SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Valsartan and Hydrochlorothiazide 320mg/12.5mg Film-coated tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 320mg valsartan and 12.5mg hydrochlorothiazide. For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Pink, biconvex, oval shaped film-coated tablets measuring approximately 16.717.7mm by 7.7-8.7mm and 5.4-6.4mm thickness and weighing approximately 618.0mg.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of essential hypertension in adults.

Valsartan and Hydrochlorothiazide Film-coated tablets 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 Valsartan and Hydrochlorothiazide 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 and 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 and Hydrochlorothiazide Film-coated tablets 320 mg/25 mg Tablets.

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 and Hydrochlorothiazide Film-coated tablets can be taken with or without food and should be administered with water.

Special _ populations

Patients with 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, Valsartan and Hydrochlorothiazide Film-coated tablets are contraindicated in patients with severe renal impairment (GFR < 30 mL/min) and anuria (see sections 4.3, 4.4 and 5.2).

Patients with 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). No adjustment of the hydrochlorothiazide dose is required for patients with mild to moderate hepatic impairment. Due to the valsartan component, Valsartan and Hydrochlorothiazide Film-coated tablets are contraindicated in patients with severe hepatic impairment or with biliary cirrhosis and cholestasis (see sections 4.3, 4.4 and 5.2).

Older people

No dose adjustment is required in elderly patients.

Paediatric patients

Valsartan and 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 the active substances, other sulfonamide-derived medicinal products or to any of the excipients listed in section 6.1.

-    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.

-    Concomitant use of Valsartan and Hydrochlorothiazide Film-coated tablets with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²) (see sections 4.5 and 5.1).

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 and Hydrochlorothiazide Tablets. Sodium and/or volume depletion should be corrected before starting treatment with Valsartan and Hydrochlorothiazide 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 and/or death. Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renal function. The use of Valsartan and Hydrochlorothiazide Film-coated tablets 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 and Hydrochlorothiazide Film-coated tablets as well may be associated with impairment of the renal function. Valsartan and Hydrochlorothiazide Film-coated tablets should not be used in these patients.

Renal artery stenosis

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

Kidney transplantation

There is currently no experience on the safe use of Valsartan and Hydrochlorothiazide Film-coated tablets in patients who have recently undergone kidney transplantation.

Hepatic impairment

In patients with mild to moderate hepatic impairment without cholestasis, Valsartan and Hydrochlorothiazide Film-coated tablets should be used with caution (see sections 4.2 and 5.2). 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 has been reported in patients treated with valsartan; some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Valsartan and Hydrochlorothiazide Film-coated tablets should be immediately discontinued in patients who develop angioedema, and Valsartan and Hydrochlorothiazide Film-coated tablets should not be re-administered (see section 4.8).

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.

Acute Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, has been associated 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)

There is evidence that 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). Syncope and stroke also have been reported in susceptible individuals, especially if combining medicinal products that affect this system. Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).

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.

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.

Since renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity may presumably be increased further with Valsartan and Hydrochlorothiazide Film-coated tablets. If the combination proves necessary, a careful monitoring of serum lithium levels is recommended.

Concomitant use requiring caution

Other antihypertensive agents

Valsartan and Hydrochlorothiazide Film-coated tablets 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 Valsartan and Hydrochlorothiazide Film-coated tablets 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

Clinical trial data has shown that 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 a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

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 (e.g. rifampin, ciclosporin) or efflux transporter (e.g. 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 and Hydrochlorothiazide Film-coated tablets (see interactions related to hydrochlorothiazide).

Interactions related to hydrochlorothiazide

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 hydrochlorothiazide-valsartan combination, monitoring of potassium plasma levels is advised (see section 4.4).

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 (see section 4.4).

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 predisposed 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 thiazide-type 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.

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.

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.

Breast-feeding

No information is available regarding the use of Valsartan and Hydrochlorothiazide Film-coated tablets during breast-feeding. Hydrochlorothiazide is excreted in human milk. Therefore the use of Valsartan and 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 and 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 post-marketing 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

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: 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.

Additional information on the individual components

Adverse reactions previously reported with one of the individual components may be potential undesirable effects with Valsartan and Hydrochlorothiazide Film-coated tablets as well, even if not observed in clinical trials or during post-marketing 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, 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, dermatitis bullous, 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 and Hydrochlorothiazide. The following adverse reactions have been reported in patients treated with monotherapy of thiazide diuretics, including hydrochlorothiazide:

Blood and lymphatic system disorders

Rare: Thrombocytopenia sometimes with purpura

Very rare: Agranulocytosis, leucopenia, haemolytic anaemia, bone marrow failure Not known: Aplastic anemia

Immune system disorders

Very rare: Hypersensitivity reactions

Metabolism and nutrition disorders

Very common: Hypokalaemia, blood lipids increased (mainly at higher doses)

Common: Hyponatraemia, hypomagnesaemia, hyperuricaemia

Rare: Hypercalcaemia, hyperglycaemia, glycosuria and worsening of diabetic metabolic state

Very rare: Hypochloraemic alkalosis

Psychiatric disorders

Rare: Depression, sleep disturbances

Nervous system disorders

Rare: Headache, dizziness, paraesthesia

Eye disorders

Rare: Visual impairment

Not known: Acute angle-closure glaucoma

Cardiac disorders Rare: Cardiac arrhythmias

Vascular disorders Common: Postural hypotension

Respiratory, thoracic and mediastinal disorders

Very rare: Respiratory distress including pneumonitis and pulmonary oedema Gastrointestinal disorders

Common: Loss of appetite, mild nausea and vomiting Rare: Constipation, gastrointestinal discomfort, diarrhoea Very rare: Pancreatitis

Hepatobiliary disorders

Rare: Intrahepatic cholestasis or jaundice

Renal and urinary disorders

Not known: Renal dysfunction, acute renal failure

Skin and subcutaneous tissue disorders Common: Urticaria and other forms of rash Rare: Photosensitisation

Very rare: Necrotising vasculitis and toxic epidermal necrolysis, cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus

Not known: Erythema multiforme

General disorders and administration site conditions Not known: Pyrexia, asthenia

Musculoskeletal and connective tissue disorders Not known: Muscle spasm

Reproductive system and breast disorders Common: Impotence

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

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 valsartan 320 mg, significantly greater mean systolic/diastolic BP reductions were observed with both the combination of valsartan/hydrochlorothiazide 320/25 mg (15.4/10.4 mmHg) and valsartan/hydrochlorothiazide 320/12.5 mg (13.6/9.7 mmHg) compared to valsartan 320 mg (6.1/5.8 mmHg).

The difference in systolic BP reduction between the 320/25 mg and 320/12.5 mg doses also reached statistical significance. In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction >10 mmHg) with valsartan/hydrochlorothiazide 320/25 mg (75%) and 320/12.5 mg (69%) compared to valsartan 320 mg (53%).

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 320/12.5 mg (21.7/15.0 mmHg) and 320/25 mg (24.7/16.6 mmHg) compared to placebo (7.0/5.9 mmHg) and the respective monotherapies, i.e., hydrochlorothiazide 12.5 mg (11.1/9.0 mmHg), hydrochlorothiazide 25 mg (14.5/10.8 mmHg) and valsartan 320 mg (13.7/11.3 mmHg). In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction >10 mmHg) with valsartan/hydrochlorothiazide 320/25 mg (85%) and 320/12.5 mg (83%) compared to placebo (45%) and the respective monotherapies, i.e., hydrochlorothiazide 12.5 mg (60%), hydrochlorothiazide 25 mg (66%), and valsartan 320 mg (69%).

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 (80-160 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.

Other: Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.

ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

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.

5.2 Pharmacokinetic properties

Valsartan/hydrochlorothiazide

The systemic availability of hydrochlorothiazide is reduced by about 30% when coadministered with valsartan. The kinetics of valsartan is 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 anti-hypertensive effect, greater than that obtained with either active substance given alone, or placebo.

Valsartan

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 (94 - 97%), 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 (t/_2a <1 h and t/^ 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). The increase in mean AUC is linear and dose proportional in the therapeutic range.

The effect of food on hydrochlorothiazide absorption, if any, has little clinical significance. Absolute bioavailability of hydrochlorothiazide is 70% after oral administration.

Distribution

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 3 times the level in plasma.

Elimination

Hydrochlorothiazide is eliminated predominantly as unchanged drug. Hydrochlorothiazide is eliminated from plasma with a half-life averaging 6 to 15 hours in the terminal elimination phase. There is no change in the kinetics of hydrochlorothiazide on repeated dosing, and accumulation is minimal when dosed once daily. There is more than 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.

Special populations

Older people

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 and Hydrochlorothiazide Film-coated tablets no dose adjustment is required for patients with a Glomerular Filtration Rate (GFR) of 30-70 ml/min.

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

In the presence of renal impairment, mean peak plasma levels and AUC values of hydrochlorothiazide are increased and the urinary excretion rate is reduced. In patients with mild to moderate renal impairment, a 3-fold increase in hydrochlorothiazide AUC has been observed. In patients with severe renal impairment an 8-fold increase in AUC has been observed. Hydrochlorothiazide is contraindicated in patients with severe renal impairment (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 2-fold compared with healthy volunteers (see sections 4.2 and 4.4).

There is 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 Film-coated tablets on a mg/m² basis. These doses in marmoset, respectively, represent 0.3 and 1.2-times the maximum recommended human dose (MRHD) of Valsartan and Hydrochlorothiazide Film-coated tablets 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 Film-coated tablets 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 Film-coated tablets 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).

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 Film-coated tablets on a mg/m² basis. These doses in rat, respectively, represent 18 and 73 times the maximum recommended human dose (MRHD) of Valsartan and Hydrochlorothiazide Film-coated tablets 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).

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

Core:

Microcrystalline cellulose Crospovidone Sodium starch glycolate Magnesium stearate Silica, colloidal anhydrous

Coating:

Polyvinyl alcohol - part. Hydrolysed Titanium dioxide (E171)

Talc (E553b)

Macrogol 3350 Lecithin (soya) (E322)

Iron oxide red (E172)

Iron oxide black (E172)

Iron oxide yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3    Shelf life

36 months.

6.4    Special precautions for storage

Do not store above 30°C.

6.5    Nature and contents of container

PVC/PE/PVDC-Aluminium blister packs containing 28 tablets per pack.

6.6    Special precautions for disposal

No special requirements for disposal.

7    MARKETING AUTHORISATION HOLDER

Crescent Pharma Limited,

Units 3 & 4, Quidhampton Business Units,

Polhampton Lane, Overton,

Hants RG25 3ED United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 20416/0339

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

19/10/2016

10    DATE OF REVISION OF THE TEXT

19/10/2016