Treatment of essential hypertension in adults. Diozad is fixed-dose combination. It is indicated in patients whose blood pressure is not adequately controlled on valsartan or hydrochlorothiazide monotherapy

The recommended dose of Diozad 80/12.5mg or 160/12.5mg 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. The clinical response to Diozad 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 Diozad 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 of treatment may be required. This should be taken into account during dose-titration

Method of administration Diozad 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 (Glomerular Filtration Rate (GFR) ≥ 30 ml/min). Due to the hydrochlorothiazide component, Diozad is contraindicated in patients with severe renal impairment (GFR < 30 mL/min) and anuria. Hepatic impairment In patients with mild to moderate hepatic impairment without cholestasis the dose of valsartan should not exceed 80 mg. No adjustment of the hydrochlorothiazide dose is required for patients with mild to moderate hepatic impairment. Due to the valsartan component, Diozad is contraindicated in patients with severe hepatic impairment or with biliary cirrhosis and cholestasis. Older People No dose adjustment is required in elderly patients. Paediatric patients Diozad is not recommended for use in children below the age of 18 years due to a lack of data on safety and efficacy.

 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 may occur under treatment with thiazide diuretics, including hydrochlorothiazide. Frequent monitoring of serum potassium is recommended. Treatment with thiazide diuretics, including hydrochlorothiazide may occur 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 Diozad. Sodium and/or volume depletion should be corrected before starting treatment with Diozad. 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 reninangiotensin-aldosterone system (e.g. patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors may occur with oliguria and/or progressive azotaemia, and in rare cases with acute renal failure and/or death. Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renal function. The use of Diozad in patients with severe chronic heart failure has not been established. Hence it cannot be excluded that because of the inhibition of the reninangiotensin-aldosterone system the application of Diozad as well may be associated with impairment of the renal function. Diozad should not be used in these patients. Renal artery stenosis Diozad 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 Diozad 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. Periodic monitoring of serum potassium, creatinine and uric acid levels is recommended when Diozad is used in patients with renal impairment. Kidney transplantation There is currently no experience on the safe use of Diozad in patients who have recently undergone kidney transplantation. Hepatic impairment In patients with mild to moderate hepatic impairment without cholestasis, Diozad should be used with caution. Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. History of angioedema Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue may occur in patients treated with valsartan; some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Diozad should be immediately discontinued in patients who develop angioedema, and Diozad should not be re-administered.

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. 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 . 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. Acute Angle-Closure Glaucoma Hydrochlorothiazide, a sulfonamide, may occur with an idiosyncratic reaction resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to week of a drug initiation. Untreated acute-angle closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatment may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle closure glaucoma may include a history of sulfonamide or penicillin allergy. Dual Blockade of the Renin-Angiotensin-Aldosterone System (RAAS) The concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia, and decreased renal function (including acute renal failure). Dual blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended. If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy
 

 Interactions related to both Diozad 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 Diozad may increase the effects of other agents with antihypertensive properties (e.g. guanethidine, methyldopa, vasodilators, ACEI, ARBs, beta-blockers, calcium channel blockers and DRIs).

Pressor amines (e.g. noradrenaline, adrenaline) Possible decreased response to pressor amines. The clinical significance of this effect is uncertain and 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 Diozad 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 Dual blockade of the Renin-Angiotensin-System (RAS) with ARBs, ACEIs, or aliskiren Dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of s single RAAS-acting agent. 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. Transporters In vitro data indicates that valsartan is a substrate of the hepatic uptake transporter OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical relevance of this finding is unknown. Co-administration of inhibitors of the uptake transporter (eg. rifampin, ciclosporin) or efflux transporter (eg. ritonavir) may increase the systemic exposure to valsartan. Exercise appropriate care when initiating or ending concomitant treatment with such drugs. 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 Valsartan . Interactions related to hydrochlorothiazide Concomitant use requiring caution Medicinal products affecting serum potassium level The hypokalaemic effect of hydrochlorothiazide may be increased by concomitant administration of kaliuretic diuretics, corticosteroids, laxatives, ACTH, amphotericin, carbenoxolone, penicillin G, salicylic acid and derivatives. If these medicinal products are to be prescribed with the hydrochlorothiazidevalsartan combination, monitoring of potassium plasma levels is advised. Medicinal products that could induce torsades de pointes Due to the risk of hypokalaemia, hydrochlorothiazide should be administered with caution when associated with medicinal products that could induce torsades de pointes, in particular Class Ia and Class III antiarrhythmics and some antipsychotics. Medicinal products affecting serum sodium level The hyponatraemic effect of diuretics may be intensified by concomitant administration of drugs such as antidepressants, antipsychotics, antiepileptics, etc. Caution is advised in long-term administration of these drugs. Digitalis glycosides Thiazide-induced hypokalaemia or hypomagnesaemia may occur as undesirable 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. Concomitant use of thiazide type diuretics with calcium salts may cause hypercalcaemia in patients pre-disposed for hypercalcaemia (e.g. hyperparathyroidism, malignancy or vitamin-D-mediated conditions) by increasing tubular calcium reabsorption. Antidiabetic agents (oral agents and insulin) Thiazides may alter 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 and other medicinal products affecting gastric motility The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g. atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate. Conversely, it is anticipated that prokinetic drugs such as cisapride may decrease the bioavailability of thiazidetype diuretics. Amantadine Thiazides, including hydrochlorothiazide, may increase the risk of adverse effects caused by amantadine. Ion exchange resins Absorption of thiazide diuretics, including hydrochlorothiazide, is decreased by cholestyramine or colestipol. This could result in sub-therapeutic effects of thiazide diuretics. However, staggering the dosage of hydrochlorothiazide and resin such that hydrochlorothiazide is administered at least 4 h before or 4-6 h after the administration of resins would potentially minimise the interaction. Cytotoxic agents 

Thiazides, including hydrochlorothiazide, may reduce renal excretion of cytotoxic agents (e.g. cyclophosamide, methotrexate) and potentiate their myelosuppressive effects. Non-depolarising skeletal muscle relaxants (e.g. tubocurarine) Thiazides, including hydrochlorothiazide, potentiate the action of skeletal muscle relaxants such as curare derivatives. Ciclosporin Concomitant treatment with ciclosporin may increase the risk of hyperuricaemia and gout-type complications. Alcohol, barbiturates or narcotics Concomitant administration of thiazide diuretics with substances that also have a blood pressure lowering effect (e.g. by reducing sympathetic central nervous system activity or direct vasodilatation activity) may potentiate orthostatic hypotension. Methyldopa There have been isolated reports of haemolytic anaemia in patients receiving concomitant treatment with methyldopa and hydrochlorothiazide. 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.

Pregnancy: Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Diozad as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Diozad, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Diozad for hypotension, oliguria, and hyperkalemia. Hydrochlorothiazide Thiazides can cross the placenta, and concentrations reached in the umbilical vein approach those in the maternal plasma. Hydrochlorothiazide, like other diuretics, can cause placental hypoperfusion. It accumulates in theamniotic fluid, with reported concentrations up to 19 times higher than in umbilical vein plasma. Use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice or thrombocytopenia. Since they do not prevent or alter the course of EPH (Edema, Proteinuria, Hypertension) gestosis (pre-eclampsia), these drugs should not be used to treat hypertension in pregnant women. The use of hydrochlorothiazide for other indications (e.g. heart disease) in pregnancy should be avoided. Lactation: It is not known whether valsartan is excreted in human milk. Valsartan was excreted into the milk of lactating rats; however, animal breast milk drug levels may not accurately reflect human breast milk levels. Hydrochlorothiazide is excreted in human breast milk. Because many drugs are excreted into human milk and because of the potential for adverse reactions in nursing infants from Diozad, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

No studies on the effect of Diozad, 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.

The following listing of undesirable effects is classified as: very common (>1/10); common (>1/100, 1/1,000, 1/10,000, <1/1,000); very rare (<1/10,000), including isolated cases. 

Frequency of adverse reactions with valsartan/hydrochlorothiazide

- Metabolism and nutrition disorders : Uncommon Dehydration 

- Nervous system disorders : 

Very rare Dizziness,  

Uncommon Paraesthesia , 

Not known Syncope 

- Eye disorders

Uncommon Vision blurred 

- Ear and labyrinth disorders

Uncommon Tinnitus

- Vascular disorders

Uncommon Hypotension Respiratory, 

- thoracic and mediastinal disorders 

Uncommon Cough

Not known :  Non cardiogenic pulmonary oedema 

- Gastrointestinal disorders 

Very rare : Diarrhoea 

- Musculoskeletal and connective tissue disorders 

Uncommon :  Myalgia 

Very rare : Arthralgia 

- Renal and urinary disorders 

Not known : Impaired renal function 

- General disorders and administration site conditions 

Uncommon : Fatigue 

- Investigations 

Not known : Serum uric acid increased, Serum bilirubin and Serum creatinine increased, Hypokalaemia, Hyponatraemia, Elevation of Blood Urea Nitrogen, Neutropenia

Frequency of adverse reactions with valsartan

- Blood and lymphatic system disorders

Not known : Decrease in haemoglobin, decrease in haematocrit, thrombocytopenia 

- Immune system disorders 

Not known : Other hypersensitivity/allergic reactions including serum sickness

- Metabolism and nutrition disorders 

Not known : Increase of serum potassium,

- hyponatraemia Ear and labyrinth disorders

Uncommon: Vertigo

- Vascular disorders

Not known: Vasculitis

Gastrointestinal disorders 

Uncommon : Abdominal pain 

- Hepatobiliary disorders 

Not known: Elevation of liver function values 

- Skin and subcutaneous tissue disorders

Not known:  Angioedema, rash, pruritus

- Renal and urinary disorders

Not known : Renal failure

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.
 

Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Valsartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis. There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Valsartan has much greater affinity (about 20,000-fold) for the AT1 receptor than for the AT2 receptor. The primary metabolite of valsartan is essentially inactive with an affinity for the AT1 receptor about one 200th that of valsartan itself. Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because valsartan does not inhibit ACE (kininase II) it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. 

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of valsartan on blood pressure. Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so co administration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics. The mechanism of the antihypertensive effect of thiazides is unknown.

Valsartan: Valsartan peak plasma concentration is reached 2 to 4 hours after dosing. Valsartan shows bi-exponential decay kinetics following intravenous administration, with an average elimination half-life of about 6 hours. Absolute bioavailability for the capsule formulation is about 25% (range 10%-35%). Food decreases the exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (Cmax) by about 50%. AUC and Cmax values of valsartan increase approximately linearly with increasing dose over the clinical dosing range. Valsartan does not accumulate appreciably in plasma following repeated administration. Hydrochlorothiazide: The estimated absolute bioavailability of hydrochlorothiazide after oral administration is about 70%. Peak plasma hydrochlorothiazide concentrations (Cmax) are reached within 2 to 5 hours after oral administration. There is no clinically significant effect of food on the bioavailability of hydrochlorothiazide. Hydrochlorothiazide binds to albumin (40 to 70%) and distributes into erythrocytes. Following oral administration, plasma hydrochlorothiazide concentrations decline bi-exponentially, with a mean distribution half-life of about 2 hours and an elimination half-life of about 10 hours.

Distribution Valsartan: The steady state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (95%), mainly serum albumin. Metabolism Valsartan: The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinantCYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and co-administered drugs are unlikely because of the low extent of metabolism. Hydrochlorothiazide: Is not metabolized. Excretion Valsartan: Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites. Following intravenous administration, plasma clearance of valsartan is about 2 L/h and its renal clearance is 0.62 L/h (about 30% of total clearance). Hydrochlorothiazide: About 70% of an orally administered dose of hydrochlorothiazide is eliminated in the urine as unchanged drug.
 

Valsartan-Hydrochlorothiazide: No carcinogenicity, mutagenicity or fertility studies have been conducted with the combination of Diozad. However, these studies have been conducted for valsartan as well as hydrochlorothiazide alone. Based on the preclinical safety and human pharmacokinetic studies, there is no indication of any adverse interaction between Diozad. Valsartan: There was no evidence of carcinogenicity when valsartan was administered in the diet to mice and rats for up to 2 years at doses up to 160 and 200 mg/kg/day, respectively. These doses in mice and rats are about 2.6 and 6 times, respectively, the maximum recommended human dose on a mg/m² basis. (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.) Mutagenicity assays did not reveal any valsartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests withSalmonella (Ames) and E. coli; a gene mutation test with Chinese hamster V79 cells; a cytogenetic test with Chinese hamster ovary cells; and a rat micronucleus test. Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day. This dose is about 6 times the maximum recommended human dose on a mg/m² basis. (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.) Hydrochlorothiazide: Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella Typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1300 mcgm/mL, and in the Aspergillus Nidulans non-disjunction assay at an unspecified concentration. Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation. These doses of hydrochlorothiazide in mice and rats represent 19 and 1.5 times, respectively, the maximum recommended human dose on a mg/m² basis. (Calculations assume an oral dose of 25 mg/day and a 60-kg patient.)
 

Microcrystalline Cellulose, Crospovidone, Colloidal silicon dioxide, Magnesium stearate, Opadry Pink (80/12.5 mg and 320/25 mg), Opadry Brown (160/12.5 mg, 160/25 mg), Opadry Yellow (320/12.5) and Purified water.
 

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Store below 30 C. Store in the original carton in order to protect from light

Round white PVC, Alu BLISTER Container.

No special requirements.