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

Posology
The recommended dose of Arbaval Plus 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.
The clinical response to Arbaval Plus 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 Arbaval Plus 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
Arbaval Plus can be taken with or without food and should be administered with water.
Special populations
Renal impairment
No dose adjustment is required for patients with mild to moderate renal impairment
(Glomerular Filtration Rate (GFR) ≥ 30 ml/min). Due to the hydrochlorothiazide component,
Arbaval Plus 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 hydrochlorothiazide dose is
required for patients with mild to moderate hepatic impairment. Due to the valsartan
component, Arbaval Plus 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 patients
Arbaval Plus is not recommended for use in children below the age of 18 years due to a lack of
data on safety and efficacy.
 

− Hypersensitivity to valsartan, hydrochlorothiazide, other sulfonamide-derived medicinal products or to any of the excipients. − Second and third trimester of pregnancy (section 4.4 and 4.6). − Arbaval Plus should not be co-administered with aliskiren in patients with diabetes mellitus or renal impairment − 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 angiotensin receptor antagonists (ARBs) - including valsartan- or of angiotensin-converting enzyme inhibitors (ACEIs) with aliskiren in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m2) (see sections 4.4 and 4.5).

Dual Blockade of the Renin-Angiotensin-aldosterone System (RAAS):
Combination of Arbaval Plus with ACE inhibitors, or aliskiren may cause increased risks of
hyperkalemia, worsening of kidney function and hypotension. Therefore, this combination
should not be used, especially in patients with kidney problems.
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 Arbaval Plus. Sodium and/or volume depletion should be corrected before starting
treatment with Arbaval Plus.
Patients with severe chronic heart failure or other conditions with stimulation of the reninangiotensin-aldosterone-system
In patients whose renal function may depend on the activity of the renin-angiotensinaldosterone 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 Arbaval Plus 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 Arbaval Plus as well may be associated with impairment of the renal
function. Arbaval Plus should not be used in these patients.
Renal artery stenosis
Arbaval Plus 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 Arbaval Plus 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 Arbaval Plus is used in patients with renal impairment.
The concomitant use of ARBs - including valsartan- or of ACEIs with aliskiren is contraindicated
in patients with renal impairment (GFR < 60 mL/min/1.73 m2) (see sections 4.3 and 4.5).
Kidney transplantation
There is currently no experience on the safe use of Arbaval Plus in patients who have recently
undergone kidney transplantation.
Hepatic impairment
In patients with mild to moderate hepatic impairment without cholestasis, Arbaval Plus 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. Arbaval Plus should be immediately discontinued in patients who
develop angioedema, and Arbaval Plus 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).
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)
Hypotension, syncope, stroke, hyperkalaemia, and changes in renal function (including acute
renal failure) have been reported in susceptible individuals, especially if combining medicinal
products that affect this system. Dual blockade of the renin-angiotensin-aldosterone system by
combining aliskiren with an angiotensin converting enzyme inhibitor (ACEI) or an angiotensin II
receptor blocker (ARB) is therefore not recommended.
The use of aliskiren in combination with Diovan Comp is contraindicated in patients with
diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see section 4.3).
Galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorbtion
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or
glucose-galactose malabsorbtion should not take this medicine.
 

Dual RAAS Blockade:
The combination of Cadioval HCT with Aliskiren, ACEIs or other ARBs is contraindicated in
patients with diabetes mellitus or renal impairment.
Dual blockade (e.g by adding ACE inhibitor to Cadioval HCT ) should not be used, especially in
patients with Kidney problems.
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 Arbaval Plus. If
the combination proves necessary, a careful monitoring of serum lithium levels is
recommended.
Concomitant use requiring caution
Other antihypertensive agents
Arbaval Plus 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
Arbaval Plus 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
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-converting-enzyme 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 Arbaval Plus (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, the following drugs could induce
torsades de points: bepridil, cisapride, diphemanil, erythromycin i.v., halofantrin, ketanserin,
mizolastin, pentamidine, sparfloxacine, terfenadine, vincamine i.v.
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 longterm 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. 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.
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.
Carbamazepine
Patients receiving hydrochlorothiazide concomitantly with Carbamazepine may develop
hyponatremia. Such patients should therefore be advised about the possibility of
hyponatraemic reactions, and should be monitored accordingly.
 

Pregnancy category (D)
Pregnancy
Valsartan
The use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during first
trimester of pregnancy (see section 4.4).The use of AIIRAs is contra-indicated during the
second and third trimester of pregnancy (see sections 4.3 and 4.4).
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE
inhibitors during the first trimester of pregnancy has not been conclusive; however a small
increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the
risk with Angiotensin II Receptor Inhibitors (AIIRAs), similar risks may exist for this class of
drugs. Unless continued AIIRAs therapy is considered essential, patients planning pregnancy
should be changed to alternative anti-hypertensive treatments which have an established
safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should
be stopped immediately and, if appropriate, alternative therapy should be started.
AIIRAs therapy exposure during the second and third trimesters is known to induce human
fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and
neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see also section 5.3).
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound
check of renal function and skull is recommended.
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see also
section 4.3 and 4.4).
Hydrochlorothiazide
There is limited experience with hydrochlorothiazide during pregnancy, especially during the
first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based
on the pharmacological mechanism of action of hydrochlorothiazide its use during the second
and third trimester may compromise foeto-placental perfusion and may cause foetal and
neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.
Lactation
No information is available regarding the use of valsartan during breastfeeding.
Hydrochlorothiazide is excreted in human milk. Therefore the use of Arbaval Plus 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.
 

No studies on the effect of Arbaval Plus 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.
 

a. Summary of the safety profile:
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.
b. Tabulated list of Adverse reaction:
Adverse reactions previously reported with one of the individual components may be potential
undesirable effects with Arbaval Plus as well, even if not observed in clinical trials or during
postmarketing period.
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.

c. Paediatric population
Arbaval Plus is not recommended for use in children below the age of 18 years due to a lack
of data on safety and efficacy.
d. Other special population:
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,
Arbaval Plus 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 hydrochlorothiazide dose is
required for patients with mild to moderate hepatic impairment. Due to the valsartan
component, Arbaval Plus 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.
Kidney transplantation
There is currently no experience on the safe use of Arbaval Plus in patients who have recently
undergone kidney transplantation.
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. Arbaval Plus should be immediately discontinued in patients who
develop angioedema, and Arbaval Plus 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).
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.

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.
-The National Pharmacovigilance and Drug Safety Centre (NPC)
o Fax: +966-11-205-7662
o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340
o Toll free phone: 8002490000
o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc
Valsartan cannot be eliminated by means of haemodialysis because of its strong plasma binding
behaviour whereas clearance of hydrochlorothiazide will be achieved by dialysis.
 

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
hydrochlorothiazide 12.5 mg, significantly greater mean systolic/diastolic BP reductions were
observed with the combination of valsartan/hydrochlorothiazide 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 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 160/25 mg (14.6/11.9 mmHg) and
valsartan/hydrochlorothiazide 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 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 to their respective components, significantly
greater mean systolic/diastolic BP reductions were observed with the combination of
valsartan/hydrochlorothiazide 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
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 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 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 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
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.
Hydrochlorothiazide
The site of action of thiazide diuretics is primarily in the renal distal convoluted tubule. It has
been shown that there is a high-affinity receptor in the renal cortex as the primary binding site
for the thiazide diuretic action and inhibition of NaCl transport in the distal convoluted tubule.
The mode of action of thiazides is through inhibition of the Na+Cl- symporter perhaps by
competing for the Cl- site, thereby affecting electrolyte reabsorption mechanisms:directly
increasing sodium and chloride excretion to an approximately equal extent, and indirectly by
this diuretic action reducing plasma volume, with consequent increases in plasma renin activity,
aldosterone secretion and urinary potassium loss, and a decrease in serum potassium. The
renin-aldosterone link is mediated by angiotensin II, so with co-administration of valsartan the
reduction in serum potassium is less pronounced as observed under monotherapy with
hydrochlorothiazide.
 

Valsartan/hydrochlorothiazide
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 (Cmax) 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 (t½α <1 h and t½ß 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 (tmax 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
Hydrochlorotiazide 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 Arbaval Plus 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 Arbaval Plus. 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.
 

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/m2 basis. These doses in marmoset, respectively, represent 0.3
and 1.2-times the maximum recommended human dose (MRHD) of valsartan and
hydrochlorothiazide on a mg/m2 basis. (Calculations assume an oral dose of 320 mg/day
valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient.)
High doses of the valsartan - hydrochlorothiazide combination caused falls in red blood cell
indices (red cell count, haemoglobin, haematocrit, from 100 + 31 mg/kg/d in rats and 30 + 9
mg/kg/d in marmosets). These doses in rat, respectively, represent 3.0 and 12 times the
maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a
mg/m2 basis. These doses in marmoset, respectively, represent 0.9 and 3.5 times the maximum
recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/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 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 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 rabbitsIn 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.
 

Silicified Microcrystalline Cellulose
Crospovidone
Sodium Starch Glycolate
Magnesium Stearate
Opadry Yellow
 

Not applicable.
 

2 years.

Store below 30° C. Store in the original package in order to protect from moisture.
 

Aluminum/ Aluminum blisters.
Packs of 28 film-coated tablets
 

No special requirements.