1. Name Of The Medicinal Product
Co-Diovan® 80/12.5 mg film-coated tablets.
Co-Diovan® 160/12.5 mg film-coated tablets.
Co-Diovan® 160/25 mg film-coated tablets.
2. Qualitative And Quantitative Composition
Co-Diovan 80/12.5 mg Tablets: Each tablet contains 80mg valsartan and 12.5mg hydrochlorothiazide.
Co-Diovan 160/12.5 mg Tablets: Each tablet contains 160mg valsartan and 12.5mg hydrochlorothiazide.
Co-Diovan 160/25 mg Tablets: Each tablet contains 160mg valsartan and 25mg hydrochlorothiazide.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Co-Diovan 80/12.5 mg Tablets:
Oval, non-divisible, film-coated tablets measuring approx. 10.2 to 5.4mm in diameter and 3.7mm in thickness, and weighing approx. 156mg. The tablets are coloured light orange and imprinted with HGH on one side and CG on the other side.
Co-Diovan 160/12.5 mg Tablets:
Oval, non-divisible, film-coated tablets measuring approximately 15.2 mm by 6.2 mm and 4.4 mm in thickness, and weighing approximately 312 mg. The tablets are coloured dark red and imprinted with HHH on one side and CG on the other side.
Co-Diovan 160/25 mg Tablets:
Oval, non-divisible, film-coated tablets measuring approximately 14.2 mm by 5.7 mm and 4.5 mm in thickness, and weighing approximately 310 mg. The tablets are coloured brown orange and imprinted with HXH on one side and NVR on the other side.
4. Clinical Particulars
4.1 Therapeutic Indications
Treatment of essential hypertension in adults.
Co-Diovan fixed-dose combination is indicated in patients whose blood pressure is not adequately controlled on valsartan or hydrochlorothiazide monotherapy.
4.2 Posology And Method Of Administration
Posology
The recommended dose of Co-Diovan 80/12.5mg or 160/12.5mg or 160/25mg is one film-coated tablet once daily. Dose titration with the individual components is recommended. In each case, up- titration of individual components to the next dose should be followed in order to reduce the risk of hypotension and other adverse events.
When clinically appropriate direct change from monotherapy to the fixed combination may be considered in patients whose blood pressure is not adequately controlled on valsartan or hydrochlorothiazide monotherapy, provided the recommended dose titration sequence for the individual components is followed.
The clinical response to Co-Diovan should be evaluated after initiating therapy and if blood pressure remains uncontrolled, the dose may be increased by increasing either one of the components to a maximum dose of Co-Diovan 320 mg/25 mg.
The antihypertensive effect is substantially present within 2 weeks.
In most patients, maximal effects are observed within 4 weeks. However, in some patients, 4-8 weeks treatment may be required. This should be taken into account during dose-titration.
Method of administration
Co-Diovan can be taken with or without food and should be administered with water.
Special populations
Renal Impairment
No dose adjustment is required for patients with mild to moderate renal impairment (creatinine clearance >30ml/min). Due to the hydrochlorothiazide component, Co-Diovan is contraindicated in patients with severe renal impairment (see sections 4.3, 4.4 and 5.2).
Hepatic Impairment
In patients with mild to moderate hepatic impairment without cholestasis the dose of valsartan should not exceed 80 mg (see section 4.4). Co-Diovan is contraindicated in patients with severe hepatic impairment (see sections 4.3, 4.4 and 5.2).
Elderly
No dose adjustment is required in elderly patients.
Paediatric patients
Co-Diovan is not recommended for use in children below the age of 18 years due to a lack of data on safety and efficacy.
4.3 Contraindications
- Hypersensitivity to valsartan, hydrochlorothiazide, other sulfonamide-derived medicinal products or to any of the excipients.
- Second and third trimester of pregnancy (section 4.4 and 4.6).
- Severe hepatic impairment, biliary cirrhosis and cholestasis.
- Severe renal impairment (creatinine clearance <30 ml/min), anuria.
- Refractory hypokalaemia, hyponatraemia, hypercalcaemia, and symptomatic hyperuricaemia.
4.4 Special Warnings And Precautions For Use
Serum electrolyte changes
Valsartan
Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other agents that may increase potassium levels (heparin, etc.) is not recommended. Monitoring of potassium should be undertaken as appropriate.
Hydrochlorothiazide
Hypokalaemia has been reported under treatment with thiazide diuretics, including hydrochlorothiazide. Frequent monitoring of serum potassium is recommended.
Treatment with thiazide diuretics, including hydrochlorothiazide has been associated with hyponatraemia and hypochloraemic alkalosis. Thiazides, including hydrochlorothiazide increase the urinary excretion of magnesium, which may result in hypomagnesaemia. Calcium excretion is decreased by thiazide diuretics. This may result in hypercalcaemia.
As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.
Sodium, and/or volume-depleted patients
Patients receiving thiazide diuretics, including hydrochlorothiazide, should be observed for clinical signs of fluid or electrolyte imbalance.
In severely sodium-depleted and/or volume-depleted patients, such as those receiving high doses of diuretics, symptomatic hypotension may occur in rare cases after initiation of therapy with Co-Diovan. Sodium and/or volume depletion should be corrected before starting treatment with Co-Diovan.
Patients with severe chronic heart failure or other conditions with stimulation of the renin-angiotensin-aldosterone-system
In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors has been associated with oliguria and/or progressive azotaemia, and in rare cases with acute renal failure. The use of Co-Diovan in patients with severe chronic heart failure has not been established.
Hence it cannot be excluded that because of the inhibition of the renin-angiotensin-aldosterone system the application of Co-Diovan as well may be associated with impairment of the renal function. Co-Diovan should not be used in these patients.
Renal artery stenosis
Co-Diovan should not be used to treat hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, since blood urea and serum creatinine may increase in such patients.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism should not be treated with Co-Diovan as their renin-angiotensin system is not activated.
Aortic and mitral valve stenosis, hypertrophic obstructive cardiomyopathy
As with all other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or hypertrophic obstructive cardiomyopathy (HOCM).
Renal impairment
No dosage adjustment is required for patients with renal impairment with a creatinine clearance >30 ml/min (see section 4.2). Periodic monitoring of serum potassium, creatinine and uric acid levels is recommended when Co-Diovan is used in patients with renal impairment.
Kidney transplantation
There is currently no experience on the safe use of Co-Diovan in patients who have recently undergone kidney transplantation.
Hepatic impairment
In patients with mild to moderate hepatic impairment without cholestasis, Co-Diovan should be used with caution (see sections 4.2 and 5.2).
Systemic lupus erythematosus
Thiazide diuretics, including hydrochlorothiazide, have been reported to exacerbate or activate systemic lupus erythematosus.
Other metabolic disturbances
Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance and raise serum levels of cholesterol, triglycerides and uric acid. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic agents may be required.
Thiazides may reduce urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia may be evidence of underlying hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.
Photosensitivity
Cases of photosensitivity reactions have been reported with thiazides diuretics (see section 4.8). If photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.
Pregnancy
Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRAs therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
General
Caution should be exercised in patients who have shown prior hypersensitivity to other angiotensin II receptor antagonists. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergy and asthma.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Interactions related to both valsartan and hydrochlorothiazide
Concomitant use not recommended
Lithium
Reversible increases in serum lithium concentrations and toxicity have been reported during concurrent use of ACE inhibitors and thiazide, including hydrochlorothiazide. Due to the lack of experience with concomitant use of valsartan and lithium, this combination is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended.
Concomitant use requiring caution
Other antihypertensive agents
Co-Diovan may increase the effects of other agents with antihypertensive properties (e.g ACEI, beta-blockers, calcium channel blockers).
Pressor amines (e.g. noradrenaline, adrenaline)
Possible decreased response to pressor amines but not sufficient to preclude their use.
Non-steroidal anti-inflammatory medicines (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid>3 g/day), and non-selective NSAIDs
NSAIDS can attenuate the antihypertensive effect of both angiotensin II antagonists and hydrochlorothiazide when administered simultaneously. Furthermore, concomitant use of Co-Diovan and NSAIDs may lead to worsening of renal function and an increase in serum potassium. Therefore, monitoring of renal function at the beginning of the treatment is recommended, as well as adequate hydration of the patient.
Interactions related to valsartan
Concomitant use not recommended
Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium and other substances that may increase potassium levels
If a medicinal product that affects potassium levels is considered necessary in combination with valsartan, monitoring of potassium plasma levels is advised.
No interaction
In drug interaction studies with valsartan, no interactions of clinical significance have been found with valsartan or any of the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide. Digoxin and indomethacin could interact with the hydrochlorothiazide component of Co-Diovan (see interactions related to hydrochlorothiazide).
Interactions related to hydrochlorothiazide
Concomitant use requiring caution
Medicinal products associated with potassium loss and hypokalaemia (e.g. kaliuretic diuretics, corticosteroids, laxatives, ACTH, amphotericin, carbenoxolone, penicillin G, salicylic acid and derivatives).
If these medicinal products are to be prescribed with the hydrochlorothiazide-valsartan combination, monitoring of potassium plasma levels is advised. These medicinal products may potentiate the effect of hydrochlorothiazide on serum potassium (see section 4.4).
Medicinal products that could induce torsades de pointes
• Class Ia antiarrhythmics (e.g. quinidine, hydroquinidine, disopyramide)
• Class III antiarrhythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide)
• Some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol)
• Others (e.g. bepridil, cisapride, diphemanil, erythromycin i.v., halofantrin, ketanserin, mizolastin, pentamidine, sparfloxacine, terfenadine, vincamine i.v.)
Due to the risk of hypokalemia, hydrochlorothiazide should be administered with caution when associated with medicinal products that could induce torsades de pointes.
Digitalis glycosides
Thiazide-induced hypokalaemia or hypomagnesaemia may occur as unwanted effects favouring the onset of digitalis-induced cardiac arrhythmias.
Calcium salts and vitamin D
Administration of thiazide diuretics, including hydrochlorothiazide, with vitamin D or with calcium salts may potentiate the rise in serum calcium.
Antidiabetic agents (oral agents and insulin)
The treatment with a thiazide may influence the glucose tolerance. Dose adjustment of the antidiabetic medicinal product may be necessary.
Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to hydrochlorothiazide.
Beta blockers and diazoxide
Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta blockers may increase the risk of hyperglycaemia. Thiazide diuretics, including hydrochlorothiazide, may enhance the hyperglycaemic effect of diazoxide.
Medicinal products used in the treatment of gout (probenecid, sulfinpyrazone and allopurinol)
Dose adjustment of uricosuric medications may be necessary as hydrochlorothiazide may raise the level of serum uric acid. Increase of dosage of probenecid or sulfinpyrazone may be necessary. Co-administration of thiazide diuretics, including hydrochlorothiazide, may increase the incidence of hypersensitivity reactions to allopurinol.
Anticholinergic agents (e.g. atropine, biperiden)
The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents, apparently due to a decrease in gastrointestinal motility and the stomach emptying rate.
Amantadine
Thiazides, including hydrochlorothiazide, may increase the risk of adverse effects caused by amantadine
Cholestyramine and cholestipol resins
Absorption of thiazide diuretics, including hydrochlorothiazide is impaired in the presence of anionic exchange resins.
Cytotoxic agents (e.g. cyclophosamide, methotrexate)
Thiazides, including hydrochlorothiazide, may reduce renal excretion of cytotoxic agents and potentiate their myelosuppressive effects.
Non-depolarising skeletal muscle relaxants (e.g. tubocurarine)
Thiazides, including hydrochlorothiazide, potentiate the action of curare derivatives.
Ciclosporin
Concomitant treatment with cyclosporin may increase the risk of hyperuricaemia and gout-type complications.
Alcohol, anaesthetics and sedatives
Potentiation of orthostatic hypotension may occur.
Methyldopa
There have been isolated reports of haemolytic anaemia in patients receiving concomitant treatment with methyldopa and hydrochlorothiazide.
Carbamazepine
Patients receiving hydrochlorothiazide concomitantly with carbamazepine may develop hyponatremia. Such patients should therefore be advised about the possibility of hyponatraemic reactions, and should be monitored accordingly.
Iodine contrast media
In case of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high doses of the iodine product. Patients should be rehydrated before the administration.
4.6 Pregnancy And Lactation
Pregnancy
Valsartan
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Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II Receptor Inhibitors (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRAs therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately and, if appropriate, alternative therapy should be started.
AIIRAs therapy exposure during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see also section 5.3).
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see also section 4.3 and 4.4).
Hydrochlorothiazide
There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.
Lactation
No information is available regarding the use of valsartan during breastfeeding. Hydrochlorothiazide is excreted in human milk. Therefore the use of Co-Diovan during breast feeding is not recommended. Alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effect of Co-Diovan, on the ability to drive and use machines have been performed. When driving vehicles or operating machines it should be taken into account that occasionally dizziness or weariness may occur.
4.8 Undesirable Effects
Adverse reactions reported in clinical trials and laboratory findings occurring more frequently with valsartan plus hydrochlorothiazide versus placebo and individual postmarketing reports are presented below according to system organ class. Adverse reactions known to occur with each component given individually but which have not been seen in clinical trials may occur during treatment with valsartan/ hydrochlorothiazide.
Adverse drug reactions are ranked by frequency, the most frequent first, using the following convention: very common (< 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.
Table 1. Frequency of adverse reactions with valsartan/hydrochlorothiazide
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Additional information on the individual components
Adverse reactions previously reported with one of the individual components may be potential undesirable effects with Co-Diovan as well, even if not observed in clinical trials or during postmarketing period.
Table 2. Frequency of adverse reactions with valsartan
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Table 3. Frequency of adverse reactions with hydrocholothiazide
Hydrochlorothiazide has been extensively prescribed for many years, frequently in higher doses than those administered with Co-Diovan. The following adverse reactions have been reported in patients treated with monotherapy of thiazide diuretics, including hydrochlorothiazide:
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4.9 Overdose
Symptoms
Overdose with valsartan may result in marked hypotension, which could lead to depressed level of consciousness, circulatory collapse and/or shock. In addition, the following signs and symptoms may occur due to an overdose of the hydrochlorothiazide component: nausea, somnolence, hypovolaemia, and electrolyte disturbances associated with cardiac arrhythmias and muscle spasms.
Treatment
The therapeutic measures depend on the time of ingestion and the type and severity of the symptoms, stabilisation of the circulatory condition being of prime importance.
If hypotension occurs, the patient should be placed in the supine position and salt and volume supplementation should be given rapidly.
Valsartan cannot be eliminated by means of haemodialysis because of its strong plasma binding behaviour whereas clearance of hydrochlorothiazide will be achieved by dialysis.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Angiotensin II antagonists and diuretics, valsartan and diuretics; ATC Code: C09D A03
Valsartan/hydrochlorothiazide
In a double-blind, randomised, active-controlled trial in patients not adequately controlled on hydrochlorothiazide 12.5 mg, significantly greater mean systolic/diastolic BP reductions were observed with the combination of valsartan/hydrochlorothiazide 80/12.5 mg (14.9/11.3 mmHg) compared to hydrochlorothiazide 12.5 mg (5.2/2.9 mmHg) and hydrochlorothiazide 25 mg (6.8/5.7 mmHg). In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction
In a double-blind, randomised, active-controlled trial in patients not adequately controlled on valsartan 80 mg, significantly greater mean systolic/diastolic BP reductions were observed with the combination of valsartan/hydrochlorothiazide 80/12.5 mg (9.8/8.2 mmHg) compared to valsartan 80 mg (3.9/5.1 mmHg) and valsartan 160 mg (6.5/6.2 mmHg). In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction
In a double-blind, randomised, placebo-controlled, factorial design trial comparing various dose combinations of valsartan/hydrochlorothiazide to their respective components, significantly greater mean systolic/diastolic BP reductions were observed with the combination of valsartan/hydrochlorothiazide 80/12.5 mg (16.5/11.8 mmHg) compared to placebo (1.9/4.1 mmHg) and both hydrochlorothiazide 12.5 mg (7.3/7.2 mmHg) and valsartan 80 mg (8.8/8.6 mmHg). In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction
In a double-blind, randomised, active-controlled trial in patients not adequately controlled on hydrochlorothiazide 12.5 mg, significantly greater mean systolic/diastolic BP reductions were observed with the combination of valsartan/ hydrochlorothiazide 160/12.5 mg (12.4/7.5 mmHg) compared to hydrochlorothiazide 25 mg (5.6/2.1 mmHg). In addition, a significantly greater percentage of patients responded (BP <140/90 mmHg or SBP reduction
In a double-blind, randomised, active-controlled trial in patients not adequately controlled on valsartan 160 mg, significantly greater mean systolic/diastolic BP reductions were observed with both the combination of valsartan/hydrochlorothiazide 160/25 mg (14.6/11.9 mmHg) and valsartan/hydrochlorothiazide 160/12.5 mg (12.4/10.4 mmHg) compared to valsartan 160 mg (8.7/8.8 mmHg). The difference in BP reductions between the 160/25 mg and 160/12.5 mg doses also reached statistical significance. In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction
In a double-blind, randomised, placebo-controlled, factorial design trial comparing various dose combinations of valsartan/hydrochlorothiazide to their respective components, significantly greater mean systolic/diastolic BP reductions were observed with the combination of valsartan/hydrochlorothiazide 160/12.5 mg (17.8/13.5 mmHg) and 160/25 mg (22.5/15.3 mmHg) compared to placebo (1.9/4.1 mmHg) and the respective monotherapies, i.e., hydrochlorothiazide 12.5 mg (7.3/7.2 mmHg), hydrochlorothiazide 25 mg (12.7/9.3 mmHg) and valsartan 160 mg (12.1/9.4 mmHg). In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction
Dose-dependent decreases in serum potassium occurred in controlled clinical studies with valsartan + hydrochlorothiazide. Reduction in serum potassium occurred more frequently in patients given 25 mg hydrochlorothiazide than in those given 12.5 mg hydrochlorothiazide. In controlled clinical trials with valsartan/hydrochlorothiazide the potassium lowering effect of hydrochlorothiazide was attenuated by the potassium-sparing effect of valsartan.
Beneficial effects of valsartan in combination with hydrochlorothiazide on cardiovascular mortality and morbidity are currently unknown.
Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity.
Valsartan
Valsartan is an orally active and specific angiotensin II (Ang II) receptor antagonist. It acts selectively on the AT1 receptor subtype, which is responsible for the known actions of angiotensin II. The increased plasma levels of Ang II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor, which appears to counterbalance the effect of the AT1 receptor. Valsartan does not exhibit any partial agonist activity at the AT1 receptor and has much (about 20,000 fold) greater affinity for the AT1 receptor than for the AT2 receptor. Valsartan is not known to bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Valsartan does not inhibit ACE, also known as kininase II, which converts Ang I to Ang II and degrades bradykinin. Since there is no effect on ACE and no potentiation of bradykinin or substance P, angiotensin II antagonists are unlikely to be associated with coughing. In clinical trials where valsartan was compared with an ACE inhibitor, the incidence of dry cough was significantly (P <0.05) lower in patients treated with valsartan than in those treated with an ACE inhibitor (2.6% versus 7.9% respectively). In a clinical trial of patients with a history of dry cough during ACE inhibitor therapy, 19.5% of trial subjects receiving valsartan and 19.0% of those receiving a thiazide diuretic experienced cough compared to 68.5% of those treated with an ACE inhibitor (P <0.05).
Administration of valsartan to patients with hypertension results in reduction of blood pressure without affecting pulse rate. In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs within 2 hours, and the peak reduction of blood pressure is achieved within 4-6 hours. The antihypertensive effect persists over 24 hours after dosing. During repeated dosing, the maximum reduction in blood pressure with any dose is generally attained within 2-4 weeks and is sustained during long-term therapy. Combined with hydrochlorothiazide, a significant additional reduction in blood pressure is achieved.
Abrupt withdrawal of valsartan has not been associated with rebound hypertension or other adverse clinical events.
In hypertensive patients with type 2 diabetes and microalbuminuria, valsartan has been shown to reduce the urinary excretion of albumin. The MARVAL (Micro Albuminuria Reduction with Valsartan) study assessed the reduction in urinary albumin excretion (UAE) with valsartan (80
Hydrochlorothiazide
The site of action of thiazide diuretics is primarily in the renal distal convoluted tubule. It has been shown that there is a high
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