Drug Class Description
Angiotensin II antagonists

Generic Name
Amlodipine

Drug Description
Exforge 5 mg/80 mg film-coated tablets: Each film-coated tablet contains 5 mg of amlodipine (as amlodipine besylate) and 80 mg of valsartan.Exforge 5 mg/160 mg film-coated tablets: Each film-coated tablet contains 5 mg of amlodipine (as amlodipine besylate) and 160 mg of valsartan.Exforge 10 mg/160 mg film-coated tablets: Each film-coated tablet contains 10 mg of amlodipine (as amlodipine besylate) and 160 mg of valsartan.

Presentation
Film-coated tabletExforge 5 mg/80 mg film-coated tablets: Dark yellow, round film-coated tablet with bevelled edges, imprinted with “NVR” on one side and “NV” on the other side.Exforge 5 mg/160 mg film-coated tablets: Dark yellow, oval film-coated tablet, imprinted with “NVR” on one side and “ECE” on the other side.Exforge 10 mg/160 mg film-coated tablets: Light yellow, oval film-coated tablet, imprinted with “NVR” on one side and “UIC” on the other side.

Indications
Treatment of essential hypertension. Exforge is indicated in patients whose blood pressure is not adequately controlled on amlodipine or valsartan monotherapy.

Adult Dosage
The recommended dose of Exforge is one tablet per day.Exforge 5 mg/80 mg may be administered in patients whose blood pressure is not adequately controlled with amlodipine 5 mg or valsartan 80 mg alone.Exforge 5 mg/160 mg may be administered in patients whose blood pressure is not adequately controlled with amlodipine 5 mg or valsartan 160 mg alone.Exforge 10 mg/160 mg may be administered in patients whose blood pressure is not adequately controlled with amlodipine 10 mg or valsartan 160 mg alone or with Exforge 5 mg/160 mg.Exforge can be used with or without food. It is recommended to take Exforge with some water.Individual dose titration with the components (i.e. amlodipine and valsartan) is recommended before changing to the fixed dose combination. When clinically appropriate, direct change from monotherapy to the fixed-dose combination may be considered.For convenience, patients receiving valsartan and amlodipine from separate tablets/capsules may be switched to Exforge containing the same component doses.Renal impairmentNo dosage adjustment is required for patients with mild to moderate renal impairment. Monitoring of potassium levels and creatinine is advised in moderate renal impairment.Hepatic impairmentCaution should be exercised when administering Exforge to patients with hepatic impairment or biliary obstructive disorders. In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg valsartan.Elderly (age 65 years or over)In elderly patients, caution is required when increasing the dosage.Children and adolescentsExforge is not recommended for use in patients aged below 18 years due to a lack of data on safety and efficacy.

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

Elderly Dosage
Elderly (age 65 years or over) - In elderly patients, caution is required when increasing the dosage.

Contra Indications
Hypersensitivity to the active substances, to dihydropyridine derivatives, or to any of the excipients.Severe hepatic impairment, biliary cirrhosis or cholestasis.Severe renal impairment (GFR < 30 ml/min/1.73 m2) and patients undergoing dialysis.Second and third trimesters of pregnancy

Special Precautions
PregnancyAngiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started.Sodium- and/or volume-depleted patientsExcessive hypotension was seen in 0.4% of patients with uncomplicated hypertension treated with Exforge in placebo-controlled studies. In patients with an activated renin-angiotensin system (such as volume- and/or salt-depleted patients receiving high doses of diuretics) who are receiving angiotensin receptor blockers, symptomatic hypotension may occur. Correction of this condition prior to administration of Exforge or close medical supervision at the start of treatment is recommended.If hypotension occurs with Exforge, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. Treatment can be continued once blood pressure has been stabilised.HyperkalaemiaConcomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other medicinal products that may increase potassium levels (heparin, etc.) should be undertaken with caution and with frequent monitoring of potassium levels.Renal artery stenosisNo data are available on the use of Exforge in patients with bilateral renal artery stenosis or stenosis to a solitary kidney.Kidney transplantationTo date there is no experience of the safe use of Exforge in patients who have had a recent kidney transplantation.Hepatic impairmentValsartan is mostly eliminated unchanged via the bile, whereas amlodipine is extensively metabolised by the liver. Particular caution should be exercised when administering Exforge to patients with mild to moderate hepatic impairment or biliary obstructive disorders.In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg valsartan.Renal impairmentNo dosage adjustment of Exforge is required for patients with mild to moderate renal impairment (GFR> 30 ml/min/1.73 m2). Monitoring of potassium levels and creatinine is advised in moderate renal impairment.Primary hyperaldosteronismPatients with primary hyperaldosteronism should not be treated with the angiotensin II antagonist valsartan as their renin-angiotensin system is affected by the primary disease.Heart failureAs a consequence of the inhibition of the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotaemia and (rarely) with acute renal failure and/or death. Similar outcomes have been reported with valsartan.In a long-term, placebo-controlled study (PRAISE-2) of amlodipine in patients with NYHA (New York Heart Association Classification) III and IV heart failure of non-ischaemic aetiology, amlodipine was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo.Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathyAs with all other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.Exforge has not been studied in any patient population other than hypertension.

Interactions
Interactions linked to amlodipineCaution required with concomitant useCYP3A4 inhibitorsA study in elderly patients has shown that diltiazem inhibits the metabolism of amlodipine, probably via CYP3A4 (plasma concentration increases by approximately 50% and the effect of amlodipine is increased). The possibility that more potent inhibitors of CYP3A4 (i.e. ketoconazole, itraconazole, ritonavir) may increase the plasma concentration of amlodipine to a greater extent than diltiazem cannot be excluded.CYP3A4 inducers (anticonvulsant agents [e.g. carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone], rifampicin, Hypericum perforatum)Co-administration may lead to reduced plasma concentrations of amlodipine. Clinical monitoring is indicated, with possible dosage adjustment of amlodipine during the treatment with the inducer and after its withdrawal.To be taken into account with concomitant useOthersIn monotherapy, amlodipine has been safely administered with thiazide diuretics, beta blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, atorvastatin, sildenafil, anti-acid medicines (aluminium hydroxide gel, magnesium hydroxide, simeticone), cimetidine, non-steroidal anti-inflammatory medicines, antibiotics and oral hypoglycaemic medicines.Interactions linked to valsartan Concomitant use not recommendedLithiumReversible increases in serum lithium concentrations and toxicity have been reported during concurrent use of ACE inhibitors. Despite the lack of experience with concomitant use of valsartan and lithium, this combination is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended.Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium and other substances that may increase potassium levelsIf a medicinal product that affects potassium levels is to be prescribed in combination with valsartan, monitoring of potassium plasma levels is advised.Caution required with concomitant useNon-steroidal anti-inflammatory medicines (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day), and non-selective NSAIDsWhen angiotensin II antagonists are administered simultaneously with NSAIDs attenuation of the antihypertensive effect may occur. Furthermore, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening of renal function and an increase in serum potassium. Therefore, monitoring of renal function at the beginning of the treatment is recommended, as well as adequate hydration of the patient.OthersIn monotherapy with valsartan, no interactions of clinical significance have been found with the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indometacin, hydrochlorothiazide, amlodipine, glibenclamide.Interactions common to the combinationNo drug interaction studies were performed with Exforge and other medicinal products.To be taken into account with concomitant useOther antihypertensive agentsCommonly used antihypertensive agents (e.g. alpha blockers, diuretics) and other medicinal products which may cause hypotensive adverse effects (e.g. tricyclic antidepressants, alpha blockers for treatment of benign prostate hyperplasia) may increase the antihypertensive effect of the combination.

Adverse Reactions
The safety of Exforge has been eva luated in five controlled clinical studies with 5,175 patients, 2,613 of whom received valsartan in combination with amlodipine.Adverse reactions have been ranked under headings of frequency using the following convention: very common ( 1/10); common ( 1/100, < 1/10); uncommon ( 1/1,000, < 1/100); rare ( 1/10,000, < 1/1,000); very rare ( < 1/10,000), including isolated reports.Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.Cardiac disorders Uncommon:Tachycardia, palpitationsRare:SyncopeNervous system disorders Common: >HeadacheUncommon:Dizziness, somnolence, dizziness postural, paraesthesiaEye disordersRare:Visual disturbanceEar and labyrinth disorders Uncommon:VertigoRare:TinnitusRespiratory, thoracic and mediastinal disorders Uncommon:Cough, pharyngolaryngeal painGastrointestinal disorders Uncommon:Diarrhoea, nausea, abdominal pain, constipation, dry mouthRenal and urinary disordersRare:Pollakisuria, polyuriaSkin and subcutaneous tissue disorders Uncommon:Rash, erythemaRare:Hyperhidrosis, exanthema, pruritusMusculoskeletal and connective tissue disorders Uncommon:Joint swelling, back pain, arthralgiaRare:Muscle spasm, sensation of heavinessInfections and infestations Common:Nasopharyngitis, influenzaVascular disorders Uncommon:Orthostatic hypotensionRare:HypotensionGeneral disorders and administration site conditions Common:Oedema, pitting oedema, facial oedema, oedema peripheral, fatigue, flushing, asthenia, hot flushImmune system disorders Rare:HypersensitivityReproductive system and breast disordersRare:Erectile dysfunctionPsychiatric disordersRare:AnxietyAdditional information on the combinationPeripheral oedema, a recognised side effect of amlodipine, was generally observed at a lower incidence in patients who received the amlodipine/valsartan combination than in those who received amlodipine alone. In double-blind, controlled clinical trials, the incidence of peripheral oedema by dose was as follows:% of patients who experienced peripheral oedemaValsartan (mg)04080160320Amlodipine (mg)03.05.52.41.60.92.58.02.35.42.43.953.14.82.32.12.41010.3>NANA9.09.5The mean incidence of peripheral oedema evenly weighted across all doses was 5.1% with the amlodipine/valsartan combination.Additional information on the individual componentsAdverse drug reactions previously reported with one of the individual components (amlodipine or valsartan) may be potential undesirable effects with Exforge as well, even if not observed in clinical trials or during the post-marketing period. Amlodipine CommonVomiting.UncommonAlopecia, altered bowel habits, dyspepsia, dyspnoea, rhinitis, gastritis, gingival hyperplasia, gynaecomastia, hyperglycaemia, impotence, increased urinary frequency, leucopenia, malaise, mood changes, myalgia, peripheral neuropathy, pancreatitis, hepatitis, thrombocytopenia, vasculitis, angioedema and erythema multiforme.RareArrhythmia, myocardial infarction. Rarely, patients, particularly those with severe obstructive coronary artery disease, have developed increased frequency, duration or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. Arrhythmia (including ventricular tachycardia and atrial fibrillation) has also been reported. These adverse events may not be distinguishable from the natural history of the underlying disease.Very rareCholestatic jaundice, AST and ALT increase, purpura, rash and pruritus. Exceptional cases of extrapyramidal syndrome have been reported.Valsartan Not knownDecrease in haemoglobin, decrease in haematocrit, neutropenia, thrombocytopenia, increase of serum potassium, elevation of liver function values including increase of serum bilirubin, renal failure and impairment, elevation of serum creatinine, angioedema, myalgia, vasculitis, hypersensitivity including serum sickness.

Manufacturer
Novartis

Drug Availability
(POM)

Updated
11 August 2009