Treatment of essential hypertension.
Amlodipine/Valsartan tablets are indicated in adults whose blood pressure is not adequately controlled
on amlodipine or valsartan monotherapy.

Posology
The recommended dose of Amlodipine/Valsartan tablets is one tablet per day.
Amlodipine/Valsartan tablets may be administered in patients whose blood pressure is not adequately
controlled with amlodipine 5 mg or valsartan 160 mg alone.
Amlodipine/Valsartan tablets may be administered in patients whose blood pressure is not adequately
controlled with amlodipine 10 mg or valsartan 160 mg alone.
Amlodipine/Valsartan tablets may be administered in patients whose blood pressure is not adequately
controlled with amlodipine 5 mg or valsartan 320 mg alone.
Amlodipine/Valsartan tablets may be administered in patients whose blood pressure is not adequately
controlled with amlodipine 10 mg or valsartan 320 mg alone.
Amlodipine/Valsartan tablets can be used with or without food.
Individual dose titration with the components (i.e. amlodipine and valsartan) is recommended before
changing to the fixed dose combination. When clinically appropriate, direct change from monotherapy
to the fixed-dose combination may be considered.
For convenience, patients receiving valsartan and amlodipine from separate tablets/capsules may be
switched to Amlodipine/Valsartan tablets containing the same component doses.
Renal impairment
There are no available clinical data in severely renally impaired patients. No dosage adjustment is
required for patients with mild to moderate renal impairment. Monitoring of potassium levels and
creatinine is advised in moderate renal impairment.
Hepatic impairment
Amlodipine/Valsartan tablets is contraindicated in patients with severe hepatic impairment (see section
4.3).
Caution should be exercised when administering Amlodipine/Valsartan tablets to patients with hepatic
impairment or biliary obstructive disorders (see section 4.4). In patients with mild to moderate hepatic
impairment without cholestasis, the maximum recommended dose is 80 mg valsartan. Amlodipine
dosage recommendations have not been established in patients with mild to moderate hepatic impairment. When switching eligible hypertensive patients (see section 4.1) with hepatic impairment
to amlodipine or Amlodipine/Valsartan tablets, the lowest available dose of amlodipine monotherapy
or of the amlodipine component, respectively, should be used.
Elderly (age 65 years or over)
In elderly patients, caution is required when increasing the dosage. When switching eligible elderly
hypertensive patients (see section 4.1) to amlodipine or Amlodipine/Valsartan tablets, the lowest
available dose of amlodipine monotherapy or of the amlodipine component, respectively, should be
used.
Paediatric population
The safety and efficacy of Amlodipine/Valsartan tablets in children aged below 18 years have not been
established. No data are available.
Method of administration
Oral use.
It is recommended to take Amlodipine/Valsartan tablets with some water.

The safety and efficacy of amlodipine in hypertensive crisis have not been established.
Pregnancy
Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless
continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to
alternative antihypertensive treatments which have an established safety profile for use in pregnancy.

When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if
appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Sodium- and/or volume-depleted patients
Excessive hypotension was seen in 0.4% of patients with uncomplicated hypertension treated with
Amlodipine/Valsartan tablets in placebo-controlled studies. In patients with an activated reninangiotensin
system (such as volume- and/or salt-depleted patients receiving high doses of diuretics)
who are receiving angiotensin receptor blockers, symptomatic hypotension may occur. Correction of
this condition prior to administration of Amlodipine/Valsartan tablets or close medical supervision at
the start of treatment is recommended.
If hypotension occurs with Amlodipine/Valsartan tablets, the patient should be placed in the supine
position and, if necessary, given an intravenous infusion of normal saline. Treatment can be continued
once blood pressure has been stabilised.
Hyperkalaemia
Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing
potassium, or other medicinal products that may increase potassium levels (heparin, etc.) should be
undertaken with caution and with frequent monitoring of potassium levels.
Renal artery stenosis
Amlodipine/Valsartan tablets should be used with caution to treat hypertension in patients with
unilateral or bilateral renal artery stenosis or stenosis to a solitary kidney since blood urea and serum
creatinine may increase in such patients.
Kidney transplantation
To date there is no experience of the safe use of Amlodipine/Valsartan tablets in patients who have had
a recent kidney transplantation.
Hepatic impairment
Valsartan is mostly eliminated unchanged via the bile. The half life of amlodipine is prolonged and
AUC values are higher in patients with impaired liver function; dosage recommendations have not
been established. Particular caution should be exercised when administering Amlodipine/Valsartan
tablets to patients with mild to moderate hepatic impairment or biliary obstructive disorders.
In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended
dose is 80 mg valsartan.
Renal impairment
No dosage adjustment of Amlodipine/Valsartan tablets is required for patients with mild to moderate
renal impairment (GFR >30 ml/min/1.73 m2). Monitoring of potassium levels and creatinine is advised
in moderate renal impairment.

Primary hyperaldosteronism
Patients with primary hyperaldosteronism should not be treated with the angiotensin II antagonist
valsartan as their renin-angiotensin system is affected by the primary disease.
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 medicinal products, including ACE
inhibitors. Amlodipine/Valsartan tablets should be discontinued immediately in patients who develop
angioedema and should not be re-administered.
Heart failure/post-myocardial infarction
As a consequence of the inhibition of the renin-angiotensin-aldosterone system, changes in renal
function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal
function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE
inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive
azotaemia and (rarely) with acute renal failure and/or death. Similar outcomes have been reported with
valsartan. Evaluation of patients with heart failure or post-myocardial infarction should always include
assessment of renal function.
In a long-term, placebo-controlled study (PRAISE-2) of amlodipine in patients with NYHA (New
York Heart Association Classification) III and IV heart failure of non-ischaemic aetiology, amlodipine
was associated with increased reports of pulmonary oedema despite no significant difference in the
incidence of worsening heart failure as compared to placebo.
Calcium channel blockers, including amlodipine, should be used with caution in patients with
congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.
Aortic and mitral valve stenosis
As with all other vasodilators, special caution is indicated in patients suffering from mitral stenosis or
significant aortic stenosis that is not high grade.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that the concomitant use of ACE inhibitors, ARBs or aliskiren increases the risk of
hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual
blockade of RAAS through the combined use of ACE inhibitors, ARBs or aliskiren is therefore not
recommended (see sections 4.5 and 5.1).
If dual blockade therapy is considered absolutely necessary, this should only occur under specialist
supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
ACE inhibitors and ARBs should not be used concomitantly in patients with diabetic nephropathy.

Amlodipine/Valsartan tablets has not been studied in any patient population other than hypertension.

Interactions common to the combination
No drug-drug interaction studies have been performed with Amlodipine/Valsartan tablets and other
medicinal products.
To be taken into account with concomitant use
Other antihypertensive agents
Commonly used antihypertensive agents (e.g. alpha blockers, diuretics) and other medicinal products
which may cause hypotensive adverse effects (e.g. tricyclic antidepressants, alpha blockers for
treatment of benign prostate hyperplasia) may increase the antihypertensive effect of the combination.
Interactions linked to amlodipine
Concomitant use not recommended
Grapefruit or grapefruit juice
Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability
may be increased in some patients, resulting in increased blood pressure lowering effects.
Caution required with concomitant use
CYP3A4 inhibitors
Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole
antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to
significant increase in amlodipine exposure. The clinical translation of these pharmacokinetic
variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus
be required.
CYP3A4 inducers (anticonvulsant agents [e.g. carbamazepine, phenobarbital, phenytoin,
fosphenytoin, primidone], rifampicin, Hypericum perforatum)
Upon co-administration of known inducers of the CYP3A4, the plasma concentration of amlodipine
may vary. Therefore, blood pressure should be monitored and dose regulation considered both during
and after concomitant medication particularly with strong CYP3A4 inducers (e.g. rifampicin,
hypericum perforatum).
Simvastatin
Co-administration of multiple doses of 10 mg amlodipine with 80 mg simvastatin resulted in a 77%
increase in exposure to simvastatin compared to simvastatin alone. It is recommended to limit the dose
of simvastatin to 20 mg daily in patients on amlodipine.

Dantrolene (infusion)
In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with
hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of
hyperkalaemia, it is recommended that the co-administration of calcium channel blockers such as
amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of
malignant hyperthermia.
To be taken into account with concomitant use
Others
In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin,
warfarin or ciclosporin.
Interactions linked to valsartan
Concomitant use not recommended
Lithium
Reversible increases in serum lithium concentrations and toxicity have been reported during
concomitant administration of lithium with angiotensin converting enzyme inhibitors or angiotensin II
receptor antagonists, including valsartan. Therefore, careful monitoring of serum lithium levels is
recommended during concomitant use. If a diurectic is also used, the risk of lithium toxicity may
presumably be increased further with Amlodipine/Valsartan tablets.
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 to be prescribed 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.
Inhibitors of the uptake transporter (rifampicin, ciclosporin) or efflux transporter (ritonavir)
The results of an in vitro study with human liver tissue indicate that valsartan is a substrate of the
hepatic uptake transporter OATP1B1 and of the hepatic efflux transporter MRP2. Co-administration of inhibitors of the uptake transporter (rifampicin, ciclosporin) or efflux transporter (ritonavir) may
increase the systemic exposure to valsartan.
Dual blockade of the RAAS with ARBs, ACE inhibitors or aliskiren
Clinical trial data have shown that dual blockade of the RAAS through the combined use of ACE
inhibitors, ARBs or aliskiren is associated with a higher frequency of adverse events such as
hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to
the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).
Others
In monotherapy with valsartan, no interactions of clinical significance have been found with the
following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indometacin,
hydrochlorothiazide, amlodipine, glibenclamide.

Pregnancy
Amlodipine
The safety of amlodipine in human pregnancy has not been established. In animal studies, reproductive
toxicity was observed at high doses (see section 5.3). Use in pregnancy is only recommended when
there is no safer alternative and when the disease itself carries greater risk for the mother and foetus.
Valsartan
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 contraindicated during the second and third trimesters of
pregnancy (see sections 4.3 and 4.4).
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors
during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot
be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II
Receptor Antagonists (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
antihypertensive treatments which have an established safety profile for use in pregnancy. When
pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate,
alternative therapy should be started.
Exposure to AIIRA therapy during the second and third trimesters is known to induce human
foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal
toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3).
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check
of renal function and skull is recommended.

Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see sections
4.3 and 4.4).
Breast-feeding
Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has
been estimated with an interquartile range of 3–7%, with a maximum of 15%. The effect of amlodipine
on infants is unknown. No information is available regarding the use of Amlodipine/Valsartan tablets
during breast-feeding, therefore Amlodipine/Valsartan tablets 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
There are no clinical studies on fertility with Amlodipine/Valsartan tablets.
Valsartan
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).
Amlodipine
Reversible biochemical changes in the head of spermatozoa have been reported in some patients
treated by calcium channel blockers. Clinical data are insufficient regarding the potential effect of
amlodipine on fertility. In one rat study, adverse effects were found on male fertility (see section 5.3).

Patients taking Amlodipine/Valsartan tablets and driving vehicles or using machines should take into
account that dizziness or weariness may occasionally occur.
Amlodipine can have mild or moderate influence on the ability to drive and use machines. If patients
taking amlodipine suffer from dizziness, headache, fatigue or nausea the ability to react may be
impaired.

Summary of the safety profile
The safety of Amlodipine/Valsartan tablets has been evaluated in five controlled clinical studies with
5,175 patients, 2,613 of whom received valsartan in combination with amlodipine. The following
adverse reactions were found to be the most frequently occurring or the most significant or severe:
nasopharyngitis, influenza, hypersensitivity, headache, syncope, orthostatic hypotension, oedema,
pitting oedema, facial oedema, oedema peripheral, fatigue, flushing, asthenia and hot flush.
Tabulated list of adverse reactions

Adverse reactions have been ranked under headings of frequency 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).

* Mostly consistent with cholestasis

Additional information on the combination

Peripheral oedema, a recognised side effect of amlodipine, was generally observed at a lower incidence in patients who received the amlodipine/valsartan combination than in those who received amlodipine alone. In double-blind, controlled clinical trials, the incidence of peripheral oedema by dose was as follows:

The mean incidence of peripheral oedema evenly weighted across all doses was 5.1% with the amlodipine/valsartan combination.

Additional information on the individual components

Adverse reactions previously reported with one of the individual components (amlodipine or valsartan) may be potential adverse reactions with Exforge as well, even if not observed in clinical trials or during the post-marketing period.

Amlodipine

* mostly consistent with cholestasis

Exceptional cases of extrapyramidal syndrome have been reported.

Valsartan

To report any side effect(s):
• Saudi Arabia:
The National Pharmacovigilance and Drug Safety Centre (NPC)
Fax: +966-11-205-7662
Call NPC at +966-11-2038222,
Exts: 2317-2356-2340.
Toll free phone: 19999
E-mail: npc.drug@sfda.gov.sa
Website: https://ade.sfda.gov.sa/
• Other GCC States:
− Please contact the relevant competent authority

Symptoms
There is no experience of overdose with Amlodipine/Valsartan tablets. The major symptom of
overdose with valsartan is possibly pronounced hypotension with dizziness. Overdose with amlodipine
may result in excessive peripheral vasodilation and, possibly, reflex tachycardia. Marked and
potentially prolonged systemic hypotension up to and including shock with fatal outcome have been
reported.
Treatment
If ingestion is recent, induction of vomiting or gastric lavage may be considered. Administration of
activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine
has been shown to significantly decrease amlodipine absorption. Clinically significant hypotension due
to Amlodipine/Valsartan tablets overdose calls for active cardiovascular support, including frequent
monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating
fluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood
pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be
beneficial in reversing the effects of calcium channel blockade.
Both valsartan and amlodipine are unlikely to be removed by haemodialysis.

Pharmacotherapeutic group: Agents acting on the renin-angiotensin system; angiotensin II antagonists,
combinations; angiotensin II antagonists and calcium channel blockers, ATC code: C09DB01

Amlodipine/Valsartan tablets combines two antihypertensive compounds with complementary
mechanisms to control blood pressure in patients with essential hypertension: amlodipine belongs to
the calcium antagonist class and valsartan to the angiotensin II antagonist class of medicines. The
combination of these substances has an additive antihypertensive effect, reducing blood pressure to a
greater degree than either component alone.
Amlodipine/Valsartan
The combination of amlodipine and valsartan produces dose-related additive reduction in blood
pressure across its therapeutic dose range. The antihypertensive effect of a single dose of the
combination persisted for 24 hours.
Placebo-controlled trials
Over 1,400 hypertensive patients received Amlodipine/Valsartan tablets once daily in two placebocontrolled
trials. Adults with mild to moderate uncomplicated essential hypertension (mean sitting
diastolic blood pressure ≥95 and <110 mmHg) were enrolled. Patients with high cardiovascular risks –
heart failure, type I and poorly controlled type II diabetes and history of myocardial infarction or
stroke within one year – were excluded.
Active-controlled trials in patients who were non-responders to monotherapy
A multicentre, randomised, double-blind, active-controlled, parallel-group trial showed normalisation
of blood pressure (trough sitting diastolic blood pressure <90 mmHg at the end of the trial) in patients
not adequately controlled on valsartan 160 mg in 75% of patients treated with amlodipine/valsartan 10
mg/160 mg and 62% of patients treated with amlodipine/valsartan 5 mg/160 mg, compared to 53% of
patients remaining on valsartan 160 mg. The addition of amlodipine 10 mg and 5 mg produced an
additional reduction in systolic/diastolic blood pressure of 6.0/4.8 mmHg and 3.9/2.9 mmHg,
respectively, compared to patients who remained on valsartan 160 mg only.
A multicentre, randomised, double-blind, active-controlled, parallel-group trial showed normalisation
of blood pressure (trough sitting diastolic blood pressure <90 mmHg at the end of the trial) in patients
not adequately controlled on amlodipine 10 mg in 78% of patients treated with amlodipine/valsartan
10 mg/160 mg, compared to 67% of patients remaining on amlodipine 10 mg. The addition of
valsartan 160 mg produced an additional reduction in systolic/diastolic blood pressure of 2.9/2.1
mmHg compared to patients who remained on amlodipine 10 mg only.
Amlodipine/Valsartan tablets was also studied in an active-controlled study of 130 hypertensive
patients with mean sitting diastolic blood pressure ≥110 mmHg and <120 mmHg. In this study
(baseline blood pressure 171/113 mmHg), an Amlodipine/Valsartan tablets regimen of 5 mg/160 mg
titrated to 10 mg/160 mg reduced sitting blood pressure by 36/29 mmHg as compared to 32/28 mmHg
with a regimen of lisinopril/hydrochlorothiazide 10 mg/12.5 mg titrated to 20 mg/12.5 mg.

In two long-term follow-up studies the effect of Amlodipine/Valsartan tablets was maintained for over
one year. Abrupt withdrawal of Amlodipine/Valsartan tablets has not been associated with a rapid
increase in blood pressure.
Age, gender, race or body mass index (≥30 kg/m2, <30 kg/m2) did not influence the response to
Amlodipine/Valsartan tablets.
Amlodipine/Valsartan tablets has not been studied in any patient population other than hypertension.
Valsartan has been studied in patients with post myocardial infarction and heart failure. Amlodipine
has been studied in patients with chronic stable angina, vasospastic angina and angiographically
documented coronary artery disease.
Amlodipine
The amlodipine component of Amlodipine/Valsartan tablets inhibits the transmembrane entry of
calcium ions into cardiac and vascular smooth muscle. The mechanism of the antihypertensive action
of amlodipine is due to a direct relaxant effect on vascular smooth muscle, causing reductions in
peripheral vascular resistance and in blood pressure. Experimental data suggest that amlodipine binds
to both dihydropyridine and non-dihydropyridine binding sites. The contractile processes of cardiac
muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions
into these cells through specific ion channels.
Following administration of therapeutic doses to patients with hypertension, amlodipine produces
vasodilation, resulting in a reduction of supine and standing blood pressures. These decreases in blood
pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with
chronic dosing.
Plasma concentrations correlate with effect in both young and elderly patients.
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a
decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal
plasma flow, without change in filtration fraction or proteinuria.
As with other calcium channel blockers, haemodynamic measurements of cardiac function at rest and
during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have
generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on
left ventricular end diastolic pressure or volume. In haemodynamic studies, amlodipine has not been
associated with a negative inotropic effect when administered in the therapeutic dose range to intact
animals and humans, even when co-administered with beta blockers to humans.
Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals
or humans. In clinical studies in which amlodipine was administered in combination with beta blockers
to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters
were observed.

Use in patients with hypertension
A randomised double-blind morbidity-mortality study called the Antihypertensive and Lipid-Lowering
treatment to prevent Heart Attack Trial (ALLHAT) was performed to compare newer therapies:
amlodipine 2.5-10 mg/day (calcium channel blocker) or lisinopril 10-40 mg/day (ACE-inhibitor) as
first-line therapies to that of the thiazide-diuretic, chlorthalidone 12.5-25 mg/day in mild to moderate
hypertension.
A total of 33,357 hypertensive patients aged 55 or older were randomised and followed for a mean of
4.9 years. The patients had at least one additional coronary heart disease risk factor, including:
previous myocardial infarction or stroke (>6 months prior to enrollment) or documentation of other
atherosclerotic cardiovascular disease (overall 51.5%), type 2 diabetes (36.1%), high density
lipoprotein - cholesterol <35 mg/dl or <0.906 mmol/l (11.6%), left ventricular hypertrophy diagnosed
by electrocardiogram or echocardiography (20.9%), current cigarette smoking (21.9%).
The primary endpoint was a composite of fatal coronary heart disease or non-fatal myocardial
infarction. There was no significant difference in the primary endpoint between amlodipine-based
therapy and chlorthalidone-based therapy: risk ratio (RR) 0.98 95% CI (0.90-1.07) p=0.65. Among
secondary endpoints, the incidence of heart failure (component of a composite combined
cardiovascular endpoint) was significantly higher in the amlodipine group as compared to the
chlorthalidone group (10.2% versus 7.7%, RR 1.38, 95% CI [1.25-1.52] p<0.001). However, there was
no significant difference in all-cause mortality between amlodipine-based therapy and chlorthalidonebased
therapy RR 0.96 95% CI [0.89-1.02] p=0.20.
Valsartan
Valsartan is an orally active, potent and specific angiotensin II receptor antagonist. It acts selectively
on the receptor subtype AT1, which is responsible for the known actions of angiotensin II. The
increased plasma levels of angiotensin II following AT1 receptor blockade with valsartan may
stimulate the unblocked receptor subtype AT2, 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 does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin
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 coughing, compared to 68.5% of those treated with an ACE inhibitor (p <0.05).
Valsartan does not bind to or block other hormone receptors or ion channels known to be important in
cardiovascular regulation.

Administration of valsartan to patients with hypertension results in a drop in 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 drop in blood pressure is achieved within 4–6 hours. The antihypertensive
effect persists over 24 hours after administration. During repeated administration, the maximum
reduction in blood pressure with any dose is generally attained within 2–4 weeks and is sustained
during long-term therapy. Abrupt withdrawal of valsartan has not been associated with rebound
hypertension or other adverse clinical events.
Other: dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Two large randomised, controlled trials (ONTARGET [ONgoing Telmisartan Alone and in
combination with Ramipril Global Endpoint Trial] and VA NEPHRON-D [The Veterans Affairs
Nephropathy in Diabetes]) have examined the use of the combination of an ACE inhibitor with an
ARB.
ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular
disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D
was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and
mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as
compared to monotherapy was observed. Given their similar pharmacodynamic properties, these
results are also relevant for other ACE inhibitors and ARBs.
ACE inhibitors and ARBs should therefore not be used concomitantly in patients with diabetic
nephropathy (see section 4.4).
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints)
was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE inhibitor or
an ARB in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or
both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular
death and stroke were both numerically more frequent in the aliskiren group than in the placebo group
and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal
dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

Linearity
Amlodipine and valsartan exhibit linear pharmacokinetics.
Amlodipine/Valsartan
Following oral administration of Amlodipine/Valsartan tablets, peak plasma concentrations of
valsartan and amlodipine are reached in 3 and 6–8 hours, respectively. The rate and extent of absorption of Amlodipine/Valsartan tablets are equivalent to the bioavailability of valsartan and
amlodipine when administered as individual tablets.
Amlodipine
Absorption: After oral administration of therapeutic doses of amlodipine alone, peak plasma
concentrations of amlodipine are reached in 6–12 hours. Absolute bioavailability has been calculated
as between 64% and 80%. Amlodipine bioavailability is unaffected by food ingestion.
Distribution: Volume of distribution is approximately 21 l/kg. In vitro studies with amlodipine have
shown that approximately 97.5% of circulating drug is bound to plasma proteins.
Biotransformation: Amlodipine is extensively (approximately 90%) metabolised in the liver to
inactive metabolites.
Elimination: Amlodipine elimination from plasma is biphasic, with a terminal elimination half-life of
approximately 30 to 50 hours. Steady-state plasma levels are reached after continuous administration
for 7–8 days. Ten per cent of original amlodipine and 60% of amlodipine metabolites are excreted in
urine.
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 transformed to a high extent as only about 20% of dose is
recovered as metabolites. A hydroxy metabolite has been identified in plasma at low concentrations
(less than 10% of the valsartan AUC). This metabolite is pharmacologically inactive.
Elimination: Valsartan shows multiexponential decay kinetics (t½α <1 h and t½ß about 9 h). Valsartan is
primarily eliminated in faeces (about 83% of dose) and urine (about 13% of dose), mainly as
unchanged drug. Following intravenous administration, plasma clearance of valsartan is about 2 l/h
and its renal clearance is 0.62 l/h (about 30% of total clearance). The half-life of valsartan is 6 hours.
Special populations
Paediatric population (age below 18 years)
No pharmacokinetic data are available in the paediatric population.

Elderly (age 65 years or over)
Time to peak plasma amlodipine concentrations is similar in young and elderly patients. In elderly
patients, amlodipine clearance tends to decline, causing increases in the area under the curve (AUC)
and elimination half-life. Mean systemic AUC of valsartan is higher by 70% in the elderly than in the
young, therefore caution is required when increasing the dosage.
Renal impairment
The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. 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.
Hepatic impairment
Very limited clinical data are available regarding amlodipine administration in patients with hepatic
impairment. Patients with hepatic impairment have decreased clearance of amlodipine with resulting
increase of approximately 40–60% in AUC. On average, in patients with mild to moderate chronic
liver disease exposure (measured by AUC values) to valsartan is twice that found in healthy volunteers
(matched by age, sex and weight). Caution should be exercised in patients with liver disease (see
section 4.2).

Amlodipine/Valsartan
Adverse reactions observed in animal studies with possible clinical relevance were as follows:
Histopathological signs of inflammation of the glandular stomach was seen in male rats at an exposure
of about 1.9 (valsartan) and 2.6 (amlodipine) times the clinical doses of 160 mg valsartan and 10 mg
amlodipine. At higher exposures, there were ulceration and erosion of the stomach mucosa in both
females and males. Similar changes were also seen in the valsartan alone group (exposure 8.5–11.0
times the clinical dose of 160 mg valsartan).
An increased incidence and severity of renal tubular basophilia/hyalinisation, dilation and casts, as
well as interstitial lymphocyte inflammation and arteriolar medial hypertrophy were found at an
exposure of 8–13 (valsartan) and 7–8 (amlodipine) times the clinical doses of 160 mg valsartan and 10
mg amlodipine. Similar changes were found in the valsartan alone group (exposure 8.5–11.0 times the
clinical dose of 160 mg valsartan).
In an embryo-foetal development study in the rat, increased incidences of dilated ureters, malformed
sternebrae, and unossified forepaw phalanges were noticed at exposures of about 12 (valsartan) and 10
(amlodipine) times the clinical doses of 160 mg valsartan and 10 mg amlodipine. Dilated ureters were
also found in the valsartan alone group (exposure 12 times the clinical dose of 160 mg valsartan).
There were only modest signs of maternal toxicity (moderate reduction of body weight) in this study.

The no-observed-effect-level for developmental effects was observed at 3- (valsartan) and 4-
(amlodipine) fold the clinical exposure (based on AUC).
For the single compounds there was no evidence of mutagenicity, clastogenicity or carcinogenicity.
Amlodipine
Reproductive toxicology
Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of
labour and decreased pup survival at dosages approximately 50 times greater than the maximum
recommended dosage for humans based on mg/kg.
Impairment of fertility
There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females 14
days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended human dose
of 10 mg on a mg/m2 basis). In another rat study in which male rats were treated with amlodipine
besilate for 30 days at a dose comparable with the human dose based on mg/kg, decreased plasma
follicle-stimulating hormone and testosterone were found as well as decreases in sperm density and in
the number of mature spermatids and Sertoli cells.
Carcinogenesis, mutagenesis
Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to provide
daily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of carcinogenicity. The
highest dose (for mice, similar to, and for rats twice* the maximum recommended clinical dose of 10
mg on a mg/m2 basis) was close to the maximum tolerated dose for mice but not for rats.
Mutagenicity studies revealed no drug related effects at either the gene or chromosome levels.
* Based on patient weight of 50 kg
Valsartan
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction
and development.
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 blood urea nitrogen, 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 comparable doses, the changes were similar though more severe, particularly in the
kidney where the changes developed to a nephropathy including raised blood urea nitrogen 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.

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Do not store above 30°C.the original package, in order to protect from moisture

10/320mg are available in a box of 4 blisters, 7 tablets per each blister.
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