Valsartan/Hydrochlorothiazide ratiopharm 80 mg/12,5 mg Filmdragerad tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

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Bipacksedel Bipacksedel (PIL)

22-04-2018

Produktens egenskaper Produktens egenskaper (SPC)

28-04-2018

Aktiva substanser:
hydroklortiazid; valsartan
Tillgänglig från:
ratiopharm GmbH
ATC-kod:
C09DA03
INN (International namn):
hydrochlorothiazide; valsartan
Dos:
80 mg/12,5 mg
Läkemedelsform:
Filmdragerad tablett
Sammansättning:
hydroklortiazid 12,5 mg Aktiv substans; valsartan 80 mg Aktiv substans
Klass:
Apotek
Receptbelagda typ:
Receptbelagt
Terapiområde:
Valsartan och diuretika
Produktsammanfattning:
Förpacknings: Blister, 14 tabletter; Burk, 100 tabletter; Blister, 20 tabletter; Blister, 28 tabletter; Blister, 30 tabletter; Blister, 56 tabletter; Blister, 60 tabletter; Blister, 90 tabletter; Blister, 98 tabletter; Blister, 100 tabletter; Blister, 280 tabletter; Burk, 500 tabletter
Bemyndigande status:
Godkänd
Godkännandenummer:
26052
Tillstånd datum:
2010-02-26

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04-01-2021

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27-11-2020

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

21-02-2013

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Valsartan/Hydrochlorothiazide ratiopharm 80 mg/12.5 mg film-coated tablets

Valsartan/Hydrochlorothiazide ratiopharm 160 mg/12.5 mg film-coated tablets

Valsartan/Hydrochlorothiazide ratiopharm 160 mg/25 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Each film-coated tablet contains 160 mg valsartan and 12.5 mg hydrochlorothiazide.

Each film-coated tablet contains 160 mg valsartan and 25 mg hydrochlorothiazide.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet

80 mg/12.5 mg: Light orange, oval shaped film-coated tablet (dimension: approx. 5.3 x 10.2

mm).

160 mg/12.5 mg: Dark-red, oval shaped film-coated tablets (dimension: approx. 6.1 x 15.2 mm).

160 mg/25 mg: Brown, oval shaped, film-coated tablet, scored on one side (dimension: approx.

5.6 x 14.2 mm).

The tablet can be divided into equal doses.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Treatment of essential hypertension in adults.

Valsartan/Hydrochlorothiazide ratiopharm 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/Hydrochlorothiazide ratiopharm 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 ratiopharm 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

ratiopharm 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.

Special populations

Renal impairment

No dose adjustment is required for patients with mild to moderate renal impairment (Glomerular

Filtration Rate (GFR) ≥ 30 ml/min). Due to the hydrochlorothiazide component,

Valsartan/Hydrochlorothiazide ratiopharm is contraindicated in patients with severe renal

impairment (GFR < 30 mL/min) and anuria (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). No adjustment of the hydrochlorothiazide dose is

required for patients with mild to moderate hepatic impairment. Due to the valsartan

component, Valsartan/Hydrochlorothiazide ratiopharm 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 ratiopharm is not recommended for use in children below the

age of 18 years due to a lack of data on safety and efficacy.

Method of administration

Valsartan/Hydrochlorothiazide ratiopharm can be taken with or without food and should be

administered with water.

4.3

Contraindications

Hypersensitivity to valsartan, hydrochlorothiazide, other sulfonamide-derived medicinal

products or to any of the excipients listed in section 6.1.

2nd and 3rd trimesters of pregnancy (see sections 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 ratiopharm with aliskiren-

containing products is contraindicated in patients with diabetes mellitus or renal

impairment (GFR < 60 ml/min/1.73 m

) (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 ratiopharm Sodium and/or volume depletion should be

corrected before starting treatment with Valsartan/Hydrochlorothiazide ratiopharm.

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 ratiopharm 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 ratiopharm as well may be associated

with impairment of the renal function.

Valsartan/Hydrochlorothiazide ratiopharm should not be used in these patients.

Renal artery stenosis

Valsartan/Hydrochlorothiazide ratiopharm 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 ratiopharm as their reninangiotensin 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 ratiopharm is used in patients with

renal impairment.

Kidney transplantation

There is currently no experience on the safe use of Valsartan/Hydrochlorothiazide ratiopharm in

patients who have recently undergone kidney transplantation.

Hepatic impairment

In patients with mild to moderate hepatic impairment without cholestasis,

Valsartan/Hydrochlorothiazide ratiopharm 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 ratiopharm should be immediately

discontinued in patients who develop angioedema, and Valsartan/Hydrochlorothiazide

ratiopharm should not be re-administered.

Systemic lupus erythematosus

Thiazide diuretics, including hydrochlorothiazide, have been reported to exacerbate or activate

systemic lupus erythematosus.

Other metabolic disturbances

Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance and raise serum

levels of cholesterol, triglycerides and uric acid. In diabetic patients dosage adjustments of

insulin or oral hypoglycaemic agents may be required.

Thiazides may reduce urinary calcium excretion and cause an intermittent and slight elevation

of serum calcium in the absence of known disorders of calcium metabolism. Marked

hypercalcaemia may be evidence of underlying hyperparathyroidism. Thiazides should be

discontinued before carrying out tests for parathyroid function.

Photosensitivity

Cases of photosensitivity reactions have been reported with thiazide diuretics (see section 4.8).

If photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If

a readministration 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). 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

concomitant administration of lithium with ACE inhibitors, angiotensin II receptor antagonists

or thiazide, including hydrochlorothiazide. Since renal clearance of lithium is reduced by

thiazides, the risk of lithium toxicity may presumably be increased further with

Valsartan/Hydrochlorothiazide ratiopharm.. If the combination proves necessary, a careful

monitoring of serum lithium levels is recommended.

Concomitant use requiring caution

Other antihypertensive agents

Valsartan/Hydrochlorothiazide ratiopharm may increase the effects of other agents with

antihypertensive properties (e.g. guanethidine, methyldopa, vasodilators, ACEI, beta blockers,

calcium channel blockers, direct renin inhibitors [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 ratiopharm 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-Aldosterone System (RAAS) 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 (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 ratiopharm (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

hypomagnesaemia

occur

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 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

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.

Exposure to AIIRAs therapy 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 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 ratiopharm 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 ratiopharm 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 ratiopharm.

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 ratiopharm

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 ratiopharm 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

Hepatobiliary disorders

Not known:

Elevation of liver function values

Skin and subcutaneous tissue disorders

Not known:

Angioedema, dermatitis bullous, 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 ratiopharm 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 national reporting

system listed in Appendix V.

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 ratiopharm

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 ratiopharm 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 ratiopharm 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 ratiopharm 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 ratiopharm 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 ratiopharm to their respective components,

significantly greater mean systolic/diastolic BP reductions were observed with the combination

of Valsartan/Hydrochlorothiazide ratiopharm 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

ratiopharm 80/12.5 mg (64%) compared to placebo (29%) and hydrochlorothiazide (41%).

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 ratiopharm 160/12.5 mg

(12.4/7.5 mmHg) compared to hydrochlorothiazide 25 mg (5.6/2.1 mmHg). In addition, a

significantly greater percentage of patients responded (BP <140/90 mmHg or SBP reduction

≥20 mmHg or DBP reduction ≥10 mmHg) with Valsartan/Hydrochlorothiazide ratiopharm

160/12.5 mg (50%) compared to hydrochlorothiazide 25 mg (25%).

In a double-blind, randomised, active-controlled trial in patients not adequately controlled on

valsartan 160 mg, significantly greater mean systolic/diastolic BP reductions were observed

with both the combination of Valsartan/Hydrochlorothiazide ratiopharm 160/25 mg (14.6/11.9

mmHg) and Valsartan/Hydrochlorothiazide ratiopharm 160/12.5 mg (12.4/10.4 mmHg)

compared to valsartan 160 mg (8.7/8.8 mmHg). The difference in BP reductions between the

160/25 mg and 160/12.5 mg doses also reached statistical significance. In addition, a

significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction ≥10

mmHg) with Valsartan/Hydrochlorothiazide ratiopharm 160/25 mg (68%) and 160/12.5 mg

(62%) compared to valsartan 160 mg (49%).

In a double-blind, randomised, placebo-controlled, factorial design trial comparing various dose

combinations of Valsartan/Hydrochlorothiazide ratiopharm to their respective components,

significantly greater mean systolic/diastolic BP reductions were observed with the combination

of Valsartan/Hydrochlorothiazide ratiopharm 160/12.5 mg (17.8/13.5 mmHg) and 160/25 mg

(22.5/15.3 mmHg) compared to placebo (1.9/4.1 mmHg) and the respective monotherapies, i.e.,

hydrochlorothiazide 12.5 mg (7.3/7.2 mmHg), hydrochlorothiazide 25 mg (12.7/9.3 mmHg) and

valsartan 160 mg (12.1/9.4 mmHg). In addition, a significantly greater percentage of patients

responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with

Valsartan/Hydrochlorothiazide ratiopharm 160/25 mg (81%) and valsartan/ hydrochlorothiazide

160/12.5 mg (76%) compared to placebo (29%) and the respective monotherapies, i.e.

hydrochlorothiazide 12.5 mg (41%), hydrochlorothiazide 25 mg (54%), and valsartan 160 mg

(59%).

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 ratiopharm 160/12.5 mg

(12.4/7.5 mmHg) compared to hydrochlorothiazide 25 mg (5.6/2.1 mmHg). In addition, a

significantly greater percentage of patients responded (BP <140/90 mmHg or SBP reduction

≥20 mmHg or DBP reduction ≥10 mmHg) with Valsartan/Hydrochlorothiazide ratiopharm

160/12.5 mg (50%) compared to hydrochlorothiazide 25 mg (25%).

In a double-blind, randomised, active-controlled trial in patients not adequately controlled on

valsartan 160 mg, significantly greater mean systolic/diastolic BP reductions were observed

with both the combination of Valsartan/Hydrochlorothiazide ratiopharm 160/25 mg (14.6/11.9

mmHg) and Valsartan/Hydrochlorothiazide ratiopharm 160/12.5 mg (12.4/10.4 mmHg)

compared to valsartan 160 mg (8.7/8.8 mmHg). The difference in BP reductions between the

160/25 mg and 160/12.5 mg doses also reached statistical significance. In addition, a

significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction ≥10

mmHg) with Valsartan/Hydrochlorothiazide ratiopharm 160/25 mg (68%) and 160/12.5 mg

(62%) compared to valsartan 160 mg (49%).

In a double-blind, randomised, placebo-controlled, factorial design trial comparing various dose

combinations of Valsartan/Hydrochlorothiazide ratiopharm to their respective components,

significantly greater mean systolic/diastolic BP reductions were observed with the combination

of Valsartan/Hydrochlorothiazide ratiopharm 160/12.5 mg (17.8/13.5 mmHg) and 160/25 mg

(22.5/15.3 mmHg) compared to placebo (1.9/4.1 mmHg) and the respective monotherapies, i.e.,

hydrochlorothiazide 12.5 mg (7.3/7.2 mmHg), hydrochlorothiazide 25 mg (12.7/9.3 mmHg) and

valsartan 160 mg (12.1/9.4 mmHg). In addition, a significantly greater percentage of patients

responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with

Valsartan/Hydrochlorothiazide ratiopharm 160/25 mg (81%) and valsartan/ hydrochlorothiazide

160/12.5 mg (76%) compared to placebo (29%) and the respective monotherapies, i.e.

hydrochlorothiazide 12.5 mg (41%), hydrochlorothiazide 25 mg (54%), and valsartan 160 mg

(59%).

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 ratiopharm 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 AT

receptor subtype, which is responsible for the known actions of

angiotensin II. The increased plasma levels of Ang II following AT

receptor blockade with

valsartan may stimulate the unblocked AT

receptor, which appears to counterbalance the effect

of the AT

receptor. Valsartan does not exhibit any partial agonist activity at the AT

receptor

and has much (about 20.000-fold) greater affinity for the AT

receptor than for the AT

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 μg/min; amlodipine: 55.4 μg/min),

normal or high blood pressure and with preserved renal function (blood creatinine <120 μmol/l).

At 24 weeks, UAE was reduced (p < 0.001) by 42 % (-24.2 μg/min; 95 % CI: -40.4 to -19.1)

with valsartan and approximately 3 % (-1.7 μg/min; 95 % CI: -5.6 to 14.9) with amlodipine

despite similar rates of blood pressure reduction in both groups. The

Valsartan/Hydrochlorothiazide ratiopharm 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 μg/min; 20-700 μg/min) and preserved

renal function (mean serum creatinine = 80 μmol/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

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 ratiopharm

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 anti-

hypertensive 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

) 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

½α

< 1 h and t

½ß

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

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

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 ratiopharm 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/Hydrochlorothiazide ratiopharm. 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 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/m

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/m

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

reninproducing 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/m

basis

(calculations assume an oral dose of 320 mg/day and a 60-kg patient). Similar findings were

seen with Valsartan/Hydrochlorothiazide ratiopharm in rats and rabbits. In embryo-fetal

development (Segment II) studies with Valsartan/Hydrochlorothiazide ratiopharm 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:

Cellulose, microcrystalline

Croscarmellose sodium

Povidone (K-30)

Magnesium stearate

Film-coating:

80 mg/12.5 mg:

Polyvinyl alcohol (partially hydrolyzed)

Macrogol

Talc

Titanium dioxide (E171)

Iron oxide red (E172)

Iron oxide yellow (E172)

Iron oxide black (E172)

160 mg/12.5 mg:

Polyvinyl alcohol (partially hydrolyzed)

Macrogol

Talc

Titanium dioxide (E171)

Iron oxide red (E172)

Iron oxide yellow (E172)

160 mg/25 mg:

Polyvinyl alcohol (partially hydrolyzed)

Macrogol

Talc

Titanium dioxide (E171)

Iron oxide red (E172)

Iron oxide yellow (E172)

Iron oxide black (E172)

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

Blister

27 months

Bottle

3 years

6.4

Special precautions for storage

Blister

Do not store above 30 °C.

Store in the original package in order to protect from moisture

Bottle

Store in the original package in order to protect from moisture

6.5

Nature and contents of container

Blister pack (PVC/PE/PVDC/Aluminium)

Pack sizes:

[SE/H/0750/001-003/DC]:

14, 20, 28, 30, 56, 60, 90, 98, 100, 280 film-coated tablets.

14, 20, 28, 30, 56, 60, 90, 98, 100, 280 film-coated tablets.

14, 20, 28, 30, 56, 60, 90, 98, 100, 280 film-coated tablets.

[SE/H/0749,0751/001-003/DC]:

14, 20, 28, 30, 56, 60, 98, 100 film-coated tablets.

14, 20, 28, 30, 56, 60, 98, 100 film-coated tablets.

14, 20, 28, 30, 56, 60, 98, 100 film-coated tablets.

Bottle (HDPE) with white cap (PP)

Pack sizes: 100, 500 film-coated tablets.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal <and other handling>

No special requirements

7.

MARKETING AUTHORISATION HOLDER

[to be completed nationally]

8.

MARKETING AUTHORISATION NUMBER(S)

[to be completed nationally]

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

[to be completed nationally]

10.

DATE OF REVISION OF THE TEXT

2015-06-17

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