NANXIN SHUANGSAIPULI Benazepril Hydrochloride And HydrochlorothiazideTablets For Hypertension 10/12.5mg*14

[Drug Name]
Generic Name: Benazepril/Hydrochlorothiazide Tablets
Trade Name: Bisaprol/Benazepril/Hydrochlorothiazide Tablets 10/12.5mg x 14 Tablets

[Main Ingredients]
This product is a combination preparation containing: 10mg of benazepril hydrochloride and 12.5mg of hydrochlorothiazide per tablet.

[Appearance]
This product is a dark brown film-coated tablet that appears white or off-white after removal of the coating.

[Indications/Main Functions]
Hypertension. This fixed combination preparation is not indicated for the initial treatment of hypertension (see Dosage and Administration for details). This product is indicated for patients who have not achieved satisfactory results with monotherapy. It can also be used as an alternative treatment when two monotherapy agents are used at corresponding doses.

[Specifications]
10/12.5mg x 14 tablets

[Dosage and Administration]
The recommended dose for the treatment of hypertension is 10/12.5mg once daily. For patients whose blood pressure is not adequately controlled with angiotensin-converting enzyme inhibitors (such as benazepril hydrochloride) alone, switching to this medication once daily can achieve a greater reduction in blood pressure. For patients whose blood pressure is inadequately reduced with hydrochlorothiazide or other thiazide diuretics, switching to this medication can achieve a greater reduction in blood pressure. Patients receiving hydrochlorothiazide 25 mg (or 50 mg) once daily should discontinue diuretics for at least 3 days before starting this medication. The dose should be adjusted as needed afterward. This medication can replace combination therapy with benazepril hydrochloride and hydrochlorothiazide. No dose adjustment is required for patients with creatinine clearance >30 ml/min. For patients with severe renal failure (creatinine clearance <30 ml/min) who require diuretics, benazepril and a diuretic should be used instead of a thiazide diuretic. Therefore, this medication is not recommended for patients with severe renal impairment. Food effects: See "Pharmacokinetics."

[Adverse Reactions]
Adverse reactions reported with this product are similar to those reported with benazepril or hydrochlorothiazide; these reactions are generally mild and transient. Cardiovascular System: Common: Palpitations, orthostatic hypotension. Rare: Symptomatic hypotension, chest pain. Gastrointestinal System: Common: Nonspecific gastrointestinal disturbances. Rare: Diarrhea, constipation, nausea, vomiting, abdominal pain. Skin: Common: Rash, redness, itching, and photosensitivity. Genitourinary System: Common: Frequent urination. Rare: Hypokalemia, increased blood urea nitrogen (BUN), and serum creatinine (recoverable upon discontinuation of the drug). These changes occur more frequently in patients with renal artery stenosis (see "Precautions"). Rare: Hyponatremia. Metabolic Effects: Rare: Increased blood uric acid levels. Respiratory System: Common: Cough, respiratory symptoms. Central Nervous System: Common: Headache, dizziness, fatigue. Rare: Drowsiness, insomnia, nervousness, vertigo, anxiety, and paresthesia. Sense Organs: Rare: Tinnitus and dysgeusia. Allergic and Immune Reactions: Rare: Angioedema, facial and lip edema (see "Precautions: Allergic-like and Related Reactions"). Musculoskeletal System: Rare: Arthralgia, arthritis, myalgia, musculoskeletal pain. Laboratory Studies: Mild increases in blood urea nitrogen (BUN) and serum creatinine have been observed in patients taking 20/25 mg or higher of Benazepril, which resolve upon discontinuation of the drug (see "Precautions"). Mild decreases in serum potassium have been observed in some studies, with only 0.2% of patients taking Benazepril experiencing hypokalemia (a decrease of more than 0.5 mmol/L below normal). The following adverse reactions have also been reported in patients taking Benazepril: hyponatremia, increased serum uric acid, and decreased hemoglobin. Due to additional postmarketing experience with benazepril monotherapy and/or other ACE inhibitors, the following adverse reactions have been added: Rare: angina pectoris, arrhythmia, hepatitis (primarily cholestatic), cholestatic jaundice (see "Precautions: Liver Failure"), and pemphigus. Rare: Myocardial infarction, pancreatitis, renal impairment, thrombocytopenia (see "Precautions: Agranulocytosis/Neutropenia"). Stevens-Johnson syndrome: Hemolytic anemia. Hydrochlorothiazide has been used clinically for many years, sometimes at doses exceeding those in this product. The following are adverse reactions to monotherapy with thiazide diuretics, including hydrochlorothiazide: Electrolyte and metabolic disturbances: See "Precautions." Other: Common: Urticaria and other forms of rash, anorexia, mild nausea and vomiting, orthostatic hypotension (which may be exacerbated by alcohol, anesthetics, or sedatives), and impotence. Uncommon: Photosensitivity, abdominal pain, constipation, diarrhea, and gastrointestinal discomfort, intrahepatic cholestasis or jaundice, cardiac arrhythmia, headache, dizziness, or mild headache, sleep disturbances, depression, paresthesia, visual disturbances, especially during the first few weeks of treatment, and thrombocytopenia, sometimes accompanied by purpura. Rare: Necrotizing vasculitis, toxic epidermal necrolysis, cutaneous lupus erythematosus-like reaction, cutaneous lupus erythematosus reactivation, pancreatitis, leukopenia, agranulocytosis, bone marrow suppression, hemolytic anemia, hypersensitivity reactions, dyspnea, including pneumonia and pulmonary edema.

[Contraindications]
Known hypersensitivity to benazepril, hydrochlorothiazide, or any of the excipients in this product. Known hypersensitivity to other ACE inhibitors or other sulfonamides. History of angioedema during previous ACE inhibitor therapy. Anuria, severe renal failure (creatinine clearance <30 ml/min), and hepatic failure. Refractory hypokalemia, hyponatremia, and symptomatic hyperuricemia. Pregnancy (see "Use in Pregnant and Lactating Women").

[Drug Interactions]
Concomitant use of potassium-sparing diuretics such as spironolactone, triamterene, and amiloride, potassium supplements, or potassium-containing salts is not recommended because combined use may increase the risk of hyperkalemia. If combined use is necessary, serum potassium concentrations should be closely monitored. Use of ACE inhibitors during lithium therapy may result in increased serum lithium levels and symptoms of lithium toxicity. Because thiazolinones can reduce renal clearance of lithium, the risk of lithium toxicity may be increased when thiazolinone diuretics are used concomitantly with ACE inhibitors, such as this product. This product should be used with caution when used concomitantly with lithium, and serum lithium concentrations should be monitored regularly. Thiazines may potentiate the effects of curare derivatives and other antihypertensive medications such as guanethidine, methyldopa, beta-blockers, vasodilators, calcium channel blockers, and ACE inhibitors. Corticosteroids, ACTH, amphotericin, and carbenoxolone may potentiate the hypokalemic effect of diuretics (see "Precautions"). Sialazine diuretics may cause adverse reactions such as hypokalemia or hypomagnesemia and may precipitate digitalis-induced arrhythmias (see "Precautions"). Adjustment of insulin and oral hypoglycemic medication doses has been shown to be necessary. Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce the diuretic and antihypertensive effects of sialazine diuretics. Coadministration of indomethacin with ACE inhibitors may sometimes reduce their antihypertensive effects. However, in a controlled clinical trial, benazepril was not found to be affected by indomethacin. The presence of anion exchange resins can reduce the absorption of hydrochlorothiazide. A single dose of cholestyramine or colestipol resin binds to hydrochlorothiazide and is absorbed from the gastrointestinal tract by 85% and 43%, respectively. Concomitant use of purines also increases hypersensitivity to allopurinol, enhances the adverse effects of amantadine, increases the hypercalcemic effect of diazoxide, and reduces renal excretion of cytotoxic drugs such as cyclophosphamide and mefenamic acid, thereby increasing their bone suppression effects. Anticholinergic drugs such as atropine and bilamphenicol increase the bioavailability of purine diuretics because they increase gastrointestinal motility and delay gastrointestinal emptying. Concomitant use of purine diuretics with vitamin D or calcium salts may lead to elevated serum calcium. Concomitant use of cyclosporine may increase the risk of hyperuricemia and gout-like complications. Hemolytic anemia has been reported with the combined use of hydrochloric acid and methyldopa.

[Precautions]
Anaphylactic and Related Reactions: Because ACE inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors, including benazepril, may experience a variety of adverse reactions, some of which may be severe. Angioedema: Angioedema of the face, lips, tongue, glottis, and larynx has been reported in patients receiving ACE inhibitors, including benazepril. If angioedema occurs, discontinue use of this product immediately and institute appropriate treatment and monitoring until signs and symptoms resolve. If swelling is limited to the face and lips, symptoms usually resolve without treatment or with antihistamines. Laryngeal angioedema can be fatal. Involvement of the tongue, glottis, or larynx requires immediate and appropriate treatment, such as subcutaneous epinephrine 1:1000 (3-0.5 mL) and measures to ensure airway patency. Angioedema occurs more frequently in African Americans receiving ACE inhibitors compared with people of other skin colors. Anaphylactoid reactions during desensitization: Two patients receiving ACE inhibitors experienced life-threatening anaphylactoid reactions during desensitization to hymenoptera wasp venom; these reactions were avoided by temporarily discontinuing the ACE inhibitor. Anaphylactoid reactions to dialysis membranes: Patients receiving ACE inhibitors have experienced anaphylactoid reactions during dialysis with high-flow dialysis membranes. These reactions have also been observed in patients undergoing LDL-depletion using dextran sulfate adsorbents. Symptomatic hypotension: As with other ACE inhibitors, symptomatic hypotension is uncommon, particularly in patients with salt or fluid depletion due to long-term diuretic therapy, a low-salt diet, dialysis, diarrhea, or leaf vomiting. Salt and/or fluid depletion must be treated before initiating treatment with this medication. Caution is advised when using this medication in combination with other antihypertensive medications. The thiazide diuretic contained in this medication may potentiate the effects of other antihypertensive medications. If hypotension occurs, place the patient in the supine position and administer saline as needed. Once blood pressure and fluid levels return to normal, treatment with this medication can be resumed. However, in patients with severe congestive heart failure, treatment with ACE inhibitors may result in hypertensive episodes. (Intravenous infusion of water may be accompanied by oliguria and/or progressive azotemia, and rarely, acute renal failure.) For such patients, strict medical supervision is necessary at the start of treatment and then during the first two weeks of treatment and whenever the dose of benazepril or diuretics is increased. Renal Impairment: This medication should be used with caution in patients with renal impairment. In such patients, thiazides may cause hydrogenemia, and repeated doses may result in cumulative effects. When the renin-angiotensin-aldosterone system is inhibited by benazepril, changes in renal function may occur in sensitive patients. In patients with severe congestive heart failure, whose renal function depends on the activity of the renin-angiotensin-aldosterone system, the use of ACE inhibitors, including benazepril, can lead to oliguria and/or progressive azotemia, which can lead to acute renal failure. In a small trial of hypertensive patients with bilateral or unilateral renal artery stenosis, benazepril treatment resulted in elevated blood pressure that was reversed after discontinuation of benazepril, diuretic therapy, or both. For these patients, renal function should be monitored during the first few weeks of treatment with benazepril. Some hypertensive patients without significant renal vascular disease may experience increases in blood urea nitrogen (usually mild and transient) and serum creatinine when treated with benazepril, particularly when used in combination with diuretics. In such cases, a dose reduction of Cibadrex may be necessary. Evaluation of hypertensive patients should always include monitoring of renal function (see "Contraindications" and "Dosage and Administration"). Use in Patients with Renal Impairment and Elderly Patients: Clinical trials found no differences in efficacy or safety between elderly and younger patients receiving Cibadrex. In patients with creatinine clearance >30 m/min (serum creatinine approximately <3 mg/dL or <60 ml/min), the dose of Cibadrex is routinely titrated according to clinical response. Caution should be exercised in elderly patients and/or those with mild renal impairment (creatinine clearance <3 mg/dL or <60 ml/min). For patients with severe renal impairment requiring diuretic therapy, the dose should be determined with caution (see "Pharmacokinetics"). For patients with a 30 m/mn, it is best to give benazepril in combination with a thiazide diuretic. Therefore, this product is contraindicated in patients with severe renal impairment (see "Precautions").

[Agranulocytosis]
Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow suppression, side effects that are more common in patients with renal impairment, particularly those who also have collagen-vascular diseases such as systemic lupus erythematosus or scleroderma. Clinical trial data are insufficient to evaluate whether benazepril has a similar incidence of agranulocytosis. White blood cell counts must be monitored in patients with collagen-vascular diseases, particularly those with concomitant renal impairment. Hepatitis and liver failure: Cholestatic hepatitis and acute liver failure, sometimes fatal, have been rarely reported in patients receiving ACE inhibitors. The mechanism is unclear. Patients receiving ACE inhibitors may experience jaundice or significant If liver enzymes are elevated, dosing must be discontinued and medical monitoring is required. Hepatic Impairment: This product should be used with caution in patients with hepatic impairment or progressive liver disease, as even minor changes in fluid and electrolyte balance may precipitate hepatic coma (see "Hepatitis and Liver Failure" above). Thiazide diuretics have been reported to exacerbate or activate systemic lupus erythematosus. Serum Electrolyte Alterations: In patients with systemic lupus erythematosus receiving ACE inhibitors, including benazepril, serum potassium levels may be uncommon.Thiazide diuretics are associated with hypokalemia, hyponatremia, and hypochloremic alkalosis. These electrolyte disturbances can sometimes cause one or more of the following symptoms:Dry mouth, thirst, weakness, drowsiness, restlessness, muscle pain or cramps, muscle fatigue, hypotension, oliguria, tachycardia, and nausea. Hypokalemia increases the risk and severity of digitalis cardiotoxicity. This is particularly true in patients with cirrhosis, rapid diuretics, or oral electrolyte intake. The risk of hypokalemia is highest in patients with inadequate blood intake and those receiving concomitant corticosteroid or ACTH therapy. Serum electrolytes must be measured at the start of treatment and periodically thereafter to detect any imbalances. Patients receiving ACE inhibitors and thiazide diuretics, including this product, should avoid potassium supplements or potassium-sparing diuretics unless deemed necessary (see "Drug Interactions"). Thiazides reduce calcium excretion. Parathyroid pathology accompanied by hypercalcemia and hypophosphatemia has been reported in a few patients treated with long-term thiazide diuretics. If hypercalcemia occurs, further diagnostic work is required. Common complications associated with hyperparathyroidism, such as nephrolithiasis, bone resorption, and peptic ulcers, have not been reported. Thiazide diuretics increase urinary excretion and may cause hypomagnesemia. Other metabolic disturbances: At high doses, thiazide diuretics may cause urinary incontinence and may lead to hypomagnesemia. Urinary abnormalities may impair glucose tolerance and increase serum cholesterol, triglyceride, and uric acid levels. Cough: Persistent, dry cough has been reported in patients receiving ACE inhibitors, presumably due to inhibition of endogenous bradykinin degradation. Symptoms generally resolve after discontinuation of treatment. ACE inhibitor-induced cough must be considered in the differential diagnosis of cough. Surgery/Anesthesia: Before surgery, the anesthesiologist must be informed that the patient is receiving ACE inhibitor therapy. During anesthesia with medications that cause hypotension, ACE inhibitors may block the compensatory renin release that leads to angiotensin I formation. Decreased blood pressure during general anesthesia due to this mechanism can be corrected by volume expansion. Aortic and Mitral Stenosis: As with other vasodilatory medications, caution must be exercised when used in patients with aortic or mitral stenosis. Effects on Athletes: This product contains acetaminophen. Diuretics such as thiazides and thiazolidinedrines can affect the metabolism and excretion of stimulants, potentially reducing the sensitivity of urine tests for stimulants. Therefore, athletes should use them with caution. Effects on driving and operating machinery: As with other antihypertensive drugs, caution is advised when driving and operating machinery.

[Pediatric Use]
No studies have been conducted on the efficacy and safety of this drug in children.

[Elderly Use]
For elderly patients, monitoring of anhydride clearance between 30 and 60 m/min is necessary. See "Precautions" for details.

[Overdose]
Signs and Symptoms: No specific treatment information is available for overdose with this drug.
The following signs and symptoms may occur in cases of toxicity caused by hydrochlorothiazide overdose: dizziness, nausea, lethargy, hypovolemia, hypotension, and electrolyte imbalances, accompanied by cardiac arrhythmias and muscle cramps. There is no experience with benazepril overdose; the primary symptom of overdose may be significant hypotension. Overdose treatment: hydrochlorothiazide or benazepril There is no specific antidote for either drug; treatment is symptomatic and supportive. If an overdose has just occurred, induce vomiting or gastric lavage to clear the system of the drug. Activated charcoal can be administered to reduce drug absorption. Elevate the patient's lower extremities and replace fluids and electrolytes. Monitor the patient's renal function until the condition returns to normal. Although only a small amount of the active metabolite, benazeprilat, can be dialyzed, dialysis is believed to aid drug elimination in overdose patients with severe renal impairment (see "Precautions"). If significant hypotension occurs, appropriate symptomatic treatment should be implemented.

[Pharmacology and Toxicology]
Pharmacodynamic Properties; Therapeutic/Pharmacodynamic Classification: Antihypertensive angiotensin-converting enzyme inhibitor and diuretic. This product, in combination with the angiotensin-converting enzyme inhibitor benazepril and the diuretic dihydropyridine, has a synergistic antihypertensive effect. Benazepril inhibits renin-angiotensin-converting enzyme (ACE) inhibitors. The renin-angiotensin system can be stimulated by hydrochlorothiazine, potentially leading to a synergistic effect between the two drugs in antihypertensive treatment. Hydrochlorothiazine-induced stimulation of the renin-angiotensin system makes blood pressure more dependent on angiotensin levels, thereby enhancing the efficacy of benazepril. Controlled clinical trials have shown that the combined use of benazepril and hydrochlorothiazine has an additive effect on the stimulation of plasma renin activity and the inhibition of aldosterone. Preclinical safety data: No teratogenicity was observed in rabbits at doses up to 10 mg/kg. In rats, no drug-related adverse reactions were observed in pups or offspring after perinatal and postnatal administration. Each component of the drug, benazepril hydrochloride and hydrochlorothiazine, has been tested separately. Benazepril has been shown to be effective at doses up to 150 mg/kg/day in mice and 500 mg/kg/day in rats. No teratogenicity was observed in rabbits at doses up to 5 mg/kg/day. For hydrochlorothiazide, no teratogenicity was observed in rats (up to 100 mg/kg) or mice (up to 300 mg/kg). Mutagenicity: No mutagenic activity was detected in a series of in vitro and in vivo studies. Carcinogenicity: No carcinogenicity studies were conducted for this product. Each active ingredient, benazepril hydrochloride and hydrochlorothiazide, was tested separately. No evidence of tumorigenic activity was found in rats or mice when benazepril was administered at doses up to 150 mg/kg/day (250 times the recommended maximum human daily dose). Hydrochlorothiazide also did not demonstrate carcinogenic activity based on the data obtained from the studies. (In mice, hepatocellular carcinomas were observed only in males treated with the high dose, but the incidence did not exceed historical rates in control groups.)
Other Benazepril and Hydrochlorothiazide Tablet Instructions