View source for Enalapril/ Felodipine

{{DrugProjectFormSinglePage
|authorTag={{SS}}
|genericName=Enalapril/ Felodipine
|aOrAn=an
|drugClass=Angiotensin Converting Enzyme Inhibitor and Calcium Channel Blocker
|indication=[[hypertension]]
|hasBlackBoxWarning=Yes
|blackBoxWarningTitle=<span style="color:#FF0000;">USE IN PREGNANCY</span>
|blackBoxWarningBody=When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, LEXXEL should be discontinued as soon as possible. See WARNINGS, Fetal/Neonatal Morbidity and Mortality.
|fdaLIADAdult=<b>Hypertension</b>

* Dosing Information

:* Initial dosage for enalapril:  '''10-40 mg/day'''
|offLabelAdultGuideSupport=<b>Condition 1</b>

* Developed by: (Organization)

* Class of Recommendation: (Class) (Link)

* Strength of Evidence: (Category A/B/C) (Link)

* Dosing Information/Recommendation

:* (Dosage)
|offLabelAdultNoGuideSupport=<b>Condition 1</b>

* Dosing Information

:* There is limited information about <i>Off-Label Non–Guideline-Supported Use</i> of Enalapril/ Felodipine in adult patients.
|fdaLIADPed=<b>Condition 1</b>

* Dosing Information

:: (Dosage)
|offLabelPedGuideSupport=<b>Condition 1</b>

* Developed by: (Organization)

* Class of Recommendation: (Class) (Link)

* Strength of Evidence: (Category A/B/C) (Link)

* Dosing Information/Recommendation

:* (Dosage)
|offLabelPedNoGuideSupport=<b>Condition 1</b>

* Dosing Information

:* There is limited information about <i>Off-Label Non–Guideline-Supported Use</i> of Enalapril/ Felodipine in pediatric patients.
|contraindications=LEXXEL is contraindicated in patients who are [[hypersensitive]] to any component of this product. Because of the enalapril component, LEXXEL is contraindicated in patients with a history of [[angioedema]] related to previous treatment with an angiotensin converting enzyme inhibitor and in patients with hereditary or idiopathic angioedema.
|warnings=Anaphylactoid and Possibly Related Reactions— Presumably because [[angiotensin-converting enzyme inhibitors]] affect the metabolism of eicosanoids and polypeptides, including [[endogenous bradykinin]], patients receiving [[ACE inhibitors]] (including LEXXEL) may be subject to a variety of adverse reactions, some of them serious.
Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including enalapril. This may occur at any time during treatment. In such cases LEXXEL should be promptly discontinued, and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. In instances where swelling has been confined to the face and lips the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly provided. (See ADVERSE REACTIONS.)
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see also INDICATIONS AND USAGE and CONTRAINDICATIONS).
Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.
Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.
Hypotension— LEXXEL can occasionally cause symptomatic hypotension.
Excessive hypotension is rare in uncomplicated hypertensive patients treated with enalapril alone. Patients at risk for excessive hypotension, sometimes associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death, include those with the following conditions or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with heart failure), reduce the diuretic dose or increase salt intake cautiously before initiating therapy with enalapril maleate in patients at risk for excessive hypotension who are able to tolerate such adjustments. (See PRECAUTIONS, Drug Interactions and ADVERSE REACTIONS.) In patients at risk for excessive hypotension, therapy should be started under very close medical supervision and such patients should be followed closely for the first 2 weeks of treatment and whenever the dose of enalapril and/or diuretic is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses of enalapril maleate, which usually can be given without difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or discontinuation of enalapril or diuretic may be necessary.
Felodipine, like other calcium channel blockers, may occasionally precipitate significant hypotension and rarely syncope. It may lead to reflex tachycardia which in susceptible individuals may precipitate angina pectoris. (See ADVERSE REACTIONS.)
Neutropenia/Agranulocytosis—Another angiotensin converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients but more frequently in patients with renal impairment, especially if they also have a collagen vascular disease. Available data from clinical trials of enalapril are insufficient to show that enalapril does not cause agranulocytosis at similar rates. Marketing experience has revealed cases of neutropenia or agranulocytosis in which a causal relationship to enalapril cannot be excluded. Periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should be considered.
Hepatic Failure— Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.
Fetal/Neonatal Morbidity and Mortality— ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, LEXXEL should be discontinued as soon as possible.
The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE-inhibitor exposure.
These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of LEXXEL as soon as possible.
Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.
If oligohydramnios is observed, LEXXEL should be discontinued unless it is considered lifesaving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function. Enalapril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion, although there is no experience with the latter procedure.
No teratogenic effects of enalapril were seen in studies of pregnant rats and rabbits. On a body surface area basis, the doses used were 57 times and 12 times, respectively, the maximum recommended human daily dose (MRHDD).
In rats administered the combination of enalapril and felodipine (enalapril [E]=1.9-felodipine [F]=2.5 mg/kg/day), an increased incidence of fetuses with dilated renal pelvis/ureter was observed. However, there was no evidence of this effect in the offspring postweaning. In mice, with doses of E=23, F=30 mg/kg/day or greater, there was an increased incidence of both early and late in utero deaths. Other than a transient and slight decrease in body weight gain in the first generation offspring, there were no adverse effects in offspring with regard to sexual maturation, behavioral development, fertility or fecundity.
Enalapril-felodipine given to pregnant mice (enalapril 20.8, felodipine 27 mg/kg/day) and rats (enalapril =17.3, felodipine =22.5 mg/kg/day) produced plasma levels (Cmax and AUC values) of enalapril/enalaprilat that were 76 to 418-fold greater and plasma levels of felodipine that were 151 to 433-fold greater than those expected in humans (non-pregnant) at the dose to be used in humans.
PRECAUTIONS
General:
Aortic Stenosis/Hypertrophic Cardiomyopathy—As with all vasodilators, enalapril should be given with caution to patients with obstruction in the outflow tract of the left ventricle.
Impaired Renal Function— As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals treated with enalapril. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin converting enzyme inhibitors, including enalapril, may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.
In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine were observed in 20% of patients treated with enalapril. These increases were almost always reversible upon discontinuation of enalapril and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy.
Some enalapril-treated patients with hypertension or heart failure, with no apparent pre-existing renal vascular disease, have developed increases in blood urea and serum creatinine, usually minor and transient, especially when enalapril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of enalapril or discontinuation of the diuretic may be required.
Evaluation of the hypertensive patient should always include assessment of renal function.
Hyperkalemia—Elevated serum potassium (greater than 5.7 mEq/L) was observed in approximately 1% of hypertensive patients in clinical trials treated with enalapril alone. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause of discontinuation of therapy in 0.28% of hypertensive patients. In clinical trials in heart failure, hyperkalemia was observed in 3.8% of patients but was not a cause for discontinuation.
Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with enalapril. (See Drug Interactions.)
Elderly Patients or Patients with Impaired Liver Function— Patients over 65 years of age or patients with impaired liver function may have elevated plasma concentrations of felodipine. (See DOSAGE AND ADMINISTRATION.)
Cough— Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the diagnosis of cough.
Surgery/Anesthesia— In patients undergoing major surgery or during anesthesia with agents that produce hypotension, enalapril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.
Peripheral Edema— Peripheral edema, generally mild and not associated with generalized fluid retention, was the most common adverse event in the felodipine clinical trials. The incidence of peripheral edema was both dose and age dependent. This adverse event generally occurs within 2-3 weeks of the initiation of treatment.
|clinicalTrials=In a factorial study, combinations of [[enalapril]] at doses of 0, 5, and 20 mg and [[felodipine]] ER at doses of 0, 2.5, 5, and 10 mg were evaluated for safety in more than 700 patients with [[hypertension]]. In addition more than 500 patients received various combinations of [[enalapril]] (5 or 10 mg) and felodipine ER (2.5, 5, or 10 mg) with or without [[hydrochlorothiazide]] (12.5 mg) in an open-labeled study up to 52 weeks (mean 33 weeks). Adverse events were similar to those described with the individual components.
In general, treatment with [[enalapril]] maleate-felodipine ER was well tolerated and adverse events were mild and transient in nature. In the placebo-controlled, double-blind trial, discontinuation of therapy due to adverse events considered related (possibly, probably or definitely) occurred in 2.8% vs 1.3% of patients treated with the combination or placebo, respectively. The most frequently observed clinical adverse events considered related to treatment with the combination were [[headache]], [[edema]] or [[swelling]], and [[dizziness]].
Clinical adverse events considered related (possibly, probably, or definitely) to treatment with [[enalapril]]-[[felodipine]] ER that occurred with an incidence of 1% or greater with the combination during the placebo-controlled, double-blind trial are compared to individual components and placebo in the table below:

[[LEXXE_adverse_01.jpg|thumg|none|400px]]

Other clinical adverse events considered related (possibly, probably, or definitely) to treatment with [[enalapril]]-[[felodipine]] ER that occurred with an incidence of less than 1% in the placebo-controlled, double-blind trial are listed below. These events are listed in order of decreasing frequency within each category. 

* '''Body as a Whole''': [[Syncope]], facial edema, orthostatic effects, [[chest pain]];
* '''Cardiovascular''': [[Palpitation]], [[hypotension]], [[bradycardia]], premature ventricular contraction, increased blood pressure; 
* '''Digestive''': Dry mouth, [[constipation]], [[dyspepsia]], [[flatulence]], [[acid regurgitation]], [[vomiting]], [[diarrhea]], [[nausea]], anal/rectal pain; 
* '''Metabolic''': [[Gout]]; 
* '''Musculoskeletal''': Neck pain, joint swelling; 
* '''Nervous/Psychiatric''': [[Insomnia]], [[nervousness]], [[somnolence]], [[ataxia]], [[agitation]], [[paresthesia]], [[tremor]]; 
* '''Respiratory''': [[Dyspnea]], [[respiratory congestion]], [[pharyngeal discomfort]], dry throat; 
* '''Skin''': [[Rash]], [[angioedema]], [[pruritus]], [[alopecia]], [[dry skin]]; 
* '''Special Senses''': Increased intraocular pressure; 
* '''Urogenital''': [[Impotence]], hot flashes.

Other infrequently reported adverse events were seen in clinical trials with [[enalapril]]-[[felodipine]] ER (causal relationship unknown). These included: 

* '''Body as a Whole''': Abdominal pain, fever; 
* '''Digestive''': Dental pain; 
* '''Metabolic''': Increased ALT and AST, hyperglycemia; 
* '''Musculoskeletal''': Back pain, myalgia, foot pain, knee pain, shoulder pain, tendinitis; 
* '''Respiratory''': Upper respiratory infection, sinusitis, pharyngitis, bronchitis, nasal congestion, influenza, sinus disorder; 
* '''Special Senses''': Conjunctivitis; Urogenital: Proteinuria, pyuria, urinary tract infection.

=====[[Enalapril]] Maleate=====

Other adverse events that have been reported with [[enalapril]], without regard to causality, are listed (in decreasing severity) below:

* [[Angioedema]]— [[Angioedema]] has been reported in patients receiving [[enalapril]] maleate, with an incidence higher in black than in non-black patients. [[Angioedema]] associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with LEXXEL should be discontinued and appropriate therapy instituted immediately. (See WARNINGS.)
* '''Body as a Whole''': Anaphylactoid reactions (see WARNINGS, Anaphylactoid and Possibly Related Reactions); 
* '''Cardiovascular''': [[Cardiac arrest]], [[myocardial infarction]] or cerebrovascular accident, possibly secondary to excessive [[hypotension]] in high risk patients (see WARNINGS, [[Hypotension]]), [[orthostatic hypotension]], [[pulmonary embolism]] and [[infarction]], [[pulmonary edema]], [[rhythm disturbances]] including [[atrial tachycardia]] and [[bradycardia]], [[atrial fibrillation]], [[angina pectoris]]; 
* '''Digestive''': [[Ileus]], [[pancreatitis]], [[hepatic failure]], [[hepatitis]] (hepatocellular [proven on rechallenge] or [[cholestatic jaundice]]) (see WARNINGS, Hepatic Failure), [[melena]], [[anorexia]], [[glossitis]], [[stomatitis]]; Hematologic: Rare cases of [[neutropenia]], [[thrombocytopenia]] and [[bone marrow depression]]; 
* '''Musculoskeletal''': [[Muscle cramps]]; 
* '''Nervous/Psychiatric''': [[Depression]], [[confusion]], [[peripheral neuropathy]] (eg [[paresthesia]], [[dysesthesia]]), [[vertigo]]; 
* '''Respiratory''': [[Bronchospasm]], [[rhinorrhea]], [[sore throat]] and [[hoarseness]], [[asthma]], [[pneumonia]], [[pulmonary infiltrates]], [[eosinophilic pneumonitis]]; 
* '''Skin''': [[Exfoliative dermatitis]], [[toxic epidermal necrolysis]], [[Stevens-Johnson syndrome]], [[pemphigus]], [[herpes zoster]], [[erythema multiforme]], [[urticaria]], [[diaphoresis]], [[photosensitivity]]; 
Special Senses: [[Blurred vision]], taste alteration, [[anosmia]], [[tinnitus]], dry eyes, tearing; 
Urogenital: [[Renal failure]], [[oliguria]], [[renal dysfunction]] (see PRECAUTIONS), [[flank pain]], [[gynecomastia]]; 
* '''Miscellaneous''': A symptom complex has been reported which may include a positive ANA, an elevated erythrocyte sedimentation rate, [[arthralgia]]/[[arthritis]], [[myalgia]]/[[myositis]], [[fever]], [[serositis]], [[vasculitis]], [[leukocytosis]], [[eosinophilia]], [[photosensitivity rash]] and other dermatologic manifestations; 
* '''Fetal/Neonatal Morbidity and Mortality''': See WARNINGS, Fetal/Neonatal Morbidity and Mortality.

=====Felodipine as an Extended-Release Formulation=====

Other adverse events that have been reported with [[felodipine]] ER, without regard to causality, are listed (in decreasing severity) below:
* '''Body as a Whole''': Flu-like illness; 
* '''Cardiovascular''': [[Myocardial infarction]], [[angina pectoris]], [[arrhythmia]], [[tachycardia]], premature beats; 
* '''Digestive''': [[Gingival hyperplasia]]; 
* '''Endocrine''': [[Gynecomastia]]; 
* '''Hematologic''': [[Anemia]]; 
* '''Musculoskeletal''': [[Arthralgia]], leg pain, [[muscle cramps]], arm pain, hip pain; 
* '''Nervous/Psychiatric''': [[Depression]], [[anxiety disorders]], [[irritability]], decreased libido; 
* '''Respiratory''': [[Upper respiratory infection]], [[rhinorrhea]], [[sneezing]], [[pharyngitis]], [[influenza]], [[epistaxis]], respiratory infection; 
* '''Skin''': [[Angioedema]], [[contusion]], [[erythema]], [[urticaria]], [[leukocytoclastic vasculitis]]; 
* '''Special Senses''': Visual disturbances; 
* '''Urogenital''': [[Urinary frequency]], [[urinary urgency]], [[dysuria]], [[polyuria]].

=====Laboratory Test Findings=====

In controlled clinical trials with [[enalapril]]-[[felodipine]] ER, clinically important changes in standard laboratory parameters associated with administration of LEXXEL were rare. No changes peculiar to the combination treatment were observed.

* '''Serum Electrolytes'''— See PRECAUTIONS.
* '''Creatinine'''— Minor reversible increases in serum creatinine were observed in patients treated with LEXXEL. Increases in creatinine are more likely to occur in patients with [[renal insufficiency]] or those pretreated with a [[diuretic]] and based on experience with other [[ACE inhibitors]], would be expected to be especially likely in patients with [[renal artery stenosis]] (see PRECAUTIONS).
* '''Other'''— Minor reversible increases or decreases in serum potassium were infrequently observed in patients treated with LEXXEL; rarely were these measurements outside the normal range.
|drugInteractions=* Patients on [[diuretic]] Therapy: Patients on [[diuretics]], and especially those in whom [[diuretic]] therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with [[enalapril]]. The possibility of hypotensive effects with [[enalapril]] can be minimized by either discontinuing the [[diuretic]] or increasing the salt intake prior to initiation of treatment with [[enalapril]]. If it is necessary to continue the [[diuretic]], provide close medical supervision after the initial dose for at least two hours and until blood pressure has stabilized for at least an additional hour. (See WARNINGS and DOSAGE AND ADMINISTRATION.)

* Agents Causing Renin Release— The antihypertensive effect of [[enalapril]] is augmented by antihypertensive agents that cause renin release (eg, [[diuretics]]).
Non-steroidal Anti-inflammatory Agents— In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs, the coadministration of [[enalapril]] may result in a further deterioration of renal function. These effects are usually reversible.
In a clinical pharmacology study, [[indomethacin]] or [[sulindac]] was administered to hypertensive patients receiving VASOTEC ([[enalapril]] maleate). In this study there was no evidence of a blunting of the antihypertensive action of VASOTEC ([[enalapril]] maleate). However, reports suggest that NSAIDs may diminish the antihypertensive effect of [[ACE-inhibitors]]. This interaction should be given consideration in patients taking [[NSAIDs]] concomitantly with [[ACE-inhibitors]].

* Agents Increasing Serum Potassium— [[enalapril]] attenuates potassium loss caused by [[thiazide]]-type [[diuretics]]. Potassium-sparing [[diuretics]] (eg, [[spironolactone]], [[triamterene]], or [[amiloride]]), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use of these agents is indicated because of demonstrated [[hypokalemia]], they should be used with caution and with frequent monitoring of serum potassium.

* Lithium— Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. A few cases of lithium toxicity have been reported in patients receiving concomitant [[enalapril]] and lithium and were reversible upon discontinuation of both drugs. It is recommended that serum lithium levels be monitored frequently if [[enalapril]] is administered concomitantly with lithium.

* CYP3A4 Inhibitors—[[felodipine]] is metabolized by CYP3A4. Co-administration of CYP3A4 inhibitors (eg, [[ketoconazole]], [[itraconazole]], [[erythromycin]], grapefruit juice, [[cimetidine]]) with [[felodipine]] may lead to several-fold increases in the plasma levels of [[felodipine]], either due to an increase in bioavailability or due to a decrease in metabolism. These increases in concentration may lead to increased effects, (lower blood pressure and increased heart rate). These effects have been observed with co-administration of [[itraconazole]] (a potent CYP3A4 inhibitor). Caution should be used when CYP3A4 inhibitors are co-administered with [[felodipine]]. A conservative approach to dosing [[felodipine]] should be taken. The following specific interactions have been reported:

* [[Itraconazole]]—Co-administration of another extended release formulation of [[felodipine]] with [[itraconazole]] resulted in approximately 8-fold increase in the AUC, more than 6-fold increase in the Cmax, and 2-fold prolongation in the half-life of [[felodipine]].

* [[Erythromycin]]—Co-administration of [[felodipine]] (PLENDIL) with [[erythromycin]] resulted in approximately 2.5-fold increase in the AUC and Cmax, and about 2-fold prolongation in the half-life of [[felodipine]].

* Grapefruit juice—Co-administration of [[felodipine]] with grapefruit juice resulted in more than 2-fold increase in the AUC and Cmax, but no prolongation in the half-life of [[felodipine]].

* [[Cimetidine]]—Co-administration of [[felodipine]] with [[cimetidine]] (a non-specific CYP-450 inhibitor) resulted in an increase of approximately 50% in the AUC and the Cmax, of [[felodipine]].

* Beta-Blocking Agents— [[Enalapril]] has been used concomitantly with [[beta adrenergic-blocking agents]] without evidence of clinically significant adverse interactions.
A pharmacokinetic study of [[felodipine]] in conjunction with [[metoprolol]] demonstrated no significant effects on the pharmacokinetics of [[felodipine]]. The AUC and Cmax of metoprolol, however, were increased approximately 31% and 38%, respectively. In controlled clinical trials, however, beta blockers including [[metoprolol]] were concurrently administered with [[felodipine]] and were well tolerated.

* [[Digoxin]]— [[Enalapril]] has been used concomitantly with [[digoxin]] without evidence of clinically significant adverse interactions.
When given concomitantly with [[felodipine]] ER, the pharmacokinetics of [[digoxin]] in patients with [[heart failure]] were not significantly altered.

* [[Anticonvulsants]]— In a pharmacokinetic study, maximum plasma concentrations of [[felodipine]] were considerably lower in epileptic patients on long-term [[anticonvulsant ]]therapy (eg, [[phenytoin]], [[carbamazepine]], or [[phenobarbital]]) than in healthy volunteers. In such patients, the mean area under the [[felodipine]] plasma concentration-time curve was also reduced to approximately 6% of that observed in healthy volunteers. Since a clinically significant interaction may be anticipated, alternative antihypertensive therapy should be considered in these patients.

* [[Tacrolimus]]— [[felodipine]] may increase the blood concentration of [[tacrolimus]]. When given concomitantly with [[felodipine]], the [[tacrolimus]] blood concentration should be followed and the [[tacrolimus]] dose may need to be adjusted.

* Other Concomitant Therapy— In healthy subjects, there were no clinically significant interactions when [[felodipine]] was given concomitantly with [[indomethacin]] or [[spironolactone]].
[[Enalapril]] has been used concomitantly with [[methyldopa]], [[nitrates]], [[hydralazine]], and [[prazosin]] without evidence of clinically significant adverse interactions.
|alcohol=Alcohol-Enalapril/ Felodipine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
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