped, biconvex, film-coated, brownish-yellow tablets.

Features

The pharmacokinetics of amlodipine and valsartan are characterized by linearity.

Amlodipine/Valsartan

After oral administration of amlodipine/valsartan combination, Cmax of valsartan and amlodipine in plasma are reached after 3 h and 6-8 h respectively. The rate and degree of absorption are equivalent to the bioavailability of valsartan and amlodipine when each is taken separately.

Amlodipine

After oral administration, amlodipine is slowly and almost completely absorbed from the gastrointestinal tract. Concomitant intake of food has no effect on absorption of amlodipine. Cmax in plasma is reached 6-12 hours after intake. Mean absolute bioavailability is 64-80%. The mean Vd is 21 L/kg body weight, indicating that most of the amlodipine is in the tissues and less is in the blood. Most of the amlodipine in the blood (97.5%) is bound to plasma proteins. Css in blood plasma are reached after 7-8 days of continuous amlodipine administration. Amlodipine penetrates through the HEB and the placental barrier.

Amlodipine undergoes slow but active metabolism in the liver with no significant “first pass” effect through the liver. Metabolites have no significant pharmacological activity.

After a single dose of amlodipine, the T1/2 ranges from 35 to 50 h, with a repeat use of approximately 45 h. About 60% of the oral dose is excreted by the kidneys mainly as metabolites, 10% – unchanged, 20-25% – through the intestine with the bile. Total clearance of amlodipine is 0.116 ml/s/kg (7 ml/min/kg, 0.42 l/h/kg). Amlodipine is not eliminated by hemodialysis.

The prolongation of T1/2 in patients with hepatic impairment suggests that amlodipine cumulation in the body will be higher with long-term use (increases to 60 h).

Valsartan

After oral valsartan administration, Cmax is reached after 2-3 h. Mean absolute bioavailability is 23%. When valsartan is taken with food, a decrease in bioavailability (as measured by AUC) of approximately 40% and Cmax of approximately 50% is observed. About 8 hours after oral administration, plasma concentrations of valsartan in the dietary intake group and the fasting group equalized. The decrease in AUC is not clinically significant; therefore, Valsartan can be taken regardless of food intake.

The Vd of valsartan during equilibrium after IV administration is approximately 17 L, indicating that there is no extensive tissue distribution of valsartan. Valsartan is largely bound to serum proteins (94-97%), mainly serum albumin.

Valsartan does not undergo marked metabolism. About 20% of the administered dose is determined in plasma as metabolites. The hydroxyl metabolite is determined in plasma at low concentrations (less than 10% of the AUC of valsartan). This metabolite is pharmacologically inactive.

Valsartan is excreted biphasically: α-phase with T1/2α less than 1 h and β-phase with T1/2β about 9 h. Valsartan is eliminated mostly unchanged through the intestine (about 83%) and the kidneys (about 13%). After IV administration, plasma clearance of valsartan is approximately 2 L/h and its renal clearance is 0.62 L/h (approximately 30% of total clearance). T1/2 valsartan is 6 h.

On average, patients with mild (Child-Pugh score 5-6) and moderate (Child-Pugh score 7-9) hepatic impairment have twice the bioavailability (as measured by AUC) of valsartan compared with healthy volunteers of similar age, sex, and body weight.

Contraindications

– Severe liver failure (greater than 9 points on the Child-Pugh scale), biliary cirrhosis and cholestasis.

– Severe renal failure (CKR less than 30 ml/min), use in patients on hemodialysis.

– Severe arterial hypotension (systolic BP less than 90 mm Hg), collapse, shock (including cardiogenic shock).

– Left ventricular outflow tract obstruction (including severe aortic stenosis).

– Hemodynamically unstable heart failure after acute myocardial infarction.

– Primary hyperaldosteronism.

The safety of Vamloset® in patients after undergoing kidney transplantation as well as in children and adolescents under 18 years old has not been established.

Overdose

Symptoms

There are currently no data on overdose. In overdose with valsartan, a marked decrease in BP and dizziness can be expected. Amlodipine overdose can lead to a significant decrease in BP with possible development of reflex tachycardia and excessive peripheral vasodilation (risk of severe and sustained arterial hypotension, including with the development of shock and lethal outcome).

Treatment

The treatment is symptomatic, the nature of which depends on the time elapsed since taking the drug and the severity of the symptoms. In case of accidental overdose, vomiting should be induced (if the drug was taken recently) or gastric lavage should be performed. The use of activated charcoal in healthy volunteers immediately or within 2 hours after taking amlodipine led to a significant reduction in its absorption. In case of marked BP decrease during Vamloset ® administration, it is necessary to put the patient into “supine” position with elevated legs, take active measures to support cardiovascular system activity, including regular monitoring of heart and respiratory system function, CPR and urine output. In the absence of contraindications, vasoconstrictors may be used (with caution) to restore vascular tone and BP. Intravenous injection of calcium gluconate solution is possible to eliminate the calcium channel blockade.

Excretion of valsartan and amlodipine during hemodialysis is unlikely.

Pregnancy use

Pregnancy

The use of Vamloset® is contraindicated in pregnancy.

Considering the mechanism of action of ARA II, the risk to the fetus cannot be excluded when using in the first trimester of pregnancy.

As any other drug that has a direct effect on the renin-angiotensin-aldosterone system (RAAS), Vamloset® should not be used during pregnancy or in women planning pregnancy. When using agents acting on the RAAS, women of childbearing age should be informed about the potential risk of adverse effects of these drugs on the fetus during pregnancy. If pregnancy is planned, it is recommended that the patient be transferred to an alternative hypotensive therapy, taking into account the safety profile. If pregnancy is diagnosed, Vamloset® should be discontinued and, if necessary, transferred to alternative hypotensive therapy.

The drug Vamloset®is contraindicated in II-III trimesters of pregnancy, as well as other drugs acting directly on the RAAS, because it can cause fetotoxic effects (impaired renal function, delayed ossification of fetal skull bones, oligohydramnios) and neonatal toxic effects (renal failure, arterial hypotension, hyperkalemia) and fetal death. If the drug was still used in the II-III trimesters of pregnancy, an ultrasound examination of the fetal kidneys and skull bones should be performed. The newborns whose mothers took the drug Vamloset® during pregnancy should be monitored because the development of arterial hypotension in a newborn is possible.

Breastfeeding

Wamloset® is not recommended during breastfeeding. If it is necessary to use Vamloset®® during lactation, breastfeeding should be stopped.

Experience with amlodipine shows that amlodipine is excreted into women’s breast milk. The mean milk/plasma ratio for amlodipine concentration was 0.85 among 31 lactating women who had pregnancy-related arterial hypertension and received amlodipine at an initial dosage of 5 mg daily. The dosage was adjusted as necessary (based on mean daily dose and weight: 6 mg and 98.7 mcg/kg, respectively). The estimated daily dose of amlodipine received by the infant via breast milk is 4.17 mcg/kg.

Similarities