Compound
Exforge tablets have active ingredients such as amlodipine and valsartan , as well as the following additional components: talc, MCC, magnesium stearate, hypromellose, colloidal silicon dioxide, titanium dioxide, crospovidone, yellow iron oxide, macrogol 4000. Co
-Exforge, in turn , has the following composition:
- active ingredients – amlodipine , valsartan , hydrochlorothiazide ;
- additional substances: MCC, colloidal silicon dioxide, hypromellose, crospovidone, macrogol, magnesium stearate, titanium dioxide, talc.
Pharmacodynamics and pharmacokinetics
The active components of Exforge have a complementary mechanism of action to control blood pressure . Amlodipine belongs to the blockers of “slow” calcium channels. The second active component valsartan , is an angiotensin II receptor antagonist . The combination of these two components has a mutually complementary hypotensive effect, which causes a decrease in arterial (blood) pressure.
Amlodipine acts as a relaxant on vascular smooth muscle. It dilates the walls of blood vessels, which causes a decrease in peripheral vascular resistance and a decrease in blood pressure. With long-term use, this is not accompanied by significant changes in heart rate and catecholamine , as well as negative inotropic effects .
In people with normal left ventricular function, the drug may cause a slight increase in cardiac index without a significant effect on the rate of rise of pressure (maximum) in the left ventricle, left ventricular volume and final blood pressure.
The action of amlodipine is effective in those who have chronic stable and vasospastic angina , as well as angiographically confirmed damage to the coronary arteries .
Valsartan selectively affects AT1 receptors , blocking them, which can lead to stimulation of AT2 receptors .
With arterial hypertension , those taking valsartan experience a decrease in blood pressure without changes in heart rate . The antihypertensive effect in this case persists throughout the day. In case of heart failure (chronic) class II–IV, the number of hospitalizations decreases. In case of left ventricular failure or dysfunction of the left ventricle after myocardial infarction, a decrease in cardiovascular mortality is recorded.
The antihypertensive effect after taking the medicine becomes noticeable no later than 2 hours. The maximum reduction in blood pressure occurs after about 5 hours.
The hypotensive effect is observed for more than a day. The maximum reduction in blood pressure with repeated use can be achieved within 2-4 weeks; it remains at this level with long-term therapy. If you stop taking valsartan, there is no sharp increase in blood pressure or other undesirable consequences.
At a dosage of 10/160 mg, the drug normalizes blood pressure in most patients with inadequate blood pressure control when using amlodipine 10 mg.
When using dosages of 10/160 and 5/160 mg after using the drug, blood pressure is normalized in most patients with inadequate blood pressure control when taking valsartan 160 mg per day.
The effect of Exforge does not depend on age, race or gender.
The pharmacokinetics of this drug is characterized by linearity. After oral administration of Exforge, the maximum plasma levels of amlodipine and valsartan are achieved after approximately 7 and 3 hours, respectively.
Amlodipine is actively broken down in the liver, resulting in the formation of active metabolites . It is eliminated in two stages with a half-life of 30-50 hours. Equilibrium plasma concentrations are observed after approximately a week. 10% of the substance is excreted from the body unchanged and about 60% in the form of metabolites through the kidneys.
About 20% of the beneficial dose of valsartan is determined as metabolites . The active substance is excreted mainly unchanged through the kidneys and intestines. The half-life is about 6 hours.
The pharmacodynamics of the drug Co-Exforge, in turn, is characterized by the combined effect of three antihypertensive components, which have a complementary mechanism of action to control blood pressure . At the same time, a more significant decrease in SBP and DBP is observed when compared with the use of combinations of only two active substances included in the drug. Blood pressure targets are achieved faster.
The maximum antihypertensive effect when taking Co-Exforge can be noticed 2 weeks after the start of the course. The therapeutic effect does not depend on age, race and gender.
The maximum concentration of amlodipine , valsartan and hydrochlorothiazide after taking Co-Exforge appears after 7, 3 and 2 hours, respectively.
The bioavailability of hydrochlorothiazide when administered orally is about 70%. The half-life is 6-15 hours. The substance is excreted unchanged from the body in urine.
Use during pregnancy and children
Exforge, like any other drug that has a direct effect on the renin-angiotensin-aldosterone system (RAAS), should not be prescribed during pregnancy or to women planning pregnancy. If pregnancy is detected during treatment with Exforge, 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 the RAAS. Given the mechanism of action of angiotensin II receptor antagonists, a risk to the fetus cannot be excluded. It is known that the administration of ACE inhibitors, which affect the RAAS, to pregnant women in the second and third trimesters leads to damage or death of the developing fetus. According to a retrospective analysis, the use of ACE inhibitors in the first trimester of pregnancy was accompanied by the development of pathology in the fetus and newborn. With the unintentional use of valsartan in pregnant women, cases of spontaneous abortion, oligohydramnios and renal dysfunction in newborns have been described. It is not known whether valsartan and/or amlodipine are excreted in breast milk. Since experimental studies have shown that valsartan is excreted in breast milk, the use of Exforge during lactation (breastfeeding) is not recommended.
Contraindications
Exforge is contraindicated in case of individual intolerance to the components of the drug and pregnancy . This drug should be taken with caution in case of liver disease, mitral or aortic stenosis , hyperkalemia , hypertrophic obstructive cardiomyopathy , severe renal impairment, sodium deficiency and/or decreased volume .
Co-Exforge is contraindicated in:
- significant liver dysfunction;
- hypersensitivity to the components of the drug;
- hypokalemia , hypercalcemia , hyponatremia and hyperuricemia refractory to adequate therapy ;
- pregnancy;
- lactation;
- significant impairment of kidney function;
- childhood.
The drug should be taken with caution when:
- renal artery stenosis , as well as the artery of a single kidney, mitral or aortic stenosis ;
- decrease in BCC ;
- systemic lupus erythematosus;
- mild to moderate liver dysfunction;
- disturbances of water and electrolyte balance;
- hypertrophic obstructive cardiomyopathy ;
- diabetes mellitus.
Side effects
When taking Exforge, the following side effects are observed:
- from the respiratory system: nasopharyngitis , flu , cough, pain in the larynx and pharynx;
- from the central nervous system: paresthesia , headache , drowsiness , dizziness ;
- from the cardiovascular system: tachycardia , orthostatic hypotension , palpitations;
- skin reactions: rash, erythema ;
- from the digestive system: diarrhea / constipation , abdominal pain, dry mouth, nausea;
- from the musculoskeletal system: joint swelling, arthralgia , back pain;
- other: pastiness , peripheral edema, asthenia , flushing of the face, feeling of heat, facial swelling, increased fatigue.
In rare cases, the following were observed: increased sensitivity, visual impairment, marked decrease in blood pressure, tinnitus, anxiety , syncope, hyperhidrosis , itching, feeling of heaviness, exanthema , muscle spasms, pollakiuria , erectile dysfunction , polyuria .
In addition, side effects from each of the components may manifest themselves when consuming Exforge, even if they have not previously been observed in clinical studies.
The drug Co-Exforge has the following side effects:
- from the metabolic side: hypokalemia , anorexia , hyperlipidemia , hyponatremia , hypercalcemia ;
- from the nervous system: paresthesia , fainting , lethargy, dizziness , taste disturbances, headache , coordination problems, neuropathy ;
- from the hearing organs: vertigo ;
- from the respiratory system: cough, irritation in the throat, shortness of breath ;
- from the skin: itching, increased sweating ;
- from the kidneys and urinary tract: pollakiuria , increased plasma creatinine, renal failure ;
- general disorders: abasia , peripheral edema, increased fatigue, asthenia , pain in the chest, gait disturbances, general weakness;
- from the psyche : drowsiness , sleep disturbances;
- from the organs of vision: visual disturbances ;
- from the cardiovascular system: phlebitis , significant decrease in blood pressure, orthostatic hypotension , tachycardia , thrombophlebitis ;
- from the digestive system: dyspepsia , bad breath, abdominal discomfort, diarrhea , dry mouth, vomiting, nausea;
- from the musculoskeletal system: pain in the limbs and back, swelling of the joints, muscle spasms, muscle weakness, myalgia ;
- from the reproductive system: erectile dysfunction ;
- other: weight gain, hyperuricemia .
Exforge 10mg+160mg 28 pcs. film-coated tablets
pharmachologic effect
Combination antihypertensive agent (BMCC + angiotensin II receptor antagonist).
Composition and release form Exforge 10mg+160mg 28 pcs. film-coated tablets
Tablets - 1 tablet:
- active ingredients: amlodipine besilate - 6.94/6.94/13.87 mg (corresponding to 5.00/5.00/10.00 mg of amlodipine, respectively), valsartan - 80.00/160.00/160.00 mg ;
- excipients: microcrystalline cellulose, crospovidone, magnesium stearate, colloidal silicon dioxide;
- film shell: Premix white (hypromellose, titanium dioxide (E 171), macrogol 4000, talc); Premix yellow (hypromellose, iron oxide yellow dye (E 172), macrogol 4000, talc); Premix red (hypromellose, red iron oxide dye (E 172), macrogol 4000, talc).
7 or 14 tablets in a PVC/PVDC blister.
1, 2, 4, 8, 14 or 40 blisters of 7 tablets each; 1, 2, 4, 7 or 20 blisters of 14 tablets each along with instructions for medical use in a cardboard box.
Description of the dosage form
Light yellow, oval, film-coated tablets with beveled edges, debossed with “NVR” on one side and “UIC” on the other side.
Characteristic
A combined antihypertensive drug containing active substances with a complementary mechanism for blood pressure control.
Directions for use and doses
The drug should be taken orally with a small amount of water, 1 time per day, regardless of meal time.
The recommended daily dose is 1 tablet containing amlodipine + valsartan at a dose of 5 mg + 80 mg, or 5 mg + 160 mg, or 10 mg + 160 mg (maximum daily dose for amlodipine).
A patient receiving valsartan and amlodipine in different tablets/capsules can be switched to taking Exforge® in tablets containing the same dosage of active ingredients.
In patients who may require multicomponent drug therapy to achieve target blood pressure values, treatment can be started with Exforge®. The benefit/risk ratio should be carefully assessed when choosing Exforge® as initial therapy for hypertension.
It is recommended to start taking the drug with a dose of 5 mg + 80 mg once a day. The dose can be increased 1-2 weeks after the start of therapy. The maximum dose of amlodipine and valsartan is 10 mg + 320 mg per day. The tablets are indivisible and cannot be divided into equal doses.
Patients with impaired renal function
For patients with mild to moderate renal impairment (GFR ≥30 ml/min/1.73 m2), no initial dose adjustment is required.
Patients with liver dysfunction
Due to the presence of valsartan and amlodipine, Exforge® should be used with caution in patients with impaired liver function and obstructive diseases of the biliary tract. In patients in this category, the possibility of using an initial dose of the drug containing the lowest dose of amlodipine should be considered, i.e. one tablet containing amlodipine + valsartan at a dose of 5 mg + 80 mg or 5 mg + 160 mg.
Use in patients over 65 years of age
Since both components of the drug are equally well tolerated when used in appropriate doses in elderly patients (aged 65 years and older) or in patients younger than this age category, no adjustment of the initial dose of the drug is required in these patients. You should consider using the initial dose of the drug containing the lowest dose of amlodipine, i.e. one tablet containing amlodipine + valsartan at a dose of 5 mg + 80 mg or 5 mg + 160 mg.
Use in children and adolescents under 18 years of age
Since there is insufficient data on the safety and effectiveness of Exforge® in children and adolescents (under 18 years of age), the drug is not recommended for use in patients in this category.
Pharmacodynamics
The drug Exforge® is a combination of two antihypertensive components with a complementary mechanism for controlling blood pressure (BP) in patients with essential arterial hypertension (AH): amlodipine, a dihydropyridine derivative, belongs to the class of “slow” calcium channel blockers (SCBCs) and valsartan - to class of angiotensin II receptor antagonists (ARA II). The combination of these components has a mutually complementary antihypertensive effect, which leads to a more pronounced decrease in blood pressure compared to that during monotherapy with each drug.
Amlodipine
Amlodipine, which is part of the drug Exforge®, inhibits the transmembrane entry of calcium ions into cardiomyocytes and vascular smooth muscle cells. The mechanism of the antihypertensive effect of amlodipine is associated with a direct relaxing effect on vascular smooth muscle fibers, causing a decrease in peripheral vascular resistance and a decrease in blood pressure. Experimental data show that amlodipine binds to the dihydropyridine and non-dihydropyridine active sites of the receptor. The mechanism of contraction of the myocardium and vascular smooth muscle fibers depends on the supply of calcium ions from the intercellular space through specific ion channels.
When taken in therapeutic doses in patients with hypertension, amlodipine causes vasodilation, leading to a decrease in blood pressure (in the standing and lying position). The decrease in blood pressure is not accompanied by a significant change in heart rate (HR) and catecholamine concentrations with long-term use. Plasma concentrations correlate with effect in both young and elderly patients.
In hypertension in patients with normal renal function, amlodipine in therapeutic doses leads to a decrease in renal vascular resistance, an increase in glomerular filtration rate and effective renal plasma flow without changing the filtration fraction and the severity of proteinuria.
Just as with the use of other BMCCs, taking amlodipine in patients with normal left ventricular (LV) function caused changes in hemodynamic parameters of cardiac function at rest and during exercise: there was a slight increase in cardiac index without a significant effect on the maximum rate of increase in pressure in the LV (dP/dt) and end-diastolic pressure and volume. Hemodynamic studies in intact animals and healthy volunteers showed that the decrease in blood pressure under the influence of amlodipine in the range of therapeutic doses is not accompanied by a negative inotropic effect, even when used simultaneously with beta-blockers in humans.
Amlodipine does not alter sinoatrial node function or atrioventricular conduction in intact animals and healthy volunteers. In clinical studies when amlodipine was used in combination with beta-blockers in patients with hypertension or angina, a decrease in blood pressure was not accompanied by undesirable changes in electrocardiogram (ECG) parameters.
The clinical effectiveness of amlodipine has been proven in patients with chronic stable angina, vasospastic angina and angiographically confirmed lesions of the coronary arteries.
Valsartan
Valsartan is an active specific ARA II intended for oral administration. It acts selectively on the AT1 receptor subtype, which is responsible for the known effects of angiotensin II. An increase in plasma concentrations of free 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 any pronounced agonistic 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 angiotensin-converting enzyme (ACE), also known as kininase II, which converts angiotensin I to angiotensin II and causes the destruction of bradykinin. Since the use of ARA II does not inhibit ACE and does not accumulate bradykinin or substance P, the development of a dry cough is unlikely. In comparative clinical studies of valsartan with an ACE inhibitor, the incidence of dry cough was significantly lower (p
A decrease in blood pressure during valsartan therapy in patients with hypertension is not accompanied by a change in heart rate.
In most patients, the antihypertensive effect after a single oral dose of valsartan develops within 2 hours, with the maximum effect achieved within 4-6 hours. The duration of the antihypertensive effect is 24 hours. With repeated use, the maximum reduction in blood pressure, regardless of the dose taken, is usually achieved within 2-4 weeks and remains at the achieved level during long-term therapy. Abrupt cessation of valsartan is not accompanied by a sharp increase in blood pressure or other undesirable clinical consequences.
The use of valsartan in patients with chronic heart failure (functional classes II-IV according to the NYHA classification) leads to a significant reduction in the number of hospitalizations. This effect is most pronounced in patients not receiving ACE inhibitors or beta-blockers. In patients with clinically stable left ventricular failure or impaired LV function after myocardial infarction, therapy with valsartan leads to a reduction in cardiovascular mortality.
Pharmacokinetics
Linearity
The pharmacokinetics of valsartan and amlodipine are linear.
Amlodipine
Suction
After oral administration in therapeutic doses, the maximum concentration (Cmax) of amlodipine in the blood plasma is achieved after 6-12 hours. The value of absolute bioavailability averages 64-80%. Food intake does not affect the bioavailability of amlodipine.
Distribution
The volume of distribution (Vd) is approximately 21 l/kg. According to in vitro studies, about 97.5% of circulating amlodipine is bound to plasma proteins. Amlodipine crosses the placenta and is excreted in breast milk.
Metabolism
Amlodipine is extensively (approximately 90%) metabolized in the liver to form inactive metabolites.
Removal
The elimination of amlodipine from blood plasma is biphasic with a half-life (T1/2) of approximately 30 to 50 hours. Equilibrium concentration in blood plasma is achieved after prolonged use for 7-8 days. 10% of unchanged amlodipine and 60% of amlodipine in the form of metabolites are excreted by the kidneys.
Valsartan
Suction
After oral administration, Cmax of valsartan in blood plasma is reached within 2-4 hours. The average absolute bioavailability is 23%.
When taking valsartan with food, there is a decrease in bioavailability (based on the area under the curve of “slow” calcium channels.
The use of ACE inhibitors or ARB II in cases where the state of renal function depends on the activity of the RAAS (for example, in patients with heart failure) has been associated with the development of oliguria and/or progressive azotemia, in rare cases leading to acute renal failure and/or death. When assessing the condition of a patient with acute cardiovascular failure, the state of renal function should be determined in all cases.
Acute myocardial infarction
At the beginning of amlodipine therapy (or with an increase in its dose), angina pectoris may worsen and acute myocardial infarction may develop, especially in patients with severe coronary heart disease.
Impact on the ability to drive vehicles and operate machinery
There is no data on the effect of the drug on the ability to drive vehicles and operate machinery. Due to the possible occurrence of dizziness or increased fatigue, caution should be exercised when performing these activities.
Overdose
There are currently no data on cases of drug overdose.
In case of an overdose of valsartan, the main symptom is presumably severe arterial hypotension, accompanied by dizziness. Overdose of amlodipine can lead to excessive peripheral vasodilation and possible reflex tachycardia. Severe and prolonged systemic arterial hypotension has also been reported, leading to the development of shock with a fatal outcome.
If clinically significant arterial hypotension develops with an overdose of amlodipine, active measures are required to maintain the function of the cardiovascular system, including frequent monitoring of the functions of the cardiovascular and respiratory systems, a position with an elevated leg end, and careful monitoring of blood volume and diuresis.
Treatment
If the drug has been taken recently, induce vomiting or perform gastric lavage. The use of activated charcoal in healthy volunteers immediately after or within 2 hours after administration of amlodipine significantly reduced its absorption.
In the absence of contraindications, in order to restore vascular tone and blood pressure, it is possible to use (with caution) a vasoconstrictor. Intravenous calcium gluconate may be effective in reversing the effects of calcium channel blockade.
Elimination of valsartan and amlodipine during hemodialysis is unlikely.
Side effects Exforge 10mg+160mg 28 pcs. film-coated tablets
The safety of Exforge® has been assessed in more than 2,600 patients. Below, in accordance with the systemic organ class, are indicated adverse drug reactions (ADRs) according to clinical studies and laboratory data that were more common when using amlodipine and valsartan compared to placebo, as well as individual reports received in the post-registration period.
When assessing the frequency of occurrence of adverse drug reactions and undesirable effects, the following gradations were used: “very often” (≥1/10), “often” (>1/100 1/1000 1/10000
| System-organ class | Adverse reaction | Exforge® | Amplodipine | Valsartan |
| Infections and infestations | nasopharyngitis, flu | often | — | — |
| Blood and lymphatic system disorders | decrease in hemoglobin concentration and decrease in hematocrit, neutropenia | — | — | frequency unknown |
| leukopenia | — | very rarely | — | |
| thrombocytopenia, sometimes with purpura | — | very rarely | frequency unknown | |
| Immune system disorders | hypersensitivity | rarely | very rarely | |
| hypersensitivity, including serum sickness | — | — | frequency unknown | |
| Metabolic and nutritional disorders | anorexia, hypercalcemia, hyperlipidemia, hyperuricemia, hyponatremia | infrequently | — | — |
| hyperglycemia | — | very rarely | — | |
| hypokalemia | often | — | — | |
| Mental disorders | depression, insomnia, mood lability | — | infrequently | — |
| anxiety | rarely | — | — | |
| confusion | — | rarely | — | |
| Nervous system disorders | lack of coordination | infrequently | — | — |
| dizziness | infrequently | often | — | |
| postural vertigo | infrequently | — | — | |
| dysgeusia | — | infrequently | — | |
| extrapyramidal syndrome | — | frequency unknown | — | |
| headache | often | often | — | |
| hypertonicity | — | very rarely | — | |
| paresthesia | infrequently | infrequently | — | |
| peripheral neuropathy, neuropathy | — | very rarely | — | |
| drowsiness | infrequently | often | — | |
| fainting, tremor, hypoesthesia | — | infrequently | — | |
| Visual disorders | visual impairment | rarely | infrequently | — |
| diplopia | — | infrequently | — | |
| blurred vision | infrequently | infrequently | — | |
| Disorders of the hearing organ and labyrinth | noise in ears | rarely | infrequently | — |
| vertigo | infrequently | — | infrequently | |
| Heart disorders | feeling of heartbeat | infrequently | often | — |
| syncope | rarely | — | — | |
| tachycardia | infrequently | — | — | |
| arrhythmias, including bradycardia, atrial fibrillation, ventricular tachycardia, myocardial infarction | — | very rarely | — | |
| Vascular disorders | "flushes" of blood to the face | — | often | — |
| arterial hypotension | rarely | infrequently | — | |
| orthostatic hypotension | infrequently | — | — | |
| hypertension | — | very rarely | — | |
| vasculitis | — | very rarely | frequency unknown | |
| Respiratory, thoracic and mediastinal disorders | cough | infrequently | very rarely | infrequently |
| shortness of breath, rhinitis | — | infrequently | — | |
| pain in the pharynx and larynx | infrequently | — | — | |
| Gastrointestinal disorders | abdominal discomfort, pain in the upper abdomen | infrequently | often | infrequently |
| bowel dysfunction, dyspepsia, vomiting | — | infrequently | — | |
| constipation | infrequently | — | — | |
| diarrhea, dry mouth | infrequently | infrequently | — | |
| gastritis, pancreatitis, gum hyperplasia | — | very rarely | — | |
| nausea | infrequently | often | — | |
| Disorders of the liver and biliary tract | deviation of laboratory parameters of liver function from the norm, including an increase in the concentration of bilirubin in the blood plasma | — | very rarely* | frequency unknown |
| hepatitis, intrahepatic cholestasis, jaundice | — | very rarely | — | |
| Skin and subcutaneous tissue disorders | alopecia, photosensitivity, purpura, skin discoloration | — | infrequently | — |
| angioedema | — | very rarely | frequency unknown | |
| bullous dermatitis | — | — | frequency unknown | |
| erythema | infrequently | — | — | |
| Erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke's edema | — | very rarely | — | |
| exanthema | rarely | infrequently | — | |
| hyperhidrosis | rarely | infrequently | — | |
| itchy skin | rarely | infrequently | frequency unknown | |
| skin rash | infrequently | infrequently | frequency unknown | |
| toxic epidermal necrolysis | — | frequency unknown | — | |
| Muscle, skeletal and connective tissue disorders | arthralgia, back pain | infrequently | infrequently | — |
| joint swelling | infrequently | — | — | |
| muscle spasm | rarely | infrequently | — | |
| myalgia | — | infrequently | frequency unknown | |
| swelling of ankles | — | often | — | |
| feeling of heaviness | rarely | — | — | |
| Renal and urinary tract disorders | increased plasma creatinine concentration, renal dysfunction, including acute renal failure | — | — | frequency unknown |
| urinary disorders, nocturia | — | infrequently | — | |
| pollakiuria | rarely | infrequently | — | |
| polyuria | rarely | — | — | |
| Disorders of the reproductive system and mammary glands | impotence | — | infrequently | — |
| erectile disfunction | rarely | — | — | |
| gynecomastia | — | infrequently | — | |
| General disorders and reactions at the injection site | asthenia | often | infrequently | — |
| discomfort, malaise | — | infrequently | — | |
| increased fatigue | often | often | infrequently | |
| facial swelling, peripheral edema, flushes of blood to the face, hot flashes, pastiness | often | — | — | |
| non-cardiogenic chest pain, pain | — | infrequently | — | |
| edema | often | often | — | |
| Laboratory and instrumental data | increased potassium levels in blood plasma | — | — | frequency unknown |
| weight gain or loss | — | infrequently | — |
*predominantly associated with cholestasis.
Patients who received a combination of amlodipine with valsartan had a reduced incidence of peripheral edema, a recognized side effect of amlodipine, compared with those who received amlodipine monotherapy. In comparative and placebo-controlled clinical studies, the dose-dependent incidence of peripheral edema was as follows:
| Incidence of peripheral edema in patients (%) | Valsartan (mg) | |||||
| 0 | 40 | 80 | 160 | 320 | ||
| Amlodipine (mg) | 0 | 3,0 | 5,5 | 2,4 | 1,6 | 0,9 |
| 2,5 | 8,0 | 2,3 | 5,4 | 2,4 | 3,9 | |
| 5 | 3,1 | 4,8 | 2,3 | 2,1 | 2,4 | |
| 10 | 10,3 | — | — | 9,0 | 9,5 | |
The average incidence of peripheral edema, which was approximately equal for all dosages, when combining amlodipine with valsartan was 5.1%.
Adverse reactions previously reported with each of the components may develop with Exforge®, even if they were not observed in clinical studies.
If any of the side effects indicated in the instructions get worse, or you notice any other side effects not listed in the instructions, tell your doctor.
Drug interactions
Amlodipine
Simvastatin. Simultaneous long-term use of simvastatin at a dose of 80 mg/day and amlodipine at a dose of 10 mg/day leads to an increase in simvastatin exposure by 77%. It is recommended to reduce the dose of simvastatin in patients taking amlodipine to 20 mg/day.
Inhibitors of the CYP3A4 isoenzyme. When amlodipine is used at a dose of 5 mg/day simultaneously with diltiazem at a dose of 180 mg/day in elderly patients, a slowdown in the metabolism of amlodipine is observed by 1.6 times. When amlodipine is used concomitantly with strong CYP3A4 inhibitors (for example, ketoconazole, itraconazole and ritonavir), a marked increase in the systemic exposure of amlodipine is possible. Amlodipine should be used with caution with inhibitors of the CYP3A4 isoenzyme.
Grapefruit juice. Due to inhibition of the CYP3A4 isoenzyme, when taken concomitantly with grapefruit juice, amlodipine exposure may increase. In a clinical study in 20 healthy volunteers, however, there were no significant changes in pharmacokinetics with a single dose of amlodipine 10 mg with 240 ml of grapefruit juice.
Inducers of the CYP3A4 isoenzyme (anticonvulsants (for example, carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone), rifampicin, herbal preparations containing St. John's wort). There is no data on the effect of inducers of the CYP3A4 isoenzyme on amlodipine. The simultaneous use of amlodipine with inducers of the CYP3A4 isoenzyme may lead to a decrease in the concentration of amlodipine in the blood plasma. Caution should be exercised when using amlodipine with drugs that are inducers of the CYP3A4 isoenzyme.
When monotherapy with amlodipine, no clinically significant interaction was observed with thiazide diuretics, β-blockers, ACE inhibitors, long-acting nitrates, nitroglycerin for sublingual use, digoxin, warfarin, atorvastatin, sildenafil, magnesium hydroxide with aluminum hydroxide gel and simethicone, cimetidine, non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics and oral hypoglycemic drugs.
Ethanol. Simultaneous single and repeated administration of amlodipine at a dose of 10 mg with ethanol does not affect the pharmacokinetics of the latter.
Valsartan
Dual blockade of the RAAS using angiotensin II receptor antagonists, ACE inhibitors or aliskiren
The simultaneous use of ARA II, including valsartan, with other drugs that affect the RAAS leads to an increase in the incidence of arterial hypotension, hyperkalemia, and renal dysfunction. Dual blockade of the RAAS through the simultaneous use of an ACE inhibitor, angiotensin-converting enzyme II, or aliskiren is not recommended in the general population. However, if combination therapy with these drugs is absolutely necessary, such use should be carried out under the careful supervision of a physician, with frequent monitoring of blood pressure, renal function, and blood plasma electrolyte levels. Concomitant therapy with ACE inhibitors and ARB II should not be carried out in patients with diabetic nephropathy.
Concomitant use of drugs containing ARA II, including Exforge®, with other drugs that affect the RAAS, including aliskiren, is contraindicated in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR).
Drugs and substances affecting the potassium content in blood serum. When used simultaneously with dietary supplements containing potassium, potassium-sparing diuretics, eplerenone, potassium-containing salt substitutes, or with other drugs that may cause an increase in potassium levels in the blood (for example, heparin, etc.), caution should be exercised and the levels should be regularly monitored. potassium in the blood.
NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors. The use of angiotensin II receptor antagonists concomitantly with NSAIDs, including COX-2 inhibitors, may lead to a weakening of the antihypertensive effect. In elderly patients, patients with reduced blood volume (including those receiving diuretic therapy) or with impaired renal function, simultaneous use of ARB II and NSAIDs, including COX-2 inhibitors, may increase the risk of developing renal dysfunction. At the beginning of therapy or when adjusting the dosage regimen in patients taking ARB II and NSAIDs, including COX-2 inhibitors, it is recommended to monitor renal function.
Lithium preparations. With the simultaneous use of lithium preparations with ACE inhibitors and ARA II, a reversible increase in the lithium content in the blood serum and increased toxic manifestations were observed, and therefore, when using these drugs simultaneously, it is recommended to monitor the lithium content in the blood serum. When diuretics are used simultaneously with lithium preparations, the risk of developing its toxic effect may further increase when Exforge® is added to therapy.
Transport proteins. According to in vitro studies of human liver tissue, valsartan is a substrate of the transporter protein OATP1B1 and MRP2. Concomitant use of valsartan with inhibitors of the OATP1B1 transport protein (rifampicin, cyclosporine) and with an inhibitor of the MRP2 transport protein (ritonavir) may lead to an increase in the systemic bioavailability of valsartan.
It has been established that with valsartan monotherapy there is no clinically significant interaction with the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide.
Instructions for use of Exforge
Instructions for use of Exforge include preoral use. The drug is taken once a day with some water, regardless of the time of meals. Dosages Exforge 10/160, 10/320, 5/80, 5/160, 5/320 mg. The maximum daily dose is 10/320 mg.
For those who have been prescribed Co-Exforge, the instructions for use advise using it once daily in tablets, depending on the doctor’s prescription, containing:
- 5 mg amlodipine in combination with 160 mg valsartan and 12.5 mg hydrochlorothiazide;
- 10 mg amlodipine in combination with 160 mg valsartan and 12.5 mg hydrochlorothiazide;
- 10 mg amlodipine in combination with 320 mg valsartan and 25 mg hydrochlorothiazide (2 tablets).
The tablets are taken orally regardless of meals. They must be washed down with water.
Description of the dosage form
Film-coated tablets, 5/80 mg: dark yellow, round with beveled edges, imprinted “NVR” on one side and “NV” on the other.
Film-coated tablets, 5/160 mg: dark yellow, oval with beveled edges, imprinted “NVR” on one side and “ECE” on the other.
Film-coated tablets, 10/160 mg: light yellow, oval with beveled edges, imprinted “NVR” on one side and “UIC” on the other.
Overdose
Valsartan in high doses can lead to a pronounced decrease in blood pressure and dizziness , and amlodipine can lead to reflex tachycardia , arterial hypotension , and excessive peripheral vasodilation .
An overdose of hydrochlorothiazide may cause symptoms associated with electrolyte loss and dehydration . The most likely manifestations: nausea, muscle spasms, cardiac arrhythmia and drowsiness .
As treatment, induce vomiting or perform gastric lavage. activated charcoal may help .
In case of arterial hypotension, the patient must take a “lying” position with his legs elevated; in addition, measures are provided to maintain the normal functioning of the cardiovascular system. To normalize blood pressure, a vasoconstrictor can be prescribed .
Interaction
Clinically significant interaction is not observed when amlodipine with thiazide diuretics, Nitroglycerin for sublingual use, ACE inhibitors, Warfarin , Sildenafil , Cimetidine , antibiotics , beta-blockers, long-acting nitrates, Digoxin , Atorvastatin , Maalox , NSAIDs, oral hypoglycemic drugs .
The combination of amlodipine with Diltiazem in elderly patients causes a slowdown in the breakdown of amlodipine, which causes an increase in its plasma content by approximately half. Together with more potent CYP3A4 inhibitors, the systemic exposure of amlodipine increases.
The combination of amlodipine with inducers of the CYP3A4 isoenzyme , on the contrary, leads to a decrease in its concentration. Therefore, its content in plasma should be monitored.
There is no clinically significant interaction when valsartan with Cimetidine, Furosemide , Atenolol , Hydrochlorothiazide , Glibenclamide , Warfarin , Digoxin , Indomethacin and Amlodipine .
It is necessary to constantly monitor the potassium concentration when simultaneous use of Exforge with dietary supplements that contain potassium-sparing diuretics , potassium and potassium-containing salt substitutes, as well as with other drugs that cause an increase in potassium levels in the blood.
When taking Co-Exforge, you should also consider the interaction of hydrochlorothiazide with other drugs. Therefore, it is necessary to monitor the use of this drug in combination with lithium preparations, hypoglycemic drugs for oral administration and insulin . Dosage adjustments may be necessary.
In addition, hydrochlorothiazide potentiates the effect of peripheral muscle relaxants, can cause an increase in the hyperglycemic effect of Diazoxide , increased sensitivity to Allopurinol , an increased risk of developing side effects of Amantadine cytotoxic drugs through the kidneys , as well as their potentiation of myelosuppressive effects . In turn, combination with NSAIDs leads to a decrease in the diuretic and antihypertensive effects of hydrochlorothiazide. Together with drugs that reduce potassium concentrations, the risk of hypokalemia . Cardiac glycosides also increase the risk of its occurrence, as well as hypomagnesemia and arrhythmia .
Together with m-anticholinergics, the bioavailability of hydrochlorothiazide increases. When combined with Methyldopa cases of hemolytic anemia , with Cyclosporine - the risk of developing hyperuricemia and the development of gout , with Cabamazepine - hyponatremia , and with vitamin D and calcium salts, an increase in calcium levels in the blood serum is likely. Cholestyramine reduces the absorption of hydrochlorothiazide.
special instructions
If it is necessary to discontinue β-blockers before starting Exforge® therapy, the dose of β-blockers should be reduced gradually. Since amlodipine is not a β-blocker, the use of Exforge® does not prevent the development of withdrawal syndrome that occurs when treatment with β-blockers is abruptly stopped.
Sodium deficiency in the body and/or decrease in blood volume. In placebo-controlled studies in patients with uncomplicated arterial hypertension, severe arterial hypotension was observed in 0.4% of cases. In patients with an activated renin-angiotensin-aldosterone system (for example, with BCC and/or sodium deficiency in patients receiving high doses of diuretics), symptomatic arterial hypotension may develop when taking angiotensin receptor blockers. Before starting treatment with Exforge®, sodium levels in the body and/or blood volume should be corrected or therapy should be initiated under close medical supervision. If arterial hypotension develops, the patient should be placed with legs elevated and, if necessary, given an intravenous infusion of saline solution. After stabilization of blood pressure, treatment with Exforge® can be continued.
Hyperkalemia. When using the drug simultaneously with dietary supplements containing potassium, potassium-sparing diuretics, potassium-containing salt substitutes, or with other drugs that may cause an increase in the concentration of potassium in the blood (for example, heparin), caution should be exercised and regular monitoring of the concentration of potassium in the blood should be carried out.
Impact on the ability to drive vehicles and operate machinery. There is no data on the effect of the drug on the ability to drive vehicles and operate machinery. Due to the possible occurrence of dizziness or increased fatigue, caution should be exercised when driving vehicles or operating machinery.
Reviews of Exforge
Reviews about Exforge are both positive and negative. Many patients note its effectiveness. Some, however, say that they experienced side effects that forced them to stop taking the drug.
In fact, no specialist can rule out the occurrence of undesirable effects in advance. The drug is much more effective than taking amlodipine or valsartan alone, but its use should be well controlled. For many, in addition, it is more profitable to buy analogs of Exforge.
Reviews of Co-Exforge are generally positive. Patients note the undoubted effectiveness of this remedy and recommend it to others.
Exforge price, where to buy
The price of Exforge is considered quite high. You can buy this product in Moscow and other Russian cities for, on average, 1,400–1,800 rubles.
The price of Co-Exforge, on average, is about 2000 rubles.
- Online pharmacies in RussiaRussia
- Online pharmacies in KazakhstanKazakhstan
LuxPharma* special offer
- Exforge table
10 mg/160 mg No. 28 RUR 1,590 order - Exforge tab. 5 mg/160 mg No. 28
1650 rub. order
ZdravCity
- Co-exforge tab. p.p.o. 10mg+160mg+12.5mg n28Novartis Pharmaceutica SA
2620 rub. order
Pharmacy Dialogue
- Exforge (tablet p/o 5mg+80mg No. 28)Novartis
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- Co-exforge (0.005+0.16/0.0125 No. 28)Novartis
RUB 2,514 order
- Co-exforge (0.01+0.16/0.0125 No. 28)Novartis
RUB 2,544 order
- Exforge (tablet p/o 5mg+160mg No. 28)Novartis
RUB 2,136 order
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Release form
Film-coated tablets, 5 mg/80 mg, 5 mg/160 mg or 10 mg/160 mg. 7, 10 or 14 pcs. in a blister; 1, 2, 4, 8, 14 or 40 blisters of 7 tablets; 3, 9 or 28 blisters of 10 tablets; 1. 2, 4, 7, or 20 blisters of 14 tablets are placed in a cardboard box.
Film-coated tablets, 5 mg + 320 mg or 10 mg + 320 mg. 7 or 14 tablets in a PVC/PVDC blister. 1 blister of 7 tablets; 1, 2, 4, 7 blisters of 14 tablets each are placed in a cardboard box.
