EXFORGE® 5 mg/80 mg film-coated tablets

EXFORGE® 5 mg/160 mg film-coated tablets

EXFORGE® 10 mg/160 mg film-coated tablets

Exforge 5 mg/80 mg film-coated tablets: Each film-coated tablet contains 5 mg of amlodipine (as amlodipine besylate) and 80 mg of valsartan.

Exforge 5 mg/160 mg film-coated tablets: Each film-coated tablet contains 5 mg of amlodipine (as amlodipine besylate) and 160 mg of valsartan.

Exforge 10 mg/160 mg film-coated tablets: Each film-coated tablet contains 10 mg of amlodipine (as amlodipine besylate) and 160 mg of valsartan.

For a full list of excipients, see section 6.1.

Film-coated tablet

Exforge 5 mg/80 mg film-coated tablets: Dark yellow, round film-coated tablet with bevelled edges, imprinted with “NVR” on one side and “NV” on the other side.

Exforge 5 mg/160 mg film-coated tablets: Dark yellow, oval film-coated tablet, imprinted with “NVR” on one side and “ECE” on the other side.

Exforge 10 mg/160 mg film-coated tablets: Light yellow, oval film-coated tablet, imprinted with “NVR” on one side and “UIC” on the other side.

Treatment of essential hypertension.

Exforge is indicated in patients whose blood pressure is not adequately controlled on amlodipine or valsartan monotherapy.

The recommended dose of Exforge is one tablet per day.

Exforge 5 mg/80 mg may be administered in patients whose blood pressure is not adequately controlled with amlodipine 5 mg or valsartan 80 mg alone.

Exforge 5 mg/160 mg may be administered in patients whose blood pressure is not adequately controlled with amlodipine 5 mg or valsartan 160 mg alone.

Exforge 10 mg/160 mg may be administered in patients whose blood pressure is not adequately controlled with amlodipine 10 mg or valsartan 160 mg alone or with Exforge 5 mg/160 mg.

Exforge can be used with or without food. It is recommended to take Exforge with some water.

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 Exforge containing the same component doses.

Renal impairment

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

Caution should be exercised when administering Exforge 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.

Elderly (age 65 years or over)

In elderly patients, caution is required when increasing the dosage.

Children and adolescents

Exforge is not recommended for use in patients aged below 18 years due to a lack of data on safety and efficacy.

Hypersensitivity to the active substances, to dihydropyridine derivatives, or to any of the excipients.

Severe hepatic impairment, biliary cirrhosis or cholestasis.

Severe renal impairment (GFR <30 ml/min/1.73 m²) and patients undergoing dialysis.

Second and third trimesters of pregnancy (see sections 4.4 and 4.6).

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 Exforge in placebo-controlled studies. In patients with an activated renin-angiotensin 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 Exforge or close medical supervision at the start of treatment is recommended.

If hypotension occurs with Exforge, 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

No data are available on the use of Exforge in patients with bilateral renal artery stenosis or stenosis to a solitary kidney.

Kidney transplantation

To date there is no experience of the safe use of Exforge in patients who have had a recent kidney transplantation.

Hepatic impairment

Valsartan is mostly eliminated unchanged via the bile, whereas amlodipine is extensively metabolised by the liver. Particular caution should be exercised when administering Exforge 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 Exforge 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.

Heart failure

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 angiotensin-converting enzyme (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.

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.

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 obstructive hypertrophic cardiomyopathy.

Exforge has not been studied in any patient population other than hypertension.

Interactions linked to amlodipine

Caution required with concomitant use

CYP3A4 inhibitors

A study in elderly patients has shown that diltiazem inhibits the metabolism of amlodipine, probably via CYP3A4 (plasma concentration increases by approximately 50% and the effect of amlodipine is increased). The possibility that more potent inhibitors of CYP3A4 (i.e. ketoconazole, itraconazole, ritonavir) may increase the plasma concentration of amlodipine to a greater extent than diltiazem cannot be excluded.

CYP3A4 inducers (anticonvulsant agents [e.g. carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone], rifampicin, Hypericum perforatum)

Co-administration may lead to reduced plasma concentrations of amlodipine. Clinical monitoring is indicated, with possible dosage adjustment of amlodipine during the treatment with the inducer and after its withdrawal.

To be taken into account with concomitant use

Others

In monotherapy, amlodipine has been safely administered with thiazide diuretics, beta blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, atorvastatin, sildenafil, anti-acid medicines (aluminium hydroxide gel, magnesium hydroxide, simeticone), cimetidine, non-steroidal anti-inflammatory medicines, antibiotics and oral hypoglycaemic medicines.

Interactions linked to valsartan

Concomitant use not recommended

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concurrent use of ACE inhibitors. Despite 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 (see section 4.4).

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.

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.

Interactions common to the combination

No drug interaction studies were performed with Exforge 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.

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 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.

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).

Lactation

Because no information is available regarding the use of Exforge during breastfeeding, Exforge is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

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

The safety of Exforge has been evaluated in five controlled clinical studies with 5,175 patients, 2,613 of whom received valsartan in combination with amlodipine.

Adverse reactions have been ranked under headings of frequency using the following convention: very common ( 1/10); common ( 1/100, <1/10); uncommon ( 1/1,000, <1/100); rare ( 1/10,000, <1/1,000); very rare (<1/10,000), including isolated reports.

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

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

Amlodipine

Valsartan

Symptoms

There is no experience of overdose with Exforge. 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 Exforge 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: angiotensin II antagonists, plain (valsartan), combinations with dihydropyridine derivatives (amlodipine), ATC code: C09DB01

Exforge 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

The amlodipine component of Exforge 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.

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.

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 Exforge once daily in two placebo-controlled 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.

Exforge 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 Exforge 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 Exforge was maintained for over one year. Abrupt withdrawal of Exforge has not been associated with a rapid increase in blood pressure.

Age, gender, race or body mass index (30kg/m², <30kg/m²) did not influence the response to Exforge.

Exforge 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.

Linearity

Amlodipine and valsartan exhibit linear pharmacokinetics.

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 in hypertensive patients.

Biotransformation: Amlodipine is extensively (approximately 90%) metabolised in the liver to inactive metabolites.

Excretion: 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%. Valsartan shows multiexponential decay kinetics (t_½α <1 h and t_½ß about 9 h). Food decreases exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (C_max) 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.

Excretion: 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.

Amlodipine/Valsartan

Following oral administration of Exforge, peak plasma concentrations of valsartan and amlodipine are reached in 3 and 6–8 hours, respectively. The rate and extent of absorption of Exforge are equivalent to the bioavailability of valsartan and amlodipine when administered as individual tablets.

Special populations

Paediatric patients (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

Patients with hepatic insufficiency 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).

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.

Tablet core:

Cellulose microcrystalline

Crospovidone Type A

Silica, colloidal anhydrous

Magnesium stearate

Coating:

Hypromellose

Titanium dioxide (E171)

Iron oxide, yellow (E172)

Iron oxide, red (E172) for Exforge 10 mg/160 mg film-coated tablets only

Macrogol 4000

Talc

Not applicable.

3 years.

Do not store above 30°C.

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

PVC/PVDC blisters. One blister contains 7, 10 or 14 film-coated tablets.

Pack sizes: 7, 14, 28, 30, 56, 90, 98 or 280 film-coated tablets.

PVC/PVDC perforated unit dose blisters. One blister contains 7, 10 or 14 film-coated tablets.

Pack sizes: 56, 98 or 280 film-coated tablets and multipacks containing 280 (4 x 70) film-coated tablets.

Not all pack sizes may be marketed.

No special requirements.

Novartis Europharm Limited

Wimblehurst Road

Horsham

West Sussex, RH12 5AB

United Kingdom

Exforge 5 mg/80 mg film-coated tablets:

Exforge 5 mg/160 mg film-coated tablets:

Exforge 10 mg/160 mg film-coated tablets:

17 January 2007

27 July 2011

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu

POM