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CUENCA 320MG FILM-COATED TABLETS

Active substance(s): VALSARTAN

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Cuenca 320 mg film-coated tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

One film-coated tablet contains 160 mg of valsartan.
Excipients:

Cuenca 160 mg film-coated tablets:
Excipients with known effect:
sorbitol...................... 18.5 mg
lactose monohydrate.. 2.2 mg
sodium..................... 0.64 mg (0.03 mmol)

3

PHARMACEUTICAL FORM
Film-coated tablet.
Cuenca 320 mg film-coated tablets: oblong, coated, scored on one side, greyish-violet
film-coated tablets.
The tablet can be divided into equal halves.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Hypertension
Treatment of essential hypertension in adults, and hypertension in children and adolescents
6 to 18 years of age.
Recent myocardial infarction
Treatment of clinically stable adult patients with symptomatic heart failure or
asymptomatic left ventricular systolic dysfunction after a recent (12 hours-10 days)
myocardial infarction (see sections 4.4 and 5.1).
Heart failure

Treatment of symptomatic heart failure in adult patients when Angiotensin Converting
Enzyme (ACE) inhibitors cannot be used, or as add-on therapy to ACE inhibitors when
beta blockers cannot be used (see sections 4.4 and 5.1).

4.2

Posology and method of administration

Posology
Hypertension
The recommended starting dose of Cuenca is 80 mg once daily. The antihypertensive effect
is substantially present within 2 weeks, and maximal effects are attained within 4 weeks.
In some patients whose blood pressure is not adequately controlled, the dose can be
increased to 160 mg and to a maximum of 320 mg.
Cuenca may also be administered with other antihypertensive agents. The addition of a
diuretic such as hydrochlorothiazide will decrease blood pressure even further in these
patients.
Recent myocardial infarction
In clinically stable patients, therapy may be initiated as early as 12 hours after a myocardial
infarction. After an initial dose of 20 mg twice daily, valsartan should be titrated to 40 mg,
80 mg, and 160 mg twice daily over the next few weeks. The starting dose is provided by
the 40 mg divisible tablet.
The target maximum dose is 160 mg twice daily. In general, it is recommended that
patients achieve a dose level of 80 mg twice daily by two weeks after treatment initiation
and that the target maximum dose, 160 mg twice daily, be achieved by three months,
based on the patient's tolerability. If symptomatic hypotension or renal dysfunction occur,
consideration should be given to a dose reduction.
Valsartan may be used in patients treated with other post-myocardial infarction therapies,
e.g. thrombolytics, acetylsalicylic acid, beta blockers, statins, and diuretics. The
combination with ACE inhibitors is not recommended (see sections 4.4 and 5.1).
Evaluation of post-myocardial infarction patients should always include assessment of
renal function.
Heart failure
The recommended starting dose of Cuenca is 40 mg twice daily. Uptitration to 80 mg and
160 mg twice daily should be done at intervals of at least two weeks to the highest dose,
as tolerated by the patient.
Consideration should be given to reducing the dose of concomitant diuretics. The
maximum daily dose administered in clinical trials is 320 mg in divided doses.
Valsartan may be administered with other heart failure therapies. However, the triple
combination of an ACE inhibitor, a beta blocker and valsartan is not recommended (see
sections 4.4 and 5.1).
Evaluation of patients with heart failure should always include assessment of renal
function.
Additional information on special populations
Elderly
No dose adjustment is required in elderly patients.

Renal impairment
No dose adjustment is required for adult patients with a creatinine clearance >10 ml/min
(see sections 4.4 and 5.2). Concomitant use of Cuenca 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 Cuenca with aliskiren is contraindicated in patients with diabetes
mellitus (see section 4.3).
Hepatic impairment
Cuenca is contraindicated in patients with severe hepatic impairment, biliary cirrhosis and
in patients with cholestasis (see sections 4.3, 4.4 and 5.2). In patients with mild to
moderate hepatic impairment without cholestasis, the dose of valsartan should not exceed
80 mg.
Paediatric population
Paediatric hypertension
Children and adolescents 6 to 18 years of age
The initial dose is 40 mg once daily for children weighing below 35 kg and 80 mg
once daily for those weighing 35 kg or more. The dose should be adjusted based on
blood pressure response. For maximum doses studied in clinical trials please refer to
the table below.
Doses higher than those listed have not been studied and are therefore not recommended.
Weight

≥18 kg to <35 kg
≥35 kg to <80 kg
≥80 kg to ≤ 160 kg

Maximum dose studied in clinical trials
80 mg
160 mg
320 mg

Children less than 6 years of age
Available data are described in sections 4.8, 5.1 and 5.2. However, safety and efficacy of
Cuenca in children aged 1 to 6 years have not been established.
Use in paediatric patients aged 6 to 18 years with renal impairment
Use in paediatric patients with a creatinine clearance <30 ml/min and paediatric patients
undergoing dialysis has not been studied, therefore valsartan is not recommended in these
patients. No dose adjustment is required for paediatric patients with a creatinine clearance
>30 ml/min. Renal function and serum potassium should be closely monitored (see
sections 4.4 and 5.2).
Use in paediatric patients aged 6 to 18 years with hepatic impairment
As in adults, Cuenca is contraindicated in paediatric patients with severe hepatic
impairment, biliary cirrhosis and in patients with cholestasis (see sections 4.3, 4.4 and
5.2). There is limited clinical experience with Cuenca in paediatric patients with mild to
moderate hepatic impairment. The dose of valsartan should not exceed 80 mg in these
patients.
Paediatric heart failure and recent myocardial infarction
Cuenca is not recommended for the treatment of heart failure or recent myocardial
infarction in children and adolescents below the age of 18 years due to the lack of data on
safety and efficacy.

Method of administration
Cuenca may be taken independently of a meal and should be administered with water.

4.3
-

4.4

Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section
6.1.
Severe hepatic impairment, biliary cirrhosis and cholestasis.
Second and third trimester of pregnancy (see sections 4.4 and 4.6).
Concomitant use of angiotensin receptor antagonists (ARBs) - including Cuenca - or
of angiotensin-converting-enzyme inhibitors (ACEIs) with aliskiren in patients with
diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73m2) (see sections 4.4
and 4.5).

Special warnings and precautions for use

Hyperkalaemia
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.
Impaired renal function
There is currently no experience on the safe use in patients with a creatinine clearance <10
ml/min and patients undergoing dialysis, therefore valsartan should be used with caution
in these patients. No dose adjustment is required for adult patients with creatinine
clearance >10 ml/min (see sections 4.2 and 5.2).
Hepatic impairment
In patients with mild to moderate hepatic impairment without cholestasis, Cuenca should
be used with caution (see sections 4.2 and 5.2).
Sodium- and/or volume-depleted patients
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 Cuenca. Sodium and/or volume depletion should be corrected before starting
treatment with Cuenca, for example by reducing the diuretic dose.
Renal artery stenosis
In patients with bilateral renal artery stenosis or stenosis to a solitary kidney, the safe use
of Cuenca has not been established.
Short-term administration of Cuenca to twelve patients with renovascular hypertension
secondary to unilateral renal artery stenosis did not induce any significant changes in
renal haemodynamics, serum creatinine, or blood urea nitrogen (BUN). However, other
agents that affect the renin-angiotensin system may increase blood urea and serum
creatinine in patients with unilateral renal artery stenosis, therefore monitoring of renal
function is recommended when patients are treated with valsartan.
Kidney transplantation
There is currently no experience on the safe use of Cuenca in patients who have recently
undergone kidney transplantation.

Primary hyperaldosteronism
Patients with primary hyperaldosteronism should not be treated with Cuenca as their reninangiotensin system is not activated.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
As with all other vasodilators, special caution is indicated in patients suffering from aortic
or mitral stenosis, or hypertrophic obstructive cardiomyopathy (HOCM).
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).
Recent myocardial infarction
The combination of captopril and valsartan has shown no additional clinical benefit,
instead the risk for adverse events increased compared to treatment with the
respective therapies (see sections 4.2 and 5.1). Therefore, the combination of
valsartan with an ACE inhibitor is not recommended.
Caution should be observed when initiating therapy in post-myocardial infarction patients.
Evaluation of post-myocardial infarction patients should always include assessment of
renal function (see section 4.2). Use of Cuenca in post-myocardial infarction patients
commonly results in some reduction in blood pressure, but discontinuation of therapy
because of continuing symptomatic hypotension is not usually necessary provided dosing
instructions are followed (see section 4.2).
Heart Failure
In patients with heart failure, the triple combination of an ACE inhibitor, a beta blocker
and Cuenca has not shown any clinical benefit (see section 5.1). This combination
apparently increases the risk for adverse events and is therefore not recommended.
Caution should be observed when initiating therapy in patients with heart failure.
Evaluation of patients with heart failure should always include assessment of renal
function (see section 4.2).
Use of Cuenca in patients with heart failure commonly results in some reduction in blood
pressure, but discontinuation of therapy because of continuing symptomatic hypotension is
not usually necessary provided dosing instructions are followed (see section 4.2).
In patients whose renal function may depend on the activity of the renin-angiotensin
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. As valsartan is an
angiotensin II antagonist, it cannot be excluded that the use of Cuenca may be associated
with impairment of the renal function.
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. should be immediately discontinued in patients
who develop angioedema, and should not be re-administered (see section
4.8).

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 Cuenca is contraindicated in patients with diabetes
mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see section 4.3).

Paediatric population
Impaired renal function
Use in paediatric patients with a creatinine clearance <30 ml/min and paediatric patients
undergoing dialysis has not been studied, therefore valsartan is not recommended in these
patients. No dose adjustment is required for paediatric patients with a creatinine clearance
>30 ml/min (see sections 4.2 and 5.2). Renal function and serum potassium should be
closely monitored during treatment with valsartan. This applies particularly when
valsartan is given in the presence of other conditions (fever, dehydration) likely to impair
renal function.
The concomitant use of ARBs - including Cuenca - or of ACEIs with aliskiren is
contraindicated in patients with renal impairment (GFR < 60 mL/min/1.73m2) (see sections
4.3 and 4.5).
Impaired hepatic function
As in adults, Cuenca is contraindicated in paediatric patients with severe hepatic
impairment, biliary cirrhosis and in patients with cholestasis (see sections 4.3 and 5.2).
There is limited clinical experience with Cuenca in paediatric patients with mild to
moderate hepatic impairment. The dose of valsartan should not exceed 80 mg in these
patients.
Warning about excipients:
This medicine contains sorbitol. Patients with hereditary problems of fructose intolerance
should not take this medicine.
This medicine contains lactose. Patients with hereditary problems of galactose intolerance,
the Lapp lactase deficiency (insufficiency observed in certain populations of Laponia) or
glucose-galactose malabsorption should not take this medicine.
This medicine contains less than 23 mg of sodium per dose; that is, essentially “sodium
free”.

4.5

Interaction with other medicinal products and other forms of interaction

Dual blockade of the Renin-Angiotensin- System (RAS) with ARBs, ACEIs, or aliskiren
Caution is required while co-administering ARBs, including Cuenca, with other agents
blocking the RAAS such as ACEIs or aliskiren (see section 4.4).
Concomitant use of angiotensin receptor antagonists (ARBs) - including Cuenca - 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

Lithium
Reversible increases in serum lithium concentrations and toxicity have been reported
during concurrent use of ACE inhibitors. 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.
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.
Caution required with concomitant use
Non-steroidal anti-inflammatory medicines (NSAIDs), including selective COX-2
inhibitors, acetylsalicylic acid >3 g/day), and non-selective NSAIDs
When angiotensin II antagonists are administered simultaneously with NSAIDs,
attenuation of the antihypertensive effect may occur. Furthermore, concomitant use of
angiotensin II antagonists and NSAIDs may lead to an increased risk of 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.
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.
Others
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, indometacin, hydrochlorothiazide, amlodipine, glibenclamide.
Paediatric population
In hypertension in children and adolescents, where underlying renal abnormalities are
common, caution is recommended with the concomitant use of valsartan and other
substances that inhibit the renin angiotensin aldosterone system which may increase serum
potassium. Renal function and serum potassium should be closely monitored.
4.6

Fertility, pregnancy and lactation

Pregnancy
The use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during the
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 AIIRAs, similar risks may exist for this class of drugs. Unless
continued AIIRA 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, hyperkalemia); see also section 5.3
“Preclinical safety data”.
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 sections 4.3 and 4.4).
BreastfeedingBecause no information is available regarding the use of valsartan during
breastfeeding, Cuenca is not recommended and alternative treatments with better
established safety profiles during breast-feeding are preferable, especially while nursing a
newborn or preterm infant.
Fertility
Valsartan had no adverse effects on the reproductive performance of male or female rats at
oral doses up to 200 mg/kg/day. This dose is 6 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).

4.7

Effects on ability to drive and use machines
No studies on the effects on the ability to drive have been performed. When driving
vehicles or operating machines it should be taken into account that occasionally
dizziness or weariness may occur.

4.8

Undesirable effects

In controlled clinical studies in adult patients with hypertension, the overall incidence of
adverse reactions (ADRs) was comparable with placebo and is consistent with the
pharmacology of valsartan. The incidence of ADRs did not appear to be related to dose or
treatment duration and also showed no association with gender, age or race.
The ADRs reported from clinical studies, post-marketing experience and laboratory
findings are listed below according to system organ class.
Adverse 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.
For all the ADRs reported from post-marketing experience and laboratory findings, it is

not possible to apply any ADR frequency and therefore they are mentioned with a "not
known" frequency.
Hypertension
Blood and lymphatic system disorders
Not known
Immune system disorders
Not known
Metabolism and nutrition disorders
Not known
Ear and labyrinth system disorders
Uncommon
Vascular disorders
Not known
Respiratory, thoracic and mediastinal disorders
Uncommon
Gastrointestinal disorders
Uncommon
Hepato-biliary disorders
Not known

Decrease in haemoglobin, Decrease in
haematocrit, Neutropenia, Thrombocytopenia
Hypersensitivity including serum sickness
Increase of serum potassium, Hyponatraemia
Vertigo
Vasculitis
Cough
Abdominal pain
Elevation of liver function values including
increase of serum bilirubin

Skin and subcutaneous tissue disorders
Not known
Angioedema, Rash, Pruritus
Musculoskeletal and connective tissue disorders
Not known
Myalgia
Renal and urinary disorders
Not known
Renal failure and impairment, Elevation of serum
creatinine
General disorders and administration site conditions
Uncommon
Fatigue
Paediatric population
Hypertension
The antihypertensive effect of valsartan has been evaluated in two randomised, doubleblind clinical studies in 561 paediatric patients from 6 to 18 years of age. With the
exception of isolated gastrointestinal disorders (like abdominal pain, nausea, vomiting)
and dizziness, no relevant differences in terms of type, frequency and severity of adverse
reactions were identified between the safety profile for paediatric patients aged 6 to 18
years and that previously reported for adult patients.
Neurocognitive and developmental assessment of paediatric patients aged 6 to 16 years of
age revealed no overall clinically relevant adverse impact after treatment with Cuenca for
up to one year.
In a double-blind randomized study in 90 children aged 1 to 6 years, which was followed
by a one-year open-label extension, two deaths and isolated cases of marked liver
transaminases elevations were observed. These cases occurred in a population who had
significant comorbidities. A causal relationship to Cuenca has not been established. In a
second study in which 75 children aged 1 to 6 years were randomised, no significant liver

transaminase elevations or death occurred with valsartan treatment.
Hyperkalaemia was more frequently observed in children and adolescents aged 6 to 18
years with underlying chronic kidney disease. The safety profile seen in controlled-clinical
studies in adult patients with post-myocardial infarction and/or heart failure varies from the
overall safety profile seen in hypertensive patients. This may relate to the patients
underlying disease. ADRs that occurred in adult patients with post-myocardial infarction
and/or heart failure patients are listed below.
-

Post-myocardial infarction and/or heart failure (studied in adult patients only)

Blood and lymphatic system disorders
Not known
Thrombocytopenia
Immune system disorders
Not known
Hypersensitivity including serum sickness
Metabolism and nutrition disorders
Uncommon
Hyperkalaemia
Not known
Increase of serum potassium, Hyponatraemia
Nervous system disorders
Common
Dizziness, Postural dizziness
Uncommon
Syncope, Headache
Ear and labyrinth system disorders
Uncommon
Vertigo
Cardiac disorders
Uncommon
Cardiac failure
Vascular disorders
Common
Hypotension, Orthostatic hypotension
Not known
Vasculitis
Respiratory, thoracic and mediastinal disorders
Uncommon
Cough
Gastrointestinal disorders
Uncommon
Nausea, Diarrhoea
Hepato-biliary disorders
Not known
Elevation of liver function values
Skin and subcutaneous tissue disorders
Uncommon
Angioedema
Not known
Rash, Pruritis
Musculoskeletal and connective tissue disorders
Not known
Myalgia
Renal and urinary disorders
Common
Renal failure and impairment
Uncommon
Acute renal failure, Elevation of serum creatinine
Not known
Increase in Blood Urea Nitrogen
General disorders and administration site conditions
Uncommon
Asthenia, Fatigue
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions via the
national reporting system listed in Appendix V*.

4.9

Overdose

Symptoms
Overdose with Cuenca may result in marked hypotension, which could lead to depressed
level of consciousness, circulatory collapse and/or shock.
Therapy
The therapeutic measures depend on the time of ingestion and the type and severity of the
symptoms; stabilisation of the circulatory condition is of prime importance.If hypotension
occurs, the patient should be placed in a supine position and blood volume correction
should be undertaken.
Valsartan is unlikely to be removed by haemodialysis.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Angiotensin II Antagonists, plain, ATC code: C09CA03
Valsartan is an orally active, potent, 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) less 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).
Hypertension
Administration of Cuenca 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 antihypertensive effect is substantially present within 2 weeks, and
maximal effects are attained within 4 weeks and persist during long-term therapy.
Combined with hydrochlorothiazide, a significant additional reduction in blood pressure
is achieved.
Abrupt withdrawal of Cuenca 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 Cuenca 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 randomized 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.
Recent myocardial infarction
The VALsartan In Acute myocardial iNfarcTion trial (VALIANT) was a randomised,
controlled, multinational, double-blind study in 14,703 patients with acute myocardial
infarction and signs, symptoms or radiological evidence of congestive heart failure
and/or evidence of left ventricular systolic dysfunction (manifested as an ejection fraction
:S40% by radionuclide ventriculography or :S35% by echocardiography or ventricular
contrast angiography). Patients were randomised within 12 hours to 10 days after the onset
of myocardial infarction symptoms to valsartan, captopril, or the combination of both. The
mean treatment duration was two years. The primary endpoint was time to all-cause
mortality.
Valsartan was as effective as captopril in reducing all-cause mortality after myocardial
infarction. All-cause mortality was similar in the valsartan (19.9%), captopril (19.5%), and
valsartan + captopril (19.3%) groups. Combining valsartan with captopril did not add
further benefit over captopril alone. There was no difference between valsartan and
captopril in all-cause mortality based on age, gender, race, baseline therapies or underlying
disease. Valsartan was also effective in prolonging the time to and reducing cardiovascular
mortality, hospitalisation for heart failure, recurrent myocardial infarction, resuscitated
cardiac arrest, and non-fatal stroke (secondary composite endpoint).
The safety profile of valsartan was consistent with the clinical course of patients treated in
the post- myocardial infarction setting. Regarding renal function, doubling of serum
creatinine was observed in 4.2% of valsartan-treated patients, 4.8% of valsartan+captopriltreated patients, and 3.4% of captopril-treated patients. Discontinuations due to various
types of renal dysfunction occurred in 1.1% of valsartan-treated patients, 1.3% in
valsartan+captopril patients, and 0.8% of captopril patients. An assessment of renal
function should be included in the evaluation of patients post-myocardial infarction.
There was no difference in all-cause mortality, cardiovascular mortality or morbidity when
beta blockers were administered together with the combination of valsartan + captopril,
valsartan alone, or captopril alone. Irrespective of treatment, mortality was lower in the
group of patients treated with a beta blocker, suggesting that the known beta blocker
benefit in this population was maintained in this trial.
Heart failure
Val-HeFT was a randomised, controlled, multinational clinical trial of valsartan compared

with placebo on morbidity and mortality in 5,010 NYHA class II (62%), III (36%) and
IV (2%) heart failure patients receiving usual therapy with LVEF <40% and left
ventricular internal diastolic diameter (LVIDD)
>2.9 cm/m2. Baseline therapy included ACE inhibitors (93%), diuretics (86%), digoxin
(67%) and beta
blockers (36%). The mean duration of follow-up was nearly two years. The mean daily
dose of Cuenca in Val-HeFT was 254 mg. The study had two primary endpoints: all cause
mortality (time to death) and composite mortality and heart failure morbidity (time to first
morbid event) defined as death, sudden death with resuscitation, hospitalisation for heart
failure, or administration of intravenous inotropic or vasodilator agents for four hours or
more without hospitalisation.
All cause mortality was similar (p=NS) in the valsartan (19.7%) and placebo (19.4%)
groups. The primary benefit was a 27.5% (95% CI: 17 to 37%) reduction in risk for time
to first heart failure hospitalisation (13.9% vs. 18.5%). Results appearing to favour
placebo (composite mortality and morbidity was 21.9% in placebo vs. 25.4% in valsartan
group) were observed for those patients receiving the triple combination of an ACE
inhibitor, a beta blocker and valsartan.
In a subgroup of patients not receiving an ACE inhibitor (n=366), the morbidity benefits
were greatest. In this subgroup all-cause mortality was significantly reduced with
valsartan compared to placebo by 33% (95% CI: –6% to 58%) (17.3% valsartan vs.
27.1% placebo) and the composite mortality and morbidity risk was significantly reduced
by 44% (24.9% valsartan vs. 42.5% placebo).
In patients receiving an ACE inhibitor without a beta-blocker, all cause mortality was
similar (p=NS) in the valsartan (21.8%) and placebo (22.5%) groups. Composite mortality
and morbidity risk was significantly reduced by 18.3% (95% CI: 8% to 28%) with
valsartan compared with placebo (31.0% vs. 36.3%).
In the overall Val-HeFT population, valsartan treated patients showed significant
improvement in NYHA class, and heart failure signs and symptoms, including dyspnoea,
fatigue, oedema and rales compared to placebo. Patients treated with valsartan had a better
quality of life as demonstrated by change in the Minnesota Living with Heart Failure
Quality of Life score from baseline at endpoint than placebo. Ejection fraction in valsartan
treated patients was significantly increased and LVIDD significantly reduced from
baseline at endpoint compared to placebo.
Paediatric population
Hypertension
The antihypertensive effect of valsartan have been evaluated in four randomized, doubleblind clinical studies in 561 paediatric patients from 6 to 18 years of age and 165
paediatric patients 1 to 6 years of age. Renal and urinary disorders, and obesity were the
most common underlying medical conditions potentially contributing to hypertension in
the children enrolled in these studies.
Clinical experience in children at or above 6 years of age
In a clinical study involving 261 hypertensive paediatric patients 6 to 16 years of age,
patients who weighed
<35 kg received 10, 40 or 80 mg of valsartan tablets daily (low, medium and high doses),
and patients who weighed ≥35 kg received 20, 80, and 160 mg of valsartan tablets daily
(low, medium and high doses). At the end of 2 weeks, valsartan reduced both systolic and
diastolic blood pressure in a dose-dependent manner.
Overall, the three dose levels of valsartan (low, medium and high) significantly reduced
systolic blood pressure by 8, 10, 12 mm Hg from the baseline, respectively. Patients were
re-randomized to either continue receiving the same dose of valsartan or were switched to

placebo. In patients who continued to receive the medium and high doses of valsartan,
systolic blood pressure at trough was -4 and -7 mm Hg lower than patients who received
the placebo treatment. In patients receiving the low dose of valsartan, systolic blood
pressure at trough was similar to that of patients who received the placebo treatment.
Overall, the dose- dependent antihypertensive effect of valsartan was consistent across all
the demographic subgroups.
In another clinical study involving 300 hypertensive paediatric patients 6 to 18 years of
age, eligible patients were randomized to receive valsartan or enalapril tablets for 12
weeks. Children weighing between ≥18 kg and <35 kg received valsartan 80 mg or
enalapril 10 mg; those between ≥35 kg and <80 kg received valsartan 160 mg or enalapril
20 mg; those ≥80 kg received valsartan 320 mg or enalapril 40 mg. Reductions in systolic
blood pressure were comparable in patients receiving valsartan (15 mmHg) and enalapril
(14 mm Hg) (non-inferiority p-value <0.0001). Consistent results were observed for
diastolic blood pressure with reductions of 9.1 mmHg and 8.5 mmHg with valsartan and
enalapril, respectively.
Clinical experience in children less than 6 years of age
Two clinical studies were conducted in patients aged 1 to 6 years with 90 and 75 patients,
respectively. No children below the age of 1 year were enrolled in these studies. In the
first study, the efficacy of valsartan was confirmed compared to placebo but a doseresponse could not be demonstrated. In the second study, higher doses of valsartan were
associated with greater BP reductions, but the dose response trend did not achieve
statistical significance and the treatment difference compared to placebo was not
significant.
Because of these inconsistencies, valsartan is not recommended in this age group (see
section 4.8).
The European Medicines Agency has waived the obligation to submit the results of studies
with Cuenca in all subsets of the paediatric population in heart failure and heart failure
after recent myocardial infarction. See section 4.2 for information on paediatric use.

5.2

Pharmacokinetic properties

Absorption:
Following oral administration of valsartan alone, peak plasma concentrations of valsartan
are reached in 2– 4 hours with tablets and 1–2 hours with solution formulation. Mean
absolute bioavailability is 23% and 39% with tablets and solution formulation,
respectively. 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 (t½a <1 h and t½ß about 9 h). Valsartan
is primarily eliminated by biliary excretion in faeces (about 83% of dose) and renally in
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.
In heart failure patients:
The average time to peak concentration and elimination half-life of valsartan in heart
failure patients are similar to that observed in healthy volunteers. AUC and Cmax values
of valsartan are almost proportional with increasing dose over the clinical dosing range
(40 to 160 mg twice a day). The average accumulation factor is about 1.7. The apparent
clearance of valsartan following oral administration is approximately
4.5 l/h. Age does not affect the apparent clearance in heart failure patients.
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.
Impaired renal function
As expected for a compound where renal clearance accounts for only 30% of total plasma
clearance, no correlation was seen between renal function and systemic exposure to
valsartan. Dose adjustment is therefore not required in patients with renal impairment
(creatinine clearance >10 ml/min). There is currently no experience on the safe use in
patients with a creatinine clearance <10 ml/min and patients undergoing dialysis,
therefore valsartan should be used with caution in these patients (see sections 4.2 and
4.4).
Valsartan is highly bound to plasma protein and is unlikely to be removed by dialysis.
Hepatic impairment
Approximately 70% of the dose absorbed is eliminated in the bile, essentially in the
unchanged form. Valsartan does not undergo any noteworthy biotransformation. A
doubling of exposure (AUC) was observed in patients with mild to moderate hepatic
impairment compared to healthy subjects. However, no correlation was observed between
plasma valsartan concentration versus degree of hepatic dysfunction. Cuenca has not been
studied in patients with severe hepatic dysfunction (see sections 4.2, 4.3 and 4.4).
Paediatric population
In a study of 26 paediatric hypertensive patients (aged 1 to 16 years) given a single dose
of a suspension of valsartan (mean: 0.9 to 2 mg/kg, with a maximum dose of 80 mg), the
clearance (litres/h/kg) of valsartan was comparable across the age range of 1 to 16 years
and similar to that of adults receiving the same formulation.
Impaired renal function
Use in paediatric patients with a creatinine clearance <30 ml/min and paediatric patients
undergoing dialysis has not been studied, therefore valsartan is not recommended in these
patients. No dose adjustment is required for paediatric patients with a creatinine clearance
>30 ml/min. Renal function and serum potassium should be closely monitored (see
sections 4.2 and 4.4).

5.3

Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of
safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.
In rats, maternally toxic doses (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).
In non-clinical safety studies, high doses of valsartan (200 to 600 mg/kg body weight)
caused in rats a reduction of red blood cell parameters (erythrocytes, haemoglobin,
haematocrit) and evidence of changes in renal haemodynamics (slightly raised plasma
urea, and renal tubular hyperplasia and basophilia in males). These doses in rats (200 and
600 mg/kg/day) are approximately 6 and 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).
In marmosets at similar doses, the changes were similar though more severe, particularly
in the kidney where the changes developed to a nephropathy which included raised urea
and creatinine.
Hypertrophy of the renal juxtaglomerular cells was also seen in both species. All changes
were considered to be caused by the pharmacological action of valsartan which produces
prolonged hypotension, particularly in marmosets. For therapeutic doses of valsartan in
humans, the hypertrophy of the renal juxtaglomerular cells does not seem to have any
relevance.
Paediatric population
Daily oral dosing of neonatal/juvenile rats (from a postnatal day 7 to postnatal day 70)
with valsartan at doses as low as 1 mg/kg/day (about 10-35% of the maximum
recommended paediatric dose of 4 mg/kg/day on systemic exposure basis) produced
persistent, irreversible kidney damage. These effects above mentioned represent an
expected exaggerated pharmacological effect of angiotensin converting enzyme inhibitors
and angiotensin II type 1 blockers; such effects are observed if rats are treated during the
first 13 days of life. This period coincides with 36 weeks of gestation in humans, which
could occasionally extend up to 44 weeks after conception in humans. The rats in the
juvenile valsartan study were dosed up to day 70, and effects on renal maturation
(postnatal 4-6 weeks) cannot be excluded. Functional renal maturation is an ongoing
process within the first year of life in humans. Consequently, a clinical relevance in
children <1 year of age cannot be excluded, while preclinical data do not indicate a safety
concern for children older than 1 year.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet core
Cellulose, microcrystalline (E 460)
Silica, colloidal anhydrous (E 551)
Sorbitol (E-420)
Magnesium carbonate (E 504)

Maize starch, pregelatinised
Povidone K-25 (E 1201)
Sodium stearylfumarate
Sodium lauryl sulphate
Crospovidone Type A (E 1202)
Film coating
Lactose monohydrate
Hypromellose (E 464)
Titanium dioxide (E 171)
Macrogol 4000

Cuenca 160 mg film-coated tablets additionally: Yellow iron oxide (E 172), brown
iron oxide (E 172).

6.2

Incompatibilities
Not applicable

6.3

Shelf life
1 year

6.4

Special precautions for storage
Do not store above 30ºC. Store in the original package in order to protect from
moisture

6.5

Nature and contents of container
PVC/PE/PVDC/aluminium blister.
Pack sizes: 7, 14, 28, 56, 98, 280 film-coated tablets
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements.
Any unused product or waste should be disposed of in accordance with local
requirements.

7

MARKETING AUTHORISATION HOLDER
Laboratorios Liconsa, S.A.
Gran Vía Carlos III, 98, 7th floor
08028 Barcelona, SPAIN

8

MARKETING AUTHORISATION NUMBER(S)
PL 23218/0045

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
31/01/2013

10

DATE OF REVISION OF THE TEXT
31/01/2013

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