HUAHAI BEIYUE Irbesartan Hydrochlorothiazide Tablets For Hypertension 150mg:12.5mg*7

[Drug Name]
Generic Name: Irbesartan and Hydrochlorothiazide Tablets
Trade Name: Beiyue
English Name: Irbesartan and Hydrochlorothiazide Tablets
Chinese Pinyin: Ebeishatan Qinglvsaiqin Pian

[Ingredients]
This product is a combination preparation. Each tablet contains 75 mg of irbesartan and 6.25 mg of hydrochlorothiazide.

[Properties]
This product is a film-coated tablet. After removing the coating, it appears white or off-white.

[Indications]
For the treatment of essential hypertension. This fixed-dose combination is used to treat patients whose blood pressure is not effectively controlled with irbesartan or hydrochlorothiazide alone.

[Dosage and Administration]
Oral. Take two tablets (irbesartan/hydrochlorothiazide: 150 mg/12.5 mg) once daily, on an empty stomach or with a meal. It is indicated for patients whose blood pressure is not effectively controlled with irbesartan or hydrochlorothiazide alone. Patients are recommended to adjust their dose to the individual components (i.e., irbesartan or hydrochlorothiazide). Once-daily doses greater than irbesartan 300 mg/hydrochlorothiazide 25 mg are not recommended. If necessary, this product can be used in combination with other antihypertensive drugs (see [Drug Interactions]).

[Adverse Reactions]
1. Adverse reactions occurring in patients treated with this product were generally mild and transient. 2. In placebo-controlled and combined irbesartan and hydrochlorothiazide clinical trials, the incidence of treatment discontinuation due to any clinical or laboratory abnormality was lower in the irbesartan and hydrochlorothiazide group than in the placebo group. The incidence of adverse reactions was not associated with gender, age, race, or dose. 3. Other clinical events with an incidence of 0.5% to 1% that were possibly, probably, or not known to be treatment-related and were slightly higher in the irbesartan and hydrochlorothiazide group than in the placebo group included: edema, sexual dysfunction, diarrhea, dizziness (postural), flushing, altered libido, tachycardia, and edema of the extremities. The incidence of these events was not statistically different between the irbesartan/hydrochlorothiazide group and the placebo group. 4. In a small number of subjects, patients treated with irbesartan/hydrochlorothiazide experienced changes in laboratory parameters known to be associated with thiazide therapy (increases in blood urea nitrogen, creatinine, and creatinine kinase, and decreases in serum potassium and sodium). These changes are rarely clinically significant. 5. Postmarketing Experience: As with other angiotensin II receptor antagonists, allergic reactions (rash, urticaria, and angioedema) have been rarely reported. During postmarketing surveillance of irbesartan/hydrochlorothiazide, the following adverse reactions have been reported, also rarely: asthenia, diarrhea, dizziness, dyspepsia, headache, hyperkalemia, myalgia, nausea, tachycardia, liver function abnormalities including hepatitis, and isolated cases of renal impairment including renal failure (see [Precautions]). 6. Additional Information on Individual Components: Although observed only in clinical trials, other adverse reactions previously reported for the individual components may be potential adverse reactions of this combination. 7. Irbesartan: With the exception of headache, skeletal muscle injury, and flushing, adverse reactions (regardless of drug-related or not) occurred at the same rate in the irbesartan and placebo groups, with a significantly higher incidence of headache in the placebo group. Skeletal muscle injury of varying causes and types occurred at a significantly higher rate in the irbesartan group than in the control group; the investigators concluded that all reported cases of skeletal muscle injury were unrelated to irbesartan. 8. Flushing occurred in 0.6% of patients in the irbesartan group and none in the placebo group. Flushing was not dose-related and was not associated with other clinical events, and its relationship to irbesartan treatment is unclear. 9. The following other adverse events, regardless of treatment-related or not, were reported in clinical trials with irbesartan monotherapy at an incidence greater than 1% but did not differ significantly from placebo: respiratory tract infection, skeletal muscle pain/myalgia, cough, chest pain, dyspepsia/heartburn, abdominal pain, rash, anxiety/nervousness, and urinary tract infection. 10. No clinically significant changes in laboratory parameters were observed in the controlled clinical trials. Although clinically significant increases in plasma creatinine kinase occurred more frequently in the irbesartan group (1.7% vs. 0.7% in the placebo group), these changes were not considered serious adverse events, did not lead to treatment discontinuation, and were not associated with clinical musculoskeletal events. 11. Hydrochlorothiazide: Adverse events reported with hydrochlorothiazide alone (regardless of drug-related or not) included: decreased appetite, loss of appetite, gastric irritation, diarrhea, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis, sialadenitis, xanthoopia, leukopenia, neutropenia/agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia, bone marrow suppression, photosensitivity reactions, pyrexia, rash, cutaneous lupus erythematosus-like reactions, and cutaneous lupus erythematosus relapse. Rash, urticaria, necrotizing vasculitis (vasculitis, cutaneous vasculitis), allergic reactions, toxic epithelial necrolysis, respiratory distress (including pneumonia and pulmonary edema), hyperglycemia, glycosuria, hyperuricemia, electrolyte imbalances (including hyponatremia and hypokalemia), elevated cholesterol and triglycerides, renal insufficiency, interstitial nephritis, muscle cramps, weakness, restlessness, transient blurred vision, mild headache, orthostatic hypotension, dizziness, paresthesias, arrhythmias, sleep disturbances, and depression.

[Contraindications]
This product is contraindicated in patients with hypersensitivity to this product or its ingredients, or to other sulfonamide derivatives (hydrochlorothiazide is a sulfonamide derivative). For contraindications in pregnant and lactating women, see [Use in Pregnant and Lactating Women]. The following contraindications are associated with hydrochlorothiazide: 1. Severe renal impairment (creatinine clearance 30 ml/min). 2. Refractory hypokalemia and hypercalcemia. 3. Severe liver function damage, biliary cirrhosis and cholestasis.

[Precautions]
1. Hypotension - Volume-depleted patients: This combination is rarely associated with symptomatic hypotension in hypertensive patients without other risk factors for hypotension. Symptomatic hypotension may occur in patients with volume and sodium depletion due to the use of potent diuretics, severe salt restriction in the diet, or diarrhea and vomiting. These conditions should be corrected before treatment with this combination. 2. Renal Artery Stenosis - Renovascular Hypertension: Patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney may be at risk of severe hypotension and renal insufficiency when treated with angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists. Although this condition has not been observed in studies with this product, this effect should be considered during use. 3. Renal Impairment and Kidney Transplantation: When this product is used in patients with impaired renal function, regular monitoring of serum potassium, creatinine, and uric acid is recommended. There is no experience with the use of this product in patients who have recently undergone a renal transplant. Patients with severe renal insufficiency (creatinine clearance 30 ml/min, see [Contraindications]) should not use this product. Thiazide diuretics may cause azotemia in patients with renal impairment. No dosage adjustment is required for patients with renal impairment and a creatinine clearance ≥30 ml/min. However, this combination should be used with caution in patients with mild to moderate renal impairment (creatinine clearance 30 ml/min but 60 ml/min). 4. Hepatic Impairment: Because minor alterations in fluid and electrolyte balance may precipitate hepatic coma in patients with hepatic impairment, thiazide diuretics should be used with caution in such patients. There is no experience with the use of this combination in patients with hepatic impairment. 5. Aortic and Mitral Stenosis, Hypertrophic Obstructive Cardiomyopathy: As with other vasodilators, this product should be used with caution in patients with aortic and mitral stenosis and hypertrophic obstructive cardiomyopathy. 6. Primary Aldosteronism: Patients with primary aldosteronism generally do not respond to antihypertensive drugs that inhibit the renin-angiotensin system, so this product is not recommended for these patients. 7. Metabolic and Endocrine Effects: Thiazide diuretic therapy may impair glucose tolerance. Diabetic patients may require adjustments in insulin and oral hypoglycemic medication doses. Symptoms of occult diabetes may develop during thiazide diuretic therapy. Increased cholesterol and triglyceride levels have been associated with thiazide diuretic therapy. However, at the 12.5 mg dose contained in the compound, this effect is minimal or absent. Hyperuricemia and even gout may occur in some patients receiving thiazide diuretics. 8. Electrolyte Disturbances: As with any patient receiving diuretic therapy, serum electrolytes should be measured regularly. Thiazide diuretics, including hydrochlorothiazide, can cause fluid or electrolyte imbalances (hypokalemia, hyponatremia, and hypochloremic alkalosis). Symptoms of fluid or electrolyte imbalances include dry mouth, thirst, weakness, lethargy, drowsiness, irritability, muscle cramps and pain, muscle fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting. 9. Thiazide diuretics may induce hypokalemia, but coadministration with irbesartan can reduce diuretic-induced hypokalemia. Hypokalemia is most likely to occur in the following patients: patients with cirrhosis, patients with significant diuretic effects, patients with inadequate oral electrolyte intake, and patients taking corticosteroids or ACTH concomitantly. Conversely, irbesartan in this product may induce hyperkalemia, particularly in patients with renal impairment and/or heart failure and diabetes. Appropriate monitoring of serum potassium concentrations is recommended in these patients. Potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes should be used with caution when coadministered with this product (see [Drug Interactions]). 10. There is no evidence that irbesartan will reduce or prevent diuretic-induced hyponatremia. Decreases in blood chloride are usually mild and do not require treatment. 11. Thiazide diuretics may reduce renal calcium excretion, causing intermittent mild elevations in patients without known abnormalities in calcium metabolism. Significant hypercalcemia suggests underlying hyperparathyroidism. Thiazide diuretics should be discontinued when parathyroid function tests are being performed. 12. Thiazide diuretics have been shown to increase magnesium excretion and may cause hypomagnesemia. 13. Antistimulant Testing: The hydrochlorothiazide in this product may cause positive antistimulant testing results. 14. General Precautions: In patients whose vascular tone and renal function are primarily dependent on the activity of the renin-angiotensin-aldosterone system (such as those with severe congestive heart failure or renal disease, including renal artery stenosis), treatment with angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists may cause acute hypotension, azotemia, oliguria, or rarely, acute renal failure. As with any antihypertensive drug, excessive blood pressure reduction in patients with ischemic cardiomyopathy or ischemic cardiovascular disease may lead to myocardial infarction or stroke. 15. Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergies or bronchial asthma, but patients with such a history may be more susceptible. 16. There have been reports of exacerbations or activation of systemic lupus erythematosus in patients taking thiazide diuretics. 17. The combination is not recommended during the first three months of pregnancy. 18. Effects on Driving and Machine Operation: No studies have been conducted on the effects of this product on driving and machine operation. However, based on its pharmacodynamic properties, it is unlikely that this product will affect these abilities. When driving or operating machinery, the potential for dizziness and fatigue during antihypertensive therapy should be considered. 19. Athletes should use with caution.

[Special Population Use]
Precautions for Children:
No safety data are available for patients under 18 years of age. Use with caution in infants with jaundice, as this class of drugs can increase blood bilirubin.

Precautions for Pregnancy and Lactation:
This product is contraindicated during pregnancy and lactation. Pregnancy: See the [Precautions] section. Thiazide diuretics can cross the placental barrier and be present in umbilical cord blood, causing decreased placental perfusion, fetal electrolyte imbalances, and other effects that may occur in adults. There have been reports of neonatal thrombocytopenia and fetal or neonatal jaundice in mothers treated with thiazides. Because this product contains hydrochlorothiazide, its use in the first three months of pregnancy is not recommended. Appropriate alternative treatment should be sought when planning pregnancy. During the fourth to ninth month of pregnancy: Substances that directly act on the renin-angiotensin system can cause fetal and neonatal renal failure, fetal head dysplasia, and fetal death. Therefore, this product is contraindicated during the fourth to ninth month of pregnancy. If pregnancy is diagnosed, discontinue this medication as soon as possible. If treatment has been neglected for a prolonged period, an ultrasound examination of the head and renal function should be performed. Lactation: Due to potential adverse reactions in the infant, this medication is contraindicated during lactation. It is unknown whether irbesartan is excreted in human breast milk; however, irbesartan is excreted in rat milk. Thiazides can be found in human breast milk and may inhibit lactation.

Precautions for Elderly Patients:
Use of this medication in the elderly may cause hypotension, electrolyte imbalances, and renal impairment.

[Drug Interactions]
Other Antihypertensive Drugs: When this product is used concomitantly with other antihypertensive drugs, its antihypertensive effect may be enhanced. Irbesartan and hydrochlorothiazide (at doses up to 300 mg/25 mg) can be safely used concomitantly with other antihypertensive drugs, such as calcium channel blockers and beta-blockers. The use of irbesartan with or without thiazide diuretics may lead to volume depletion in patients who have previously received high-dose diuretics. This administration carries a risk of hypotension unless volume depletion is first corrected (see Precautions). 1. Lithium: There have been reports of reversible increases in serum lithium and toxic effects when lithium is used concomitantly with angiotensin-converting enzyme inhibitors. Furthermore, thiazide diuretics can reduce renal lithium clearance, thus increasing the risk of lithium toxicity when used concomitantly with this product. Caution should be exercised when lithium is used concomitantly with this product, and careful monitoring of serum lithium concentrations is recommended. 2. Drugs Affecting Serum Potassium: The potassium-wasting effect of hydrochlorothiazide may be attenuated by the potassium-sparing effect of irbesartan. However, the effect of hydrochlorothiazide on serum potassium may be enhanced by other drugs associated with potassium loss and causing hypokalemia (e.g., other potassium-wasting diuretics, laxatives, amphotericin, carbenoxolone, penicillin G sodium, salicylic acid derivatives). Conversely, based on clinical experience with other drugs that attenuate the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs that increase serum potassium levels may lead to increases in serum potassium. 3. Drugs Affected by Serum Potassium Disturbances: Regular monitoring of serum potassium is recommended when this combination is used with other drugs that are affected by serum potassium disturbances (e.g., digitalis glycosides, antiarrhythmic drugs). 4. Additional Information Regarding Irbesartan Interactions: In healthy male subjects, the pharmacokinetics of digoxin were not altered when coadministered with 150 mg of irbesartan. The pharmacokinetics of irbesartan were not affected when coadministered with hydrochlorothiazide. Irbesartan is primarily metabolized by CYP2C9 and, to a lesser extent, via glucuronidation. Inhibition of the glucuronyltransferase pathway does not result in clinically significant interactions. In vitro interactions have been observed between irbesartan and warfarin, tolbutamide (CYP2C9 substrates), and nifedipine (CYP2C9 inhibitor). However, no significant pharmacokinetic or pharmacodynamic interactions were observed when irbesartan was coadministered with warfarin in healthy male subjects. The pharmacokinetics of irbesartan were not affected when coadministered with nifedipine. The effects of CYP2C9 inducers, such as rifampin, on the pharmacokinetics of irbesartan have not been studied. Based on in vitro data, no interactions are expected with drugs whose metabolism is dependent on the cytochrome P450 isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1, or CYP3A4. 5. Other information about hydrochlorothiazide interactions: Interactions may occur when the following drugs are used in combination with thiazide diuretics: alcohol, barbiturates, or nicotine; orthostatic hypotension may be aggravated; 6. Antidiabetic drugs (oral medications and insulin): The dose of antidiabetic drugs may need to be adjusted when used in combination (see [Precautions]); 7. Cholestyramine and Colestipol resins: When used in combination with anionic resins, they affect the absorption of hydrochlorothiazide; 8. Corticosteroids, ACTH: Electrolyte loss may increase, especially hypokalemia; 9. Digitalis glycosides: Thiazide-induced hypokalemia and hypomagnesemia are conducive to the occurrence of digitalis-induced arrhythmias (see [Precautions]); 10. Nonsteroidal anti-inflammatory drugs: Concomitant use of nonsteroidal anti-inflammatory drugs can reduce the diuretic, natriuretic, and hypotensive effects of thiazide diuretics in some patients; 11. Vasoactive amines (such as norepinephrine): The effects of vasoactive amines may be reduced, but not enough to stop their use; 12. Non-depolarizing skeletal muscle relaxants (such as tubocurarine): The effects of non-depolarizing skeletal muscle relaxants may be enhanced by hydrochlorothiazide; 13. Anti-gout drugs: Because hydrochlorothiazide can increase serum uric acid levels, its dosage may need to be adjusted when used concomitantly; the dosage of probenecid and sulfinpyrazone may need to be increased. Concomitant use of thiazide diuretics may increase the risk of allergic reactions to allopurinol. 14. Calcium Salts: Thiazide diuretics reduce calcium secretion and may increase serum calcium levels. If calcium supplements or calcium-sparing medications (such as vitamin D therapy) are necessary, serum calcium levels should be monitored and the calcium dosage adjusted accordingly. 15. Other Drug Interactions: Thiazide diuretics may enhance the hyperglycemic response of beta-blockers and diazosin. Anticholinergics (such as atropine and beperiden) may increase the bioavailability of thiazide diuretics by reducing gastrointestinal motility and gastric emptying rate. Thiazide diuretics may increase the risk of adverse reactions caused by amantadine. Thiazide diuretics may also reduce renal excretion of cytotoxic drugs (such as cyclophosphamide and methotrexate) and enhance their bone-suppressing effects. 16. Contraindications: No data are currently available.

[Pharmacological Action]
This product is a combination of angiotensin II antagonist, irbesartan, and the thiazide diuretic hydrochlorothiazide. The combination's antihypertensive effect is synergistic and more effective than either agent alone. 1. Irbesartan is a potent, orally active, selective angiotensin II receptor (AT1 subtype) antagonist. It blocks all AT1 receptor-mediated angiotensin II actions, regardless of the source or synthetic pathway of angiotensin II. Its selective antagonism of angiotensin II (AT1) results in elevated plasma renin and angiotensin II levels and decreased plasma aldosterone levels. When administered alone at the recommended dose, irbesartan does not significantly affect serum potassium in patients without electrolyte imbalances (see [Precautions] and [Drug Interactions]). Irbesartan does not inhibit angiotensin-converting enzyme (ACE or kinase II). ACE can generate angiotensin II and degrade bradykinin into inactive metabolites. Irbesartan's activity does not require metabolic activation. Hydrochlorothiazide is a thiazide diuretic. The antihypertensive mechanism of thiazide diuretics is not yet fully understood. It can affect the renal tubular reabsorption mechanism of electrolytes, directly increasing the excretion of sodium and chloride (roughly equal amounts). Hydrochlorothiazide reduces blood volume, increases plasma renin activity, and increases aldosterone secretion, thereby increasing the excretion of potassium and bicarbonate in urine and lowering serum potassium levels. Co-administration of irbesartan can reverse the potassium loss associated with diuretics by blocking the renin-angiotensin-aldosterone system. The diuretic effect of hydrochlorothiazide begins 2 hours after administration, with the peak effect occurring approximately 4 hours later and lasting approximately 6-12 hours. 2. The combination of hydrochlorothiazide and irbesartan can produce a dose-related synergistic antihypertensive effect within its recommended therapeutic dose range. In patients whose blood pressure is inadequately controlled with irbesartan 300 mg alone, the addition of hydrochlorothiazide 12.5 mg once daily reduces placebo-corrected diastolic blood pressure trough values (24 hours after dosing) by an additional 6.1 mmHg. The combination of irbesartan 300 mg and hydrochlorothiazide 12.5 mg reduces total systolic/diastolic blood pressure by an additional 13.6/11.5 mmHg after subtracting the placebo effect. In patients with mild to moderate essential hypertension, once-daily administration of irbesartan 15 mg and hydrochlorothiazide 12.5 mg reduces placebo-corrected systolic/diastolic blood pressure trough values (24 hours after dosing) by a mean of 12.9/6.9 mmHg. Peak effect occurs 3 to 6 hours later. Using ambulatory blood pressure monitoring, the combination of irbesartan 150 mg and hydrochlorothiazide 12.5 mg once daily produces a sustained 24-hour blood pressure-lowering effect. Over 24 hours, the placebo-corrected mean systolic/diastolic blood pressure decreased by 15.8/10.0 mmHg. The trough/peak blood pressure-lowering efficacy of the compound (150mg/12.5mg) was 100% as determined by ambulatory blood pressure monitoring. During clinic visits, the trough/peak blood pressure-lowering efficacy of the 150mg/12.5mg and 300mg/12.5mg compounds was 68% and 76%, respectively, as measured by a cuff sphygmomanometer. Once daily, it does not produce an excessive peak blood pressure-lowering effect, but the blood pressure-lowering effect is safe and effective and lasts for 24 hours. For patients whose blood pressure is not effectively controlled with hydrochlorothiazide 25mg alone, the addition of irbesartan can further reduce systolic/diastolic blood pressure by an average of 11.1/7.2 mg, after deducting the placebo effect. 5. The antihypertensive effect of the combination of irbesartan and hydrochlorothiazide is evident immediately after the first dose, reaching significance within 1-2 weeks and reaching its maximum effect at 6-8 weeks. In long-term follow-up studies, the antihypertensive effect of irbesartan/hydrochlorothiazide persists for more than one year. Although the combination has not been specifically studied, rebound blood pressure elevation has not been observed with either irbesartan or hydrochlorothiazide. 6. The effect of the combination of irbesartan and hydrochlorothiazide on cardiovascular morbidity and mortality has not been studied. Epidemiological studies have shown that long-term hydrochlorothiazide treatment reduces the risk of cardiovascular morbidity and mortality. 7. The response to this combination is not different among patients of different ages and genders. When irbesartan is used in combination with low-dose hydrochlorothiazide (e.g., 12.5 mg daily), its antihypertensive effect is similar in blacks and non-blacks.

[Storage] Store in sealed containers.
[Strength] 150 mg: 12.5 mg x 7 tablets
[Packaging] Box
[Expiry Date] 24 months
Approval Number: National Medical Products Approval No. H20058709
Manufacturer: Zhejiang Huahai Pharmaceutical Co., Ltd.