Moexipril hydrochloride and hydrochlorothiazide

for 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 tablets 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 tablets 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.

PRECAUTIONS

General

Serum Electrolyte Imbalances: In clinical trials with moexipril monotherapy, persistent hyperkalemia (serum potassium above 5.4 mEq/L) occurred in approximately 1.3% of hypertensive patients receiving moexipril. 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.

Treatment with thiazide diuretics has been associated with hypokalemia, hyponatremia, and hypochloremic alkalosis. These disturbances sometimes manifest as one or more of the following: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, nausea, and vomiting. Hypokalemia has also been reported to sensitize or exaggerate the response of the heart to the toxic effects of digitalis. The risk of hypokalemia is greatest in patients with cirrhosis of the liver, in patients experiencing a brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes, and in patients receiving concomitant therapy with corticosteroids or ACTH.

The opposite effects of moexipril and hydrochlorothiazide on serum potassium will approximately counterbalance each other in many patients, so that little net effect upon serum potassium will be seen. Initial and periodic determinations of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

Chloride deficits generally are mild and require specific treatment only under extraordinary circumstances (e.g., in liver disease or renal disease). Dilutional hyponatremia may occur in edematous patients; appropriate therapy is water restriction rather than administration of salt, except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.

Calcium excretion is reduced by thiazides. In a few patients on prolonged thiazide therapy, pathological changes in the parathyroid gland have been seen, with hypercalcemia and hypophosphatemia. More serious complications of hyperparathyroidism (renal lithiasis, bone resorption, and peptic ulceration) have not been seen.Thiazides enhance urinary excretion of magnesium and hypomagnesemia may result.

Other Metabolic Disturbances: Thiazide diuretics may reduce glucose tolerance and may raise serum levels of cholesterol, triglycerides, and uric acid. These effects are usually minor, but frank gout or overt diabetes may be precipitated in susceptible patients.

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 placebo-controlled trials with moexipril hydrochloride and hydrochlorothiazide tablets, cough was present in 3% of moexipril hydrochloride and hydrochlorothiazide tablets patients and 1% of patients given placebo.

Information for Patients

Food: Patients should be advised to take moexipril hydrochloride and hydrochlorothiazide tablets one hour before a meal (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 drug until they have consulted with the prescribing physician.

Symptomatic Hypotension: Patients should be cautioned that lightheadedness can occur with moexipril hydrochloride and hydrochlorothiazide tablets, especially during the first few days of therapy. If fainting occurs, the patient should stop taking moexipril hydrochloride and hydrochlorothiazide tablets 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 moexipril hydrochloride and hydrochlorothiazide tablets 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.

Drug Interactions

Potassium Supplements and Potassium-Sparing Diuretics: As noted above (Serum Electrolyte Imbalances), the net effect of moexipril hydrochloride and hydrochlorothiazide tablets may be to elevate a patient's serum potassium, to reduce it, or to leave it unchanged. Potassium-sparing diuretics (spironolactone, amiloride, triamterene) or potassium supplements can increase the risk of hyperkalemia. 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 of moexipril monotherapy 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. Because renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity is presumably raised further when, as in therapy with moexipril hydrochloride and hydrochlorothiazide tablets, a thiazide diuretic is coadministered with the ACE inhibitor. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended.

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 moexipril hydrochloride and hydrochlorothiazide tablets.

Alcohol, Barbiturates, or Narcotics: Potentiation of orthostatic hypotension may occur in patients on thiazide diuretic therapy with concomitant use of alcohol, barbiturates, or narcotics.

Antidiabetic Agents: Use of thiazide diuretics concomitantly with antidiabetic agents (oral agents and insulin) may require dosage adjustment of the antidiabetic agent. Moexipril has been used in clinical trials concomitantly with oral hypoglycemic agents and there was no evidence of any clinically important adverse interactions.

Cholestyramine and Colestipol Resins: Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.

Corticosteroids, ACTH: Use of thiazide diuretics concomitantly with corticosteroids or ACTH may intensify electrolyte depletion, particularly hypokalemia.

Pressor Amines: Thiazide diuretics may decrease arterial responsiveness to pressor amines (e.g. norepinephrine), but not enough to preclude effectiveness of the pressor agent for therapeutic use.

Skeletal Muscle Relaxants, Nondepolarizing: Thiazide diuretics may increase the responsiveness to tubocurarine. 

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 and hydrochlorothiazide, as well as the diuretic and natriuretic effects of hydrochlorothiazide, may be attenuated by NSAIDS.

Dual Blockade of the Renin-Angiotensin System (RAS): Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on moexipril hydrochloride and hydrochlorothiazide tablets and other agents that affect the RAS.

Do not co-administer aliskiren with moexipril hydrochloride and hydrochlorothiazide tablets in patients with diabetes. Avoid use of aliskiren with moexipril hydrochloride and hydrochlorothiazide tablets in patients with renal impairment (GFR <60 mL/min).

Other Agents: No clinically important pharmacokinetic interactions occurred when moexipril was administered concomitantly with digoxin or cimetidine.

Moexipril has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H₂ blockers, digoxin, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. In general, ACE inhibitors have less than additive effects with beta-adrenergic blockers, presumably because both work by inhibiting the renin-angiotensin system.

Coadministration of propantheline or guanabenz increased the absorption of hydrochlorothiazide.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Moexipril Hydrochloride

No evidence of carcinogenicity was detected in long-term studies when moexipril was administered to 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 (CHO) 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.

Hydrochlorothiazide

Under the auspices of the National Toxicology Program, rats and mice received hydrochlorothiazide in their feed for two years, at doses up to 600 mg/kg/day in mice and up to 100 mg/kg/day in rats. These studies uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in rats or female mice, but there was equivocal evidence of hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (the Ames test); in the CHO test for chromosomal aberrations; or in in vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes; and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) test and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide of 43-1300 mcg/mL. Positive test results were also obtained in the Aspergillus nidulans nondisjunction assay, using an unspecified concentration of hydrochlorothiazide.

Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diets, to doses up to 100 and 4 mg/kg/day, respectively, prior to mating and throughout gestation.

Nursing Mothers

It is not known whether moexipril or moexiprilat is excreted in human milk. Thiazides are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from hydrochlorothiazide and the unknown effects of moexipril or moexiprilat in infants, a decision should be made whether to discontinue nursing or to discontinue moexipril hydrochloride and hydrochlorothiazide tablets, taking into account the importance of the drug to the mother.

Pediatric Use

Neonates with a history of in utero exposure to moexipril hydrochloride and hydrochlorothiazide tablets : 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 moexipril hydrochloride and hydrochlorothiazide tablets in pediatric patients have not been established.

Geriatric Use

Of the patients who received moexipril hydrochloride and hydrochlorothiazide tablets in controlled clinical studies, 24% were 65 years of age or older. No overall differences in effectiveness or safety were observed between these patients and younger patients. In elderly patients receiving moexipril, plasma levels of drug are slightly higher and renal clearance is reduced when compared to younger patients, but these effects did not have detectable consequences. Hydrochlorothiazide is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

MOEXIPRIL HYDROCHLORIDE AND HYDROCHLOROTHIAZIDE ADVERSE REACTIONS

Moexipril hydrochloride and hydrochlorothiazide tablets have 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 tablets have 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 tablets 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 tablets and in 8.4% of patients treated with placebo.

The most common reasons for discontinuation of therapy with moexipril hydrochloride and hydrochlorothiazide tablets 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 tablets and that were at least as frequent in the moexipril hydrochloride and hydrochlorothiazide tablets group as in the placebo group are shown in the following table.

Adverse Events in Placebo-Controlled Trials

Other adverse experiences occurring in more than 1% of patients treated with moexipril hydrochloride and hydrochlorothiazide tablets are 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 tablets 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, and 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 tablets 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 tablets. 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 tablets administration.

OVERDOSAGE

No specific information is available on the treatment of overdosage with moexipril hydrochloride and hydrochlorothiazide tablets. Treatment should be symptomatic and supportive. Therapy with moexipril hydrochloride and hydrochlorothiazide tablets 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 LD50 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 LD50 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.

MOEXIPRIL HYDROCHLORIDE AND HYDROCHLOROTHIAZIDE 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 WARNINGS) 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 Moexipril hydrochloride and hydrochlorothiazide tablets 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.

Dose Titration Guided by Clinical Effect: A patient whose blood pressure is not adequately controlled with either moexipril or hydrochlorothiazide monotherapy may be given Moexipril hydrochloride and hydrochlorothiazide tablets 7.5 mg / 12.5 mg, Moexipril hydrochloride and hydrochlorothiazide tablets 15 mg / 12.5 mg or Moexipril hydrochloride and hydrochlorothiazide tablets 15 mg / 25 mg one hour before a meal. Further increases of moexipril, hydrochlorothiazide or both depend on clinical response. The hydrochlorothiazide dose should generally not be increased until 2-3 weeks have elapsed.

Total daily doses above 30 mg / 50 mg a day have not been studied in hypertensive patients. Patients whose blood pressures are adequately controlled with 25 mg of hydrochlorothiazide daily, but who experience significant potassium loss with this regimen, may achieve blood pressure control without electrolyte disturbance if they are switched to moexipril3.75 mg / hydrochlorothiazide 6.25 mg (one-half of the moexipril hydrochloride and hydrochlorothiazide tablets^{7.5 mg / 12.5 mg tablet). For patients who experience an excessive reduction in blood pressure with moexipril hydrochloride and hydrochlorothiazide tablets 7.5 mg / 12.5 mg, the physician may consider prescribing moexipril 3.75 mg/hydrochlorothiazide 6.25 mg.}

Replacement Therapy: The combination may be substituted for the titrated individual active ingredients.

Use in Renal Impairment: The usual dosage regimen of moexipril hydrochloride and hydrochlorothiazide tablets does not need to be adjusted as long as the patient's creatinine clearance is > 40 mL/min/1.73 m² (serum creatinine approximately ≤ 3 mg/dL or 265 μmol/L). In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so moexipril hydrochloride and hydrochlorothiazide tablets is not recommended (see PRECAUTIONS, General).

HOW SUPPLIED

Moexipril hydrochloride and hydrochlorothiazide tablets 7.5 mg / 12.5 mg are Orange colored, oval shaped, biconvex, film coated tablets scored on one side and debossed with ‘H 35’ on other side.

They are supplied as follows:

Bottles of 100                      NDC 23155-035-01

Bottles of 500                      NDC 23155-035-05

Moexipril hydrochloride/hydrochlorothiazide tablets 15 mg / 12.5 mg are white to off-white colored, oval shaped, biconvex, film coated tablets scored on one side and debossed with ‘H 36’ on other side.

They are supplied as follows:

Bottles of 100                      NDC 23155-036-01

Bottles of 500                      NDC 23155-036-05

Moexipril hydrochloride/hydrochlorothiazide tablets 15 mg / 25 mg are Orange colored, oval shaped, biconvex, film coated tablets scored on one side and debossed with ‘H 37’ on other side.

They are supplied as follows:

Bottles of 100                      NDC 23155-037-01

Bottles of 500                      NDC 23155-037-05

Store, tightly closed, at controlled room temperature 20° -25°C (68° -77°F). Protect from excessive moisture.

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

Manufactured for:

Heritage Pharmaceuticals Inc.

Eatontown, NJ07724

1.866.901. DRUG (3784)

Rev. 03/2014

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC 23155-035-01

Rx only

Moexipril Hydrochloride & Hydrochlorothiazide Tablets

7.5 mg/12.5 mg

100 Tablets

NDC 23155-036-01

Rx only

Moexipril Hydrochloride & Hydrochlorothiazide Tablets

15 mg/12.5 mg

100 Tablets

NDC 23155-037-01

Rx only

Moexipril Hydrochloride & Hydrochlorothiazide Tablets

15 mg/25 mg

100 Tablets