4.1. Therapeutic indications

Treatment of essential hypertension in adults.

Valsartan and Hydrochlorothiazide fixed-dose combination is indicated in patients whose blood pressure is not adequately controlled on valsartan or hydrochlorothiazide monotherapy (see section 4.3, 4.4, 4.5 and 5.1)

4.2. Posology and method of administration

Posology

The recommended dose of Valsartan and Hydrochlorothiazide 160 mg/12.5 mg 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 (see sections 4.3, 4.4 4.5 and 5.1).

The clinical response to Valsartan/Hydrochlorothiazide 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 and Hydrochlorothiazide 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 (GRF) ≥30 ml/min). Due to the hydrochlorothiazide component, Valsartan/Hydrochlorothiazide is contraindicated in patients with severe renal impairment (GFR < 30 mL/min) and anuria (see sections 4.3, 4.4 and 5.2). Concomitant use of valsartan with aliskiren is contraindicated in patients with renal impairment (GFR < 60 mL/min/1.73 m2) (see section 4.3).

Diabetes Mellitus

Concomitant use of valsartan with aliskiren is contraindicated in patients with diabetes mellitus (see section 4.3).

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 hydrochloro-thiazide dose is required for patients with mild to moderate hepatic impairment. Due to the valsartan component, Valsartan/Hydrochlorothiazide is contraindicated in patients with severe hepatic impairment or with biliary cirrhosis and cholestasis (see sections 4.3, 4.4 and 5.2).

Elderly

No dose adjustment is required in elderly patients.

Paediatric population

Valsartan/Hydrochlorothiazide is not recommended for use in children below the age of 18 years due to a lack of data on safety and efficacy.

4.3. Contraindications

- Hypersensitivity to valsartan, hydrochlorothiazide, other sulfonamide-derived medicinal products or to any of the excipients listed in section 6.1.

- Second and third trimester of pregnancy (see 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.

- The concomitant use of Valsartan/Hydrochlorothiazide 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/Hydrochlorothiazide. Sodium and/or volume depletion should be corrected before starting treatment with Valsartan/Hydrochlorothiazide.

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/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 should not be used in these patients.

Renal artery stenosis

Valsartan/Hydrochlorothiazide 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 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/Hydrochlorothiazide 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 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/Hydrochlorothiazide should be immediately discontinued in patients who develop angioedema, and Valsartan/Hydrochlorothiazide 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 thiazide 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).

Choroidal effusion, Acute myopia and Secondary Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, has been associated with an idiosyncratic reaction resulting in choroidal effusion with visual field defect, 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 weeks 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.

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.

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). Dual blockade of the RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see section 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.

Non-melanoma skin cancer

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide (HCTZ) exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. Photosensitizing actions of HCTZ could act as a possible mechanism for NMSC.

Patients taking HCTZ should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of HCTZ may also need to be reconsidered in patients who have experienced previous NMSC (see also section 4.8).

Acute Respiratory Toxicity

Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS) have been reported after taking hydrochlorothiazide. Pulmonary oedema typically develops within minutes to hours after hydrochlorothiazide intake. At the onset, symptoms include dyspnoea, fever, pulmonary deterioration and hypotension. If diagnosis of ARDS is suspected, Valsartan and Hydrochlorothiazide should be withdrawn and appropriate treatment given. Hydrochlorothiazide should not be administered to patients who previously experienced ARDS following hydrochlorothiazide intake.

Intestinal angioedema

Intestinal angioedema has been reported in patients treated with angiotensin II receptor antagonists, [including Valsartan] (see section 4.8). These patients presented with abdominal pain, nausea, vomiting and diarrhoea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, Valsartan should be discontinued and appropriate monitoring should be initiated until complete resolution of symptoms has occurred.

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Valsartan/Hydrochlorothiazide contains Sodium

This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially 'sodium-free'.

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 concomitant administration of lithium with ACE inhibitors, angiotensin II receptor antagonists or thiazides, including hydrochlorothiazide. Since renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity may presumably be increased further with Valsartan/Hydrochlorothiazide. If the combination proves necessary, a careful monitoring of serum lithium levels is recommended.

Concomitant use requiring caution

Other antihypertensive agents

Valsartan/Hydrochlorothiazide 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/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

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).

Caution is required while co-administering ARBs, including valsartan, with other agents blocking the RAAS such as ACEIs or aliskiren (see section 4.4).

Concomitant use of angiotensin receptor antagonists (ARBs) – including valsartan – or of angiotensin-convertingenzyme inhibitors (ACEIs) with aliskiren in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73m2) is contraindicated (see section 4.3).

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/Hydrochlorothiazide (see interactions related to hydrochlorothiazide).

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 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 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. Coadministration 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.

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 narcoticsConcomitant 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 antihypertensive 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 during breastfeeding. Hydrochlorothiazide is excreted in human milk. Therefore the use of Valsartan/Hydrochlorothiazide 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

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/Hydrochlorothiazide 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, hyponatraemia

Ear and labyrinth disorders

Uncommon

Vertigo

Vascular disorders

Not known

Vasculitis

Gastrointestinal disorders

Uncommon

Abdominal pain

Very Rare

Intestinal angioedema

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/Hydrochlorothiazide. The following adverse reactions have been reported in patients treated with monotherapy of thiazide diuretics, including hydrochlorothiazide:

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)

Not known

Non-melanoma skin cancer (Basal cell carcinoma and Squamous cell carcinoma)

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

Choroidal effusion

Cardiac disorders

Rare

Cardiac arrhythmias

Vascular disorders

Common

Postural hypotension

Respiratory, thoracic and mediastinal disorders

Very rare

Acute respiratory distress syndrome (ARDS) (see section 4.4) 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

Description of selected adverse reactions

Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ and NMSC has been observed (see also sections 4.4 and 5.1).

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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.