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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Valsartan/Hydrochlorothiazide 80 mg/12.5 mg Film-coated Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 80 mg valsartan and 12.5 mg hydrochlorothiazide.

Excipients: Each Valsartan/Hydrochlorothiazide 80 mg/12.5 mg Film-coated Tablet contains 29.75 mg lactose monohydrate and 0.25 mg lecithin soya (contains soya oil).

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet

Pink, biconvex, oval, 11 mm x 5.8 mm. Marked ‘V’ on one side and ‘H’ on the other.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of essential hypertension in adults.

Valsartan/Hydrochlorothiazide film-coated tablet 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

The recommended dose of Valsartan/Hydrochlorothiazide 80 mg/12.5 mg Film-coated Tablets 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 Valsartan/Hydrochlorothiazide film-coated tablets 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 Valsartan/Hydrochlorothiazide 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

Valsartan/Hydrochlorothiazide film-coated tablets 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 >    30 ml/min). Due to the

hydrochlorothiazide component, Valsartan/Hydrochlorothiazide Film-coated Tablets are 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). Valsartan/Hydrochlorothiazide film-coated tablets are 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

Valsartan/Hydrochlorothiazide Film-coated Tablets are 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 sulphonamide-derived medicinal products, soya oil, peanut oil 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 valsartan/hydrochlorothiazide. Sodium and/or volume depletion should be corrected before starting treatment with Valsartan/Hydrochlorothiazide Film-coated Tablets.

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 valsartan/hydrochlorothiazide 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

valsartan/hydrochlorothiazide as well may be associated with impairment of the renal function. Valsartan/Hydrochlorothiazide Film-coated Tablets should not be used in these patients.

Renal artery stenosis

Valsartan/Hydrochlorothiazide Film-coated Tablets 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 Valsartan/Hydrochlorothiazide Film-coated Tablets 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 > 30ml/min (see section 4.2). Periodic monitoring of serum potassium, creatinine and uric acid levels is recommended when Valsartan/Hydrochlorothiazide Film-coated Tablets is used in patients with renal impairment.

Kidney transplantation

There is currently no experience on the safe use of valsartan/hydrochlorothiazide in patients who have recently undergone kidney transplantation.

Hepatic impairment

In patients with mild to moderate hepatic impairment without cholestasis, Valsartan/Hydrochlorothiazide Film-coated Tablets 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.

Galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Lecithin soya

If a patient is hypersensitive to peanut or soya, this medicine should not be used.

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

Valsartan/Hydrochlorothiazide Film-coated Tablets 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 valsartan/hydrochlorothiazide 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, indometacin, hydrochlorothiazide, amlodipine, glibenclamide. Digoxin and indometacin could interact with the hydrochlorothiazide component of Valsartan/Hydrochlorothiazide Film-coated Tablets (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 ciclosporin 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 Fertility, Pregnancy and lactation

Pregnancy

Valsartan

The use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during first trimester of pregnancy (see section 4.4).The use of AIIRAs is contra-indicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).

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 Valsartan/Hydrochlorothiazide Film-coated Tablets 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 valsartan/hydrochlorothiazide, 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 (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 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

Metabolism and nutrition disorders

Uncommon

Nervous system disorders

Very rare Uncommon Not known Eye disorders

Uncommon

Ear and labyrinth disorders

Uncommon Vascular disorders

Uncommon

Respiratory, thoracic and mediastinal disorders

Uncommon Not known

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

Additional information on the individual components

Adverse reactions previously reported with one of the individual components may be potential undesirable effects with Valsartan/Hydrochlorothiazide Film-coated Tablets as well, even if not observed in clinical trials or during postmarketing period.

Table 2. 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
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

Table 3. Frequency of adverse reactions with hydrochlorothiazide

Hydrochlorothiazide has been extensively prescribed for many years, frequently in higher doses than those administered with Valsartan/Hydrochlorothiazide Film-coated Tablets. The following adverse reactions have been reported in patients treated with monotherapy of thiazide diuretics, including hydrochlorothiazide:

Blood and lymphatic system disorders

Rare

Very rare

Respiratory, thoracic and mediastinal disorders

Very rare    Respiratory distress including

pneumonitis and pulmonary oedema

Gastrointestinal disorders

Common

Rare Very rare

Hepatobiliary disorders

Rare

Skin and subcutaneous tissue disorders

Common

Rare

Very rare    Necrotising vasculitis and toxic

epidermal necrolysis, cutaneous lupus    erythematosus-like

reactions, reactivation of cutaneous lupus erythematosus

Reproductive system and breast disorders

Impotence

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.

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 ATi receptor subtype, which is responsible for the known actions of angiotensin II. The increased plasma levels of Ang II following ATi receptor blockade with valsartan may stimulate the unblocked AT₂ receptor, which appears to counterbalance the effect of the ATi receptor. Valsartan does not exhibit any partial agonist activity at the ATi 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 9.0% 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 46 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 (80-160 mg/od) versus amlodipine (5-10 mg/od), in 332 type 2 diabetic patients (mean age: 58 years; 265 men) with microalbuminuria (valsartan: 58 pg/min; amlodipine: 55.4 pg/min), normal or high blood pressure and with preserved renal function (blood creatinine <120 pmol/l). At 24 weeks, UAE was reduced (p <0.001) by 42% (-24.2 pg/min; 95% CI: - 40.4 to -19.1) with valsartan and approximately 3% (-1.7 pg/min; 95% CI: -5.6 to 14.9) with amlodipine despite similar rates of blood pressure reduction in both groups. The Diovan Reduction of Proteinuria (DROP) study further examined the efficacy of valsartan in reducing UAE in 391 hypertensive patients (BP=150/88 mmHg) with type 2 diabetes, albuminuria (mean=102 pg/min; 20- 700 pg/min) and preserved renal function (mean serum creatinine = 80 pmol/l). Patients were randomised to one of 3 doses of valsartan (160, 320 and 640 mg/od) and treated for 30 weeks. The purpose of the study was to determine the optimal dose of valsartan for reducing UAE in hypertensive patients with type 2 diabetes. At 30 weeks, the percentage change in UAE was significantly reduced by 36% from baseline with valsartan 160 mg (95%CI: 22 to 47%), and by 44% with valsartan 320 mg (95%CI: 31 to 54%). It was concluded that 160-320 mg of valsartan produced clinically relevant reductions in UAE in hypertensive patients with type 2 diabetes.

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-affinity receptor in the renal cortex as the primary binding site for the thiazide diuretic action and inhibition of NaCl transport in the distal convoluted tubule. The mode of action of thiazides is through inhibition of the Na⁺Cl" symporter perhaps by competing for the Cl" site, thereby affecting electrolyte reabsorption mechanisms: directly increasing sodium and chloride excretion to an approximately equal extent, and indirectly by this diuretic action reducing plasma volume, with consequent increases in plasma renin activity, aldosterone secretion and urinary potassium loss, and a decrease in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so with co-administration of valsartan the reduction in serum potassium is less pronounced as observed under monotherapy with hydrochlorothiazide.

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 >10 mmHg) with

valsartan/hydrochlorothiazide 80/12.5 mg (60    %) compared to

hydrochlorothiazide 12.5 mg (25 %) and hydrochlorothiazide 25 mg (27 %).

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 >10 mmHg) with valsartan/hydrochlorothiazide 80/12.5 mg (51 %) compared to valsartan 80 mg (36 %) and valsartan 160 mg (37 %).

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 >10 mmHg) with valsartan/hydrochlorothiazide 80/12.5 mg (64 %) compared to placebo (29 %) and hydrochlorothiazide (41 %).

5.2 Pharmacokinetic properties

Valsartan/hydrochlorothiazide

The systemic availability of hydrochlorothiazide is reduced by about 30 % when co-administered with valsartan. The kinetics of valsartan are not markedly affected by the co-administration of hydrochlorothiazide. This observed interaction has no impact on the combined use of valsartan and hydrochlorothiazide, since controlled clinical trials have shown a clear antihypertensive effect, greater than that obtained with either active substance given alone, or placebo.

Valsartan

Absorption

Following oral administration of valsartan alone, peak plasma concentrations of valsartan are reached in 2-4 hours. Mean absolute bioavailability is 23 %. Food decreases exposure (as measured by AUC) to valsartan by about 40 % and peak plasma concentration (C_max) by about 50 %, although from about 8 h post dosing plasma valsartan concentrations are similar for the fed and fasted groups. This reduction in AUC is not, however, accompanied by a clinically significant reduction in the therapeutic effect, and valsartan can therefore be given either with or without food.

Distribution

The steady-state volume of distribution of valsartan after intravenous administration is about 17 litres, indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (9497 %), mainly serum albumin.

Biotransformation

Valsartan is not biotransformed to a high extent as only about 20 % of dose is recovered as metabolites. A hydroxy metabolite has been identified in plasma at low concentrations (less than 10 % of the valsartan AUC). This metabolite is pharmacologically inactive.

Elimination

Valsartan shows multiexponential decay kinetics (ti/₂₍₁ <1 h and t_/2e about 9 h). Valsartan is primarily eliminated in faeces (about 83% of dose) and urine (about 13% of dose), mainly as unchanged drug. 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). The half-life of valsartan is 6 hours.

Hydrochlorothiazide

Absorption

The absorption of hydrochlorothiazide, after an oral dose, is rapid (t_max about 2 h), with similar absorption characteristics for both suspension and tablet formulations. Absolute bioavailability of hydrochlorothiazide is 60-80 % after oral administration. Concomitant administration with food has been reported to both increase and decrease the systemic availability of hydrochlorothiazide compared with the fasted state. The magnitude of these effects is small and has minimal clinical importance. The increase in mean AUC is linear and dose proportional in the therapeutic range. There is no change in the kinetics of hydrochlorothiazide on repeated dosing, and accumulation is minimal when dosed once daily.

Distribution

The distribution and elimination kinetics have generally been described by a bi-exponential decay function. The apparent volume of distribution is 4-8 l/kg.

Circulating hydrochlorothiazide is bound to serum proteins (40-70 %), mainly serum albumin. Hydrochlorothiazide also accumulates in erythrocytes at approximately 1.8 times the level in plasma.

For hydrochlorotiazide, >95 % of the absorbed dose being excreted as unchanged compound in the urine. The renal clearance is composed of passive filtration and active secretion into the renal tubule. The terminal half-life is 615 h.

Special _ populations

Elderly

A somewhat higher systemic exposure to valsartan was observed in some elderly subjects than in young subjects; however, this has not been shown to have any clinical significance.

Limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers.

Renal impairment

At the recommended dose of Valsartan/Hydrochlorothiazide Film-coated tablets no dose adjustment is required for patients with a creatinine clearance of 30-70mL/min.

In patients with severe renal impairment (creatinine clearance <30mL/min) and patients undergoing dialysis, no data are available for Valsartan/Hydrochlorothiazide Film-coated Tablets. Valsartan is highly bound to plasma protein and is not to be removed by dialysis, whereas clearance of hydrochlorothiazide will be achieved by dialysis.

Renal clearance of hydrochlorothiazide is composed of passive filtration and active secretion into the renal tubule. As expected for a compound which is cleared almost exclusively via the kidneys, renal function has a marked effect on the kinetics of hydrochlorothiazide (see Section 4.3).

Hepatic impairment

In a pharmacokinetics trial in patients with mild (n=6) to moderate (n=5) hepatic dysfunction, exposure to valsartan was increased approximately twofold compared with healthy volunteers.

There are no data available on the use of valsartan in patients with severe hepatic dysfunction (see section 4.3). Hepatic disease does not significantly affect the pharmacokinetics of hydrochlorothiazide.

5.3 Preclinical safety data

The potential toxicity of the valsartan - hydrochlorothiazide combination after oral administration was investigated in rats and marmosets in studies lasting up to six months. No findings emerged that would exclude the use of therapeutic doses in man.

The changes produced by the combination in the chronic toxicity studies are most likely to have been caused by the valsartan component. The toxicological target organ was the kidney, the reaction being more marked in the marmoset than the rat. The combination led to kidney damage (nephropathy with tubular basophilia, rises in plasma urea, plasma creatinine and serum potassium, increases in urine volume and urinary electrolytes from 30 mg/kg/day valsartan + 9 mg/kg/day hydrochlorothiazide in rats and 10 + 3 mg/kg/d in marmosets), probably by way of altered renal haemodynamics. These doses in rat, respectively, represent 0.9 and 3.5-times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m basis. These doses in marmoset, respectively, represent 0.3 and 1.2-times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m² basis. (Calculations assume an oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient.)

High doses of the valsartan - hydrochlorothiazide combination caused falls in red blood cell indices (red cell count, haemoglobin, haematocrit, from 100 + 31 mg/kg/d in rats and 30 + 9 mg/kg/d in marmosets). These doses in rat, respectively, represent 3.0 and 12 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m² basis. These doses in marmoset, respectively, represent 0.9 and 3.5 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m basis. (Calculations assume an oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient).

In marmosets, damage was observed in the gastric mucosa (from 30 + 9 mg/kg/d). The combination also led in the kidney to hyperplasia of the afferent aterioles (at 600 + 188 mg/kg/d in rats and from 30 + 9 mg/kg/d in marmosets). These doses in marmoset, respectively, represent 0.9 and 3.5 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m basis. These doses in rat, respectively, represent 18 and 73 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m basis. (Calculations assume an oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient).

The above mentioned effects appear to be due to the pharmacological effects of high valsartan doses (blockade of angiotensin II-induced inhibition of renin

release, with stimulation of the renin-producing cells) and also occur with ACE inhibitors. These findings appear to have no relevance to the use of therapeutic doses of valsartan in humans.

The valsartan - hydrochlorothiazide combination was not tested for mutagenicity, chromosomal breakage or carcinogenicity, since there is no evidence of interaction between the two substances. However, these tests were performed separately with valsartan and hydrochlorothiazide, and produced no evidence of mutagenicity, chromosomal breakage or carcinogenicity.

In rats, maternally toxic doses of valsartan (600 mg/kg/day) during the last days of gestation and lactation led to lower survival, lower weight gain and delayed development (pinna detachment and ear-canal opening) in the offspring (see section 4.6). These doses in rats (600 mg/kg/day) are approximately 18 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). Similar findings were seen with valsartan/hydrochlorothiazide in rats and rabbits. In embryo-fetal development (Segment II) studies with valsartan/hydrochlorothiazide in rat and rabbit, there was no evidence of teratogenicity; however, fetotoxicity associated with maternal toxicity was observed.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Tablet core

Microcrystalline Cellulose Lactose Monohydrate Croscarmellose Sodium Povidone K29-K32 Talc

Magnesium Stearate Colloidal Anhydrous Silica Coating

Opadry II 85G34642 Pink:

Polyvinyl Alcohol Talc

Titanium Dioxide (E171)

Macrogol 3350 Lecithin soya (E322)

Iron Oxide Red (E172) Iron Oxide Yellow (E172) Iron Oxide Black (E172)

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

4    years for tablets packed in PVC/PE/PVDC-Al blisters

5    years for tablets packed in polyethylene tablet containers

6.4    Special precautions for storage

Tablets packed in PVC/PE/PVDC-Al blisters: Do not store above 30°C.

Tablets packed in polyethylene tablet containers: This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PVC/PE/PVDC-Al blisters and HDPE containers with PE closure.

Pack sizes of 7, 14, 28, 30, 56, 98 and 280 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements

Any unused or waste material should be disposed of in accordance to local requirements.

7 MARKETING AUTHORISATION HOLDER

Aptil Pharma Limited

9^th Floor, CP House

97-107 Uxbridge Road, Ealing

London

W5 5TL

8    MARKETING AUTHORISATION NUMBER(S)

PL 40378/0083

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

17/12/2010

10 DATE OF REVISION OF THE TEXT

28/12/2012