EXFORGE 5mg / 80mg tablets medication leaflet

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 ofvalsartan.

For the 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. Approximate size: diameter 8.20 mm.

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.

Approximate size: 14.2 mm (length) x 5.7 mm (width).

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.

Approximate size: 14.2 mm (length) x 5.7 mm (width).

Treatment of essential hypertension.

Exforge is indicated in adults whose blood pressure is not adequately controlled on amlodipine orvalsartan 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 adequatelycontrolled with amlodipine 5 mg or valsartan 80 mg alone.

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

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

Exforge can be used with or without food.

Individual dose titration with the components (i.e. amlodipine and valsartan) is recommended beforechanging to the fixed dose combination. When clinically appropriate, direct change from monotherapyto the fixed-dose combination may be considered.

For convenience, patients receiving valsartan and amlodipine from separate tablets/capsules may beswitched to Exforge containing the same component doses.

There are no available clinical data in severely renally impaired patients. No dosage adjustment isrequired for patients with mild to moderate renal impairment. Monitoring of potassium levels andcreatinine is advised in moderate renal impairment.

Exforge is contraindicated in patients with severe hepatic impairment (see section 4.3).

Caution should be exercised when administering Exforge to patients with hepatic impairment orbiliary obstructive disorders (see section 4.4). In patients with mild to moderate hepatic impairmentwithout cholestasis, the maximum recommended dose is 80 mg valsartan. Amlodipine dosagerecommendations 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 amlodipineor Exforge, 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 elderlyhypertensive patients (see section 4.1) to amlodipine or Exforge, the lowest available dose ofamlodipine monotherapy or of the amlodipine component, respectively, should be used.

The safety and efficacy of Exforge in children aged below 18 years have not been established. No dataare available.

Oral use.

It is recommended to take Exforge with some water.

* Hypersensitivity to the active substances, to dihydropyridine derivatives, or to any of theexcipients listed in section 6.1.

* Severe hepatic impairment, biliary cirrhosis or cholestasis.

* Concomitant use of Exforge with aliskiren-containing products in patients with diabetesmellitus or renal impairment (GFR <60 ml/min/1.73 m2) (see sections 4.5 and 5.1).

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

* Severe hypotension.

* Shock (including cardiogenic shock).

* Obstruction of the outflow tract of the left ventricle (e.g. hypertrophic obstructivecardiomyopathy and high grade aortic stenosis).

* Haemodynamically unstable heart failure after acute myocardial infarction.

The safety and efficacy of amlodipine in hypertensive crisis have not been established.

Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unlesscontinued AIIRA therapy is considered essential, patients planning pregnancy should be changed toalternative antihypertensive treatments which have an established safety profile for use in pregnancy.

When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, ifappropriate, 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 asvolume- and/or salt-depleted patients receiving high doses of diuretics) who are receiving angiotensinreceptor blockers, symptomatic hypotension may occur. Correction of this condition prior toadministration 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, ifnecessary, given an intravenous infusion of normal saline. Treatment can be continued once bloodpressure has been stabilised.

Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containingpotassium, or other medicinal products that may increase potassium levels (heparin, etc.) should beundertaken with caution and with frequent monitoring of potassium levels.

Renal artery stenosis

Exforge should be used with caution to treat hypertension in patients with unilateral or bilateral renalartery stenosis or stenosis to a solitary kidney since blood urea and serum creatinine may increase insuch patients.

Kidney transplantation

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

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 notbeen established. Particular caution should be exercised when administering Exforge to patients withmild to moderate hepatic impairment or biliary obstructive disorders.

In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommendeddose is 80 mg valsartan.

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 moderaterenal impairment.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism should not be treated with the angiotensin II antagonistvalsartan as their renin-angiotensin system is affected by the primary disease.

Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swellingof the face, lips, pharynx and/or tongue, has been reported in patients treated with valsartan. Some ofthese patients previously experienced angioedema with other medicinal products, including ACEinhibitors. Exforge should be discontinued immediately in patients who develop angioedema andshould not be re-administered.

Intestinal angioedema

Intestinal angioedema has been reported in patients treated with angiotensin II receptor antagonists,including valsartan (see section 4.8). These patients presented with abdominal pain, nausea, vomitingand diarrhoea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. Ifintestinal angioedema is diagnosed, valsartan should be discontinued and appropriate monitoringshould be initiated until complete resolution of symptoms has occurred.

Heart failure/post-myocardial infarction

As a consequence of the inhibition of the renin-angiotensin-aldosterone system, changes in renalfunction may be anticipated in susceptible individuals. In patients with severe heart failure whoserenal 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/orprogressive azotaemia and (rarely) with acute renal failure and/or death. Similar outcomes have beenreported with valsartan. Evaluation of patients with heart failure or post-myocardial infarction shouldalways 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, amlodipinewas associated with increased reports of pulmonary oedema despite no significant difference in theincidence of worsening heart failure as compared to placebo.

Calcium channel blockers, including amlodipine, should be used with caution in patients withcongestive 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 orsignificant aortic stenosis that is not high grade.

There is evidence that the concomitant use of ACE inhibitors, ARBs or aliskiren increases the risk ofhypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dualblockade of RAAS through the combined use of ACE inhibitors, ARBs or aliskiren is therefore notrecommended (see sections 4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, this should only occur under specialistsupervision 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.

Exforge 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 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 productswhich may cause hypotensive adverse effects (e.g. tricyclic antidepressants, alpha blockers fortreatment of benign prostate hyperplasia) may increase the antihypertensive effect of the combination.

Interactions linked to amlodipine

Grapefruit or grapefruit juice

Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailabilitymay be increased in some patients, resulting in increased blood pressure lowering effects.

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azoleantifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise tosignificant increase in amlodipine exposure. The clinical translation of these pharmacokineticvariations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thusbe 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 amlodipinemay vary. Therefore, blood pressure should be monitored and dose regulation considered both duringand 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 doseof simvastatin to 20 mg daily in patients on amlodipine.

Dantrolene (infusion)

In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association withhyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk ofhyperkalaemia, it is recommended that the co-administration of calcium channel blockers such asamlodipine be avoided in patients susceptible to malignant hyperthermia and in the management ofmalignant hyperthermia.

There is a risk of increased tacrolimus blood levels when co-administered with amlodipine. In order toavoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requiresmonitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.

To be taken into account with concomitant use

In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin,warfarin or ciclosporin.

Interactions linked to valsartan

Reversible increases in serum lithium concentrations and toxicity have been reported duringconcomitant administration of lithium with angiotensin converting enzyme inhibitors or angiotensin IIreceptor antagonists, including valsartan. Therefore, careful monitoring of serum lithium levels isrecommended during concomitant use. If a diurectic is also used, the risk of lithium toxicity maypresumably be increased further with Exforge.

Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium and othersubstances 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.

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 theantihypertensive 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 serumpotassium. 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 thehepatic uptake transporter OATP1B1 and of the hepatic efflux transporter MRP2. Co-administrationof inhibitors of the uptake transporter (rifampicin, ciclosporin) or efflux transporter (ritonavir) mayincrease 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 ACEinhibitors, ARBs or aliskiren is associated with a higher frequency of adverse events such ashypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared tothe use of a single RAAS-acting agent (see sections pct. 4.3, pct. 4.4 and 5.1).

In monotherapy with valsartan, no interactions of clinical significance have been found with thefollowing substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indometacin,hydrochlorothiazide, amlodipine, glibenclamide.

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 onlyrecommended when there is no safer alternative and when the disease itself carries greater risk for themother and foetus.

The use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during the firsttrimester of pregnancy (see section 4.4). The use of AIIRAs is contraindicated during the second andthird trimesters of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitorsduring the first trimester of pregnancy has not been conclusive; however a small increase in riskcannot 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 alternativeantihypertensive treatments which have an established safety profile for use in pregnancy. Whenpregnancy 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 humanfoetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonataltoxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3).

Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound checkof renal function and skull is recommended.

Infants whose mothers have taken AIIRAs should be closely observed for hypotension (seesections 4.3 and 4.4).

Amlodipine is excreted in human milk . The proportion of the maternal dose received by the infant hasbeen estimated with an interquartile range of 3-7%, with a maximum of 15%. The effect ofamlodipine on infants is unknown. No information is available regarding the use of Exforge duringbreast-feeding, therefore Exforge is not recommended and alternative treatments with betterestablished safety profiles during breast-feeding are preferable, especially while nursing a newborn orpreterm infant.

There are no clinical studies on fertility with Exforge.

Valsartan had no adverse effects on the reproductive performance of male or female rats at oral dosesup 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 patientstreated by calcium channel blockers. Clinical data are insufficient regarding the potential effect ofamlodipine on fertility. In one rat study, adverse effects were found on male fertility (see section 5.3).

Patients taking Exforge and driving vehicles or using machines should take into account that dizzinessor weariness may occasionally occur.

Amlodipine can have mild or moderate influence on the ability to drive and use machines. If patientstaking amlodipine suffer from dizziness, headache, fatigue or nausea the ability to react may beimpaired.

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

Adverse reactions have been ranked under headings of frequency using the following convention: verycommon (≥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).

MedDRA Adverse reactions Frequency

System organ Exforge Amlodipine Valsartanclass

Infections and Nasopharyngitis Common -- --infestations Influenza Common -- --

Blood and Haemoglobin and -- -- Not knownlymphatic system haematocrit decreaseddisorders Leukopenia -- Very rare --

Neutropenia -- -- Not known

Thrombocytopenia, -- Very rare Not knownsometimes with purpura

Immune system Hypersensitivity Rare Very rare Not knowndisorders

Metabolism and Hyperglycaemia -- Very rare --nutrition Hyponatraemia Uncommon -- --disorders

Psychiatric Depression -- Uncommon --disorders Anxiety Rare -- --

Insomnia/sleep disorders -- Uncommon --

Mood swings -- Uncommon --

Confusion -- Rare --

Nervous system Coordination abnormal Uncommon -- --disorders Dizziness Uncommon Common --

Dizziness postural Uncommon -- --

Dysgeusia -- Uncommon --

Extrapyramidal syndrome -- Not known --

Headache Common Common --

Hypertonia -- Very rare --

Paraesthesia Uncommon Uncommon --

Peripheral neuropathy, -- Very rare --neuropathy

Somnolence Uncommon Common --

Syncope -- Uncommon --

Tremor -- Uncommon --

Hypoesthesia -- Uncommon --

Eye disorders Visual disturbance Rare Uncommon --

Visual impairment Uncommon Uncommon --

Ear and labyrinth Tinnitus Rare Uncommon --disorders Vertigo Uncommon -- Uncommon

Cardiac disorders Palpitations Uncommon Common --

Syncope Rare -- --

Tachycardia Uncommon -- --

Arrhythmias (including -- Very rare --bradycardia, ventriculartachycardia, and atrialfibrillation)

Myocardial infarction -- Very rare --

Vascular Flushing -- Common --disorders Hypotension Rare Uncommon --

Orthostatic hypotension Uncommon -- --

Vasculitis -- Very rare Not known

Respiratory, Cough Uncommon Very rare Uncommonthoracic and Dyspnoea -- Uncommon --mediastinal Pharyngolaryngeal pain Uncommon -- --disorders Rhinitis -- Uncommon --

Gastrointestinal Abdominal discomfort, Uncommon Common Uncommondisorders abdominal pain upper

Change of bowel habit -- Uncommon --

Constipation Uncommon -- --

Diarrhoea Uncommon Uncommon --

Dry mouth Uncommon Uncommon --

Dyspepsia -- Uncommon --

Gastritis -- Very rare --

Gingival hyperplasia -- Very rare --

Nausea Uncommon Common --

Pancreatitis -- Very rare --

Vomiting -- Uncommon --

Intestinal angioedema -- -- Very rare

Hepatobiliary Liver function test abnormal, -- Very rare* Not knowndisorders including blood bilirubinincrease

Hepatitis -- Very rare --

Intrahepatic cholestasis, -- Very rare --jaundice

Skin and Alopecia -- Uncommon --subcutaneous Angioedema -- Very rare Not knowntissue disorders Dermatitis bullous -- -- Not known

Erythema Uncommon -- --

Erythema multiforme -- Very rare --

Exanthema Rare Uncommon --

Hyperhidrosis Rare Uncommon --

Photosensitivity reaction -- Uncommon --

Pruritus Rare Uncommon Not known

Purpura -- Uncommon --

Rash Uncommon Uncommon Not known

Skin discolouration -- Uncommon --

Urticaria and other forms of -- Very rare --rash

Exfoliative dermatitis -- Very rare --

Stevens-Johnson syndrome -- Very rare --

Quincke oedema -- Very rare --

Toxic Epidermal Necrolysis -- Not known --

Musculoskeletal Arthralgia Uncommon Uncommon --and connective Back pain Uncommon Uncommon --tissue disorders Joint swelling Uncommon -- --

Muscle spasm Rare Uncommon --

Myalgia -- Uncommon Not known

Ankle swelling -- Common --

Sensation of heaviness Rare -- --

Renal and Blood creatinine increased -- -- Not knownurinary disorders Micturition disorder -- Uncommon --

Nocturia -- Uncommon --

Pollakiuria Rare Uncommon --

Polyuria Rare -- --

Renal failure and -- -- Not knownimpairment

Reproductive Impotence -- Uncommon --system and Erectile dysfunction Rare -- --breast disorders Gynaecomastia -- Uncommon --

General disorders Asthenia Common Uncommon --and Discomfort, malaise -- Uncommon --administration Fatigue Common Common Uncommonsite conditions Facial oedema Common -- --

Flushing, hot flush Common -- --

Non cardiac chest pain -- Uncommon --

Oedema Common Common --

Oedema peripheral Common -- --

Pain -- Uncommon --

Pitting oedema Common -- --

Investigations Blood potassium increased -- -- Not known

Weight increase -- Uncommon --

Weight decrease -- Uncommon --

* Mostly consistent with cholestasis

Additional information on the combination

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

% of patients who experienced Valsartan (mg)peripheral oedema0 40 80 160 3200 3.0 5.5 2.4 1.6 0.9

Amlodipine (mg) 2.5 8.0 2.3 5.4 2.4 3.95 3.1 4.8 2.3 2.1 2.410 10.3 NA NA 9.0 9.5

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

Additional information on the individual components

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

Amlodipine

Common Somnolence, dizziness, palpitations, abdominal pain, nausea, ankle swelling.

Uncommon Insomnia, mood changes (including anxiety), depression, tremor, dysgeusia,syncope, hypoesthesia, visual disturbance (including diplopia), tinnitus,hypotension, dyspnoea, rhinitis, vomiting, dyspepsia, alopecia, purpura, skindiscolouration, hyperhidrosis, pruritus, exanthema, myalgia, muscle cramps, pain,micturition disorder, increased urinary frequency, impotence, gynaecomastia,chest pain, malaise, weight increase, weight decrease.

Rare Confusion.

Very rare Leukocytopenia, thrombocytopenia, allergic reactions, hyperglycaemia,hypertonia, peripheral neuropathy, myocardial infarction, arrhythmia (includingbradycardia, ventricular tachycardia and atrial fibrillation), vasculitis, pancreatitis,gastritis, gingival hyperplasia, hepatitis, jaundice, hepatic enzymes increased*,angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-

Johnson syndrome, Quincke oedema, photosensitivity.

Not known Toxic Epidermal Necrolysis

* mostly consistent with cholestasis

Exceptional cases of extrapyramidal syndrome have been reported.

Not known Decrease in haemoglobin, decrease in haematocrit, neutropenia,thrombocytopenia, increase of serum potassium, elevation of liver function valuesincluding increase of serum bilirubin, renal failure and impairment, elevation ofserum creatinine, angioedema, myalgia, vasculitis, hypersensitivity includingserum sickness.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no experience of overdose with Exforge. The major symptom of overdose with valsartan ispossibly pronounced hypotension with dizziness. Overdose with amlodipine may result in excessiveperipheral vasodilation and, possibly, reflex tachycardia. Marked and potentially prolonged systemichypotension, including shock with fatal outcome, have been reported with amlodipine.

Non-cardiogenic pulmonary oedema has rarely been reported as a consequence of amlodipineoverdose that may manifest with a delayed onset (24-48 hours post-ingestion) and require ventilatorysupport. Early resuscitative measures (including fluid overload) to maintain perfusion and cardiacoutput may be precipitating factors.

If ingestion is recent, induction of vomiting or gastric lavage may be considered. Administration ofactivated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipinehas been shown to significantly decrease amlodipine absorption. Clinically significant hypotensiondue to Exforge overdose calls for active cardiovascular support, including frequent monitoring ofcardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume andurine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, providedthat there is no contraindication to its use. Intravenous calcium gluconate may be beneficial inreversing 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

Exforge combines two antihypertensive compounds with complementary mechanisms to control bloodpressure in patients with essential hypertension: amlodipine belongs to the calcium antagonist classand valsartan to the angiotensin II antagonist class of medicines. The combination of these substanceshas an additive antihypertensive effect, reducing blood pressure to a greater degree than eithercomponent alone.

Amlodipine/Valsartan

The combination of amlodipine and valsartan produces dose-related additive reduction in bloodpressure across its therapeutic dose range. The antihypertensive effect of a single dose of thecombination persisted for 24 hours.

Placebo-controlled trials

Over 1,400 hypertensive patients received Exforge once daily in two placebo-controlled trials. Adultswith 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 andpoorly controlled type II diabetes and history of myocardial infarction or stroke within one year - wereexcluded.

Active-controlled trials in patients who were non-responders to monotherapy

A multicentre, randomised, double-blind, active-controlled, parallel-group trial showed normalisationof blood pressure (trough sitting diastolic blood pressure <90 mmHg at the end of the trial) in patientsnot adequately controlled on valsartan 160 mg in 75% of patients treated with amlodipine/valsartan10 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 anadditional 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 normalisationof blood pressure (trough sitting diastolic blood pressure <90 mmHg at the end of the trial) in patientsnot adequately controlled on amlodipine 10 mg in 78% of patients treated with amlodipine/valsartan10 mg/160 mg, compared to 67% of patients remaining on amlodipine 10 mg. The addition ofvalsartan 160 mg produced an additional reduction in systolic/diastolic blood pressure of2.9/2.1 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 sittingdiastolic blood pressure ≥110 mmHg and <120 mmHg. In this study (baseline blood pressure171/113 mmHg), an Exforge regimen of 5 mg/160 mg titrated to 10 mg/160 mg reduced sitting bloodpressure by 36/29 mmHg as compared to 32/28 mmHg with a regimen oflisinopril/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. Abruptwithdrawal of Exforge 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

Exforge.

Exforge has not been studied in any patient population other than hypertension. Valsartan has beenstudied in patients with post myocardial infarction and heart failure. Amlodipine has been studied inpatients with chronic stable angina, vasospastic angina and angiographically documented coronaryartery disease.

Amlodipine

The amlodipine component of Exforge inhibits the transmembrane entry of calcium ions into cardiacand vascular smooth muscle. The mechanism of the antihypertensive action of amlodipine is due to adirect relaxant effect on vascular smooth muscle, causing reductions in peripheral vascular resistanceand in blood pressure. Experimental data suggest that amlodipine binds to both dihydropyridine andnon-dihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smoothmuscle are dependent upon the movement of extracellular calcium ions into these cells throughspecific ion channels.

Following administration of therapeutic doses to patients with hypertension, amlodipine producesvasodilation, resulting in a reduction of supine and standing blood pressures. These decreases in bloodpressure are not accompanied by a significant change in heart rate or plasma catecholamine levels withchronic 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 adecrease in renal vascular resistance and an increase in glomerular filtration rate and effective renalplasma flow, without change in filtration fraction or proteinuria.

As with other calcium channel blockers, haemodynamic measurements of cardiac function at rest andduring exercise (or pacing) in patients with normal ventricular function treated with amlodipine havegenerally demonstrated a small increase in cardiac index without significant influence on dP/dt or onleft ventricular end diastolic pressure or volume. In haemodynamic studies, amlodipine has not beenassociated with a negative inotropic effect when administered in the therapeutic dose range to intactanimals and humans, even when co-administered with beta blockers to humans.

Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animalsor humans. In clinical studies in which amlodipine was administered in combination with betablockers to patients with either hypertension or angina, no adverse effects on electrocardiographicparameters were observed.

Use in patients with hypertension

A randomised double-blind morbidity-mortality study called the Antihypertensive and Lipid-Loweringtreatment 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) asfirst-line therapies to that of the thiazide-diuretic, chlorthalidone 12.5-25 mg/day in mild to moderatehypertension.

A total of 33,357 hypertensive patients aged 55 or older were randomised and followed for a mean of4.9 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 otheratherosclerotic cardiovascular disease (overall 51.5%), type 2 diabetes (36.1%), high densitylipoprotein - cholesterol <35 mg/dl or <0.906 mmol/l (11.6%), left ventricular hypertrophy diagnosedby electrocardiogram or echocardiography (20.9%), current cigarette smoking (21.9%).

The primary endpoint was a composite of fatal coronary heart disease or non-fatal myocardialinfarction. There was no significant difference in the primary endpoint between amlodipine-basedtherapy and chlorthalidone-based therapy: risk ratio (RR) 0.98 95% CI (0.90-1.07) p=0.65. Amongsecondary endpoints, the incidence of heart failure (component of a composite combinedcardiovascular endpoint) was significantly higher in the amlodipine group as compared to thechlorthalidone group (10.2% versus 7.7%, RR 1.38, 95% CI [1.25-1.52] p<0.001). However, there wasno significant difference in all-cause mortality between amlodipine-based therapy and chlorthalidone-based therapy RR 0.96 95% CI [0.89-1.02] p=0.20.

Valsartan is an orally active, potent and specific angiotensin II receptor antagonist. It acts selectivelyon the receptor subtype AT1, which is responsible for the known actions of angiotensin II. Theincreased plasma levels of angiotensin II following AT1 receptor blockade with valsartan maystimulate the unblocked receptor subtype AT2, which appears to counterbalance the effect of the AT1receptor. 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 orsubstance P, angiotensin II antagonists are unlikely to be associated with coughing. In clinical trialswhere 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 ACEinhibitor therapy, 19.5% of trial subjects receiving valsartan and 19.0% of those receiving a thiazidediuretic 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 incardiovascular regulation.

Administration of valsartan to patients with hypertension results in a drop in blood pressure withoutaffecting pulse rate.

In most patients, after administration of a single oral dose, onset of antihypertensive activity occurswithin 2 hours, and the peak drop in blood pressure is achieved within 4-6 hours. The antihypertensiveeffect persists over 24 hours after administration. During repeated administration, the maximumreduction in blood pressure with any dose is generally attained within 2-4 weeks and is sustainedduring long-term therapy. Abrupt withdrawal of valsartan has not been associated with reboundhypertension 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 incombination 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 cerebrovasculardisease, 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 andmortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension ascompared to monotherapy was observed. Given their similar pharmacodynamic properties, theseresults are also relevant for other ACE inhibitors and ARBs.

ACE inhibitors and ARBs should therefore not be used concomitantly in patients with diabeticnephropathy (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 inhibitoror an ARB in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovasculardisease, 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 inthe 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 theplacebo group.

Amlodipine and valsartan exhibit linear pharmacokinetics.

Amlodipine/Valsartan

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

Amlodipine

Absorption: After oral administration of therapeutic doses of amlodipine alone, peak plasmaconcentrations of amlodipine are reached in 6-12 hours. Absolute bioavailability has been calculated asbetween 64% and 80%. Amlodipine bioavailability is unaffected by food ingestion.

Distribution: Volume of distribution is approximately 21 l/kg. In vitro studies with amlodipine haveshown that approximately 97.5% of circulating drug is bound to plasma proteins.

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

Elimination: Amlodipine elimination from plasma is biphasic, with a terminal elimination half-life ofapproximately 30 to 50 hours. Steady-state plasma levels are reached after continuous administration for7-8 days. Ten per cent of original amlodipine and 60% of amlodipine metabolites are excreted in urine.

Absorption: Following oral administration of valsartan alone, peak plasma concentrations of valsartanare reached in 2-4 hours. Mean absolute bioavailability is 23%. Food decreases exposure (as measuredby AUC) to valsartan by about 40% and peak plasma concentration (Cmax) by about 50%, althoughfrom 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 thetherapeutic effect, and valsartan can therefore be given either with or without food.

Distribution: The steady-state volume of distribution of valsartan after intravenous administration isabout 17 litres, indicating that valsartan does not distribute into tissues extensively. Valsartan is highlybound to serum proteins (94-97%), mainly serum albumin.

Biotransformation: Valsartan is not transformed to a high extent as only about 20% of dose isrecovered 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 isprimarily eliminated in faeces (about 83% of dose) and urine (about 13% of dose), mainly asunchanged drug. Following intravenous administration, plasma clearance of valsartan is about 2 l/hand its renal clearance is 0.62 l/h (about 30% of total clearance). The half-life of valsartan is 6 hours.

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 elderlypatients, 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 theyoung, therefore caution is required when increasing the dosage.

The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. As expectedfor a compound where renal clearance accounts for only 30% of total plasma clearance, no correlationwas seen between renal function and systemic exposure to valsartan.

Very limited clinical data are available regarding amlodipine administration in patients with hepaticimpairment. Patients with hepatic impairment have decreased clearance of amlodipine with resultingincrease of approximately 40-60% in AUC. On average, in patients with mild to moderate chronicliver 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 (seesection 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 exposureof about 1.9 (valsartan) and 2.6 (amlodipine) times the clinical doses of 160 mg valsartan and 10 mgamlodipine. At higher exposures, there were ulceration and erosion of the stomach mucosa in bothfemales 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, aswell as interstitial lymphocyte inflammation and arteriolar medial hypertrophy were found at anexposure of 8-13 (valsartan) and 7-8 (amlodipine) times the clinical doses of 160 mg valsartan and10 mg amlodipine. Similar changes were found in the valsartan alone group (exposure 8.5-11.0 timesthe clinical dose of 160 mg valsartan).

In an embryo-foetal development study in the rat, increased incidences of dilated ureters, malformedsternebrae, 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 werealso 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 studies in rats and mice have shown delayed date of delivery, prolonged duration oflabour and decreased pup survival at dosages approximately 50 times greater than the maximumrecommended dosage for humans based on mg/kg.

There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended humandose of 10 mg on a mg/m2 basis). In another rat study in which male rats were treated with amlodipinebesilate for 30 days at a dose comparable with the human dose based on mg/kg, decreased plasmafollicle-stimulating hormone and testosterone were found as well as decreases in sperm density and inthe 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 providedaily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of carcinogenicity. Thehighest dose (for mice, similar to, and for rats twice* the maximum recommended clinical dose of10 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

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproductionand development.

In rats, maternally toxic doses (600 mg/kg/day) during the last days of gestation and lactation led tolower 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 themaximum recommended human dose on a mg/m2 basis (calculations assume an oral dose of320 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 areduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit) and evidence ofchanges in renal haemodynamics (slightly raised blood urea nitrogen, and renal tubular hyperplasiaand basophilia in males). These doses in rats (200 and 600 mg/kg/day) are approximately 6 and18 times the maximum recommended human dose on a mg/m2 basis (calculations assume an oral doseof 320 mg/day and a 60-kg patient).

In marmosets at comparable doses, the changes were similar though more severe, particularly in thekidney where the changes developed to a nephropathy including raised blood urea nitrogen andcreatinine.

Hypertrophy of the renal juxtaglomerular cells was also seen in both species. All changes wereconsidered to be caused by the pharmacological action of valsartan which produces prolongedhypotension, particularly in marmosets. For therapeutic doses of valsartan in humans, the hypertrophyof the renal juxtaglomerular cells does not seem to have any relevance.

Exforge 5 mg/80 mg film-coated tablets

Cellulose microcrystalline

Crospovidone (type A)

Silica, colloidal anhydrous

Magnesium stearate

Hypromellose, substitution type 2910 (3 mPa.s)

Titanium dioxide (E171)

Iron oxide, yellow (E172)

Macrogol 4000

Talc

Exforge 5 mg/160 mg film-coated tablets

Cellulose microcrystalline

Crospovidone (type A)

Silica, colloidal anhydrous

Magnesium stearate

Hypromellose, substitution type 2910 (3 mPa.s)

Titanium dioxide (E171)

Iron oxide, yellow (E172)

Macrogol 4000

Talc

Exforge 10 mg/160 mg film-coated tablets

Cellulose microcrystalline

Crospovidone (type A)

Silica, colloidal anhydrous

Magnesium stearate

Hypromellose, substitution type 2910 (3 mPa.s)

Titanium dioxide (E171)

Iron oxide, yellow (E172)

Iron oxide, red (E172)

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 and multipacks containing 280 (4x70 or20x14) 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.

Not all pack sizes may be marketed.

No special requirements.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

Exforge 5 mg/80 mg film-coated tablets

EU/1/06/370/001

EU/1/06/370/002

EU/1/06/370/003

EU/1/06/370/004

EU/1/06/370/005

EU/1/06/370/006

EU/1/06/370/007

EU/1/06/370/008

EU/1/06/370/025

EU/1/06/370/026

EU/1/06/370/027

EU/1/06/370/034

EU/1/06/370/037

Exforge 5 mg/160 mg film-coated tablets

EU/1/06/370/009

EU/1/06/370/010

EU/1/06/370/011

EU/1/06/370/012

EU/1/06/370/013

EU/1/06/370/014

EU/1/06/370/015

EU/1/06/370/016

EU/1/06/370/028

EU/1/06/370/029

EU/1/06/370/030

EU/1/06/370/035

EU/1/06/370/038

Exforge 10 mg/160 mg film-coated tablets

EU/1/06/370/017

EU/1/06/370/018

EU/1/06/370/019

EU/1/06/370/020

EU/1/06/370/021

EU/1/06/370/022

EU/1/06/370/023

EU/1/06/370/024

EU/1/06/370/031

EU/1/06/370/032

EU/1/06/370/033

EU/1/06/370/036

EU/1/06/370/039

Date of first authorisation: 17 January 2007

Date of latest renewal: 22 November 2011

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu