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  • CLASSES

    Diuretic, Direct Renin Inhibitor, and Calcium Channel Blocker Combinations

    BOXED WARNING

    Pregnancy

    Aliskiren; amlodipine; hydrochlorothiazide is classified in FDA pregnancy risk category D. Once pregnancy is detected, every effort should be made to discontinue aliskiren; amlodipine; hydrochlorothiazide therapy. The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters can cause fetal and neonatal morbidity and even death. Drugs such as ACE inhibitors have been associated with fetal and neonatal injury when administered to pregnant women. The reported adverse fetal and neonatal effects include low blood pressure, neonatal skull hypoplasia and craniofacial deformation, fetal limb contractures, hypoplastic lung development, anuria, oligohydramnios, reversible or irreversible renal failure, and death. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. Women taking aliskiren; amlodipine; hydrochlorothiazide should tell their healthcare professionals if they are planning to become pregnant or think they might be pregnant. Inform women of reproductive age about the potential fetal risks of aliskiren; amlodipine; hydrochlorothiazide exposure throughout pregnancy. While it was previously thought that adverse effects do not result from first-trimester drug exposure, an observational study based on Tennessee Medicaid data reported that the risk of congenital malformations is significantly increased during first-trimester exposure to ACE inhibitors. However, a much larger observational study (n = 465,754) found that the risk of birth defects was similar in newborns exposed to ACE inhibitors during the first trimester, in those exposed to other antihypertensives during the first trimester, and in those whose mothers were hypertensive but were not treated. Newborns born to mothers with hypertension, either treated or untreated, had a higher risk of birth defects than those born to mothers without hypertension. The authors concluded that the presence of hypertension likely contributed to the development of birth defects rather than the use of medications. Pregnant women should only be prescribed drugs acting on the renin-angiotensin system if the expected benefits clearly exceed the potential risks. Rarely (probably less often than once per every thousand pregnancies), no alternative to this type of medications will be found. In these rare cases, the pregnant women should be apprised of the potential hazards to their fetus, and serial ultrasound examinations should be performed to assess the intraamniotic environment. In addition, hydrochlorothiazide crosses the placenta and neonatal jaundice, thrombocytopenia, and possible other reactions reported in adults may occur with the maternal use of thiazide diuretics.

    DEA CLASS

    Rx

    DESCRIPTION

    Combination direct renin inhibitor (aliskiren), dihydropyridine calcium-channel blocker (amlodipine), and thiazide diuretic (hydrochlorothiazide)
    Used for hypertension
    Black box warning for use during pregnancy

    COMMON BRAND NAMES

    Amturnide

    HOW SUPPLIED

    Amturnide Oral Tab: 150-5-12.5mg, 300-10-12.5mg, 300-10-25mg, 300-5-12.5mg, 300-5-25mg

    DOSAGE & INDICATIONS

    For the treatment of hypertension.
    NOTE: Aliskiren; amlodipine; hydrochlorothiazide is not indicated for initial therapy of hypertension.
    Oral dosage
    Adults and Geriatric patients <= 74 years

    1 tablet PO once daily. The combination product may be substituted for the individually titrated components or as add-on/switch therapy in patients not achieving optimal blood pressure control with any 2 of the following: aliskiren, dihydropyridine calcium-channel blockers, and thiazide diuretics. When necessary, the dose may be titrated after 2 weeks of therapy to a maximum of 300 mg aliskiren; 10 mg amlodipine; 25 mg hydrochlorothiazide. A patient who experiences dose-limiting adverse reactions while taking 2 of the individual components may be switched to the combination product at a lower dose of the component causing the ADR to achieve similar blood pressure reductions.

    Geriatric patients >= 75 years

    1 tablet PO once daily. The combination product may be substituted for the individually titrated components or as add-on/switch therapy in patients not achieving optimal blood pressure control with any 2 of the following: aliskiren, dihydropyridine calcium-channel blockers, and thiazide diuretics. If the patient is currently stable on a thiazide diuretic and aliskiren, and amlodipine is to be initiated, the initial recommended dose of amlodipine is 2.5 mg/day PO. The lowest available dose of amlodipine in Amturnide is 5 mg. Therefore, the triple combination should not be used until the the patient is taking amlodipine 5 mg PO once daily. When necessary, the dose may be titrated after 2 weeks of therapy to a maximum of 300 mg aliskiren; 10 mg amlodipine; 25 mg hydrochlorothiazide. A patient who experiences dose-limiting adverse reactions while taking 2 of the individual components may be switched to the combination product at a lower dose of the component causing the ADR to achieve similar blood pressure reductions.

    MAXIMUM DOSAGE

    Adults

    300 mg/day PO aliskiren; 10 mg/day PO amlodipine; 25 mg/day PO hydrochlorothiazide.

    Geriatric

    300 mg/day PO aliskiren; 10 mg/day PO amlodipine; 25 mg/day PO hydrochlorothiazide.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No initial dosage adjustment is required in patients with mild or moderate hepatic disease. In patients with severely impaired hepatic function, an initial amlodipine dose of 2.5 mg PO once daily is recommended since amlodipine is extensively metabolized by the liver. Of note, the lowest available dose of amlodipine in Amturnide is 5 mg. In general, diuretics should be titrated slowly in patients with hepatic disease since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

    Renal Impairment

    CrCl >= 30 ml/min: No dosage adjustments needed. Titrate hydrochlorothiazide slowly as azotemia may be precipitated.
    CrCl < 30 ml/min: The safety and efficacy of aliskiren; amlodipine; hydrochlorothiazide have not been established in patients with severe renal impairment. In general, loop diuretics are preferred to thiazides in this population as thiazides are not effective in severe renal impairment.

    ADMINISTRATION

    Oral Administration

    May be given with or without food. However, administer consistently with or without meals; high fat meals can significantly decrease drug absorption and may alter the clinical efficacy.

    STORAGE

    Amturnide:
    - Protect from extreme heat
    - Protect from moisture
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    NOTE: This monograph discusses the use of the combination product aliskiren; amlodipine; hydrochlorothiazide, HCTZ. Clinicians may wish to consult the individual drug monographs for more information.
     
    Thiazide diuretics have been associated with a slight increase in serum cholesterol and triglyceride concentrations. Data from long-term studies, however, suggest diuretic-induced cholesterol changes are not clinically significant and do not contribute to coronary heart disease risk.

    Anuria, hypovolemia, renal artery stenosis, renal failure, renal impairment

    The safety and efficacy of aliskiren; amlodipine; hydrochlorothiazide have not been established in patients with severe renal impairment (CrCl <= 30 ml/min) or renal failure. Hydrochlorothiazide is contraindicated in patients with anuria. In patients with moderate renal impairment (GFR < 60 ml/min), use of aliskiren in combination with angiotensin-converting enzyme inhibitors (ACE inhibitors) or angiotensin II receptor antagonists (ARBs) should be avoided. Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe CHF, or hypovolemia) or patients receiving ARBs, ACE inhibitors, or NSAIDs may be at particular risk of developing acute renal failure on aliskiren; amlodipine; hydrochlorothiazide. Azotemia can be precipitated in patients with drug-induced hypovolemia; also, in patients with hypovolemia, symptomatic low blood pressure may occur in patients receiving renin-angiotensin-aldosterone system blockers. Hypovolemia should be corrected prior to initiation of therapy with aliskiren; amlodipine; hydrochlorothiazide. With the exception of metolazone, thiazide diuretics are considered ineffective when the creatinine clearance is less than 30 ml/minute. Interrupt or discontinue treatment in patients who develop a clinically significant decrease in renal function.

    Asthma, penicillin hypersensitivity, sulfonamide hypersensitivity, thiazide diuretic hypersensitivity

    Aliskiren; amlodipine; hydrochlorothiazide is contraindicated in patients with known thiazide diuretic hypersensitivity and/or sulfonamide hypersensitivity. Hypersensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma; however, reactions are more likely to occur in patients with such history. Hypersensitivity reactions may range from urticaria to anaphylaxis. Although thiazide diuretics are sulfonamide derivatives, sulfonamide cross-sensitivity has been rarely documented. Thiazide diuretics do not contain the N4-aromatic amine or the N1-substituent which are present in sulfonamide antibiotics. Non-arylamine sulfonamide derivatives, such as thiazide diuretics, have been proposed to have a lower risk of allergic reactions in patients with sulfonamide allergy, presumably due to lack of an arylamine group at the N4 position (a proposed structural site of action for sulfonamide allergy). One large retrospective cohort study has reported that in patients with the presence of an allergic reaction after exposure to a sulfonamide antibiotic, 9.9% had an allergic reaction after receiving a non-antibiotic sulfonamide derivative, while in patients who lacked an allergic reaction after sulfonamide antibiotic exposure, 1.6% had an allergic reaction after administration of a non-antibiotic sulfonamide derivative (adjusted odds ratio 2.8; 95% CI, 2.1—3.7). A causal relationship between sulfonamide hypersensitivity and allergic reactions with non-arylamine sulfonamide derivatives has not been definitively established and remains controversial. In general, patients with a documented sulfonamide allergy are considered to be predisposed for development of allergic drug reactions. Also, patients with a history of sulfonamide hypersensitivity or penicillin hypersensitivity who receive hydrochlorothiazide may also be at increased risk for the development of an idiosyncratic reaction resulting in transient myopia and acute angle-closure glaucoma. Discontinue hydrochlorothiazide promptly if this reaction occurs (see Adverse Reactions).

    ACE-inhibitor induced angioedema, angioedema, Black patients, hereditary angioedema, surgery

    Following administration of aliskiren, angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has been reported; discontinue aliskiren; amlodipine; hydrochlorothiazide, HCTZ and provide appropriate therapy and monitoring until complete and sustained resolution of the signs and symptoms has occurred. Angioedema may occur at any time during treatment, and has been reported in patients with and without a history of angioedema from ACE-inhibitors or angiotension receptor blockers. It is unknown if the occurrence of angioedema is higher in Black patients compared to other demographic subgroups, as has been reported with the use of angiotensin-converting enzyme inhibitors (ACE inhibitors). Black patients do, however, experience a slightly smaller reduction in blood pressure as compared to other subgroups, a trend that is consistent with experience in ACE inhibitor and angiotensin receptor antagonists therapy. Patients may require prolonged observation even with minor reactions where only swelling of the tongue is initially seen, without respiratory complications. In these patients, treatment with antihistamines and corticosteroids may not be sufficient to prevent respiratory involvement. Also, experience with ACE inhibitors has shown that rare fatalities can occur in patients with angioedema associated with laryngeal edema or tongue edema. Patients with involvement of the tongue, glottis, or larynx, and especially a history of airway surgery are more likely to experience airway obstruction. ACE-inhibitors are contraindicated in patients with a history of ACE-inhibitor induced angioedema, hereditary angioedema, or idiopathic angioedema, similar precautions should be observed when administering aliskiren.

    Breast-feeding

    According to the manufacturer, it is not known whether aliskiren or amlodipine is excreted in human milk; thiazide diuretics are distributed into breast milk. Aliskiren is excreted into the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue breast-feeding or discontinue aliskiren; amlodipine; hydrochlorothiazide, taking into account the importance of the drug to the mother. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Aortic stenosis, hyponatremia, hypotension, orthostatic hypotension, sympathectomy

    Aliskiren; amlodipine; hydrochlorothiazide, HCTZ should be used with caution in patients who exhibit hypotension. A transient hypotensive response is not a contraindication to further treatment, and the drug can usually be continued without difficulty once the blood pressure has stabilized. Rarely (0.3%), an excessive fall in blood pressure was observed in patients with uncomplicated hypertension treated with aliskiren; amlodipine; hydrochlorothiazide, HCTZ. Symptomatic hypotension is more likely to occur during amlodipine therapy in patients with severe aortic stenosis. Hypotension is also more likely to occur if aliskiren; amlodipine; hydrochlorothiazide, HCTZ is administered to patients with preexisting hypovolemia or hyponatremia or with combined use of aliskiren and other agents acting on the renin-angiotensin-aldosterone system. Volume depletion should be corrected prior to the administration of aliskiren; amlodipine; hydrochlorothiazide, HCTZ. In addition, orthostatic hypotension may occur during treatment with thiazide diuretics. Orthostatic hypotension can be exacerbated by concurrent use of alcohol, narcotics, or antihypertensive drugs. Excessive hypotension during thiazide diuretic therapy can result in syncope. The antihypertensive effects of thiazides may be enhanced in other patients predisposed for orthostatic hypotension, including the post-sympathectomy patient.

    Angina, coronary artery disease, myocardial infarction

    Rarely, an increase in the frequency, duration, and/or severity of angina or myocardial infarction have occurred during calcium channel blocker (such as amlodipine) initiation or dosage increase, particularly in those patients with severe obstructive coronary artery disease. Additionally. the addition of aliskiren to optimal medical therapy (i.e., antiplatelets, statins, beta-blockers, and either an ACE inhibitor or an angiotensin-receptor blocker) in patients who have had a myocardial infarction accompanied by left ventricular dysfunction may not improve outcomes and may result in increased adverse events. The Aliskiren Study in Post-MI Patients to Reduce Remodeling (ASPIRE) randomized 820 patients with left ventricular dysfunction to placebo or aliskiren 75 mg/day PO and titrated the dose up to 300 mg daily within two weeks. After 36 weeks, there was no significant reduction in left ventricular end-systolic volume compared to placebo as well as no significant difference in the ejection fraction or the end-diastolic volume. There was also a higher incidence of low potassium concentrations, low blood pressure, and kidney dysfunction in patients receiving aliskiren compared to placebo. Use aliskiren; amlodipine; hydrochlorothiazide with caution in this population.

    Biliary cirrhosis, hepatic disease

    Aliskiren; amlodipine; hydrochlorothiazide, HCTZ should be used with caution in patients with severe hepatic disease. Because hepatobiliary excretion seems to be prominent in the elimination of aliskiren, clinicians should observe caution when prescribing aliskiren; amlodipine; hydrochlorothiazide, HCTZ in patients with biliary cirrhosis or Child-Pugh class B or C until further data become available. Hydrochlorothiazide-induced fluctuations in serum electrolyte concentration can occur rapidly and precipitate hepatic coma in susceptible patients. Also, amlodipine is extensively metabolized by the liver; clearance is decreased in patients with hepatic impairment. A lower initial dose of amlodipine may be required.

    Heart failure

    Aliskiren; amlodipine; hydrochlorothiazide has not been studied in patients with heart failure. In patients with severe congestive heart failure, renal function may depend in part on the activity of the renin-angiotensin system, and these patients may therefore be at increased risk of developing acute renal failure if treated with aliskiren. An increase in the AUC of amlodipine of approximately 40—60% has been observed in patients with heart failure. In general, most calcium-channel blockers are not recommended in patients with heart failure (HF), because they can lead to worsening HF and have been associated with an increased risk of cardiovascular events. However, amlodipine has not been shown to adversely affect survival in these patients. The PRAISE-1 and PRAISE-2 trials have shown that amlodipine did not worsen heart failure in patients with NYHA Class II or III heart failure. In the Prospective Randomized Amlodipine Survival Evaluation (PRAISE) trial, 1153 patients (80% with class III heart failure, either due to ischemic or nonischemic disease) were randomized to receive amlodipine 5—10 mg PO once daily or placebo. One month after randomization, the average amlodipine dosage was 8.8 +/- 0.6 mg/day PO. In the ischemic heart failure subgroup of PRAISE-1, the results with amlodipine therapy were similar to placebo. In the subgroup of patients with nonischemic dilated cardiomyopathy, however, amlodipine-treated patients demonstrated a significant decrease in the primary endpoint of combined risk of either death or life-threatening cardiovascular event after 14 months. A follow-up trial (PRAISE-2) of non-ischemic heart failure (NYHA Class III or IV) demonstrated no significant benefit with amlodipine. In the PRAISE-2 trial, no difference was observed in all-cause mortality vs. placebo, but there were more reports of pulmonary edema.

    Systemic lupus erythematosus (SLE)

    Use aliskiren; amlodipine; hydrochlorothiazide, HCTZ with caution in patients with systemic lupus erythematosus (SLE). Thiazide diuretics have been reported to activate or exacerbate SLE.

    Geriatric

    Although in clinical evaluation of aliskiren; amlodipine; hydrochlorothiazide, blood pressure responses and adverse events were similar in geriatric patients as compared to younger patients, greater sensitivity of some older individuals, particularly those with hepatic or renal impairment, cannot be ruled out.

    Acid/base imbalance, electrolyte imbalance, hyperaldosteronism, hypercalcemia, hyperkalemia, hypochloremia, hypokalemia, hypomagnesemia, metabolic alkalosis

    Correct any electrolyte imbalance, such as pre-existing hyperkalemia, hyponatremia, hypokalemia, hypomagnesemia, and/or hypercalcemia, before initiating aliskiren; amlodipine; hydrochlorothiazide. Hyperkalemia may be associated with serious cardiac arrhythmias. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes, and the concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin II receptor antagonists (ARBs), NSAIDs, potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes. Initiation of thiazide diuretics in patients with electrolyte imbalances such as hypokalemia or hyponatremia can produce life-threatening situations such as cardiac arrhythmias, hypotension, and seizures. Hydrochlorothiazide has been shown to increase the urinary excretion of magnesium and potassium. Thiazide diuretics may induce metabolic alkalosis associated with hypokalemia and hypochloremia; this acid/base imbalance is effectively treated with potassium chloride replacement. Hyperaldosteronism, secondary to cirrhosis or nephrosis, can predispose patients to hypokalemia when hydrochlorothiazide is administered. Low dietary potassium intake, potassium intake, potassium-wasting states, or administration of potassium-wasting drugs can also predispose patients to hydrochlorothiazide-induced hypokalemia. Hydrochlorothiazide can also increase serum calcium concentrations by decreasing excretion of urinary calcium. In clinical trials of aliskiren; amlodipine; hydrochlorothiazide in patients not concomitantly treated with an ACE inhibitor or an ARB, increases in serum potassium > 5.5 mEq/L were infrequent (3%); decreases in serum potassium < 3.5 mEq/L occurred at an incidence of 11%. In contrast, when aliskiren was administered to patients with diabetes and renal disease receiving an ACE inhibitor or an ARB, the incidence of hyperkalemia was 36.9% compared to 27.1% in the placebo group. Hyperkalemia resulting in a serious adverse event was also reported more frequently in the aliskiren group compared to placebo (1.1% vs. 0.3%, respectively).Closely monitor patients receiving aliskiren; amlodipine; hydrochlorothiazide for clinical signs of reduced renal function and fluid or electrolyte imbalance.

    Diabetes mellitus

    Aliskiren-containing products are contraindicated in patients with diabetes mellitus who are receiving angiotensin-converting enzyme inhibitors (ACE inhibitors) or angiotensin II receptor antagonists (ARBs). In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of renal impairment (14.5% vs. 12.4%), hypotension (19.9% vs. 16.3%), and hyperkalemia (38.9% vs. 28.8%) compared to placebo. These adverse events were also reported as serious adverse events more frequently in aliskiren-treated patients compared to placebo: renal impairment (5.7% vs. 4.3%), hypotension (2.3% vs. 1.9%), and hyperkalemia (1% vs. 0.5%). The risk of stroke (3.4% vs. 2.7%) and death (8.4% vs. 8%) were numerically higher in aliskiren-treated patients. In patients with diabetes who are not receiving ACE inhibitors or ARBs, aliskiren; amlodipine; hydrochlorothiazide is still a treatment option, but it should be used with caution. Hyperglycemia, impaired glucose tolerance, and glycosuria can occur during hydrochlorothiazide therapy, and blood and/or urine glucose levels should be assessed more carefully in patients with diabetes mellitus who are receiving hydrochlorothiazide. Although hyperglycemia did occur, chlorthalidone, a related thiazide diuretic, has been shown to reduce cardiovascular disease events in older diabetic patients with isolated systolic hypertension. Patients with diabetes mellitus may also have an increased risk for hyperkalemia associated with aliskiren.

    Children, infants, neonates

    The safety and efficacy of aliskiren; amlodipine; hydrochlorothiazide in neonates, infants, children, and adolescents have not been established. FDA-approved labeling warns that preclinical studies suggest a potential for substantially increased aliskiren exposure in pediatric patients; however, this warning is based on animal data from 8 to 14 day old rats. The increased aliskiren exposure in newborn rats appears to be primarily attributed to the lack of maturation of P-glycoprotein (P-gp). There are limited data on the ontogeny of P-gp in humans; however, growth and development may be important determinants of its expression and activity.

    Pregnancy

    Aliskiren; amlodipine; hydrochlorothiazide is classified in FDA pregnancy risk category D. Once pregnancy is detected, every effort should be made to discontinue aliskiren; amlodipine; hydrochlorothiazide therapy. The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters can cause fetal and neonatal morbidity and even death. Drugs such as ACE inhibitors have been associated with fetal and neonatal injury when administered to pregnant women. The reported adverse fetal and neonatal effects include low blood pressure, neonatal skull hypoplasia and craniofacial deformation, fetal limb contractures, hypoplastic lung development, anuria, oligohydramnios, reversible or irreversible renal failure, and death. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. Women taking aliskiren; amlodipine; hydrochlorothiazide should tell their healthcare professionals if they are planning to become pregnant or think they might be pregnant. Inform women of reproductive age about the potential fetal risks of aliskiren; amlodipine; hydrochlorothiazide exposure throughout pregnancy. While it was previously thought that adverse effects do not result from first-trimester drug exposure, an observational study based on Tennessee Medicaid data reported that the risk of congenital malformations is significantly increased during first-trimester exposure to ACE inhibitors. However, a much larger observational study (n = 465,754) found that the risk of birth defects was similar in newborns exposed to ACE inhibitors during the first trimester, in those exposed to other antihypertensives during the first trimester, and in those whose mothers were hypertensive but were not treated. Newborns born to mothers with hypertension, either treated or untreated, had a higher risk of birth defects than those born to mothers without hypertension. The authors concluded that the presence of hypertension likely contributed to the development of birth defects rather than the use of medications. Pregnant women should only be prescribed drugs acting on the renin-angiotensin system if the expected benefits clearly exceed the potential risks. Rarely (probably less often than once per every thousand pregnancies), no alternative to this type of medications will be found. In these rare cases, the pregnant women should be apprised of the potential hazards to their fetus, and serial ultrasound examinations should be performed to assess the intraamniotic environment. In addition, hydrochlorothiazide crosses the placenta and neonatal jaundice, thrombocytopenia, and possible other reactions reported in adults may occur with the maternal use of thiazide diuretics.

    Gastroesophageal reflux disease (GERD), hiatal hernia

    Aliskiren; amlodipine; hydrochlorothiazide should be used cautiously in patients with gastroesophageal reflux disease (GERD) or hiatal hernia associated with reflux esophagitis. Calcium channel blockers such as amlodipine relax the lower esophageal sphincter.

    Gout, hyperuricemia

    Use caution when aliskiren; amlodipine; hydrochlorothiazide is administered to patients with gout or hyperuricemia since thiazide diuretics have been reported to reduce the clearance of uric acid. An increase in uric acid of greater than 50% from baseline was more commonly observed in patients treated with aliskiren; amlodipine; hydrochlorothiazide (4.7%) compared with the dual combinations of aliskiren; amlodipine and aliskiren; hydrochlorothiazide (0.4—2.8%). Gout was reported less often (0.3% in aliskiren; amlodipine; hydrochlorothiazide-treated patients) and renal stones were not reported.

    Sunlight (UV) exposure

    Photosensitivity has been reported with thiazide diuretics. Instruct patients receiving aliskiren; amlodipine; hydrochlorothiazide to avoid excessive sunlight (UV) exposure; discontinued therapy if phototoxicity occurs.

    ADVERSE REACTIONS

    Severe

    hyperkalemia / Delayed / 3.0-3.0
    atrial fibrillation / Early / 0-1.0
    vasculitis / Delayed / 0-1.0
    ventricular tachycardia / Early / 0-1.0
    arrhythmia exacerbation / Early / 0-1.0
    bradycardia / Rapid / 0-1.0
    pancreatitis / Delayed / 0-1.0
    seizures / Delayed / 0-1.0
    visual impairment / Early / 0-1.0
    teratogenesis / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    pulmonary edema / Early / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    azotemia / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    ocular hypertension / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known

    Moderate

    hypokalemia / Delayed / 11.0-11.0
    peripheral edema / Delayed / 7.1-7.1
    elevated hepatic enzymes / Delayed / 2.7-2.7
    orthostatic hypotension / Delayed / 0-1.0
    chest pain (unspecified) / Early / 0-1.0
    leukopenia / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    constipation / Delayed / 0-1.0
    dysphagia / Delayed / 0-1.0
    gingival hyperplasia / Delayed / 0-1.0
    peripheral neuropathy / Delayed / 0-1.0
    conjunctivitis / Delayed / 0-1.0
    erythema / Early / 0-1.0
    depression / Delayed / 0-1.0
    dyspnea / Early / 0-1.0
    hypotension / Rapid / 0.3-0.3
    pneumonitis / Delayed / Incidence not known
    metabolic alkalosis / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known
    hypomagnesemia / Delayed / Incidence not known
    hypochloremia / Delayed / Incidence not known
    glycosuria / Early / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    hyperuricemia / Delayed / Incidence not known
    nephrolithiasis / Delayed / Incidence not known
    gout / Delayed / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    hypercholesterolemia / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    sialadenitis / Delayed / Incidence not known
    myopia / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    xanthopsia / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known

    Mild

    dizziness / Early / 3.6-3.6
    headache / Early / 3.6-3.6
    pharyngitis / Delayed / 2.6-2.6
    diarrhea / Early / 2.3-2.3
    dyspepsia / Early / 0-2.0
    pruritus / Rapid / 0-2.0
    asthenia / Delayed / 0-2.0
    muscle cramps / Delayed / 0-2.0
    cough / Delayed / 1.1-1.1
    syncope / Early / 0-1.0
    increased urinary frequency / Early / 0-1.0
    nocturia / Early / 0-1.0
    purpura / Delayed / 0-1.0
    anorexia / Delayed / 0-1.0
    xerostomia / Early / 0-1.0
    vomiting / Early / 0-1.0
    flatulence / Early / 0-1.0
    tremor / Early / 0-1.0
    paresthesias / Delayed / 0-1.0
    vertigo / Early / 0-1.0
    tinnitus / Delayed / 0-1.0
    diplopia / Early / 0-1.0
    diaphoresis / Early / 0-1.0
    maculopapular rash / Early / 0-1.0
    myalgia / Early / 0-1.0
    weight loss / Delayed / 0-1.0
    arthralgia / Delayed / 0-1.0
    flushing / Rapid / 0-1.0
    malaise / Early / 0-1.0
    weight gain / Delayed / 0-1.0
    back pain / Delayed / 0-1.0
    insomnia / Early / 0-1.0
    nightmares / Early / 0-1.0
    anxiety / Delayed / 0-1.0
    epistaxis / Delayed / 0-1.0
    fever / Early / Incidence not known
    photosensitivity / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    abdominal pain / Early / Incidence not known
    gastroesophageal reflux / Delayed / Incidence not known
    restlessness / Early / Incidence not known
    ocular pain / Early / Incidence not known
    gynecomastia / Delayed / Incidence not known
    libido decrease / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acarbose: Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Acebutolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Acetaminophen; Butalbital; Caffeine; Codeine: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Acetaminophen; Caffeine; Dihydrocodeine: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Acetaminophen; Codeine: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Acetaminophen; Dextromethorphan; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Acetaminophen; Dichloralphenazone; Isometheptene: Isometheptene has sympathomimetic properties. Patients taking antihypertensive agents may need to have their therapy modified. Careful blood pressure monitoring is recommended.
    Acetaminophen; Guaifenesin; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Acetaminophen; Hydrocodone: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Acetaminophen; Oxycodone: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Acetaminophen; Propoxyphene: Amlodipine is a CYP3A4 substrate. CYP3A4 inhibitors, such as propoxyphene, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when propoxyphene is coadministered with amlodipine; therapeutic response should be monitored.
    Acetaminophen; Pseudoephedrine: Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Acetazolamide: Acetazolamide promotes electrolyte excretion including hydrogen ions, sodium, and potassium. It can enhance the sodium depleting effects of other diuretics when used concurrently. Pre-existing hypokalemia and hyperuricemia can also be potentiated by carbonic anhydrase inhibitors. Monitor serum potassium to determine the need for potassium supplementation and alteration in drug therapy.
    Acetohexamide: Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Acrivastine; Pseudoephedrine: Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Albiglutide: Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Albuterol: Hypokalemia associated with thiazide diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
    Albuterol; Ipratropium: Hypokalemia associated with thiazide diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
    Aldesleukin, IL-2: Calcium channel blockers may potentiate the hypotension seen with aldesleukin, IL 2. Thiazide diuretics may potentiate the hypotension seen with aldesleukin, IL 2.
    Alemtuzumab: Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Alendronate; Cholecalciferol: Dose adjustment of vitamin D or vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D or vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Alfentanil: Alfentanil may cause bradycardia. The risk of significant hypotension and/or bradycardia during therapy with alfentanil is increased in patients receiving calcium-channel blockers. In addition to additive hypotensive effects, calcium-channel blockers that are CYP3A4 inhibitors (e.g., diltiazem, nicardipine, and verapamil) can theoretically decrease hepatic metabolism of some opiates (CYP3A4 substrates), such as alfentanil. Diltiazem increases the half-life of alfentanil by 50% via inhibition of cytochrome P450 (CYP) 3A4 metabolism and may delay tracheal extubation after anesthesia. Reduced clearance of alfentanil should be considered when recovery from alfentanil infusions for anesthesia is evaluated in patients receiving concurrent diltiazem therapy. Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Aliskiren; Valsartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Allopurinol: The occurrence of certain hypersensitivity reactions may be increased in patients with renal impairment who receive allopurinol and thiazide diuretics in combination. The precise mechanism for such events is unclear but likely immune-mediated and may be related to an effect of oxypurinol; elevated oxypurinol concentrations appear to be associated with hypersensitivity reactions; decreased clearance of this metabolite may occur with renal impairment and with the concurrent use of thiazide diuretics. Severe skin reactions include exfoliative dermatitis, toxic epidermal necrolysis and Steven's Johnson syndrome; some reactions have been fatal. In addition, thiazide diuretics, like hydrochlorothiazide, can cause hyperuricemia. Since thiazides reduce the clearance of uric acid, patients with gout or hyperuricemia may have exacerbations of their disease.
    Alogliptin: Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Alogliptin; Metformin: Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity. Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary.
    Alogliptin; Pioglitazone: Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity. Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as pioglitazone, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Alpha-glucosidase Inhibitors: Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Alprostadil: The concomitant use of systemic alprostadil injection and antihypertensive agents, like calcium channel blockers, may cause additive hypotension. Caution is advised with this combination. Systemic drug interactions with the urethral suppository (MUSE) or alprostadil intracavernous injection are unlikely in most patients because low or undetectable amounts of the drug are found in the peripheral venous circulation following administration. In those men with significant corpora cavernosa venous leakage, hypotension might be more likely. Use caution with in-clinic dosing for erectile dysfunction (ED) and monitor for the effects on blood pressure. In addition, the presence of medications in the circulation that attenuate erectile function may influence the response to alprostadil. However, in clinical trials with alprostadil intracavernous injection, anti-hypertensive agents had no apparent effect on the safety and efficacy of alprostadil. The concomitant use of systemic alprostadil injection and antihypertensive agents, such as thiazide diuretics, may cause additive hypotension. Caution is advised with this combination. Systemic drug interactions with the urethral suppository (MUSE) or alprostadil intracavernous injection are unlikely in most patients because low or undetectable amounts of the drug are found in the peripheral venous circulation following administration. In those men with significant corpora cavernosa venous leakage, hypotension might be more likely. Use caution with in-clinic dosing for erectile dysfunction (ED) and monitor for the effects on blood pressure. In addition, the presence of medications in the circulation that attenuate erectile function may influence the response to alprostadil. However, in clinical trials with alprostadil intracavernous injection, anti-hypertensive agents had no apparent effect on the safety and efficacy of alprostadil.
    Aluminum Hydroxide; Magnesium Hydroxide: Diuretics may interfere with the kidneys ability to regulate magnesium concentrations. Long-term use of diuretics may impair the magnesium-conserving ability of the kidneys and lead to hypomagnesemia.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: Diuretics may interfere with the kidneys ability to regulate magnesium concentrations. Long-term use of diuretics may impair the magnesium-conserving ability of the kidneys and lead to hypomagnesemia.
    Amantadine: Hydrochlorothiazide can reduce the renal clearance of amantadine, with subsequent increased serum concentrations and possible toxicity. This interaction has been reported with a combination product of hydrochlorothiazide and triamterene. Since it is unclear which component was responsible for the interaction, caution should be exercised when administering either drug concurrently with amantadine.
    Amifostine: Patients receiving antihypertensive agents should be closely monitored during amifostine infusions due to additive effects. If possible, patients should not take their antihypertensive medication 24 hours before receiving amifostine. Patients who can not stop their antihypertensive agents should not receive amifostine or be closely monitored during the infusion and, possibly, given lower doses. Patients receiving antihypertensive agents should be closely monitored during amifostine infusions due to additive effects. If possible, patients should not take their antihypertensive medication 24 hours before receiving amifostine. Patients who can not stop their antihypertensive agents should not receive amifostine or be closely monitored during the infusion and, possibly, given lower doses.
    Amiloride: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium-sparing diuretics, should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren. Aliskiren can enhance the effects of diuretics on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Also, patients with hyponatremia or hypovolemia may become hypotensive and/or develop reversible renal insufficiency when given aliskiren and diuretics.
    Amiloride; Hydrochlorothiazide, HCTZ: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium-sparing diuretics, should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren. Aliskiren can enhance the effects of diuretics on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Also, patients with hyponatremia or hypovolemia may become hypotensive and/or develop reversible renal insufficiency when given aliskiren and diuretics.
    Amiodarone: Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy. Use caution when coadministering amiodarone with drugs which may induce hypokalemia and, or hypomagnesemia including thiazide diuretics. Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as amiodarone, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when amiodarone is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Atorvastatin: Coadministration of atorvastatin resulted in an approximate 50% increase in aliskiren Cmax and AUC after multiple doses; the pharmacokinetics of atorvastatin were not affected. Monitor blood pressure in patients taking both of these medications.
    Amlodipine; Benazepril: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury. Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Amlodipine; Olmesartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Amlodipine; Telmisartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Amlodipine; Valsartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Amobarbital: Concurrent use of amobarbital with antihypertensive agents may lead to hypotension. Monitor for decreases in blood pressure during times of coadministration.
    Amoxicillin; Clarithromycin; Lansoprazole: Coadministration of clarithromycin and calcium-channel blockers should be avoided if possible, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. Most reports of acute kidney injury were with the combination of clarithromycin with calcium channel blockers metabolized by CYP3A4 and involved elderly patients at least 65 years of age. Clarithromycin may decrease the clearance of calcium-channel blockers (e.g., amlodipine, diltiazem, felodipine, nifedipine, and verapamil) via inhibition of CYP3A4 metabolism. A retrospective, case cross-over study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). One case of a possible verapamil-clarithromycin interaction was reported, which was associated with hypotension. If the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy, azithromycin is the preferred agent. Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Amoxicillin; Clarithromycin; Omeprazole: Coadministration of clarithromycin and calcium-channel blockers should be avoided if possible, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. Most reports of acute kidney injury were with the combination of clarithromycin with calcium channel blockers metabolized by CYP3A4 and involved elderly patients at least 65 years of age. Clarithromycin may decrease the clearance of calcium-channel blockers (e.g., amlodipine, diltiazem, felodipine, nifedipine, and verapamil) via inhibition of CYP3A4 metabolism. A retrospective, case cross-over study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). One case of a possible verapamil-clarithromycin interaction was reported, which was associated with hypotension. If the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy, azithromycin is the preferred agent. Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Amphetamine; Dextroamphetamine Salts: Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as calcium-channel blockers. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed. Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents. Due to the risk of unopposed alpha-adrenergic activity, amphetamines should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. In particular, amphetamines can inhibit the antihypertensive response to guanadrel, an adrenergic antagonist that causes depletion of norepinephrine in the synapse. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Amphotericin B cholesteryl sulfate complex (ABCD): The risk of developing severe hypokalemia can be increased when amphotericin B is coadministered with thiazide diuretics. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required.
    Amphotericin B lipid complex (ABLC): The risk of developing severe hypokalemia can be increased when amphotericin B is coadministered with thiazide diuretics. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required.
    Amphotericin B liposomal (LAmB): The risk of developing severe hypokalemia can be increased when amphotericin B is coadministered with thiazide diuretics. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required.
    Amphotericin B: The risk of developing severe hypokalemia can be increased when amphotericin B is coadministered with thiazide diuretics. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required.
    Amprenavir: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Amyl Nitrite: Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary. Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
    Angiotensin II receptor antagonists: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Angiotensin-converting enzyme inhibitors: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury. Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Anticholinergics: Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Apomorphine: Patients receiving apomorphine may experience orthostatic hypotension, hypotension, and/or syncope. Extreme caution should be exercised if apomorphine is used concurrently with antihypertensive agents, or vasodilators such as nitrates.
    Apraclonidine: Alpha blockers as a class may reduce heart rate and blood pressure. While no specific drug interactions have been identified with systemic agents and apraclonidine during clinical trials, it is theoretically possible that additive blood pressure reductions could occur when apraclonidine is combined with the use of antihypertensive agents. Patients using cardiovascular drugs concomitantly with apraclonidine should have their pulse and blood pressure monitored periodically. Alpha blockers as a class may reduce heart rate and blood pressure. While no specific drug interactions have been identified with systemic agents and apraclonidine during clinical trials, it is theoretically possible that additive blood pressure reductions could occur when apraclonidine is combined with the use of antihypertensive agents. Patients using cardiovascular drugs concomitantly with apraclonidine should have their pulse and blood pressure monitored periodically.
    Aprepitant, Fosaprepitant: Use caution if aliskiren and aprepitant, fosaprepitant are used concurrently and monitor for an increase in aliskiren-related adverse effects for several days after administration of a multi-day aprepitant regimen. Aliskiren is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of aliskiren. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Use caution if amlodipine and a multi-day regimen of oral aprepitant are used concurrently; monitor for an increase in amlodipine-related adverse effects for several days after administration. Amlodipine is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of amlodipine. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Arformoterol: Hypokalemia associated with thiazide diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
    Aripiprazole: Aripiprazole may enhance the hypotensive effects of antihypertensive agents.
    Armodafinil: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as armodafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Arsenic Trioxide: Avoid concomitant use of arsenic trioxide with thiazide diuretics. Electrolyte abnormalities, such as hypokalemia and hypomagnesemia, may increase the risk for QT prolongation and torsade de pointes. Monitor electrocardiograms and serum electrolytes more frequently if concurrent use cannot be avoided.
    Articaine; Epinephrine: Sympathomimetics can antagonize the effects of antihypertensives such as metolazone when administered concomitantly.
    Asenapine: Secondary to alpha-blockade, asenapine can produce vasodilation that may result in additive effects during concurrent use of antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of asenapine and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Aspirin, ASA; Caffeine; Dihydrocodeine: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Aspirin, ASA; Carisoprodol; Codeine: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Aspirin, ASA; Omeprazole: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Aspirin, ASA; Oxycodone: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Atazanavir: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. The plasma concentrations of aliskiren may be elevated when administered concurrently with atazanavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Atazanavir is a CYP3A4 inhibitor. Aliskiren is a substrate of CYP3A4.
    Atazanavir; Cobicistat: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. Coadministration of cobicistat (a CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as amlodipine, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate dose reductions are advised. The plasma concentrations of aliskiren may be elevated when administered concurrently with atazanavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Atazanavir is a CYP3A4 inhibitor. Aliskiren is a substrate of CYP3A4. The plasma concentrations of aliskiren may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and aliskiren is a CYP3A4 and P-gp substrate.
    Atenolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Atenolol; Chlorthalidone: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Atorvastatin: Coadministration of atorvastatin resulted in an approximate 50% increase in aliskiren Cmax and AUC after multiple doses; the pharmacokinetics of atorvastatin were not affected. Monitor blood pressure in patients taking both of these medications.
    Atorvastatin; Ezetimibe: Coadministration of atorvastatin resulted in an approximate 50% increase in aliskiren Cmax and AUC after multiple doses; the pharmacokinetics of atorvastatin were not affected. Monitor blood pressure in patients taking both of these medications.
    Atracurium: Concomitant administration of hydrochlorothiazide to patients receiving nondepolarizing neuromuscular blockers (e.g., tubocurarine) can cause prolonged neuromuscular blockade due to hydrochlorothiazide-induced hypokalemia. Serum potassium concentrations should be determined and corrected (if necessary) prior to initiation of neuromuscular blockade therapy.
    Atropine: Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde. Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Atropine; Difenoxin: Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Atropine; Diphenoxylate: Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Atropine; Edrophonium: Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Avanafil: Avanafil is a substrate of and primarily metabolized by CYP3A4. Particular caution should be used when prescribing avanafil to patients receiving concomitant CYP3A4 substrates, such as amlodipine. Coadministration of avanafil with amlodipine increased the Cmax and AUC of avanafil by approximately 22% and 70%, respectively. The half-life of avanafil was prolonged to approximately 10 hrs. The Cmax and AUC of amlodipine decreased by approximately 9% and 4%, respectively. In addition, in a clinical pharmacology trial, additional reductions in blood pressure of 3 to 5 mmHg occurred following co-administration of a single avanafil (200 mg) dose with amlodipine compared with placebo. Patients should be monitored carefully and drug dosages should be adjusted based on clinical response.
    Axitinib: Use caution if coadministration of axitinib with amlodipine is necessary, due to the risk of increased axitinib-related adverse reactions. Axitinib is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor. Coadministration with a strong CYP3A4/5 inhibitor, ketoconazole, significantly increased the plasma exposure of axitinib in healthy volunteers.The manufacturer of axitinib recommends a dose reduction in patients receiving strong CYP3A4 inhibitors, but recommendations are not available for moderate or weak CYP3A4 inhibitors.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents, especially calcium-channel blockers. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise. Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Azilsartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Azilsartan; Chlorthalidone: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Baclofen: Baclofen has been associated with hypotension. Concurrent use with baclofen and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Barbiturates: Barbiturates may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine, and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers; monitor blood pressure closely. Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: Because of the potential to cause coronary vasospasm , ergotamine theoretically could antagonize the therapeutic effects of calcium-channel blockers. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties, such as diltiazem, nicardipine, and verapamil, may also reduce the hepatic metabolism of ergotamine and increase the risk of ergot toxicity. Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Belladonna; Opium: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Benazepril: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury. Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Benazepril; Hydrochlorothiazide, HCTZ: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury. Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Bendroflumethiazide; Nadolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde. Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Benzonatate: Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Benzphetamine: Benzphetamine can increase both systolic and diastolic blood pressure and may counteract the activity of calcium-channel blockers. This represents a pharmacodynamic, and not a pharmacokinetic, interaction. Close monitoring of blood pressure, especially in patients who are taking antihypertensive agents, may be needed
    Benztropine: Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Beta-agonists: Hypokalemia associated with thiazide diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
    Beta-blockers: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Betaxolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Bexarotene: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as bexarotene, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Bisoprolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Bisoprolol; Hydrochlorothiazide, HCTZ: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Black Cohosh, Cimicifuga racemosa: Actein and certain acids isolated from the rhizome of Cimicifuga spp. have been noted to antagonize the influx of calcium and norepinephrine-induced contraction of the aorta in rats. Black cohosh, Cimicifuga racemosa has potentiated the effects of antihypertensive medications in some animal studies, and actein may have peripheral vasodilatory activity. Clinical reports of interactions between black cohosh and antihypertensive agents in humans are not available, and remain theoretical. However, isolated cases of hypertension or hypotension have been reported with black cohosh use.
    Boceprevir: Close clinical monitoring is advised when administering aliskiren with boceprevir due to an increased potential for aliskiren-related adverse events. If aliskiren dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of aliskiren. Aliskiren is metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated aliskiren plasma concentrations. Close clinical monitoring is advised when administering amlodipine with boceprevir due to an increased potential for amlodipine-related adverse events. A reduction in the dose of amlodipine may be considered. If amlodipine dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Predictions about the interaction can be made based on the metabolic pathway of amlodipine. Amlodipine is metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated amlodipine plasma concentrations.
    Bortezomib: Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
    Bosentan: Although no specific interactions have been documented, bosentan has vasodilatory effects and may contribute additive hypotensive effects when given with calcium-channel blockers. In addition, bosentan may induce hepatic metabolism of calcium-channel blockers metabolized by CYP3A4 isoenzymes. Diltiazem and verapamil have potential to inhibit CYP3A4 metabolism of bosentan. Bosentan has been shown to have no pharmacokinetic interactions with nimodipine. Although no specific interactions have been documented, bosentan has vasodilatory effects and may contribute additive hypotensive effects when given with diuretics.
    Brexpiprazole: Due to brexpiprazole's antagonism at alpha 1-adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents.
    Brimonidine; Timolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Bromocriptine: Bromocriptine has only minimal affinity for adrenergic receptors; however, hypotension can occur during bromocriptine administration. Orthostatic hypotension occurs in 6% of acromegaly patients receiving the drug. Hypotension occurred frequently (approximately 30%) in postpartum studies, which in rare cases approached a decline in supine pressure of almost 60 mmHg. It is unknown if bromocriptine is the exact cause of this effect. However, the drug should be used cautiously with other medications known to lower blood pressure such as antihypertensive agents. Monitoring of blood pressure should be considered, especially during the initial weeks of concomitant therapy.
    Brompheniramine; Carbetapentane; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Brompheniramine; Guaifenesin; Hydrocodone: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Brompheniramine; Hydrocodone; Pseudoephedrine: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Brompheniramine; Pseudoephedrine: Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Budesonide; Formoterol: Hypokalemia associated with thiazide diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
    Bumetanide: Aliskiren can enhance the effects of loop-diuretics on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Patients with hyponatremia or hypovolemia may also develop reversible renal insufficiency. When aliskiren is administered in combination with furosemide, the AUC and Cmax of furosemide are reduced by approximately 30% and 50%, respectively; the pharmacokinetics of aliskiren are not affected. Patients should be monitored for loss of effect of furosemide when aliskiren is initiated. Blood pressure and electrolytes should be routinely monitored.
    Bupivacaine; Lidocaine: Concomitant use of systemic lidocaine and amlodipine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; amlodipine inhibits CYP3A4.
    Buprenorphine: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Buprenorphine; Naloxone: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Cabergoline: Cabergoline has minimal affinity for adrenergic receptors; however, it has been associated with hypotension in some instances. Cabergoline should be used cautiously in those receiving antihypertensive agents.
    Cabozantinib: Monitor for an increase in aliskiren-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of aliskiren may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and aliskiren is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Caffeine; Ergotamine: Because of the potential to cause coronary vasospasm , ergotamine theoretically could antagonize the therapeutic effects of calcium-channel blockers. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties, such as diltiazem, nicardipine, and verapamil, may also reduce the hepatic metabolism of ergotamine and increase the risk of ergot toxicity.
    Calcium Carbonate; Magnesium Hydroxide: Diuretics may interfere with the kidneys ability to regulate magnesium concentrations. Long-term use of diuretics may impair the magnesium-conserving ability of the kidneys and lead to hypomagnesemia.
    Calcium Phosphate, Supersaturated: Concomitant use of medicines with potential to alter renal perfusion or function such as diuretics, may increase the risk of acute phosphate nephropathy in patients taking sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous.
    Calcium: The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Calcium; Vitamin D: Dose adjustment of vitamin D or vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D or vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Canagliflozin: When canagliflozin is initiated in patients already receiving diuretics, symptomatic hypotension can occur. Patients with impaired renal function (eGFR < 60 ml/min/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Before initiating canagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, thiazide diuretics, can also decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose concentrations. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. Thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients receiving canagliflozin should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Canagliflozin; Metformin: Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary. When canagliflozin is initiated in patients already receiving diuretics, symptomatic hypotension can occur. Patients with impaired renal function (eGFR < 60 ml/min/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Before initiating canagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, thiazide diuretics, can also decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose concentrations. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. Thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients receiving canagliflozin should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Candesartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Candesartan; Hydrochlorothiazide, HCTZ: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Captopril: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury. Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Captopril; Hydrochlorothiazide, HCTZ: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury. Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Carbamazepine: Both thiazide diuretics and carbamazepine are associated with hyponatremia. Coadministration may result in an additive risk of developing hyponatremia. When concurrent therapy with a thiazide diuretic and carbamazepine is necessary, monitor patients for hyponatremia. Carbamazepine may induce the hepatic metabolism of calcium-channel blockers by the CYP3A4 isoenzyme; which reduces the oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
    Carbetapentane; Chlorpheniramine; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbetapentane; Diphenhydramine; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbetapentane; Guaifenesin; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbetapentane; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbetapentane; Phenylephrine; Pyrilamine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbetapentane; Pseudoephedrine: Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Carbidopa; Levodopa: Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Carbidopa; Levodopa; Entacapone: Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Carbinoxamine; Hydrocodone; Phenylephrine: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Carbinoxamine; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbinoxamine; Pseudoephedrine: Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Cardiac glycosides: Thiazide diuretics can cause hypokalemia, hypomagnesemia, or hypercalcemia which may increase digoxin's pharmacologic effect. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity. It is also recommended that serum potassium, magnesium, and calcium be monitored regularly in patients receiving digoxin.
    Cariprazine: Orthostatic vital signs should be monitored in patients who are at risk for hypotension, such as those receiving cariprazine in combination with antihypertensive agents. Atypical antipsychotics may cause orthostatic hypotension and syncope, most commonly during treatment initiation and dosage increases. Patients should be informed about measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning, or rising slowly from a seated position. Consider a cariprazine dose reduction if hypotension occurs.
    Carteolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Carvedilol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Celecoxib: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Cetirizine; Pseudoephedrine: Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Chlophedianol; Guaifenesin; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Chloramphenicol: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as chloramphenicol, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when chloramphenicol is coadministered with amlodipine; therapeutic response should be monitored.
    Chlordiazepoxide; Clidinium: Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Chloroprocaine: Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Chlorpheniramine; Codeine: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Chlorpheniramine; Hydrocodone: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Chlorpheniramine; Hydrocodone; Phenylephrine: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Chlorpheniramine; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Chlorpheniramine; Pseudoephedrine: Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Chlorpropamide: Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Cholecalciferol, Vitamin D3: Dose adjustment of vitamin D or vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D or vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Cholestyramine: Cholestyramine, an ion exchange resin, binds hydrochlorothiazide and reduces its absorption from the gastrointestinal tract by up to 85% when co-administered as single doses. Although the manufacturer for Questran recommends that other medicines be taken at least 1 hour before or 4-6 hours after cholestyramine, it has been recommended that thiazides be administered at least 4 hours before or after cholestyramine to minimize the reduction in absorption. By administering hydrochlorothiazide at least 4 hours before cholestyramine, the decrease in absorption of hydrochlorothiazide is approximately 30-35%.
    Chondroitin; Glucosamine: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium salts or salt substitutes containing potassium should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren.
    Cidofovir: The administration of cidofovir with another potentially nephrotoxic agent, such as diuretics, is contraindicated. Diuretics should be discontinued at least 7 days prior to beginning cidofovir.
    Ciprofloxacin: Administering amlodipine with CYP3A4 inhibitors, such as ciprofloxacin, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when ciprofloxacin is coadministered with amlodipine; therapeutic response should be monitored. The plasma concentrations of aliskiren may be elevated when administered concurrently with ciprofloxacin. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Ciprofloxacin is a CYP3A4 inhibitor and aliskiren is a CYP3A4 substrate.
    Cisapride: Cisapride should be used with great caution in patients receiving thiazide diuretics. Drugs that are associated with depletion of electrolytes may cause cisapride-induced cardiac arrhythmias. Serum electrolytes and creatinine should be assessed prior to administration of cisapride and whenever conditions develop that may affect electrolyte imbalance or renal function.
    Cisatracurium: Concomitant administration of hydrochlorothiazide to patients receiving nondepolarizing neuromuscular blockers (e.g., tubocurarine) can cause prolonged neuromuscular blockade due to hydrochlorothiazide-induced hypokalemia. Serum potassium concentrations should be determined and corrected (if necessary) prior to initiation of neuromuscular blockade therapy.
    Citalopram: Citalopram causes dose-dependent QT interval prolongation. Concurrent use of citalopram and medications known to cause electrolyte imbalance may increase the risk of developing QT prolongation. Therefore, caution is advisable during concurrent use of citalopram and diuretics. In addition, patients receiving a diuretic during treatment with citalopram may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of citalopram should be considered in patients who develop symptomatic hyponatremia.
    Citric Acid; Potassium Citrate: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium salts or salt substitutes containing potassium should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren.
    Citric Acid; Potassium Citrate; Sodium Citrate: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium salts or salt substitutes containing potassium should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren.
    Clarithromycin: Coadministration of clarithromycin and calcium-channel blockers should be avoided if possible, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. Most reports of acute kidney injury were with the combination of clarithromycin with calcium channel blockers metabolized by CYP3A4 and involved elderly patients at least 65 years of age. Clarithromycin may decrease the clearance of calcium-channel blockers (e.g., amlodipine, diltiazem, felodipine, nifedipine, and verapamil) via inhibition of CYP3A4 metabolism. A retrospective, case cross-over study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). One case of a possible verapamil-clarithromycin interaction was reported, which was associated with hypotension. If the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy, azithromycin is the preferred agent.
    Clindamycin; Tretinoin: A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
    Clobazam: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as clobazam, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Clopidogrel: Administer clopidogrel and amlodipine together with caution and monitor for reduced therapeutic response to clopidogrel. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps. The CYP3A4 isoenzyme is involved in one of the metabolic steps. Amlodipine is a weak inhibitor of CYP3A4 and may decrease the hepatic metabolism of clopidogrel to its active metabolite. In a study of 200 patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI), coadministration with a calcium-channel blocker (CCB) was associated with a reduced response to clopidogrel. Concomitant use of a CCB was also associated with a worse clinical outcome with the primary end point, a composite of death from cardiovascular causes, non-fatal myocardial infarction, stent thrombosis, and revascularization (PCI or CABG surgery), occurring more frequently in patients receiving a concomitant CCB. Amlodipine represented the largest subgroup of CCBs in the study, therefore it is unknown if these results can be applied to all CCBs. Another study compared concomitant use of amlodipine, a non-P-glycoprotein (P-gp) inhibiting CCB, with concomitant use of a P-gp inhibiting CCB (e.g., verapamil, nifedipine, diltiazem) on the effect of clopidogrel. Only amlodipine was associated with a poor response to clopidogrel suggesting the interaction between amlodipine and clopidogrel may be more clinically relevant compared to P-gp inhibiting CCBs. The authors theorized that by inhibiting P-gp, the intestinal efflux of clopidogrel may be decreased, thereby increasing clopidogrel plasma concentrations and counteracting the effect of CCB-induced CYP3A4 inhibition.
    Clozapine: Caution is advisable during concurrent use of clozapine and thiazide diuretics. Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Concurrent use of clozapine and medications known to cause electrolyte imbalance may increase the risk of QT prolongation. Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Cobicistat: Coadministration of cobicistat (a CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as amlodipine, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate dose reductions are advised. The plasma concentrations of aliskiren may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and aliskiren is a CYP3A4 and P-gp substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: Coadministration of cobicistat (a CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as amlodipine, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate dose reductions are advised. The plasma concentrations of aliskiren may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and aliskiren is a CYP3A4 and P-gp substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: Coadministration of cobicistat (a CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as amlodipine, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate dose reductions are advised. The plasma concentrations of aliskiren may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and aliskiren is a CYP3A4 and P-gp substrate.
    Cod Liver Oil: Dose adjustment of vitamin D or vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D or vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine. Fish oil supplements may cause mild, dose-dependent reductions in systolic or diastolic blood pressure in untreated hypertensive patients. Relatively high doses of fish oil are required to produce any blood pressure lowering effect. Additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents. High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Codeine: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Codeine; Guaifenesin: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Codeine; Phenylephrine; Promethazine: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Codeine; Promethazine: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Co-Enzyme Q10, Ubiquinone: Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10.
    Colestipol: Although to a lesser extent than cholestyramine, colestipol also has been shown to inhibit the GI absorption and therapeutic response of thiazide diuretics. Single doses of colestipol resins reduce the absorption of HCTZ by up to 43%. Administering thiazide diuretics at least 2 hours before colestipol has been suggested to minimize the interaction.
    Conivaptan: Avoid concomitant use of conivaptan, a strong CYP3A4 inhibitor, and amlodipine, a CYP3A4 substrate. Oral conivaptan 40 mg twice daily has resulted in a 2-fold increase in the AUC and half-life of amlodipine. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as amlodipine, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Based on the pharmacology of conivaptan, there is potential for additive hypotensive effects when coadministered with calcium-channel blockers. Intravenous infusion of conivaptan has been associated with orthostatic hypotension. Monitor blood pressure and fluid volume status closely in patients receiving conivaptan infusion. Avoid concurrent use of conivaptan and aliskiren. Coadministration of conivaptan and aliskiren may result in increased serum concentrations of aliskiren. Conivaptan inhibits CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of CYP3A4 and P-gp. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with aliskiren. Subsequent treatment with CYP3A substrates, such as aliskiren, may be initiated no sooner than 1 week after completion of conivaptan therapy. There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Corticosteroids: Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required.
    Cosyntropin: Use cosyntropin cautiously in patients receiving diuretics. Cosyntropin may accentuate the electrolyte loss associated with diuretic therapy.
    Crizotinib: Concomitant use of crizotinib and amlodipine may result in increased amlodipine concentrations. Crizotinib is a CYP3A4 and P-glycoprotein (PGP) inhibitor, while amlodipine is a CYP3A4 substrate. Monitor patients for toxicity, such as hypotension, with coadministration.
    Cyclophosphamide: Coadministration of thiazide diuretics and antineoplastic agents such as cyclophosphamide may result in reduced renal excretion of the antineoplastic agent and therefore increased myelosuppressive effects.
    Cyclosporine: Concomitant use of aliskiren with cyclosporine is not recommended because of significantly increased aliskiren blood concentrations and an increase in the number and/or intensity of adverse events such as headache, hot flushes, nausea, vomiting, and somnolence. Cyclosporine is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of CYP3A4 and P-gp. As compared with aliskiren monotherapy, the maximum serum concentration (Cmax) of aliskiren was increased approximately 2.5-fold, and the systemic exposure was increased approximately 4.3-fold after a single 75 mg dose was given with a single cyclosporine 200 mg dose to healthy patients. Also, as compared with aliskiren receipt alone, prolongation of the median aliskiren elimination half-life (43 to 45 hours versus 26 hours) and the time to the maximum serum concentration (1.5 to 2 hours versus 0.5 hours) were noted. The mean systemic exposure and Cmax of cyclosporine were comparable to reported literature values. Caution should be used when cyclosporine is coadministered with amlodipine; therapeutic response should be monitored, including cyclosporine levels as necessary. Amlodipine may increase cyclosporine concentrations. In one study, whole blood cyclosporine trough concentrations increased from 140.2 +/- 18.2 to 200 +/- 21.9 mcg/L after amlodipine addition. In another study, the systemic exposure (AUC) of cyclosporine increased following the addition of amlodipine, and was decreased in the absence of the drug. The postulated mechanism is the inhibitory effect of amlodipine on the P-glycoprotein-mediated efflux of cyclosporine from intestinal epithelial cells. Also, amlodipine is a CYP3A4 substrate and theoretically, cyclosporine, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals.
    Dabrafenib: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as dabrafenib, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Daclatasvir: Systemic exposure of aliskiren, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of aliskiren; monitor patients for potential adverse effects.
    Danazol: Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as danazol , are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
    Dantrolene: Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Dapagliflozin: Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Dapagliflozin; Metformin: Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary.
    Darifenacin: Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Darunavir: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. The plasma concentrations of aliskiren may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor. Aliskiren is a substrate of CYP3A4.
    Darunavir; Cobicistat: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. Coadministration of cobicistat (a CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as amlodipine, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate dose reductions are advised. The plasma concentrations of aliskiren may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and aliskiren is a CYP3A4 and P-gp substrate. The plasma concentrations of aliskiren may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor. Aliskiren is a substrate of CYP3A4.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. The plasma concentrations of aliskiren may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Ritonavir is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of both CYP3A4 and P-gp.
    Dasatinib: Dasatinib inhibits CYP3A4. Therefore, caution is warranted when drugs that are metabolized by this enzyme, such as calcium-channel blockers, are administered concurrently with dasatinib as increased adverse reactions may occur. Diltiazem, nicardipine and verapamil may also inhibit the metabolism of dasatinib.
    Deferasirox: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as deferasirox, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Delavirdine: Administering amlodipine with CYP3A4 inhibitors, such as delavirdine, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when delavirdine is coadministered with amlodipine; therapeutic response should be monitored.
    Desloratadine; Pseudoephedrine: Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Desvenlafaxine: Patients receiving a diuretic during treatment with venlafaxine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH may occur during therapy with SNRIs, including venlafaxine. Cases involving serum sodium levels lower than 110 mmol/l have been reported. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of the SNRI should be considered in patients who develop symptomatic hyponatremia.
    Dexamethasone: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as dexamethasone, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Dexlansoprazole: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Dexmedetomidine: In general, the concomitant administration of dexmedetomidine with antihypertensive agents could lead to additive hypotensive effects. Dexmedetomidine can produce bradycardia or AV block and should be used cautiously in patients who are receiving antihypertensive drugs that lower the heart rate such as calcium-channel blockers.
    Dexmethylphenidate: Dexmethylphenidate may reduce the hypotensive effect of antihypertensive agents, such as calcium-channel blockers. Dexmethylphenidate may reduce the hypotensive effect of antihypertensive agents. Periodic evaluation of blood pressure is advisable during concurrent use of dexmethylphenidate and antihypertensive agents, particularly during initial co-administration and after dosage increases of dexmethylphenidate. Methylphenidate reduces the hypotensive effect of antihypertensive agents. Methylphenidate reduces the hypotensive effect of antihypertensive agents. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial co-administration and after dosage increases of methylphenidate.
    Dextromethorphan; Diphenhydramine; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Dextromethorphan; Guaifenesin; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: Due to the risk of hyperkalemia, drugs that increase serum potassium concentration, such as potassium salts or salt substitutes containing potassium should be used cautiously in patients taking aliskiren. Electrolytes should be routinely monitored in patients receiving aliskiren.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Dextromethorphan; Quinidine: Quinidine can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents due to the potential for additive hypotension.
    Diazoxide: Additive hypotensive effects can occur with the concomitant administration of diazoxide with other antihypertensive agents. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly. The manufacturer advises that IV diazoxide should not be administered to patients within 6 hours of receiving other antihypertensive agents. Aliskiren can enhance the effects of vasodilators on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Blood pressure and electrolytes should be routinely monitored in patients receiving aliskiren. Enhanced hyperglycemia is possible during concurrent use of diazoxide and thiazide diuretics. Additive hypotensive effects can also occur with the concomitant administration of diazoxide with thiazide diuretics.
    Dichlorphenamide: Use dichlorphenamide and diuretics together with caution. Dichlorphenamide increases potassium excretion and can cause hypokalemia and should be used cautiously with other drugs that may cause hypokalemia including loop diuretics and thiazide diuretics. Measure potassium concentrations at baseline and periodically during dichlorphenamide treatment. If hypokalemia occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
    Diclofenac: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Diclofenac; Misoprostol: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Dicyclomine: Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Diethylpropion: Diethylpropion has vasopressor effects and may limit the benefit of calcium-channel blockers. Although leading drug interaction texts differ in the potential for an interaction between diethylpropion and this group of antihypertensive agents, these effects are likely to be clinically significant and have been described in hypertensive patients on these medications. Diethylpropion has vasopressor effects and may limit the benefit of thiazide diuretics. Although leading drug interaction texts differ in the potential for an interaction between diethylpropion and this group of antihypertensive agents, these effects are likely to be clinically significant and have been described in hypertensive patients on these medications.
    Diflunisal: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Digitoxin: Thiazide diuretics can cause hypokalemia, hypomagnesemia, or hypercalcemia which may increase digoxin's pharmacologic effect. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity. It is also recommended that serum potassium, magnesium, and calcium be monitored regularly in patients receiving digoxin.
    Digoxin: Thiazide diuretics can cause hypokalemia, hypomagnesemia, or hypercalcemia which may increase digoxin's pharmacologic effect. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity. It is also recommended that serum potassium, magnesium, and calcium be monitored regularly in patients receiving digoxin.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Dihydroergotamine: Because of the potential to cause coronary vasospasm, dihydroergotamine theoretically could antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. Dihydroergotamine is contraindicated for use in patients with coronary heart disease or hypertension. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties (e.g., diltiazem, nicardipine, verapamil) may also reduce the hepatic metabolism of dihydroergotamine and increase the risk of ergot toxicity.
    Diltiazem: Amlodipine is a CYP3A4 substrate; coadministration of diltiazem 180 mg/day PO (CYP3A4 inhibitor) with amlodipine 5 mg/day PO in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. This effect might lead to hypotension or edema in some individuals. Caution should be used when diltiazem is coadministered with amlodipine; therapeutic response should be monitored.
    Diphenhydramine; Hydrocodone; Phenylephrine: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Diphenhydramine; Ibuprofen: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Diphenhydramine; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Dobutamine: Sympathomimetics can antagonize the effects of antihypertensives such as metolazone when administered concomitantly.
    Dofetilide: Hypokalemia or hypomagnesemia may occur with administration of potassium-depleting drugs such as loop diuretics and thiazide diuretics, increasing the potential for dofetilide-induced torsade de pointes. Additionally, in patients treated with either hydrochlorothiazide 50 mg or hydrochlorothiazide/triamterene 50 mg/100 mg daily in combination with dofetilide 500 mcg twice daily for 5 days, dofetilide AUC and Cmax concentrations increased by 27% and 21%, respectively, for the hydrochlorothiazide alone group and by 30% and 16%, respectively, for the hydrochlorothiazide/triamterene group. Furthermore, a 197% and 190% QTc increase over time was seen in the hydrochlorothiazide and hydrochlorothiazide/triamterene groups, respectively. Based on these findings, the manufacturer of dofetilide contraindicates the concomitant use of hydrochlorothiazide (alone or in combination with other drugs such as triamterene); these findings can be explained both by an increase in the plasma concentration of dofetilide and a reduction in the serum potassium concentration. In a population pharmacokinetic analysis of plasma dofetilide concentrations, the mean dofetilide clearance of dofetilide was 16% lower in patients on thiazide diuretics. It is prudent to avoid the use of any thiazide diuretic in combination with dofetilide.
    Dolasetron: The manufacturer warns that the coadministration of dolasetron with diuretics associated with hypokalemia could increase the risk of QT prolongation. Patients taking certain diuretics may develop an electrolyte abnormality that may lead to cardiac dysrhythmias and/or QT prolongation. Hypokalemia or hypomagnesemia may occur with administration of potassium-depleting drugs such as thiazide diuretics, increasing the potential for cardiac arrhythmias. Potassium levels should be within the normal range prior to and during therapy with dolasetron.
    Donepezil; Memantine: Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Dopamine: Sympathomimetics can antagonize the effects of antihypertensives such as metolazone when administered concomitantly.
    Dorzolamide; Timolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Doxacurium: Concomitant administration of hydrochlorothiazide to patients receiving nondepolarizing neuromuscular blockers (e.g., tubocurarine) can cause prolonged neuromuscular blockade due to hydrochlorothiazide-induced hypokalemia. Serum potassium concentrations should be determined and corrected (if necessary) prior to initiation of neuromuscular blockade therapy.
    Dronabinol, THC: Use caution if coadministration of dronabinol with amlodipine is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; amlodipine is a weak inhibitor of CYP3A4. Concomitant use may result in elevated plasma concentrations of dronabinol.
    Dronedarone: Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Diltiazem and verapamil are inhibitors of CYP3A4 and substrates of CYP3A and P-gp; nifedipine and amlodipine are substrates for CYP3A4. In clinical trials, the coadministration of dronedarone and calcium-channel blockers (diltiazem, verapamil, and nifedipine) resulted in an increase in exposure of calcium channel blockers by 1.4 to 1.5 fold and an increase in dronedarone exposure by 1.4 to1.7 fold. Furthermore, calcium channel blockers may potentiate the electrophysiologic effects of dronedarone (e.g., decreased AV and sinus node conduction). If coadministration of calcium channel blockers and dronedarone cannot be avoided, administer low doses of the calcium channel blocker and increase dosage only after ECG verification of tolerability. Dronedarone is metabolized by and is an inhibitor of CYP3A. Aliskiren is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Droperidol: Caution is advised when using droperidol in combination with thiazide diuretics which may lead to electrolyte abnormalities, especially hypokalemia or hypomagnesemia, as such abnormalities may increase the risk for QT prolongation or cardiac arrhythmias.
    Drospirenone; Ethinyl Estradiol: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Drospirenone; Ethinyl Estradiol; Levomefolate: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Dulaglutide: Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Duloxetine: Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary. Patients receiving a diuretic during treatment with venlafaxine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH may occur during therapy with SNRIs, including venlafaxine. Cases involving serum sodium levels lower than 110 mmol/l have been reported. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of the SNRI should be considered in patients who develop symptomatic hyponatremia.
    Dutasteride; Tamsulosin: The concomitant administration of tamsulosin with other antihypertensive agents can cause additive hypotensive effects. In addition, diltiazem, nicardipine, and verapamil may increase tamsulosin plasma concentrations via CYP3A4 inhibition. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly.
    Efavirenz: Use caution and careful monitoring when coadministering efavirenz with calcium-channel blockers; efavirenz induces CYP3A4, potentially altering serum concentrations of drugs metabolized by this enzyme such as some calcium-channel blockers. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments should be made for diltiazem based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, nicardipine, and verapamil); as with diltiazem, calcium-channel blocker doses should be adjusted based on clinical response.
    Efavirenz; Emtricitabine; Tenofovir: Use caution and careful monitoring when coadministering efavirenz with calcium-channel blockers; efavirenz induces CYP3A4, potentially altering serum concentrations of drugs metabolized by this enzyme such as some calcium-channel blockers. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments should be made for diltiazem based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, nicardipine, and verapamil); as with diltiazem, calcium-channel blocker doses should be adjusted based on clinical response.
    Elbasvir; Grazoprevir: Administering elbasvir; grazoprevir with amlodipine may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Amlodipine is a substrate and weak inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
    Eletriptan: Eletriptan may reduce the effectiveness of antihypertensive agents, such as thiazide diuretics. Patients on antihypertensives need to have their blood pressure adequately controlled if they are to receive eletriptan. If eletriptan is used, regular blood pressure monitoring is recommended. Eletriptan may reduce the effectiveness of antihypertensive agents. Patients on antihypertensives need to have their blood pressure adequately controlled if they are to receive eletriptan. If eletriptan is used, regular blood pressure monitoring is recommended.
    Empagliflozin: Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control. Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Empagliflozin; Linagliptin: Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control. Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Empagliflozin; Metformin: Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control. Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary.
    Enalapril, Enalaprilat: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury. Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Enalapril; Felodipine: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury. Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Enalapril; Hydrochlorothiazide, HCTZ: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ACE inhibitors in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury. Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Enflurane: The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression. General anesthetics can potentiate the hypotensive effects of antihypertensive agents. General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with aliskiren may increase the risk of developing hypotension.
    Enzalutamide: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as enzalutamide, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Ephedrine: The cardiovascular effects of sympathomimetics, such as ephedrine, may reduce the antihypertensive effects produced by calcium-channel blockers. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved. The cardiovascular effects of sympathomimetics, such as ephedrine, may reduce the antihypertensive effects produced by thiazide diuretics. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Epinephrine: Sympathomimetics can antagonize the effects of antihypertensives such as metolazone when administered concomitantly.
    Epirubicin: Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant treatment with epirubicin and calcium-channel blockers. Individuals receiving these medications concurrently are at increased risk of developing heart failure.
    Eplerenone: Amlodipine can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Epoprostenol: Aliskiren can enhance the effects of epoprostenol on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Blood pressure and electrolytes should be routinely monitored in patients receiving aliskiren. Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response. Epoprostenol can have additive effects when administered with other antihypertensive agents. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Eprosartan: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Eprosartan; Hydrochlorothiazide, HCTZ: Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin II receptor antagonists (ARBs) and aliskiren do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAAS inhibitors particularly in patients with CrCl < 60 mL/min. Closely monitor blood pressure, renal function, and electrolytes if aliskiren is combined with another RAAS inhibitor. Aliskiren-containing products are contraindicated in combination with ARBs in patients with diabetes mellitus. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury.
    Ergocalciferol, Vitamin D2: Dose adjustment of vitamin D or vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D or vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Ergonovine: Because of its potential to cause coronary vasospasm, ergonovine could theoretically antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. In addition, calcium-channel blockers with CYP3A4 inhibitory properties, such as diltiazem, nicardipine, and verapamil, may also reduce the hepatic metabolism of ergonovine and increase the risk of ergot toxicity.
    Ergotamine: Because of the potential to cause coronary vasospasm , ergotamine theoretically could antagonize the therapeutic effects of calcium-channel blockers. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties, such as diltiazem, nicardipine, and verapamil, may also reduce the hepatic metabolism of ergotamine and increase the risk of ergot toxicity.
    Erlotinib: Use caution if coadministration of erlotinib with amlodipine is necessary due to the risk of increased erlotinib-related adverse reactions, and avoid coadministration with erlotinib if the patient is additionally taking a CYP1A2 inhibitor. If the patient is taking both amlodipine and a CYP1A2 inhibitor and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements; the manufacturer of erlotinib makes the same recommendations for toxicity-related dose reductions in patients taking strong CYP3A4 inhibitors without concomitant CYP1A2 inhibitors. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Amlodipine is a weak CYP3A4 inhibitor. Coadministration of erlotinib with ketoconazole, a strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%. Coadministration of erlotinib with ciprofloxacin, a moderate inhibitor of CYP3A4 and CYP1A2, increased the erlotinib AUC by 39% and the Cmax by 17%. Coadministration with amlodipine may also increase erlotinib exposure.
    Erythromycin: Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapami) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Erythromycin; Sulfisoxazole: Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapami) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Escitalopram: Patients receiving a diuretic during treatment with escitalopram may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of escitalopram should be considered in patients who develop symptomatic hyponatremia.
    Eslicarbazepine: In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as amlodipine, may result in decreased serum concentrations of the substrates. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered with eslicarbazepine. Appropriate dose adjustments may be necessary.
    Esmolol: Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Esomeprazole: Proton pump inhibitors, such as esomeprazole, have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Esomeprazole; Naproxen: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren. Proton pump inhibitors, such as esomeprazole, have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Estradiol Cypionate; Medroxyprogesterone: Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Estradiol: Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Ethacrynic Acid: Aliskiren can enhance the effects of loop-diuretics on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Patients with hyponatremia or hypovolemia may also develop reversible renal insufficiency. When aliskiren is administered in combination with furosemide, the AUC and Cmax of furosemide are reduced by approximately 30% and 50%, respectively; the pharmacokinetics of aliskiren are not affected. Patients should be monitored for loss of effect of furosemide when aliskiren is initiated. Blood pressure and electrolytes should be routinely monitored.
    Ethanol: Ethanol interacts with antihypertensive agents by potentiating their hypotensive effect. Ethanol may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Ethinyl Estradiol: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Desogestrel: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Ethynodiol Diacetate: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Etonogestrel: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Levonorgestrel: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norelgestromin: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norethindrone Acetate: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norethindrone: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norgestimate: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norgestrel: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethotoin: Hydantoins (phenytoin, fosphenytoin, or ethotoin) may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving hydantoins.
    Etodolac: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Etomidate: The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression. General anesthetics can potentiate the hypotensive effects of antihypertensive agents. General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with aliskiren may increase the risk of developing hypotension.
    Etoposide, VP-16: Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with aldesleukin, IL-2. Aldesleukin is a weak inhibitor of CYP3A4 and etoposide, VP-16 is a CYP3A4 substrate. Coadministration may increase etoposide concentrations.
    Etravirine: Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as etravirine, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Exenatide: Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Ezetimibe; Simvastatin: Simvastatin and amlodipine should be coadministered with caution due to an increased risk of myopathy, including rhabdomyolysis. If amlodipine and simvastatin must be administered together, do not exceed 20 mg/day simvastatin in adults. For adult patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, the m