Moexipril Hydrochloride

INDICATIONS AND USAGE Moexipril hydrochloride tablets are indicated for treatment of patients with hypertension. They may be used alone or in combination with thiazide diuretics. In using moexipril hydrochloride tablets, consideration should be given to the fact that another ACE inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen-vascular disease. Available data are insufficient to show that moexipril hydrochloride tablets do not have a similar risk (see WARNINGS ). In considering use of moexipril hydrochloride tablets, it should be noted that in controlled trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. In addition, ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients (see WARNINGS, Angioedema ).

DOSAGE AND ADMINISTRATION Hypertension The recommended initial dose of moexipril hydrochloride tablets in patients not receiving diuretics is 7.5 mg, one hour prior to meals, once daily. Dosage should be adjusted according to blood pressure response. The antihypertensive effect of moexipril hydrochloride tablets may diminish towards the end of the dosing interval. Blood pressure should, therefore, be measured just prior to dosing to determine whether satisfactory blood pressure control is obtained. If control is not adequate, increased dose or divided dosing can be tried. The recommended dose range is 7.5 to 30 mg daily, administered in one or two divided doses one hour before meals. Total daily doses above 60 mg a day have not been studied in hypertensive patients. In patients who are currently being treated with a diuretic, symptomatic hypotension may occasionally occur following the initial dose of moexipril hydrochloride tablets. The diuretic should, if possible, be discontinued for 2 to 3 days before therapy with moexipril hydrochloride tablets is begun, to reduce the likelihood of hypotension (see WARNINGS ). If the patient’s blood pressure is not controlled with moexipril hydrochloride tablets alone, diuretic therapy may then be reinstituted. If diuretic therapy cannot be discontinued, an initial dose of 3.75 mg of moexipril hydrochloride tablets should be used with medical supervision until blood pressure has stabilized (see WARNINGS and PRECAUTIONS, Drug Interactions ). Dosage Adjustment in Renal Impairment For patients with a creatinine clearance ≤40 mL/min/1.73 m 2 , an initial dose of 3.75 mg once daily should be given cautiously. Doses may be titrated upward to a maximum daily dose of 15 mg.

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 moexipril hydrochloride, may be subject to a variety of adverse reactions, some of them serious. Head and Neck Angioedema: Angioedema involving the face, extremities, lips, tongue, glottis, and/or larynx has been reported in patients treated with ACE inhibitors, including moexipril hydrochloride. Symptoms suggestive of angioedema or facial edema occurred in < 0.5% of moexipril-treated patients in placebo-controlled trials. None of the cases were considered life-threatening and all resolved either without treatment or with medication (antihistamines or glucocorticoids). One patient treated with hydrochlorothiazide alone experienced laryngeal edema. No instances of angioedema were reported in placebo-treated patients. In cases of angioedema, treatment should be promptly discontinued and the patient carefully observed until the swelling disappears. 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 involvement of the tongue, glottis, or larynx, may be fatal due to airway obstruction. Appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 mL) and/or measures to ensure a patent airway, should be promptly provided (see ADVERSE REACTIONS ). Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. 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 did not occur when ACE inhibitors were temporarily withheld, but they reappeared when the ACE inhibitors were inadvertently readministered. 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 Moexipril hydrochloride can cause symptomatic hypotension, although, as with other ACE inhibitors, this is unusual in uncomplicated hypertensive patients treated with moexipril hydrochloride alone. Symptomatic hypotension was seen in 0.5% of patients given moexipril and led to discontinuation of therapy in about 0.25%. Symptomatic hypotension is most likely to occur in patients who have been salt- and volume- depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume- and salt-depletion should be corrected and, in general, diuretics stopped, before initiating therapy with moexipril hydrochloride (see PRECAUTIONS, Drug Interactions , and ADVERSE REACTIONS ). In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or progressive azotemia, and rarely, with acute renal failure and death. In these patients, moexipril hydrochloride therapy should be started under close medical supervision, and patients should be followed cl…

CONTRAINDICATIONS Moexipril hydrochloride is contraindicated in patients who are hypersensitive to this product and in patients with a history of angioedema related to previous treatment with an ACE inhibitor. Do not co-administer aliskiren with moexipril hydrochloride in patients with diabetes (see PRECAUTIONS, Drug Interactions ).

Drug Interactions Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with moexipril hydrochloride can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with moexipril hydrochloride. If this is not possible, the starting dose of moexipril should be reduced. (See WARNINGS and DOSAGE AND ADMINISTRATION ). Potassium Supplements and Potassium-Sparing Diuretics: Moexipril hydrochloride can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient’s serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Gold : Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including moexipril hydrochloride. 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, co-administration of NSAIDS, including selective COX-2 inhibitors, with ACE inhibitors, including moexipril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving moexipril and NSAID therapy. The antihypertensive effect of ACE inhibitors, including moexipril, may be attenuated by NSAIDS. 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. Closely monitor blood pressure, renal function and electrolytes in patients on moexipril hydrochloride and other agents that affect the RAS. Do not co-administer aliskiren with moexipril hydrochloride in patients with diabetes. Avoid use of aliskiren with moexipril hydrochloride in patients with renal impairment (GFR <60 mL/min). Other Agents: No clinically important pharmacokinetic interactions occurred when moexipril hydrochloride was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. Moexipril hydrochloride has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H 2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions.

Nursing Mothers It is not known whether moexipril hydrochloride is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when moexipril hydrochloride is given to a nursing mother.

ADVERSE REACTIONS Moexipril hydrochloride has been evaluated for safety in more than 2500 patients with hypertension; more than 250 of these patients were treated for approximately one year. The overall incidence of reported adverse events was only slightly greater in patients treated with moexipril hydrochloride than patients treated with placebo. Reported adverse experiences were usually mild and transient, and there were no differences in adverse reaction rates related to gender, race, age, duration of therapy, or total daily dosage within the range of 3.75 mg to 60 mg. Discontinuation of therapy because of adverse experiences was required in 3.4% of patients treated with moexipril hydrochloride and in 1.8% of patients treated with placebo. The most common reasons for discontinuation in patients treated with moexipril hydrochloride were cough (0.7%) and dizziness (0.4%). All adverse experiences considered at least possibly related to treatment that occurred at any dose in placebo-controlled trials of once-daily dosing in more than 1% of patients treated with moexipril hydrochloride alone and that were at least as frequent in the moexipril hydrochloride group as in the placebo group are shown in the following table: ADVERSE EVENTS IN PLACEBO-CONTROLLED STUDIES ADVERSE EVENT MOEXIPRIL HYDROCHLORIDE (N=674) PLACEBO (N=226) N (%) N (%) Cough Increased 41 (6.1) 5 (2.2) Dizziness 29 (4.3) 5 (2.2) Diarrhea 21 (3.1) 5 (2.2) Flu Syndrome 21 (3.1) 0 (0) Fatigue 16 (2.4) 4 (1.8) Pharyngitis 12 (1.8) 2 (0.9) Flushing 11 (1.6) 0 (0) Rash 11 (1.6) 2 (0.9) Myalgia 9 (1.3) 0 (0) Other adverse events occurring in more than 1% of patients on moexipril that were at least as frequent on placebo include: headache, upper respiratory infection, pain, rhinitis, dyspepsia, nausea, peripheral edema, sinusitis, chest pain, and urinary frequency. See WARNINGS and PRECAUTIONS for discussion of anaphylactoid reactions, angioedema, hypotension, neutropenia/agranulocytosis, second and third trimester fetal/neonatal morbidity and mortality, hyperkalemia, and cough. Other potentially important adverse experiences reported in controlled or uncontrolled clinical trials in less than 1% of moexipril patients or that have been attributed to other ACE inhibitors include the following: Cardiovascular: Symptomatic hypotension, postural hypotension, or syncope were seen in 9/1750 (0.51%) patients; these reactions led to discontinuation of therapy in controlled trials in 3/1254 (0.24%) patients who had received moexipril hydrochloride monotherapy and in 1/344 (0.3%) patients who had received moexipril hydrochloride with hydrochlorothiazide (see PRECAUTIONS and WARNINGS ). Other adverse events included angina/myocardial infarction, palpitations, rhythm disturbances, and cerebrovascular accident. Renal: Of hypertensive patients with no apparent preexisting renal disease, 1% of patients receiving moexipril hydrochloride alone and 2% of patients receiving moexipril hydrochloride with hydrochlorothiazide experienced increases in serum creatinine to at least 140% of their baseline values (see PRECAUTIONS and DOSAGE AND ADMINISTRATION ). Gastrointestinal: Abdominal pain, constipation, vomiting, appetite/weight change, dry mouth, pancreatitis, hepatitis. Respiratory: Bronchospasm, dyspnea, eosinophilic pneumonitis. Urogenital: Renal insufficiency, oliguria. Dermatologic: Apparent hypersensitivity reactions manifested by urticaria, rash, pemphigus, pruritus, photosensitivity, alopecia. Neurological and Psychiatric: Drowsiness, sleep disturbances, nervousness, mood changes, anxiety. Other: Angioedema (see WARNINGS ), taste disturbances, tinnitus, sweating, malaise, arthralgia, hemolytic anemia. Clinical Laboratory Test Findings Serum Electrolytes: Hyperkalemia (see PRECAUTIONS ), hyponatremia. Creatinine and Blood Urea Nitrogen: As with other ACE inhibitors, minor increases in blood urea nitrogen or serum creatinine, reversible upon discontinuation of therapy, were observed in…