Amlodipine + Valsartan - instructions for use, dose, side effects, contraindications

Combined antihypertensive drug containing active substances with a complementary mechanism for monitoring blood pressure. Amlodipine, a derivative of dihydropyridine, belongs to the class of slow calcium channel blockers (BCCC), valsartan - 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 decrease in blood pressure compared to that of monotherapy with each drug.

Amlodipine / valsartan

In patients with hypertension who received the drug once a day, the antihypertensive effect persisted for 24 hours.

The drug in doses of 5/80 mg and 5/160 mg in patients with baseline systolic BP 153-157 mm Hg. Art. and diastolic blood pressure> 95 mm Hg. and less than 110 mm Hg. reduces blood pressure by 20-28 / 14-19 mm Hg. (compared with 7-13 / 7-9 mmHg when taking placebo).

The combination of amlodipine and valsartan in a dose of 10/160 mg and 5/160 mg normalizes blood pressure (a decrease in diastolic blood pressure in a sitting position less than 90 mm Hg at the end of the study) in 75% and 62% of patients with inadequate control of BP against monotherapy valsartan in a dose of 160 mg / day.

The drug at a dose of 10/160 mg normalizes blood pressure in 78% of patients with inadequate control of blood pressure amlodipine monotherapy with a dose of 10 mg. In patients with arterial hypertension with a combination of valsartan 160 mg with amlodipine at doses of 10 mg and 5 mg, an additional reduction in systolic and diastolic blood pressure is achieved at 6.0 / 4.8 mm Hg. and 3.9 / 2.9 mm Hg. respectively, compared to patients who continued to receive only valsartan in a dose of 160 mg or only amlodipine in a dose of 5 and 10 mg.

When titrating the dose of the drug from 5/160 mg to 10/160 mg in patients with arterial hypertension with diastolic blood pressure ≥110 mm Hg. and less than 120 mm Hg. there was a decrease in blood pressure in the sitting position by 36/29 mm Hg, comparable with a decrease in blood pressure when titrating the dose of the combination of an ACE inhibitor and a thiazide diuretic.

In two long-term studies with a long follow-up period, the effect of the drug persisted for 1 year. Sudden withdrawal is not accompanied by a sharp increase in blood pressure.

In patients with an adequate control of blood pressure, but developed pronounced swelling with amlodipine monotherapy, combined therapy was used to achieve comparable control of blood pressure with a lower probability of edema development.

The therapeutic effectiveness does not depend on the age, sex and race of the patient.

Pharmacokinetics:

The pharmacokinetics of valsartan and amlodipine are characterized by linearity.

Amlodipine / valsartan

After ingestion of the drug C_maxValsartan and amlodipine are reached after 3 hours and 6-8 hours, respectively. The rate and extent of absorption are equivalent to the bioavailability of valsartan and amlodipine when each is taken in separate tablets.

Pharmacokinetics in special clinical cases

Pharmacokinetic features of use in children under 18 years of age have not been established.

Time to reach C_max Amlodipine in blood plasma in young and elderly patients is the same. In elderly patients, clearance of amlodipine is slightly reduced, which leads to an increase in AUC and T_1/2.

In elderly patients, the systemic effect of valsartan was somewhat more pronounced than in young patients, but this was not clinically significant. Since tolerability of the drug components in the elderly and in younger patients is equally good, it is recommended to use the usual dosing regimens.

In patients with impaired renal function, the pharmacokinetic parameters of amlodipine do not change significantly. There was no correlation between renal function (CC) and systemic exposure to valsartan (AUC) in patients with varying degrees of renal impairment. It is not required to change the initial dose in patients with initial and moderate impairment of kidney function (QA 30-50 ml / min).

Patients with hepatic insufficiency have a reduced clearance of amlodipine, which leads to an increase in AUC of approximately 40-60%. On average, in patients with chronic liver diseases of mild to moderate degree, valsartan's bioavailability (AUC) is doubled compared to healthy volunteers (of the appropriate age, sex, and body weight).

Indications:

Arterial hypertension (for patients who are shown combined therapy).

ICD-10

IX.I10-I15.I10 Essential [primary] hypertension

Contraindications:

Pregnancy; hypersensitivity to the components of the drug.

The safety of use in patients with unilateral or bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney, in patients after recent kidney transplantation, as well as children and adolescents under 18 years is not established. With caution appoint a drug for: violations of the liver (especially in obstructive diseases of the biliary tract); severe renal dysfunction (CC <10 mL / min); patients with mitral or aortic stenosis, hypertrophic obstructive cardiomyopathy; with hyperkalemia, a deficiency in the body of sodium and / or a decrease in bcc.

Carefully:

With caution appoint a drug for: violations of the liver (especially in obstructive diseases of the biliary tract); severe renal dysfunction (CC <10 mL / min); patients with mitral or aortic stenosis, hypertrophic obstructive cardiomyopathy; with hyperkalemia, a deficiency in the body of sodium and / or a decrease in bcc.

Pregnancy and lactation:

Like any other drug that directly affects RAAS, it should not be prescribed in pregnancy and women who want to become pregnant. If pregnancy is detected during treatment, the drug should be discontinued as soon as possible.

Patients of childbearing age should be informed of the possible risk to the fetus associated with the use of drugs that affect RAAS.

Given the mechanism of action of angiotensin II receptor antagonists, the risk to the fetus can not be ruled out. It is known that the appointment of ACE inhibitors that affect RAAS, pregnant in the II and III trimesters, leads to damage or death of the developing fetus. According to a retrospective analysis of the use of ACE inhibitors in the first trimester of pregnancy, the development of fetal and newborn pathology was accompanied. In case of unintended admission of valsartan in pregnant women, cases of spontaneous abortion, malignancy and renal dysfunction in newborns are described.

It is not known whether valsartan and / or amlodipine with breast milk. Since in experimental studies, the isolation of valsartan with breast milk is noted, it is not recommended to use the drug during lactation (breastfeeding).

Dosing and Administration:

The drug should be taken orally, washed down with a small amount of water, 1 time / day, regardless of the time of ingestion.

The recommended daily dose is 1 tablet. in a dose of 5/80 mg or 5/160 mg or 10/160 mg.

When appointing elderly patients, patients with initial or moderate renal dysfunction (CK> 30 ml / min), with impaired liver function or with liver disease, with cholestasis, a change in the dosing regimen is not required.

Side effects:

On the part of the respiratory system: often - nasopharyngitis, influenza; sometimes - cough, pain in the throat and larynx.

From the senses: rarely - visual impairment, tinnitus; sometimes - dizziness associated with impaired vestibular apparatus.

From the side of the central nervous system and peripheral nervous system: often - headache; sometimes - dizziness, drowsiness, orthostatic dizziness, paresthesia; rarely - anxiety.

From the cardiovascular system: sometimes - tachycardia, palpitation, orthostatic hypotension; rarely - syncopal condition, marked decrease in blood pressure.

From the digestive system: sometimes - diarrhea, nausea, abdominal pain, constipation, dry mouth.

Dermatological reactions: sometimes - skin rash, erythema; rarely - hyperhidrosis, exanthema, itching.

From the musculoskeletal system: sometimes - puffiness of the joints, back pain, arthralgia; rarely - muscle spasms, a feeling of heaviness in the whole body.

From the urinary system: rarely - pollakiuria, polyuria.

On the part of the reproductive system: rarely - erectile dysfunction.

Other: often - pastovnost, edema of the face, peripheral edema, increased fatigue, flushes of blood to the face, asthenia, a feeling of heat.

Overdose:

There are no data on drug overdose cases at the present time.

With an overdose of valsartan, one can expect the development of a pronounced decrease in blood pressure and dizziness. An overdose of amlodipine can lead to excessive peripheral vasodilation and possible reflex tachycardia. There was also reported the emergence of severe and prolonged systemic arterial hypotension until the development of shock with a lethal outcome.

Treatment: In case of accidental overdose, you should induce vomiting (if the drug was taken recently) or to wash the stomach, prescribe Activated carbon. The use of activated carbon in healthy volunteers immediately or 2 hours after taking amlodipine significantly reduced its absorption. When clinically pronounced arterial hypotension caused by the drug should be put the patient with raised legs, take active measures to maintain the cardiovascular system, including frequent monitoring of heart and respiratory system, bcc and the amount of excreted urine. In the absence of contraindications to restore vascular tone and blood pressure, it is possible to use (with caution) a vasoconstrictor. In / in the administration of calcium gluconate can be effective to eliminate blockade of calcium channels. The excretion of valsartan and amlodipine during hemodialysis is unlikely.

Interaction:

Amlodipine

Inhibitors of the isoenzyme CYP3A4. When amlodipine is used together with diltiazem, amlodipine metabolism slows down in elderly patients, probably due to inhibition of the CYP3A4 isoenzyme, which leads to an increase in the concentration of amlodipine in the blood plasma by approximately 50% and an increase in the clinical effect.When using amlodipine together with powerful inhibitors of CYP3A4 (for example, ketoconazole, itracona and ritonavir) a marked increase in the systemic exposure of amlodipine.

Inductors of isoenzyme CYP3A4. Since the use of amlodipine together with isoenzyme inducers
CYP3A4 (e.g., carbamazepine, phenobarbital, phenytoin, phosphenytoin, primidon, rifampicin, grapefruit juice, herbal preparations containing St. John's wort pitted), can lead to a marked decrease in its concentration in the blood plasma; when prescribing amlodipine with inductors CYP3A4, it should monitor its clinical effect.

In monotherapy with amlodipine, there is no clinically significant interaction with thiazide diuretics, beta-adrenoblockers, ACE inhibitors, long-acting nitrates, nitroglycerin for sublingual use, digoxin, warfarin, atorvastatin, sildenafil, maalox (aluminum hydroxide gel, magnesium hydroxide, simethicone), cimetidine, NSAIDs, antibiotics and oral hypoglycemic drugs.

Valsartan

It is established,that when monotherapy with valsartan there is no clinically significant interaction with the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide.

Drugs and substances that affect the potassium content in blood serum: when administered simultaneously with dietary supplements containing potassium, potassium-sparing diuretics, potassium-containing salt substitutes, or with other drugs that can cause an increase in the potassium content in the blood (for example, with heparin), be careful and carry out frequent monitoring of potassium in the blood.

NSAIDs, including selective inhibitors of COX-2: the administration of angiotensin II receptor antagonists concomitantly with NSAIDs may lead to a weakening of the hypotensive effect. In elderly patients, patients with BCC deficiency (including those receiving diuretic therapy) or with renal dysfunction, concomitant use of angiotensin II receptor antagonists and NSAIDs may lead to an increased risk of impaired renal function. When starting or changing the regimen of angiotensin II receptor antagonists with NSAIDs, regular monitoring of renal function is recommended.

Special instructions:

Caution should be exercised in appointing patients with liver disease (especially with obstructive diseases of the biliary tract). Valsartan is mainly excreted unchanged with bile, while amlodipine intensively metabolized in the liver.

Patients with initial and moderate renal dysfunction (KK 30-50 ml / min) do not need dose adjustment. Caution should be used when prescribing the drug to patients with severe impairment of renal function (CC <10 ml / min), because it is not necessary. data on the safety of the use of the drug in such cases are not obtained.

As with the use of other vasodilators, special care should be taken when administering the drug to patients with mitral or aortic stenosis, hypertrophic obstructive cardiomyopathy.

If it is necessary to cancel beta-blockers before starting therapy, the dose of beta-blockers should be reduced gradually. Because the amlodipine is not a beta-adrenoblocker, the use of the drug does not prevent the development of withdrawal syndrome that occurs when the beta-blockers are discontinued.

In placebo-controlled studies in patients with uncomplicated arterial hypertension, severe arterial hypotension was observed in 0.4% of cases. In patients with activated RAAS (eg, with a deficiency of bcc and / or sodium in patients receiving high doses of diuretics), the development of symptomatic arterial hypotension is possible with the admission of angiotensin receptor blockers. Before starting treatment, you should correct the sodium content in the body and / or BCC, or start therapy under close medical supervision.

In the case of development of arterial hypotension, the patient should be laid with raised legs, if necessary, an intravenous infusion of physiological saline. After stabilization of blood pressure treatment can be continued.

With simultaneous use of the drug with dietary supplements containing potassium, potassium-sparing diuretics, potassium-containing salt substitutes, or with other drugs that can cause an increase in the potassium concentration in the blood (for example, with heparin), care should be taken and regular monitoring of potassium concentration in the blood .

There are no data on the effect of the drug on the ability to drive vehicles and work with mechanisms. In connection with the possible occurrence of dizziness or increased fatigue should be careful when driving vehicles or working with mechanisms.

Instructions

Amlodipine + Valsartan (Amlodipinum + Valsartanum)