Lexxel

LEXXEL (enalapril maleate-felodipine ER) is a combination product, consisting of an outer layer of enalapril maleate surrounding a core tablet of an extended-release felodipine formulation.

Enalapril maleate is the maleate salt of enalapril, the ethyl ester of a long-acting angiotensin converting enzyme inhibitor, enalaprilat. Enalapril maleate is chemically described as (S)-1-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L- alanyl]-L-proline, (Z)-2-butenedioate salt (1:1). Its empirical formula is C20H28N2O5•C4H4O4, and its structural formula is:

Enalapril maleate is a white to off-white, crystalline powder with a molecular weight of 492.53. It is sparingly soluble in water, soluble in ethanol, and freely soluble in methanol.

Felodipine, a calcium channel blocker, is a dihydropyridine derivative that is chemically described as ± ethyl methyl 4- (2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5- pyridinedicarboxylate. Its empirical formula is C18H19Cl2NO4 and its structural formula is:

Felodipine is a slightly yellowish, crystalline powder with a molecular weight of 384.26. It is insoluble in water and is freely soluble in dichloromethane and ethanol. Felodipine is a racemic mixture; however, S-felodipine is the more biologically active enantiomer.

LEXXEL (enalapril maleate-felodipine) is available for oral use as tablets containing 5 mg of enalapril maleate and 5 mg of felodipine as an extended release formulation.

Inactive ingredients include: propyl gallate, polyoxyl 40 hydrogenated castor oil, cellulose compounds, lactose, aluminum silicate, sodium stearyl fumarate, carnauba wax, and black iron oxide. The tablets are imprinted with an ink of synthetic black iron oxide which contains pharmaceutical glaze in SD-45, n-butyl alcohol, propylene glycol, isopropyl alcohol, ammonium hydroxide, and methyl alcohol.

No. 3661 - Tablets LEXXEL (enalapril maleate-felodipine) , 5-5 are white, round/biconvex-shaped, film-coated tablets, coded LEXXEL (enalapril maleate-felodipine) 1, 5-5 on one side and no markings on the other. Each tablet contains 5 mg of enalapril maleate and 5 mg of felodipine as an extended-release formulation. They are supplied as follows:

NDC 0186-0001-31 unit of use bottles of 30 (with desiccants)
NDC 0186-0001-68 bottles of 100 (with desiccants)

Storage:

Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [See USP Controlled Room Temperature]. Keep container tightly closed. Protect from moisture and light. Dispense in a tight container, if product package is subdivided.

Revised 12/04. LEXXEL (enalapril maleate-felodipine) is a trademark of the AstraZeneca group of companies. Manufactured for: AstraZeneca LP, Wilmington, DE 19850. By: Merck & Co., Inc., Whitehouse Station, NJ 08889, USA. FDA rev date: 10/4/2007

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:

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 (enalapril maleate-felodipine) 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 (enalapril maleate-felodipine) 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 (enalapril maleate-felodipine) . 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 (enalapril maleate-felodipine) ; rarely were these measurements outside the normal range.

Lexxel is a prescription medication used to treat high blood pressure. Lexxel is a single product containing 2 medications: enalapril and felodipine. The enalapril component belongs to a group of drugs called angiotensin-converting enzyme (ACE) inhibitors. Enalapril works by blocking the ACE enzyme, which helps blood vessels to relax and lowers blood pressure. The felodipine component belongs to a group of drugs called calcium channel blockers, which work by relaxing the blood vessels, making it easier for the heart to pump blood.

This medication comes in tablet form and is typically given once daily. Lexxel can be taken either with food or without food, just take it the same way every time. For example, if you take it without food then always take it without food. 

Common side effects of Lexxel include headache, dizziness, and swelling. 

This brand is no longer available.

Lexxel is part of the drug class:

• ACE inhibitors and calcium channel blockers

Use in pregnancy.

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. 

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/AgranulocytosisAnother 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.

General:

Aortic Stenosis/Hypertrophic CardiomyopathyAs 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.

HyperkalemiaElevated 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.

Information for Patients

Patients should be instructed to take Lexxel whole and not to divide, crush or chew the tablet.

All patients should be advised to consult their physician if they experience any of the following conditions:

Angioedema Angioedema, including laryngeal edema, may occur at any time during treatment with angiotensin converting enzyme inhibitors, including enalapril. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have consulted with the prescribing physician.

Hypotension Patients should be cautioned to report light- headedness especially during the first few days of therapy. If actual syncope occurs, the patients should be told to discontinue Lexxel until they have consulted with the prescribing physician. All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion, such as vomiting or diarrhea, may also lead to a fall in blood pressure; patients should be advised to consult with the physician.

Hyperkalemia Patients should be told not to use salt substitutes containing potassium without consulting their physician.

Neutropenia Patients should be told to report promptly any indication of infection (eg, sore throat, fever) which may be a sign of neutropenia.

Pregnancy Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to ACE inhibitors, and they should also be told that these consequences do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible.

Gingival Hyperplasia Patients should be told that mild gingival hyperplasia (gum swelling) has been reported. Good dental hygiene decreases its incidence and severity.

Note: As with many other drugs, certain advice to patients being treated with Lexxel is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.

Drug Interactions

Hypotension 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 InhibitorsFelodipine 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:

ItraconazoleCo-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.

ErythromycinCo-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 juiceCo-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.

CimetidineCo-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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term carcinogenicity tests have been performed with the combination. Enalapril-felodipine was not mutagenic with or without metabolic activation in vitro in the Ames microbial mutation assay, the V-79 mammalian cell forward mutation assay, the alkaline elution assay with rat hepatocytes or the CHO mammalian cell cytogenetics assay. An in vivo mouse bone marrow cytogenetics assay was also negative.

In rats given enalapril-felodipine, there was no effect on fertility in males at doses up to 6.9/9 mg/kg/day, and in females at doses up to 17.3/22.5 mg/kg/day.

There was no evidence of a tumorigenic effect when enalapril was administered for 106 weeks to male and female rats at doses up to 90 mg/kg/day or for 94 weeks to male and female mice at doses up to 90 and 180 mg/kg/day, respectively. These doses are 26 times (in rats and female mice) and 13 times (in male mice) the maximum recommended human daily dose (MRHDD) when compared on a body surface area basis.

Neither enalapril maleate nor the active diacid was mutagenic in the Ames microbial mutagen test with or without metabolic activation. Enalapril was also negative in the following genotoxicity studies: rec-assay, reverse mutation assay with E. coli, sister chromatid exchange with cultured mammalian cells, and the micronucleus test with mice, as well as in an in vivo cytogenic study using mouse bone marrow.

There were no adverse effects on reproductive performance of male and female rats treated with up to 90 mg/kg/day of enalapril (26 times the MRHDD when compared on a body surface area basis).

In a 2-year carcinogenicity study in rats fed felodipine at doses of 7.7, 23.1 or 69.3 mg/kg/day (up to 61 times3 the maximum recommended human dose on a mg/m2 basis), a dose-related increase in the incidence of benign interstitial cell tumors of the testes (Leydig cell tumors) was observed in treated male rats. These tumors were not observed in a similar study in mice at doses up to 138.6 mg/kg/day (61 times3 the maximum recommended human dose on a mg/m2 basis). Felodipine, at the doses employed in the 2-year rat study, has been shown to lower testicular testosterone and to produce a corresponding increase in serum luteinizing hormone in rats. The Leydig cell tumor development is possibly secondary to these hormonal effects which have not been observed in man.

In this same rat study, a dose-related increase in the incidence of focal squamous cell hyperplasia, compared to control, was observed in the esophageal groove of male and female rats in all dose groups. No other drug-related esophageal or gastric pathology was observed in the rats or with chronic administration in mice and dogs. The latter species, like man, has no anatomical structure comparable to the esophageal groove.

Felodipine was not carcinogenic when fed to mice at doses of up to 138.6 mg/kg/day (61 times3 the maximum recommended human dose on a mg/m2 basis) for periods of up to 80 weeks in males and 99 weeks in females.

Felodipine did not display any mutagenic activity in vitro in the Ames microbial mutagenicity test or in the mouse lymphoma forward mutation assay. No clastogenic potential was seen in vivo in the mouse micronucleus test at oral doses up to 2500 mg/kg (1100 times3 the maximum recommended human dose on a mg/m2 basis) or in vitro in a human lymphocyte chromosome aberration assay.

A fertility study in which male and female rats were administered doses of 3.8, 9.6, or 26.9 mg/kg/day (up to 24 times3 the maximum recommended human dose on a mg/m2 basis) showed no significant effect of felodipine on reproductive performance.

Pregnancy

Pregnancy Categories C (first trimester) and D (second and third trimesters) See WARNINGS, Fetal/Neonatal Morbidity and Mortality.

Teratogenic Effects– Studies in pregnant rabbits administered doses of felodipine 0.46, 1.2, 2.3, and 4.6 mg/kg/day (from 0.8 to 8 times3 the maximum recommended human dose on a mg/m2 basis) showed digital anomalies consisting of reduction in size and degree of ossification of the terminal phalanges in the fetuses. The frequency and severity of the changes appeared dose-related and were noted even at the lowest dose. These changes have been shown to occur with other members of the dihydropyridine class and are possibly a result of compromised uterine blood flow. Similar fetal anomalies were not observed in rats given felodipine.

In a teratology study in cynomolgus monkeys, no reduction in the size of the terminal phalanges was observed, but an abnormal position of the distal phalanges was noted in about 40% of the fetuses.

Nonteratogenic Effects– A prolongation of parturition with difficult labor and an increased frequency of fetal and early postnatal deaths were observed in rats administered felodipine doses of 9.6 mg/kg/day (8 times3 the maximum human dose on a mg/m2 basis) and above.

Significant enlargement of the mammary glands, in excess of the normal enlargement for pregnant rabbits, was found with doses greater than or equal to 1.2 mg/kg/day (2.1 times the maximum human dose on a mg/m2 basis). This effect occurred only in pregnant rabbits and regressed during lactation. Similar changes in the mammary glands were not observed in rats or monkeys.

There are no adequate and well-controlled studies with felodipine in pregnant women. If felodipine is used during pregnancy, or if the patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus, possible digital anomalies of the infant, and the potential effects of felodipine on labor and delivery, and on the mammary glands of pregnant females.

Nursing Mothers

Enalapril and enalaprilat are detected in human breast milk. It is not known whether felodipine administered as monotherapy is secreted in human milk; studies of the combination of enalapril and felodipine in rats indicate that felodipine concentrates in milk to a level almost ten-fold that found in plasma.

Because of the potential for serious adverse reactions from enalapril and felodipine in the infant, a decision should be made either to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Therefore, caution should be exercised when Lexxel is given to a nursing mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Lexxel did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Elderly patients may have elevated plasma concentrations of felodipine and may respond to lower doses of felodipine. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION for information on the individual components of Lexxel).

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Evaluation of the hypertensive patient should always include assessment of renal function (see CLINICAL PHARMACOLOGY).

No. 3661 Tablets Lexxel, 5-5 are white, round/biconvex-shaped, film-coated tablets, coded Lexxel 1, 5-5 on one side and no markings on the other. Each tablet contains 5 mg of enalapril maleate and 5 mg of felodipine as an extended-release formulation. They are supplied as follows:

NDC 0186-0001-31 unit of use bottles of 30 (with desiccants)

NDC 0186-0001-68 bottles of 100 (with desiccants)

Storage:

Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [See USP Controlled Room Temperature]. Keep container tightly closed. Protect from moisture and light. Dispense in a tight container, if product package is subdivided.

Revised 12/04

Lexxel is a trademark of the AstraZeneca group of companies.

© AstraZeneca 2002, 2003, 2004

Manufactured for: AstraZeneca LP

Wilmington, DE 19850

By:  Merck & Co., Inc., Whitehouse Station, NJ 08889, USA

9176509

620008-09