U.S. BRAND NAMES — Amytal®
PHARMACOLOGIC CATEGORY
Barbiturate
DOSING: ADULTS
Hypnotic: I.M., I.V.: 65-200 mg at bedtime (maximum single dose: 1000 mg)
Sedative: I.M., I.V.: 30-50 mg 2-3 times/day (maximum single dose: 1000 mg)
"Amytal® interview" (unlabeled use): I.V.: 50-100 mg/minute for total dose of 200-1000 mg or until patient experiences drowsiness, impaired attention, slurred speech, or nystagmus
Wada test (unlabeled use): Intra-arterial: 100 mg over 4-5 seconds via percutaneous transfemoral catheter
DOSING: PEDIATRIC
(For additional information see "Amobarbital: Pediatric drug information")
Sedative: I.M., I.V.: 6-12 years: Manufacturer's dosing range: 65-500 mg
Hypnotic (unlabeled use): I.M.: 2-3 mg/kg (maximum: 500 mg)
DOSING: ELDERLY — Refer to adult dosing.
DOSING: RENAL IMPAIRMENT — Dosing should be reduced; specific recommendations not available.
DOSING: HEPATIC IMPAIRMENT — Dosing should be reduced; specific recommendations not available.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution, as sodium:
Amytal®: 500 mg
DOSAGE FORMS: CONCISE
Injection, powder for reconstitution:
Amytal®: 500 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION
I.M.: Administer deeply into a large muscle. Do not use more than 5 mL at any single site (may cause tissue damage). I.M. dosages should not exceed 500 mg. Use 20% solution to facilitate larger doses.
I.V.: Use only when I.M. administration is not feasible. Administer by slow I.V. injection (maximum: 50 mg/minute in adults).
COMPATIBILITY — Stable in D5LR, D5NS, D5W, D10W, D20W, LR, NS.
Compatibility when admixed: Compatible: Amikacin, aminophylline, sodium bicarbonate. Incompatible: Cefazolin, cimetidine, clindamycin, diphenhydramine, droperidol, hydroxyzine, insulin (regular), levorphanol, meperidine, morphine, norepinephrine, pancuronium, pentazocine, penicillin G potassium, procaine, streptomycin, vancomycin. Variable (consult detailed reference): Atracurium, dimenhydrinate, hydrocortisone sodium succinate, isoproterenol, metaraminol, methyldopate, norepinephrine, succinylcholine.
USE — Hypnotic in short-term treatment of insomnia; reduce anxiety and provide sedation preoperatively
USE - UNLABELED / INVESTIGATIONAL — Therapeutic or diagnostic "Amytal® Interviewing"; Wada test
ADVERSE REACTIONS SIGNIFICANT — Frequency not defined and is reported as barbiturate use (not specifically amobarbital).
Cardiovascular: Bradycardia, hypotension, syncope
Central nervous system: Agitation, anxiety, ataxia, confusion, CNS depression, dizziness, fever, hallucinations, headache, insomnia, nightmares, nervousness, psychiatric disturbances, somnolence, thinking abnormal
Gastrointestinal: Constipation, nausea, vomiting
Hematologic: Megaloblastic anemia (following chronic phenobarbital use)
Hepatic: Liver damage
Local: Injection site reaction
Neuromuscular & skeletal: Hyperkinesia
Respiratory: Apnea, atelectasis (postoperative), hypoventilation
Miscellaneous: Hypersensitivity reaction (including angioedema, rash, and exfoliative dermatitis)
CONTRAINDICATIONS — Hypersensitivity to barbiturates or any component of the formulation; marked hepatic impairment; dyspnea or airway obstruction; porphyria
WARNINGS / PRECAUTIONS
Concerns related to adverse effects: CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Hypersensitivity reactions: Postmarketing studies have indicated that the use of hypnotic/sedative agents for sleep has been associated with hypersensitivity reactions including anaphylaxis as well as angioedema. Paradoxical responses: May cause paradoxical responses, including agitation and hyperactivity, particularly in acute pain, chronic pain and pediatric patients. Sleep-related activities: An increased risk for hazardous sleep-related activities such as sleep-driving; cooking and eating food, and making phone calls while asleep has been noted with sedative-hypnotic medications. Discontinue treatment in patients who report a sleep-driving episode.
Disease-related concerns: Cardiovascular disease: Use with caution in patients with cardiovascular disease; may cause hypotension. Depression: Use with caution in patients with depression or suicidal tendencies. Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use. Hepatic impairment: Use with caution in patients with hepatic impairment, decreased dosage may be needed; contraindicated in severe impairment. Insomnia: Appropriate use: When used as a hypnotic for the treatment of insomnia, effectiveness is limited to ≤ 2 weeks. Renal impairment: Use with caution in patients with renal impairment; decreased dosage may be needed.
Concurrent drug therapy issues: Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol.
Special populations: Elderly: Use with caution in the elderly; not recommended for use. Closely monitor elderly or debilitated patients for impaired cognitive or motor performance. Pediatrics: Safety and efficacy have not been established in children <6 years of age; use with caution in children ≥ 6 years of age.
Dosage form specific issues: Alkaline solution: Solution for injection is highly alkaline and extravasation may cause local tissue damage.
Other warnings/precautions: Rapid administration: Rapid I.V. administration may cause respiratory depression, apnea, and hypotension. Withdrawal: Gradual withdrawal is recommended if used over extended periods of time.
RESTRICTIONS — C-II
METABOLISM / TRANSPORT EFFECTS — Induces CYP2A6 (strong)
DRUG INTERACTIONS
Acetaminophen: Barbiturates may increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Beta-Blockers: Barbiturates may decrease the serum concentration of Beta-Blockers. Exceptions: Atenolol; Levobunolol; Metipranolol; Nadolol. Risk C: Monitor therapy
Calcium Channel Blockers: Barbiturates may increase the metabolism of Calcium Channel Blockers. Exceptions: Clevidipine. Risk D: Consider therapy modification
Chloramphenicol: May decrease the metabolism of Barbiturates. Barbiturates may increase the metabolism of Chloramphenicol. Risk D: Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
Contraceptive (Progestins): Barbiturates may diminish the therapeutic effect of Contraceptive (Progestins). Contraceptive failure is possible. Risk D: Consider therapy modification
Corticosteroids (Systemic): Barbiturates may increase the metabolism of Corticosteroids (Systemic). Risk C: Monitor therapy
CycloSPORINE: Barbiturates may increase the metabolism of CycloSPORINE. Risk D: Consider therapy modification
CYP2A6 Substrates: CYP2A6 Inducers (Strong) may increase the metabolism of CYP2A6 Substrates. Risk C: Monitor therapy
Disopyramide: Barbiturates may increase the metabolism of Disopyramide. Risk D: Consider therapy modification
Doxycycline: Barbiturates may decrease the serum concentration of Doxycycline. Risk D: Consider therapy modification
Etoposide: Barbiturates may increase the metabolism of Etoposide. Risk C: Monitor therapy
Etoposide Phosphate: Barbiturates may decrease the serum concentration of Etoposide Phosphate. Barbiturates may increase the metabolism, via CYP isoenzymes, of etoposide phosphate. Risk C: Monitor therapy
Felbamate: May increase the serum concentration of Barbiturates. Risk C: Monitor therapy
Griseofulvin: Barbiturates may decrease the absorption of Griseofulvin. Risk D: Consider therapy modification
LamoTRIgine: Barbiturates may increase the metabolism of LamoTRIgine. Risk D: Consider therapy modification
Meperidine: Barbiturates may enhance the CNS depressant effect of Meperidine. Risk C: Monitor therapy
Methadone: Barbiturates may increase the metabolism of Methadone. Risk D: Consider therapy modification
Oral Contraceptive (Estrogens): Barbiturates may diminish the therapeutic effect of Oral Contraceptive (Estrogens). Contraceptive failure is possible. Risk D: Consider therapy modification
Primidone: May enhance the adverse/toxic effect of Barbiturates. Primidone is converted to phenobarbital, and thus becomes additive with existing barbiturate therapy. Risk C: Monitor therapy
Propafenone: Barbiturates may increase the metabolism of Propafenone. Risk D: Consider therapy modification
Pyridoxine: May increase the metabolism of Barbiturates. Apparent in high pyridoxine doses (eg, 200 mg/day) Risk C: Monitor therapy
QuiNIDine: Barbiturates may increase the metabolism of QuiNIDine. Risk D: Consider therapy modification
Rifamycin Derivatives: May increase the metabolism of Barbiturates. Risk C: Monitor therapy
Teniposide: Barbiturates may increase the metabolism of Teniposide. Risk C: Monitor therapy
Theophylline Derivatives: Barbiturates may increase the metabolism of Theophylline Derivatives. Exceptions: Dyphylline. Risk C: Monitor therapy
Thiazide Diuretics: Barbiturates may enhance the orthostatic effect of Thiazide Diuretics. Risk C: Monitor therapy
Tricyclic Antidepressants: Barbiturates may increase the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification
Valproic Acid: May decrease the metabolism of Barbiturates. Barbiturates may decrease the serum concentration of Valproic Acid. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Barbiturates may increase the metabolism of Vitamin K Antagonists. Risk D: Consider therapy modification
Voriconazole: Barbiturates may decrease the serum concentration of Voriconazole. Risk X: Avoid combination
ETHANOL / NUTRITION / HERB INTERACTIONS — Ethanol: Avoid ethanol (may increase CNS depression).
PREGNANCY RISK FACTOR — D (show table)
PREGNANCY IMPLICATIONS — Barbiturates cross the placenta and distribute in fetal tissue. Teratogenic effects have been reported with 1st trimester exposure. Exposure during the 3rd trimester may lead to symptoms of acute withdrawal following delivery; symptoms may be delayed up to 14 days.
LACTATION — Excretion in breast milk unknown/use caution
BREAST-FEEDING CONSIDERATIONS — Small amounts of barbiturates are excreted in breast milk; information specific for amobarbital is not available.
MONITORING PARAMETERS — Vital signs should be monitored during injection and for several hours after administration.
REFERENCE RANGE
Therapeutic: 1-5 mcg/mL (SI: 4-22 µmol/L)
Toxic: >10 mcg/mL (SI: >44 µmol/L)
Lethal: >50 mcg/mL
CANADIAN BRAND NAMES — Amytal®
INTERNATIONAL BRAND NAMES — Amybital (TW); Amycal (NO); Amytal Sodium (AU); Barbamyl (IL); Dorlotin (HU); Dorlotyn (HU); Eunoctal (FR); Isoamitil Sedante (ES); Isomytal (JP); Neur-Amyl (AU); Placidel (ES); Sodium Amytal (GB); Transital (ES)
MECHANISM OF ACTION — Interferes with transmission of impulses from the thalamus to the cortex of the brain resulting in an imbalance in central inhibitory and facilitatory mechanisms
PHARMACODYNAMICS / KINETICS
Onset of action: I.V.: Within 5 minutes
Distribution: Readily crosses placenta; small amounts enter breast milk
Metabolism: Primarily hepatic via microsomal enzymes
Half-life elimination: 15-40 hours (mean: 25 hours)
Excretion: Urine, feces
Monday, August 2, 2010
Sunday, August 1, 2010
Amlodipine, valsartan, and hydrochlorothiazide
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.
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
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
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 Receptor 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.
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.
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
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
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 Receptor 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.
Amlodipine, valsartan, and hydrochlorothiazide
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.
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
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
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 Receptor 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.
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.
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
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
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 Receptor 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.
Amlodipine and valsarta
U.S. BRAND NAMES — Exforge®
PHARMACOLOGIC CATEGORY
Angiotensin II Receptor Blocker
Calcium Channel Blocker
Calcium Channel Blocker, Dihydropyridine
DOSING: ADULTS — Note: Dose is individualized; combination product may be used as initial therapy or substituted for individual components in patients currently maintained on both agents separately or in patients not adequately controlled with monotherapy (using one of the agents or an agent within same antihypertensive class).
Hypertension: Oral:
Initial therapy: Amlodipine 5 mg and valsartan 160 mg once daily, dose may be titrated after 1-2 weeks of therapy. Maximum recommended doses: Amlodipine 10 mg/day; valsartan 320 mg/day
Add-on/replacement therapy: Amlodipine 5-10 mg and valsartan 160-320 mg once daily; dose may be titrated after 3-4 weeks of therapy. Maximum recommended doses: Amlodipine 10 mg/day; valsartan 320 mg/day
DOSING: ELDERLY — Refer to adult dosing. Initiate amlodipine at 2.5 mg/day; due to decreased clearance.
DOSING: RENAL IMPAIRMENT
Clcr >10 mL/minute: No dosage adjustment necessary.
Clcr ≤ 10 mL/minute: Use caution; titrate slowly.
DOSING: HEPATIC IMPAIRMENT — Mild-to-moderate hepatic impairment: No initial dosage adjustment required, titrate slowly. Amlodipine and valsartan exposure increased in presence of hepatic impairment.
Amlodipine: Use caution in severe hepatic impairment; lower initial doses may be required.
Valsartan: Mild-to-moderate hepatic impairment: No dosage adjustment required; however, patients with mild-to-moderate chronic disease have twice the exposure as healthy volunteers.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet:
Exforge®:
5/160: Amlodipine 5 mg and valsartan 160 mg
5/320 mg: Amlodipine 5 mg and valsartan 320 mg
10/160: Amlodipine 10 mg and valsartan 160 mg
10/320: Amlodipine 10 mg and valsartan 320 mg
DOSAGE FORMS: CONCISE
Tablet:
Exforge®:
5/160: Amlodipine 5 mg and valsartan 160 mg
5/320 mg: Amlodipine 5 mg and valsartan 320 mg
10/160: Amlodipine 10 mg and valsartan 160 mg
10/320: Amlodipine 10 mg and valsartan 320 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Administer with or without food.
USE — Treatment of hypertension
ADVERSE REACTIONS SIGNIFICANT — Reactions/percentages reported with combination product; also refer to individual agents
>10%: Central nervous system: Headache (11%)
1% to 10%:
Cardiovascular: Peripheral edema (5% to 8%)
Central nervous system: Anxiety (3%), somnolence (3%), dizziness (2%)
Endocrine & metabolic: Hyperkalemia (3% to 10%)
Gastrointestinal: Abdominal pain (upper; 3%), diarrhea (3%), nausea (3%)
Renal: BUN increased (6%)
Respiratory: Nasopharyngitis (4%), upper respiratory tract infection (3%), cough (2%)
Miscellaneous: Influenza (2%)
<1% (Limited to important or life-threatening): Exanthema, hypersensitivity, hypotension, orthostatic hypotension, postural dizziness, syncope, tinnitus, visual disturbance
Frequency not defined, but occurred at ≥ 0.2% incidence (limited to important or life-threatening): Abdominal discomfort/distension, abdominal pain, arthralgia, cardiac murmur, chest pain, colitis, constipation, cystitis, depression, diabetes, dyspepsia, edema (including pitting), erectile dysfunction, erythema, fever, flatulence, flushing, gastritis, hematuria, hypercholesterolemia, infection, LFTs increased, lymphadenopathy, myalgia, nephrolithiasis, palpitation, paresthesia, pharyngitis, pneumonia, pruritus, rash, tachycardia, vomiting, weakness
CONTRAINDICATIONS — There are no contraindications listed within the FDA-approved labeling.
WARNINGS / PRECAUTIONS
Boxed warnings: Pregnancy: .
Concerns related to adverse effects: Angina/MI: Increased angina and/or MI has occurred with initiation or dosage titration of calcium channel blockers. Hyperkalemia: May occur with valsartan use; risk factors include renal dysfunction, diabetes mellitus, 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. Hypotension/syncope: Symptomatic hypotension with or without syncope can rarely occur; use caution during initiation of therapy, particularly in patients with heart failure, severe aortic stenosis, 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. Reflex tachycardia: May occur with amlodipine use. Renal function deterioration: Valsartan 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.
Disease-related concerns: Aortic/mitral stenosis: Use with caution in patients with significant aortic/mitral stenosis. Heart failure: Use caution when initiating in heart failure; may need to adjust dose, and/or concurrent diuretic therapy. Hepatic impairment: Use with caution in patients with hepatic impairment; amlodipine and valsartan exposure increased in hepatic dysfunction. 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 and severe renal impairment.
Special populations: Elderly: Initiate at a lower dose in the elderly. Pediatrics: Safety and efficacy have not been established in children. 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.
Other warnings/precautions: Titration: Dosage titration should occur after 3-4 weeks if blood pressure control inadequate.
METABOLISM / TRANSPORT EFFECTS
Amlodipine: Substrate of CYP3A4 (major); Inhibits CYP1A2 (moderate), 2A6 (weak), 2B6 (weak), 2C8 (weak), 2C9 (weak), 2D6 (weak), 3A4 (weak)
Valsartan: Inhibits CYP2C9 (weak)
DRUG INTERACTIONS
ACE Inhibitors: Angiotensin II Receptor Blockers may enhance the adverse/toxic effect of ACE Inhibitors. 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
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
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: 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
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
Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
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: 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
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 Angiotensin II Receptor 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
Food: Decreases rate and extent of valsartan absorption by 50% and 40%, respectively.
Herb/Nutraceutical: Avoid dong quai if using for hypertension (has estrogenic activity). Avoid ephedra, yohimbe, ginseng (may worsen hypertension). Avoid garlic (may have increased antihypertensive effects).
PREGNANCY RISK FACTOR — D (show table)
PREGNANCY IMPLICATIONS — See individual agents.
LACTATION — Excretion in breast milk unknown/not recommended
BREAST-FEEDING CONSIDERATIONS — See individual agents.
DIETARY CONSIDERATIONS — Avoid salt substitutes which contain potassium. May be taken with or without food.
PRICING — (data from drugstore.com)
Tablets (Exforge)
5-160 mg (30): $87.29
5-320 mg (30): $111.04
10-160 mg (30): $99.48
10-320 mg (30): $118.95
MONITORING PARAMETERS — Baseline and periodic electrolyte panels, renal and liver function, urinalysis; BP, heart rate, peripheral edema; in CHF, serum potassium during dose escalation and periodically thereafter
INTERNATIONAL BRAND NAMES — Copalia (EE, SE); Diovan/Amlibon (VE); Exforge (BE, CH, CZ, DE, DK, EE, ES, FR, GB, HK, ID, IE, KP, MY, NO, PH, SE, SG, TH); Imprida (EE, SE)
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.
PHARMACOLOGIC CATEGORY
Angiotensin II Receptor Blocker
Calcium Channel Blocker
Calcium Channel Blocker, Dihydropyridine
DOSING: ADULTS — Note: Dose is individualized; combination product may be used as initial therapy or substituted for individual components in patients currently maintained on both agents separately or in patients not adequately controlled with monotherapy (using one of the agents or an agent within same antihypertensive class).
Hypertension: Oral:
Initial therapy: Amlodipine 5 mg and valsartan 160 mg once daily, dose may be titrated after 1-2 weeks of therapy. Maximum recommended doses: Amlodipine 10 mg/day; valsartan 320 mg/day
Add-on/replacement therapy: Amlodipine 5-10 mg and valsartan 160-320 mg once daily; dose may be titrated after 3-4 weeks of therapy. Maximum recommended doses: Amlodipine 10 mg/day; valsartan 320 mg/day
DOSING: ELDERLY — Refer to adult dosing. Initiate amlodipine at 2.5 mg/day; due to decreased clearance.
DOSING: RENAL IMPAIRMENT
Clcr >10 mL/minute: No dosage adjustment necessary.
Clcr ≤ 10 mL/minute: Use caution; titrate slowly.
DOSING: HEPATIC IMPAIRMENT — Mild-to-moderate hepatic impairment: No initial dosage adjustment required, titrate slowly. Amlodipine and valsartan exposure increased in presence of hepatic impairment.
Amlodipine: Use caution in severe hepatic impairment; lower initial doses may be required.
Valsartan: Mild-to-moderate hepatic impairment: No dosage adjustment required; however, patients with mild-to-moderate chronic disease have twice the exposure as healthy volunteers.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet:
Exforge®:
5/160: Amlodipine 5 mg and valsartan 160 mg
5/320 mg: Amlodipine 5 mg and valsartan 320 mg
10/160: Amlodipine 10 mg and valsartan 160 mg
10/320: Amlodipine 10 mg and valsartan 320 mg
DOSAGE FORMS: CONCISE
Tablet:
Exforge®:
5/160: Amlodipine 5 mg and valsartan 160 mg
5/320 mg: Amlodipine 5 mg and valsartan 320 mg
10/160: Amlodipine 10 mg and valsartan 160 mg
10/320: Amlodipine 10 mg and valsartan 320 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Administer with or without food.
USE — Treatment of hypertension
ADVERSE REACTIONS SIGNIFICANT — Reactions/percentages reported with combination product; also refer to individual agents
>10%: Central nervous system: Headache (11%)
1% to 10%:
Cardiovascular: Peripheral edema (5% to 8%)
Central nervous system: Anxiety (3%), somnolence (3%), dizziness (2%)
Endocrine & metabolic: Hyperkalemia (3% to 10%)
Gastrointestinal: Abdominal pain (upper; 3%), diarrhea (3%), nausea (3%)
Renal: BUN increased (6%)
Respiratory: Nasopharyngitis (4%), upper respiratory tract infection (3%), cough (2%)
Miscellaneous: Influenza (2%)
<1% (Limited to important or life-threatening): Exanthema, hypersensitivity, hypotension, orthostatic hypotension, postural dizziness, syncope, tinnitus, visual disturbance
Frequency not defined, but occurred at ≥ 0.2% incidence (limited to important or life-threatening): Abdominal discomfort/distension, abdominal pain, arthralgia, cardiac murmur, chest pain, colitis, constipation, cystitis, depression, diabetes, dyspepsia, edema (including pitting), erectile dysfunction, erythema, fever, flatulence, flushing, gastritis, hematuria, hypercholesterolemia, infection, LFTs increased, lymphadenopathy, myalgia, nephrolithiasis, palpitation, paresthesia, pharyngitis, pneumonia, pruritus, rash, tachycardia, vomiting, weakness
CONTRAINDICATIONS — There are no contraindications listed within the FDA-approved labeling.
WARNINGS / PRECAUTIONS
Boxed warnings: Pregnancy: .
Concerns related to adverse effects: Angina/MI: Increased angina and/or MI has occurred with initiation or dosage titration of calcium channel blockers. Hyperkalemia: May occur with valsartan use; risk factors include renal dysfunction, diabetes mellitus, 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. Hypotension/syncope: Symptomatic hypotension with or without syncope can rarely occur; use caution during initiation of therapy, particularly in patients with heart failure, severe aortic stenosis, 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. Reflex tachycardia: May occur with amlodipine use. Renal function deterioration: Valsartan 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.
Disease-related concerns: Aortic/mitral stenosis: Use with caution in patients with significant aortic/mitral stenosis. Heart failure: Use caution when initiating in heart failure; may need to adjust dose, and/or concurrent diuretic therapy. Hepatic impairment: Use with caution in patients with hepatic impairment; amlodipine and valsartan exposure increased in hepatic dysfunction. 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 and severe renal impairment.
Special populations: Elderly: Initiate at a lower dose in the elderly. Pediatrics: Safety and efficacy have not been established in children. 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.
Other warnings/precautions: Titration: Dosage titration should occur after 3-4 weeks if blood pressure control inadequate.
METABOLISM / TRANSPORT EFFECTS
Amlodipine: Substrate of CYP3A4 (major); Inhibits CYP1A2 (moderate), 2A6 (weak), 2B6 (weak), 2C8 (weak), 2C9 (weak), 2D6 (weak), 3A4 (weak)
Valsartan: Inhibits CYP2C9 (weak)
DRUG INTERACTIONS
ACE Inhibitors: Angiotensin II Receptor Blockers may enhance the adverse/toxic effect of ACE Inhibitors. 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
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
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: 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
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
Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
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: 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
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 Angiotensin II Receptor 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
Food: Decreases rate and extent of valsartan absorption by 50% and 40%, respectively.
Herb/Nutraceutical: Avoid dong quai if using for hypertension (has estrogenic activity). Avoid ephedra, yohimbe, ginseng (may worsen hypertension). Avoid garlic (may have increased antihypertensive effects).
PREGNANCY RISK FACTOR — D (show table)
PREGNANCY IMPLICATIONS — See individual agents.
LACTATION — Excretion in breast milk unknown/not recommended
BREAST-FEEDING CONSIDERATIONS — See individual agents.
DIETARY CONSIDERATIONS — Avoid salt substitutes which contain potassium. May be taken with or without food.
PRICING — (data from drugstore.com)
Tablets (Exforge)
5-160 mg (30): $87.29
5-320 mg (30): $111.04
10-160 mg (30): $99.48
10-320 mg (30): $118.95
MONITORING PARAMETERS — Baseline and periodic electrolyte panels, renal and liver function, urinalysis; BP, heart rate, peripheral edema; in CHF, serum potassium during dose escalation and periodically thereafter
INTERNATIONAL BRAND NAMES — Copalia (EE, SE); Diovan/Amlibon (VE); Exforge (BE, CH, CZ, DE, DK, EE, ES, FR, GB, HK, ID, IE, KP, MY, NO, PH, SE, SG, TH); Imprida (EE, SE)
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.
Amlodipine and valsarta
U.S. BRAND NAMES — Exforge®
PHARMACOLOGIC CATEGORY
Angiotensin II Receptor Blocker
Calcium Channel Blocker
Calcium Channel Blocker, Dihydropyridine
DOSING: ADULTS — Note: Dose is individualized; combination product may be used as initial therapy or substituted for individual components in patients currently maintained on both agents separately or in patients not adequately controlled with monotherapy (using one of the agents or an agent within same antihypertensive class).
Hypertension: Oral:
Initial therapy: Amlodipine 5 mg and valsartan 160 mg once daily, dose may be titrated after 1-2 weeks of therapy. Maximum recommended doses: Amlodipine 10 mg/day; valsartan 320 mg/day
Add-on/replacement therapy: Amlodipine 5-10 mg and valsartan 160-320 mg once daily; dose may be titrated after 3-4 weeks of therapy. Maximum recommended doses: Amlodipine 10 mg/day; valsartan 320 mg/day
DOSING: ELDERLY — Refer to adult dosing. Initiate amlodipine at 2.5 mg/day; due to decreased clearance.
DOSING: RENAL IMPAIRMENT
Clcr >10 mL/minute: No dosage adjustment necessary.
Clcr ≤ 10 mL/minute: Use caution; titrate slowly.
DOSING: HEPATIC IMPAIRMENT — Mild-to-moderate hepatic impairment: No initial dosage adjustment required, titrate slowly. Amlodipine and valsartan exposure increased in presence of hepatic impairment.
Amlodipine: Use caution in severe hepatic impairment; lower initial doses may be required.
Valsartan: Mild-to-moderate hepatic impairment: No dosage adjustment required; however, patients with mild-to-moderate chronic disease have twice the exposure as healthy volunteers.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet:
Exforge®:
5/160: Amlodipine 5 mg and valsartan 160 mg
5/320 mg: Amlodipine 5 mg and valsartan 320 mg
10/160: Amlodipine 10 mg and valsartan 160 mg
10/320: Amlodipine 10 mg and valsartan 320 mg
DOSAGE FORMS: CONCISE
Tablet:
Exforge®:
5/160: Amlodipine 5 mg and valsartan 160 mg
5/320 mg: Amlodipine 5 mg and valsartan 320 mg
10/160: Amlodipine 10 mg and valsartan 160 mg
10/320: Amlodipine 10 mg and valsartan 320 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Administer with or without food.
USE — Treatment of hypertension
ADVERSE REACTIONS SIGNIFICANT — Reactions/percentages reported with combination product; also refer to individual agents
>10%: Central nervous system: Headache (11%)
1% to 10%:
Cardiovascular: Peripheral edema (5% to 8%)
Central nervous system: Anxiety (3%), somnolence (3%), dizziness (2%)
Endocrine & metabolic: Hyperkalemia (3% to 10%)
Gastrointestinal: Abdominal pain (upper; 3%), diarrhea (3%), nausea (3%)
Renal: BUN increased (6%)
Respiratory: Nasopharyngitis (4%), upper respiratory tract infection (3%), cough (2%)
Miscellaneous: Influenza (2%)
<1% (Limited to important or life-threatening): Exanthema, hypersensitivity, hypotension, orthostatic hypotension, postural dizziness, syncope, tinnitus, visual disturbance
Frequency not defined, but occurred at ≥ 0.2% incidence (limited to important or life-threatening): Abdominal discomfort/distension, abdominal pain, arthralgia, cardiac murmur, chest pain, colitis, constipation, cystitis, depression, diabetes, dyspepsia, edema (including pitting), erectile dysfunction, erythema, fever, flatulence, flushing, gastritis, hematuria, hypercholesterolemia, infection, LFTs increased, lymphadenopathy, myalgia, nephrolithiasis, palpitation, paresthesia, pharyngitis, pneumonia, pruritus, rash, tachycardia, vomiting, weakness
CONTRAINDICATIONS — There are no contraindications listed within the FDA-approved labeling.
WARNINGS / PRECAUTIONS
Boxed warnings: Pregnancy: .
Concerns related to adverse effects: Angina/MI: Increased angina and/or MI has occurred with initiation or dosage titration of calcium channel blockers. Hyperkalemia: May occur with valsartan use; risk factors include renal dysfunction, diabetes mellitus, 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. Hypotension/syncope: Symptomatic hypotension with or without syncope can rarely occur; use caution during initiation of therapy, particularly in patients with heart failure, severe aortic stenosis, 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. Reflex tachycardia: May occur with amlodipine use. Renal function deterioration: Valsartan 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.
Disease-related concerns: Aortic/mitral stenosis: Use with caution in patients with significant aortic/mitral stenosis. Heart failure: Use caution when initiating in heart failure; may need to adjust dose, and/or concurrent diuretic therapy. Hepatic impairment: Use with caution in patients with hepatic impairment; amlodipine and valsartan exposure increased in hepatic dysfunction. 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 and severe renal impairment.
Special populations: Elderly: Initiate at a lower dose in the elderly. Pediatrics: Safety and efficacy have not been established in children. 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.
Other warnings/precautions: Titration: Dosage titration should occur after 3-4 weeks if blood pressure control inadequate.
METABOLISM / TRANSPORT EFFECTS
Amlodipine: Substrate of CYP3A4 (major); Inhibits CYP1A2 (moderate), 2A6 (weak), 2B6 (weak), 2C8 (weak), 2C9 (weak), 2D6 (weak), 3A4 (weak)
Valsartan: Inhibits CYP2C9 (weak)
DRUG INTERACTIONS
ACE Inhibitors: Angiotensin II Receptor Blockers may enhance the adverse/toxic effect of ACE Inhibitors. 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
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
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: 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
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
Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
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: 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
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 Angiotensin II Receptor 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
Food: Decreases rate and extent of valsartan absorption by 50% and 40%, respectively.
Herb/Nutraceutical: Avoid dong quai if using for hypertension (has estrogenic activity). Avoid ephedra, yohimbe, ginseng (may worsen hypertension). Avoid garlic (may have increased antihypertensive effects).
PREGNANCY RISK FACTOR — D (show table)
PREGNANCY IMPLICATIONS — See individual agents.
LACTATION — Excretion in breast milk unknown/not recommended
BREAST-FEEDING CONSIDERATIONS — See individual agents.
DIETARY CONSIDERATIONS — Avoid salt substitutes which contain potassium. May be taken with or without food.
PRICING — (data from drugstore.com)
Tablets (Exforge)
5-160 mg (30): $87.29
5-320 mg (30): $111.04
10-160 mg (30): $99.48
10-320 mg (30): $118.95
MONITORING PARAMETERS — Baseline and periodic electrolyte panels, renal and liver function, urinalysis; BP, heart rate, peripheral edema; in CHF, serum potassium during dose escalation and periodically thereafter
INTERNATIONAL BRAND NAMES — Copalia (EE, SE); Diovan/Amlibon (VE); Exforge (BE, CH, CZ, DE, DK, EE, ES, FR, GB, HK, ID, IE, KP, MY, NO, PH, SE, SG, TH); Imprida (EE, SE)
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.
PHARMACOLOGIC CATEGORY
Angiotensin II Receptor Blocker
Calcium Channel Blocker
Calcium Channel Blocker, Dihydropyridine
DOSING: ADULTS — Note: Dose is individualized; combination product may be used as initial therapy or substituted for individual components in patients currently maintained on both agents separately or in patients not adequately controlled with monotherapy (using one of the agents or an agent within same antihypertensive class).
Hypertension: Oral:
Initial therapy: Amlodipine 5 mg and valsartan 160 mg once daily, dose may be titrated after 1-2 weeks of therapy. Maximum recommended doses: Amlodipine 10 mg/day; valsartan 320 mg/day
Add-on/replacement therapy: Amlodipine 5-10 mg and valsartan 160-320 mg once daily; dose may be titrated after 3-4 weeks of therapy. Maximum recommended doses: Amlodipine 10 mg/day; valsartan 320 mg/day
DOSING: ELDERLY — Refer to adult dosing. Initiate amlodipine at 2.5 mg/day; due to decreased clearance.
DOSING: RENAL IMPAIRMENT
Clcr >10 mL/minute: No dosage adjustment necessary.
Clcr ≤ 10 mL/minute: Use caution; titrate slowly.
DOSING: HEPATIC IMPAIRMENT — Mild-to-moderate hepatic impairment: No initial dosage adjustment required, titrate slowly. Amlodipine and valsartan exposure increased in presence of hepatic impairment.
Amlodipine: Use caution in severe hepatic impairment; lower initial doses may be required.
Valsartan: Mild-to-moderate hepatic impairment: No dosage adjustment required; however, patients with mild-to-moderate chronic disease have twice the exposure as healthy volunteers.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet:
Exforge®:
5/160: Amlodipine 5 mg and valsartan 160 mg
5/320 mg: Amlodipine 5 mg and valsartan 320 mg
10/160: Amlodipine 10 mg and valsartan 160 mg
10/320: Amlodipine 10 mg and valsartan 320 mg
DOSAGE FORMS: CONCISE
Tablet:
Exforge®:
5/160: Amlodipine 5 mg and valsartan 160 mg
5/320 mg: Amlodipine 5 mg and valsartan 320 mg
10/160: Amlodipine 10 mg and valsartan 160 mg
10/320: Amlodipine 10 mg and valsartan 320 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Administer with or without food.
USE — Treatment of hypertension
ADVERSE REACTIONS SIGNIFICANT — Reactions/percentages reported with combination product; also refer to individual agents
>10%: Central nervous system: Headache (11%)
1% to 10%:
Cardiovascular: Peripheral edema (5% to 8%)
Central nervous system: Anxiety (3%), somnolence (3%), dizziness (2%)
Endocrine & metabolic: Hyperkalemia (3% to 10%)
Gastrointestinal: Abdominal pain (upper; 3%), diarrhea (3%), nausea (3%)
Renal: BUN increased (6%)
Respiratory: Nasopharyngitis (4%), upper respiratory tract infection (3%), cough (2%)
Miscellaneous: Influenza (2%)
<1% (Limited to important or life-threatening): Exanthema, hypersensitivity, hypotension, orthostatic hypotension, postural dizziness, syncope, tinnitus, visual disturbance
Frequency not defined, but occurred at ≥ 0.2% incidence (limited to important or life-threatening): Abdominal discomfort/distension, abdominal pain, arthralgia, cardiac murmur, chest pain, colitis, constipation, cystitis, depression, diabetes, dyspepsia, edema (including pitting), erectile dysfunction, erythema, fever, flatulence, flushing, gastritis, hematuria, hypercholesterolemia, infection, LFTs increased, lymphadenopathy, myalgia, nephrolithiasis, palpitation, paresthesia, pharyngitis, pneumonia, pruritus, rash, tachycardia, vomiting, weakness
CONTRAINDICATIONS — There are no contraindications listed within the FDA-approved labeling.
WARNINGS / PRECAUTIONS
Boxed warnings: Pregnancy: .
Concerns related to adverse effects: Angina/MI: Increased angina and/or MI has occurred with initiation or dosage titration of calcium channel blockers. Hyperkalemia: May occur with valsartan use; risk factors include renal dysfunction, diabetes mellitus, 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. Hypotension/syncope: Symptomatic hypotension with or without syncope can rarely occur; use caution during initiation of therapy, particularly in patients with heart failure, severe aortic stenosis, 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. Reflex tachycardia: May occur with amlodipine use. Renal function deterioration: Valsartan 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.
Disease-related concerns: Aortic/mitral stenosis: Use with caution in patients with significant aortic/mitral stenosis. Heart failure: Use caution when initiating in heart failure; may need to adjust dose, and/or concurrent diuretic therapy. Hepatic impairment: Use with caution in patients with hepatic impairment; amlodipine and valsartan exposure increased in hepatic dysfunction. 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 and severe renal impairment.
Special populations: Elderly: Initiate at a lower dose in the elderly. Pediatrics: Safety and efficacy have not been established in children. 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.
Other warnings/precautions: Titration: Dosage titration should occur after 3-4 weeks if blood pressure control inadequate.
METABOLISM / TRANSPORT EFFECTS
Amlodipine: Substrate of CYP3A4 (major); Inhibits CYP1A2 (moderate), 2A6 (weak), 2B6 (weak), 2C8 (weak), 2C9 (weak), 2D6 (weak), 3A4 (weak)
Valsartan: Inhibits CYP2C9 (weak)
DRUG INTERACTIONS
ACE Inhibitors: Angiotensin II Receptor Blockers may enhance the adverse/toxic effect of ACE Inhibitors. 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
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
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: 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
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
Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
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: 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
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 Angiotensin II Receptor 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
Food: Decreases rate and extent of valsartan absorption by 50% and 40%, respectively.
Herb/Nutraceutical: Avoid dong quai if using for hypertension (has estrogenic activity). Avoid ephedra, yohimbe, ginseng (may worsen hypertension). Avoid garlic (may have increased antihypertensive effects).
PREGNANCY RISK FACTOR — D (show table)
PREGNANCY IMPLICATIONS — See individual agents.
LACTATION — Excretion in breast milk unknown/not recommended
BREAST-FEEDING CONSIDERATIONS — See individual agents.
DIETARY CONSIDERATIONS — Avoid salt substitutes which contain potassium. May be taken with or without food.
PRICING — (data from drugstore.com)
Tablets (Exforge)
5-160 mg (30): $87.29
5-320 mg (30): $111.04
10-160 mg (30): $99.48
10-320 mg (30): $118.95
MONITORING PARAMETERS — Baseline and periodic electrolyte panels, renal and liver function, urinalysis; BP, heart rate, peripheral edema; in CHF, serum potassium during dose escalation and periodically thereafter
INTERNATIONAL BRAND NAMES — Copalia (EE, SE); Diovan/Amlibon (VE); Exforge (BE, CH, CZ, DE, DK, EE, ES, FR, GB, HK, ID, IE, KP, MY, NO, PH, SE, SG, TH); Imprida (EE, SE)
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.
Amlodipine and olmesartan
U.S. BRAND NAMES — Azor™
PHARMACOLOGIC CATEGORY
Angiotensin II Receptor Blocker
Calcium Channel Blocker
Calcium Channel Blocker, Dihydropyridine
DOSING: ADULTS — Dose is individualized; combination product may be substituted for individual components in patients currently maintained on both agents separately or in patients not adequately controlled with monotherapy (using one of the agents or an agent within the same antihypertensive class). May also be used as initial therapy in patients who are likely to need >1 antihypertensive to control blood pressure.
Hypertension: Oral:
Initial therapy (antihypertensive naive): Amlodipine 5 mg/olmesartan 20 mg once daily; dose may be increased after 1-2 weeks of therapy. Maximum recommended dose: Amlodipine 10 mg/day; olmesartan 40 mg/day.
Add-on/replacement therapy: Amlodipine 5-10 mg and olmesartan 20-40 mg once daily depending upon previous doses, current control, and goals of therapy; dose may be titrated after 2 weeks of therapy. Maximum recommended dose: Amlodipine 10 mg/day; olmesartan 40 mg/day.
DOSING: ELDERLY — Initial therapy is not recommended in patients ≥ 75 years of age.
DOSING: RENAL IMPAIRMENT — No specific guidelines for dosage adjustment.
DOSING: HEPATIC IMPAIRMENT — Initial therapy is not recommended.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet:
Azor™ 5/20: Amlodipine besylate 5 mg and olmesartan medoxomil 20 mg
Azor™ 5/40: Amlodipine besylate 5 mg and olmesartan medoxomil 40 mg
Azor™ 10/20: Amlodipine besylate 10 mg and olmesartan medoxomil 20 mg
Azor™ 10/40: Amlodipine besylate 10 mg and olmesartan medoxomil 40 mg
DOSAGE FORMS: CONCISE
Tablet:
Azor™ : 5/20: Amlodipine besylate 5 mg and olmesartan medoxomil 20 mg; 5/40: Amlodipine besylate 5 mg and olmesartan medoxomil 40 mg; 10/20: Amlodipine besylate 10 mg and olmesartan medoxomil 20 mg; 10/40: Amlodipine besylate 10 mg and olmesartan medoxomil 40 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Administer with or without food.
USE — Treatment of hypertension, including initial treatment in patients who will require multiple antihypertensives for adequate control
ADVERSE REACTIONS SIGNIFICANT — Reactions/percentages reported with combination product; also refer to individual agents
>10%: Cardiovascular: Peripheral edema (dose related: 18% to 26%)
Frequency not defined (limited to important or life-threatening): Hypotension, nocturia, orthostatic hypotension, palpitation, pruritus, rash, urinary frequency
CONTRAINDICATIONS — There are no contraindications listed in manufacturer's labeling.
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. Hyperkalemia: May occur with olmesartan use; risk factors include renal dysfunction, diabetes mellitus, 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. Hypotension/syncope: Symptomatic hypotension with or without syncope can rarely occur; use caution during initiation of therapy, particularly in patients with heart failure, severe aortic stenosis, post-MI patients, volume- or salt-depleted 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. Reflex tachycardia: May occur with amlodipine use. Renal function deterioration: Olmesartan 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.
Disease-related concerns: Aortic/mitral stenosis: Use with caution in patients with significant aortic/mitral stenosis. Heart failure: Use caution when initiating in heart failure; may need to adjust dose, and/or concurrent diuretic therapy. Hepatic impairment: Use with caution in patients with hepatic impairment; amlodipine and olmesartan exposure increased in hepatic dysfunction. Initial therapy is not recommended; the appropriate combination dosage form is not available. Hypovolemia: Avoid use or use a smaller dose in patients who are volume depleted; correct depletion first. Renal artery stenosis: Use olmesartan 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 and severe renal impairment.
Special populations: Elderly: Initial therapy is not recommended in patients ≥ 75 years of age; the appropriate combination dosage form is not available. Pediatrics: Safety and efficacy of this combination have not been established in children. 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.
Other warnings/precautions: Titration: Dosage titration may occur after 1-2 weeks in antihypertensive naive patients and 2-4 weeks in add-on or replacement therapy if blood pressure control inadequate. This may be done by increasing one component at a time or by increasing both components to achieve more rapid control of blood pressure.
METABOLISM / TRANSPORT EFFECTS — Amlodipine: Substrate of CYP3A4 (major); Inhibits CYP1A2 (moderate), 2A6 (weak), 2B6 (weak), 2C8 (weak), 2C9 (weak), 2D6 (weak), 3A4 (weak)
DRUG INTERACTIONS
ACE Inhibitors: Angiotensin II Receptor Blockers may enhance the adverse/toxic effect of ACE Inhibitors. 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
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
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: 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
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
Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
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: 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
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 Angiotensin II Receptor 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: Avoid bayberry, blue cohosh, cayenne, ephedra, ginger, ginseng (American), kola, licorice (may worsen hypertension). Avoid black cohosh, California poppy, coleus, golden seal, hawthorn, mistletoe, periwinkle, quinine, shepherd's purse (may enhance antihypertensive effects).
PREGNANCY RISK FACTOR — C/D (show table) (2nd and 3rd trimesters)
PREGNANCY IMPLICATIONS — See individual agents.
LACTATION — Excretion in breast milk unknown/not recommended
BREAST-FEEDING CONSIDERATIONS — See individual agents.
DIETARY CONSIDERATIONS — Avoid salt substitutes which contain potassium. May be taken with or without food.
PRICING — (data from drugstore.com)
Tablets (Azor)
5-20 mg (30): $89.36
5-40 mg (30): $107.30
10-20 mg (30): $96.25
10-40 mg (90): $337.74
MONITORING PARAMETERS — Baseline and periodic electrolyte panels, renal and liver function, urinalysis; BP, heart rate, peripheral edema; in CHF, serum potassium during dose escalation and periodically thereafter
MECHANISM OF ACTION — See individual agents.
PHARMACODYNAMICS / KINETICS — See individual agents.
PHARMACOLOGIC CATEGORY
Angiotensin II Receptor Blocker
Calcium Channel Blocker
Calcium Channel Blocker, Dihydropyridine
DOSING: ADULTS — Dose is individualized; combination product may be substituted for individual components in patients currently maintained on both agents separately or in patients not adequately controlled with monotherapy (using one of the agents or an agent within the same antihypertensive class). May also be used as initial therapy in patients who are likely to need >1 antihypertensive to control blood pressure.
Hypertension: Oral:
Initial therapy (antihypertensive naive): Amlodipine 5 mg/olmesartan 20 mg once daily; dose may be increased after 1-2 weeks of therapy. Maximum recommended dose: Amlodipine 10 mg/day; olmesartan 40 mg/day.
Add-on/replacement therapy: Amlodipine 5-10 mg and olmesartan 20-40 mg once daily depending upon previous doses, current control, and goals of therapy; dose may be titrated after 2 weeks of therapy. Maximum recommended dose: Amlodipine 10 mg/day; olmesartan 40 mg/day.
DOSING: ELDERLY — Initial therapy is not recommended in patients ≥ 75 years of age.
DOSING: RENAL IMPAIRMENT — No specific guidelines for dosage adjustment.
DOSING: HEPATIC IMPAIRMENT — Initial therapy is not recommended.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet:
Azor™ 5/20: Amlodipine besylate 5 mg and olmesartan medoxomil 20 mg
Azor™ 5/40: Amlodipine besylate 5 mg and olmesartan medoxomil 40 mg
Azor™ 10/20: Amlodipine besylate 10 mg and olmesartan medoxomil 20 mg
Azor™ 10/40: Amlodipine besylate 10 mg and olmesartan medoxomil 40 mg
DOSAGE FORMS: CONCISE
Tablet:
Azor™ : 5/20: Amlodipine besylate 5 mg and olmesartan medoxomil 20 mg; 5/40: Amlodipine besylate 5 mg and olmesartan medoxomil 40 mg; 10/20: Amlodipine besylate 10 mg and olmesartan medoxomil 20 mg; 10/40: Amlodipine besylate 10 mg and olmesartan medoxomil 40 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Administer with or without food.
USE — Treatment of hypertension, including initial treatment in patients who will require multiple antihypertensives for adequate control
ADVERSE REACTIONS SIGNIFICANT — Reactions/percentages reported with combination product; also refer to individual agents
>10%: Cardiovascular: Peripheral edema (dose related: 18% to 26%)
Frequency not defined (limited to important or life-threatening): Hypotension, nocturia, orthostatic hypotension, palpitation, pruritus, rash, urinary frequency
CONTRAINDICATIONS — There are no contraindications listed in manufacturer's labeling.
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. Hyperkalemia: May occur with olmesartan use; risk factors include renal dysfunction, diabetes mellitus, 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. Hypotension/syncope: Symptomatic hypotension with or without syncope can rarely occur; use caution during initiation of therapy, particularly in patients with heart failure, severe aortic stenosis, post-MI patients, volume- or salt-depleted 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. Reflex tachycardia: May occur with amlodipine use. Renal function deterioration: Olmesartan 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.
Disease-related concerns: Aortic/mitral stenosis: Use with caution in patients with significant aortic/mitral stenosis. Heart failure: Use caution when initiating in heart failure; may need to adjust dose, and/or concurrent diuretic therapy. Hepatic impairment: Use with caution in patients with hepatic impairment; amlodipine and olmesartan exposure increased in hepatic dysfunction. Initial therapy is not recommended; the appropriate combination dosage form is not available. Hypovolemia: Avoid use or use a smaller dose in patients who are volume depleted; correct depletion first. Renal artery stenosis: Use olmesartan 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 and severe renal impairment.
Special populations: Elderly: Initial therapy is not recommended in patients ≥ 75 years of age; the appropriate combination dosage form is not available. Pediatrics: Safety and efficacy of this combination have not been established in children. 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.
Other warnings/precautions: Titration: Dosage titration may occur after 1-2 weeks in antihypertensive naive patients and 2-4 weeks in add-on or replacement therapy if blood pressure control inadequate. This may be done by increasing one component at a time or by increasing both components to achieve more rapid control of blood pressure.
METABOLISM / TRANSPORT EFFECTS — Amlodipine: Substrate of CYP3A4 (major); Inhibits CYP1A2 (moderate), 2A6 (weak), 2B6 (weak), 2C8 (weak), 2C9 (weak), 2D6 (weak), 3A4 (weak)
DRUG INTERACTIONS
ACE Inhibitors: Angiotensin II Receptor Blockers may enhance the adverse/toxic effect of ACE Inhibitors. 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
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
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: 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
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
Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
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: 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
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 Angiotensin II Receptor 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: Avoid bayberry, blue cohosh, cayenne, ephedra, ginger, ginseng (American), kola, licorice (may worsen hypertension). Avoid black cohosh, California poppy, coleus, golden seal, hawthorn, mistletoe, periwinkle, quinine, shepherd's purse (may enhance antihypertensive effects).
PREGNANCY RISK FACTOR — C/D (show table) (2nd and 3rd trimesters)
PREGNANCY IMPLICATIONS — See individual agents.
LACTATION — Excretion in breast milk unknown/not recommended
BREAST-FEEDING CONSIDERATIONS — See individual agents.
DIETARY CONSIDERATIONS — Avoid salt substitutes which contain potassium. May be taken with or without food.
PRICING — (data from drugstore.com)
Tablets (Azor)
5-20 mg (30): $89.36
5-40 mg (30): $107.30
10-20 mg (30): $96.25
10-40 mg (90): $337.74
MONITORING PARAMETERS — Baseline and periodic electrolyte panels, renal and liver function, urinalysis; BP, heart rate, peripheral edema; in CHF, serum potassium during dose escalation and periodically thereafter
MECHANISM OF ACTION — See individual agents.
PHARMACODYNAMICS / KINETICS — See individual agents.
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