HIGHLIGHTS OF PRESCRIBING INFORMATION ------------------------------CONTRAINDICATIONS ------------------------------

These highlights do not include all the information needed to use Known hypersensitivity to any component; Do not coadminister aliskiren with
EXFORGE safely and effectively. See full prescribing information for Exforge in patients with diabetes (4)
EXFORGE.
-----------------------WARNINGS AND PRECAUTIONS -----------------------
EXFORGE® (amlodipine and valsartan) tablets, for oral use  Hypotension: Correct volume depletion prior to initiation (5.2)
Initial U.S. Approval: 2007  Increased angina and/or myocardial infarction (5.3)
 Monitor renal function and potassium in susceptible patients (5.4, 5.5)
WARNING: FETAL TOXICITY
See full prescribing information for complete boxed warning. ------------------------------ADVERSE REACTIONS ------------------------------
 When pregnancy is detected, discontinue Exforge as soon as possible. In placebo-controlled clinical trials, discontinuation due to side effects
(5.1) occurred in 1.8% of patients in the Exforge-treated patients and 2.1% in the
 Drugs that act directly on the renin-angiotensin system can cause placebo-treated group. The most common reasons for discontinuation of
injury and death to the developing fetus. (5.1) therapy with Exforge were peripheral edema and vertigo. The adverse
experiences that occurred in clinical trials (≥ 2% of patients) at a higher
---------------------------INDICATIONS AND USAGE --------------------------- incidence than placebo included peripheral edema, nasopharyngitis, upper
Exforge is the combination tablet of amlodipine, a dihydropyridine calcium respiratory tract infection, and dizziness. (6.1)
channel blocker (DHP CCB), and valsartan, an angiotensin II receptor blocker
(ARB). Exforge is indicated for the treatment of hypertension, to lower blood To report SUSPECTED ADVERSE REACTIONS, contact Novartis
pressure: Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-
 In patients not adequately controlled on monotherapy (1) 1088 or www.fda.gov/medwatch.
 As initial therapy in patients likely to need multiple drugs to achieve their ------------------------------DRUG INTERACTIONS ------------------------------
blood pressure goals (1)  If simvastatin is coadministered with amlodipine, do not exceed doses
Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular greater than 20 mg daily of simvastatin (7)
events, primarily strokes and myocardial infarctions.  Non-Steroidal Anti-Inflammatory Drug (NSAID) use may lead to
increased risk of renal impairment and loss of anti-hypertensive effect
-----------------------DOSAGE AND ADMINISTRATION----------------------- (7)
General Considerations:  Dual inhibition of the renin-angiotensin system: Increased risk of renal
 Majority of effect attained within 2 weeks (2.1) impairment, hypotension, and hyperkalemia (7)
 May be administered with other antihypertensive agents (2.1)  Lithium: Increases in serum lithium level and lithium toxicity (7)
Hypertension:
 May be used as add-on therapy for patients not controlled on monotherapy -----------------------USE IN SPECIFIC POPULATIONS -----------------------
(2.2) Lactation: Breastfeeding is not recommended (8.2)
 Patients who experience dose-limiting adverse reactions on monotherapy Geriatric Patients: Not recommended for initial therapy (8.5)
may be switched to Exforge containing a lower dose of that component Hepatic Impairment: Not recommended for initial therapy (8.7)
(2.2) See 17 for PATIENT COUNSELING INFORMATION and FDA-
 May be substituted for titrated components (2.3) approved patient labeling.
 When used as initial therapy: Initiate with 5/160 mg, then titrate upwards
as necessary to a maximum of 10/320 mg once daily (2.4)
Revised: 4/2021
---------------------DOSAGE FORMS AND STRENGTHS ---------------------
Tablets (amlodipine/valsartan mg): 5/160, 10/160, 5/320, 10/320 (3)

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: FETAL TOXICITY
1 INDICATIONS AND USAGE 8.1 Pregnancy
1.1 Hypertension 8.2 Lactation
2 DOSAGE AND ADMINISTRATION 8.4 Pediatric Use
2.1 General Considerations 8.5 Geriatric Use
2.2 Add-on Therapy 8.6 Renal Impairment
2.3 Replacement Therapy 8.7 Hepatic Impairment
2.4 Initial Therapy 10 OVERDOSAGE
3 DOSAGE FORMS AND STRENGTHS 11 DESCRIPTION
4 CONTRAINDICATIONS 12 CLINICAL PHARMACOLOGY
5 WARNINGS AND PRECAUTIONS 12.1 Mechanism of Action
5.1 Fetal Toxicity 12.2 Pharmacodynamics
5.2 Hypotension 12.3 Pharmacokinetics
5.3 Risk of Myocardial Infarction or Increased Angina 13 NONCLINICAL TOXICOLOGY
5.4 Impaired Renal Function 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
5.5 Hyperkalemia 14 CLINICAL STUDIES
6 ADVERSE REACTIONS 16 HOW SUPPLIED/STORAGE AND HANDLING
6.1 Clinical Trials Experience 17 PATIENT COUNSELING INFORMATION
6.2 Postmarketing Experience *Sections or subsections omitted from the full prescribing information are not
7 DRUG INTERACTIONS listed.
8 USE IN SPECIFIC POPULATIONS
FULL PRESCRIBING INFORMATION
WARNING: FETAL TOXICITY
 When pregnancy is detected, discontinue Exforge as soon as possible. (5.1)
 Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. (5.1)
1 INDICATIONS AND USAGE
1.1 Hypertension
Exforge (amlodipine and valsartan) is indicated for the treatment of hypertension, to lower blood pressure.
Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and
myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide
variety of pharmacologic classes, including amlodipine and the angiotensin II receptor blocker (ARB) class to
which valsartan principally belongs. There are no controlled trials demonstrating risk reduction with Exforge.
Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as
appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and
limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific
advice on goals and management, see published guidelines, such as those of the National High Blood Pressure
Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High
Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of
action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it
can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs,
that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has
been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also
have been seen regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per
mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide
substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with
varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their
hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to
benefit from more aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many
antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or
diabetic kidney disease). These considerations may guide selection of therapy. Exforge (amlodipine and
valsartan) is indicated for the treatment of hypertension.
Exforge may be used in patients whose blood pressure is not adequately controlled on either monotherapy.
Exforge may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their
blood pressure goals.
The choice of Exforge as initial therapy for hypertension should be based on an assessment of potential benefits
and risks including whether the patient is likely to tolerate the lowest dose of Exforge.
Patients with stage 2 hypertension (moderate or severe) are at a relatively higher risk for cardiovascular events
(such as strokes, heart attacks, and heart failure), kidney failure and vision problems, so prompt treatment is
clinically relevant. The decision to use a combination as initial therapy should be individualized and should be
shaped by considerations such as baseline blood pressure, the target goal and the incremental likelihood of
achieving goal with a combination compared to monotherapy. Individual blood pressure goals may vary based
upon the patient’s risk.
Data from the high-dose multifactorial study [see Clinical Studies (14)] provide estimates of the probability of
reaching a blood pressure goal with Exforge compared to amlodipine or valsartan monotherapy. The figures
below provide estimates of the likelihood of achieving systolic or diastolic blood pressure control with Exforge
10/320 mg, based upon baseline systolic or diastolic blood pressure. The curve of each treatment group was
estimated by logistic regression modeling. The estimated likelihood at the right tail of each curve is less reliable
due to small numbers of subjects with high baseline blood pressures.

Figure 1: Probability of Achieving Systolic Blood Pressure Figure 2: Probability of Achieving Diastolic Blood Pressure
<140 mmHg at Week 8 <90 mmHg at Week 8

Figure 3: Probability of Achieving Systolic Blood Pressure Figure 4: Probability of Achieving Diastolic Blood Pressure
<130 mmHg at Week 8 <80 mmHg at Week 8

For example, a patient with a baseline blood pressure of 160/100 mmHg has about a 67% likelihood of
achieving a goal of < 140 mmHg (systolic) and 80% likelihood of achieving < 90 mmHg (diastolic) on
amlodipine alone, and the likelihood of achieving these goals on valsartan alone is about 47% (systolic) or 62%
(diastolic). The likelihood of achieving these goals on Exforge rises to about 80% (systolic) or 85% (diastolic).
The likelihood of achieving these goals on placebo is about 28% (systolic) or 37% (diastolic).
2 DOSAGE AND ADMINISTRATION
2.1 General Considerations
Dose once daily. The dosage can be increased after 1 to 2 weeks of therapy to a maximum of one 10/320 mg
tablet once daily as needed to control blood pressure. The majority of the antihypertensive effect is attained
within 2 weeks after initiation of therapy or a change in dose.
Exforge may be administered with other antihypertensive agents.
2.2 Add-on Therapy
A patient whose blood pressure is not adequately controlled with amlodipine (or another dihydropyridine
calcium-channel blocker) alone or with valsartan (or another ARB) alone may be switched to combination
therapy with Exforge.
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 to 4 weeks of therapy, the dose may be titrated up to a maximum of 10/320 mg.
2.3 Replacement Therapy
For convenience, patients receiving amlodipine and valsartan from separate tablets may instead wish to receive
tablets of Exforge containing the same component doses.
2.4 Initial Therapy
A patient may be initiated on Exforge if it is unlikely that control of blood pressure would be achieved with a
single agent. The usual starting dose is Exforge 5/160 mg once daily in patients who are not volume-depleted.
3 DOSAGE FORMS AND STRENGTHS
Exforge (amlodipine and valsartan) tablets are available as follows:
5/160 mg tablets, debossed with NVR/ECE (side 1/side 2)
10/160 mg tablets, debossed with NVR/UIC
5/320 mg tablets, debossed with NVR/CSF
10/320 mg tablets, debossed with NVR/LUF
4 CONTRAINDICATIONS
Do not use in patients with known hypersensitivity to any component.
Do not coadminister aliskiren with Exforge in patients with diabetes [see Drug Interactions (7)].
5 WARNINGS AND PRECAUTIONS
5.1 Fetal Toxicity
Exforge can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-
angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and
increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung
hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria,
hypotension, renal failure, and death. When pregnancy is detected, discontinue Exforge as soon as possible [see
Use in Specific Populations (8.1)].
5.2 Hypotension
Excessive hypotension was seen in 0.4% of patients with uncomplicated hypertension treated with Exforge in
placebo-controlled studies. In patients with an activated renin-angiotensin system, such as volume- and/or salt-
depleted patients receiving high doses of diuretics, symptomatic hypotension may occur in patients receiving
angiotensin receptor blockers. Volume depletion should be corrected prior to administration of Exforge.
Treatment with Exforge should start under close medical supervision.
Initiate therapy cautiously 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, place the patient in a supine position and, if necessary, give
intravenous 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.
5.3 Risk of Myocardial Infarction or Increased Angina
Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of
amlodipine, particularly in patients with severe obstructive coronary artery disease.
5.4 Impaired Renal Function
Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin
system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-
angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart
failure, or volume depletion) may be at particular risk of developing acute renal failure on Exforge. Monitor
renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who
develop a clinically significant decrease in renal function on Exforge [see Drug Interactions (7)].
5.5 Hyperkalemia
Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Monitor serum electrolytes
periodically.
Some patients with heart failure have developed increases in potassium with valsartan therapy. These effects are
usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment.
Dosage reduction and/or discontinuation of Exforge may be required [see Adverse Reactions (6.1)].
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not
reflect the rates observed in practice. The adverse reaction information from clinical trials does, however,
provide a basis for identifying the adverse events that appear to be related to drug use and for approximating
rates.
Studies with Exforge:
Exforge has been evaluated for safety in over 2600 patients with hypertension; over 1440 of these patients were
treated for at least 6 months and over 540 of these patients were treated for at least 1 year. Adverse reactions
have generally been mild and transient in nature and have only infrequently required discontinuation of therapy.
The hazards [see Warnings and Precautions (5)] 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.
The overall frequency of adverse reactions 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 reactions 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=1437) 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.
Studies with Valsartan:
Diovan® has been evaluated for safety in more than 4000 hypertensive patients in clinical trials. In trials in
which valsartan was compared to an angiotensin-converting enzyme (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).
Clinical Lab Test Findings:
Creatinine: In heart failure patients, greater than 50% increases in creatinine were observed in 3.9% of
valsartan-treated patients compared to 0.9% of placebo-treated patients. In post-myocardial infarction patients,
doubling of serum creatinine was observed in 4.2% of valsartan-treated patients and 3.4% of captopril-treated
patients.
Blood Urea Nitrogen (BUN): In hypertensive patients, greater than 50% increases in BUN were observed in
5.5% of Exforge-treated patients compared to 4.7% of placebo-treated patients. In heart failure patients, greater
than 50% increases in BUN were observed in 16.6% of valsartan-treated patients compared to 6.3% of placebo-
treated patients [see Warnings and Precautions (5.4)].
Neutropenia: Neutropenia was observed in 1.9% of patients treated with Diovan and 0.8% of patients treated
with placebo.
6.2 Postmarketing Experience
The following additional adverse reactions have been reported in postmarketing experience. Because these
reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably
estimate their frequency or establish a causal relationship to drug exposure.
Amlodipine: Gynecomastia has been reported infrequently and a causal relationship is uncertain. Jaundice and
hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to
require hospitalization, have been reported in association with use of amlodipine.
Valsartan: The following additional adverse reactions have been reported in postmarketing experience with
valsartan:
Hypersensitivity: Angioedema has been reported. Some of these patients previously experienced angioedema
with other drugs including ACE inhibitors. Diovan should not be re-administered to patients who have had
angioedema.
Digestive: Elevated liver enzymes and reports of hepatitis
Musculoskeletal: Rhabdomyolysis
Renal: Impaired renal function, renal failure
Dermatologic: Alopecia, bullous dermatitis
Blood and Lymphatic: Thrombocytopenia
Vascular: Vasculitis
7 DRUG INTERACTIONS
No drug interaction studies have been conducted with Exforge and other drugs, although studies have been
conducted with the individual amlodipine and valsartan components.
Amlodipine
Impact of Other Drugs on Amlodipine
CYP3A Inhibitors
Coadministration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to
amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine
is coadministered with CYP3A inhibitors to determine the need for dose adjustment [see Clinical
Pharmacology (12.3)].
CYP3A Inducers
No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure
should be closely monitored when amlodipine is coadministered with CYP3A inducers (e.g. rifampicin, St.
John’s Wort).
Sildenafil
Monitor for hypotension when sildenafil is coadministered with amlodipine [see Clinical Pharmacology
(12.2)].
Impact of Amlodipine on Other Drugs
Simvastatin
Coadministration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose
of simvastatin in patients on amlodipine to 20 mg daily [see Clinical Pharmacology (12.3)].
Immunosuppressants
Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when coadministered. Frequent
monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when
appropriate [see Clinical Pharmacology (12.3)].
Valsartan
Agents Increasing Serum Potassium: Concomitant use of valsartan with other agents that block the renin-
angiotensin system, potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium
supplements, salt substitutes containing potassium or other drugs that may increase potassium levels (e.g.,
heparin) may lead to increases in serum potassium and in heart failure patients to increases in serum creatinine.
If co-medication is considered necessary, monitoring of serum potassium is advisable.
Non-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors):
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal
function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor
antagonists, including valsartan, may result in deterioration of renal function, including possible acute renal
failure. These effects are usually reversible. Monitor renal function periodically in patients receiving valsartan
and NSAID therapy.
The antihypertensive effect of angiotensin II receptor antagonists, including valsartan, may be attenuated by
NSAIDs including selective COX-2 inhibitors.
Dual Blockade of the Renin-Angiotensin System (RAS): Dual blockade of the RAS with angiotensin receptor
blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and
changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the
combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general,
avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in
patients on valsartan and other agents that affect the RAS.
Do not coadminister aliskiren with Exforge in patients with diabetes. Avoid use of aliskiren with Exforge in
patients with renal impairment (GFR <60 mL/min).
Lithium: Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant
administration of lithium with angiotensin II receptor antagonists. Monitor serum lithium levels during
concomitant use.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Exforge can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-
angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and
increases fetal and neonatal morbidity and death. Most epidemiologic studies examining fetal abnormalities
after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-
angiotensin system from other antihypertensive agents. Published reports include cases of anhydramnios and
oligohydramnios in pregnant women treated with valsartan (see Clinical Considerations).
When pregnancy is detected, discontinue EXFORGE as soon as possible.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general
population, the estimated background risk of major birth defects and miscarriage in clinically recognized
pregnancies is 2-4% and 15-20%, respectively.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal risk
Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature
delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage).
Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women
with hypertension should be carefully monitored and managed accordingly.
Fetal/Neonatal Adverse Reactions
Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and
third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal
failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension and death.
Perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be
appropriate, based on the week of gestation. Patients and physicians should be aware, however, that
oligohydramnios may not appear until after the fetus has sustained irreversible injury. If oligohydramnios is
observed, consider alternative drug treatment. Closely observe neonates with histories of in utero exposure to
Exforge for hypotension, oliguria, and hyperkalemia. In neonates with a history of in utero exposure to Exforge,
if oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusions or dialysis
may be required as a means of reversing hypotension and replacing renal function.
Data
Animal Data
In rats, administered 20 mg/kg/day amlodipine plus 320 mg/kg/day valsartan, treatment-related maternal and
fetal effects (developmental delays and alterations noted in the presence of significant maternal toxicity) were
noted with the high dose combination. This corresponds to dose multiples of 9 and 19.5 times, respectively, the
maximum recommended human dose (MRHD) of 10 mg/day for amlodipine and 320 mg/day for valsartan
(based on body surface area and considering a 60 kg patient).
8.2 Lactation
Risk Summary
There is limited information regarding the presence of Exforge in human milk, the effects on the breastfed
infant, or the effects on milk production. Valsartan is present in rat milk. Limited published studies report that
amlodipine is present in human milk. Because of the potential for serious adverse reactions in breastfed infants,
advise a nursing woman that breastfeeding is not recommended during treatment with Exforge.
Data
Valsartan was detected in the milk of lactating rats 15 minutes after oral administration of a 3 mg/kg dose.
8.4 Pediatric Use
Safety and effectiveness of Exforge in pediatric patients have not been established.
8.5 Geriatric Use
In controlled clinical trials, 323 (22.5%) hypertensive patients treated with Exforge were ≥ 65 years and
79 (5.5%) 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.
Amlodipine: The recommended starting dose of amlodipine 2.5 mg is not an available strength with Exforge.
Clinical studies of amlodipine besylate tablets did not include sufficient numbers of subjects aged 65 and over
to determine whether they respond differently from younger subjects. Other reported clinical experience has not
identified differences in responses between the elderly and younger patients. In general, dose selection for an
elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater
frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
Elderly patients have decreased clearance of amlodipine with a resulting increase of area under the curve (AUC)
of approximately 40% to 60%.
Valsartan: In the controlled clinical trials of valsartan, 1214 (36.2%) of hypertensive patients treated with
valsartan were ≥ 65 years and 265 (7.9%) were ≥ 75 years. No overall difference in the efficacy or safety of
valsartan was observed in this patient population, but greater sensitivity of some older individuals cannot be
ruled out.
8.6 Renal Impairment
Safety and effectiveness of Exforge in patients with severe renal impairment (CrCl < 30 mL/min) have not been
established. No dose adjustment is required in patients with mild (CrCl 60 to 90 mL/min) or moderate (CrCl 30
to 60 mL/min) renal impairment.
8.7 Hepatic Impairment
Amlodipine
Exposure to amlodipine is increased in patients with hepatic insufficiency [see Clinical Pharmacology (12.3)].
The recommended initial dose of amlodipine in patients with hepatic impairment is 2.5 mg, which is not an
available strength with Exforge.
Valsartan
No dose adjustment is necessary for patients with mild-to-moderate disease. No dosing recommendations can
be provided for patients with severe liver disease.
10 OVERDOSAGE
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. Marked and potentially prolonged systemic
hypotension up to and including shock with fatal outcome have been reported.
If massive overdose should occur, initiate active cardiac and respiratory monitoring. 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, consider administration of vasopressors (such as phenylephrine) with attention
to circulating volume and urine output. As amlodipine is highly protein bound, hemodialysis is not likely to be
of benefit. Administration of activated charcoal to healthy volunteers immediately or up to two hours after
ingestion of amlodipine has been shown to significantly decrease amlodipine absorption.
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, institute supportive treatment.
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 MRHD on a mg/m2 basis) (Calculations assume an oral dose of
320 mg/day and a 60 kg patient).
11 DESCRIPTION
Exforge 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 4 strengths for oral administration with a combination of amlodipine besylate
(6.9 mg or 13.9 mg, equivalent to 5 mg or 10 mg of amlodipine respectively), 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.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Amlodipine
Amlodipine is a dihydropyridine calcium channel blocker that inhibits the transmembrane influx of calcium
ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both
dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular
smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific
ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on
vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro
but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not
affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and
its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and
dissociation with the receptor binding site, resulting in a gradual onset of effect.
Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction
in peripheral vascular resistance and reduction in blood pressure.
Valsartan
Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE,
kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that
include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal
reabsorption of sodium. Valsartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II
by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular
smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II
synthesis.
There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular
homeostasis. Valsartan has much greater affinity (about 20,000-fold) for the AT1 receptor than for the AT2
receptor. The increased plasma levels of angiotensin following AT1 receptor blockade with valsartan may
stimulate the unblocked AT2 receptor. The primary metabolite of valsartan is essentially inactive with an
affinity for the AT1 receptor about one-200th that of valsartan itself.
Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II
from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation
of bradykinin, a reaction also catalyzed by ACE. Because valsartan does not inhibit ACE (kininase II), it does
not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Valsartan
does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular
regulation.
Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin
secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome
the effect of valsartan on blood pressure.
12.2 Pharmacodynamics
Amlodipine
Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation
resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not
accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing.
Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases
heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of
amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in
normotensive patients with angina.
With chronic, once-daily administration, antihypertensive effectiveness is maintained for at least 24 hours.
Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in
blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals
with moderate hypertension (diastolic pressure 105-114 mmHg) had about a 50% greater response than patients
with mild hypertension (diastolic pressure 90-104 mmHg). Normotensive subjects experienced no clinically
significant change in blood pressure (+1/-2 mmHg).
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in
renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without
change in filtration fraction or proteinuria.
As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during
exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally
demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end
diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative
inotropic effect when administered in the therapeutic dose range to intact animals and man, even when
coadministered with beta-blockers to man. Similar findings, however, have been observed in normal or well-
compensated patients with heart failure with agents possessing significant negative inotropic effects.
Amlodipine does not change sinoatrial nodal function or atrioventricular (AV) conduction in intact animals or
man. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H
and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients
receiving amlodipine and concomitant beta-blockers. In clinical studies in which amlodipine was administered
in combination with beta-blockers to patients with either hypertension or angina, no adverse effects of
electrocardiographic (ECG) parameters were observed. In clinical trials with angina patients alone, amlodipine
therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.
Amlodipine has indications other than hypertension which can be found in the Norvasc* package insert.
Drug Interactions
Sildenafil
When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood
pressure lowering effect [see Drug Interactions (7)].
Valsartan
Valsartan inhibits the pressor effect of angiotensin II infusions. An oral dose of 80 mg inhibits the pressor effect
by about 80% at peak with approximately 30% inhibition persisting for 24 hours. No information on the effect
of larger doses is available.
Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin and consequent
rise in angiotensin II plasma concentration in hypertensive patients. Minimal decreases in plasma aldosterone
were observed after administration of valsartan; very little effect on serum potassium was observed.
In multiple dose studies in hypertensive patients with stable renal insufficiency and patients with renovascular
hypertension, valsartan had no clinically significant effects on glomerular filtration rate, filtration fraction,
creatinine clearance, or renal plasma flow.
Administration of valsartan to patients with essential hypertension results in a significant reduction of sitting,
supine, and standing systolic blood pressure, usually with little or no orthostatic change. Valsartan has
indications other than hypertension which can be found in the Diovan package insert.
Exforge
Exforge has been shown to be effective in lowering blood pressure. Both amlodipine and valsartan lower blood
pressure by reducing peripheral resistance, but calcium influx blockade and reduction of angiotensin II
vasoconstriction are complementary mechanisms.
12.3 Pharmacokinetics
Amlodipine
Peak plasma concentrations of amlodipine are reached 6 to 12 hours after administration of amlodipine alone.
Absolute bioavailability has been estimated to be between 64% and 90%. The bioavailability of amlodipine is
not altered by the presence of food.
The apparent volume of distribution of amlodipine is 21 L/kg. Approximately 93% of circulating amlodipine is
bound to plasma proteins in hypertensive patients.
Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of
the parent compound and 60% of the metabolites excreted in the urine.
Elimination of amlodipine from the plasma is biphasic with a terminal elimination half-life of about 30 to
50 hours. Steady state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.
Valsartan
Following oral administration of valsartan alone peak plasma concentrations of valsartan are reached in 2 to
4 hours. Absolute bioavailability is about 25% (range 10% to 35%). Food decreases the exposure (as measured
by AUC) to valsartan by about 40% and peak plasma concentration (Cmax) by about 50%.
The steady state volume of distribution of valsartan after intravenous administration is 17 L, indicating that
valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (95%), mainly
serum albumin.
Valsartan shows biexponential decay kinetics following intravenous administration with an average elimination
half-life of about 6 hours. The recovery is mainly as unchanged drug, with only about 20% of dose recovered as
metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro
metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is
responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at
clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and coadministered
drugs are unlikely because of the low extent of metabolism.
Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine
(about 13% of dose). Following intravenous administration, plasma clearance of valsartan is about 2 L/h and its
renal clearance is 0.62 L/h (about 30% of total clearance).
Exforge
Following oral administration of Exforge in normal healthy adults, peak plasma concentrations of valsartan and
amlodipine are reached in 3 and 6 to 8 hours, respectively. The rate and extent of absorption of valsartan and
amlodipine from Exforge are the same as when administered as individual tablets. The bioavailabilities of
amlodipine and valsartan are not altered by the coadministration of food. Exforge may be administered with or
without food.
Specific Populations
Geriatric
Amlodipine: Elderly patients have decreased clearance of amlodipine with a resulting increase in peak plasma
levels, elimination half-life and AUC.
Valsartan: Exposure (measured by AUC) to valsartan is higher by 70% and the half-life is longer by 35% in the
elderly than in the young. No dosage adjustment is necessary.
Gender
Valsartan: Pharmacokinetics of valsartan does not differ significantly between males and females.
Renal Insufficiency
Amlodipine: The pharmacokinetics of amlodipine is not significantly influenced by renal impairment.
Valsartan: There is no apparent correlation between renal function (measured by creatinine clearance) and
exposure (measured by AUC) to valsartan in patients with different degrees of renal impairment. Consequently,
dose adjustment is not required in patients with mild-to-moderate renal dysfunction. No studies have been
performed in patients with severe impairment of renal function (creatinine clearance <10 mL/min). Valsartan is
not removed from the plasma by hemodialysis. In the case of severe renal disease, exercise care with dosing of
valsartan.
Hepatic Insufficiency
Amlodipine: Patients with hepatic insufficiency have decreased clearance of amlodipine with resulting increase
in AUC of approximately 40% to 60%.
Valsartan: On average, patients with mild-to-moderate chronic liver disease have twice the exposure (measured
by AUC values) to valsartan of healthy volunteers (matched by age, sex and weight). In general, no dosage
adjustment is needed in patients with mild-to-moderate liver disease. Care should be exercised in patients with
liver disease.
Drug Interactions
Amlodipine
In vitro data in human plasma indicate that amlodipine has no effect on the protein binding of digoxin,
phenytoin, warfarin and indomethacin.
Impact of Other Drugs on Amlodipine
Coadministered cimetidine, magnesium-and aluminum hydroxide antacids, sildenafil, and grapefruit juice have
no impact on the exposure to amlodipine.
CYP3A Inhibitors: Co-administration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly
hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. Erythromycin co-
administration in healthy volunteers did not significantly change amlodipine systemic exposure. However,
strong inhibitors of CYP3A (e.g., itraconazole, clarithromycin) may increase the plasma concentrations of
amlodipine to a greater extent [see Drug Interactions (7)].
Impact of Amlodipine on Other Drugs
Coadministered amlodipine does not affect the exposure to atorvastatin, digoxin, ethanol and the warfarin
prothrombin response time.
Simvastatin: Coadministration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a
77% increase in exposure to simvastatin compared to simvastatin alone [see Drug Interactions (7)].
Cyclosporine: A prospective study in renal transplant patients (N=11) showed an average of 40% increase in
trough cyclosporine levels when concomitantly treated with amlodipine [see Drug Interactions (7)].
Tacrolimus: A prospective study in healthy Chinese volunteers (N=9) with CYP3A5 expressers showed a 2.5-
to 4-fold increase in tacrolimus exposure when concomitantly administered with amlodipine compared to
tacrolimus alone. This finding was not observed in CYP3A5 non-expressers (N=6). However, a 3-fold increase
in plasma exposure to tacrolimus in a renal transplant patient (CYP3A5 non-expresser) upon initiation of
amlodipine for the treatment of post-transplant hypertension resulting in reduction of tacrolimus dose has been
reported. Irrespective of the CYP3A5 genotype status, the possibility of an interaction cannot be excluded with
these drugs [see Drug Interactions (7)].
Valsartan
No clinically significant pharmacokinetic interactions were observed when valsartan was coadministered 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.
Coadministration of valsartan and warfarin did not change the pharmacokinetics of valsartan or the time-course
of the anticoagulant properties of warfarin.
Transporters: The results from an in vitro study with human liver tissue indicate that valsartan is a substrate of
the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Coadministration of
inhibitors of the uptake transporter (rifampin, cyclosporine) or efflux transporter (ritonavir) may increase the
systemic exposure to valsartan.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Amlodipine
Rats and mice treated with amlodipine maleate in the diet for up to 2 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 MRHD of 10 mg
amlodipine/day. For the rat, the highest dose was, on a mg/m2 basis, about 2.5 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).
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 MRHD on a mg/m2 basis.
14 CLINICAL STUDIES
Exforge was studied in 2 placebo-controlled and 4 active-controlled trials in hypertensive patients. In a double-
blind, placebo-controlled study, a total of 1012 patients with mild-to-moderate hypertension received treatments
of 3 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. All doses with the exception of the 5/320 mg dose were initiated at the
randomized dose. The high dose was titrated to that dose after a week at a dose of 5/160 mg. At week 8, the
combination treatments were statistically significantly superior to their monotherapy components in reduction
of diastolic and systolic blood pressures.
Table 1: Effect of Exforge on Sitting Diastolic Blood Pressure
Amlodipine Valsartan dosage
dosage
0 mg 80 mg 160 mg 320 mg

Mean Placebo- Mean Placebo- Mean Placebo- Mean Placebo-

Change* subtracted Change* subtracted Change* subtracted Change* subtracted

0 mg -6.4 --- -9.5 -3.1 -10.9 -4.5 -13.2 -6.7

5 mg -11.1 -4.7 -14.2 -7.8 -14.0 -7.6 -15.7 -9.3

*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.

Table 2: Effect of Exforge on Sitting Systolic Blood Pressure

Amlodipine Valsartan dosage
dosage
0 mg 80 mg 160 mg 320 mg

Mean Placebo- Mean Placebo- Mean Placebo- Mean Placebo-

Change* subtracted Change* subtracted Change* subtracted Change* subtracted

0 mg -6.2 --- -12.9 -6.8 -14.3 -8.2 -16.3 -10.1

5 mg -14.8 -8.6 -20.7 -14.5 -19.4 -13.2 -22.4 -16.2

*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 1246 patients with mild to moderate hypertension
received treatments of 2 combinations of amlodipine and valsartan (10/160, 10/320 mg), or amlodipine alone
(10 mg), valsartan alone (160 or 320 mg) or placebo. With the exception of the 10/320 mg dose, treatment was
initiated at the randomized dose. The high dose was initiated at a dose of 5/160 mg and titrated to the
randomized dose after 1 week. At week 8, the combination treatments were statistically significantly superior to
their monotherapy components in reduction of diastolic and systolic blood pressures.
Table 3: Effect of Exforge on Sitting Diastolic Blood Pressure
Amlodipine dosage Valsartan dosage

0 mg 160 mg 320 mg

Mean Placebo- Mean Placebo- Mean Placebo-

Change* subtracted Change* subtracted Change* subtracted

0 mg -8.2 --- -12.8 -4.5 -12.8 -4.5

10 mg -15.0 -6.7 -17.2 -9.0 -18.1 -9.9

*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.

Table 4: Effect of Exforge on Sitting Systolic Blood Pressure

Amlodipine dosage Valsartan dosage

0 mg 160 mg 320 mg

Mean Placebo- Mean Placebo- Mean Placebo-

Change* subtracted Change* subtracted Change* subtracted

0 mg -11.0 --- -18.1 -7.0 -18.5 -7.5

10 mg -22.2 -11.2 -26.6 -15.5 -26.9 -15.9

*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 2 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.
Table 5: Effect of Exforge on Sitting Diastolic/Systolic Blood Pressure
Treatment Group Diastolic BP Systolic BP

Mean change* Treatment Mean change* Treatment

Difference** Difference**

Exforge -11.4 -4.8 -13.9 -5.7

10/160 mg

Exforge -9.6 -3.1 -12.0 -3.9

5/160 mg

Valsartan 160 mg -6.6 --- -8.2 ---

*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.
Table 6: Effect of Exforge on Sitting Diastolic/Systolic Blood Pressure
Treatment Group Diastolic BP Systolic BP

Mean change* Treatment Mean change* Treatment Difference**

Difference**

Exforge -11.8 -1.8 -12.7 -1.9

10/160 mg

Amlodipine 10 mg -10.0 --- -10.8 ---

*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 to 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 Asian patients each represented approximately 4% of the population
in the studied Exforge group.
Two additional double-blind, active-controlled studies were conducted in which Exforge was administered as
initial therapy. In 1 study, a total of 572 black patients with moderate to severe hypertension were randomized
to receive either combination amlodipine/valsartan or amlodipine monotherapy for 12 weeks. The initial dose of
amlodipine/valsartan was 5/160 mg for 2 weeks with forced titration to 10/160 mg for 2 weeks, followed by
optional titration to 10/320 mg for 4 weeks and optional addition of HCTZ 12.5 mg for 4 weeks. The initial
dose of amlodipine was 5 mg for 2 weeks with forced titration to 10 mg for 2 weeks, followed by optional
titration to 10 mg for 4 weeks and optional addition of HCTZ 12.5 mg for 4 weeks. At the primary endpoint of 8
weeks, the treatment difference between amlodipine/valsartan and amlodipine was 6.7/2.8 mmHg.
In the other study of similar design, a total of 646 patients with moderate to severe hypertension (MSSBP of ≥
160 mmHg and < 200 mmHg) were randomized to receive either combination amlodipine/valsartan or
amlodipine monotherapy for 8 weeks. The initial dose of amlodipine/valsartan was 5/160 mg for 2 weeks with
forced titration to 10/160 mg for 2 weeks, followed by the optional addition of HCTZ 12.5 mg for 4 weeks. The
initial dose of amlodipine was 5 mg for 2 weeks with forced titration to 10 mg for 2 weeks, followed by the
optional addition of HCTZ 12.5 mg for 4 weeks. At the primary endpoint of 4 weeks, the treatment difference
between amlodipine/valsartan and amlodipine was 6.6/3.9 mmHg.
There are no trials of the Exforge combination tablet demonstrating reductions in cardiovascular risk in patients
with hypertension, but the amlodipine component and several ARBs, which are the same pharmacological class
as the valsartan component, have demonstrated such benefits.
16 HOW SUPPLIED/STORAGE AND HANDLING
Exforge is available as non-scored tablets containing amlodipine besylate (6.9 mg or 13.9 mg, equivalent to 5
mg or 10 mg of amlodipine respectively) 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 tablets.
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
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
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
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
Store at 20°C-25°C (68°F-77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [See USP
Controlled Room Temperature]. Protect from moisture.
17 PATIENT COUNSELING INFORMATION
Information for Patients
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Pregnancy: Advise female patients of childbearing age about the consequences of exposure to Exforge during
pregnancy. Discuss treatment options with women planning to become pregnant. Ask patients to report
pregnancies to their physicians as soon as possible [see Warnings and Precautions (5.1), Use in Specific
Populations (8.1)].
Lactation: Advise women not to breastfeed during treatment with Exforge [see Use in Specific Populations
(8.2)].
Symptomatic Hypotension: Advise patients that lightheadedness can occur, especially during the first days of
therapy, and that it should be reported to their healthcare provider. Tell patients that if syncope occurs to
discontinue Exforge until the physician has been consulted. Caution all patients that inadequate fluid intake,
excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same
consequences of lightheadedness and possible syncope [see Warnings and Precautions (5.2)].
Hyperkalemia: Advise patients not to use salt substitutes without consulting their healthcare provider [see Drug
Interactions (7)].
T2021-18
FDA-APPROVED PATIENT LABELING
PATIENT INFORMATION
EXFORGE® (X-phorj)
(amlodipine and valsartan) Tablets
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. If you have any questions about EXFORGE, ask your doctor or pharmacist.
What is the most important information I should know about EXFORGE?

 EXFORGE can cause harm or death to an unborn baby.

 Talk to your doctor about other ways to lower your blood pressure if you plan to become pregnant.
 If you get pregnant while taking EXFORGE, tell your doctor right away.
What is EXFORGE?
EXFORGE contains 2 prescription medicines:
1. amlodipine, a calcium channel blocker
2. valsartan, an angiotensin receptor blocker (ARB).
EXFORGE may be used to lower high blood pressure (hypertension) in adults
 when 1 medicine to lower your high blood pressure is not enough
 as the first medicine to lower high blood pressure if your doctor decides you are likely to need more than
1 medicine.
EXFORGE has not been studied in children under 18 years of age.
What should I tell my doctor before taking EXFORGE?
Tell your doctor about all of your medical conditions, including if you:
 are pregnant or plan to become pregnant. See “What is the most important information I should
know about EXFORGE?”
 are breastfeeding or plan to breastfeed. EXFORGE is present in human milk. It is not known whether
EXFORGE affects your breastfed baby or milk production. Do not breastfeed while you are taking
EXFORGE.
 have heart problems
 have liver problems
 have kidney problems
 are vomiting or having a lot of diarrhea
 have ever had a reaction called angioedema to another blood pressure medicine. Angioedema causes
swelling of the face, lips, tongue, throat, and may cause difficulty breathing.
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:
 simvastatin or other cholesterol-lowering medicine
 other medicines for high blood pressure or a heart problem
 water pills (diuretics)
 potassium supplements. Your doctor may check the amount of potassium in your blood periodically.
 a salt substitute. Your doctor may check the amount of potassium in your blood periodically.
 nonsteroidal anti-inflammatory drugs (like ibuprofen or naproxen)
 medicines used to prevent and treat fungal skin infections (such as ketoconazole, itraconazole)
 medicines used to treat bacterial infections (such as clarithromycin, telithromycin)
 certain antibiotics (rifamycin group), a drug used to protect against transplant rejection (cyclosporine) or an
antiretroviral drug used to treat HIV/AIDS infection (ritonavir). These drugs may increase the effect of
valsartan.
 lithium, a medicine used in some types of depression
Know the medicines you take. Keep a list of your medicines and show it to your doctor or pharmacist when you
get a new medicine. Talk to your doctor or pharmacist before you start taking any new medicine. Your doctor or
pharmacist will know what medicines are safe to take together.
How should I take EXFORGE?
 Take EXFORGE exactly as your doctor tells you.
 Take EXFORGE once each day.
 EXFORGE can be taken with or without food.
 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 your 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 should I avoid while taking EXFORGE?
You should not take EXFORGE during pregnancy. See “What is the most important information I should
know about EXFORGE?”
What are the possible side effects of EXFORGE?
EXFORGE may cause serious side effects including:
 harm to an unborn baby causing injury and even death. 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:
o take water pills
o are on a low-salt diet
o get dialysis treatments
o have heart problems
o get sick with vomiting or diarrhea
o drink alcohol
Lie down if you feel faint or dizzy. Call your doctor right away.
 more heart attacks and chest pain (angina) 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 become worse in people that already have kidney disease. Some
people will have changes in blood tests for kidney function and may need a lower dose of EXFORGE. Call
your doctor if you have swelling in your feet, ankles, or hands or unexplained weight gain. If you have heart
failure, your doctor should check your kidney function before prescribing EXFORGE.
 laboratory blood test changes in people with heart failure. Some people with heart failure who take
valsartan, 1 of the medicines in EXFORGE, have changes in blood tests including increased potassium and
decreased kidney function.
The most common side effects of EXFORGE include:
 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.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store EXFORGE?
 Store EXFORGE at room temperature between 59°F and 86°F (15°C and 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 1-888-839-3674.
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.
What is high blood pressure (hypertension)?
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. Medicines that lower blood pressure lower your chance of having a stroke or heart
attack.
High blood pressure makes the heart work harder to pump blood throughout the body and causes damage to
blood vessels. If high blood pressure is not treated, it can lead to stroke, heart attack, heart failure, kidney
failure, and vision problems.
*Norvasc® is a registered trademark of Pfizer, Inc.
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
©Novartis
T2020-29
Revised: March 2020