AMLODIPINA/VALSARTAN MYLAN 5mg / 160mg film-coated tablets medication leaflet

Amlodipine/Valsartan Mylan 5 mg/80 mg film-coated tablets

Amlodipine/Valsartan Mylan 5 mg/160 mg film-coated tablets

Amlodipine/Valsartan Mylan 10 mg/160 mg film-coated tablets

Amlodipine/Valsartan Mylan 5 mg/80 mg film-coated tablets

Each film-coated tablet contains 5 mg of amlodipine (as amlodipine besilate) and 80 mg of valsartan.

Amlodipine/Valsartan Mylan 5 mg/160 mg film-coated tablets

Each film-coated tablet contains 5 mg of amlodipine (as amlodipine besilate) and 160 mg of valsartan.

Amlodipine/Valsartan Mylan 10 mg/160 mg film-coated tablets

Each film-coated tablet contains 10 mg of amlodipine (as amlodipine besilate) and 160 mg ofvalsartan.

For the full list of excipients, see section 6.1.

Film-coated tablet

Amlodipine/Valsartan Mylan 5 mg/80 mg film-coated tablets

Light yellow, round, approximately 9 mm diameter, biconvex film-coated tablet debossed with “AV1”on one side and “M” on the other side.

Amlodipine/Valsartan Mylan 5 mg/160 mg film-coated tablets

Yellow, oval, approximately 15.6 mm × 7.8 mm, biconvex film-coated tablet debossed with “AV2” onone side and “M” on the other side.

Amlodipine/Valsartan Mylan 10 mg/160 mg film-coated tablets

Light brown, oval, approximately 15.6 mm × 7.8 mm, biconvex film-coated tablet debossed with“AV3” on one side and “M” on the other side.

Treatment of essential hypertension.

Amlodipine/Valsartan Mylan is indicated in adults whose blood pressure is not adequately controlledon amlodipine or valsartan monotherapy.

The recommended dose of Amlodipine/Valsartan Mylan is one tablet per day.

Amlodipine/Valsartan Mylan 5 mg/80 mg film-coated tablets

Amlodipine/Valsartan Mylan 5 mg/80 mg may be administered in patients whose blood pressure is notadequately controlled with amlodipine 5 mg or valsartan 80 mg alone.

Amlodipine/Valsartan Mylan 5 mg/160 mg film-coated tablets

Amlodipine/Valsartan Mylan 5 mg/160 mg may be administered in patients whose blood pressure isnot adequately controlled with amlodipine 5 mg or valsartan 160 mg alone.

Amlodipine/Valsartan Mylan 10 mg/160 mg film-coated tablets

Amlodipine/Valsartan Mylan 10 mg/160 mg may be administered in patients whose blood pressure isnot adequately controlled with amlodipine 10 mg or valsartan 160 mg alone or with

Amlodipine/Valsartan Mylan 5 mg/160 mg.

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 Amlodipine/Valsartan Mylan containing the same component doses.

There are no available clinical data in severely renally impaired patients.

No dose adjustment is required for patients with mild to moderate renal impairment. Monitoring ofpotassium levels and creatinine is advised in moderate renal impairment.

Amlodipine/valsartan is contraindicated in patients with severe hepatic impairment (see section 4.3).

Caution should be exercised when administering amlodipine/valsartan to patients with hepatic impairmentor biliary 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. Whenswitching eligible hypertensive patients (see section 4.1) with hepatic impairment to amlodipine oramlodipine/valsartan, the lowest available dose of amlodipine monotherapy or of the amlodipinecomponent, 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 amlodipine/valsartan, the lowest availabledose of amlodipine monotherapy or of the amlodipine component, respectively, should be used.

The safety and efficacy of amlodipine/valsartan in children aged below 18 years have not beenestablished. No data are available.

Oral use.

It is recommended to take Amlodipine/Valsartan Mylan with some water. The medicinal product canbe used with or without food.

* 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 Amlodipine/Valsartan Mylan with aliskiren-containing medicinal productsin patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m2) (see sections4.5 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 withamlodipine/valsartan in placebo-controlled studies. In patients with an activated renin-angiotensinsystem (such as volume- and/or salt-depleted patients receiving high doses of diuretics) who arereceiving angiotensin receptor blockers, symptomatic hypotension may occur. Correction of thiscondition prior to administration of amlodipine/valsartan or close medical supervision at the start oftreatment is recommended.

If hypotension occurs with amlodipine/valsartan, the patient should be placed in the supine positionand, if necessary, given an intravenous infusion of normal sodium chloride solution. Treatment can becontinued once blood pressure 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

Amlodipine/valsartan should be used with caution to treat hypertension in patients with unilateral orbilateral renal artery stenosis or stenosis to a solitary kidney since blood urea and serum creatininemay increase in such patients.

Kidney transplantation

To date there is no experience of the safe use of amlodipine/valsartan in patients who have had arecent kidney transplantation.

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 amlodipine/valsartan topatients with mild 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 amlodipine/valsartan is required for patients with mild to moderate renalimpairment (GFR >30 ml/min/1.73 m2). Monitoring of potassium levels and creatinine is advised inmoderate renal 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, includingangiotensin converting enzyme (ACE) inhibitors. Amlodipine/valsartan should be discontinuedimmediately 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 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, angiotensin II receptor blockers (ARBs)or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (includingacute renal failure). Dual blockade of RAAS through the combined use of ACE inhibitors, ARBs oraliskiren is therefore not recommended (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.

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

Interactions common to the combination

No interaction studies have been performed.

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 reaction (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 medicinal product 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.

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 amlodipine/valsartan.

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 drug (NSAIDs), including selective COX-2 inhibitors, acetylsalicylicacid (>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 AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). Theuse of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3and 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 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 havean 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 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 (see sections4.3 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/valsartan on infants is unknown. No information is available regarding the use ofamlodipine/valsartan during breast-feeding. Therefore Amlodipine/Valsartan Mylan is notrecommended and alternative treatments with better established safety profiles during breast-feedingare preferable, especially while nursing a newborn or preterm infant.

There are no clinical studies on fertility with amlodipine/valsartan.

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 amlodipine/valsartan and driving vehicles or using machines should take into accountthat dizziness or 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 amlodipine/valsartan has been evaluated in five controlled clinical studies with 5,175patients, 2,613 of whom received valsartan in combination with amlodipine. The following adversereactions 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.

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 Amlodipine/Valsartan Amlodipine Valsartanclass

Infections and Nasopharyngitis Common - -infestations Influenza Common - -

Blood and Haemoglobin and - - Not knownlymphatic haematocritsystem disorders decreased

Leukopenia - Very rare -

Neutropenia - - Not known

Thrombocytopenia, - Very rare Not knownsometimes withpurpura

Immune system Hypersensitivity Rare Very rare Not knowndisorders

Metabolism and Anorexia Uncommon - -nutrition Hypercalcaemia Uncommon - -disorders Hyperglycaemia - Very rare -

Hyperlipidaemia Uncommon - -

Hyperuricaemia Uncommon - -

Hypokalaemia Common - -

Hyponatraemia Uncommon - -

Psychiatric Depression - Uncommon -disorders Anxiety Rare - -

Insomnia/sleep - Uncommon -disorders

Mood swings - Uncommon -

Confusion - Rare -

Nervous system Coordination Uncommon - -disorders abnormal

Dizziness Uncommon Common -

Dizziness postural Uncommon - -

Dysgeusia - Uncommon -

Extrapyramidal - Not known -disorder

Headache Common Common -

Hypertonia - Very rare -

Paraesthesia Uncommon Uncommon -

Peripheral - Very rare -neuropathy,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 Palpitations Uncommon Common -disorders Syncope Rare - -

Tachycardia Uncommon - -

Arrhythmias - Very rare -(includingbradycardia,ventriculartachycardia, and atrialfibrillation)

Myocardial infarction - Very rare -

Vascular Flushing - Common -disorders Hypotension Rare Uncommon -

Orthostatic Uncommon - -hypotension

Vasculitis - Very rare Not known

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

Rhinitis - Uncommon -

Gastrointestinal Abdominal Uncommon Common Uncommondisorders discomfort,abdominal pain upper

Change of bowel - Uncommon -habit

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 -

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

Hepatitis - Very rare -

Intrahepatic - Very rare -cholestasis, jaundice

Alopecia - Uncommon -

Skin and Angioedema - Very rare Not knownsubcutaneous Dermatitis bullous - - Not knowntissue disorders Erythema Uncommon - -

Erythema multiforme - Very rare -

Exanthema Rare Uncommon -

Hyperhidrosis Rare Uncommon -

Photosensitivity - Uncommon -reaction

Pruritus Rare Uncommon Not known

Purpura - Uncommon -

Rash Uncommon Uncommon Not known

Skin discolouration - Uncommon -

Urticaria and other - Very rare -forms of rash

Exfoliative dermatitis - Very rare -

Stevens-Johnson - Very rare -syndrome

Toxic Epidermal - Not known -

Necrolysis

Quincke oedema - Very rare -

Musculoskeletal Arthralgia Uncommon Uncommon -and connectivetissue disorders Back pain Uncommon Uncommon -

Joint swelling Uncommon - -

Muscle spasm Rare Uncommon -

Myalgia - Uncommon Not known

Ankle swelling - Common -

Sensation of Rare - -heaviness

Renal and Blood creatinine - - Not knownurinary disorders increased

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

Flushing, hot flush Common - -

Non cardiac chest - Uncommon -pain

Oedema Common Common -

Oedema peripheral Common - -

Pain - Uncommon -

Pitting oedema Common - -

Investigations Blood potassium - - Not knownincreased

Weight increase - Uncommon -

Weight decrease - Uncommon -

* Mostly consistent with cholestasis

Additional information on the combination

Peripheral oedema, a recognised adverse reaction 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 0.92.5 8.0 2.3 5.4 2.4 3.9

Amlodipine (mg)5 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 amlodipine/valsartan as well, even if not observedin clinical trials 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, skin discolouration,hyperhidrosis, pruritus, exanthema, myalgia, muscle cramps, pain, micturitiondisorder, 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 (including bradycardia,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 values including increase ofserum bilirubin, renal failure and impairment, elevation of serum creatinine,angioedema, myalgia, vasculitis, hypersensitivity including serum 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 amlodipine/valsartan. The major symptom of overdose withvalsartan is possibly pronounced hypotension with dizziness. Overdose with amlodipine may result inexcessive peripheral vasodilation and, possibly, reflex tachycardia. Marked and potentially prolongedsystemic hypotension up to and including shock with fatal outcome have been reported.

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 amlodipine/valsartan overdose calls for active cardiovascular support, including frequentmonitoring of cardiac and respiratory function, elevation of extremities, and attention to circulatingfluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and bloodpressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may bebeneficial 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 receptorblockers (ARBs), combinations; angiotensin II receptor blockers (ARBs) and calcium channelblockers, ATC code: C09DB01

Amlodipine/Valsartan Mylan combines two antihypertensive compounds with complementarymechanisms to control blood pressure in patients with essential hypertension: amlodipine belongs tothe calcium antagonist class and valsartan to the angiotensin II antagonist class of medicinal products.

The combination of these substances has an additive antihypertensive effect, reducing blood pressureto a greater degree than either component 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 amlodipine/valsartan once daily in two placebo-controlledtrials. Adults with mild to moderate uncomplicated essential hypertension (mean sitting diastolic bloodpressure ≥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 oneyear - were excluded.

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 to53 % of patients remaining on valsartan 160 mg. The addition of amlodipine 10 mg and 5 mgproduced an additional reduction in systolic/diastolic blood pressure of 6.0/4.8 mmHg and3.9/2.9 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.

Amlodipine/valsartan was also studied in an active-controlled study of 130 hypertensive patients withmean sitting diastolic blood pressure ≥110 mmHg and <120 mmHg. In this study (baseline bloodpressure 171/113 mmHg), an amlodipine/valsartan regimen of 5 mg/160 mg titrated to 10 mg/160 mgreduced sitting blood pressure 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 amlodipine/valsartan was maintained for over oneyear. Abrupt withdrawal of amlodipine/valsartan has not been associated with a rapid increase inblood pressure.

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

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

Valsartan has been studied in patients with post myocardial infarction and heart failure. Amlodipinehas been studied in patients with chronic stable angina, vasospastic angina and angiographicallydocumented coronary artery disease.

Amlodipine

The amlodipine component of Amlodipine/Valsartan Mylan inhibits the transmembrane entry ofcalcium ions into cardiac and vascular smooth muscle. The mechanism of the antihypertensive actionof amlodipine is due to a direct relaxant effect on vascular smooth muscle, causing reductions inperipheral vascular resistance and in blood pressure. Experimental data suggest that amlodipine bindsto both dihydropyridine and non-dihydropyridine binding sites. The contractile processes of cardiacmuscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ionsinto these cells through specific 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, therewas no significant difference in all-cause mortality between amlodipine-based therapy andchlorthalidone-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 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 amlodipine/valsartan, peak plasma concentrations of valsartan andamlodipine are reached in 3 and 6-8 hours, respectively. The rate and extent of absorption ofamlodipine/valsartan are equivalent to the bioavailability of valsartan and amlodipine whenadministered as individual tablets.

Amlodipine

After oral administration of therapeutic doses of amlodipine alone, peak plasma concentrations ofamlodipine are reached in 6-12 hours. Absolute bioavailability has been calculated as between 64 %and 80 %. Amlodipine bioavailability is unaffected by food ingestion.

Volume of distribution is approximately 21 L/kg. In vitro studies with amlodipine have shown thatapproximately 97.5 % of circulating drug is bound to plasma proteins.

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

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 administrationfor 7-8 days. Ten per cent of original amlodipine and 60 % of amlodipine metabolites are excreted inurine.

Following oral administration of valsartan alone, peak plasma concentrations of valsartan are reachedin 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 about8 h post dosing plasma valsartan concentrations are similar for the fed and fasted groups. Thisreduction in AUC is not, however, accompanied by a clinically significant reduction in the therapeuticeffect, and valsartan can therefore be given either with or without food.

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 toserum proteins (94-97 %), mainly serum albumin.

Valsartan is not transformed to a high extent as only about 20 % of dose is recovered as metabolites. Ahydroxy metabolite has been identified in plasma at low concentrations (less than 10 % of thevalsartan AUC). This metabolite is pharmacologically inactive.

Valsartan shows multiexponential decay kinetics (t½α <1 h and t½ß about 9 h). Valsartan is primarilyeliminated 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 renalclearance 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 and10 mg amlodipine. At higher exposures, there were ulceration and erosion of the stomach mucosa inboth females and males. Similar changes were also seen in the valsartan alone group (exposure8.5-11.0 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) and10 (amlodipine) times the clinical doses of 160 mg valsartan and 10 mg amlodipine. Dilated ureterswere 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 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 females 14days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended human doseof 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 and 18times the maximum recommended human dose on a mg/m2 basis (calculations assume an oral dose of320 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.

Amlodipine/Valsartan Mylan 5 mg/80 mg film-coated tablets

Cellulose microcrystalline

Crospovidone

Magnesium stearate

Colloidal anhydrous silica

Hypromellose

Titanium dioxide (E171)

Macrogol 8000

Talc

Iron oxide yellow (E172)

Amlodipine/Valsartan Mylan 5 mg/160 mg film-coated tablets

Cellulose microcrystalline

Crospovidone

Magnesium stearate

Colloidal anhydrous silica

Iron oxide yellow

Hypromellose

Titanium dioxide (E171)

Macrogol 8000

Talc

Iron oxide yellow (E172)

Amlodipine/Valsartan Mylan 10 mg/160 mg film-coated tablets

Cellulose microcrystalline

Crospovidone

Magnesium stearate

Colloidal anhydrous silica

Hypromellose

Titanium dioxide (E171)

Macrogol 8000

Talc

Iron oxide yellow (E172)

Iron oxide red (E172)

Iron oxide black (E172)

Not applicable.

2 years.

Bottle packs after first opening:

To be used within 100 days.

This medicinal product does not require any special storage conditions.

PVC/PCTFE blisters.

Pack sizes: 14, 28, 56, 98 film-coated tablets, and 14x1,28x1, 30x1, 56x1, 90x1, 98x1 film-coatedtablets.

White high density polyethylene (HDPE) bottle with white opaque polypropylene cap with aluminiuminduction sealing liner wad.

Pack sizes: 28, 56 or 98 film-coated tablets.

Not all pack sizes may be marketed.

No special requirements.

Mylan Pharmaceuticals Limited

Damastown Industrial Park,

Mulhuddart, Dublin 15,

DUBLIN

Ireland

EU/1/16/1092/001

EU/1/16/1092/002

EU/1/16/1092/003

EU/1/16/1092/004

EU/1/16/1092/005

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EU/1/16/1092/037

EU/1/16/1092/038

EU/1/16/1092/039

Date of first authorisation: 22 March 2016

Date of latest renewal: 14 January 2021

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

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