Univasc

Overdose

Human overdoses of moexipril have not been reported. In case reports of overdoses with other ACE inhibitors, hypotension has been the principal adverse effect noted. Single oral doses of 2 g/kg moexipril were associated with significant lethality in mice. Rats, however, tolerated single oral doses of up to 3 g/kg.

No data are available to suggest that physiological maneuvers (e.g., maneuvers to change the pH of the urine) would accelerate elimination of moexipril and its metabolites. The dialyzability of moexipril is not known.

Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of moexipril overdose, but angiotensin II is essentially unavailable outside of research facilities. Because the hypotensive effect of moexipril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat moexipril overdose by infusion of normal saline solution. In addition, renal function and serum potassium should be monitored.

Contraindications

univasc® 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.

Undesirable effects

univasc® has been evaluated for safety in more than 2 500 patients with hypertension; more than 2 50 of these patients were treated for approximately one year. The overall incidence of reported adverse events was only slightly greater in patients treated with univasc® 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 univasc® and in 1.8% of patients treated with placebo. The most common reasons for discontinuation in patients treated with univasc® 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 univasc® alone and that were at least as frequent in the univasc® group as in the placebo group are shown in the following table:

ADVERSE EVENTS IN PLACEBO-CONTROLLED STUDIES

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 3/12 54 (0.2 4%) patients who had received univasc® monotherapy and in 1/344 (0.3%) patients who had received univasc® with hydrochlorothiazide (see WARNINGS and PRECAUTIONS). 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 univasc® alone and 2 % of patients receiving univasc® 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.

Hyperkalemia (see PRECAUTIONS), hyponatremia.

As with other ACE inhibitors, minor increases in blood urea nitrogen or serum creatinine, reversible upon discontinuation of therapy, were observed in approximately 1% of patients with essential hypertension who were treated with univasc®. Increases are more likely to occur in patients receiving concomitant diuretics and in patients with compromised renal function (see PRECAUTIONS, General).

Clinically important changes in standard laboratory tests were rarely associated with univasc® administration.

Elevations of liver enzymes and uric acid have been reported. In trials, less than 1% of moexipril-treated patients discontinued univasc® treatment because of laboratory abnormalities. The incidence of abnormal laboratory values with moexipril was similar to that in the placebo-treated group.

Therapeutic indications

univasc® is indicated for treatment of patients with hypertension. It may be used alone or in combination with thiazide diuretics.

In using univasc®, 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 univasc® does not have a similar risk (see WARNINGS).

In considering use of univasc®, 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).

Name of the medicinal product

Qualitative and quantitative composition

univasc® (moexipril hydrochloride) 7.5 mg tablets are pink colored, biconvex, film-coated and scored with engraved code 707 on the unscored side and SP above and 7.5 below the score. They are supplied as follows:

Bottles of 90 (Unit-of-Use) - NDC 0091-3707-09
Bottles of 100 - NDC 0091-3707-01

univasc® (moexipril hydrochloride) 15 mg tablets are salmon colored, biconvex, film-coated, and scored with engraved code 715 on the unscored side and SP above and 15 below the score. They are supplied as follows:

Bottles of 90 (Unit-of-Use) - NDC 0091-3715-09
Bottles of 100 - NDC 0091-3715-01

Store, tightly closed, at controlled room temperature. Protect from excessive moisture.

If product package is subdivided, dispense in tight containers as described in USP-NF.

Manufactured for: UCB, Inc. Smyrna, GA 30080.

Special warnings and precautions for use

Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors, including univasc®, may be subject to a variety of adverse reactions, some of them serious.

Angioedema involving the face, extremities, lips, tongue, glottis, and/or larynx has been reported in patients treated with ACE inhibitors, including univasc®. Symptoms suggestive of angioedema or facial edema occurred in < 0.5% of moexipriltreated 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 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.

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 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.

univasc® can cause symptomatic hypotension, although, as with other ACE inhibitors, this is unusual in uncomplicated hypertensive patients treated with univasc® alone. Symptomatic hypotension was seen in 0.5% of patients given moexipril and led to discontinuation of therapy in about 0.2 5%. 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 univasc® (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, univasc® therapy should be started under close medical supervision, and patients should be followed closely for the first two weeks of treatment and whenever the dose of moexipril or an accompanying diuretic is increased. Care in avoiding hypotension should also be taken in patients with ischemic heart disease, aortic stenosis, or cerebrovascular disease, in whom an excessive decrease in blood pressure could result in a myocardial infarction or a cerebrovascular accident.

If hypotension occurs, the patient should be placed in a supine position and, if necessary, treated with an intravenous infusion of normal saline. univasc® treatment usually can be continued following restoration of blood pressure and volume.

Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in patients with uncomplicated hypertension, but more frequently in hypertensive patients with renal impairment, especially if they also have a collagen-vascular disease such as systemic lupus erythematosus or scleroderma. Although there were no instances of severe neutropenia (absolute neutrophil count < 500/mm3) among patients given univasc®, as with other ACE inhibitors, monitoring of white blood cell counts should be considered for patients who have collagen-vascular disease, especially if the disease is associated with impaired renal function. Available data from clinical trials of univasc® are insufficient to show that univasc® does not cause agranulocytosis at rates similar to captopril.

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue univasc® as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue univasc®, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to univasc® for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS, Pediatric Use).

No embryotoxic, fetotoxic, or teratogenic effects were seen in rats or in rabbits treated with up to 90.9 and 0.7 times, respectively, the Maximum Recommended Human Dose (MRHD) on a mg/m2 basis.

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.

As a consequence of inhibition of the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. There is no clinical experience of univasc® in the treatment of hypertension in patients with renal failure.

Some hypertensive patients with no apparent preexisting renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when univasc® has been given concomitantly with a thiazide diuretic. This is more likely to occur in patients with preexisting renal impairment. There may be a need for dose adjustment of univasc® and/or the discontinuation of the thiazide diuretic.

Evaluation of hypertensive patients should always include assessment of renal function (see DOSAGE AND ADMINISTRATION).

In hypertensive patients with severe congestive heart failure, whose renal function may depend on the activity of the reninangiotensin-aldosterone system, treatment with ACE inhibitors, including univasc®, may be associated with oliguria and/or progressive azotemia and, rarely, acute renal failure and/or death.

In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine have been observed in some patients following ACE inhibitor therapy. These increases were almost always reversible upon discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy.

In clinical trials, persistent hyperkalemia (serum potassium above 5.4 mEq/L) occurred in approximately 1.3% of hypertensive patients receiving univasc®. Risk factors for the development of hyperkalemia with ACE inhibitors 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 univasc® (see PRECAUTIONS: DRUG INTERACTIONS).

In patients undergoing major surgery or during anesthesia with agents that produce hypotension, moexipril may block the effects of compensatory renin release. If hypotension occurs in this setting and is considered to be due to this mechanism, it can be corrected by volume expansion.

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 differential diagnosis of cough. In controlled trials with moexipril, cough was present in 6.1% of moexipril patients and 2.2 % of patients given placebo.

No evidence of carcinogenicity was detected in long-term studies in mice and rats at doses up to 14 or 2 7.3 times the Maximum Recommended Human Dose (MRHD) on a mg/m² basis.

No mutagenicity was detected in the Ames test and microbial reverse mutation assay, with and without metabolic activation, or in an in vivo nucleus anomaly test. However, increased chromosomal aberration frequency in Chinese hamster ovary cells was detected under metabolic activation conditions at a 2 0-hour harvest time.

Reproduction studies have been performed in rabbits at oral doses up to 0.7 times the MRHD on a mg/m² basis, and in rats up to 90.9 times the MRHD on a mg/m² basis. No indication of impaired fertility, reproductive toxicity, or teratogenicity was observed.

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

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

Safety and effectiveness of univasc® in pediatric patients have not been established.

Clinical studies of univasc® 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. 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.

Dosage (Posology) and method of administration

The recommended initial dose of univasc® 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 univasc® 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 univasc®. The diuretic should, if possible, be discontinued for 2 to 3 days before therapy with univasc® is begun, to reduce the likelihood of hypotension (see WARNINGS). If the patient's blood pressure is not controlled with univasc® alone, diuretic therapy may then be reinstituted. If diuretic therapy cannot be discontinued, an initial dose of 3.75 mg of univasc® should be used with medical supervision until blood pressure has stabilized (see WARNINGS and PRECAUTIONS: DRUG INTERACTIONS).

For patients with a creatinine clearance ≤ 40 mL/min/1.73 m², 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.

Interaction with other medicinal products and other forms of interaction

For patients with a creatinine clearance ≤ 40 mL/min/1.73 m², 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.

univasc® (moexipril hydrochloride) 7.5 mg tablets are pink colored, biconvex, film-coated and scored with engraved code 707 on the unscored side and SP above and 7.5 below the score. They are supplied as follows:

Bottles of 90 (Unit-of-Use) - NDC 0091-3707-09
Bottles of 100 - NDC 0091-3707-01

univasc® (moexipril hydrochloride) 15 mg tablets are salmon colored, biconvex, film-coated, and scored with engraved code 715 on the unscored side and SP above and 15 below the score. They are supplied as follows:

Bottles of 90 (Unit-of-Use) - NDC 0091-3715-09
Bottles of 100 - NDC 0091-3715-01

Store, tightly closed, at controlled room temperature. Protect from excessive moisture.

If product package is subdivided, dispense in tight containers as described in USP-NF.

Manufactured for: UCB, Inc. Smyrna, GA 30080.

univasc® has been evaluated for safety in more than 2 500 patients with hypertension; more than 2 50 of these patients were treated for approximately one year. The overall incidence of reported adverse events was only slightly greater in patients treated with univasc® 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 univasc® and in 1.8% of patients treated with placebo. The most common reasons for discontinuation in patients treated with univasc® 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 univasc® alone and that were at least as frequent in the univasc® group as in the placebo group are shown in the following table:

ADVERSE EVENTS IN PLACEBO-CONTROLLED STUDIES

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 3/12 54 (0.2 4%) patients who had received univasc® monotherapy and in 1/344 (0.3%) patients who had received univasc® with hydrochlorothiazide (see WARNINGS and PRECAUTIONS). 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 univasc® alone and 2 % of patients receiving univasc® 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.

Hyperkalemia (see PRECAUTIONS), hyponatremia.

As with other ACE inhibitors, minor increases in blood urea nitrogen or serum creatinine, reversible upon discontinuation of therapy, were observed in approximately 1% of patients with essential hypertension who were treated with univasc®. Increases are more likely to occur in patients receiving concomitant diuretics and in patients with compromised renal function (see PRECAUTIONS, General).

Clinically important changes in standard laboratory tests were rarely associated with univasc® administration.

Elevations of liver enzymes and uric acid have been reported. In trials, less than 1% of moexipril-treated patients discontinued univasc® treatment because of laboratory abnormalities. The incidence of abnormal laboratory values with moexipril was similar to that in the placebo-treated group.

Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with univasc® can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with univasc®. If this is not possible, the starting dose of moexipril should be reduced. (See WARNINGS and DOSAGE AND ADMINISTRATION).

univasc® 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.

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.

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 univasc®.

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.

No clinically important pharmacokinetic interactions occurred when univasc® was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine.

univasc® has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions.