Amlodipine + Losartan (Amlodipinum + Losartanum)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
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Clinical and pharmacological group: & nbsp

Calcium channel blockers

Angiotensin II receptor antagonists (AT1 subtype)

Included in the formulation
  • Amsaar
    pills inwards 
    MSD FARMASYUTIKALS, LLC     Russia
  • Lortense
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    KRKA-RUS, LLC     Russia
    • Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

    VED

    ONLS

    АТХ:

    C.08.C.A.01   Amlodipine

    C.09.C.A.01   Losartan

    Pharmacodynamics:

    Combined antihypertensive drug containing active components with complementary hypotensive action: amlodipine (slow calcium channel blockers, BCCC, dihydropyridine derivative) and losartan (angiotensin II receptor antagonist). Active components of the drug have a different mechanism for hypotensive action: amlodipine - due to vasodilatation it reduces OPSS, losartan - due to the effect on RAAS, it inhibits the effects of angiotensin II, which leads to a more pronounced decrease in blood pressure compared to that of monotherapy with each drug.

    Pharmacokinetics:

    Amlodipine besylate

    When taken in therapeutic doses amlodipine well absorbed, and Cmax in blood plasma is observed after 6-12 hours. Absolute bioavailability is estimated in the range from 64 to 80%. Food intake does not affect the absorption of amlodipine.

    Css is achieved after 7-8 days of admission. Vd is about 21 l / kg. Binding to plasma proteins - 98%.

    Plasma clearance is 7 ml / min / kg. Amlodipine is largely metabolized in the liver to inactive metabolites.

    T1/2 is 30-40 hours. 10% of amlodipine and 60% of metabolites are excreted by the kidneys.

    Amlodipine camsylate

    A comparative study of the pharmacokinetics of amlodipine camsylate and the reference preparation of amlodipine besylate with a single dose of 5 mg showed similar absorption profiles. Cmax in plasma, on the average, were 3.6 ng / ml for amlodipine besylate and 3.7 ng / ml for amlodipine camsylate, and the time to achieve them was 6.9 hours and 7.3 hours, respectively.1/2 were respectively 42.2 hours and 39.3 hours. The data obtained correspond to the instructions for use and the literature data for amlodipine besylate. Thus, the bioequivalence of amlodipine camsilate in a dose of 5 mg to the original amlodipine besylate preparation was given in the same dose.

    Losartan

    When ingestion, losartan well absorbed. Systemic bioavailability of losartan tablets is about 33%, Cmax losartan and its active metabolite in plasma is observed after 1 and 3-4 hours, respectively.

    how losartan, and its active metabolite more than 99% bind to plasma proteins, mainly - with albumin. Vd losartan is 34 liters.

    Losartan undergoes a metabolism of the primary passage through the liver to form an active carboxylated metabolite, as well as other, inactive metabolites. About 14% in / in the dose of losartan administered or taken orally is converted into its active metabolite. With IV administration or ingestion 14C-labeled losartan potassium, most of the radioactive label in the bloodstream corresponded to losartan and its active metabolite. The minimum level of biotransformation of losartan to the active metabolite observed in clinical trials was 1%.

    The clearance of losartan and its active metabolite is 60 ml / min and 50 ml / min, respectively. Kidney clearance - 74 ml / min and 26 ml / min, respectively. When ingested, about 4% of the dose is excreted by the kidneys unchanged, and 6% - in the form of an active metabolite. The pharmacokinetics of losartan and its active metabolite is linear when administered in doses up to 200 mg.

    When ingested, the concentration of losartan and its active metabolite decreases polyexponentially, with a finite T1/2 about 2 hours and 6-9 hours, respectively. In a dose of 100 mg when taken 1 time / day, nor losartan, nor its active metabolite is not cumulated in plasma.

    Losartan and its metabolites are excreted by the kidneys and through the intestines with bile. Ingestion and / in the introduction 14C-labeled losartan in humans, 35% and 43% of radioactivity, respectively, of losartan and its active metabolite is found in urine, 58% and 50% in feces.

    Combination amlodipine + losartan

    In the comparative clinical trials of amlodipine-camsylate and losartan combined with amlodipine-camsylate with losartan at doses of 5/50 mg and 5/100 mg, the pharmacokinetic parameters in both cases were the same for both amlodipine and losartan and its active metabolite E-3174 . The bioequivalence between the combination and the co-administration on the values ​​of Cmax, AUC for amlodipine camsylate, losartan and E-3174 in both doses, with the exception of Cmax losartan in a combination of 5/50 mg. Since the therapeutic activity of losartan is mainly due to its active metabolite, it was concluded that a combination of 5/50 mg is therapeutically equivalent to 5 mg of co-administered amlodipine and 50 mg of losartan.

    Indications:

    Arterial hypertension in patients who are shown combined therapy.

    ICD-10

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

    Contraindications:

    Severe hepatic impairment; hemodynamically expressed stenosis of the aortic aorta; shock; age under 18 years (effectiveness and safety not established); severe arterial hypotension; pregnancy; lactation period (breastfeeding); hypersensitivity to the components of the drug. With caution - Patients with reduced BCC, for example, when taking diuretics in high doses, severe diarrhea, vomiting and other conditions leading to hypovolemia; patients on a diet with restriction of table salt; patients with renal insufficiency (CC <20 ml / min) and patients on hemodialysis; hyperkalemia; arterial hypotension; liver failure; SSSU (pronounced bradycardia, tachycardia, chronic heart failure of non-ischemic etiology (II-IV functional class according to NYHA classification), aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy, acute myocardial infarction (and within 1 month after it), elderly age.

    Carefully:

    Patients with reduced bcc, for example, when taking diuretics in high doses, severe diarrhea,vomiting and other conditions leading to hypovolemia; patients on a diet with restriction of table salt; patients with renal insufficiency (CC <20 ml / min) and patients on hemodialysis; hyperkalemia; arterial hypotension; liver failure; SSSU (pronounced bradycardia, tachycardia, chronic heart failure of non-ischemic etiology (II-IV functional class according to NYHA classification), aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy, acute myocardial infarction (and within 1 month after it), elderly age.

    Pregnancy and lactation:

    Contraindications during pregnancy, and its reception should be immediately stopped when pregnancy is established.

    Lactation period

    It is not known whether amlodipine and / or losartan are excreted into breast milk, but in preclinical studies, the animals exhibited significant concentrations of amlodipine and / or the active metabolite of losartan in breast milk. It is not recommended to use in the period of breastfeeding.

    Dosing and Administration:

    The drug is taken orally, regardless of food intake, with a small amount of water 1 time / day.Root drug treatment is required when the pre-titration doses of amlodipine and losartan, respectively, 1 tablet of 5 mg or 50 mg + 5 mg + 100 mg. If necessary, a direct transition from monotherapy with amlodipine or losartan to drug therapy is possible.

    losartan amlodipine or at the same doses that are present in the combination (5/50 mg or 5/100 mg) may be administered to patients whose blood pressure is not sufficiently controlled.

    Patients simultaneously taking losartan and amlodipine, can be transferred to a combination with the same doses of these drugs.

    In patients with renal insufficiency with KK from 50 to 20 ml / min dose adjustment is not required. It is not recommended to use in patients with CC less than 20 ml / min and in patients on hemodialysis, since a dose adjustment of the drug components may be required.

    It is not recommended to use the drug in patients with reduced BCC (for example, when taking diuretics in high doses). At the same time in the case of replenishment of BCC reception is possible, if not recommended a lower dose of losartan - 25 mg.

    The use of the drug is possible in patients with hepatic insufficiency, which, according to the doctor's decision, allows the appointment of losartan in a dose of 50 mg.

    It can be used in patients older than 65 years with the tolerability of losartan 50 mg.

    It is not recommended for use in children and adolescents under the age of 18 due to insufficient data on efficacy and safety in this group.

    Side effects:

    From the side of the nervous system: often - dizziness, headache; infrequently - drowsiness.

    From the digestive system: infrequently - constipation, abdominal discomfort, dyspepsia, vomiting, esophageal reflux.

    From the skin and subcutaneous tissues: infrequently - itching, hives.

    From the side of the cardiovascular system: infrequently - a feeling of palpitations, "hot flashes" of blood to the skin of the face, orthostatic hypotension.

    On the part of the respiratory system: infrequently - shortness of breath.

    From the side of the hearing organ and labyrinthine disorders: infrequently - systemic dizziness.

    From the urinary system: infrequently - increased frequency of urination.

    Common disorders: infrequent - asthenia, discomfort or chest pain, feeling of overflow in the abdomen, peripheral edema.

    Side effects noted with the separate administration of the components of the drug (amlodipine and losartan), may also be its potential side effects,that these side effects were not observed in clinical trials and post-marketing period of the drug.

    Overdose:

    Cases of overdose are unknown. Below are the data on the overdose of amlodipine and losartan, taken separately.

    Amlodipine

    Symptoms: an overdose of amlodipine may lead to excessive peripheral vasodilation and, possibly, reflex tachycardia. In the cases described, there was a long, pronounced hypotensive effect, up to a shock and death.

    Treatment: taking activated charcoal by healthy volunteers directly or within 2 hours after ingestion of 10 mg of amlodipine significantly reduces absorption of the latter. If necessary, gastric lavage is indicated. Clinically significant arterial hypotension with an overdose requires a set of measures to normalize the state of the cardiovascular system, it is necessary to raise the patient's legs, carry out constant monitoring of the functional parameters of the heart and respiratory system, bcc and volume of diuresis. To restore the tone of blood vessels and blood pressure, it may be necessary to administer vasoconstrictors, having first ascertained that there are no contraindications to their use.To eliminate calcium channel blockade, intravenous calcium gluconate is effective. Removal of amlodipine by hemodialysis is unlikely.

    Losartan

    There are limited data on the drug overdose in humans.

    Symptoms: arterial hypotension and tachycardia; possibly the development of bradycardia due to parasympathetic (vagal) stimulation.

    Treatment: if symptomatic arterial hypotension occurs, supportive therapy should be prescribed. Neither losartan, nor its active metabolite can not be removed from the body by hemodialysis.

    Interaction:

    The hypotensive effect can be intensified with simultaneous use with other antihypertensive drugs, so the simultaneous administration of various antihypertensive drugs should be justified.

    Amlodipine

    Amlodipine can be safely used for the therapy of arterial hypertension along with thiazide diuretics, alpha-adrenoblockers or ACE inhibitors. Unlike other BCCI, clinically significant interaction of amlodipine (III generation of BCCI) was not detected when combined with NSAIDs, including. and with indomethacin.It is possible to intensify the hypotensive effect of BCCC when combined with thiazide and loop diuretics, ACE inhibitors and nitrates, as well as enhance their hypotensive effect when combined with alpha1adrenoblockers, neuroleptics.

    The combined use of amlodipine with CYP3A4 inhibitors requires careful monitoring of the symptoms of hypotension and peripheral edema. With the simultaneous administration of diltiazem in a dose of 180 mg / day and amlodipine at a dose of 5 mg / day in older patients, the system exposure of amlodipine increases by 60%. Erythromycin when combined, increases Cmax Amlodipine in young patients by 22%, and in the elderly by 50%. At the same time, strong inhibitors of CYP3A4 (ketoconazole, itraconazole, ritonavir) can increase the concentration of amlodipine in plasma even more.

    Despite the fact that the exact quantitative evaluation of the interaction of amlodipine and inducers of CYP3A4 (for example, rifampicin, St. John's wort) has not been obtained, against the background of their combined use, it is recommended to have constant blood pressure control.

    Beta-adrenoblockers with simultaneous administration with amlodipine may cause an exacerbation of the course of heart failure.

    Although no negative inotropic effects were usually observed in the study of amlodipine, nevertheless, some BCCCs can increase the negative inotropic effect of antiarrhythmic agents that cause prolongation of the QT interval (for example, amiodarone and quinidine).

    A single dose of 100 mg of sildenafil in patients with arterial hypertension does not affect the pharmacokinetics of amlodipine.

    The repeated use of amlodipine in a dose of 10 mg and atorvastatin at a dose of 80 mg is not accompanied by significant changes in the pharmacokinetics of atorvastatin.

    Ethanol (drinks containing alcohol): amlodipine at a single and repeated application in a dose of 10 mg does not affect the pharmacokinetics of ethanol.

    Neuroleptics and isoflurane - Increased hypotensive effect of dihydropyridine derivatives.

    With iv introduction of dantrolene against the background of amlodipine treatment, collapse, arrhythmias, a decrease in the force of the heart contractions and hyperkalemia are possible.

    Calcium preparations can reduce the effect of BCCC.

    When amlodipine is used together with lithium preparations, it is possible to intensify manifestations of neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus).

    Amlodipine does not change the pharmacokinetics of cyclosporine.

    Does not affect the serum concentration of digoxin and its renal clearance.

    Has no significant effect on the effect of warfarin (prothrombin time).

    Cimetidine does not affect the pharmacokinetics of amlodipine.

    In vitro studies amlodipine does not affect the binding of blood plasma proteins digoxin, phenytoin, warfarin and indomethacin.

    Grapefruit juice: simultaneous single intake of 240 mg of grapefruit juice and 10 mg of amlodipine inwards is not accompanied by a significant change in the pharmacokinetics of amlodipine.

    Aluminum- or magnesium-containing antacids: their single administration does not have a significant effect on the pharmacokinetics of amlodipine.

    Losartan

    As with the use of other agents that block the formation of angiotensin II and its effects, the concomitant use of potassium-sparing diuretics (for example, spironolactone, triamterene, amiloride), potassium supplements and potassium-containing salt substitutes, can lead to an increase in serum potassium.

    In some patients with impaired renal function who have been treated with NSAIDs, including selective COX-2 inhibitors, simultaneous administration of ACE inhibitors and / or APA drugs, including losartan, can cause further impairment of kidney function until the development of acute renal failure. Usually, this effect is reversible. NSAIDs, including selective inhibitors of COX-2, may reduce the effect of angiotensin II receptor blockers, including losartan. Therefore, the antihypertensive effect of angiotensin II receptor antagonists can be weakened by the simultaneous use of NSAIDs, in particular selective COX-2 inhibitors. Thus, the simultaneous use of a combination with NSAIDs should be carried out with caution in patients with impaired renal function.

    Double blockade of RAAS: it has been established that in patients with atherosclerosis, heart failure or diabetes with target organ damage, the double blockade of RAAS (concomitant use of ACE inhibitors and ARA drugs) is associated with more frequent complications of therapy in the form of arterial hypotension, syncope (syncope), hyperkalemia and impaired renal function (including, acute renal failure) compared with monotherapy with each drug. In this regard, combined treatment with ACE inhibitors and with APA drugs requires an individualized approach and constant monitoring of the functional activity of the kidneys.

    There was no pharmacokinetically significant drug interaction with such drugs as hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital. Taking rifampin, an inducer of drug metabolism, reduces the concentration of losartan and its active metabolite.

    In humans, two inhibitors of the isoenzyme CYP3A4 have been studied. Ketoconazole does not affect the biotransformation of losartan administered intravenously to the active metabolite, and erythromycin does not have a clinically significant effect on the pharmacokinetics of losartan when taken orally.

    Fluconazole, an inhibitor of the isoenzyme CYP2C9, decreases the concentration of the active metabolite and increases the concentration of losartan in the blood plasma, however, the pharmacodynamic significance of the joint use of losartan and inhibitors of the isoenzyme CYP2C9 is not established. It is shown that in individuals whose body does not convert losartan in the active metabolite, there is a very rare and specific defect in the isoenzyme CYP2C9. These data suggest that the biotransformation of losartan to the active metabolite is mediated predominantly by the isoenzyme CYP2C9, rather than CYP3A4.

    Special instructions:

    In patients with reduced BCC (eg, with high doses of diuretics, severe diarrhea, vomiting, and other conditions leading to hypovolemia), symptomatic arterial hypotension may develop at the onset of therapy. Before prescribing the drug, the BCC deficiency should be eliminated. For patients whose daily dose of losartan is 25 mg, the use is not recommended.

    Special instructions and precautions related to amlodipine

    Thanks to the long T1/2 in blood plasma, vasodilation, developed as a result of amlodipine, may persist even after its withdrawal. Therefore, the appointment of another vasodilator after amlodipine withdrawal should be done with caution, with individual dose assessment, dosing interval and active monitoring of the patient's condition.

    In the period of treatment, it is necessary to control body weight and intake of table salt, the appointment of an appropriate diet. It is necessary to maintain dental hygiene and frequent visits to the dentist (to prevent soreness, bleeding and gingival hyperplasia).

    Special instructions and precautions related to losartan

    Hyperkalemia (potassium content in the plasma> 5.5 mmol / l) was noted in 1.5% of patients taking losartan in the form of monotherapy. In none of these cases was it necessary to cancel the drug. Combined with losartan, the appointment of potassium-sparing diuretics (eg, spironolactone, triamterene, amiloride), potassium preparations, potassium-containing salt substitutes, and preparations that can lead to an increase in potassium concentration in plasma (eg heparin) should be justified (especially in the elderly patients with impaired renal function), and the potassium content in the plasma should be controlled.

    The administration of losartan can lead to transient arterial hypotension, accompanied by shock, fainting and shortness of breath.

    According to studies of pharmacokinetics, in patients with cirrhosis of the liver, a significant increase in the concentration of losartan in plasma is observed. The use of losartan is not recommended in patients with severe hepatic impairment, as well as in patients with hepatic insufficiency who are recommended to reduce the dose of losartan to 25 mg / day.

    Due to the suppression of RAAS in some patients who took losartan, there were reversible changes in kidney function when the drug was withdrawn.

    In patients whose renal function may depend on the activity of the RAAS (e.g., chronic heart failure III-IV functional class NYHA classification), ACE inhibitors accompanied oliguria and / or increasing azotemia and, occasionally, acute renal failure and / or death . A similar picture was observed with the use of losartan in such patients. In clinical trials of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, resulting in an increase in concentration of creatinine and urea nitrogen in plasma. A similar effect was observed when taking losartan in this group, it was reversible when the drug was withdrawn.

    Patients should be careful in managing vehicles and other mechanisms when taking the drug, taking into account the risk of developing dizziness.

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