Enalapril maleate and hydrochlorothiazide

INDICATIONS AND USAGE Enalapril maleate and hydrochlorothiazide tablets are indicated for the treatment of hypertension. These fixed dose combinations are not indicated for initial treatment (see DOSAGE AND ADMINISTRATION ). In using enalapril maleate and hydrochlorothiazide tablets, consideration should be given to the fact that another angiotensin converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease, and that available data are insufficient to show that enalapril does not have a similar risk (see WARNINGS ). In considering use of Enalapril maleate and hydrochlorothiazide tablets, it should be noted that black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks (see WARNINGS, Head and Neck Angioedema ).

DOSAGE AND ADMINISTRATION Enalapril and hydrochlorothiazide are effective treatments for hypertension. The usual dosage range of enalapril is 10 to 40 mg per day administered in a single or two divided doses; hydrochlorothiazide is effective in doses of 12.5 to 50 mg daily. The side effects (see WARNINGS ) of enalapril are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with any combination of enalapril and hydrochlorothiazide will be associated with both sets of dose-independent side effects but the addition of enalapril in clinical trials blunted the hypokalemia normally seen with diuretics. To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy. Dose Titration Guided by Clinical Effect A patient whose blood pressure is not adequately controlled with either enalapril or hydrochlorothiazide monotherapy may be given enalapril maleate and hydrochlorothiazide tablets 5 mg/12.5 mg or enalapril maleate and hydrochlorothiazide tablets 10 mg/25 mg. Further increases of enalapril, hydrochlorothiazide or both depend on clinical response. The hydrochlorothiazide dose should generally not be increased until 2-3 weeks have elapsed. In general, patients do not require doses in excess of 20 mg of enalapril or 50 mg of hydrochlorothiazide. The daily dosage should not exceed four tablets of enalapril maleate and hydrochlorothiazide tablets 5 mg/12.5 mg or two tablets of enalapril maleate and hydrochlorothiazide tablets 10 mg/25 mg. Replacement Therapy The combination may be substituted for the titrated components. Use in Renal Impairment The usual regimens of therapy with enalapril maleate and hydrochlorothiazide tablets need not be adjusted as long as the patient's creatinine clearance is >30 mL/min/1.73m 2 (serum creatinine approximately ≤3 mg/dL or 265 μmol/L). In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so enalapril maleate– hydrochlorothiazide is not recommended (see WARNINGS, Anaphylactoid reactions during membrane exposure ).

CONTRAINDICATIONS Enalapril maleate and hydrochlorothiazide is contraindicated in patients who are hypersensitive to any component of this product and 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. Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs. Enalapril maleate and hydrochlorothiazide is contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer enalapril maleate and hydrochlorothiazide within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor (see WARNINGS ). Do not co-administer aliskiren with enalapril maleate and hydrochlorothiazide in patients with diabetes (see PRECAUTIONS, Drug Interactions ).

ADVERSE REACTIONS Enalapril maleate and hydrochlorothiazide has been evaluated for safety in more than 1500 patients, including over 300 patients treated for one year or more. In clinical trials with enalapril maleate and hydrochlorothiazide no adverse experiences peculiar to this combination drug have been observed. Adverse experiences that have occurred, have been limited to those that have been previously reported with enalapril or hydrochlorothiazide. The most frequent clinical adverse experiences in controlled trials were: dizziness (8.6 percent), headache (5.5 percent), fatigue (3.9 percent) and cough (3.5 percent). Generally, adverse experiences were mild and transient in nature. Adverse experiences occurring in greater than two percent of patients treated with enalapril maleate and hydrochlorothiazide in controlled clinical trials are shown below. Percent of Patients in Controlled Studies Enalapril maleate and hydrochlorothiazide (n=1580) Incidence (discontinuation) Placebo (n=230) Incidence Dizziness 8.6 (0.7) 4.3 Headache 5.5 (0.4) 9.1 Fatigue 3.9 (0.8) 2.6 Cough 3.5 (0.4) 0.9 Muscle Cramps 2.7 (0.2) 0.9 Nausea 2.5 (0.4) 1.7 Asthenia 2.4 (0.3) 0.9 Orthostatic Effects 2.3 (<0.1) 0.0 Impotence 2.2 (0.5) 0.5 Diarrhea 2.1 (<0.1) 1.7 Clinical adverse experiences occurring in 0.5 to 2.0 percent of patients in controlled trials included: Body As A Whole: Syncope, chest pain, abdominal pain Cardiovascular: Orthostatic hypotension, palpitation, tachycardia Digestive: Vomiting, dyspepsia, constipation, flatulence, dry mouth Nervous/Psychiatric: Insomnia, nervousness, paresthesia, somnolence, vertigo Skin: Pruritus, rash Other: Dyspnea, gout, back pain, arthralgia, diaphoresis, decreased libido, tinnitus, urinary tract infection Angioedema: Angioedema has been reported in patients receiving enalapril maleate and hydrochlorothiazide, 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 enalapril maleate and hydrochlorothiazide should be discontinued and appropriate therapy instituted immediately (see WARNINGS ). Hypotension: In clinical trials, adverse effects relating to hypotension occurred as follows: hypotension (0.9 percent), orthostatic hypotension (1.5 percent), other orthostatic effects (2.3 percent). In addition syncope occurred in 1.3 percent of patients (see WARNINGS ). Cough: See PRECAUTIONS, Cough . Clinical Laboratory Test Findings Serum Electrolytes: See PRECAUTIONS . Creatinine, Blood Urea Nitrogen: In controlled clinical trials minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 0.6 percent of patients with essential hypertension treated with enalapril maleate and hydrochlorothiazide. More marked increases have been reported in other enalapril experience. Increases are more likely to occur in patients with renal artery stenosis (see PRECAUTIONS ). Serum Uric Acid, Glucose, Magnesium, and Calcium: See PRECAUTIONS . Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.3 g percent and 1.0 vol percent, respectively) occur frequently in hypertensive patients treated with enalapril maleate and hydrochlorothiazide but are rarely of clinical importance unless another cause of anemia coexists. In clinical trials, less than 0.1 percent of patients discontinued therapy due to anemia. Liver Function Tests: Rarely, elevations of liver enzymes and/or serum bilirubin have occurred (see WARNINGS, Hepatic Failure ). Other adverse reactions that have been reported with the individual components are listed below and, within each category, are in order of decreasing severity. Enalapril Maleate Enalapril has been evaluated for safety in more than 10,000 patients. In clinical trials adverse reactions which occurred with enalapril were also seen …

Drug Interactions Neprilysin Inhibitors Patients taking concomitant neprilysin inhibitors may be at increased risk for angioedema (see WARNINGS ). Enalapril Maleate Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on enalapril maleate and hydrochlorothiazide and other agents that affect the RAS. Do not coadminister aliskiren with enalapril maleate and hydrochlorothiazide in patients with diabetes. Avoid use of aliskiren with enalapril maleate and hydrochlorothiazide in patients with renal impairment (GFR <60 mL/min). 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 medical supervision 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 (e.g., diuretics). Non-steroidal Anti-inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including enalapril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving enalapril and NSAID therapy. In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving enalapril maleate. In this study there was no evidence of a blunting of the antihypertensive action of enalapril maleate. However, reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. Other Cardiovascular Agents Enalapril has been used concomitantly with beta adrenergic-blocking agents, methyldopa, nitrates, calcium-blocking agents, hydralazine and prazosin without evidence of clinically significant adverse interactions. Agents Increasing Serum Potassium Enalapril attenuates diuretic-induced potassium loss. Potassium-sparing diuretics (e.g., 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. Gold Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with inj …

Mechanism of Action Enalapril, after hydrolysis to enalaprilat, inhibits angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. Although the latter decrease is small, it results in small increases of serum potassium. In hypertensive patients treated with enalapril maleate alone for up to 48 weeks, mean increases in serum potassium of approximately 0.2 mEq/L were observed. In patients treated with enalapril maleate plus a thiazide diuretic, there was essentially no change in serum potassium (see PRECAUTIONS ). Removal of angiotensin II negative feedback on rennin secretion leads to increased plasma renin activity. ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of enalapril remains to be elucidated. While the mechanism through which enalapril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, enalapril is antihypertensive even in patients with low-renin hypertension. Although enalapril was antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to enalapril maleate monotherapy than non-black patients. In contrast, hydrochlorothiazide was more effective in black patients than enalapril. Concomitant administration of enalapril maleate and hydrochlorothiazide was equally effective in black and non-black patients.

DESCRIPTION Enalapril maleate and hydrochlorothiazide combines an angiotensin converting enzyme inhibitor, enalapril maleate, and a diuretic, hydrochlorothiazide. 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 C 20 H 28 N 2 O 5 ∙C 4 H 4 O 4 , 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. Enalapril is a pro-drug; following oral administration, it is bioactivated by hydrolysis of the ethyl ester to enalaprilat, which is the active angiotensin converting enzyme inhibitor. Hydrochlorothiazide is 6-chloro-3,4-dihydro-2 H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C 7 H 8 ClN 3 O 4 S 2 and its structural formula is: It is a white, or practically white, crystalline powder with a molecular weight of 297.74, which is slightly soluble in water, but freely soluble in sodium hydroxide solution. Enalapril maleate and hydrochlorothiazide is available in two tablet combinations of enalapril maleate with hydrochlorothiazide: enalapril maleate and hydrochlorothiazide 5/12.5 mg, containing 5 mg enalapril maleate and 12.5 mg hydrochlorothiazide and contain the following inactive ingredients: ferric oxide black, ferric oxide yellow, lactose monohydrate, magnesium stearate, pregelatinized starch, purified water, and sodium bicarbonate. Enalapril maleate and hydrochlorothiazide 10/25 mg, containing 10 mg enalapril maleate and 25 mg hydrochlorothiazide and contain the following inactive ingredients: ferrix oxide yellow, ferric oxide red, lactose monohydrate, magnesium stearate, pregelatinized starch, purified water, and sodium bicarbonate. Chemical Structure Chemical Structure

OVERDOSAGE No specific information is available on the treatment of overdosage with enalapril maleate and hydrochlorothiazide tablets. Treatment is symptomatic and supportive. Therapy with enalapril maleate and hydrochlorothiazide tablets should be discontinued and the patient observed closely. Suggested measures include induction of emesis and/or gastric lavage, and correction of dehydration, electrolyte imbalance and hypotension by established procedures. Enalapril Maleate Single oral doses of enalapril above 1,000 mg/kg and ≥ 1,775 mg/kg were associated with lethality in mice and rats, respectively. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution. Enalaprilat may be removed from general circulation by hemodialysis and has been removed from neonatal circulation by peritoneal dialysis (see WARNINGS, Anaphylactoid reactions during membrane exposure ). Hydrochlorothiazide Lethality was not observed after administration of an oral dose of 10 g/kg to mice and rats. The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.

HOW SUPPLIED Enalapril Maleate and Hydrochlorothiazide Tablets USP, 5/12.5 mg , are ivory, caplet-shaped compressed tablets, engraved on one side with T4. Each tablet contains 5 mg of enalapril maleate and 12.5 mg of hydrochlorothiazide. They are supplied as follows: NDC 51672-4045-1 bottles of 100 (with desiccant). NDC 51672-4045-3 bottles of 1,000 (with desiccant). Enalapril Maleate and Hydrochlorothiazide Tablets USP, 10/25 mg , are peach colored, capsule shaped, tablets. One side scored and engraved "T" to the left of the score and "3" to the right of the score. Other side scored. Each tablet contains 10 mg of enalapril maleate and 25 mg of hydrochlorothiazide. They are supplied as follows: NDC 51672-4046-1 bottles of 100 (with desiccant). NDC 51672-4046-3 bottles of 1,000 (with desiccant). Storage Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Keep container tightly closed. Protect from moisture. Dispense in a tight container as per USP, if product package is subdivided.