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Amlodipine, valsartan, and hydrochlorothiazide

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U.S. BRAND NAMES — Exforge HCT®

PHARMACOLOGIC CATEGORY
Angiotensin II Receptor Blocker
Calcium Channel Blocker
Calcium Channel Blocker, Dihydropyridine
Diuretic, Thiazide

DOSING: ADULTS — Note: Not for initial therapy. Dose is individualized; combination product may be substituted for individual components in patients currently maintained on all three agents separately or in patients not adequately controlled with any two of the following antihypertensive classes: calcium channel blockers, angiotensin II receptor blockers, and diuretics.

Hypertension: Oral: Add-on/switch/replacement therapy: Amlodipine 5-10 mg and Valsartan 160-320 mg and hydrochlorothiazide 12.5-25 mg once daily; dose may be titrated after 2 weeks of therapy. Maximum recommended daily dose: Amlodipine 10 mg/valsartan 320 mg/hydrochlorothiazide 25 mg

DOSING: ELDERLY — Refer to adult dosing.

DOSING: RENAL IMPAIRMENT
Clcr >30 mL/minute: No adjustment needed.

Clcr ≤ 30 mL/minute: Use of combination not recommended; contraindicated in patients with anuria.

DOSING: HEPATIC IMPAIRMENT — Use of combination is not recommended in severe hepatic impairment. Use with caution in mild-to-moderate hepatic impairment; monitor for worsening of hepatic or renal function and adverse reactions.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, oral:
Exforge HCT®:
Amlodipine 5 mg, valsartan 160 mg, and hydrochlorothiazide 12.5 mg
Amlodipine 5 mg, valsartan 160 mg, and hydrochlorothiazide 25 mg
Amlodipine 10 mg, valsartan 160 mg, and hydrochlorothiazide 12.5 mg
Amlodipine 10 mg, valsartan 160 mg, and hydrochlorothiazide 25 mg
Amlodipine 10 mg, valsartan 320 mg, and hydrochlorothiazide 25 mg

DOSAGE FORMS: CONCISE
Tablet, oral:
Exforge HCT®: Amlodipine 5 mg, valsartan 160 mg, and hydrochlorothiazide 12.5 mg; Amlodipine 5 mg, valsartan 160 mg, and hydrochlorothiazide 25 mg; Amlodipine 10 mg, valsartan 160 mg, and hydrochlorothiazide 12.5 mg; Amlodipine 10 mg, valsartan 160 mg, and hydrochlorothiazide 25 mg; Amlodipine 10 mg, valsartan 320 mg, and hydrochlorothiazide 25 mg

GENERIC EQUIVALENT AVAILABLE — No

ADMINISTRATION — Administer with or without food.

USE — Treatment of hypertension (not for initial therapy)

ADVERSE REACTIONS SIGNIFICANT — Reactions/percentages reported with combination product; also refer to individual agents.

>10%: Renal: BUN increased (30%)

2% to 10%:
Cardiovascular: Edema (7%)
Central nervous system: Dizziness (8%), headache (5%), fatigue (2%)
Endocrine & metabolic: Hypokalemia (7%), hyperkalemia (4%)
Gastrointestinal: Dyspepsia (2%), nausea (2%)
Neuromuscular & Skeletal: Back pain (2%), muscle spasms (2%)
Renal: Serum creatinine increased (2%)
Respiratory: Nasopharyngitis (2%)

<2% (Limited to important or life-threatening): Abdominal pain, anorexia, anxiety, appetite increased, arthralgia, asthenia, attention disturbed, bronchitis, chest pain (noncardiac), chills, constipation, cough, CPK increased, dehydration, depression, diabetes mellitus, diarrhea, dyspnea, dysuria, erectile dysfunction, extremity pain, gastritis, hyperhidrosis, hyperlipidemia, hyponatremia, hypotension, influenza, insomnia, joint swelling, lethargy, liver function tests increased, malaise, musculoskeletal pain, musculoskeletal stiffness, nasal congestion, night sweats, orthostatic hypotension, osteoarthritis, paresthesia, pharyngolaryngeal pain, pharyngitis, pollakiuria, postural dizziness, pruritus, rash, respiratory tract infection, rhinitis, somnolence, syncope, tachycardia, taste abnormal, tendonitis, tinnitus, tremor, upper respiratory tract infection, uric acid increased, urinary tract infection, vertigo, viral gastroenteritis, viral infection, vision blurred, vomiting, weakness, weight loss, xerostomia CONTRAINDICATIONS — Hypersensitivity to sulfonamide-derived drugs; anuria WARNINGS / PRECAUTIONS
Boxed warnings: Pregnancy: See “Special populations” below.

Concerns related to adverse effects: Angina/MI: Increased angina and/or MI has occurred with initiation or dosage titration of dihydropyridine calcium channel blockers; reflex tachycardia may occur resulting in angina and/or MI in patients with obstructive coronary disease especially in the absence of concurrent beta-blockade. Electrolyte disturbances: Hyperkalemia may occur with angiotensin II receptor antagonists; risk factors include renal dysfunction, diabetes mellitus, and concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salts. Use cautiously, if at all, with these agents and monitor potassium closely. Thiazide diuretics may cause hypokalemia, hypochloremic alkalosis, hypomagnesemia, and hyponatremia. Hypotension/syncope: Symptomatic hypotension with or without syncope can rarely occur; use caution during initiation, particularly in patients with heart failure, or in post-MI patients or those undergoing surgery or dialysis. Peripheral edema: The most common side effect of amlodipine is peripheral edema; occurs within 2-3 weeks of starting therapy. Photosensitivity: Photosensitization may occur. Renal function deterioration: May be associated with deterioration of renal function and/or increases in serum creatinine, particularly in patients with low renal blood flow (eg, renal artery stenosis, heart failure) whose glomerular filtration rate (GFR) is dependent on efferent arteriolar vasoconstriction by angiotensin II; deterioration may result in oliguria, acute renal failure, and progressive azotemia. Small increases in serum creatinine may occur following initiation; consider discontinuation only in patients with progressive and/or significant deterioration in renal function. Sulfa allergy: Chemical similarities are present among sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides, and loop diuretics (except ethacrynic acid). Use in patients with sulfonamide allergy is specifically contraindicated in product labeling. Discontinue if signs of hypersensitivity are noted.

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Disease-related concerns: Aortic/mitral stenosis: Do not initiate in patients with significant aortic/mitral stenosis. Asthma: Hypersensitivity to hydrochlorothiazide may be observed more frequently in patients with bronchial asthma. Diabetes: Use hydrochlorothiazide with caution in patients with prediabetes or diabetes mellitus; may see a change in glucose control. Gout: In certain patients with a history of gout, a familial predisposition to gout, or chronic renal failure, gout can be precipitated by hydrochlorothiazide. Heart failure: Use of combination product in heart failure has not been studied; use with caution; may need to adjust dose, and/or concurrent diuretic therapy. Hepatic impairment: Avoid use in patients with severe hepatic impairment. In patients with mild-to-moderate hepatic impairment, monitor for worsening of hepatic or renal function, fluid status, electrolytes, and adverse reactions. In cirrhosis, avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy. Hypercholesterolemia: Use with caution in patients with moderate or high cholesterol concentrations; increased cholesterol and triglyceride levels have been reported with thiazides. Hypertrophic cardiomyopathy (HCM) with outflow tract obstruction: Do not initiate in patients with HCM and outflow tract obstruction since reduction in afterload may worsen symptoms associated with this condition. Hypovolemia: Avoid use or use a smaller dose in patients who are volume depleted; correct depletion first. Renal artery stenosis: Use valsartan with caution in patients with unstented unilateral/bilateral renal artery stenosis. When unstented bilateral renal artery stenosis is present
, use is generally avoided due to the elevated risk of deterioration in renal function unless possible benefits outweigh risks. Renal impairment: Use with caution with pre-existing renal insufficiency. Avoid use in severe renal impairment (Clcr ≤ 30 mL/minute). May precipitate azotemia; discontinue or consider withholding if renal impairment occurs. Contraindicated in patients with anuria. Systemic lupus erythematosus (SLE): Hydrochlorothiazide can cause SLE exacerbation or activation.

Special populations: Pediatrics: Canadian labeling: Use is not approved in patients <18 years of age. Pregnancy: [U.S. Boxed Warning]: Based on human data, drugs that act on the angiotensin system can cause injury and death to the developing fetus when used in the second and third trimesters. Angiotensin receptor blockers should be discontinued as soon as possible once pregnancy is detected. DRUG INTERACTIONS
ACE Inhibitors: Thiazide Diuretics may enhance the hypotensive effect of ACE Inhibitors. Specifically, postural hypotension which can accompany ACE Inhibitor initiation. Thiazide Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Risk C: Monitor therapy

ACE Inhibitors: Angiotensin II Receptor Blockers may enhance the adverse/toxic effect of ACE Inhibitors. Risk C: Monitor therapy

Alcohol (Ethyl): May enhance the orthostatic effect of Thiazide Diuretics. Risk C: Monitor therapy

Allopurinol: Thiazide Diuretics may enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Thiazide Diuretics may increase the serum concentration of Allopurinol. Specifically, Thiazide Diuretics may increase the concentration of Oxypurinolol, an active metabolite of Allopurinol. Risk C: Monitor therapy

Alpha1-Blockers: May enhance the hypotensive effect of Calcium Channel Blockers. Risk C: Monitor therapy

Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification

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Analgesics (Opioid): May enhance the orthostatic effect of Thiazide Diuretics. Risk C: Monitor therapy

Antidiabetic Agents: Thiazide Diuretics may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Calcium Channel Blockers. Risk D: Consider therapy modification

Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy

Barbiturates: May increase the metabolism of Calcium Channel Blockers. Risk D: Consider therapy modification

Barbiturates: May enhance the orthostatic effect of Thiazide Diuretics. Risk C: Monitor therapy

Bile Acid Sequestrants: May decrease the absorption of Thiazide Diuretics. The diuretic response is likewise decreased. Risk D: Consider therapy modification

Calcitriol: Thiazide Diuretics may enhance the hypercalcemic effect of Calcitriol. Risk C: Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): May enhance the hypotensive effect of Calcium Channel Blockers (Dihydropyridine). Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of Calcium Channel Blockers (Dihydropyridine). Risk C: Monitor therapy

Calcium Salts: Thiazide Diuretics may decrease the excretion of Calcium Salts. Continued concomitant use can also result in metabolic alkalosis. Risk C: Monitor therapy

Calcium Salts: May diminish the therapeutic effect of Calcium Channel Blockers. Risk C: Monitor therapy

CarBAMazepine: May increase the metabolism of Calcium Channel Blockers (Dihydropyridine). Risk C: Monitor therapy

Clopidogrel: Calcium Channel Blockers may diminish the therapeutic effect of Clopidogrel. Risk C: Monitor therapy

Corticosteroids (Orally Inhaled): May enhance the hypokalemic effect of Thiazide Diuretics. Risk C: Monitor therapy

Corticosteroids (Systemic): May enhance the hypokalemic effect of Thiazide Diuretics. Risk C: Monitor therapy

CycloSPORINE: May decrease the metabolism of Calcium Channel Blockers (Dihydropyridine). Nicardipine may likewise inhibit the metabolism of cyclosporine. Cyclosporine dosage adjustments might be needed. Risk C: Monitor therapy

CYP1A2 Substrates: CYP1A2 Inhibitors (Moderate) may decrease the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Dofetilide: Thiazide Diuretics may enhance the QTc-prolonging effect of Dofetilide. Thiazide Diuretics may increase the serum concentration of Dofetilide. Risk X: Avoid combination

Eltrombopag: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Management: According to eltrombopag prescribing information, consideration of a preventative dose reduction may be warranted. Risk D: Consider therapy modification

Eplerenone: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy

Fluconazole: May decrease the metabolism of Calcium Channel Blockers. Risk C: Monitor therapy

Grapefruit Juice: May increase the serum concentration of AmLODIPine. Risk C: Monitor therapy

Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Lithium: Thiazide Diuretics may decrease the excretion of Lithium. Risk D: Consider therapy modification

Lithium: Angiotensin II Receptor Blockers may increase the serum concentration of Lithium. Management: Lithium dosage reductions will likely be needed following the addition of an angiotensin II receptor antagonist. Risk D: Consider therapy modification

Macrolide Antibiotics: May decrease the metabolism of Calcium Channel Blockers. Exceptions: Azithromycin; Dirithromycin [Off Market]; Spiramycin. Risk D: Consider therapy modification

Magnesium Salts: Calcium Channel Blockers may enhance the adverse/toxic effect of Magnesium Salts. Magnesium Salts may enhance the hypotensive effect of Calcium Channel Blockers. Risk C: Monitor therapy

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MAO Inhibitors: May enhance the orthostatic effect of Orthostasis Producing Agents. Risk C: Monitor therapy

Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Nafcillin: May increase the metabolism of Calcium Channel Blockers. Risk D: Consider therapy modification

Neuromuscular-Blocking Agents (Nondepolarizing): Calcium Channel Blockers may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Risk C: Monitor therapy

Nitroprusside: Calcium Channel Blockers may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May diminish the therapeutic effect of Thiazide Diuretics. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May diminish the therapeutic effect of Angiotensin II Rece
ptor Blockers. The combination of these two agents may also significantly decrease glomerular filtration and renal function. Risk C: Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Phenytoin: Calcium Channel Blockers may decrease the metabolism of Phenytoin. Risk D: Consider therapy modification

Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Potassium Salts: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy

Potassium-Sparing Diuretics: Angiotensin II Receptor Blockers may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Protease Inhibitors: May decrease the metabolism of Calcium Channel Blockers (Dihydropyridine). Risk D: Consider therapy modification

QuiNIDine: Calcium Channel Blockers (Dihydropyridine) may decrease the serum concentration of QuiNIDine. Risk C: Monitor therapy

Quinupristin: May decrease the metabolism of Calcium Channel Blockers. Risk C: Monitor therapy

Rifamycin Derivatives: May increase the metabolism of Calcium Channel Blockers. This primarily affects oral forms of calcium channel blockers. Risk D: Consider therapy modification

RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification

Tacrolimus: Calcium Channel Blockers (Dihydropyridine) may increase the serum concentration of Tacrolimus. Risk C: Monitor therapy

Tolvaptan: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy

Trimethoprim: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy

Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

ETHANOL / NUTRITION / HERB INTERACTIONS — Herb/Nutraceutical: St John’s wort may decrease amlodipine levels. Avoid bayberry, blue cohosh, cayenne, ephedra, ginger, ginseng (American), kola, licorice (may diminish antihypertensive effect). Avoid black cohosh, California poppy, coleus, golden seal, hawthorn, mistletoe, periwinkle, quinine, shepherd’s purse (may enhance hypotensive effect).

PREGNANCY RISK FACTOR — D (show table)

PREGNANCY IMPLICATIONS — See individual agents.

LACTATION — Excretion in breast milk unknown/not recommended

BREAST-FEEDING CONSIDERATIONS — Excretion of amlodipine and valsartan into breast milk is not known and use during nursing is not recommended; hydrochlorothiazide is excreted in breast milk

DIETARY CONSIDERATIONS — Avoid salt substitutes which contain potassium. May be taken with or without food.

MONITORING PARAMETERS — Blood pressure, orthostasis; baseline and periodic electrolyte panels, renal function; peripheral edema

MECHANISM OF ACTION
Amlodipine inhibits calcium ion from entering the “slow channels” or select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization, producing a relaxation of coronary vascular smooth muscle and coronary vasodilation; increases myocardial oxygen delivery in patients with vasospastic angina.

Valsartan produces direct antagonism of the angiotensin II (AT2) receptors, unlike the ACE inhibitors. It displaces angiotensin II from the AT1 receptor and produces its blood pressure-lowering effects by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses. This action results in more efficient blockade of the cardiovascular effects of angiotensin II and fewer side effects than the ACE inhibitors.

Hydrochlorothiazide inhibits sodium reabsorption in the distal tubules causing increased excretion of sodium and water as well as potassium and hydrogen ions.

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