FDA label cb4b703e-e2ae-481e-afe5-1be759c5a8f1

WARNING: FETAL TOXICITY • When pregnancy is detected, discontinue moexipril hydrochloride and hydrochlorothiazideas soon as possible. • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. See WARNINGS: Fetal Toxicity

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 and 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 and 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 and hydrochlorothiazide can cause symptomatic hypotension, although, as with other ACE inhibitors, this is unusual in uncomplicated hypertensive patients treated with moexipril hydrochloride and 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 and hydrochlorothiazide (see ADVERSE REACTIONS ). The thiazide component of moexipril hydrochloride and hydrochlorothiazide 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 and 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 and 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 and hydrochlorothiazide treatment usually can be continued following restoration of blood pressure and volume. Impaired Renal Function Moexipril hydrochloride and 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 and 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 and 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 Toxicity 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 events include skull hypoplasia, anuria, hypotension, renal failure and death. When pregnancy is detected, discontinue moexipril hydrochloride and hydrochlorothiazide 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 moexipril hydrochloride and hydrochlorothiazide, 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 moexipril hydrochloride and hydrochlorothiazidefor hypotension, oliguria, and hyperkalemia (see PRECAUTIONS, Pediatric Use ). 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 and 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 and 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. Acute Myopia and Secondary Angle-Closure Glaucoma Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

ADVERSE REACTIONS Moexipril hydrochloride and 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 and 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 and 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 and hydrochlorothiazide and in 8.4% of patients treated with placebo. The most common reasons for discontinuation of therapy with moexipril hydrochloride and 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 and hydrochlorothiazide and that were at least as frequent in the moexipril hydrochloride and hydrochlorothiazide group as in the placebo group are shown in the following table. Adverse Events in Placebo-Controlled Trials ADVERSE EVENT MOEXIPRIL HYDROCHLORIDE AND HYDROCHLOROTHIAZIDE (N=506) N (%) PLACEBO (N=202) 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 and 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 and 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, leukorrhea. 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 and 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 and 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 and hydrochlorothiazide administration.

<table ID="_RefIDD51E0664189543D992D4922A52B0F646" width="100%"> <caption>Adverse Events in Placebo-Controlled Trials </caption> <col width="26%"/> <col width="53%"/> <col width="21%"/> <tbody> <tr> <td styleCode="Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">ADVERSE EVENT</content> </paragraph> </td> <td styleCode="Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">MOEXIPRIL HYDROCHLORIDE AND HYDROCHLOROTHIAZIDE </content> </paragraph> <paragraph> <content styleCode="bold">(N=506)</content> </paragraph> <paragraph> <content styleCode="bold"> N (%)</content> </paragraph> </td> <td styleCode="Toprule " valign="top"> <paragraph> <content styleCode="bold">PLACEBO </content> </paragraph> <paragraph> <content styleCode="bold">(N=202) </content> </paragraph> <paragraph> <content styleCode="bold">N (%</content>)</paragraph> </td> </tr> <tr> <td styleCode="Lrule " valign="top"> <paragraph>Cough</paragraph> </td> <td styleCode="Lrule " valign="top"> <paragraph>15 (3)</paragraph> </td> <td valign="top"> <paragraph>2 (1)</paragraph> </td> </tr> <tr> <td styleCode="Lrule " valign="top"> <paragraph>Dizziness</paragraph> </td> <td styleCode="Lrule " valign="top"> <paragraph>7 (1.4)</paragraph> </td> <td valign="top"> <paragraph>2 (1)</paragraph> </td> </tr> <tr> <td styleCode="Botrule Lrule " valign="top"> <paragraph>Fatigue</paragraph> </td> <td styleCode="Botrule Lrule " valign="top"> <paragraph>5 (1)</paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>1 (0.5)</paragraph> </td> </tr> </tbody> </table>