CAPTOPRIL AND HYDROCHLOROTHIAZIDE

INDICATIONS & USAGE Captopril and hydrochlorothiazide tablets are indicated for the treatment of hypertension. The blood pressure lowering effects of captopril and thiazides are approximately additive. This fixed combination drug may be used as initial therapy or substituted for previously titrated doses of the individual components. When captopril and hydrochlorothiazide are given together it may not be necessary to administer captopril in divided doses to attain blood pressure control at trough (before the next dose). Also, with such a combination, a daily dose of 15 mg of hydrochlorothiazide may be adequate. Treatment may, therefore, be initiated with captopril and hydrochlorothiazide tablets 25 mg/15 mg once daily. Subsequent titration should be with additional doses of the components (captopril, hydrochlorothiazide) as single agents or as captopril and hydrochlorothiazide tablets 50 mg/15 mg, 25 mg/25 mg, or 50 mg/25 mg (see DOSAGE AND ADMINISTRATION ). In using captopril and hydrochlorothiazide, consideration should be given to the risk of neutropenia/agranulocytosis (see WARNINGS ). Captopril and hydrochlorothiazide may be used for patients with normal renal function, in whom the risk is relatively low. In patients with impaired renal function, particularly those with collagen vascular disease, captopril and hydrochlorothiazide should be reserved for hypertensives who have either developed unacceptable side effects on other drugs, or have failed to respond satisfactorily to other drug combinations. ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients (see WARNINGS: Captopril: Head and Neck Angioedema and Intestinal Angioedema ).

DOSAGE & ADMINISTRATION DOSAGE MUST BE INDIVIDUALIZED ACCORDING TO PATIENT'S RESPONSE. Captopril and hydrochlorothiazide tablets may be substituted for the previously titrated individual components. Alternatively, therapy may be instituted with a single tablet of captopril and hydrochlorothiazide 25 mg/15 mg taken once daily. For patients insufficiently responsive to the initial dose, additional captopril or hydrochlorothiazide may be added as individual components or by using captopril and hydrochlorothiazide tablets 50 mg/15 mg, 25 mg/25 mg or 50 mg/25 mg, or divided doses may be used. Because the full effect of a given dose may not be attained for 6 to 8 weeks, dosage adjustments should generally be made at 6 week intervals, unless the clinical situation demands more rapid adjustment. In general, daily doses of captopril should not exceed 150 mg and of hydrochlorothiazide should not exceed 50 mg. Captopril and hydrochlorothiazide tablets should be taken one hour before meals. Dosage Adjustment in Renal Impairment: Because captopril and hydrochlorothiazide are excreted primarily by the kidneys, excretion rates are reduced in patients with impaired renal function. These patients will take longer to reach steady-state captopril levels and will reach higher steady-state levels for a given daily dose than patients with normal renal function. Therefore, these patients may respond to smaller or less frequent doses of captopril and hydrochlorothiazide. After the desired therapeutic effect has been achieved, the dose intervals should be increased or the total daily dose reduced until the minimal effective dose is achieved. When concomitant diuretic therapy is required in patients with severe renal impairment, a loop diuretic (e.g., furosemide), rather than a thiazide diuretic is preferred for use with captopril; therefore, for patients with severe renal dysfunction the captopril-hydrochlorothiazide combination tablet is not usually recommended. (See WARNINGS: Captopril: Anaphylactoid Reactions During Membrane Exposure and PRECAUTIONS: Hemodialysis ).

CONTRAINDICATIONS Captopril : This product is contraindicated in patients who are hypersensitive to captopril or any other angiotensin-converting enzyme inhibitor (e.g., a patient who has experienced angioedema during therapy with any other ACE inhibitor). Hydrochlorothiazide : Hydrochlorothiazide is contraindicated in anuria. It is also contraindicated in patients who have previously demonstrated hypersensitivity to hydrochlorothiazide or other sulfonamide-derived drugs.

WARNINGS Captopril : Anaphylactoid and Possible Related Reactions : Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including captopril) may be subject to a variety of adverse reactions, some of them serious. Head and Neck Angioedema : Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been seen in patients treated with ACE inhibitors, including captopril. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Emergency therapy, including but not necessarily limited to, subcutaneous administration of a 1:1000 solution of epinephrine should be promptly instituted. Swelling confined to the face, mucous membranes of the mouth, lips and extremities has usually resolved with discontinuation of treatment; some cases required medical therapy. (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS: Captopril .) 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 were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. 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. Neutropenia/Agranulocytosis : Neutropenia (< 1000/mm 3 ) with myeloid hypoplasia has resulted from use of captopril. About half of the neutropenic patients developed systemic or oral cavity infections or other features of the syndrome of agranulocytosis. The risk of neutropenia is dependent on the clinical status of the patient: In clinical trials in patients with hypertension who have normal renal function (serum creatinine less than 1.6 mg/dL and no collagen vascular disease), neutropenia has been seen in one patient out of over 8,600 exposed. In patients with some degree of renal failure (serum creatinine at least 1.6 mg/dL) but no collagen vascular disease, the risk of neutropenia in clinical trials was about 1 per 500, a frequency over 15 times that for uncomplicated hypertension. Daily doses of captopril were relatively high in these patients, particularly in view of their diminished renal function. In foreign marketing experience in patients with renal failure, use of allopurinol concomitantly with captopril has been associated with neutropenia but this association has not appeared in U.S. reports. In patients with collagen vascular diseases (e.g., systemic lupus erythematosus, scleroderma) and impaired renal function, neutropenia occurred in 3.7 percent of patients in clinical trials. While none of the over 750 patients in formal clinical trials of heart failure developed neutropenia, it has occurred during the subsequent clinical experience. About half of the reported cases had serum creatinine ≥ 1.6 mg/dL and more than 75 percent were in patients also receiving procainamide. In heart failure, it appears that the same risk factors for neutropenia are present. The neutropenia has usually been detected within three months after captopril was started. Bone marrow examinations in patients with neutropenia consistently showed myeloid hypoplasia, frequently accompanied by erythroid hypoplasia and decreased numbers of megakaryocytes (e.g., hypoplastic bone marrow and pancytopenia); anemia and thrombocytopenia were sometimes seen. In general, neutrophils returned to normal in about two weeks after captopril was discontinued, and serious infections were limited to clinically complex patients. About 13 percent of the cases of neutropenia have ended fatally, but almost all fatalities were in patients with serious illness, having collagen vascular disease, renal failure, heart failure or immunosuppressant therapy, or a combination of these complicating factors. Evaluation of the hypertensive or heart failure patient should always include assessment of renal function. If captopril is used in patients with impaired renal function, white blood cell and differential counts should be evaluated prior to starting treatment and at approximately two-week intervals for about three months, then periodically. In patients with collagen vascular disease or who are exposed to other drugs known to affect the white cells or immune response, particularly when there is impaired renal function, captopril should be used only after an assessment of benefit and risk, and then with caution. All patients treated with captopril should be told to report any signs of infection (e.g., sore throat, fever). If infection is suspected, white cell counts should be performed without delay. Since discontinuation of captopril and other drugs has generally led to prompt return of the white count to normal, upon confirmation of neutropenia (neutrophil count < 1000/mm 3 ) the physician should withdraw captopril and closely follow the patient’s course. Proteinuria : Total urinary proteins greater than 1 g per day were seen in about 0.7 percent of patients receiving captopril. About 90 percent of affected patients had evidence of prior renal disease or received relatively high doses of captopril (in excess of 150 mg/day), or both. The nephrotic syndrome occurred in about one-fifth of proteinuric patients. In most cases, proteinuria subsided or cleared within six months whether or not captopril was continued. Parameters of renal function, such as BUN and creatinine, were seldom altered in the patients with proteinuria. Hypotension : Excessive hypotension was rarely seen in hypertensive patients but is a possible consequence of captopril use in salt/volume depleted persons (such as those treated vigorously with diuretics), patients with heart failure or those patients undergoing renal dialysis. (See PRECAUTIONS: Drug Interactions .) 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 occurrences were due to the ACE-inhibitor exposure. These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of captopril 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, captopril 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 appear 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 dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. While captopril may be removed from the adult circulation by hemodialysis, there is inadequate data concerning the effectiveness of hemodialysis for removing it from the circulation of neonates or children. Peritoneal dialysis is not effective for removing captopril; there is no information concerning exchange transfusion for removing captopril from the general circulation. When captopril was given to rabbits at doses about 0.8 to 70 times (on a mg/kg basis) the maximum recommended human dose, low incidences of craniofacial malformations were seen. No teratogenic effects of captopril were seen in studies of pregnant rats and hamsters. On a mg/kg basis, the doses used were up to 150 times (in hamsters) and 625 times (in rats) the maximum recommended human dose. 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. Hydrochlorothiazide : Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function. Thiazides 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. Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma. The possibility of exacerbation or activation of systemic lupus erythematosus has been reported. In general, lithium should not be given with diuretics (see PRECAUTIONS: Drug Interactions: Hydrochlorothiazide ).

Drug Interactions: Captopril : Hypotension—Patients On Diuretic Therapy : Patients on diuretics and especially those in whom diuretic therapy was recently instituted, as well as those on severe dietary salt restrictions or dialysis, may occasionally experience a precipitous reduction of blood pressure usually within the first hour after receiving the initial dose of captopril. The possibility of hypotensive effects with captopril can be minimized by either discontinuing the diuretic or increasing the salt intake approximately one week prior to initiation of treatment with captopril or initiating therapy with small doses (6.25 or 12.5 mg). Alternatively, provide medical supervision for at least one hour after the initial dose. If hypotension occurs, the patient should be placed in a supine position and, if necessary, receive an intravenous infusion of normal saline. This transient hypotensive response is not a contraindication to further doses which can be given without difficulty once the blood pressure has increased after volume expansion. Agents Having Vasodilator Activity : Data on the effect of concomitant use of other vasodilators in patients receiving captopril for heart failure are not available; therefore, nitroglycerin or other nitrates (as used for management of angina) or other drugs having vasodilator activity should, if possible, be discontinued before starting captopril. If resumed during captopril therapy, such agents should be administered cautiously, and perhaps at lower dosage. Agents Causing Renin Release : Captopril’s effect will be augmented by antihypertensive agents that cause renin release. For example, diuretics (e.g., thiazides) may activate the renin-angiotensin-aldosterone system. Agents Affecting Sympathetic Activity : The sympathetic nervous system may be especially important in supporting blood pressure in patients receiving captopril alone or with diuretics. Therefore, agents affecting sympathetic activity (e.g., ganglionic blocking agents or adrenergic neuron blocking agents) should be used with caution. Beta-adrenergic blocking drugs add some further antihypertensive effect to captopril, but the overall response is less than additive. Agents Increasing Serum Potassium : Since captopril decreases aldosterone production, elevation of serum potassium may occur. Potassium-sparing diuretics such as spironolactone, triamterene, or amiloride, or potassium supplements, should be given only for documented hypokalemia, and then with caution, since they may lead to a significant increase of serum potassium. Salt substitutes containing potassium should also be used with caution. 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 captopril and hydrochlorothiazide tablets. Inhibitors of Endogenous Prostaglandin Synthesis : It has been reported that indomethacin may reduce the antihypertensive effect of captopril, especially in cases of low renin hypertension. Other non-steroidal anti-inflammatory agents (e.g., aspirin) may also have this effect. Lithium : Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, it may increase the risk of lithium toxicity (see PRECAUTIONS: Drug Interactions: Hydrochlorothiazide: Lithium ). Hydrochlorothiazide : When administered concurrently the following drugs may interact with thiazide diuretics: Alcohol, Barbiturates, or Narcotics : potentiation of orthostatic hypotension may occur. Amphotericin B, Corticosteroids, or Corticotropin (ACTH) : may intensify electrolyte imbalance, particularly hypokalemia. Monitor potassium levels; use potassium replacements if necessary. Anticoagulants (Oral) : dosage adjustments of anticoagulant medication may be necessary since hydrochlorothiazide may decrease their effects. Antigout Medications : dosage adjustments of antigout medication may be necessary since hydrochlorothiazide may raise the level of blood uric acid. Other Antihypertensive Medications (e.g., Ganglionic or Peripheral Adrenergic Blocking Agents) : dosage adjustments may be necessary since hydrochlorothiazide may potentiate their effects. Antidiabetic Drugs (Oral Agents and Insulin): since thiazides may elevate blood glucose levels, dosage adjustments of antidiabetic agents may be necessary. Calcium Salts : Increased serum calcium levels due to decreased excretion may occur. If calcium must be prescribed, monitor serum calcium levels and adjust calcium dosage accordingly. Cardiac Glycosides : enhanced possibility of digitalis toxicity associated with hypokalemia. Monitor potassium levels (see PRECAUTIONS: Drug Interactions: Captopril ). 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 percent, respectively. Diazoxide : enhanced hyperglycemic, hyperuricemic, and antihypertensive effects. Be cognizant of possible interaction; monitor blood glucose and serum uric acid levels. Lithium : diuretic agents reduce the renal clearance of lithium and increase the risk of lithium toxicity. These drugs should be coadministered with caution and frequent monitoring of serum lithium levels is recommended (see PRECAUTIONS: Drug Interactions: Captopril: Lithium ). MAO Inhibitors : dosage adjustments of one or both agents may be necessary since hypotensive effects are enhanced. Nondepolarizing Muscle Relaxants, Preanesthetics and Anesthetics Used in Surgery (e.g., Tubocurarine Chloride and Gallamine Triethiodide) : effects of these agents may be potentiated; dosage adjustments may be required. Monitor and correct any fluid and electrolyte imbalances prior to surgery if feasible. Non-steroidal Anti-inflammatory Agents : in some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effect of loop, potassium-sparing or thiazide diuretics. Therefore, when hydrochlorothiazide and non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. Methenamine : possible decreased effectiveness due to alkalinization of the urine. Pressor Amines (e.g., Norepinephrine) : decreased arterial responsiveness, but not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Use caution in patients taking both medications who undergo surgery. Administer preanesthetic and anesthetic agents in reduced dosage, and if possible, discontinue hydrochlorothiazide therapy one week prior to surgery. Probenecid or Sulfinpyrazone : increased dosage of these agents may be necessary since hydrochlorothiazide may have hyperuricemic effects.

ADVERSE REACTIONS Captopril : Reported incidences are based on clinical trials involving approximately 7000 patients. Renal : About one of 100 patients developed proteinuria (see WARNINGS ). Each of the following has been reported in approximately 1 to 2 of 1000 patients and are of uncertain relationship to drug use: renal insufficiency, renal failure, nephrotic syndrome, polyuria, oliguria, and urinary frequency. Hematologic : Neutropenia/agranulocytosis has occurred (see WARNINGS ). Cases of anemia, thrombocytopenia, and pancytopenia have been reported. Dermatologic : Rash, often with pruritus, and sometimes with fever, arthralgia, and eosinophilia, occurred in about 4 to 7 (depending on renal status and dose) of 100 patients, usually during the first four weeks of therapy. It is usually maculopapular, and rarely urticarial. The rash is usually mild and disappears within a few days of dosage reduction, short-term treatment with an antihistaminic agent, and/or discontinuing therapy; remission may occur even if captopril is continued. Pruritus, without rash, occurs in about 2 of 100 patients. Between 7 and 10 percent of patients with skin rash have shown eosinophilia and/or positive ANA titers. A reversible associated pemphigoid-like lesion, and photosensitivity, have also been reported. Flushing or pallor has been reported in 2 to 5 of 1000 patients. Cardiovascular : Hypotension may occur; see WARNINGS and PRECAUTIONS (Drug Interactions) for discussion of hypotension with captopril therapy. Tachycardia, chest pain, and palpitations have each been observed in approximately 1 of 100 patients. Angina pectoris, myocardial infarction, Raynaud’s syndrome, and congestive heart failure have each occurred in 2 to 3 of 1000 patients. Dysgeusia : Approximately 2 to 4 (depending on renal status and dose) of 100 patients developed a diminution or loss of taste perception. Taste impairment is reversible and usually self-limited (2 to 3 months) even with continued drug administration. Weight loss may be associated with the loss of taste. Angioedema : Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been reported in approximately one in 1000 patients. Angioedema involving the upper airways has caused fatal airway obstruction. (See WARNINGS: Captopril: Head and Neck Angioedema and Intestinal Angioedema and PRECAUTIONS: Information for Patients ). Cough : Cough has been reported in 0.5 to 2% of patients treated with captopril in clinical trials (see PRECAUTIONS: General: Captopril: Cough ). The following have been reported in about 0.5 to 2 percent of patients but did not appear at increased frequency compared to placebo or other treatments used in controlled trials: gastric irritation, abdominal pain, nausea, vomiting, diarrhea, anorexia, constipation, aphthous ulcers, peptic ulcer, dizziness, headache, malaise, fatigue, insomnia, dry mouth, dyspnea, alopecia, paresthesias. Other clinical adverse effects reported since the drug was marketed are listed below by body system. In this setting, an incidence or causal relationship cannot be accurately determined. Body as a Whole : Anaphylactoid reactions (see WARNINGS: Captopril: Anaphylactoid and Possibly Related Reactions and PRECAUTIONS: Hemodialysis ). General : asthenia, gynecomastia. Cardiovascular : cardiac arrest, cerebrovascular accident/insufficiency, rhythm disturbances, orthostatic hypotension, syncope. Dermatologic : bullous pemphigus, erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis. Gastrointestinal : pancreatitis, glossitis, dyspepsia. Hematologic : anemia, including aplastic and hemolytic. Hepatobiliary : jaundice, hepatitis, including rare cases of necrosis, cholestasis. Metabolic : symptomatic hyponatremia. Musculoskeletal : myalgia, myasthenia. Nervous/Psychiatric : ataxia, confusion, depression, nervousness, somnolence. Respiratory : bronchospasm, eosinophilic pneumonitis, rhinitis. Special Senses : blurred vision. Urogenital : impotence. As with other ACE inhibitors, a syndrome has been reported which may include: fever, myalgia, arthralgia, interstitial nephritis, vasculitis, rash or other dermatologic manifestations, eosinophilia and an elevated ESR. Fetal/Neonatal Morbidity and Mortality: See WARNINGS: Captopril: Fetal/Neonatal Morbidity and Mortality . Hydrochlorothiazide : Gastrointestinal System : anorexia, gastric irritation, nausea, vomiting, cramping, diarrhea, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis, and sialadenitis. Central Nervous System : dizziness, vertigo, paresthesias, headache, and xanthopsia. Hematologic : leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, and hemolytic anemia. Cardiovascular : orthostatic hypotension. Hypersensitivity : purpura, photosensitivity, rash, urticaria, necrotizing angiitis (vasculitis; cutaneous vasculitis), fever, respiratory distress including pneumonitis, and anaphylactic reactions. Other : hyperglycemia, glycosuria, hyperuricemia, muscle spasm, weakness, restlessness, and transient blurred vision. Whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or therapy withdrawn. Altered Laboratory Findings: Serum Electrolytes : Hyperkalemia: small increases in serum potassium, especially in patients with renal impairment (see PRECAUTIONS: Captopril ). Hyponatremia : particularly in patients receiving a low sodium diet or concomitant diuretics. BUN/Serum Creatinine : Transient elevations of BUN or serum creatinine especially in volume or salt depleted patients or those with renovascular hypertension may occur. Rapid reduction of longstanding or markedly elevated blood pressure can result in decreases in the glomerular filtration rate and, in turn, lead to increases in BUN or serum creatinine. Hematologic : A positive ANA has been reported. Liver Function Tests : Elevations of liver transaminases, alkaline phosphatase, and serum bilirubin have occurred. Postmarketing Experience : Non-melanoma Skin Cancer : Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. In a study conducted in the Sentinel System, increased risk was predominantly for squamous cell carcinoma (SCC) and in white patients taking large cumulative doses. The increased risk for SCC in the overall population was approximately 1 additional case per 16,000 patients per year, and for white patients taking a cumulative dose of ≥ 50,000 mg the risk increase was approximately 1 additional SCC case for every 6,700 patients per year. To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharma Holdings, Inc. at 1-844- 874-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Pregnancy Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to ACE inhibitors, and they should also be told that these consequences do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible.