Exforge HCT
amlodipine valsartan and hydrochlorothiazide · Tablet, Film Coated · Oral
Uses
Exforge HCT (amlodipine, valsartan, and hydrochlorothiazide) 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, hydrochlorothiazide, and the angiotensin II receptor blocker (ARB) class to which valsartan principally belongs. There are no controlled trials demonstrating risk reduction with Exforge HCT. 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 (e.g., 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. Limitations of Use Exforge HCT is not indicated for the initial therapy of hypertension [see Dosage and Administration (2)] . Exforge HCT is a combination tablet of amlodipine, a dihydropyridine calcium channel blocker (DHP CCB), valsartan, an angiotensin II receptor blocker (ARB), and hydrochlorothiazide, a thiazide diuretic. Exforge HCT 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. ( 1 ) Limitations of Use Exforge HCT is not indicated for initial treatment of hypertension. ( 1 )
Dosage and administration
Dose once-daily. Titrate up to a maximum dose of 10/320/25 mg. ( 2.1 ) Exforge HCT may be used as add-on/switch therapy for patients not adequately controlled on any two of the following antihypertensive classes: calcium channel blockers, angiotensin receptor blockers, and diuretics. ( 2.2 ) Exforge HCT may be substituted for its individually titrated components. ( 2.3 ) 2.1 General Considerations Dose once-daily. The dosage may be increased after 2 weeks of therapy. The full blood pressure lowering effect was achieved 2 weeks after being on the maximal dose of Exforge HCT. The maximum recommended dose of Exforge HCT is 10/320/25 mg. 2.2 Add-on/Switch Therapy Exforge HCT may be used for patients not adequately controlled on any 2 of the following antihypertensive classes: calcium channel blockers, angiotensin receptor blockers, and diuretics. A patient who experiences dose-limiting adverse reactions to an individual component while on any dual combination of the components of Exforge HCT may be switched to Exforge HCT containing a lower dose of that component to achieve similar blood pressure reductions. 2.3 Replacement Therapy Exforge HCT may be substituted for the individually titrated components. 2.4 Use With Other Antihypertensive Drugs Exforge HCT may be administered with other antihypertensive agents.
Dosage forms and strengths
Exforge HCT tablets are available as follows: 5 mg amlodipine/160 mg valsartan/12.5 mg hydrochlorothiazide tablets – White, non-scored, film-coated tablet, ovaloid, biconvex with beveled edge with debossing “NVR” on one side and “VCL” on the other side. 10 mg amlodipine/160 mg valsartan/12.5 mg hydrochlorothiazide tablets – Pale yellow, non-scored, film-coated tablet, ovaloid, biconvex with beveled edge with debossing “NVR” on one side and “VDL” on the other side. 5 mg amlodipine/160 mg valsartan/25 mg hydrochlorothiazide tablets – Yellow, non-scored, film-coated tablet, ovaloid, biconvex with beveled edge with debossing “NVR” on one side and “VEL” on the other side. 10 mg amlodipine/160 mg valsartan/25 mg hydrochlorothiazide tablets – Brown-yellow, non-scored, film-coated tablet, ovaloid, biconvex with beveled edge with debossing “NVR” on one side and “VHL” on the other side. 10 mg amlodipine/320 mg valsartan/25 mg hydrochlorothiazide tablets – Brown-yellow, non-scored, film-coated tablet, ovaloid, biconvex with beveled edge with debossing “NVR” on one side and “VFL” on the other side. Tablets: (amlodipine/valsartan/hydrochlorothiazide mg) 5/160/12.5, 10/160/12.5, 5/160/25, 10/160/25, 10/320/25 ( 3 )
Contraindications
Do not use in patients with anuria, hypersensitivity to other sulfonamide-derived drugs, or hypersensitivity to any component of this product. Do not coadminister aliskiren with Exforge HCT in patients with diabetes [see Drug Interactions (7)] . Anuria ( 4 ) Hypersensitivity to sulfonamide-derived drugs ( 4 ) Known hypersensitivity to any component ( 4 ) Do not coadminister aliskiren with Exforge HCT in patients with diabetes ( 4 )
Warnings and precautions
Hypotension: Correct volume depletion prior to initiation ( 5.2 ) Increased angina and/or myocardial infarction ( 5.3 ) Monitor renal function and potassium in susceptible patients ( 5.4 , 5.5 ) Exacerbation or activation of systemic lupus erythematosus ( 5.7 ) Observe for signs of fluid or electrolyte imbalance ( 5.9 ) Acute angle-closure glaucoma ( 5.10 ) 5.1 Fetal Toxicity Valsartan Exforge HCT 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 HCT as soon as possible [see Use in Specific Populations (8.1)]. Hydrochlorothiazide Thiazides cross the placenta, and use of thiazides during pregnancy is associated with fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults. 5.2 Hypotension in Volume- or Salt-Depleted Patients Excessive hypotension, including orthostatic hypotension, was seen in 1.7% of patients treated with the maximum dose of Exforge HCT (10/320/25 mg) compared to 1.8% of valsartan/HCTZ (320/25 mg) patients, 0.4% of amlodipine/valsartan (10/320 mg) patients, and 0.2% of HCTZ/amlodipine (25/10 mg) patients in a controlled trial in patients with moderate to severe uncomplicated hypertension. In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur in patients receiving angiotensin receptor blockers. Correct this condition prior to administration of Exforge HCT. Exforge HCT has not been studied in patients with heart failure, recent myocardial infarction, or in patients undergoing surgery or dialysis. Patients with heart failure or post-myocardial infarction who were 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. Do not initiate treatment with Exforge HCT in patients with aortic or mitral stenosis or obstructive hypertrophic cardiomyopathy. If excessive hypotension occurs with Exforge HCT, 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 Increased Angina and/or Myocardial Infarction 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 HCT. 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 HCT [see Drug Interactions (7)] . 5.5 Potassium Abnormalities In the controlled trial of Exforge HCT in moderate to severe hypertensive patients, the incidence of hypokalemia (serum potassium < 3.5 mEq/L) at any time post-baseline with the maximum dose of Exforge HCT (10/320/25 mg) was 10% compared to 25% with HCTZ/amlodipine (25/10 mg), 7% with valsartan/HCTZ (320/25 mg), and 3% with amlodipine/valsartan (10/320 mg). One patient (0.2%) discontinued therapy due to an adverse event of hypokalemia in each of the Exforge HCT and HCTZ/amlodipine groups. The incidence of hyperkalemia (serum potassium > 5.7 mEq/L) was 0.4% with Exforge HCT compared to 0.2% to 0.7% with the dual therapies. Some patients with heart failure have developed increases in potassium on valsartan. 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 the diuretic and/or valsartan may be required. Hydrochlorothiazide can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Monitor serum electrolytes periodically. If hypokalemia is accompanied by clinical signs (e.g., muscular weakness, paresis, or ECG alterations), Exforge HCT should be discontinued. Correction of hypokalemia and any coexisting hypomagnesemia is recommended prior to the initiation of thiazides. 5.6 Hypersensitivity Reaction Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.
Side effects
Most common adverse events (≥ 2% incidence) are dizziness, peripheral edema, headache, dyspepsia, fatigue, muscle spasms, back pain, nausea, and nasopharyngitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. In the controlled trial of Exforge HCT, where only the maximum dose (10/320/25 mg) was evaluated, safety data were obtained in 582 patients with hypertension. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. The overall frequency of adverse reactions was similar between men and women, younger (< 65 years) and older ( > 65 years) patients, and black and white patients. In the active controlled clinical trial, discontinuation because of adverse events occurred in 4.0% of patients treated with Exforge HCT 10/320/25 mg compared to 2.9% of patients treated with valsartan/HCTZ 320/25 mg, 1.6% of patients treated with amlodipine/valsartan 10/320 mg, and 3.4% of patients treated with HCTZ/amlodipine 25/10 mg. The most common reasons for discontinuation of therapy with Exforge HCT were dizziness (1.0%) and hypotension (0.7%). The most frequent adverse events that occurred in the active controlled clinical trial in at least 2% of patients treated with Exforge HCT are presented in the following table. Preferred Term Aml/Val/HCTZ 10/320/25 mg N=582 n (%) Val/HCTZ 320/25 mg N=559 n (%) Aml/Val 10/320 mg N=566 n (%) HCTZ/Aml 25/10 mg N=561 n (%) Dizziness 48 (8.2) 40 (7.2) 14 (2.5) 23 (4.1) Edema 38 (6.5) 8 (1.4) 65 (11.5 ) 63 (11.2) Headache 30 (5.2) 31 (5.5) 30 (5.3) 40 (7.1) Dyspepsia 13 (2.2) 5 (0.9) 6 (1.1) 2 (0.4) Fatigue 13 (2.2) 15 (2.7) 12 (2.1) 8 (1.4) Muscle spasms 13 (2.2) 7 (1.3) 7 (1.2) 5 (0.9) Back pain 12 (2.1) 13 (2.3) 5 (0.9) 12 (2.1) Nausea 12 (2.1) 7 (1.3) 10 (1.8) 12 (2.1) Nasopharyngitis 12 (2.1) 13 (2.3) 13 (2.3) 12 (2.1) Orthostatic events (orthostatic hypotension and postural dizziness) were seen in 0.5% of patients. Valsartan Valsartan has been evaluated for safety in more than 4000 hypertensive patients in clinical trials. In trials in which valsartan was compared to an ACE inhibitor with or without placebo, the incidence of dry cough was significantly greater in the ACE inhibitor group (7.9%) than in the groups who received valsartan (2.6%) or placebo (1.5%). In a 129-patient trial limited to patients who had 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 Laboratory Test Findings Clinical laboratory test findings for Exforge HCT were obtained in a controlled trial of Exforge HCT administered at the maximal dose of 10/320/25 mg compared to maximal doses of dual therapies, i.e., valsartan/HCTZ 320/25 mg, amlodipine/valsartan 10/320 mg, and HCTZ/amlodipine 25/10 mg. Findings for the components of Exforge HCT were obtained from other trials. 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 30% of Exforge HCT-treated patients compared to 29% of valsartan/HCTZ patients, 15.8% of amlodipine/valsartan patients, and 18.5% of HCTZ/amlodipine patients. In heart failure patients, greater than 50% increases in BUN were observed in 17% of valsartan-treated patients compared to 6% of placebo-treated patients [see Warnings and Precautions (5.4)] . Neutropenia: Neutropenia (< 1500/L) was observed in 1.9% of patients treated with valsartan 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 With 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 or valsartan/hydrochlorothiazide: Blood and Lymphatic: Decrease in hemoglobin, decrease in hematocrit, neutropenia Hypersensitivity: Angioedema has been reported. Some of these patients previously experienced angioedema with other drugs, including ACE inhibitors. Exforge HCT should not be re-administered to patients who have had angioedema.
Drug interactions
No drug interaction studies have been conducted with Exforge HCT and other drugs, although studies have been conducted with the individual components. A pharmacokinetic drug-drug interaction study has been conducted to address the potential for pharmacokinetic interaction between the triple combination, Exforge HCT, and the corresponding 3 double combinations. No clinically relevant interaction was observed. 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 (NSAID) 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 valsartan in patients with diabetes. Avoid use of aliskiren with valsartan in patients with renal impairment (GFR < 60 mL/min). Valsartan – Hydrochlorothiazide Lithium: Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists or thiazides. Monitor lithium levels in patients taking Exforge HCT. Hydrochlorothiazide When administered concurrently, the following drugs may interact with thiazide diuretics: Antidiabetic Drugs (oral agents and insulin): Dosage adjustment of the antidiabetic drug may be required. Non-Steroidal Anti-inflammatory Drugs (NSAIDs and COX-2 selective inhibitors): When Exforge HCT and nonsteroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of diuretic is obtained. Carbamazepine: May lead to symptomatic hyponatremia. Ion Exchange Resins: Staggering the dosage of hydrochlorothiazide and ion exchange resins (e.g., cholestyramine, colestipol) such that hydrochlorothiazide is administered at least 4 hours before or 4 to 6 hours after the administration of resins, would potentially minimize the interaction [see Clinical Pharmacology (12.3)] . Cyclosporine: Concomitant treatment with cyclosporine may increase the risk of hyperuricemia and gout-type complications. If simvastatin is coadministered with amlodipine, do not exceed doses greater than 20 mg daily of simvastatin. ( 7 ) Antidiabetic drugs: Dosage adjustment of antidiabetic may be required. ( 7 ) Cholestyramine and Colestipol: Reduced absorption of thiazides. ( 12.3 ) Lithium: Increased risk of lithium toxicity. Monitor serum lithium concentrations during concurrent use. ( 7 ) Non-Steroidal Anti-Inflammatory Drug (NSAID) use may lead to increased risk of renal impairment and loss of anti-hypertensive effect. ( 7 ) Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia. ( 7 )
Use in specific populations
Lactation: Breastfeeding is not recommended ( 8.2 ) Geriatric Patients: Not recommended for initial therapy ( 8.5 ) Hepatic Impairment: Not recommended for initial therapy ( 8.7 ) 8.1 Pregnancy Risk Summary Exforge HCT 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 HCT 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 Valsartan 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 HCT for hypotension, oliguria, and hyperkalemia. In neonates with a history of in utero exposure to Exforge HCT, 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. Hydrochlorothiazide Thiazides can cross the placenta, and concentrations reached in the umbilical vein approach those in the maternal plasma. Hydrochlorothiazide, like other diuretics, can cause placental hypoperfusion. It accumulates in the amniotic fluid, with reported concentrations up to 19 times higher than in umbilical vein plasma. Use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice or thrombocytopenia. Since they do not prevent or alter the course of EPH (Edema, Proteinuria, Hypertension) gestosis (preeclampsia), these drugs should not be used to treat hypertension in pregnant women. The use of HCTZ for other indications (e.g., heart disease) in pregnancy should be avoided. Data Animal Data Valsartan and Amlodipine 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). Hydrochlorothiazide No teratogenic effects were observed when hydrochlorothiazide was administered to mice and rats via gavage at doses of up to 3,000 and 1,000 mg/kg/day (608 and 405 times the MRHD), on gestation days 6 through 15. 8.2 Lactation Risk Summary There is limited information regarding the presence of Exforge HCT in human milk, the effects on the breastfed infant, or the effects on milk production. Hydrochlorothiazide is present in human milk and 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 HCT. 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 The safety and effectiveness of Exforge HCT in pediatric patients have not been established. 8.5 Geriatric Use Amlodipine 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 AUC of approximately 40% to 60% [see Clinical Pharmacology (12.3)] . The recommended starting dose of amlodipine 2.5 mg is not an available strength with Exforge HCT [see Clinical Studies (14)] .
Pregnancy
8.1 Pregnancy Risk Summary Exforge HCT 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 HCT 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 Valsartan 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 HCT for hypotension, oliguria, and hyperkalemia. In neonates with a history of in utero exposure to Exforge HCT, 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. Hydrochlorothiazide Thiazides can cross the placenta, and concentrations reached in the umbilical vein approach those in the maternal plasma. Hydrochlorothiazide, like other diuretics, can cause placental hypoperfusion. It accumulates in the amniotic fluid, with reported concentrations up to 19 times higher than in umbilical vein plasma. Use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice or thrombocytopenia. Since they do not prevent or alter the course of EPH (Edema, Proteinuria, Hypertension) gestosis (preeclampsia), these drugs should not be used to treat hypertension in pregnant women. The use of HCTZ for other indications (e.g., heart disease) in pregnancy should be avoided. Data Animal Data Valsartan and Amlodipine 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). Hydrochlorothiazide No teratogenic effects were observed when hydrochlorothiazide was administered to mice and rats via gavage at doses of up to 3,000 and 1,000 mg/kg/day (608 and 405 times the MRHD), on gestation days 6 through 15.
Pediatric use
8.4 Pediatric Use The safety and effectiveness of Exforge HCT in pediatric patients have not been established.
Geriatric use
8.5 Geriatric Use Amlodipine 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 AUC of approximately 40% to 60% [see Clinical Pharmacology (12.3)] . The recommended starting dose of amlodipine 2.5 mg is not an available strength with Exforge HCT [see Clinical Studies (14)] .
Overdosage
Limited data are available related to overdosage in humans. The most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, institute supportive treatment. 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 MRHD on a mg/m 2 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, initiate cardiovascular support, including elevation of the extremities and the judicious administration of fluids. 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 Depressed level of consciousness, circulatory collapse, and shock have been reported. Valsartan is not removed from the plasma by hemodialysis. Valsartan was without grossly observable adverse effects at single oral doses up to 2,000 mg/kg in rats and up to 1,000 mg/kg in marmosets, except for salivation and diarrhea in the rat and vomiting in the marmoset at the highest dose (60 and 31 times, respectively, the MRHD on a mg/m 2 basis) (calculations assume an oral dose of 320 mg/day and a 60-kg patient). Hydrochlorothiazide The degree to which hydrochlorothiazide is removed by hemodialysis has not been established. The most common signs and symptoms observed in patients are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. The oral LD 50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats, 2000 and 4000 times, respectively, the MRHD on a mg/m 2 basis (calculations assume an oral dose of 25 mg/day and a 60-kg patient). Valsartan and Hydrochlorothiazide In rats and marmosets, single oral doses of valsartan up to 1524 and 762 mg/kg in combination with hydrochlorothiazide at doses up to 476 and 238 mg/kg, respectively, were very well tolerated without any treatment-related effects. These no adverse effect doses in rats and marmosets, respectively, represent 46.5 and 23 times the MRHD of valsartan and 188 and 113 times the MRHD of hydrochlorothiazide on a mg/m 2 basis (calculations assume an oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60 kg patient).
Description
Exforge HCT is a fixed combination of amlodipine, valsartan, and hydrochlorothiazide. Exforge HCT contains the besylate salt of amlodipine, a dihydropyridine calcium channel blocker (CCB). Amlodipine besylate, USP 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 (±)-2-[(2-aminoethoxy)methyl]-4-( o -chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulfonate; its structural formula is: Its empirical formula is C 20 H 25 ClN 2 O 5
• C 6 H 6 O 3 S and its molecular weight is 567.1. Valsartan, USP is a nonpeptide, orally active, and specific angiotensin II antagonist acting on the AT 1 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′-(1 H -tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-L-valine; its structural formula is: Its empirical formula is C 24 H 29 N 5 O 3 and its molecular weight is 435.5. Hydrochlorothiazide, USP is a white, or practically white, practically odorless, crystalline powder. It is slightly soluble in water; freely soluble in sodium hydroxide solution, in n -butylamine, and in dimethylformamide; sparingly soluble in methanol; and insoluble in ether, in chloroform, and in dilute mineral acids. Hydrochlorothiazide is chemically described as 6-chloro-3,4-dihydro-2 H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Hydrochlorothiazide is a thiazide diuretic. Its empirical formula is C 7 H 8 ClN 3 O 4 S 2 , its molecular weight is 297.73, and its structural formula is: Exforge HCT (amlodipine, valsartan, and hydrochlorothiazide) is available as film-coated 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, and hydrochlorothiazide 12.5 mg or 25 mg, providing for the following available combinations: 5/160/12.5 mg, 10/160/12.5 mg, 5/160/25 mg, 10/160/25 mg, and 10/320/25 mg. The inactive ingredients for all strengths of the tablets include microcrystalline cellulose; crospovidone; colloidal anhydrous silica; magnesium stearate; hypromellose, macrogol 4000, and talc. Additionally, the 5/160/12.5 mg strength contains titanium dioxide; the 10/160/12.5 mg strength contains titanium dioxide and yellow and red iron oxides; the 5/160/25 mg strength contains titanium dioxide and yellow iron oxide, and the 10/160/25 mg and 10/320/25 mg strengths both contain yellow iron oxide. amlodipine structural formula Valsartan structural formula Hydrochlorothiazide structural formula
Mechanism of action
12.1 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 AT 1 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 AT 2 receptor found in many tissues, but AT 2 is not known to be associated with cardiovascular homeostasis. Valsartan has much greater affinity (about 20,000-fold) for the AT 1 receptor than for the AT 2 receptor. The increased plasma levels of angiotensin following AT 1 receptor blockade with valsartan may stimulate the unblocked AT 2 receptor. The primary metabolite of valsartan is essentially inactive with an affinity for the AT 1 receptor about one-200 th 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.
How supplied
Exforge HCT (amlodipine, valsartan, and hydrochlorothiazide) is available as film-coated 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, and hydrochlorothiazide 12.5 mg or 25 mg, providing for the following available combinations: 5/160/12.5 mg, 10/160/12.5 mg, 5/160/25 mg, 10/160/25 mg, and 10/320/25 mg. All strengths are packaged in bottles of 30 tablets. 5 mg amlodipine/160 mg valsartan /12.5 mg hydrochlorothiazide tablets – White, non-scored, film-coated tablet, ovaloid, biconvex with beveled edge with debossing “NVR” on one side and “VCL” on the other side. Bottles of 30 NDC 0078-0559-15 10 mg amlodipine/160 mg valsartan /12.5 mg hydrochlorothiazide tablets – Pale yellow, non-scored, film-coated tablet, ovaloid, biconvex with beveled edge with debossing “NVR” on one side and “VDL” on the other side. Bottles of 30 NDC 0078-0561-15 5 mg amlodipine/160 mg valsartan /25 mg hydrochlorothiazide tablets – Yellow, non-scored, film-coated tablet, ovaloid, biconvex with beveled edge with debossing “NVR” on one side and “VEL” on the other side. Bottles of 30 NDC 0078-0560-15 10 mg amlodipine/160 mg valsartan /25 mg hydrochlorothiazide tablets – Brown-yellow, non-scored, film-coated tablet, ovaloid, biconvex with beveled edge with debossing “NVR” on one side and “VHL” on the other side. Bottles of 30 NDC 0078-0562-15 10 mg amlodipine/320 mg valsartan /25 mg hydrochlorothiazide tablets – Brown-yellow, non-scored, film-coated tablet, ovaloid, biconvex with beveled edge with debossing “NVR” on one side and “VFL” on the other side. Bottles of 30 NDC 0078-0563-15 Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP controlled room temperature]. Protect from moisture. Dispense in tight container (USP).
Patient information
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 HCT 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) and Use in Specific Populations (8.1)] Lactation: Advise women not to breastfeed during treatment with Exforge HCT [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 HCT 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)] . Potassium Supplements: Advise patients not to use salt substitutes without consulting their healthcare provider [see Drug Interactions (7)] . Non-melanoma Skin Cancer: Instruct patients taking hydrochlorothiazide to protect skin from the sun and undergo regular skin cancer screening [see Adverse Reactions (6.2)] . T2021-12
Label text from the FDA structured product label by Novartis Pharmaceuticals Corporation (revised Dec 12, 2025). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Amlodipine Besylate in 5 products
- Valsartan in 5 products
- Hydrochlorothiazide in 5 products
Exforge HCT NDC products (5)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 0078-0559 | Amlodipine Besylate 5 mg/1; Valsartan 160 mg/1; Hydrochlorothiazide 12.5 mg/1 Tablet, Film Coated | Novartis Pharmaceuticals Corporation | NDA |
| 0078-0560 | Amlodipine Besylate 5 mg/1; Valsartan 160 mg/1; Hydrochlorothiazide 25 mg/1 Tablet, Film Coated | Novartis Pharmaceuticals Corporation | NDA |
| 0078-0561 | Amlodipine Besylate 10 mg/1; Valsartan 160 mg/1; Hydrochlorothiazide 12.5 mg/1 Tablet, Film Coated | Novartis Pharmaceuticals Corporation | NDA |
| 0078-0562 | Amlodipine Besylate 10 mg/1; Valsartan 160 mg/1; Hydrochlorothiazide 25 mg/1 Tablet, Film Coated | Novartis Pharmaceuticals Corporation | NDA |
| 0078-0563 | Amlodipine Besylate 10 mg/1; Valsartan 320 mg/1; Hydrochlorothiazide 25 mg/1 Tablet, Film Coated | Novartis Pharmaceuticals Corporation | NDA |
Frequently asked questions
What is Exforge HCT used for?
Exforge HCT (amlodipine, valsartan, and hydrochlorothiazide) 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…
What are the side effects of Exforge HCT?
Most common adverse events (≥ 2% incidence) are dizziness, peripheral edema, headache, dyspepsia, fatigue, muscle spasms, back pain, nausea, and nasopharyngitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under… See the full label for the complete list.
Who makes Exforge HCT?
Exforge HCT is listed by 1 labeler in the FDA NDC directory, including Novartis Pharmaceuticals Corporation.