Treatment of essential hypertension in adults.

Co-Tabuvan fixed-dose combination is indicated in patients whose blood pressure is not

adequately controlled on valsartan or hydrochlorothiazide monotherapy.

Posology

The recommended dose of Co-Tabuvan 80/12.5mg or 160/12.5mg or 160/25mg 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 Co-Tabuvan 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 Co-Tabuvan 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

Co-Tabuvan 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, Co-Tabuvan 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, Co-Tabuvan 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

Co-Tabuvan 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). - Severe hepatic impairment, biliary cirrhosis and cholestasis. - Severe renal impairment (creatinine clearance < 30 ml/min), anuria. Tabuk Pharmaceutical Mfg. Co. Co-Tabuvan 320/12.5 mg Tablets - Refractory hypokalaemia, hyponatraemia, hypercalcaemia, and symptomatic hyperuricaemia.

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 Co-Tabuvan. Sodium and/or volume depletion should be corrected before

starting treatment with Co-Tabuvan.

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 Co-Tabuvan in patients with severe chronic heart failure has not been

established.

Hence it cannot be excluded that because of the inhibition of the renin-angiotensinaldosterone

system the application of Co-Tabuvan as well may be associated with

impairment of the renal function. Co-Tabuvan should not be used in these patients.

Renal artery stenosis

Co-Tabuvan 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 Co-Tabuvan 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 Co-Tabuvan is used in patients with

renal impairment.

Kidney transplantation

There is currently no experience on the safe use of Co-Tabuvan in patients who have

recently undergone kidney transplantation.

Hepatic impairment

In patients with mild to moderate hepatic impairment without cholestasis, Co-Tabuvan

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. Co-Tabuvan should be immediately discontinued in 

patients who develop angioedema, and Co-Tabuvan should not be re-administered (see

section 4.8).

Systemic lupus erythematosus

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

activate systemic lupus erythematosus.

Other metabolic disturbances

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

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

adjustments of insulin or oral hypoglycaemic agents may be required.

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

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

Marked hypercalcaemia may be evidence of underlying hyperparathyroidism. Thiazides

should be discontinued before carrying out tests for parathyroid function.

Photosensitivity

Cases of photosensitivity reactions have been reported with thiazides diuretics (see section

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

treatment. If a re-administration of the diuretic is deemed necessary, it is recommended to

protect exposed areas to the sun or to artificial UVA.

Pregnancy

Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy.

Unless continued AIIRAs therapy is considered essential, patients planning pregnancy

should be changed to alternative anti-hypertensive treatments which have an established

safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs

should be stopped immediately, and, if appropriate, alternative therapy should be started

(see sections 4.3 and 4.6).

General

Caution should be exercised in patients who have shown prior hypersensitivity to other

angiotensin II receptor antagonists. Hypersensitivity reactions to hydrochlorothiazide are

more likely in patients with allergy and asthma.

Acute Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, has been associated with an idiosyncratic reaction

resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include

acute onset of decreased visual acuity or ocular pain and typically occur within hours to

week of a drug initiation. Untreated acute-angle closure glaucoma can lead to permanent

vision loss.

The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt

medical or surgical treatment may need to be considered if the intraocular pressure remains

uncontrolled. Risk factors for developing acute angle closure glaucoma may include a

history of sulfonamide or penicillin allergy.

Interactions related to both valsartan and hydrochlorothiazide

Concomitant use not recommended

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported

during concurrent use of ACE inhibitors and thiazide, including hydrochlorothiazide. Due

to the lack of experience with concomitant use of valsartan and lithium, this combination is

not recommended. If the combination proves necessary, careful monitoring of serum

lithium levels is recommended.

Concomitant use requiring caution

Other antihypertensive agents

Co-Tabuvan 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

Co-Tabuvan and NSAIDs may lead to worsening of renal function and an increase in

serum potassium. Therefore, monitoring of renal function at the beginning of the treatment

is recommended, as well as adequate hydration of the patient 

Interactions related to valsartan

Concomitant use not recommended

Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium

and other substances that may increase potassium levels

If a medicinal product that affects potassium levels is considered necessary in combination

with valsartan, monitoring of potassium plasma levels is advised.

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 Co-Tabuvan

(see interactions related to hydrochlorothiazide).

Interactions related to hydrochlorothiazide

Concomitant use requiring caution

Medicinal products affecting serum potassium level

The hypokalaemic effect of hydrochlorothiazide may be increased by concomitant

administration of kaliuretic diuretics, corticosteroids, laxatives, ACTH, amphotericin,

carbenoxolone, penicillin G, salicylic acid and derivatives.

If these medicinal products are to be prescribed with the hydrochlorothiazide-valsartan

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

Medicinal products that could induce torsades de pointes

Due to the risk of hypokalaemia, hydrochlorothiazide should be administered with caution

when associated with medicinal products that could induce torsades de pointes, in

particular Class Ia and Class III antiarrhythmics and some antipsychotics.

Medicinal products affecting serum sodium level

The hyponatraemic effect of diuretics may be intensified by concomitant administration of

drugs such as antidepressants, antipsychotics, antiepileptics, etc. Caution is advised in

long-term administration of these drugs.

Digitalis glycosides

Thiazide-induced hypokalaemia or hypomagnesaemia may occur as undesirable effects

favouring the onset of digitalis-induced cardiac arrhythmias (see section 4.4).

Calcium salts and vitamin D

Administration of thiazide diuretics, including hydrochlorothiazide, with vitamin D or with

calcium salts may potentiate the rise in serum calcium. Concomitant use of thiazide type

diuretics with calcium salts may cause hypercalcaemia in patients pre-disposed for

hypercalcaemia (e.g. hyperparathyroidism, malignancy or vitamin-D-mediated conditions)

by increasing tubular calcium reabsorption.

Antidiabetic agents (oral agents and insulin)

Thiazides may alter glucose tolerance. Dose adjustment of the antidiabetic medicinal

product may be necessary.

Metformin should be used with caution because of the risk of lactic acidosis induced by

possible functional renal failure linked to hydrochlorothiazide.

Beta blockers and diazoxide

Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta blockers

may increase the risk of hyperglycaemia. Thiazide diuretics, including

hydrochlorothiazide, may enhance the hyperglycaemic effect of diazoxide.

Medicinal products used in the treatment of gout (probenecid, sulfinpyrazone and

allopurinol)

Dose adjustment of uricosuric medications may be necessary as hydrochlorothiazide may

raise the level of serum uric acid. Increase of dosage of probenecid or sulfinpyrazone may

be necessary. 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 gouttype

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

Pregnancy

Pregnancy Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters

of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and

death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal

deformations. Potential neonatal adverse effects include skull hypoplasia, anuria,

hypotension, renal failure, and death. When pregnancy is detected, discontinue valsartan

and hydrochlorothiazide tablets as soon as possible. These adverse outcomes are usually

associated with use of these drugs in the second and third trimester of pregnancy. Most

epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use

in the first trimester have not distinguished drugs affecting the renin-angiotensin system

from other antihypertensive agents. Appropriate management of maternal hypertension

during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting

the renin-angiotensin system for a particular patient, apprise the mother of the potential risk

to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic

environment. If oligohydramnios is observed, discontinue valsartan and

hydrochlorothiazide tablets, unless it is considered lifesaving for the mother. Fetal testing

may be appropriate, based on the week of pregnancy. Patients and physicians should be

aware, however, that oligohydramnios may not appear until after the fetus has sustained

irreversible injury. Closely observe infants with histories of in utero exposure to valsartan

and hydrochlorothiazide tablets for hypotension, oliguria, and hyperkalemia.

Hydrochlorothiazide

Thiazides can cross the placenta, and concentrations reached in the umbilical vein

approach those in the maternal plasma. Hydrochlorothiazide, like other diuretics, can cause

placental hypoperfusion. It accumulates in the amniotic fluid, with reported concentrations

up to 19 times higher than in umbilical vein plasma. Use of thiazides during pregnancy is

associated with a risk of fetal or neonatal jaundice or thrombocytopenia. Since they do not

prevent or alter the course of EPH (Edema, Proteinuria, and Hypertension) gestosis (preeclampsia),

these drugs should not be used to treat hypertension in pregnant women. The

use of hydrochlorothiazide for other indications (e.g., heart disease) in pregnancy should be

avoided.

Lactation

No information is available regarding the use of valsartan during breastfeeding.

Hydrochlorothiazide is excreted in human milk. Therefore the use of Co-Tabuvan 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 Co-Tabuvan, on the ability to drive and use machines have been

Co-Tabuvan 320/12.5 mg Tablets

performed. When driving vehicles or operating machines it should be taken into account

that occasionally dizziness or weariness may occur.

Adverse reactions reported in clinical trials and laboratory findings occurring more

frequently with valsartan plus hydrochlorothiazide versus placebo and individual

postmarketing reports are presented below according to system organ class. Adverse

reactions known to occur with each component given individually but which have not been

seen in clinical trials may occur during treatment with valsartan/ hydrochlorothiazide.

Adverse drug reactions are ranked by frequency, the most frequent first, using the

following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥

1/1,000 to < 1/100); rare(≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known

(cannot be estimated from the available data). Within each frequency grouping, adverse

reactions are ranked in order of decreasing seriousness.

Table 1. Frequency of adverse reactions with valsartan/hydrochlorothiazide

Metabolism and nutrition disorders

Uncommon 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

Tabuk Pharmaceutical Mfg. Co.

Co-Tabuvan 320/12.5 mg Tablets

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 Co-Tabuvan 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

Tabuk Pharmaceutical Mfg. Co.

Co-Tabuvan 320/12.5 mg Tablets

Gastrointestinal disorders

Uncommon Abdominal pain

Hepatobiliary disorders

Not known Elevation of liver function values

Skin and subcutaneous tissue disorders

Not known Angioedema, rash, pruritus

Renal and urinary disorders

Not known Renal failure

Table 3. Frequency of adverse reactions with hydrochlorothiazide

Hydrochlorothiazide has been extensively prescribed for many years, frequently in higher

doses than those administered with Co-Tabuvan. 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

Tabuk Pharmaceutical Mfg. Co.

Co-Tabuvan 320/12.5 mg Tablets

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

Tabuk Pharmaceutical Mfg. Co.

Co-Tabuvan 320/12.5 mg Tablets

Musculoskeletal and connective tissue disorders

Not known Muscle spasm

Reproductive system and breast disorders

Common Impotence

 

Please report adverse drug events to:

• Saudi Arabia

The National Pharmacovigilance Center (NPC):

Fax: +966-11-205-7662

SFDA Call Center: 19999

E-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa

• Other GCC States:

Please contact the relevant competent authority

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.

Pharmacotherapeutic group: Angiotensin II antagonists and diuretics, valsartan and

diuretics; ATC Code: C09D A03

Valsartan/hydrochlorothiazide

Co-Tabuvan 80/12.5 mg Tablets only:

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

controlled on hydrochlorothiazide 12.5 mg, significantly greater mean systolic/diastolic

BP reductions were observed with the combination of valsartan/hydrochlorothiazide

80/12.5 mg (14.9/11.3 mmHg) compared to hydrochlorothiazide 12.5 mg (5.2/2.9

mmHg) and hydrochlorothiazide 25 mg (6.8/5.7 mmHg). In addition, a significantly

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

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

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

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

controlled on valsartan 80 mg, significantly greater mean systolic/diastolic BP reductions

were observed with the combination of valsartan/hydrochlorothiazide 80/12.5 mg

(9.8/8.2 mmHg) compared to valsartan 80 mg (3.9/5.1 mmHg) and valsartan 160 mg

(6.5/6.2 mmHg). In addition, a significantly greater percentage of patients responded

(diastolic BP <90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide

80/12.5 mg (51%) compared to valsartan 80 mg (36%) and valsartan 160 mg (37%).

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

various dose combinations of valsartan/hydrochlorothiazide to their respective

components, significantly greater mean systolic/diastolic BP reductions were observed

with the combination of valsartan/hydrochlorothiazide 80/12.5 mg (16.5/11.8 mmHg)

compared to placebo (1.9/4.1 mmHg) and both hydrochlorothiazide 12.5 mg (7.3/7.2

mmHg) and valsartan 80 mg (8.8/8.6 mmHg). In addition, a significantly greater

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

valsartan/hydrochlorothiazide 80/12.5 mg (64%) compared to placebo (29%) and

hydrochlorothiazide (41%).

Co-Tabuvan 160/12.5 mg and 160/25mg Tablets only:

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%).

Co-Tabuvan 80/12.5mg, 160/12.5 mg and 160/25mg Tablets:

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 potassiumsparing

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 AT1receptor 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 Tabuvan 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+Clsymporter

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 coadministered

with valsartan. The kinetics of valsartan are not markedly affected by the coadministration

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 (tóα <1 h and tóß 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

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 Co-Tabuvan 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 Co-Tabuvan. 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 rabbits. In

embryo-fetal development (Segment II) studies with valsartan/hydrochlorothiazide in rat

and rabbit, there was no evidence of teratogenicity; however, fetotoxicity associated with

maternal toxicity was observed.

Core:

Microcrystalline Cellulose

Crospovidone

Colloidal Silicone Dioxide

Magnesium Stearate

Coating:

Opadry

Ferric Oxide Red

Carnauba Wax

Not applicable.

2 years

Do not store above 30°C.

Store in the original package in order to protect from moisture.

Five Aluminum – Aluminum blisters of 6 tablets each, packed in a printed carton with

a folded leaflet

No specific instructions for use or handling.