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Amlodipine, Valsartan, Hydrochlorothiazide

Novartis
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2019-09-19
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Clinical Pharmacology

CO-EXFORGE is a combination of three antihypertensive components with a BP control mechanism that complements each other: amlodipine (a derivative of dihydropyridine), a blocker of slow calcium channels, valsartan, an angiotensin II receptor antagonist and hydrochlorothiazide thiazide diuretic. The combination of these components leads to a more pronounced decrease in blood pressure compared to that on the background of monotherapy with each drug separately.

Amlodipine

Amlodipine, which is part of Co-Exforge, inhibits transmembrane entry of calcium ions into cardiomyocytes and vascular smooth muscle cells. The mechanism of antihypertensive action of amlodipine is associated with a direct relaxing effect on vascular smooth muscle, causing a decrease in round neck and a decrease in blood pressure.

After ingestion in therapeutic doses in patients with arterial hypertension, amlodipine causes dilation of blood vessels, leading to a decrease in blood pressure (in the patient's position "lying" and "standing"). Reduced blood pressure is not accompanied by a significant change in heart rate and catecholamine activity with prolonged use.

Plasma drug concentrations correlate with a therapeutic response in both young and elderly patients.

In hypertensive patients with normal renal function, amlodipine at therapeutic doses reduces renal vascular resistance, increases glomerular filtration rate and effective plasma renal blood flow without changing the filtration fraction and the severity of proteinuria.

As with the use of other slow calcium channel blockers, amlodipine in patients with normal left ventricular function showed a change in hemodynamic cardiac function at rest and during exercise: a slight increase in cardiac index, without a significant effect on the maximum pressure buildup rate in the left ventricle, end-diastolic pressure and volume of the left ventricle. Hemodynamic studies in intact animals and healthy volunteers have shown that a 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-adrenoblockers.

Amlodipine does not change the function of the sinoatrial node and does not affect AV conduction in intact animals and healthy volunteers. When using amlodipine in combination with beta-blockers in patients with arterial hypertension or with angina, the decrease in blood pressure is not accompanied by undesirable changes in electrocardiographic parameters.

The clinical efficacy of amlodipine in patients with stable angina, vasospastic angina, and angiographically confirmed coronary artery disease has been proven.

In a long-term placebo-controlled study (PRAISE-2) in patients with chronic heart failure (III and IV functional class according to the NYHA classification) of non-ischemic etiology, with the use of amlodipine there was an increase in the incidence of pulmonary edema, in the absence of significant differences in the incidence of worsening chronic heart failure versus placebo.

The risk of myocardial infarction or an increase in the severity of angina: rarely at the beginning of therapy with slow calcium channel blockers or an increase in their dose in patients, especially with hypertrophic obstructive cardiomyopathy, severe obstructive coronary artery disease, an increase in the frequency, duration and severity of angina or developed angina or developed coronary artery disease; myocardium. Arrhythmia (including ventricular tachycardia and atrial fibrillation) has also been noted with the use of slow calcium channel blockers. These adverse events were impossible to differentiate from the natural course of the disease.

Valsartan

Valsartan is an active and specific angiotensin II receptor antagonist, intended for oral administration. It acts selectively on the AT1 receptor subtype, which is responsible for the effects of angiotensin II. An increase in plasma concentration of unbound angiotensin II due to blockade of AT1 receptors under the influence of valsartan can stimulate unblocked AT2 receptors, which counteract the effects of stimulation of AT1 receptors. Valsartan does not have any pronounced agonistic activity against AT1 receptors. The affinity of valsartan for the AT1 receptor subtype is about 20,000 times higher than that for the AT2 receptor subtype.

Valsartan does not inhibit ACE, which converts angiotensin I to angiotensin II and causes the destruction of bradykinin. Since When using angiotensin II antagonists, ACE inhibition and accumulation of bradykinin or substance P do not occur, the development of dry cough is unlikely.

In comparative clinical studies of valsartan with an ACE inhibitor, the incidence of dry cough was significantly lower (p
When treating valsartan in patients with arterial hypertension, a decrease in blood pressure is observed, which is not accompanied by a change in heart rate.

The antihypertensive effect is manifested within 2 hours in most patients after a single dose of valsartan inside. The maximum decrease in blood pressure develops after 4-6 hours. After taking valsartan, the duration of the hypotensive effect lasts for more than 24 hours. With repeated use, the maximum reduction in blood pressure, regardless of the dose, is usually reached within 2-4 weeks and maintained at the reached 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 class II-IV according to the NYHA classification) leads to a significant reduction in the number of hospitalizations for cardiovascular diseases (which is especially pronounced in patients not receiving ACE inhibitors or beta-blockers). When taking valsartan in patients with left ventricular failure (stable clinical course) or in violation of left ventricular function after myocardial infarction, a decrease in cardiovascular mortality is noted.

Hydrochlorothiazide

The point of application of the action of thiazide diuretics are distal convoluted renal tubules. When thiazide diuretics are exposed to highly sensitive receptors of the distal tubules of the cortical layer of the kidneys, the reabsorption of sodium ions (Na +) and chlorine (Сl-) is suppressed. Suppression of the co-transport system of Na + and Сl-, apparently, occurs due to competition for the binding sites of Cl-ions in this system. As a result, the excretion of sodium ions and chlorine increases approximately equally. As a result of the diuretic effect, a decrease in the BCC is observed, as a result of which renin activity increases, aldosterone secretion, kidney excretion of potassium and, consequently, a decrease in the content of potassium in the blood serum increases.

Amlodipine + valsartan + hydrochlorothiazide

The use of triple combination therapy with amlodipine + valsartan + hydrochlorothiazide showed a more pronounced decrease in systolic and diastolic blood pressure, compared with the use of double combinations: valsartan + hydrochlorothiazide, amlodipine + valsartan and amlodipine + hydrochlorothiazide. In patients with grade II and III arterial hypertension (baseline mean blood pressure of 170/107 mm Hg) when using combination therapy with amlodipine + valsartan + hydrochlorothiazide in a daily dose of 10 mg + 320 mg + 25 mg for 8 weeks, the average decrease in systolic and diastolic blood pressure was 39.7 / 24.7 mmHg. (compared to 32.0 / 19.7 mm Hg, 33.5 / 21.5 mm Hg, 31.5 / 19.5 mm Hg in combination with valsartan + hydrochlorothiazide combination therapy at a dose of 320 mg + 25 mg, amlodipine + valsartan at a dose 10 mg + 320 mg and amlodipine + hydrochlorothiazide at a dose of 10 mg + 25 mg, respectively).

The greatest antihypertensive effect of Co-Exforge is observed 2 weeks after the start of the use of the drug in the maximum individual oral dose.

With the use of Co-Exforge, the achievement of target blood pressure (less than 140/90 mm Hg) was noted in 71% of patients, compared with 45-54% with the use of double combinations.

After taking the drug, the antihypertensive effect lasts for 24 hours.

The therapeutic efficacy of Co-Exforge does not depend on the age, gender and race of patients.

Indications

Arterial hypertension II and III degree.

Composition

Amlodipine besylate 6.94 mg, which corresponds to the content of amlodipine 5 mg, valsartan 160 mg, hydrochlorothiazide 12.5 mg.

Excipients: microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate.

The composition of the film shell: hypromellose, titanium dioxide (E171), macrogol, talc.

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Amlodipine, Valsartan, Hydrochlorothiazide

Dosage and Administration

The drug should be taken orally (preferably in the morning), washed down with a small amount of water, regardless of the meal.

For convenience, patients receiving therapy with amlodipine, valsartan and hydrochlorothiazide in separate pills can be transferred to therapy with Co-Exforge, containing the same doses of active ingredients, as well as with insufficient blood pressure control on the background of double combination therapy (valsartan + hydrochlorothiazide, amlodipine + valsartan and amlodipine + hydrochlorothiazide), patients can be transferred to a triple combination treatment with Co-Exforge in appropriate doses.

If a patient has dose-related side effects when using dual-combination therapy with any of the components of Co-Exforge, Co-Exforge may be prescribed to achieve a similar reduction in blood pressure, containing a lower dose of the active component that caused this side effect.

The recommended daily doses of Co-Exforge are:

- 5 mg + 160 mg + 12.5 mg (1 tablet containing amlodipine + valsartan + hydrochlorothiazide in doses of 5 mg + 160 mg + 12.5 mg);

- 10 mg + 160 mg + 12.5 mg (1 tablet containing amlodipine + valsartan + hydrochlorothiazide in doses of 10 mg + 160 mg + 12.5 mg);

- 10 mg + 320 mg + 25 mg (2 pills containing amlodipine + valsartan + hydrochlorothiazide in doses of 5 mg + 160 mg + 12.5 mg).

The maximum antihypertensive effect of the drug is observed 2 weeks after increasing the dose. The maximum dose of the drug is 10 mg + 320 mg + 25 mg /

Patients over 65 years of age do not require dose adjustment.

Since the safety and efficacy of Co-Exforge in children and adolescents (under 18) have not yet been established, the drug is not recommended for use in this category of patients.

In patients with mild and moderate renal dysfunction (CC more than 30 ml / min) and liver (5-9 points on the Child-Pugh scale), dose adjustment is not required.

Adverse reactions

The following criteria were used to estimate the frequency (according to the WHO classification): very often (≥1 / 10); often (≥1 / 100,

Metabolism: often - hypokalemia; infrequently - anorexia, hypercalcemia, hyperlipidemia, hyponatremia.

From the nervous system: often - dizziness, headache; infrequently - insomnia / sleep disorders, lack of coordination, postural dizziness and dizziness due to exercise, taste disorders, lethargy, paresthesia, neuropathy, incl. peripheral, drowsiness, fainting.

From the senses: infrequently - visual disturbances, vertigo.

Since the cardiovascular system: often - a pronounced decrease in blood pressure; infrequently - tachycardia, orthostatic hypotension, phlebitis, thrombophlebitis.

On the part of the respiratory system: Infrequently - cough, shortness of breath, irritation in the throat.

On the part of the digestive system: often - dyspepsia; infrequently - abdominal discomfort, pain in the upper abdomen, bad breath, diarrhea, dry mouth, nausea, vomiting.

Dermatological reactions: infrequently - increased sweating, itching.

On the part of the musculoskeletal system and connective tissue: rarely - back pain, swelling in the joints, muscle spasms, muscle weakness, myalgia, pain in the extremities.

On the part of the urinary system: often - pollakiuria; infrequently - an increase in plasma creatinine concentration, acute renal failure.

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

On the part of the body as a whole: often - peripheral edema, fatigue; infrequently - abasia, gait disturbances, asthenia, general weakness, pain in the chest.

From the laboratory indicators: infrequently - an increase in the content of urea nitrogen in the blood plasma, hyperuricemia, increase in body weight.

Contraindications

  • Hypersensitivity to amlodipine, valsartan, hydrochlorothiazide, other sulfonamide derivatives, dihydropyridine derivatives and other auxiliary components of the drug;
  • Pregnancy and breastfeeding period;
  • Severe liver dysfunction (more than 9 points on the Child-Pough scale);
  • Severe dysfunction (Cl creatinine less than 30 ml / min), anuria;
  • Hypokalemia, hyponatremia, hypercalcemia, as well as hyperuricemia with clinical manifestations;
  • Age up to 18 years (efficacy and safety have not been established).

Drug interactions

Amlodipine
In monotherapy with amlodipine, there is no clinically significant interaction with thiazide diuretics, beta-adrenergic blockers, ACE inhibitors, long-acting nitrates, nitroglycerin for sublingual use, digoxin, warfarin, atorvastatin, sildenafil, antacid preparations (magnesium hydroxides, ants;); , NSAIDs, antibiotics and hypoglycemic drugs for oral administration.
Inhibitors of the isoenzyme CYP 3A4. When using amlodipine together with diltiazem, elderly patients have a slower metabolism of amlodipine, probably due to inhibition of CYP3A4 isoenzyme, which leads to an increase in plasma concentration of amlodipine by approximately 50% and an increase in its systemic exposure. When using amlodipine together with powerful inhibitors of CYP3A4 (for example, ketoconazole, itraconazole and ritonavir), a marked increase in systemic exposure to amlodipine is possible.
Inductors of CYP3A4 isofermept. Since the use of amlodipine together with inducers of CYP3A4 isoenzyme (for example, carbamazepine, phenobarbital, phenytoin, fosfenitoin, primidone, rifampicin, grapefruit juice, herbal preparations containing St. John's wort), can cause a significant decrease in blood plasma, containing St. John's wort), a veneer, can cause a significant decrease in the blood plasma, containing a St. John's wort), hovering holed), give a dosage to a decrease in its concentration in the blood plasma, containing St. John CYP3A4, its plasma levels should be monitored.

Valsartan
When monotherapy with valsartan, there is no clinically significant interaction with the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide.
When used simultaneously with dietary supplements containing potassium, potassium-sparing diuretics, potassium-containing salt substitutes, or with other drugs that can cause an increase in blood potassium (for example, with heparin), caution should be exercised and regular monitoring of the content of capillary in the blood.
When using valsartan together with NSAIDs, it is possible to reduce the antihypertensive effect of valsartan.

Hydrochlorothiazide
Lithium. With simultaneous use with ACE inhibitors and diuretics, cases of a reversible increase in the plasma concentration of lithium and its toxic action have been reported. Therefore, with simultaneous use of hydrochlorothiazide and lithium preparations, it is recommended to control the concentration of lithium in the blood plasma.
Peripheral muscle relaxants. Thiazide diuretics, including hydrochlorothiazide, potentiate the effects of peripheral muscle relaxants.
NSAIDs. It is possible to reduce the diuretic and antihypertensive effects of the thiazide component of Co-Exforge when used simultaneously with NSAIDs, for example, with acetylsalicylic acid, indomethacin. Concomitant hypovolemia can lead to the development of acute renal failure.
Drugs that can cause an increase in the content of potassium in the blood plasma. The risk of hypokalemia increases with the simultaneous appointment of other diuretics, GCS, ACTH, amphotericin B, carbenoxolone and acetylsalicylic acid (in a dose of more than 3 g). Care should be taken with simultaneous use of Co-Exforge with potassium salts, potassium-sparing diuretics, potassium-containing substitutes for edible salt, as well as drugs that can cause an increase in blood potassium (for example, heparin).
Cardiac glycosides.Thiazide diuretics can cause undesirable effects such as hypokalemia or hypomagnesemia; These conditions increase the risk of developing arrhythmias with simultaneous use of cardiac glycosides.
Hypoglycemic agents for oral administration and insulin. When using the drug in patients with diabetes mellitus, it may be necessary to adjust the dose of insulin or hypoglycemic agents for oral administration. Since the use of hydrochlorothiazide together with metformin may develop lactic acidosis (due to impaired function during hydrochlorothiazide therapy), caution should be exercised when using the drug Co-Exforge in patients receiving treatment with metformin.
Anticholinergics. It is possible to increase the bioavailability of thiazide diuretic with simultaneous use of m-anticholinergics (for example, atropine, biperiden), which, apparently, is associated with a decrease in gastrointestinal motility and slowing the rate of gastric emptying.
Methyldopa Cases of hemolytic anemia have been reported with simultaneous administration of hydrochlorothiazide and methyldopa.
Kolestiramin reduces the absorption of thiazide diuretics, including hydrochlorothiazide.
Vitamin D and calcium salts. The combined use of thiazide diuretics, including hydrochlorothiazide, with vitamin D or calcium salts may increase the calcium content in blood serum.
Cyclosporine. Simultaneous administration of cyclosporine may increase the risk of developing hyperuricemia and the appearance of symptoms resembling the worsening of gout.
Carbamazepine. In patients taking hydrochlorothiazide concurrently with carbamazepine may develop hyponatremia. Since in patients receiving hydrochlorothiazide and carbamazepine at the same time, the development of hyponatremia is possible, when administering Co-Exforge along with carbamazepine, it is necessary to carry out an appropriate control of plasma sodium.
Other types of interaction. The simultaneous appointment of thiazide diuretics, including hydrochlorothiazide, may lead to an increase in the frequency of hypersensitivity reactions to allopurinol; increased risk of side effects of amantadine; increased hyperglycemic action of diazoxide; reduction of kidney excretion of cytotoxic agents (eg, cyclophosphamide, methotrexate) and potentiation of their myelosuppressive action.

Pregnancy and Lactation

Contraindicated.

Special instructions

Renal dysfunction

When using the drug Co-Exforge, it is necessary to regularly monitor creatinine and potassium in the blood plasma.

Cancel beta-blockers

If you need to cancel beta-blockers before the start of therapy with Co-Exforge, the dose of beta-blockers should be reduced gradually. Since the beta-blocker is not included in the composition of Co-Exforge, the use of the drug does not prevent the development of the "withdrawal" syndrome that occurs when the beta-blockers are abruptly discontinued.

A pronounced decrease in blood pressure

In controlled studies with the use of Co-Exforge at the maximum daily dose (10 mg + 320 mg + 25 mg) in patients with grade II and III arterial hypertension, in 1.7% of cases there was a marked decrease in blood pressure, including orthostatic hypotension (compared to 1.8%, 0.4% and 0.2% in combination with valsartan + hydrochlorothiazide at a dose of 320 mg + 25 mg, amlodipine + valsartan at a dose of 10 mg + 320 mg and amlodipine + hydrochlorothiazide at 10 mg + 25 mg, respectively). In the event of arterial hypotension, the patient should be laid with his legs raised, if necessary, hold in / in infusion of 0.9% sodium chloride solution. After stabilization of blood pressure, treatment with Co-Exforge can be continued.

Hyponatremia and / or reduction in BCC

Patients with activated RAAS (for example, with a BCC deficiency and / or hyponatremia, as well as patients receiving high doses of diuretics), while taking angiotensin receptor antagonists, may develop symptomatic arterial hypotension. Before starting treatment with Co-Exforge, the sodium content in the body and / or the BCC should be corrected or therapy should be started under close medical supervision. When using the drug Co-Exforge, it is necessary to regularly monitor the content of electrolytes in the blood plasma.

Change in plasma potassium concentration

In controlled studies, when using the combination amlodipine + valsartan + hydrochlorothiazide in the maximum daily dose of 10 mg + 320 mg + 25 mg in patients with moderate and severe arterial hypertension, the incidence of hypokalemia (plasma content of potassium less than 3.5 mmol / l) was 9.9% compared with 24.5%, 6.6% and 2.7% in combination therapy with amlodipine + hydrochlorothiazide at a dose of 10 mg + 25 mg, valsartan + hydrochlorothiazide at a dose of 320 mg + 25 mg and amlodipine + valsartan at a dose of 10 mg + 320 mg, respectively. The frequency of discontinuation of therapy due to the development of hypokalemia was 0.2% (one patient) in the groups of Co-Exforge and amlodipine + hydrochlorothiazide. In patients treated with Co-Exforge, hyperkalemia (potassium content in the blood plasma of more than 5.7 mmol / l) was observed in 0.4% of cases (compared with 0.2-0.7% against the background of the use of double combinations). With the use of Co-Exforge in a controlled study, the mutually opposite effects of valsartan at a dose of 320 mg / day and hydrochlorothiazide at a dose of 25 mg / day on serum potassium almost completely balanced each other in many patients. In other cases, patients had either hypo- or hyperkalemia. When using the drug Co-Exforge, it is necessary to regularly monitor the content of potassium in the blood plasma.

Systemic lupus erythematosus

With the use of thiazide diuretics, including hydrochlorothiazide, it has been reported that the course or the development of systemic lupus erythematosus is exacerbated.

Other metabolic disorders

Thiazide diuretics can impair glucose tolerance and increase plasma concentrations of cholesterol, triglycerides, and uric acid.

When using thiazide diuretics, calcium excretion may be reduced, leading to the development of moderate hypercalcemia. Severe hypercalcemia during therapy with Co-Exforge may indicate latent hyperparathyroidism.

Influence on ability to drive motor transport and control mechanisms

Some side effects of the drug, incl. dizziness or visual impairment, may adversely affect the ability to drive vehicles and perform potentially hazardous activities that require increased concentration of attention and speed of psychomotor reactions.

Overdosage

Data on cases of overdose of the drug is currently not available.

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. It was also reported about the occurrence of a pronounced and prolonged decrease in blood pressure up to the development of a fatal shock.

The main clinical manifestations of hydrochlorothiazide overdose are symptoms associated with the loss of electrolytes (hypokalemia, hypochloremia) and dehydration due to stimulation of diuresis. The most common symptoms of an overdose are nausea and drowsiness. Hypokalemia may be accompanied by muscle spasms. With the concomitant use of cardiac glycosides (or other antiarrhythmic drugs), hypokalemia can increase cardiac arrhythmia.

Treatment: in case of accidental overdose, induce vomiting (if the drug has been taken recently) or gastric lavage. The use of activated carbon in healthy volunteers immediately or 2 hours after taking amlodipine significantly reduced its absorption. With a marked decrease in the patient's blood pressure, the patient should be laid with raised legs, and active measures should be taken to increase blood pressure, maintain the activity of the cardiovascular system, including regular monitoring of the function of the heart and respiratory system, BCC and the amount of urine released. In the absence of contraindications to restore vascular tone and blood pressure, it is possible to use (with caution) a vasoconstrictor. In / in the introduction of solutions of calcium salts can be effective to eliminate blockade of calcium channels. Removal of valsartan and amlodipine during hemodialysis is unlikely. Hydrochlorothiazide can be removed from the systemic circulation by hemodialysis.

  • Brand name: Co-exforge
  • Active ingredient: Amlodipine, Valsartan, Hydrochlorothiazide
  • Dosage form: Pills.
  • Manufacturer: Novartis
  • Country of Origin: Switzerland

Studies and clinical trials of Amlodipine, Valsartan, Hydrochlorothiazide (Click to expand)

  1. Effects of valsartan/ hydrochlorothiazide and amlodipine on ambulatory blood pressure and plasma norepinephrine levels in high-risk hypertensive patients
  2. Amlodipine/valsartan/hydrochlorothiazide triple combination therapy in moderate/severe hypertension: Secondary analyses evaluating efficacy and safety
  3. Lack of pharmacokinetic interactions of aliskiren, a novel direct renin inhibitor for the treatment of hypertension, with the antihypertensives amlodipine, valsartan, hydrochlorothiazide (HCTZ) and ramipril in healthy volunteers
  4. Fixed-dose valsartan + hydrochlorothiazide combination therapy compared with amlodipine monotherapy in hypertensive patients with additional cardiovascular risk factors: The vast study
  5. Efficacy and tolerability of combination therapy with valsartan plus hydrochlorothiazide compared with amlodipine monotherapy in hypertensive patients with other cardiovascular risk factors: The VAST study
  6. Tolerability and blood pressure-lowering efficacy of the combination of amlodipine plus valsartan compared with lisinopril plus hydrochlorothiazide in adult patients with stage 2 hypertension
  7. Efficacy and tolerability of the valsartan+hydrochlorothiazide combination therapy in the treatment of stage I and II essential hypertension: comparison with amlodipine monotherapy
  8. Moderate versus intensive treatment of hypertension using amlodipine/valsartan and with the addition of hydrochlorothiazide for patients uncontrolled on angiotensin receptor blocker monotherapy: results in racial/ethnic subgroups
  9. Comparison of the Efficacy and Safety Profiles of Two Fixed-Dose Combinations of Antihypertensive Agents, Amlodipine/Benazepril Versus Valsartan/Hydrochlorothiazide, in Patients With Type 2 Diabetes Mellitus and Hypertension: A 16-Week, Multicenter, Randomized, Double-Blind, Noninferiority Study
  10. PCV58 The Cost Effectiveness of Amlodipine Valsartan and Hydrochlorothiazide Single Pill Combination in Turkey
  11. PCV44 Economic Evaluation of a Single-Pill Triple Combination With Valsartan, Amlodipine and Hydrochlorothiazide Against Its Dual Components in Greece. The Generic Substitution Case
  12. PCV53 Economic Evaluation of a Single Pill Triple Antihypertensive Therapy With Valsartan, Amlodipine, and Hydrochlorothiazide Against Its Dual Components in Greece
  13. Simple RP-HPLC method for determination of triple drug combination of valsartan, amlodipine and hydrochlorothiazide in human plasma
  14. Comparative study between derivative spectrophotometry and multivariate calibration as analytical tools applied for the simultaneous quantitation of Amlodipine, Valsartan and Hydrochlorothiazide
  15. QUANTITATIVE SIMULTANEOUS DETERMINATION OF AMLODIPINE, VALSARTAN, AND HYDROCHLOROTHIAZIDE IN “EXFORGE HCT” TABLETS USING HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY AND HIGH-PERFORMANCE THIN-LAYER CHROMATOGRAPHY
  16. GRADIENT HPLC-DAD DETERMINATION OF THE ANTIHYPERTENSIVE MIXTURE OF AMLODIPINE BESYLATE, VALSARTAN, AND HYDROCHLOROTHIAZIDE IN COMBINED PHARMACEUTICAL TABLETS
  17. DEVELOPMENT AND VALIDATION OF AN HPLC METHOD FOR THE SIMULTANEOUS DETERMINATION OF AMLODIPINE, HYDROCHLOROTHIAZIDE, AND VALSARTAN IN TABLETS OF THEIR NOVEL TRIPLE COMBINATION AND BINARY PHARMACEUTICAL ASSOCIATIONS
  18. Effects of valsartan or ramipril addition to amlodipine/hydrochlorothiazide combination on left ventricular mass in diabetic hypertensive patients with left ventricular hypertrophy
  19. Validated RP-HPLC method for the simultaneous determination of amlodipine besylate, valsartan, and hydrochlorothiazide in bulk and in pharmaceutical formulation
  20. Validated stability-indicating HPLC-DAD method of analysis for the antihypertensive triple mixture of amlodipine besylate, valsartan and hydrochlorothiazide in their tablets
  21. Valsartan ± hydrochlorothiazide equally as effective as amlodipine in hypertension

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