FDA label eadb10fe-b683-4299-8d0a-00d30be2d2c3

USE IN PREGNANCY When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, moexipril hydrochloride and hydrochlorothiazide tablets should be discontinued as soon as possible. See WARNINGS , Fetal/Neonatal Morbidity and Mortality .

WARNINGS Anaphylactoid and Possibly Related Reactions Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors, including moexipril hydrochloride/hydrochlorothiazide, may be subject to a variety of adverse reactions, some of them serious. Head and Neck Angioedema Angioedema involving the face, extremities, lips, tongue, glottis, and/or larynx has been reported in patients treated with ACE inhibitors, including moexipril. 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 with moexipril hydrochloride/hydrochlorothiazide should be promptly discontinued and the patient carefully observed until the swelling disappears. In instances where swelling has been confined to the face and lips, the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with involvement of the tongue, glottis, or larynx may be fatal due to airway obstruction. Appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 mL) and/or measures to ensure a patent airway, should be promptly provided (see ADVERSE REACTIONS ). Intestinal Angioedema Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. Anaphylactoid Reactions During Desensitization Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions did not occur when ACE inhibitors were temporarily withheld, but they reappeared when the ACE inhibitors were inadvertently readministered. Anaphylactoid Reactions During Membrane Exposure Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. Hypotension Moexipril hydrochloride/hydrochlorothiazide can cause symptomatic hypotension, although, as with other ACE inhibitors, this is unusual in uncomplicated hypertensive patients treated with moexipril hydrochloride/hydrochlorothiazide 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 moexipril hydrochloride/hydrochlorothiazide (see ADVERSE REACTIONS ). The thiazide component of moexipril hydrochloride and hydrochlorothiazide tablets 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, moexipril hydrochloride/hydrochlorothiazide 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 hydrochloride/hydrochlorothiazide 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. Moexipril hydrochloride/hydrochlorothiazide treatment usually can be continued following restoration of blood pressure and volume. Impaired Renal Function Moexipril hydrochloride/hydrochlorothiazide 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 moexipril hydrochloride/hydrochlorothiazide 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 moexipril hydrochloride/hydrochlorothiazide. 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 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. Neutropenia/Agranulocytosis 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/mm 3 ) among patients given moexipril, 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 moexipril are insufficient to show that moexipril does not cause agranulocytosis at rates similar to captopril. Fetal/Neonatal Morbidity and Mortality 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 moexipril hydrochloride and hydrochlorothiazide tablets 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, moexipril hydrochloride and hydrochlorothiazide tablets 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 in utero 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. Hepatic Failure 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 Hepatic Function Moexipril hydrochloride/hydrochlorothiazide should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. In patients with mild to moderate cirrhosis given single 15 mg doses of moexipril, the C max­ of moexipril was increased by about 50% and the AUC increased by about 120%, while the C max for moexiprilat was decreased by about 50% and the AUC increased by almost 300%. No formal pharmacokinetic studies have been carried out with moexipril hydrochloride/hydrochlorothiazide in hypertensive patients with impaired liver function. Systemic Lupus Erythematosus Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.

ADVERSE REACTIONS Moexipril hydrochloride/hydrochlorothiazide has been evaluated for safety in more than 1140 patients with hypertension with more than 120 treated for more than one year. Moexipril hydrochloride/hydrochlorothiazide 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 moexipril hydrochloride/hydrochlorothiazide 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 moexipril hydrochloride/hydrochlorothiazide and in 8.4% of patients treated with placebo. The most common reasons for discontinuation of therapy with moexipril hydrochloride/hydrochlorothiazide 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 moexipril hydrochloride/hydrochlorothiazide and that were at least as frequent in the moexipril hydrochloride/hydrochlorothiazide group as in the placebo group are shown in the following table. Adverse Events in Placebo-Controlled Trials ADVERSE EVENT MOEXIPRIL HYDROCHLORIDE/HYDROCHLOROTHIAZIDE (N = 506) PLACEBO (N = 202) N (%) N (%) Cough 15 (3) 2 (1) Dizziness 7 (1.4) 2 (1) Fatigue 5 (1) 1 (0.5) Other adverse experiences occurring in more than 1% of patients treated with moexipril hydrochloride/hydrochlorothiazide 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 WARNINGS and PRECAUTIONS 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 moexipril hydrochloride/hydrochlorothiazide 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. Cardiovascular: palpitation, flushing, syncope, tachycardia, myocardial infarct, hypotension, postural hypotension, arrhythmia, first degree AV block, ventricular extrasystoles, atrial fibrillation, migraine, hemorrhage, sinus bradycardia, bigeminy, bradycardia, bundle branch block, heart arrest, myocardial ischemia, peripheral vascular disorder, prolonged QT interval, inverted T wave, ventricular fibrillation Dermatologic: eczema, pruritus, sweating, acne, dry skin, herpes simplex, contact dermatitis, herpes zoster, psoriasis, alopecia, angioedema, erythema nodosum, fungal dermatitis, furunculosis, maculopapular rash, purpuric rash, skin carcinoma, subcutaneous nodule, urticaria, pemphigus Gastrointestinal: vomiting, constipation, gastroenteritis, periodontal abscess, cholelithiasis, gastritis, gingivitis, esophagitis, flatulence, anorexia, colitis, dysphagia, tooth caries, cheilitis, enteritis, eructation, gastrointestinal carcinoma, gastrointestinal hemorrhage, glossitis, increased appetite, jaundice, melena, rectal hemorrhage, stomatitis, tongue discoloration, tongue edema Hematologic: anemia, hypochromic anemia, leukopenia, abnormal erythrocytes, ecchymosis, lymphocytosis, hemolysis, lymphadenopathy, eosinophilia, petechia, abnormal WBC, hemolytic anemia Metabolic: hyperlipemia, increased SGOT, gout, bilirubinemia, increased creatinine, hypercholesterolemia, increased BUN, increased CPK, diabetes mellitus, hyponatremia, thirst, edema, increased alkaline phosphatase, increased amylase, dehydration, decreased glucose tolerance, goiter, hypercalcemia, hyperkalemia, hypocalcemia, hypochloremia, hypoproteinemia, weight gain Neurologic/Psychiatric : insomnia, postural dizziness, somnolence, dry mouth, anxiety, nervousness, paresthesia, depression, neuritis, hypesthesia, decreased libido, neuralgia, amnesia, ataxia, cerebral infarct, emotional lability, facial paralysis, hypokinesia, neurosis, vocal cord paralysis Renal: albuminuria, urinary frequency, hematuria, glycosuria, cystitis, dysuria, nocturia, polyuria, kidney calculus, pyelonephritis, urate crystalluria, urinary casts, urinary retention Respiratory: epistaxis, pneumonia, dyspnea, asthma, lung carcinoma, hemoptysis, laryngitis, voice alteration, eosinophilic pneumonitis Urogenital: vaginal hemorrhage, breast carcinoma, scrotal edema, vaginitis, breast enlargement, breast pain, dysmenorrhea, leucorrhea Other: asthenia, conjunctivitis, myalgia, arthralgia, arthrosis, hernia, neck pain, cyst, tenosynovitis, abnormal vision, allergic reaction, arthritis, cataract, cellulitis, moniliasis, otitis media, eye hemorrhage, chills, abscess, bursitis, deafness, ear pain, glaucoma, iritis, neck rigidity, photosensitivity, retinal degeneration, tinnitus 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 moexipril hydrochloride/hydrochlorothiazide trials. Hydrochlorothiazide The following adverse reactions have been reported with hydrochlorothiazide and, within each organ system, are listed by decreasing severity. Cardiovascular: orthostatic hypotension (may be potentiated by alcohol, barbiturates, or narcotics) Gastrointestinal: pancreatitis, jaundice (intrahepatic cholestatic, see WARNINGS ), sialadenitis, vomiting, diarrhea, cramping, nausea, gastric irritation, constipation, anorexia Neurologic/Psychiatric: vertigo, dizziness, transient blurred vision, headache, paresthesia, xanthopsia, weakness, restlessness Musculoskeletal: muscle spasm Hematologic: aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia Metabolic: hyperglycemia, glycosuria, hyperuricemia Hypersensitivity: necrotizing angiitis, Stevens-Johnson syndrome, respiratory distress including pneumonitis and pulmonary edema, purpura, urticaria, rash, photosensitivity Clinical Laboratory Test Findings Serum Electrolytes See PRECAUTIONS , General . 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 less than 1% of patients with essential hypertension who were treated with moexipril hydrochloride/hydrochlorothiazide. Increases are more likely to occur in patients with compromised renal function (see PRECAUTIONS , General ). Other (causal relationship unknown) Clinically important changes in standard laboratory tests were rarely associated with moexipril hydrochloride/hydrochlorothiazide administration.

<table border="1" width="351" ID="inv-ddc8e41b-72d7-4c1d-a595-9a2a3656bf9e"> <caption ID="inv-13be212e-2272-4afb-8630-93edb38f4d1d">Adverse Events in Placebo-Controlled Trials</caption> <col width="32.8%"/> <col width="14.8%"/> <col width="16.8%"/> <col width="16.8%"/> <col width="18.8%"/> <tbody> <tr ID="id_da9c11e8-28a3-40c9-8583-afe841e06b69"> <td align="center" valign="top" rowspan="2" styleCode="Botrule Toprule Rrule Lrule"> <content styleCode="bold">ADVERSE EVENT</content> </td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule"> <content styleCode="bold">MOEXIPRIL HYDROCHLORIDE/HYDROCHLOROTHIAZIDE (N = 506)</content> </td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule"> <content styleCode="bold">PLACEBO (N = 202)</content> </td> </tr> <tr ID="id_25854d31-6f9b-4802-b7ba-7e299669171e"> <td align="center" valign="top" styleCode="Lrule Botrule Rrule"> <content styleCode="bold">N </content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">(%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">N </content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">(%)</content> </td> </tr> <tr ID="id_9da6edfd-c71a-4c79-9baa-d0971f95b5b5"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Cough </td> <td align="center" valign="top" styleCode="Botrule Rrule"> 15 </td> <td align="center" valign="top" styleCode="Botrule Rrule"> (3) </td> <td align="center" valign="top" styleCode="Botrule Rrule"> 2 </td> <td align="center" valign="top" styleCode="Botrule Rrule"> (1) </td> </tr> <tr ID="id_4a749663-2385-4e79-bfdc-fec844621ec8"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Dizziness </td> <td align="center" valign="top" styleCode="Botrule Rrule"> 7 </td> <td align="center" valign="top" styleCode="Botrule Rrule"> (1.4) </td> <td align="center" valign="top" styleCode="Botrule Rrule"> 2 </td> <td align="center" valign="top" styleCode="Botrule Rrule"> (1) </td> </tr> <tr ID="id_0ae35eee-ae0d-4758-ba46-8849303e0b9e"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Fatigue </td> <td align="center" valign="top" styleCode="Rrule"> 5 </td> <td align="center" valign="top" styleCode="Rrule"> (1) </td> <td align="center" valign="top" styleCode="Rrule"> 1 </td> <td align="center" valign="top" styleCode="Botrule Rrule"> (0.5) </td> </tr> </tbody> </table>