Uniretic Information
Uniretic ()
Uniretic ()
Uniretic () Description
Uniretic () (moexipril hydrochloride/hydrochlorothiazide) is a combination of an angiotensin-converting enzyme (ACE) inhibitor, moexipril hydrochloride, and a diuretic, hydrochlorothiazide. Moexipril hydrochloride is a fine white to off-white powder. It is soluble (about 10% weight-to-volume) in distilled water at room temperature. It has the empirical formula CHNO•HCl and a molecular weight of 535.04. It is chemically described as [3S-[2[R*(R*)],3R*]]-2-[2-[[1-(Ethoxycarbonyl)-3-phenyl-propyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquino-linecarboxylic acid, monohydrochloride. Moexipril hydrochloride is a non-sulfhydryl containing precursor of the active ACE inhibitor moexiprilat and its structural formula is:
Hydrochlorothiazide is a white, or practically white, crystalline powder. It is slightly soluble in water, freely soluble in sodium hydroxide solution, in n-butylamine and in dimethylformamide. Hydrochlorothiazide has the empirical formula CHClNOS and a molecular weight of 297.75. It is chemically described as 2-1,2,4-Benzothiadiazine-7-sulfonamide,6-chloro-3,4-dihydro-,1,1-dioxide. Hydrochlorothiazide is a thiazide diuretic and its structural formula is:
Uniretic () is available for oral administration in three tablet strengths. The inactive ingredients in all strengths are lactose, magnesium oxide, crospovidone, magnesium stearate and gelatin. The film coating in all strengths contains hydroxypropyl cellulose, hypromellose, polyethylene glycol 6000, magnesium stearate and titanium dioxide. In addition, the film coating for Uniretic () 7.5 mg / 12.5 mg and Uniretic () 15 mg / 25 mg contains ferric oxide.
Uniretic () Indications And Usage
Uniretic () is indicated for treatment of patients with hypertension.
In using Uniretic () , 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 Uniretic () does not have a similar risk (see ). In addition, ACE inhibitors, for which adequate data are available, cause a higher rate of angioedema in black than in nonblack patients (see ).
Uniretic () Contraindications
Uniretic () is contraindicated in patients who are hypersensitive to any component of this product and in patients with a history of angioedema related to previous treatment with an ACE inhibitor. Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs. Hypersensitivity reactions are more likely to occur in patients with a history of allergy or bronchial asthma.
Uniretic () Warnings
Angioedema involving the face, extremities, lips, tongue, glottis, and/or larynx has been reported in patients treated with ACE inhibitors, including moexipril. Symptoms suggestive of angioedema or facial edema occurred in
In cases of angioedema, treatment with Uniretic () 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
ADVERSE REACTIONS
Uniretic () can cause symptomatic hypotension, although, as with other ACE inhibitors, this is unusual in uncomplicated hypertensive patients treated with Uniretic () alone. Symptomatic hypotension is most likely to occur in patients who have been salt- and/or volume-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume- and/or salt-depletion should be corrected before initiating therapy with Uniretic () (see ).
The thiazide component of Uniretic () may potentiate the action of other antihypertensive drugs, especially ganglionic or peripheral adrenergic-blocking drugs. The antihypertensive effects of the thiazide component may also be enhanced in the postsympathectomy patient.
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, Uniretic () 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 Uniretic () 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. Uniretic () treatment usually can be continued following restoration of blood pressure and volume.
Uniretic () should be used with caution in patients with severe renal disease. Thiazide diuretics may precipitate azotemia in such patients and the effects of repeated dosing may be cumulative.
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 Uniretic () 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 moexipril 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 Uniretic () . (see ).
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 moexipril, 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.
ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible.
The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these were caused by the ACE inhibitor exposure.
Fetal and neonatal morbidity do not appear to have resulted from intrauterine ACE inhibitor exposure limited to the first trimester. Mothers who have used ACE inhibitors only during the first trimester should be informed of this. Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of Uniretic () as soon as possible.
Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment.
If oligohydramnios is observed, Uniretic () should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not be detected until after the fetus has sustained irreversible injury.
Infants with histories of exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or peritoneal dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function. Theoretically, the ACE inhibitor could be removed from the neonatal circulation by exchange transfusion, but no experience with this procedure has been reported.
Intrauterine exposure to thiazide diuretics is associated with fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.
Reproduction studies with the combination of moexipril hydrochloride and hydrochlorothiazide (ratio 7.5:12.5) indicated that the combination possessed no teratogenic properties up to the lethal dose of 800 mg/kg/day in rats and up to the maternotoxic dose of 160 mg/kg/day in rabbits.
Uniretic () Adverse Reactions
Uniretic () has been evaluated for safety in more than 1140 patients with hypertension with more than 120 treated for more than one year. Uniretic () has not demonstrated a potential for causing adverse experiences different from those previously associated with other ACE inhibitor/diuretic combinations. The overall incidence of reported adverse events was slightly less in patients treated with Uniretic () than patients treated with placebo.
Adverse experiences were usually mild and transient, and there was no relationship between adverse experiences and gender, race, age, or total daily dosage (except for serum potassium decreases at 50 mg hydrochlorothiazide) within the moexipril/hydrochlorothiazide dosage range of 3.75 mg / 3.125 mg to 30 mg / 50 mg. Discontinuation of therapy due to adverse experiences was required in 5.3% of patients treated with Uniretic () and in 8.4% of patients treated with placebo. The most common reasons for discontinuation of therapy with Uniretic () were cough (0.5%) and dizziness (0.5%).
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 Uniretic () and that were at least as frequent in the Uniretic () group as in the placebo group are shown in the following table.
Other adverse experiences occurring in more than 1% of patients treated with Uniretic () in controlled or uncontrolled trials, some of which were of uncertain drug relationship, listed in decreasing frequency include: upper respiratory infection, headache, pain, flu syndrome, pharyngitis, hyperuricemia, diarrhea, back pain, rhinitis, sinusitis, abnormal ECG, infection, abdominal pain, chest pain, dyspepsia, hyperglycemia, hypokalemia, rash, vertigo, nausea, hypertonia, increased SGPT, urinary tract infection, impotence, peripheral edema, pyuria, bronchitis, and fever. See and for discussion of anaphylactoid reactions, angioedema, hypotension, neutropenia/agranulocytosis, fetal/neonatal morbidity and mortality, serum electrolyte imbalances, and cough.
The following adverse experiences, some of which are of uncertain drug relationship, were reported in Uniretic () controlled or uncontrolled clinical trials in less than 1% of patients or have been attributed to other ACE inhibitors. Within each organ system, adverse experiences are listed in decreasing frequency.
Monotherapy with moexipril has been evaluated for safety in over 3000 patients. In clinical trials, the observed adverse experiences with moexipril were similar to those seen in the Uniretic () trials.
Uniretic () Overdosage
No specific information is available on the treatment of overdosage with Uniretic () . Treatment should be symptomatic and supportive. Therapy with Uniretic () should be discontinued and the patient observed closely. Suggested measures include induction of emesis and/or gastric lavage and correction of dehydration, electrolyte imbalance and hypotension by established procedures.
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. The oral LD of hydrochlorothiazide is greater than 10 g/kg in mice and rats. For the combination of moexipril hydrochloride and hydrochlorothiazide (ratio 7.5:12.5), the approximate LD was around 10 g/kg for mice and above 10 g/kg for rats. Addition of hydrochlorothiazide to moexipril hydrochloride did not increase the acute toxicity due to moexipril hydrochloride.
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. The most common signs and symptoms observed with an overdose of hydrochlorothiazide have been those of dehydration and electrolyte depletion (hypokalemia, hypochloremia, hyponatremia). If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.
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.
Uniretic () Dosage And Administration
Moexipril and hydrochlorothiazide are effective treatments for hypertension. The recommended dosage range of moexipril is 7.5 to 30 mg daily, administered in a single or two divided doses one hour before meals, while hydrochlorothiazide is effective in a dosage of 12.5 to 50 mg daily.
The side effects (see ) of moexipril are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with any combination of moexipril and hydrochlorothiazide will be associated with both sets of dose-independent side effects, but regimens in which moexipril is combined with low doses of hydrochlorothiazide produce minimal effects on serum potassium. In Uniretic () controlled clinical trials, the average change in serum potassium was near zero in subjects who received 3.75 mg / 6.25 mg or 7.5 mg / 12.5 mg, but subjects who received 15 mg / 12.5 mg or 15 mg / 25 mg experienced a mild decrease in serum potassium, similar to that experienced by subjects who received the same dose of hydrochlorothiazide monotherapy. To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy.
Uniretic () How Supplied
Uniretic () (moexipril hydrochloride/hydrochlorothiazide) 7.5 mg / 12.5 mg tablets are yellow, oval, film-coated and scored with engraved code 712 on the unscored side and S and P on either side of the score. They are supplied as follows:
Uniretic () (moexipril hydrochloride/hydrochlorothiazide) 15 mg / 12.5 mg tablets are white, oval, film-coated and scored with engraved code 720 on the unscored side and S and P on either side of the score. They are supplied as follows:
Uniretic () (moexipril hydrochloride/hydrochlorothiazide) 15 mg / 25 mg tablets are yellow, oval, film-coated and scored with engraved code 725 on the unscored side and S and P on either side of the score. They are supplied as follows:
Uniretic ()
Uniretic () Principal Display Panel - . Mg / . Mg Tablet Bottle Label
Uniretic () Principal Display Panel - Mg / . Mg Tablet Bottle Label
Uniretic () Principal Display Panel - Mg / Mg Tablet Bottle Label
