Exforge HCT

You should not take this medication if you are allergic to amlodipine (Norvasc), hydrochlorothiazide (HCTZ, HydroDiuril, Hyzaar, Vaseretic, Zestoretic and others), valsartan (Diovan), or sulfa drugs, or if you are unable to urinate.

To make sure you can safely take amlodipine, hydrochlorothiazide, and valsartan, tell your doctor if you have any of these other conditions:

• kidney disease;
• liver disease;
• congestive heart failure;
• glaucoma;
• asthma or allergies;
• low or high levels of magnesium or potassium in your blood;
• gout;
• lupus;
• diabetes; or
• a penicillin allergy.

FDA pregnancy category D. Do not use this medication if you are pregnant. Stop using this medication and tell your doctor right away if you become pregnant. Amlodipine, hydrochlorothiazide, and valsartan can cause injury or death to the unborn baby if you take the medicine during your second or third trimester. Use effective birth control while taking amlodipine, hydrochlorothiazide, and valsartan.

Amlodipine, hydrochlorothiazide, and valsartan can pass into breast milk and may harm a nursing baby. You should not breast-feed while you are using amlodipine, hydrochlorothiazide, and valsartan.

This medication may cause serious side effects including:

• harm to an unborn baby causing injury or death. See “Drug Precautions”.
• low blood pressure (hypotension). Low blood pressure is most likely to happen if you:
  • take water pills
  • are on a low salt diet
  • have heart problems
  • get dialysis treatments
  • get sick with vomiting or diarrhea
  • drink alcohol

Lie down if you feel faint or dizzy. If you faint (lose consciousness), stop taking Exforge HCT. Call your doctor right away.

• 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 HCT. 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 this medication.
• laboratory blood test changes in people with congestive heart failure. Some people with congestive heart failure who take valsartan, one of the medicines in Exforge HCT, have changes in blood tests including increased potassium and decreased kidney function.
• allergic reactions 
• skin rash. Call your doctor right away if you get an unusual skin rash.
• eye problems. One of the medicines in Exforge HCT can cause eye problems that may lead to vision loss. Symptoms of eye problems can happen within hours to weeks of starting this medication. Tell your doctor right away if you have:
  • decrease in vision
  • eye pain

The most common side effects include:

• dizziness 
• swelling (edema) of the hands, ankles, or feet
• headache
• indigestion
• tiredness
• muscle spasms
• back pain
• nausea.

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 HCT. 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.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends may be based on the following:

• the condition being treated
• other medications you are taking
• other medical conditions you have
• how you respond to this medication

The maximum recommended dose of Exforge HCT (amlodipine/valsartan/hydrochlorothiazide) is 10/320/25 mg/day.

Amlodipine is a calcium channel blocker that relaxes (widens) blood vessels and improves blood flow.

Hydrochlorothiazide is a thiazide diuretic (water pill) that helps prevent your body from absorbing too much salt, which can cause fluid retention.

Valsartan is an angiotensin II receptor antagonist that keeps blood vessels from narrowing, which lowers blood pressure and improves blood flow.

Amlodipine, hydrochlorothiazide, and valsartan is a combination medicine used to treat high blood pressure (hypertension).

This medicine is usually given after other blood pressure medicines have been tried without successful treatment of symptoms.

Amlodipine, hydrochlorothiazide, and valsartan may also be used for purposes not listed in this medication guide.

Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.

You may take this medicine with or without food.

Your chest pain may become worse when you first start taking this medicine or when your dose is increased. Call your doctor if your chest pain is severe or ongoing.

Your blood pressure will need to be checked often.

Vomiting, diarrhea, or heavy sweating can cause you to become dehydrated. This can lead to very low blood pressure, electrolyte disorders, or kidney failure while you are taking amlodipine, hydrochlorothiazide, and valsartan. Drink plenty of water each day while you are taking this medication.

Call your doctor if you are sick with vomiting or diarrhea, or if you are sweating more than usual.

If you need surgery or dental work, tell the surgeon or dentist ahead of time that you are using this medicine.

It may take up to 2 weeks before your blood pressure improves. Keep using this medicine as directed, even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.

Store at room temperature away from moisture and heat.

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly. Blood and urine tests may be needed to check for unwanted effects.

Using this medicine while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using the medicine, tell your doctor right away.

Dizziness, lightheadedness, or fainting may also occur, especially when you get up from a lying or sitting position or if you have been taking a diuretic (water pill). Make sure you know how you react to the medicine before you drive, use machines, or do other things that could be dangerous if you are dizzy or not alert. If you feel dizzy, lie down so you do not faint. Then sit for a few moments before standing to prevent the dizziness from returning. If you faint, call your doctor right away.

Check with your doctor right away if you become sick while taking this medicine, especially with severe or continuing nausea, vomiting, or diarrhea. These conditions may cause you to lose too much water or salt and may lead to low blood pressure. You can also lose water by sweating, so drink plenty of water during exercise or in hot weather.

This medicine may worsen the symptoms of angina (chest pain) or cause a heart attack in certain patients with severe heart or blood vessel disease. Check with your doctor right away if you are having chest pain or discomfort, fast or uneven heartbeat, nausea or vomiting, pain or discomfort in the arms, jaw, back, or neck, shortness of breath, or sweating.

Check with your doctor immediately if blurred vision, difficulty in reading, eye pain, or any other change in vision occurs during or after treatment. This could be a sign of a serious eye problem. Your doctor may want an eye doctor to check your eyes.

Make sure any doctor or dentist who treats you knows that you are using this medicine. You may need to stop using this medicine several days before having surgery.

Hyperkalemia (high potassium in the blood) may occur in certain people receiving this medicine. Check with your doctor right away if you have the following symptoms: abdominal or stomach pain, confusion, difficulty with breathing, irregular heartbeat, nausea or vomiting, nervousness, numbness or tingling in the hands, feet, or lips, shortness of breath, or weakness or heaviness of the legs. Ask your doctor before you use any medicines, supplements, or salt substitutes that contain potassium without first checking with your doctor.

Do not take other medicines unless they have been discussed with your doctor. This especially includes over-the-counter (nonprescription) medicines for appetite control, asthma, colds, cough, hay fever, or sinus problems, since they may increase your blood pressure.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

     Mechanism of Action

The active ingredients of Exforge HCT target 3 separate mechanisms involved in blood pressure regulation. Specifically, amlodipine blocks the contractile effects of calcium on cardiac and vascular smooth muscle cells; valsartan blocks the vasoconstriction and sodium retaining effects of angiotensin II on cardiac, vascular smooth muscle, adrenal and renal cells; and hydrochlorothiazide directly promotes the excretion of sodium and chloride in the kidney leading to reductions in intravascular volume. A more detailed description of the mechanism of action of each individual component follows.

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 20000-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.

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics.

The mechanism of the antihypertensive effect of thiazides is unknown.

     Pharmacodynamics

Exforge HCT has been shown to be effective in lowering blood pressure. The 3 components of Exforge HCT (amlodipine, valsartan, hydrochlorothiazide) lower the blood pressure through complementary mechanisms, each working at a separate site and blocking different effector pathways. The pharmacodynamics of each individual component are described below.

Exforge HCT has not been studied in indications other than hypertension.

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 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 ECG intervals or produce higher degrees of AV blocks.

Amlodipine has indications other than hypertension which are described in its full prescribing information.

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.

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 are described in its full prescribing information.

Hydrochlorothiazide

After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.

     Pharmacokinetics

Exforge HCT

Following oral administration of Exforge HCT in normal healthy adults, peak plasma concentrations of amlodipine, valsartan and HCTZ are reached in about 6 hours, 3 hours, and 2 hours, respectively. The rate and extent of absorption of amlodipine, valsartan and HCTZ from Exforge HCT are the same as when administered as individual dosage forms.

The bioavailability of amlodipine, valsartan, and HCTZ were not altered when Exforge HCT was administered with food. Exforge HCT may be administered with or without food.

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 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%).

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 CYP450 enzymes indicated that the CYP2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP450 isozymes at clinically relevant concentrations. CYP450 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).

Hydrochlorothiazide

The estimated absolute bioavailability of hydrochlorothiazide after oral administration is about 70%. Peak plasma hydrochlorothiazide concentrations (Cmax) are reached within 2 to 5 hours after oral administration. There is no clinically significant effect of food on the bioavailability of hydrochlorothiazide.

Hydrochlorothiazide binds to albumin (40% to 70%) and distributes into erythrocytes. Following oral administration, plasma hydrochlorothiazide concentrations decline biexponentially, with a mean distribution half-life of about 2 hours and an elimination half-life of about 10 hours.

About 70% of an orally administered dose of hydrochlorothiazide is eliminated in the urine as unchanged drug.

Special Populations

Geriatric: Elderly patients have decreased clearance of amlodipine with a resulting increase in peak plasma levels, elimination half-life, and AUC. 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. Limited amount of data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers.

Gender: Pharmacokinetics of valsartan do not differ significantly between males and females.

Race: Pharmacokinetic differences due to race have not been studied.

Renal Insufficiency: The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. 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. Valsartan has not been studied in patients with severe impairment of renal function (creatinine clearance <10 mL/min). Valsartan is not removed from the plasma by hemodialysis.

In a study in individuals with impaired renal function, the mean elimination half-life of hydrochlorothiazide was doubled in individuals with mild/moderate renal impairment (30< CrCl <90 mL/min) and tripled in severe renal impairment (CrCl ≤30 mL/min), compared to individuals with normal renal function (CrCl >90 mL/min) [see Use in Specific Populations (8.6)].

Hepatic Insufficiency: Patients with hepatic insufficiency have decreased clearance of amlodipine with resulting increase in AUC of approximately 40% to 60%. 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) [see Use in Specific Populations (8.7)].

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

Co-administered 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

Co-administered amlodipine does not affect the exposure to atorvastatin, digoxin, ethanol and the warfarin prothrombin response time.

Simvastatin: Co-administration 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 on 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)].

Hydrochlorothiazide:

Drugs that alter gastrointestinal motility: The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g., atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate. Conversely, pro-kinetic drugs may decrease the bioavailability of thiazide diuretics.

Cholestyramine: In a dedicated drug interaction study, administration of cholestyramine 2 hours before hydrochlorothiazide resulted in a 70% reduction in exposure to hydrochlorothiazide. Further, administration of hydrochlorothiazide 2 hours before cholestyramine resulted in 35% reduction in exposure to hydrochlorothiazide.

Antineoplastic agents (e.g., cyclophosphamide, methotrexate): Concomitant use of thiazide diuretics may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects.

Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur.

Skeletal muscle relaxants: Possible increased responsiveness to muscle relaxants such as curare derivatives.

Digitalis glycosides: Thiazide-induced hypokalemia or hypomagnesemia may predispose the patient to digoxin toxicity.

Exforge HCT was studied in a double-blind, active controlled study in hypertensive patients. A total of 2271 patients with moderate to severe hypertension (mean baseline systolic/diastolic blood pressure was 170/107 mmHg) received treatments of amlodipine/valsartan/HCTZ 10/320/25 mg, valsartan/HCTZ 320/25 mg, amlodipine/valsartan 10/320 mg, or HCTZ/amlodipine 25/10 mg. At study initiation patients assigned to the 2-component arms received lower doses of their treatment combination while patients assigned to the Exforge HCT arm received 160/12.5 mg valsartan/hydrochlorothiazide. After 1 week, Exforge HCT patients were titrated to 5/160/12.5 mg amlodipine/valsartan/hydrochlorothiazide, while all other patients continued receiving their initial doses. After 2 weeks, all patients were titrated to their full treatment dose. A total of 55% of patients were male, 14% were 65 years or older, 72% were Caucasian, and 17% were black.

At week 8, the triple combination therapy produced greater reductions in blood pressure than each of the 3 dual combination treatments (p<0.0001 for both diastolic and systolic blood pressures reductions). The reductions in systolic/diastolic blood pressure with Exforge HCT were 7.6/5.0 mmHg greater than with valsartan/HCTZ, 6.2/3.3 mmHg greater than with amlodipine/valsartan, and 8.2/5.3 mmHg greater than with amlodipine/HCTZ (see Figure 1). The full blood pressure lowering effect was achieved 2 weeks after being on the maximal dose of Exforge HCT (see Figure 2 and Figure 3). As the pivotal study was an active-controlled trial, the treatment effects shown in Figures 1, 2, and 3 include a placebo effect of unknown size.

Figure 1: Reduction in Mean Blood Pressure at Endpoint

Figure 2: Mean Sitting Diastolic Blood Pressure by Treatment and Week

Figure 3: Mean Sitting Systolic Blood Pressure by Treatment and Week

A subgroup of 283 patients was studied with ambulatory blood pressure monitoring. The blood pressure lowering effect in the triple therapy group was maintained throughout the 24-hour period (see Figure 4 and Figure 5).

Figure 4: Mean Ambulatory Diastolic Blood Pressure at Endpoint by Treatment and Hour

Figure 5: Mean Ambulatory Systolic Blood Pressure at Endpoint by Treatment and Hour

There are no trials of the Exforge HCT combination tablet demonstrating reductions in cardiovascular risk in patients with hypertension, but both the amlodipine and hydrochlorothiazide components and several ARBs, which are the same pharmacological class as the valsartan component, have demonstrated such benefits.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to Exforge HCT during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.

Symptomatic Hypotension: A patient receiving Exforge HCT should be cautioned that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician. The patients should be told that if syncope occurs, Exforge HCT should be discontinued until the physician has been consulted.

All patients should be cautioned 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.

Potassium Supplements: A patient receiving Exforge HCT should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician.

T2015-124
July 2015

Information for Patients

Patient Information

Exforge HCT (X-phorj HCT)
(amlodipine and valsartan and hydrochlorothiazide) Tablets

Read the Patient Information that comes with Exforge HCT 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 the most important information I should know about Exforge HCT?

• Exforge HCT 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 HCT, tell your doctor right away.

What is Exforge HCT?

Exforge HCT contains 3 prescription medicines:

1. amlodipine, a calcium channel blocker
   
2. valsartan, an angiotensin receptor blocker, and
   
3. hydrochlorothiazide, a diuretic (water pill)

Exforge HCT may be used to lower blood pressure in adults when 2 medicines to lower your high blood pressure are not enough.

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

Who should not take Exforge HCT?

Do not take Exforge HCT if you have low or no urine output (anuria).

What should I tell my doctor before taking Exforge HCT?

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 HCT?”
  
• are breastfeeding or plan to breastfeed. Exforge HCT may pass into your milk. Do not breastfeed while you are taking Exforge HCT.
  
• are allergic to any of the ingredients in Exforge HCT. See the end of this leaflet for a list of the ingredients in Exforge HCT.
  
• have heart problems
  
• have liver problems
  
• have kidney problems
  
• are vomiting or having a lot of diarrhea
  
• have or had gallstones
  
• have Lupus
  
• have low levels of potassium (with or without symptoms such as muscle weakness, muscle spasms, abnormal heart rhythm) or magnesium in your blood
  
• have high levels of calcium in your blood (with or without symptoms such as nausea, vomiting, constipation, stomach pain, frequent urination, thirst, muscle weakness, and twitching).
  
• have high levels of uric acid in the blood.
• have ever had a reaction called angioedema, to another blood pressure medicine. Angioedema causes swelling of the face, lips, tongue, 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 HCT 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.
  
• salt substitute containing potassium. Your doctor may check the amount of potassium in your blood periodically.
  
• diabetes medicine including insulin
  
• narcotic pain medicines
  
• sleeping pills and antiseizure medicines called barbiturates
  
• lithium, a medicine used to treat some types of depression
  
• aspirin or other medicines called nonsteroidal anti-inflammatory drugs (NSAIDs), like ibuprofen or naproxen
  
• steroids
  
• alcohol
  
• digoxin or other digitalis glycosides (a heart medicine)
  
• muscle relaxants (medicines used during operations)
  
• certain cancer medicines, like cyclophosphamide or methotrexate
  
• medicines used to prevent and treat fungal 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.

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.

How should I take Exforge HCT?

• Take Exforge HCT exactly as your doctor tells you.
  
• Take Exforge HCT one time each day.
  
• Exforge HCT 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 the regular time.
  
• If you take too much Exforge HCT, call your doctor or Poison Control Center, or go to the emergency room.
  
• Tell all your doctors and dentist you are taking Exforge HCT. This is especially important if you:
  • are going to have surgery
    
  • go for kidney dialysis

What are the possible side effects of Exforge HCT?

Exforge HCT may cause serious side effects including:

• harm to an unborn baby causing injury or death. See “What is the most important information I should know about Exforge HCT?”
  
• low blood pressure (hypotension). Low blood pressure is most likely to happen if you:
  • take water pills
    
  • are on a low salt diet
    
  • have heart problems
    
  • get dialysis treatments
    
  • get sick with vomiting or diarrhea
    
  • drink alcohol.

Lie down if you feel faint or dizzy. If you faint (lose consciousness), stop taking Exforge HCT. Call your doctor right away.

• 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 HCT. 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 HCT.
  
• laboratory blood test changes in people with heart failure. Some people with heart failure who take valsartan, one of the medicines in Exforge HCT, have changes in blood tests including increased potassium and decreased kidney function.
  
• allergic reactions
  
• skin rash. Call your doctor right away if you get an unusual skin rash.
• eye problems. One of the medicines in Exforge HCT can cause eye problems that may lead to vision loss. Symptoms of eye problems can happen within hours to weeks of starting Exforge HCT. Tell your doctor right away if you have:
  • decrease in vision
    
  • eye pain

The most common side effects of Exforge HCT include:

• dizziness
  
• swelling (edema) of the hands, ankles, or feet
  
• headache
  
• indigestion
  
• tiredness
  
• muscle spasms
  
• back pain
  
• nausea

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 HCT. 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 HCT?

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

Keep Exforge HCT and all medicines out of the reach of children.

General Information about Exforge HCT

Medicines are sometimes prescribed for conditions that are not mentioned in the patient information leaflet. Do not use Exforge HCT for a condition for which it was not prescribed. Do not give Exforge HCT 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 HCT. If you would like more information about Exforge HCT, talk with your doctor. You can ask your doctor or pharmacist for information about Exforge HCT 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 HCT?

Active ingredients: amlodipine besylate, valsartan, and hydrochlorothiazide

The inactive ingredients of all strengths of the tablets are crospovidone, magnesium stearate, microcrystalline cellulose, and colloidal anhydrous silica. The film coating contains hypromellose, talc, macrogol 4000, and may contain titanium dioxide or yellow and red iron oxides.

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 HCT 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.

Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936

© Novartis

T2015-125
July 2015

PRINCIPAL DISPLAY PANEL

Package Label – 5 mg / 160 mg / 12.5 mg

Rx Only             NDC 0078-0559-15

Exforge HCT®

(amlodipine, valsartan, hydrochlorothiazide)

5 mg* / 160 mg / 12.5 mg

*each tablet contains 6.9 mg of amlodipine besylate

30 Tablets

PRINCIPAL DISPLAY PANEL

Package Label – 10 mg / 160 mg / 12.5 mg

Rx Only             NDC 0078-0561-15

Exforge HCT®

(amlodipine, valsartan, hydrochlorothiazide)

10 mg* / 160 mg / 12.5 mg

*each tablet contains 13.9 mg of amlodipine besylate

30 Tablets

PRINCIPAL DISPLAY PANEL

Package Label – 5 mg / 160 mg / 25 mg

Rx Only             NDC 0078-0560-15

Exforge HCT®

(amlodipine, valsartan, hydrochlorothiazide)

5 mg* / 160 mg / 25 mg

*each tablet contains 6.9 mg of amlodipine besylate

30 Tablets

PRINCIPAL DISPLAY PANEL

Package Label – 10 mg / 160 mg / 25 mg

Rx Only             NDC 0078-0562-15

Exforge HCT®

(amlodipine, valsartan, hydrochlorothiazide)

10 mg* / 160 mg / 25 mg

*each tablet contains 13.9 mg of amlodipine besylate

30 Tablets

PRINCIPAL DISPLAY PANEL

Package Label – 10 mg / 320 mg / 25 mg

Rx Only             NDC 0078-0563-15

Exforge HCT®

(amlodipine, valsartan, hydrochlorothiazide)

10 mg* / 320 mg / 25 mg

*each tablet contains 13.9 mg of amlodipine besylate

30 Tablets

Exforge HCT contains a combination of amlodipine, hydrochlorothiazide and valsartan. Amlodipine is a calcium channel blocker that relaxes (widens) blood vessels and improves blood flow.

Hydrochlorothiazide is a thiazide diuretic (water pill) that helps prevent your body from absorbing too much salt, which can cause fluid retention.

Valsartan is an angiotensin II receptor antagonist that keeps blood vessels from narrowing, which lowers blood pressure and improves blood flow.

Exforge HCT is used to treat high blood pressure (hypertension).

Exforge HCT is usually given after other blood pressure medicines have been tried without successful treatment of symptoms.

Do not use potassium supplements or salt substitutes while you are taking this medicine, unless your doctor has told you to.

Drinking alcohol can further lower your blood pressure and may increase certain side effects of this medicine.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.