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Definition of Hypersensitivity Vasculitis: An acute form of vasculitis which may affect the skin only, but also may involve other organs, with a polymorphonuclear infiltrate in the walls of and surrounding small
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Medical Encyclopedia:
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Univasc® (moexipril hydrochloride), the hydrochloride salt of moexipril, has the empirical formula C27H34N2O7•HCl and a molecular weight of 535.04. It is chemically described as [3S - [2[R*(R*)],3R*]] - 2 - [2 - [[1 - (ethoxycarbonyl) - 3 - phenylpropyl]amino] - 1 - oxopropyl] - 1,2,3,4 - tetrahydro - 6,7 - dimethoxy - 3 - isoquinolinecarboxylic acid, monohydrochloride. It is a non-sulfhydryl containing precursor of the active angiotensin-converting enzyme (ACE) inhibitor moexiprilat and its structural formula is:
Moexipril hydrochloride is a fine white to off-white powder. It is soluble (about 10% weight-to-volume) in distilled water at room temperature.
Univasc® is supplied as scored, coated tablets containing 7.5 mg and 15 mg of moexipril hydrochloride for oral administration. In addition to the active ingredient, moexipril hydrochloride, the tablet core contains the following inactive ingredients: lactose, magnesium oxide, crospovidone, magnesium stearate and gelatin. The film coating contains hydroxypropyl cellulose, hypromellose, polyethylene glycol 6000, magnesium stearate, titanium dioxide, and ferric oxide.
Moexipril hydrochloride is a prodrug for moexiprilat, which inhibits ACE in humans and animals. The mechanism through which moexiprilat lowers blood pressure is believed to be primarily inhibition of ACE activity. ACE is a peptidyl dipeptidase that catalyzes the conversion of the inactive decapeptide angiotensin I to the vasoconstrictor substance angiotensin II. Angiotensin II is a potent peripheral vasoconstrictor that also stimulates aldosterone secretion by the adrenal cortex and provides negative feedback on renin secretion. ACE is identical to kininase II, an enzyme that degrades bradykinin, an endothelium-dependent vasodilator. Moexiprilat is about 1000 times as potent as moexipril in inhibiting ACE and kininase II. Inhibition of ACE results in decreased angiotensin II formation, leading to decreased vasoconstriction, increased plasma renin activity, and decreased aldosterone secretion. The latter results in diuresis and natriuresis and a small increase in serum potassium concentration (mean increases of about 0.25 mEq/L were seen when moexipril was used alone, see PRECAUTIONS).
Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of moexipril remains to be elucidated. Although the principal mechanism of moexipril in blood pressure reduction is believed to be through the renin-angiotensin-aldosterone system, ACE inhibitors have some effect on blood pressure even in apparent low-renin hypertension. As is the case with other ACE inhibitors, however, the antihypertensive effect of moexipril is considerably smaller in black patients, a predominantly low-renin population, than in non-black hypertensive patients.
Moexipril's antihypertensive activity is almost entirely due to its deesterified metabolite, moexiprilat. Bioavailability of oral moexipril is about 13% compared to intravenous (I.V.) moexipril (both measuring the metabolite moexiprilat), and is markedly affected by food, which reduces the peak plasma level (Cmax) and AUC (see Absorption). Moexipril should therefore be taken in a fasting state. The time of peak plasma concentration (Tmax) of moexiprilat is about 1½ hours and elimination half-life (t½) is estimated at 2 to 9 hours in various studies, the variability reflecting a complex elimination pattern that is not simply exponential. Like all ACE inhibitors, moexiprilat has a prolonged terminal elimination phase, presumably reflecting slow release of drug bound to the ACE. Accumulation of moexiprilat with repeated dosing is minimal, about 30%, compatible with a functional elimination t½ of about 12 hours. Over the dose range of 7.5 to 30 mg, pharmacokinetics are approximately dose proportional.
Moexipril is incompletely absorbed, with bioavailability as moexiprilat of about 13%. Bioavailability varies with formulation and food intake which reduces Cmax and AUC by about 70% and 40% respectively after the ingestion of a low-fat breakfast or by 80% and 50% respectively after the ingestion of a high-fat breakfast.
The clearance (CL) for moexipril is 441 mL/min and for moexiprilat 232 mL/min with a t½ of 1.3 and 9.8 hours, respectively. Moexiprilat is about 50% protein bound. The volume of distribution of moexiprilat is about 183 liters.
Moexipril is relatively rapidly converted to its active metabolite moexiprilat, but persists longer than some other ACE inhibitor prodrugs, such that its t½ is over one hour and it has a significant AUC. Both moexipril and moexiprilat are converted to diketopiperazine derivatives and unidentified metabolites. After I.V. administration of moexipril, about 40% of the dose appears in urine as moexiprilat, about 26% as moexipril, with small amounts of the metabolites; about 20% of the I.V. dose appears in feces, principally as moexiprilat. After oral administration, only about 7% of the dose appears in urine as moexiprilat, about 1% as moexipril, with about 5% as other metabolites. Fifty-two percent of the dose is recovered in feces as moexiprilat and 1% as moexipril.
The effective elimination t½ and AUC of both moexipril and moexiprilat are increased with decreasing renal function. There is insufficient information available to characterize this relationship fully, but at creatinine clearances in the range of 10 to 40 mL/min, the t½ of moexiprilat is increased by a factor of 3 to 4.
In patients with mild to moderate cirrhosis given single 15 mg doses of moexipril, the Cmax of moexipril was increased by about 50% and the AUC increased by about 120%, while the Cmax for moexiprilat was decreased by about 50% and the AUC increased by almost 300%.
In elderly male subjects (65-80 years old) with clinically normal renal and hepatic function, the AUC and Cmax of moexiprilat is about 30% greater than those of younger subjects (19-42 years old).
No clinically important pharmacokinetic interactions occurred when Univasc® was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine.
Single and multiple doses of 15 mg or more of Univasc® gives sustained inhibition of plasma ACE activity of 80-90%, beginning within 2 hours and lasting 24 hours (80%).
In controlled trials, the peak effects of orally administered moexipril increased with the dose administered over a dose range of 7.5 to 60 mg, given once a day. Antihypertensive effects were first detectable about 1 hour after dosing, with a peak effect between 3 and 6 hours after dosing. Just before dosing (i.e., at trough), the antihypertensive effects were less prominently related to dose and the antihypertensive effect tended to diminish during the 24-hour dosing interval when the drug was administered once a day.
In multiple dose studies in the dose range of 7.5 to 30 mg once daily, Univasc® lowered sitting diastolic and systolic blood pressure effects at trough by 3 to 6 mmHg and 4 to 11 mmHg more than placebo, respectively. There was a tendency toward increased response with higher doses over this range. These effects are typical of ACE inhibitors but, to date, there are no trials of adequate size comparing moexipril with other antihypertensive agents.
The trough diastolic blood pressure effects of moexipril were approximately 3 to 6 mmHg in various studies. Generally, higher doses of moexipril leave a greater fraction of the peak blood pressure effect still present at trough. During dose titration, any decision as to the adequacy of a dosing regimen should be based on trough blood pressure measurements. If diastolic blood pressure control is not adequate at the end of the dosing interval, the dose can be increased or given as a divided (BID) regimen.
During chronic therapy, the antihypertensive effect of any dose of Univasc® is generally evident within 2 weeks of treatment, with maximal reduction after 4 weeks. The antihypertensive effects of Univasc® have been proven to continue during therapy for up to 24 months.
Univasc®, like other ACE inhibitors, is less effective in decreasing trough blood pressures in blacks than in non-blacks. Placebo-corrected trough group mean diastolic blood pressure effects in blacks in the proposed dose range varied between +1 to -3 mmHg compared with responses in non-blacks of -4 to -6 mmHg.
The effectiveness of Univasc® was not significantly influenced by patient age, gender, or weight. Univasc® has been shown to have antihypertensive activity in both pre- and postmenopausal women who have participated in placebo-controlled clinical trials.
Formal interaction studies with moexipril have not been carried out with antihypertensive agents other than thiazide diuretics. In these studies, the added effect of moexipril was similar to its effect as monotherapy. In general, ACE inhibitors have less than additive effects with beta-adrenergic blockers, presumably because both work by inhibiting the renin-angiotensin system.
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).
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.
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 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 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 0.25%. 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 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.
Pregnancy Category D
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.
Impaired Renal Function
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).
Hypertensive Patients With Congestive Heart Failure
In hypertensive patients with severe congestive heart failure, whose renal function may depend on the activity of the renin-angiotensin-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.
Hypertensive Patients With Renal Artery Stenosis
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.
Hyperkalemia
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).
Surgery/Anesthesia
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.
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 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.
Food
Patients should be advised to take moexipril one hour before meals (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Angioedema
Angioedema, including laryngeal edema, may occur with treatment with ACE inhibitors, usually occurring early in therapy (within the first month). Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of the face, extremities, eyes, lips, tongue, difficulty in breathing) and to take no more Univasc® until they have consulted with the prescribing physician.
Symptomatic Hypotension
Patients should be cautioned that lightheadedness can occur with Univasc®, especially during the first few days of therapy. If fainting occurs, the patient should stop taking Univasc® and consult 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 their physician if they develop these conditions.
Hyperkalemia
Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting their physician.
Neutropenia
Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) that could be a sign of neutropenia.
Pregnancy
Female patients of childbearing age should be told about the consequences of exposure to Univasc® during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.
Diuretics
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).
Potassium Supplements and Potassium-Sparing Diuretics
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.
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 Univasc®.
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.
Other Agents
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.
No evidence of carcinogenicity was detected in long-term studies in mice and rats at doses up to 14 or 27.3 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 20-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.
Univasc® 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 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 EVENT | Univasc (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 Univasc® monotherapy and in 1/344 (0.3%) patients who had received Univasc® 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 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.
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 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).
Other (causal relationship unknown)
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.
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.
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.
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
Rev. 4E 01/2012
NDC 0091-3707-01
Univasc® tablets
(moexipril HCl)
7.5 mg
Rx only
100 tablets
NDC 0091-3715-01
Univasc® tablets
(moexipril HCl)
15 mg
Rx only
100 tablets
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| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| NDA | NDA020312 | 07/15/1995 | |
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Generic Name: atropine ophthalmic (A troe peen)
Brand names: Atropine-1, Atropine-Care, Atropisol, Isopto Atropine, Ocu-Tropine, Atrosulf-1
Atropine ophthalmic causes the muscles in your eye to become relaxed. This widens your pupil. Your pupil will remain wide and will not respond to light.
Atropine ophthalmic may also be used for purposes other than those listed in this medication guide.
Apply light pressure to the inside corner of your eye (near your nose) for 1 to 3 minutes after each drop or ointment application to prevent the medicine from draining down your tear duct.
Do not use atropine ophthalmic if you have glaucoma that is not being treated.
Atropine ophthalmic eye drops contain a preservative (benzalkonium chloride), so do not wear soft contact lenses when the eye drops are being inserted.
Use atropine ophthalmic eye drops or ointment exactly as directed by your doctor. If you do not understand these instructions, ask your doctor, pharmacist, or nurse to explain them to you.
Wash your hands before and after using your eye drops or ointment.
To apply the eye drops:
Tilt your head back slightly and pull down on your lower eyelid. Position the dropper above your eye. Look up and away from the dropper. Squeeze out a drop and close your eye. Apply gentle pressure to the inside corner of your eye (near your nose) for 1 to 3 minutes to prevent the liquid from draining down your tear duct. If you are using more than one drop in the same eye or drops in both eyes, repeat the process with about 5 minutes between drops.
To apply the ointment:
Hold the tube in your hand for a few minutes to warm it up so that the ointment comes out easily. Tilt your head back slightly and pull down gently on your lower eyelid. Apply a thin film of the ointment into your lower eyelid. Apply gentle pressure to the inside corner of your eye near your nose for 1 to 3 minutes to prevent the ointment from draining down your tear duct. Close your eye and roll your eyeball around in all directions for 1 to 2 minutes. If you are applying another eye medication, allow at least 10 minutes before your next application.
Apply the missed dose as soon as you remember. However, if it is almost time for your next regularly scheduled dose, skip the missed dose and apply the next one as directed. Do not use a double dose of this medication.
Symptoms of an atropine ophthalmic overdose include headache, fast heartbeat, dry mouth and skin, unusual drowsiness, flushing, coma, and death.
Atropine ophthalmic eye drops contain a preservative (benzalkonium chloride), so do not wear soft contact lenses when the eye drops are being inserted.
an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives);
an irregular or fast heart rate;
hallucinations or unusual behavior (especially in children); or
a swollen or distended stomach (in infants).
Other, less serious side effects may be more likely to occur. Continue to use atropine ophthalmic and talk to your doctor if you experience
blurred vision,
sensitivity to sunlight,
stinging and burning, or
swelling of the eyelids.
Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects to FDA at 1-800-FDA-1088.
Usual Adult Dose for Uveitis:
Solution: 1 to 2 drops to the affected eye(s) up to 4 times a day
Ointment: 0.3 to 0.5 cm in the conjunctival sac of the affected eye(s) 1 to 3 times a day
Usual Adult Dose for Refraction:
1 to 2 drops (1% solution) to the affected eye(s) one time, 1 hour before the anticipated examination.
Usual Pediatric Dose for Pupillary Dilation:
As an alternative to occlusion for amblyopia:
3 to 7 years: Instill 1 drop (1% solution) in the affected eye once daily. Frequency may be reduced to twice weekly if adequate improvement in visual acuity.
Usual Pediatric Dose for Refraction:
1 to 18 years:
Ointment: 0.3 cm in the conjunctival sac of the affected eye(s) up to 3 times a day for 1 to 3 days before the procedure.
Solution: 1 to 2 drops (0.5% solution) to the affected eye(s) twice daily for 1 to 3 days before the procedure.
Usual Pediatric Dose for Uveitis:
1 to 18 years:
Ointment: 0.3 to 0.5 cm in the conjunctival sac of the affected eye(s) 1 to 3 times a day.
Solution: 1 to 2 drops (0.5% solution) to the affected eye(s) 1 to 3 times a day.
Avoid other eye medications unless they are approved by your doctor.
Drugs other than those listed here may also interact with atropine ophthalmic. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines.
The following drugs and medications are in some way related to, or used in the treatment of Ophthalmic Surgery. This service should be used as a supplement to, and NOT a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners.
The active components in ipratropium bromide and albuterol sulfate inhalation solution are albuterol sulfate and iprotrium bromide.
Albuterol sulfate, is a salt of racemic albuterol and a relatively selective β2-adrenergic bronchodilator chemically described as α1-[(tert-butylamino)methyl]-4-hydroxy-m-xylene-α,α'-diol sulfate (2:1) (salt). It is a white crystalline powder, soluble in water and slightly soluble in ethanol. The World Health Organization recommended name for albuterol base is salbutamol. It has the following structural formula:
(C13H21NO3)2•H2SO4 M.W. 576.7
Ipratropium bromide is an anticholinergic bronchodilator chemically described as 8-azoniabicyclo [3.2.1]-octane, 3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8methyl-8-(1-methylethyl)-, bromide, monohydrate (endo, syn)-, (±)-; a synthetic quaternary ammonium compound, chemically related to atropine. It is a white crystalline substance, freely soluble in water and lower alcohols, and insoluble in lipophilic solvents such as ether, chloroform, and fluorocarbons. It has the following structural formula:
C20H30BrNO3•H2O M.W. 430.4
Each 3 mL vial of ipratropium bromide and albuterol sulfate inhalation solution contains 3 mg (0.1%) of albuterol sulfate (equivalent to 2.5 mg (0.083%) of albuterol base) and 0.5 mg (0.017%) of ipratropium bromide in an isotonic, sterile, aqueous solution containing disodium edetate dihydrate, hydrochloric acid, sodium chloride, and water for injection.
Ipratropium bromide and albuterol sulfate inhalation solution is a clear, colorless solution. It does not require dilution prior to administration by nebulization. For ipratropium bromide and albuterol sulfate inhalation solution, like all other nebulized treatments, the amount delivered to the lungs will depend on patient factors, the jet nebulizer utilized, and compressor performance. Using the nebulizer (with face mask or mouth piece) connected to a compressor system, under in vitro conditions, the mean delivered dose from the mouthpiece (% nominal dose) was approximately 46% of albuterol and 42% of ipratropium bromide at a mean flow rate of 3.6 L/min. The mean nebulization time was 15 minutes or less. Ipratropium bromide and albuterol sulfate inhalation solution should be administered from jet nebulizers at adequate flow rates, via face masks or mouthpieces (see DOSAGE AND ADMINISTRATION).
Ipratropium bromide and albuterol sulfate inhalation solution is a combination of the β2-adrenergic bronchodilator, albuterol sulfate, and the anticholinergic bronchodilator, ipratropium bromide.
The prime action of β-adrenergic drugs is to stimulate adenyl cyclase, the enzyme that catalyzes the formation of cyclic-3',5'-adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). The cAMP thus formed mediates the cellular responses. In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on β2-adrenergic receptors compared with isoproterenol. While it is recognized that β2-adrenergic receptors are the predominant receptors in bronchial smooth muscle, recent data indicated that 10% to 50% of the β-receptors in the human heart may be β2-receptors. The precise function of these receptors, however, is not yet established. Albuterol has been shown in most controlled clinical trials to have more effect on the respiratory tract, in the form of bronchial smooth muscle relaxation, than isoproterenol at comparable doses while producing fewer cardiovascular effects. Controlled clinical studies and other clinical experience have shown that inhaled albuterol, like other β-adrenergic agonist drugs, can produce a significant cardiovascular effect in some patients.
Albuterol sulfate is longer acting than isoproterenol in most patients by any route of administration, because it is not a substrate for the cellular uptake processes for catecholamine nor for the metabolism of catechol-O-methyl transferase. Instead the drug is conjugatively metabolized to albuterol 4'-O-sulfate.
Intravenous studies in rats with albuterol sulfate have demonstrated that albuterol crosses the blood-brain barrier and reaches brain concentrations amounting to approximately 5% of plasma concentrations. In structures outside of the blood-brain barrier (pineal and pituitary glands), albuterol concentrations were found to be 100 times those found in whole brain.
Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrythmias and sudden death (with histological evidence of myocardial necrosis) when beta-agonists and methyl-xanthines are administered concurrently. The clinical significance of these findings is unknown.
Ipratropium bromide is an anticholinergic (parasympatholytic) agent, which blocks the muscarinic receptors of acetylcholine, and, based on animal studies, appears to inhibit vagally mediated reflexes by antagonizing the action of acetylcholine, the transmitter agent released from the vagus nerve. Anticholinergics prevent the increases in intracellular concentration of cyclic guanosine monophosphate (cGMP), resulting from the interaction of acetylcholine with the muscarinic receptors of bronchial smooth muscle.
The bronchodilation following inhalation of ipratropium is primarily a local, site-specific effect, not a systemic one. Much of an inhaled dose is swallowed as shown by fecal excretion studies. Following nebulization of a 1-mg dose to healthy volunteers, a mean of 4% of the dose was excreted unchanged in the urine.
Ipratropium bromide is minimally (0% to 9% in vitro) bound to plasma albumin and α1-acid glycoproteins. It is partially metabolized to inactive ester hydrolysis products. Following intravenous administration, approximately one-half is excreted unchanged in the urine. The half-life of elimination is about 1.6 hours after intravenous administration. Ipratropium bromide that reaches the systemic circulation is reportedly removed by the kidneys rapidly at a rate that exceeds the glomerular filtration rate. The pharmacokinetics of ipratropium bromide and albuterol sulfate inhalation solution or ipratropium bromide have not been studied in the elderly and in patients with hepatic or renal insufficiency (see PRECAUTIONS).
Autoradiographic studies in rats have shown that ipratropium does not penetrate the blood-brain barrier.
Ipratropium bromide and albuterol sulfate inhalation solution is expected to maximize the response to treatment in patients with chronic obstructive pulmonary disease (COPD) by reducing bronchospasm through two distinctly different mechanisms: sympathomimetic (albuterol sulfate) and anticholinergic/parasympatholytic (ipratropium bromide). Simultaneous administration of both an anticholinergic and a β2-sympathomimetic is designed to produce greater bronchodilation effects than when either drug is utilized alone at its recommended dosage.
In 30-day studies in Sprague-Dawley rats and Beagle dogs, subcutaneous doses of up to 205.5 mcg/kg of ipratropium administered with up to 1000 mcg/kg albuterol in rats and 3.16 mcg/kg ipratropium and 15 mcg/kg albuterol in dogs (less than the maximum recommended daily inhalation dose for adults on a mg/m2 basis) did not cause death or potentiation of the cardiotoxicity induced by albuterol administered alone.
In a double blind, double period, crossover study, 15 male and female subjects were administered single doses of ipratropium bromide and albuterol sulfate inhalation solution or albuterol sulfate inhalation solution at two times the recommended single doses as two inhalations separated by 15 minutes. The total nebulized dose of albuterol sulfate from both treatments was 6 mg and the total dose of ipratropium bromide from ipratropium bromide and albuterol sulfate inhalation solution was 1 mg. Peak albuterol plasma concentrations occurred at 0.8 hours after dosing for both treatments. The mean peak albuterol concentration following administration of albuterol sulfate alone was 4.86 (± 2.65) mg/mL and it was 4.65 (± 2.92) mg/mL for ipratropium bromide and albuterol sulfate inhalation solution. Mean AUC values for the two treatments were 26.6 (± 15.2) ng•hr/mL (albuterol sulfate alone) versus 24.2 (± 14.5) ng•hr/mL (ipratropium bromide and albuterol sulfate inhalation solution). The mean t1/2 values were 7.2 (± 1.3) hours (albuterol sulfate alone) and 6.7 (± 1.7) hours (ipratropium bromide and albuterol sulfate inhalation solution). A mean of 8.4 (± 8.9)% of the albuterol dose was excreted unchanged in urine following administration of two vials of ipratropium bromide and albuterol sulfate inhalation solution which is similar to 8.8 (± 7.3)% that was obtained from albuterol sulfate inhalation solution. There were no statistically significant differences in the pharmacokinetics of albuterol between the two treatments. For ipratropium, a mean of 3.9 (± 5.1)% of the ipratropium bromide dose was excreted unchanged in urine following two vials of ipratropium bromide and albuterol sulfate inhalation solution, which is comparable with previously reported data.
In a 12 week, randomized, double-blind, positive-control, crossover study of albuterol sulfate, ipratropium bromide, and ipratropium bromide and albuterol sulfate inhalation solution, 863 COPD patients were evaluated for bronchodilator efficacy comparing ipratropium bromide and albuterol sulfate inhalation solution with albuterol sulfate and ipratropium bromide alone.
Ipratropium bromide and albuterol sulfate inhalation solution demonstrated significantly better changes in FEV1, as measured from baseline to peak response, when compared with either albuterol sulfate or ipratropium bromide. Ipratropium bromide and albuterol sulfate inhalation solution was also shown to have the rapid onset associated with albuterol sulfate, with a mean time to peak FEV1 of 1.5 hours, and the extended duration associated with ipratropium bromide with a duration of 15% response in FEV1 of 4.3 hours.
Figure 3. 1-3. Mean Change in FEV1 - Measured on Day 14
This study demonstrated that each component of ipratropium bromide and albuterol sulfate inhalation solution contributed to the improvement in pulmonary function, especially during the first 4 to 5 hours after dosing, and that ipratropium bromide and albuterol sulfate inhalation solution was significantly more effective than albuterol sulfate or ipratropium bromide alone.
Ipratropium bromide and albuterol sulfate inhalation solution is indicated for the treatment of bronchospasm associated with COPD in patients requiring more than one bronchodilator.
Ipratropium bromide and albuterol sulfate inhalation solution is contraindicated in patients with a history of hypersensitivity to any of its components, or to atropine and its derivatives.
In the clinical study of ipratropium bromide and albuterol sulfate inhalation solution, paradoxical bronchospasm was not observed. However, paradoxical bronchospasm has been observed with both inhaled ipratropium bromide and albuterol products and can be life-threatening. If this occurs, ipratropium bromide and albuterol sulfate inhalation solution should be discontinued immediately and alternative therapy instituted.
Fatalities have been reported in association with excessive use of inhaled products containing sympathomimetic amines and with the home use of nebulizers.
Ipratropium bromide and albuterol sulfate inhalation solution, like other beta adrenergic agonists, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon for ipratropium bromide and albuterol sulfate inhalation solution at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta agonists have been reported to produce ECG changes, such as flattening of the T-wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, ipratropium bromide and albuterol sulfate inhalation solution, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
Immediate hypersensitivity reactions to albuterol and/or ipratropium bromide may occur after the administration of ipratropium bromide and albuterol sulfate inhalation solution as demonstrated by rare cases of urticaria, angioedema, rash, pruritus, oropharyngeal edema, bronchospasm, and anaphylaxis.
1. Effects Seen with Sympathomimetic Drugs: As with all products containing sympathomimetic amines, ipratropium bromide and albuterol sulfate inhalation solution should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Large doses of intravenous albuterol have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis. Additionally, β-agonists may cause a decrease in serum potassium in some patients, possibly through intracellular shunting. The decrease is usually transient, not requiring supplementation.
2. Effects Seen with Anticholinergic Drugs: Due to the presence of ipratropium bromide in ipratropium bromide and albuterol sulfate inhalation solution, it should be used with caution in patients with narrow-angle glaucoma, prostatic hypertrophy, or bladder-neck obstruction.
3. Use in Hepatic or Renal Disease: Ipratropium bromide and albuterol sulfate inhalation solution has not been studied in patients with hepatic or renal insufficiency. It should be used with caution in these patient populations.
The action of ipratropium bromide and albuterol sulfate inhalation solution should last up to 5 hours. Ipratropium bromide and albuterol sulfate inhalation solution should not be used more frequently than recommended. Patients should be instructed not to increase the dose or frequency of ipratropium bromide and albuterol sulfate inhalation solution without consulting their healthcare provider. If symptoms worsen, patients should be instructed to seek medical consultation.
Patients must avoid exposing their eyes to this product as temporary papillary dilation, blurred vision, eye pain, or precipitation or worsening of narrow-angle glaucoma may occur, and therefore proper nebulizer technique should be assured, particularly if a mask is used.
If a patient becomes pregnant or begins nursing while on ipratropium bromide and albuterol sulfate inhalation solution, they should contact their healthcare provider about use of ipratropium bromide and albuterol sulfate inhalation solution.
See the illustrated Patient's Instruction for Use in the product package insert.
Although ipratropium bromide is minimally absorbed into the systemic circulation, there is some potential for an additive interaction with concomitantly used anticholinergic medications. Caution is, therefore, advised in the co-administration of ipratropium bromide and albuterol sulfate inhalation solution with other drugs having anticholinergic properties.
Caution is advised in the co-administration of ipratropium bromide and albuterol sulfate inhalation solution and other sympathomimetic agents due to the increased risk of adverse cardiovascular effects.
These agents and albuterol sulfate inhibit the effect of each other. β-receptor blocking agents should be used with caution in patients with hyperreactive airways, and if used, relatively selective β1 selective agents are recommended.
The electrocardiogram (ECG) changes and/or hypokalemia that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by β-agonists, especially when the recommended dose of the β-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the co-administration of β-agonist-containing drugs, such as ipratropium bromide and albuterol sulfate inhalation solution, with non-potassium sparing diuretics.
Ipratropium bromide and albuterol sulfate inhalation solution should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents because the action of albuterol sulfate on the cardiovascular system may be potentiated.
In a 2-year study in Sprague-Dawley rats, albuterol sulfate caused a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium at and above dietary doses of 2 mg/kg (approximately equal to the maximum recommended daily inhalation dose for adults on a mg/m2 basis). In another study, this effect was blocked by the coadministration of propranolol, a non-selective beta-adrenergic antagonist.
In an 18-month study in CD-1 mice, albuterol sulfate showed no evidence of tumorigenicity at dietary doses up to 500 mg/kg (approximately 140 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis). In a 22-month study in Golden hamsters, albuterol sulfate showed no evidence of tumorigenicity at dietary doses up to 50 mg/kg (approximately 20 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis).
Albuterol sulfate was not mutagenic in the Ames test or a mutation test in yeast. Albuterol sulfate was not clastogenic in a human peripheral lymphocyte assay or in an AH1 strain mouse micronucleous assay.
Reproduction studies in rats demonstrated no evidence of impaired fertility at oral doses of albuterol sulfate up to 50 mg/kg (approximately 25 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis).
In 2-year studies in Sprague-Dawley rats and CD-1 mice, ipratropium bromide showed no evidence of tumorigenicity at oral doses up to 6 mg/kg (approximately 15 times and 8 times the maximum recommended daily inhalation dose for adults in rats and mice respectively, on a mg/m2 basis).
Ipratropium bromide was not mutagenic in the Ames test and mouse dominant lethal test. Ipratropium bromide was not clastogenic in a mouse micronucleous assay.
A reproduction study in rats demonstrated decreased conception and increased resorptions when ipratropium bromide was administered orally at a dose of 90 mg/kg (approximately 240 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis). These effects were not seen with a dose of 50 mg/kg (approximately 140 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis).
Albuterol sulfate has been shown to be teratogenic in mice. A study in CD-1 mice given albuterol sulfate subcutaneously showed cleft palate formation in 5 of 111 (4.5%) fetuses at 0.25 mg/kg (less than the maximum recommended daily inhalation dose for adults on a mg/m2 basis) and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg (approximately equal to the maximum recommended daily inhalation dose for adults on a mg/m2 basis). The drug did not induce cleft palate formation when administered subcutaneously at a dose of 0.025 mg/kg (less than the maximum recommended daily inhalation dose for adults on a mg/m2 basis). Cleft palate formation also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with 2.5 mg/kg isoproterenol (positive control).
A reproduction study in Stride rabbits revealed cranioschisis in 7 of 19 (37%) fetuses when albuterol was administered orally at a dose of 50 mg/kg (approximately 55 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis).
A study in which pregnant rats were dosed with radiolabeled albuterol sulfate demonstrated that drug-related material is transferred from the maternal circulation to the fetus.
During worldwide marketing experience, various congenital anomalies, including cleft palate and limb defects, have been reported in the offspring of patients being treated with albuterol. Some of the mothers were taking multiple medications during their pregnancies. Because no consistent pattern of defects can be discerned, a relationship between albuterol use and congenital anomalies has not been established.
Reproduction studies in CD-1 mice, Sprague-Dawley rats and New Zealand rabbits demonstrated no evidence of teratogenicity at oral doses up to 10, 100, and 125 mg/kg, respectively (approximately 15, 270, and 680 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis). Reproduction studies in rats and rabbits demonstrated no evidence of teratogenicity at inhalation doses up to 1.5 and 1.8 mg/kg, respectively (approximately 4 and 10 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis). There are no adequate and well-controlled studies of the use of ipratropium bromide and albuterol sulfate inhalation solution, albuterol sulfate, or ipratropium bromide in pregnant women. Ipratropium bromide and albuterol sulfate inhalation solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Oral albuterol sulfate has been shown to delay preterm labor in some reports. Because of the potential of albuterol to interfere with uterine contractility, use of ipratropium bromide and albuterol sulfate inhalation solution during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.
It is not known whether the components of ipratropium bromide and albuterol sulfate inhalation solution are excreted in human milk. Although lipid-insoluble quaternary bases pass into breast milk, it is unlikely that ipratropium bromide would reach the infant to an important extent, especially when taken as a nebulized solution. Because of the potential for tumorigenicity shown for albuterol sulfate in some animals, a decision should be made whether to discontinue nursing or discontinue ipratropium bromide and albuterol sulfate inhalation solution, taking into account the importance of the drug to the mother.
The safety and effectiveness of ipratropium bromide and albuterol sulfate inhalation solution in patients below 18 years of age have not been established.
Of the total number of subjects in clinical studies of ipratropium bromide and albuterol sulfate inhalation solution, 62 percent were 65 and over, while 19 percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Adverse reaction information concerning ipratropium bromide and albuterol sulfate inhalation solution was derived from the 12-week controlled clinical trial.
| Body System | Albuterol | Ipratropium | Ipratropium Bromide and Albuterol Sulfate Inhalation Solution |
| COSTART Term | n (%) | n (%) | n (%) |
| NUMBER OF PATIENTS | 761 | 754 | 765 |
| N (%) Patients with AE | 327 (43.0) | 329 (43.6) | 367 (48.0) |
| BODY AS A WHOLE | |||
| Pain | 8 (1.1) | 4 (0.5) | 10 (1.3) |
| Pain chest | 11 (1.4) | 14 (1.9) | 20 (2.6) |
| DIGESTIVE | |||
| Diarrhea | 5 (0.7) | 9 (1.2) | 14 (1.8) |
| Dyspepsia | 7 (0.9) | 8 (1.1) | 10 (1.3) |
| Nausea | 7 (0.9) | 6 (0.8) | 11 (1.4) |
| MUSCULO-SKELETAL | |||
| Cramps leg | 8 (1.1) | 6 (0.8) | 11 (1.4) |
| RESPIRATORY | |||
| Bronchitis | 11 (1.4) | 13 (1.7) | 13 (1.7) |
| Lung Disease | 36 (4.7) | 34 (4.5) | 49 (6.4) |
| Pharyngitis | 27 (3.5) | 27 (3.6) | 34 (4.4) |
| Pneumonia | 7 (0.9) | 8 (1.1) | 10 (1.3) |
| UROGENITAL | |||
| Infection urinary tract | 3 (0.4) | 9 (1.2) | 12 (1.6) |
Additional adverse reactions reported in more than 1% of patients treated with ipratropium bromide and albuterol sulfate inhalation solution included constipation and voice alterations.
In the clinical trial, there was a 0.3% incidence of possible allergic-type reactions, including skin rash, pruritus, and urticaria.
Additional information derived from the published literature on the use of albuterol sulfate and ipratropium bromide singly or in combination includes precipitation or worsening of narrow-angle glaucoma, acute eye pain, blurred vision, paradoxical bronchospasm, wheezing, exacerbation of COPD symptoms, drowsiness, aching, flushing, upper respiratory tract infection, palpitations, taste perversion, elevated heart rate, sinusitis, back pain, sore throat, and metabolic acidosis. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The effects of overdosage with ipratropium bromide and albuterol sulfate inhalation solution are expected to be related primarily to albuterol sulfate, since ipratropium bromide is not well-absorbed systemically after oral or aerosol administration. The expected symptoms with overdosage are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of symptoms such as seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats per minute, arrhythmia, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, and exaggeration of pharmacological effects listed in ADVERSE REACTIONS. Hypokalemia may also occur. As with all sympathomimetic aerosol medications, cardiac arrest and even death may be associated with abuse of ipratropium bromide and albuterol sulfate inhalation solution. Treatment consists of discontinuation of ipratropium bromide and albuterol sulfate inhalation solution together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of ipratropium bromide and albuterol sulfate inhalation solution.
The oral median lethal dose of albuterol sulfate in mice is greater than 2000 mg/kg (approximately 540 times the maximum recommended daily inhalation dose of ipratropium bromide and albuterol sulfate inhalation solution on a mg/m2 basis). The subcutaneous median lethal dose of albuterol sulfate in mature rats and small young rats is approximately 450 and 2000 mg/kg respectively (approximately 240 and 1100 times the maximum recommended daily inhalation dose of ipratropium bromide and albuterol sulfate inhalation solution on a mg/m2 basis, respectively). The inhalation median lethal dose has not been determined in animals. The oral median lethal dose of ipratropium bromide in mice, rats and dogs is greater than 1000 mg/kg, approximately 1700 mg/kg and approximately 400 mg/kg, respectively (approximately 1400, 4600, and 3600 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis, respectively).
The recommended dose of ipratropium bromide and albuterol sulfate inhalation solution is one 3 mL vial administered 4 times per day via nebulization with up to 2 additional 3 mL doses allowed per day, if needed. Safety and efficacy of additional doses or increased frequency of administration of ipratropium bromide and albuterol sulfate inhalation solution beyond these guidelines has not been studied and the safety and efficacy of extra doses of albuterol sulfate or ipratropium bromide in addition to the recommended doses of ipratropium bromide and albuterol sulfate inhalation solution have not been studied.
The use of ipratropium bromide and albuterol sulfate inhalation solution can be continued as medically indicated to control recurring bouts of bronchospasm. If a previously effective regimen fails to provide the usual relief, medical advice should be sought immediately, as this is often a sign of worsening COPD, which would require reassessment of therapy.
A nebulizer (with face mask or mouthpiece) connected to a compressor was used to deliver ipratropium bromide and albuterol sulfate inhalation solution to each patient in one U.S. clinical study. The safety and efficacy of ipratropium bromide and albuterol sulfate inhalation solution delivered by other nebulizers and compressors have not been established.
Ipratropium bromide and albuterol sulfate inhalation solution should be administered via jet nebulizer connected to an air compressor with an adequate air flow, equipped with a mouthpiece or suitable face mask.
Ipratropium Bromide 0.5 mg and Albuterol Sulfate 3 mg* Inhalation Solution is supplied as a 3 mL sterile solution for nebulization in sterile low-density polyethylene unit-dose vials. Store in pouch until time of use. Cards of five vials are placed into a foil pouch. Supplied in unit-dose boxes of 30 vials and unit-dose boxes of 60 vials (2 x 30).
NDC 0093-6723-73 30 vials per carton/5 vials per foil pouch
NDC 0093-6723-74 60 vials per carton/5 vials per foil pouch
Store at 2°C to 25°C (36°F to 77°F). Protect from light.
*Equivalent to 2.5 mg albuterol base
Manufactured In England By:
IVAX PHARMACEUTICALS UK
Runcorn, Cheshire WA7 3FA England
Manufactured For:
TEVA PHARMACEUTICALS USA
Sellersville, PA 18960
Rev. B 9/2011
Ipratropium Bromide 0.5 mg and Albuterol Sulfate 3 mg* Inhalation Solution
*Equivalent to 2.5 mg albuterol base
Patient's Instructions for Use
Read this patient information completely every time your prescription is filled as information may have changed. Keep these instructions with your medication as you may want to read them again.
Ipratropium bromide and albuterol sulfate inhalation solution should only be used under the direction of a physician. Your physician and pharmacist have more information about ipratropium bromide and albuterol sulfate inhalation solution and the condition for which it has been prescribed. Contact them if you have additional questions.
Storing your Medicine
Store ipratropium bromide and albuterol sulfate inhalation solution between 2°C and 25°C (36°F and 77°F). Vials should be protected from light before use, therefore, keep unused vials in the foil pouch or carton. Do not use after the expiration (EXP) date printed on the carton.
Dose
Ipratropium bromide and albuterol sulfate inhalation solution is supplied as a single-dose, ready-to-use vial containing 3 mL of solution. No mixing or dilution is needed. Use one new vial for each nebulizer treatment.
FOLLOW THESE DIRECTIONS FOR USE OF YOUR NEBULIZER/COMPRESSOR OR THE DIRECTIONS GIVEN BY YOUR HEALTHCARE PROVIDER. A TYPICAL EXAMPLE IS SHOWN BELOW.
Instructions for Use
1. Remove one vial from the foil pouch. Place remaining vials back into pouch for storage.
2. Twist the cap completely off the vial and squeeze the contents into the nebulizer reservoir (Figure 1).
3. Connect the nebulizer to the mouthpiece or face mask (Figure 2).
4. Connect the nebulizer to the compressor.
5. Sit in a comfortable, upright position; place the mouthpiece in your mouth (Figure 3) or put on the face mask (Figure 4); and turn on the compressor.
6. Breathe as calmly, deeply and evenly as possible through your mouth until no more mist is formed in the nebulizer chamber (about 5-15 minutes). At this point, the treatment is finished.
7. Clean the nebulizer (see manufacturer's instructions).
Manufactured In England By:
IVAX PHARMACEUTICALS UK
Runcorn, Cheshire WA7 3FA England
Manufactured For:
TEVA PHARMACEUTICALS USA
Sellersville, PA 18960
Rev. B 9/2011
Steri-Neb™ is a trademark of Norton Healthcare Limited.
IPRATROPIUM BROMIDE and ALBUTEROL SULFATE INHALATION SOLUTION
ADDITIONAL INSTRUCTIONS
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Ipratropium Bromide 0.5 mg/Albuterol Sulfate 3 mg* Inhalation Solution
*Equivalent to 2.5 mg albuterol base
Prescription Only.
Read the patient information that comes with ipratropium bromide and albuterol sulfate inhalation solution before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment.
What is ipratropium bromide and albuterol sulfate inhalation solution?
Ipratropium bromide and albuterol sulfate inhalation solution is a combination of two medicines called bronchodilators. Ipratropium bromide and albuterol sulfate inhalation solution contains albuterol sulfate, which is a beta-adrenergic agonist, and ipratropium bromide, which is an anticholinergic. These two medicines work together to help open the airways in your lungs. Ipratropium bromide and albuterol sulfate inhalation solution is used to help treat airway narrowing (bronchospasm) that happens with chronic obstructive pulmonary disease (COPD) in adult patients who need to use more than one bronchodilator medicine.
Who should not use ipratropium bromide and albuterol sulfate inhalation solution?
Do not use ipratropium bromide and albuterol sulfate inhalation solution if you: Are allergic to any of the ingredients in ipratropium bromide and albuterol sulfate inhalation solution or to atropine. The active ingredients are albuterol sulfate and ipratropium bromide. See the end of this leaflet for a complete list of ingredients in ipratropium bromide and albuterol sulfate inhalation solution.
Ipratropium bromide and albuterol sulfate inhalation solution has not been studied in patients younger than 18 years of age.
What should I tell my doctor before I start using ipratropium bromide and albuterol sulfate inhalation solution?
Tell your doctor about all of your conditions, including if you:
Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins and herbal supplements. Ipratropium bromide and albuterol sulfate inhalation solution and other medicines can interact. This may cause serious side effects. Especially tell your doctor if you take:
Ask your doctor or pharmacist if you are not sure if you take any of these types of medicines. Know the medicines you take. Keep a list of them and show it to your doctor and pharmacists when you get a new medicine.
How should I use ipratropium bromide and albuterol sulfate inhalation solution?
