Exforge

When used in pregnancy, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus.  When pregnancy is detected, Exforge^® (amlodipine and valsartan) should be discontinued as soon as possible.

See WARNINGS: Fetal/Neonatal Morbidity and Mortality

Exforge^® (amlodipine and valsartan) is a fixed combination of amlodipine and valsartan.

Exforge® contains the besylate salt of amlodipine, a dihydropyridine calcium channel blocker (CCB). Amlodipine besylate is a white to pale yellow crystalline powder, slightly soluble in water and sparingly soluble in ethanol. Amlodipine besylate’s chemical name is 3-Ethyl-5- methyl (4RS)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate benzenesulphonate; its structural formula is

Its empirical formula is C₂₀H₂₅ClN₂O₅•C₆H₆O₃S and its molecular weight is 567.1.

Valsartan is a nonpeptide, orally active, and specific angiotensin II antagonist acting on the AT₁ receptor subtype. Valsartan is a white to practically white fine powder, soluble in ethanol and methanol and slightly soluble in water. Valsartan’s chemical name is N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl) [1,1′-biphenyl]-4-yl]methyl]-L-valine; its structural formula is

Its empirical formula is C₂₄H₂₉N₅O₃ and its molecular weight is 435.5.

Exforge^® tablets are formulated in four strengths for oral administration with a combination of amlodipine besylate, equivalent to 5 mg or 10 mg of amlodipine free-base, with 160 mg, or 320 mg of valsartan providing for the following available combinations:  5/160 mg, 10/160 mg, 5/320 mg, and 10/320 mg.

The inactive ingredients for all strengths of the tablets are colloidal silicon dioxide, crospovidone, magnesium stearate and microcrystalline cellulose. Additionally the 5/320 mg and 10/320 mg strengths contain iron oxide yellow and sodium starch glycolate. The film coating contains hypromellose, iron oxides, polyethylene glycol, talc and titanium dioxide.  

Exforge was studied in 2 placebo-controlled and 2 active-controlled trials in hypertensive patients. In a double-blind, placebo controlled study, a total of 1018 patients with mild-to-moderate hypertension received treatments of three combinations of amlodipine and valsartan (5/80, 5/160, 5/320 mg), or amlodipine alone (5 mg), valsartan alone (80, 160, or 320 mg) or placebo. At week 8, the combination treatments were statistically significantly superior to their monotherapy components in reduction of diastolic and systolic blood pressures.

*Mean Change and Placebo-Subtracted Mean Change from Baseline (mmHg) at Week 8 in Sitting Diastolic Blood Pressure. Mean baseline diastolic BP was 99.3 mmHg.

*Mean Change and Placebo-Subtracted Mean Change from Baseline (mmHg) at Week 8 in Sitting Systolic Blood Pressure. Mean baseline systolic BP was 152.8 mmHg.

In a double-blind, placebo controlled study, a total of 1,250 patients with mild to moderate hypertension received treatments of two combinations of amlodipine and valsartan (10/160, 10/320 mg), or amlodipine alone (10 mg), valsartan alone (160 or 320 mg) or placebo. At week 8, the combination treatments were statistically significantly superior to their monotherapy components in reduction of diastolic and systolic blood pressures.

*Mean Change and Placebo-Subtracted Mean Change from Baseline (mmHg) at Week 8 in Sitting Diastolic Blood Pressure. Mean baseline diastolic BP was 99.1 mmHg.

*Mean Change and Placebo-Subtracted Mean Change from Baseline (mmHg) at Week 8 in Sitting Systolic Blood Pressure. Mean baseline systolic BP was 156.7 mmHg.

In a double-blind, active-controlled study, a total of 947 patients with mild to moderate hypertension who were not adequately controlled on valsartan 160 mg received treatments of two combinations of amlodipine and valsartan (10/160, 5/160 mg), or valsartan alone (160 mg). At week 8, the combination treatments were statistically significantly superior to the monotherapy component in reduction of diastolic and systolic blood pressures.

*Mean Change from Baseline at Week 8 in Sitting Diastolic/Systolic Blood Pressure. Mean baseline BP was 149.5/ 96.5 (systolic/diastolic) mmHg

**Treatment Difference = difference in mean BP reduction between Exforge and the control group (Valsartan 160 mg) 

In a double-blind, active-controlled study, a total of 944 patients with mild to moderate hypertension who were not adequately controlled on amlodipine 10 mg received a combination of amlodipine and valsartan (10/160 mg), or amlodipine alone (10 mg). At week 8, the combination treatment was statistically significantly superior to the monotherapy component in reduction of diastolic and systolic blood pressures.

*Mean Change from Baseline at Week 8 in Sitting Diastolic/Systolic Blood Pressure. Mean baseline BP was 147.0/ 95.1 (systolic/diastolic) mmHg

**Treatment Difference = difference in mean BP reduction between Exforge and the control group (Amlodipine 10 mg) 

Exforge was also evaluated for safety in a 6-week, double-blind, active-controlled trial of 130 hypertensive patients with severe hypertension (mean baseline BP of 171/113 mmHg). Adverse events were similar in patients with severe hypertension and mild/moderate hypertension treated with Exforge. 

A wide age range of the adult population, including the elderly was studied (range 19-92 years, mean 54.7 years). Women comprised almost half of the studied population (47.3%). Of the patients in the studied Exforge group, 87.6% were Caucasian. Black and Oriental patients each represented approximately 4% of the population in the studied Exforge group.

Exforge^® (amlodipine and valsartan) is indicated for the treatment of hypertension.   

This fixed combination drug is not indicated for the initial therapy of hypertension (see DOSAGE AND ADMINISTRATION).

Exforge^® (amlodipine and valsartan) is contraindicated in patients who are hypersensitive to any component of this product.

Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin-converting enzyme inhibitors. There have been reports of spontaneous abortion, oligohydramnios and newborn renal dysfunction when pregnant women have taken valsartan. When pregnancy is detected, valsartan should be discontinued as soon as possible.

The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus ateriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.

In addition, first trimester use of ACE inhibitors, a specific class of drugs acting on the renin-angiotensin system, has been associated with a potential risk of birth defects in retrospective data. Healthcare professionals that prescribe drugs acting directly on the renin-angiotensin system should counsel women of childbearing potential about the potential risks of these agents during pregnancy.

Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin system will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, valsartan should be discontinued unless it is considered life- saving for the mother. Contraction stress testing (CST), a nonstress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.

Excessive hypotension was seen in 0.4% of patients with uncomplicated hypertension treated with Exforge^® (amlodipine and valsartan) 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, symptomatic hypotension may occur in patients receiving angiotensin receptor blockers. This condition should be corrected prior to administration of Exforge, or the treatment should start under close medical supervision.  

Caution should be observed when initiating therapy in patients with heart failure or recent myocardial infarction and in patients undergoing surgery or dialysis. Patients with heart failure or post-myocardial infarction patients given valsartan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. In controlled trials in heart failure patients, the incidence of hypotension in valsartan-treated patients was 5.5% compared to 1.8% in placebo-treated patients. In the Valsartan in Acute Myocardial Infarction Trial (VALIANT), hypotension in post-myocardial infarction patients led to permanent discontinuation of therapy in 1.4% of valsartan-treated patients and 0.8% of captopril-treated patients.

Since the vasodilation induced by amlodipine is gradual in onset, acute hypotension has rarely been reported after oral administration. Nonetheless, caution, as with any other peripheral vasodilator, should be exercised when administering amlodipine, particularly in patients with severe aortic stenosis.

If excessive hypotension occurs with Exforge, the patient should be placed in a supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

Rarely, patients, particularly those with severe obstructive coronary artery disease, have developed documented increased frequency, duration and or/severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.

No drug interaction studies have been conducted with Exforge and other drugs, although studies have been conducted with the individual amlodipine and valsartan components, as described below:

Studies with Amlodipine:

In clinical trials, amlodipine has been safely administered with thiazide diuretics, beta- blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.

Cimetidine: Co-administration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.

Grapefruit juice: Co-administration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine.

Maalox® (antacid): Co-administration of the antacid Maalox with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.

Sildenafil: A single 100 mg dose of sildenafil (Viagra^®**) in subjects with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.

Atorvastatin: Co-administration of multiple 10 mg doses of amlodipine with 80 mg of atorvastatin resulted in no significant change in the steady state pharmacokinetic parameters of atorvastatin.

Digoxin: Co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.

Warfarin: Co-administration of amlodipine with warfarin did not change the warfarin prothrombin response time.

Studies with Valsartan:

No clinically significant pharmacokinetic interactions were observed when valsartan was co-administered with amlodipine, atenolol, cimetidine, digoxin, furosemide, glyburide, hydrochlorothiazide, or indomethacin. The valsartan-atenolol combination was more antihypertensive than either component, but it did not lower the heart rate more than atenolol alone. 

Warfarin: Co-administration of valsartan and warfarin did not change the pharmacokinetics of valsartan or the time-course of the anticoagulant properties of warfarin.

Studies with amlodipine: The bioavailability of amlodipine is not altered by the presence of food.

Studies with valsartan: Food decreases the exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (C_max) by about 50%.

Studies with amlodipine: Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg amlodipine/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on mg/m² basis, similar to the maximum recommended human dose [MRHD] of 10 mg amlodipine/day. For the rat, the highest dose was, on a mg/m² basis, about two and a half times the MRHD. (Calculations based on a 60 kg patient.)

Mutagenicity studies conducted with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level.

There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of up to 10 mg amlodipine/kg/day (about 10 times the MRHD of 10 mg/day on a mg/m² basis).

Studies with valsartan: There was no evidence of carcinogenicity when valsartan was administered in the diet to mice and rats for up to 2 years at concentrations calculated to provide doses of up to 160 and 200 mg/kg/day, respectively. These doses in mice and rats are about 2.4 and 6 times, respectively, the MRHD of 320 mg/day on a mg/m² basis. (Calculations based on a 60 kg patient.)

Mutagenicity assays did not reveal any valsartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella and E. coli, a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with Chinese hamster ovary cells, and a rat micronucleus test.

Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses of up to 200 mg/kg/day. This dose is about 6 times the maximum recommended human dose on a mg/m² basis.

The effect of Exforge on labor and delivery has not been studied.

It is not known whether amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while amlodipine is administered.

It is not known whether valsartan is excreted in human milk, but valsartan was excreted in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Safety and effectiveness of Exforge in pediatric patients have not been established.

In controlled clinical trials, 323 hypertensive patients treated with Exforge were ≥ 65 years and 79 were ≥ 75 years. No overall differences in the efficacy or safety of Exforge was observed in this patient population, but greater sensitivity of some older individuals cannot be ruled out.

Exforge

Exforge^® (amlodipine and valsartan) has been evaluated for safety in over 2,600 patients with hypertension; over 1,440 of these patients were treated for at least 6 months and over 540 of these patients were treated for at least one year. Adverse experiences have generally been mild and transient in nature and have only infrequently required discontinuation of therapy.  

The overall frequency of adverse experiences was neither dose-related nor related to gender, age, or race. In placebo-controlled clinical trials, discontinuation due to side effects occurred in 1.8% of patients in the Exforge-treated patients and 2.1% in the placebo-treated group. The most common reasons for discontinuation of therapy with Exforge were peripheral edema (0.4%), and vertigo (0.2%).

The adverse experiences that occurred in placebo-controlled clinical trials in at least 2% of patients treated with Exforge but at a higher incidence in amlodipine/valsartan patients (n=1,437) than placebo (n=337) included peripheral edema (5.4% vs. 3.0%), nasopharyngitis (4.3% vs. 1.8%), upper respiratory tract infection (2.9% vs 2.1%) and dizziness (2.1% vs 0.9%).   

Orthostatic events (orthostatic hypotension and postural dizziness) were seen in less than 1% of patients.  

Other adverse experiences that occurred in placebo-controlled clinical trials with Exforge (≥ 0.2%) are uled below. It cannot be determined whether these events were causally related to Exforge.

Blood and Lymphatic System Disorders: Lymphadenopathy

Cardiac Disorders: Palpitations, tachycardia

Ear and Labyrinth Disorders: Ear pain

Gastrointestinal Disorders: Diarrhea, nausea, constipation, dyspepsia, abdominal pain, abdominal pain upper, gastritis, vomiting, abdominal discomfort, hemorrhoids, abdominal distention, dry mouth, flatulence, toothache, colitis

General Disorders and Administration Site Conditions: Fatigue, chest pain, asthenia, pitting edema, pyrexia, edema, pain

Immune System Disorders: seasonal allergies

Infections and Infestations: Nasopharyngitis, sinusitis, influenza, bronchitis, pharyngitis, urinary tract infection, gastroenteritis, pharyngotonsillitis, bronchitis acute, viral infection, tonsillitis, tooth abscess, cystitis, pneumonia

Injury, Poisoning and Procedural Complications: Contusion, epicondylitis, joint sprain, limb injury, post procedural pain

Investigations: Cardiac murmur

Metabolism and Nutrition Disorders: Gout, non-insulin dependent diabetes mellitus, hypercholesterolemia

Musculoskeletal and Connective Tissue Disorders: Arthralgia, back pain, muscle spasms, pain in extremity, myalgia, osteoarthritis, joint swelling, musculoskeletal chest pain

Nervous System Disorders: Headache, sciatica, parasthesia, cerviocobrachial syndrome, carpal tunnel syndrome, hypoaesthesia, sinus headache, somnolence

Psychiatric Disorders: Insomnia, anxiety, depression

Renal and Urinary Disorders: Hematuria, nephrolithiasis, pollakiuria

Reproductive System and Breast Disorders: Erectile dysfunction

Respiratory, Thoracic and Mediastinal Disorders: Cough, pharyngolaryngeal pain, sinus congestion, dyspnea, epistaxis, productive cough, dysphonia, nasal congestion

Skin and Subcutaneous Tissue Disorders: Pruritus, rash, hyperhidrosis, eczema, erythema

Vascular Disorders: Flushing, hot flush 

Isolated cases of the following clinically notable adverse events were also observed in clinical trials: exanthema, syncope, visual disturbance, hypersensitivity, tinnitus, and hypotension.

Norvasc^® has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. Other adverse events that have been reported <1% but >0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain were:

Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, postural hypotension, vasculitis

Central and Peripheral Nervous System: neuropathy peripheral, tremor 

Gastrointestinal: anorexia, dysphagia, pancreatitis, gingival hyperplasia

General: allergic reaction, hot flushes, malaise, rigors, weight gain, weight loss

Musculoskeletal System: arthrosis, muscle cramps

Psychiatric: sexual dysfunction (male and female), nervousness, abnormal dreams, depersonalization

Respiratory System: dyspnea

Skin and Appendages: angioedema, erythema multiforme, rash erythematous, rash maculopapular

Special Senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus

Urinary System: micturation frequency, micturation disorder, nocturia

Autonomic Nervous System: sweating increased

Metabolic and Nutritional: hyperglycemia, thirst

Hemopoietic: leukopenia, purpura, thrombocytopenia

Other events reported with amlodipine at a frequency of ≤ 0.1% of patients include: cardiac failure, pulse irregularity, extrasystoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia. Other reactions occurred sporadically and cannot be distinguished from medications or concurrent disease states such as myocardial infarction and angina.   

Adverse reactions reported for amlodipine for indications other than hypertension may be found in the prescribing information for Norvasc®.

Diovan^® has been evaluated for safety in more than 4,000 hypertensive patients in clinical trials. In trials in which valsartan was compared to an ACE inhibitor with or without placebo, the incidence of dry cough was significantly greater in the ACE inhibitor group (7.9%) than in the groups who received valsartan (2.6%) or placebo (1.5%). In a 129 patient trial limited to patients who had had dry cough when they had previously received ACE inhibitors, the incidences of cough in patients who received valsartan, HCTZ, or lisinopril were 20%, 19%, and 69% respectively (p<0.001).

Other adverse events, not uled above, occurring in >0.2% of patients in controlled clinical trials with valsartan are:

Body as a Whole: allergic reaction, asthenia

Musculoskeletal: muscle cramps

Neurologic and Psychiatric: paresthesia

Respiratory: sinusitis, pharyngitis

Urogenital: Impotence

Other reported events seen less frequently in clinical trials were: angioedema.

Adverse reactions reported for valsartan for indications other than hypertension may be found in the prescribing information for Diovan.

Information on Amlodipine

Single oral doses of amlodipine maleate equivalent to 40 mg/kg and 100 mg/kg amlodipine in mice and rats, respectively, caused deaths. Single oral doses equivalent to 4 or more mg/kg amlodipine in dogs (11 or more times the maximum recommended human dose on a mg/m² basis) caused a marked peripheral vasodilation and hypotension.

Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension. In humans, experience with intentional overdosage of amlodipine is limited. Reports of intentional overdosage include a patient who ingested 250 mg and was asymptomatic and was not hospitalized; another (120 mg) who was hospitalized underwent gastric lavage and remained normotensive; the third (105 mg) was hospitalized and had hypotension (90/50 mmHg) which normalized following plasma expansion. A case of accidental drug overdose has been documented in a 19-month-old male who ingested 30 mg amlodipine (about 2 mg/kg). During the emergency room presentation, vital signs were stable with no evidence of hypotension, but a heart rate of 180 bpm. Ipecac was administered 3.5 hours after ingestion and on subsequent observation (overnight) no sequelae was noted.

If massive overdose should occur, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements are essential. Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine) should be considered with attention to circulating volume and urine output. Intravenous calcium gluconate may help to reverse the effects of calcium entry blockade. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.

Information on Valsartan

Limited data are available related to overdosage in humans. The most likely effect of overdose with valsartan would be peripheral vasodilation, hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. Depressed level of consciousness, circulatory collapse and shock have been reported. If symptomatic hypotension should occur, supportive treatment should be instituted.

Valsartan is not removed from the plasma by hemodialysis.

Valsartan was without grossly observable adverse effects at single oral doses up to 2000 mg/kg in rats and up to 1000 mg/kg in marmosets, except for the salivation and diarrhea in the rat and vomiting in the marmoset at the highest dose (60 and 37 times, respectively, 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 is an effective treatment of hypertension in once daily doses of 2.5 mg-10 mg while valsartan is effective in doses of 80 mg-320 mg. In clinical trials with Exforge^® (amlodipine and valsartan) using amlodipine doses of 5 mg-10 mg and valsartan doses of 160 mg-320 mg, the antihypertensive effects increased with increasing doses.

The hazards (see WARNINGS) of valsartan are generally independent of dose; those of amlodipine are a mixture of dose-dependent phenomena (primarily peripheral edema) and dose-independent phenomena, the former much more common than the latter. Therapy with any combination of amlodipine and valsartan will thus be associated with both sets of dose-independent hazards. 

A patient who experiences dose-limiting adverse reactions on either component alone may be switched to Exforge containing a lower dose of that component in combination with the other to achieve similar blood pressure reductions. The clinical response to Exforge should be subsequently evaluated and if blood pressure remains uncontrolled after 3-4 weeks of therapy, the dose may be titrated up to a maximum of 10/320 mg. 

To minimize dose-independent hazards, it is usually appropriate to begin therapy with Exforge only after a patient has failed to achieve the desired antihypertensive effect with one or the other monotherapy.

A patient whose blood pressure is not adequately controlled with amlodipine (or another DHP CCB) alone or with valsartan (or another ARB) alone may be switched to combination therapy with Exforge.

For convenience, patients receiving amlodipine and valsartan from separate tablets may instead wish to receive tablets of Exforge containing the same component doses.

Exforge^® (amlodipine and valsartan) is available as tablets containing amlodipine besylate equivalent to 5 mg, or 10 mg of amlodipine free-base with valsartan 160 mg or 320 mg, providing for the following available combinations: 5/160 mg, 10/160 mg, 5/320 mg and 10/320 mg.

All strengths are packaged in bottles of 30 and 90 count, and unit dose buler packages.

5/160 mg Tablets - dark yellow, ovaloid shaped, film coated tablet with beveled edge, debossed with “NVR” on one side and “ECE” on the other side.  

      Bottles of 30                               NDC # 0078-0488-15

      Bottles of 90                               NDC # 0078-0488-34

      Unit Dose 100 tablets (10 X 10 tablets buler cards)      NDC # 0078-0488-35

10/160 mg Tablets - light yellow, ovaloid shaped, film coated tablet with beveled edge, debossed with “NVR” on one side and “UIC” on the other side.

      Bottles of 30                               NDC # 0078-0489-15

      Bottles of 90                               NDC # 0078-0489-34

      Unit Dose 100 tablets (10 X 10 tablets buler cards)      NDC # 0078-0489-35

5/320 mg Tablets - very dark yellow, ovaloid shaped, film coated tablet with beveled edge, debossed with “NVR” on one side and “CSF” on the other side.

      Bottles of 30                               NDC # 0078-0490-15

      Bottles of 90                               NDC # 0078-0490-34

      Unit Dose 100 tablets (10 X 10 tablets buler cards)      NDC # 0078-0490-35

10/320 mg Tablets - dark yellow, ovaloid shaped, film coated tablet with beveled edge, debossed with “NVR” on one side and “LUF” on the other side.

      Bottles of 30                               NDC # 0078-0491-15

      Bottles of 90                               NDC # 0078-0491-34

      Unit Dose 100 tablets (10 X 10 tablets buler cards)      NDC # 0078-0491-35

Store at 25^oC (77^oF); excursions permitted to 15-30^oC (59-86^oF). [See USP Controlled Room Temperature.] Protect from moisture.

*Norvasc^® is a registered trademark of Pfizer, Inc.

**Viagra^® is a registered trademark of Pfizer, Inc.

Distributed by:

Novartis Pharmaceuticals Corporation

East Hanover, New Jersey 07936

©Novartis

April 2007

Exforge^®‚ (X-phorj)

(amlodipine and valsartan) Tablets

5/160 mg, 10/160 mg, 5/320 mg, 10/320 mg

Rx only

Read the Patient Information that comes with EXFORGE before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or treatment.

What is EXFORGE?

EXFORGE is a prescription medicine used to treat high blood pressure (hypertension). EXFORGE contains two prescription medicines that work together to lower blood pressure: amlodipine, a calcium channel blocker, and valsartan, an angiotensin receptor blocker. EXFORGE should not be used before other medicines have been tried first to treat high blood pressure.

Blood pressure is the force of blood in your blood vessels when your heart beats and when your heart rests. You have high blood pressure when the force is too much. EXFORGE can help your blood vessels relax so your blood pressure is lower. Drugs that lower blood pressure lower your chance of having a stroke or heart attack.

EXFORGE has not been studied in children under 18 years of age.

Who should NOT take EXFORGE?

Do not take EXFORGE if you are allergic to any of the ingredients in EXFORGE. See the end of this leaflet for a complete ul of ingredients in EXFORGE.

What should I tell my doctor before taking EXFORGE?

Tell your doctor about all of your medical conditions, including if you:

• have heart problems
  
• have liver problems
  
• have kidney problems
  
• are vomiting or having a lot of diarrhea
  
• are pregnant or plan to become pregnant. See “What is the most important information I should know about EXFORGE?”
  
• are breast-feeding or plan to breast-feed. EXFORGE may pass into your milk. Do not breast-feed while you are taking EXFORGE.

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Some of your other medicines and EXFORGE could affect each other, causing serious side effects.

Especially tell your doctor if you take:

• other medicines for high blood pressure or a heart problem
  
• water pills (also called “diuretics”)
  
• potassium supplements
  
• a salt substitute

If you take a beta blocker medicine and your doctor tells you to stop taking it while you are taking EXFORGE, follow your doctor’s instructions very carefully to slowly and safely stop the beta blocker medicine. Stopping beta blocker medicines too quickly can cause chest pain (angina), heart attack, abnormal heart rhythm or high blood pressure. Taking EXFORGE does not help to prevent these effects. If you do not know if you take a beta blocker medicine, contact your doctor or pharmacist.

Know the medicines you take. Keep a ul of your medicines and show it to your doctor or pharmacist when you get a new medicine.

How do I take EXFORGE?

• Take EXFORGE exactly as your doctor tells you.
  
• Take EXFORGE at the same time each day.
  
• If you miss a dose, take it as soon as you remember. If it is close to your next dose, do not take the missed dose. Just take the next dose at the regular time. 
  
• If you take too much EXFORGE, call your doctor or Poison Control Center, or go to the emergency room.
  
• Tell all your doctors or dentist you are taking EXFORGE if you:
  • are going to have surgery
    
  • go for kidney dialysis

What are the possible side effects of EXFORGE?

EXFORGE may cause serious side effects including:

• injury or death of unborn babies. See “What is the most important information I should know about EXFORGE?”
  
• low blood pressure (hypotension). Low blood pressure is most likely to happen if you also take water pills, are on a low salt diet, have heart problems, or get sick with vomiting or diarrhea. Lie down if you feel faint or dizzy. Call your doctor right away.
  
• more chest pain (angina) and heart attacks in people that already have severe heart problems. This may happen when you start EXFORGE or when there is an increase in your dose of EXFORGE. Get emergency help if you get worse chest pain or chest pain that does not go away.
  
• kidney problems. Kidney problems may get worse in people that already have kidney disease. Some people will have changes in blood tests for kidney function and need a lower dose of EXFORGE. Call your doctor if you get swelling in your feet, ankles, or hands or unexplained weight gain.

• laboratory blood test changes in patients with congestive heart failure. In studies with valsartan, some patients with congestive heart failure had blood tests that showed increased potassium and decrease in kidney function.
  
• allergic reactions

The most common side effects that occur more frequently with EXFORGE than placebo (sugar pill) are:

• swelling (edema) of the hands, ankles, or feet.      
  
• nasal congestion, sore throat and discomfort when swallowing
  
• upper respiratory tract infection (head or chest cold)
  
• dizziness

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of EXFORGE. For more information, ask your doctor or pharmacist.

How should I store EXFORGE?

• Store EXFORGE at room temperature between 59°F to 86°F (15°C to 30°C).
  
• Keep EXFORGE dry (protect it from moisture).

Keep EXFORGE and all medicines out of the reach of children.

General Information about EXFORGE

Medicines are sometimes prescribed for conditions that are not mentioned in the patient information leaflet. Do not use EXFORGE for a condition for which it was not prescribed. Do not give EXFORGE to other people, even if they have the same symptoms that you have. It may harm them.

This patient information leaflet summarizes the most important information about EXFORGE. If you would like more information about EXFORGE, talk with your doctor. You can ask your doctor or pharmacist for information about EXFORGE that is written for health professionals. For more information go to www.EXFORGE.com or call 1-888-8-EXFORGE (1-888-839-3674).

What are the ingredients in EXFORGE?

Active ingredients: amlodipine besylate and valsartan

The inactive ingredients of all strengths of the tablets are colloidal silicon dioxide, crospovidone, magnesium stearate and microcrystalline cellulose. Additionally, the 5/320 mg and 10/320 mg strengths contain iron oxide yellow and sodium starch glycolate. The film coating contains hypromellose, iron oxides, polyethylene glycol, talc and titanium dioxide.

April 2007                               Printed in U.S.A.                       

© Novartis

Distributed by:     

Novartis Pharmaceuticals Corp.

East Hanover, New Jersey 07936