Date of approval.
Date of revision.
Irbesartan Hydrochlorothiazide Tablets Instructions
Please read the instructions carefully and use under the guidance of your physician
The use of this product should be discontinued as soon as pregnancy is detected. Drugs that act directly on the renin-angiotensin system may cause damage or even death in the developing embryo.
Hydrochlorothiazide contained in this product may give a positive anti-doping test result. Use with caution in athletes.
Drug Name
Generic name: Irbesartan Hydrochlorothiazide Tablets
English name: Irbesartan and Hydrochlorothiazide Tablets
Hanyu Pinyin: Ebeishatan Qinglüsaiqin Pian
Ingredients
This product is a compound preparation, its composition is: each tablet contains Irbesartan 150mg and Hydrochlorothiazide 12.5mg.
Chemical structure formula.
Irbesartan: Hydrochlorothiazide: Molecular formula: Irbesartan: C25H28N6O; Hydrochlorothiazide: C7H8ClN3O4S2
Molecular weight: Irbesartan: 428.5; Hydrochlorothiazide: 297.2
Properties
This product is a film-coated tablet, which appears white after removing the coating.
Indications
For the treatment of primary hypertension.
This fixed-dose combination is used to treat patients whose blood pressure cannot be effectively controlled with Irbesartan or Hydrochlorothiazide alone.
Specification
Each tablet contains 150mg of Irbesartan and 12.5mg of Hydrochlorothiazide.
Dosage]
Take orally, on an empty stomach or with a meal. The usual starting and maintenance dose is 1 tablet once daily. For the treatment of patients whose blood pressure cannot be effectively controlled by irbesartan or hydrochlorothiazide alone.
It is recommended that patients adjust the dose of a single component (i.e., irbesartan or hydrochlorothiazide) in a combination prior to using a fixed-dose combination, which may be substituted when the dose of each single agent is fixed in the combination.
Direct conversion from single-component to fixed-combination therapy may be considered in the following situations: the 150 mg/12.5 mg combination of this product may be used in patients whose blood pressure is not effectively controlled with hydrochlorothiazide or irbesartan 150 mg alone.
If necessary, this product may be used in combination with other blood pressure-lowering drugs (see [Drug Interactions]).
[Adverse Reactions].
The incidence of the adverse reactions listed below are defined using the following conventions.
Very common (³1/10); common (³1/100,<1/10); occasional (³1/1000,<1/100); rare (³1/10,000,<1/1000); very rare (<1/10,000).
Irbesartan/hydrochlorothiazide combination tablets.
In placebo-controlled trials in hypertensive patients, the overall incidence of adverse reactions did not differ between the irbesartan/hydrochlorothiazide group and the placebo group. The incidence of treatment discontinuation due to clinical or laboratory adverse events was lower in the irbesartan/hydrochlorothiazide treatment group than in the placebo-treated group. Adverse events occurred independently of dose (within the recommended dose range), sex, age, race, or treatment period. Adverse events were reported in placebo-controlled trials of 898 hypertensive patients receiving various doses of irbesartan/hydrochlorothiazide (ranging from: 37.5 mg/6.25 mg to 300 mg/25 mg irbesartan/hydrochlorothiazide), as follows
Neurological abnormalities
Common: Dizziness
Occasional: upright dizziness
Cardiac abnormalities
Occasional: hypotension, edema, syncope, tachycardia
Vascular abnormalities
Occasional: flushing
Gastrointestinal abnormalities
Common: nausea/vomiting
Occasionally: diarrhea, dry mouth
Skeletal muscle, connective tissue and bone abnormalities
Occasional: edema of distal extremities, muscle/bone pain
Skin and subcutaneous tissue abnormalities
Occasionally: rash
Renal and urinary tract abnormalities
Common: urinary abnormalities
Reproductive system and breast abnormalities
Occasionally: changes in libido, sexual dysfunction
Systemic abnormalities and administration site conditions
Common: Fatigue
Occasionally: weakness
Examination.
Patients in the irbesartan/hydrochlorothiazide group had changes in laboratory parameters that were rarely clinically significant.
Common: increased BUN (urea nitrogen), creatinine and creatine kinase
Occasionally: decreased serum potassium and sodium levels
In addition, the following adverse reactions have been reported since the introduction of the irbesartan/hydrochlorothiazide combination.
Immune system abnormalities
Rare: Like other angiotensin-II receptor antagonists, hypersensitivity reactions such as rash, urticaria, angioneurotic edema have been reported in a few cases since the introduction of irbesartan alone.
Metabolic and nutritional abnormalities
Hyperkalemia
Neurological abnormalities
Headache, vertigo
Ear and vagus abnormalities
Tinnitus
Respiratory, chest and diaphragm abnormalities
Cough
Gastrointestinal abnormalities
Taste disorders, indigestion
Hepatobiliary abnormalities
Hepatitis, elevated liver enzymes, jaundice
Skeletal muscle, connective tissue and bone abnormalities
Arthralgia, myalgia
Renal and urinary tract abnormalities
Renal impairment, including renal failure in individual patients at high risk of developing renal failure
Additional information on single ingredients: In addition to the adverse reactions listed above for combination products, previously reported adverse reactions occurring with the application of one of the single ingredients are also potential adverse reactions to be aware of.
Irbesartan.
Cardiac Abnormalities
Occasionally: ECG abnormalities
Gastrointestinal abnormalities
Occasionally: abdominal pain
Skin and subcutaneous tissue abnormalities
Occasionally: pruritus
Systemic abnormalities and administration site conditions
Occasionally: chest pain, extreme weakness
Post-marketing experience with single ingredients is listed below.
Irbesartan.
Similar to other angiotensin-II receptor antagonists, hypersensitivity reactions (angioedema, urticaria, tachyphylaxis (including tachyphylactic shock)) have been reported since the introduction of irbesartan monotherapy. In post-marketing surveillance, the following very rare adverse reactions were reported: vertigo, weakness, hyperkalemia, jaundice, myalgia, elevated liver function test levels, hepatitis, tinnitus, and impaired renal function, including occasional renal failure in the at-risk population.
Blood and lymphatic system abnormalities.
Thrombocytopenia
Skin and subcutaneous tissue-like abnormalities.
Psoriasis, photosensitivity
Hydrochlorothiazide.
Adverse events that have been reported with hydrochlorothiazide alone (whether or not associated with the administration of the drug) include
Hematologic and lymphatic system.
Developmental dysplasia, bone marrow suppression, hemolytic anemia, leukopenia, neutropenia/granulocytopenia, thrombocytopenia
Mental system abnormalities.
Depression, sleep disorders
Neurological abnormalities.
Dizziness, sensory abnormalities, restlessness, dizziness
Eye abnormalities.
Temporary blurred vision, yellow vision
Cardiac abnormalities.
Cardiac arrhythmias
Vascular abnormalities.
Orthostatic hypotension
Respiratory, thoracic, diaphragmatic abnormalities.
Respiratory distress (including pneumonia, pulmonary edema)
Gastrointestinal abnormalities.
Pancreatitis, anorexia, constipation, diarrhea, gastric irritability, loss of appetite, salivary adenitis
Hepatobiliary abnormalities.
Jaundice (intrahepatic cholestatic jaundice)
Skin and subcutaneous tissue abnormalities.
Allergic reactions, toxic epidermolysis bullosa, cutaneous lupus erythematosus-like reactions, necrotizing vasculitis (phlebitis, cutaneous phlebitis), photoallergic reactions, rash, urticaria
Skeletal muscle, connective tissue and bone abnormalities
Muscle spasms, weakness
Kidney and urinary tract abnormalities
Interstitial nephritis, renal dysfunction
Systemic abnormalities and drug administration site conditions
Fever
Examination.
Electrolyte disturbances (including hypokalemia and hyponatremia), glycosuria, hyperglycemia, elevated blood uric acid, elevated cholesterol and triglycerides
Benign, malignant and tumors of unknown nature (including cysts and polypoid).
Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma)
[Contraindicated].
4th to 9th trimester of pregnancy (see [Pregnancy and Lactation])
Lactation (see [Use in Pregnant and Lactating Women]).
Known hypersensitivity to the active ingredient or any of the excipient components of this product or to other sulfonamide derivatives (hydrochlorothiazide is a sulfonamide derivative). Overall, allergic reactions are more likely to occur in patients with a history of allergy or bronchial asthma.
This product is contraindicated in patients with anuria.
The following contraindications are associated with hydrochlorothiazide.
-Severe renal impairment (creatinine clearance <30 ml/min) -Recalcitrant hypokalemia, hypercalcemia
-Severe hepatic impairment, biliary cirrhosis and cholestasis.
Irbesartan hydrochlorothiazide in combination with aliskiren is contraindicated in patients with diabetes mellitus or moderate to severe renal impairment (glomerular filtration rate GRF<60mL/min/1.73m2).
Irbesartan hydrochlorothiazide in combination with angiotensin-converting enzyme inhibitors (ACEIs) is contraindicated in patients with diabetic nephropathy.
[Precautions].
General Precautions.
Acute hypotension, azotemia, oliguria, or, rarely, acute renal failure and/or death may occur with treatment with angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists in patients whose vascular tone and renal function are largely dependent on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure or renal disease including renal artery stenosis). As with any antihypertensive drug, excessive lowering of blood pressure in patients with ischemic cardiomyopathy or ischemic cardiovascular disease may result in myocardial infarction or stroke.
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, and overall, patients with a history of allergy or bronchial asthma are more likely to have an allergic reaction (see [Contraindications]).
Fetal/neonatal morbidity and mortality.
Although there is no experience with the use of this product in pregnant women, in utero exposure to ACE inhibitors during mid- to late-term pregnancy has been reported to result in possible developmental fetal injury and death. Therefore, similar to any drug that acts directly on the renin-angiotensin-aldosterone system, this product should not be used during pregnancy. If pregnancy is detected during treatment, treatment with this product must be discontinued as soon as possible.
Hydrochlorothiazide can cross the placental barrier and appear in the cord blood. The use of hydrochlorothiazide during pregnancy increases the risk of fetal or neonatal jaundice, thrombocytopenia, and may be associated with other adverse reactions that occur in adults.
Hypotension-hypovolemia: This compound is rarely associated with symptomatic hypotension when used in hypertensive patients without other predisposing risk factors for hypotension. Symptomatic hypotension may occur in patients with inadequate blood volume and sodium due to the use of potent diuretics, strict salt restriction in the diet, and diarrhea and vomiting. These conditions should be corrected prior to treatment with this combination. Thiazides may potentiate the effects of other antihypertensive agents.
Renal artery stenosis-renal vascular hypertension: Increased serum creatinine and or urea nitrogen levels have been reported in patients with the presence of bilateral renal artery stenosis or stenosis occurring in the arteries of a single functioning kidney with drugs that affect the renin-angiotensin-aldosterone system. Although there is no experience with this product in patients with unilateral or bilateral renal artery stenosis, similar effects of angiotensin II receptor antagonists should be considered.
Renal impairment and renal transplantation.
This product should not be used in patients with severe renal insufficiency (creatinine clearance <30 ml/min) (see [Contraindications]).
Patients with mild to moderate renal impairment (creatinine clearance ³ 30 ml/min but <60 ml/min) do not require drug dose adjustment. However, this compound should be used with caution. Azotemia associated with thiazide diuretics may occur in patients with renal impairment. When this product is used in patients with renal impairment, serum potassium, creatinine and uric acid should be monitored regularly.
Changes in renal function can occur in sensitive patients following treatment with renin-angiotensin-aldosterone system inhibitors. In patients whose renal function is largely dependent on renin-angiotensin-aldosterone system activity (e.g., patients with severe congestive heart failure or renal dysfunction), the use of angiotensin-converting enzyme (ACE) inhibitors results in oliguria and/or progressive azotemia and, in rare cases, acute renal failure and/or death.
There is no experience with the use of this product in patients who have recently undergone renal transplantation.
Hepatic impairment: Caution should be exercised in the use of thiazide diuretics in patients with hepatic impairment because of the potential for hepatic coma due to minor alterations in fluid and electrolyte balance. There is no experience with the use of this compound in patients with hepatic impairment.
Aortic and mitral stenosis, hypertrophic obstructive cardiomyopathy: As with other vasodilators, caution should be exercised when using this product in patients with aortic and mitral stenosis and hypertrophic obstructive cardiomyopathy.
Primary aldosteronism: Patients with primary aldosteronism usually do not respond to anti-hypertensive drugs that inhibit the renin-angiotensin system, so this product is not recommended for these patients.
Metabolic and endocrine effects: Thiazide diuretic therapy may reduce glucose tolerance. Dose adjustment of insulin and oral hypoglycemic agents may be required in diabetic patients. Symptoms of latent diabetes mellitus may occur with thiazide diuretic therapy. Elevated cholesterol and triglyceride levels have been associated with thiazide diuretic therapy. However, at the dose of 12.5 mg contained in the compound, this effect is minimal or absent. Hyperuricemia and even gout may occur in some patients treated with thiazide diuretics.
Electrolyte disturbances: As in any patient treated with diuretics, serum electrolytes should be measured periodically. Thiazide diuretics, including hydrochlorothiazide, can cause fluid or electrolyte disturbances (hypokalemia, hyponatremia, and hypochloremic alkalosis). Signs of fluid or electrolyte disturbances are dry mouth, thirst, weakness, lethargy, drowsiness, irritability, muscle cramps and pain, muscle fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting.
Hypokalemia may be induced by the use of thiazide diuretics, but the combination with irbesartan may reduce diuretic-induced hypokalemia. Hypokalemia is most likely to occur in patients with cirrhosis, in patients with significant diuretic effects, in patients with inappropriate oral intake of electrolytes, and in patients on concomitant corticosteroids or ACTH. Conversely, irbesartan in this product may induce hyperkalemia, particularly in patients with renal impairment and/or heart failure and diabetes mellitus. Appropriate monitoring of serum potassium concentrations is recommended for these patients. Caution should be exercised when potassium-protective diuretics, potassium supplements, or potassium salt-containing substitutes are used in combination with this product (see [Drug Interactions]).
There is no evidence that irbesartan will reduce or prevent diuretic-induced hyponatremia. Blood chloride reductions are usually mild and do not require treatment.
Thiazide diuretics may reduce renal excretion of calcium, causing intermittent mild elevations in those patients with no known abnormalities of calcium metabolism. Significant hypercalcemia suggests possible underlying hyperparathyroidism. Thiazide diuretics should be discontinued while parathyroid function is being measured. Thiazide diuretics have been shown to increase magnesium excretion and may lead to hypomagnesemia.
Acute myopia and secondary acute angle-closure glaucoma: Transient myopia and acute angle-closure glaucoma can be caused by aminophenazone or aminophenazone derivatives (drugs that may cause idiosyncratic reactions). Although hydrochlorothiazide is a sulfonamide, only isolated cases of hydrochlorothiazide causing acute angle-closure glaucoma (without clear causation) have been reported to date. Symptoms include an acute onset of vision loss or eye pain and usually occur within a few hours to a few weeks of taking the drug.
Acute closed-angle glaucoma may lead to permanent vision loss if left untreated. The primary treatment is to stop taking the medication as soon as possible. If intraocular pressure remains uncontrolled, prompt drug or surgical treatment may need to be considered. Risk factors for the development of acute angle-closure glaucoma may include a history of aminoglutethimide or penicillin allergy.
Exacerbation or activation of SLE with thiazide diuretics has been reported.
The hypotensive effect of thiazide diuretics may be increased in post-sympathectomy patients.
Effects on driving and machine operation: Based on its pharmacodynamic properties, irbesartan is unlikely to affect the ability to drive and operate machines. The occurrence of dizziness or fatigue should be considered when driving or operating machinery during hypertension treatment.
Anti-doping tests: The hydrochlorothiazide contained in this product may result in a positive anti-doping test result. Use with caution in athletes.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): Dual blockade of the renin-angiotensin-aldosterone system by irbesartan hydrochlorothiazide in combination with an angiotensin-converting enzyme inhibitor (ACEI) or aliskiren is not recommended because of the increased risk of hypotension, hyperkalemia, and altered renal function. The combination of irbesartan hydrochlorothiazide and aliskiren is contraindicated in patients with diabetes mellitus or renal insufficiency (GFR <60ml/min/1.73m2).
Irbesartan hydrochlorothiazide in combination with angiotensin-converting enzyme inhibitors (ACEIs) is contraindicated in patients with diabetic nephropathy.
For use in patients with psoriasis or a history of psoriasis: this should be carefully weighed, as the irbesartan in this product may exacerbate psoriasis.
Cases of photosensitivity reactions have been reported with the administration of thiazide diuretics. If photosensitivity reactions occur during treatment, discontinuation of treatment is recommended. If readministration of diuretics is deemed necessary, avoiding exposure of exposed areas to sunlight or artificial UVA is recommended.
Lactose: This product should not be used in patients with rare genetic disorders such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.
Non-melanoma skin cancer: An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative doses of hydrochlorothiazide (HCTZ) exposure was observed in two epidemiologic studies in the Danish National Cancer Registry.The photosensitizing effect of HCTZ may serve as a possible mechanism for NMSC.
Based on available data from epidemiological studies, a cumulative dose-dependent relationship between HCTZ and NMSC was observed. One study included by 71,533 cases of BCC (basal cell carcinoma) and 8,629 cases of SCC (squamous cell carcinoma), corresponding to 1,430,833 and 172,462 control populations, respectively. high dose use of HCTZ (≥50,000 mg cumulative) involved a corrected OR (ratio) of 1.29 (95% CI (confidence interval). 1.23-1.35) for basal cell carcinoma and 3.98 (95% CI: 3.68-4.31) for squamous cell carcinoma. A significant cumulative dose-response relationship was observed in both basal cell carcinoma and squamous cell carcinoma. Another study showed a possible association between lip cancer (SCC) risk and HCTZ exposure: 633 lip cancers were matched to 63,067 population pairs using a risk set sampling strategy. A corrected ratio of 2.1 (95% CI: 1.7-2.6) for former users of hydrochlorothiazide, a corrected ratio of 3.9 (3.0-4.9) for high dose users of hydrochlorothiazide (~25,000 mg) and a corrected ratio of 7.7 (5.7-10.5) for the highest cumulative dose users of hydrochlorothiazide (~100,000 mg) suggested a cumulative dose-response relationship. There are no data from studies in Asian populations to suggest this.
Patients taking hydrochlorothiazide should be made aware of the risk of NMSC and this population should be advised to regularly check for any new skin lesions and report any suspected skin lesions. Possible preventive measures, such as limiting exposure to sunlight and UV light and, in the case of exposure, giving patients adequate protection to minimize the risk of skin cancer, should be recommended. Prompt examination of suspicious skin lesions, including histological examination by biopsy, should be performed. Careful consideration should also be given to the use of HCTZ-containing drugs in patients with prior NMSC.
Pregnant women and nursing mothers
Pregnancy: See [Contraindications] and [Precautions] sections.
Drugs that act directly on the renin-angiotensin system may cause damage or even death to the developing embryo. The use of this product should be discontinued as soon as pregnancy is detected. As a safety measure, it is best not to use this product during the first trimester of pregnancy. Switch to appropriate alternative therapy when pregnancy is planned. During the fourth to ninth trimester, substances that act directly on the renin-angiotensin system can cause fetal and neonatal renal failure, fetal craniosynostosis and fetal death; therefore, this product is contraindicated in pregnancies from the fourth to the ninth trimester. If pregnancy is detected, the product should be discontinued as soon as possible, and cranial and renal function should be checked by ultrasound if treatment has been given for a longer period due to negligence.
Thiazide diuretics can cross the placental barrier and appear in the blood of the umbilical cord, causing decreased placental perfusion, fetal electrolyte disturbances and other effects that may occur in adults. Neonatal thrombocytopenia, fetal or neonatal jaundice have been reported in mothers treated with thiazides. Because this compound contains hydrochlorothiazide, its use is not recommended in the first trimester of pregnancy. Conversion to appropriate alternative therapy should be made at the time of planned pregnancy.
Lactation: This product is contraindicated during lactation due to potential adverse reactions in the infant (see [Contraindications]). It is not known whether irbesartan is secreted into human breast milk. Irbesartan can be secreted into the milk of rats. High doses of thiazides may inhibit lactation due to their significant diuretic effect and are not recommended during lactation.
Pediatric Use]
The safety and efficacy of this product have not been studied in patients younger than 18 years of age.
Geriatric Use]
Geriatric patients do not require dosage adjustment.
Drug Interactions]
Other antihypertensive drugs: The hypotensive effect may be enhanced when this product is used in combination with other hypotensive drugs. Irbesartan and hydrochlorothiazide (Irbesartan and hydrochlorothiazide in doses up to 300mg/25mg) can be safely combined with other blood pressure lowering drugs such as calcium channel blockers and b-blockers. Combination or incompatibility of irbesartan with thiazide diuretic therapy may result in reduced blood volume if high-dose diuretics have been used previously, and there is a risk of hypotension when administered unless the volume deficit is first corrected (see [Precautions]).
Lithium: The concomitant use of lithium and thiazide diuretics has been reported to cause reversible increases in serum lithium concentrations and lithium toxicity. So far, it is very rare to report similar effects with irbesartan administration. In addition, thiazide diuretics can reduce renal clearance of lithium and therefore have an increased risk of lithium toxicity when combined with this product. Therefore, the combination of lithium and this product is not recommended. Care should be taken when combining lithium with this product, and careful monitoring of serum lithium concentrations is recommended.
Drugs affecting blood potassium: The potassium-removal effect of hydrochlorothiazide can be attenuated by the potassium-preserving effect of irbesartan. However, the effect of hydrochlorothiazide on serum potassium can be enhanced by other drugs associated with potassium loss and hypokalemia (e.g., other potassium-eliminating diuretics, laxatives, amphotericin, carbenoxolone, penicillin G sodium salt, salicylic acid derivatives). Conversely, the combination of potassium-preserving diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs that increase serum potassium levels may lead to an increase in serum potassium based on clinical experience with other drugs that affect the renin-angiotensin system. Severe increases in potassium may sometimes occur and close monitoring of potassium levels is required. Concomitant treatment with hydrochlorothiazide may reduce the incidence of this reaction.
Drugs affected by serum potassium disorders: When this combination is used with other drugs affected by serum potassium disorders (e.g., digitalis glycosides, antiarrhythmic drugs), regular monitoring of serum potassium is recommended.
Additional information on Irbesartan interactions: In healthy male subjects, the pharmacokinetics were not altered when digoxin was combined with Irbesartan 150 mg. Irbesartan pharmacokinetics were not affected when co-administered with hydrochlorothiazide. Irbesartan is metabolized primarily by CYP2C9 and to a lesser extent by glucuronidase. Inhibition of the glucuronosyltransferase pathway does not result in clinically meaningful interactions. In in vitro assays, interactions between irbesartan and warfarin, tosylbutazone (CYP2C9 substrate) and nifedipine (CYP2C9 inhibitor) can be observed. However, in healthy male subjects, no meaningful pharmacokinetic and pharmacodynamic interactions were observed when irbesartan and warfarin were combined. The pharmacokinetics of irbesartan were not affected when combined with nifedipine, and the effect of CYP2C9 inducers such as rifampicin on the pharmacokinetics of irbesartan was not studied. Based on in vitro data, no interaction occurs with drugs whose metabolism is dependent on the cytochrome P450 isozymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1, or CYP3A4.
Additional information on hydrochlorothiazide interactions: Interactions may occur when the following drugs are combined with thiazide diuretics.
Alcohol, barbiturates or nicotine: may aggravate the development of upright hypotension.
antidiabetic drugs (oral and insulin): the dose of antidiabetic drugs may need to be adjusted when combined (see [Precautions]).
Abilify and Colestipol resin: affects the absorption of hydrochlorothiazide when combined with anionic resin.
Corticosteroids, ACTH: electrolyte loss may be increased, especially in hypokalemia.
Digitalis glycosides: thiazide-induced hypokalemia and hypomagnesemia favoring digitalis-induced arrhythmias (see [Precautions]).
Non-steroidal anti-inflammatory drugs including cyclooxygenase 2 inhibitors (COX-2 inhibitors): angiotensin II antagonists may impair their antihypertensive effects when combined with NSAIDs. Combination therapy of angiotensin II (including irbesartan) with NSAIDs including cyclooxygenase 2 inhibitors (COX-2 inhibitors) in elderly, hypovolemic patients (including those treated with diuretics) or patients with pre-existing renal impairment may result in an increased risk of worsening renal function, including possible acute renal failure, which is usually reversible. Combinations should be administered with caution and renal function should be monitored regularly.
Vasoactive amines (e.g., norepinephrine): Vasoactive amine effects may be reduced but are not sufficient to discontinue use.
Non-depolar skeletal muscle relaxants (e.g., cylindrotoxin): The effects of non-depolar skeletal muscle relaxants may be potentiated by hydrochlorothiazide.
Antigout medications: Because hydrochlorothiazide increases serum uric acid levels, its drug dose may need to be adjusted when combined; increased dosages of probenecid and benzosulfanilone may be required. The combination of thiazide diuretics may increase the risk of allergic reactions to allopurinol.
Calcium salts: Thiazide diuretics decrease calcium secretion and may increase serum calcium levels. If calcium supplements or calcium-preserving medications (e.g., vitamin D therapy) must be used, serum calcium levels should be monitored and the calcium dose adjusted accordingly.
Carbamazepine: Concomitant use of carbamazepine and hydrochlorothiazide is associated with a risk of symptomatic hyponatremia. Electrolytes should be monitored during concomitant medication. Another class of diuretics should be used if possible.
Other drug interactions: Thiazide diuretics may increase the hyperglycemic effects of b-blockers and diazoxide. Anticholinergics (e.g., atropine, Beperiden) may increase the bioavailability of thiazide diuretics by decreasing gastrointestinal motility and gastric emptying rate. Thiazide diuretics may increase the risk of adverse reactions caused by amantadine. Thiazide diuretics may reduce renal excretion of cytotoxic drugs (e.g., cyclophosphamide, methotrexate) and enhance their myelosuppressive effects.
Compounding contraindications: no information is available.
The combination of irbesartan hydrochlorothiazide and aliskiren is contraindicated in patients with diabetes mellitus or moderate to severe renal impairment (GRF<60mL/min/1.73m2).
Angiotensin-converting enzyme inhibitors (ACEIs): The combination of ACEIs and irbesartan hydrochlorothiazide is not recommended. The combination of Irbesartan Hydrochlorothiazide Tablets and ACEIs is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.
Overdose]
There is no specific information related to the treatment of overdose of this product. Patients should be monitored closely and treatment should be general and supportive. Treatment depends on the duration of drug intake and severity of symptoms. Recommended measures include emetic and/or gastric lavage. Activated charcoal is useful for drug overdose treatment. Serum electrolytes and creatinine levels should be monitored regularly. If hypotension occurs, the patient should be placed in the prone position with rapid salt and blood volume replacement.
Irbesartan overdose is most likely to manifest as hypotension and tachycardia; bradycardia also occurs.
In hydrochlorothiazide overdose, electrolyte depletion (hypokalemia, hypochlorhydria, hyponatremia) and dehydration occur due to excessive diuresis. The most common signs and symptoms of overdose are nausea and drowsiness. Hypokalemia can cause muscle spasms and/or exacerbate arrhythmias associated with co-administered digitalis glycosides or certain antiarrhythmic drugs.
Hemodialysis does not clear irbesartan. The extent to which hemodialysis clears hydrochlorothiazide has also not been studied.
Pharmacology and Toxicology
Pharmacological effects
Irbesartan hydrochlorothiazide is a combination of the angiotensin-II receptor antagonist irbesartan and the thiazide diuretic hydrochlorothiazide.
Irbesartan selectively binds to the AT1 angiotensin-II receptor with an affinity 8,500 times higher than the affinity of the AT2 receptor, but has no agonist activity. Erbesartan blocks the vasoconstrictive and pro-aldosterone secretion of angiotensin II by specifically binding to AT1 receptors. blockade of AT1 receptors inhibits the negative feedback effect of angiotensin II on renin secretion, but the increase in serum renin activity and angiotensin II does not completely counteract the blood pressure-lowering effect of erbesartan.
Hydrochlorothiazide affects the mechanism of electrolyte reabsorption by the renal tubules, leading directly to increased excretion of sodium and chloride (in roughly equal amounts). Thus, hydrochlorothiazide decreases blood volume, increases plasma renin activity, and increases aldosterone secretion, thereby increasing urinary excretion of potassium and bicarbonate and decreasing serum potassium levels. The combination of irbesartan reverses potassium loss by blocking the renin-angiotensin-aldosterone system.
The combination of hydrochlorothiazide and irbesartan produces a synergistic hypotensive effect within its recommended therapeutic dose range.
Toxicological studies
Genotoxicity
Irbesartan hydrochlorothiazide combination has not been shown to be mutagenic in in vitro tests (Ames test and Chinese hamster lactating cell forward mutation test) and has not induced chromosomal aberrations (in vitro – human lymphocyte test, in vivo – mouse micronucleus test).
Irbesartan was not mutagenic in in vitro tests (Ames test, rat hepatocyte DNA repair test, V79 mammalian cell forward mutation test) and was negative in chromosomal aberration tests (in vitro-human lymphocyte test, in vivo-mouse micronucleus test).
Hydrochlorothiazide was negative in the Ames test, the Chinese hamster ovary (CHO) cell chromosome aberration test, the mouse germ cell chromosome test, the Chinese hamster bone marrow chromosome test, and the Drosophila concomitant recessive lethality test. Hydrochlorothiazide (43-1300 μg/ml) was positive in the in vitro CHO cell sister chromatid interchange test and the mouse lymphocyte test.
Reproductive toxicity
No standard fertility test was performed for Irbesartan hydrochlorothiazide combination. Rats given oral irbesartan/hydrochlorothiazide 50/50, 150/150 mg/kg/day showed no increase in embryonic development compared to the single formulation.
No effects on fertility or mating ability were seen in rats given orally irbesartan 650 mg/kg/day with a systemic exposure equivalent to 5 times the maximum recommended human dose (MRHD, 300 mg/day). Increased incidence of embryonic pelvic cavity, edema, and/or loss of renal papillae was seen in rats given oral irbesartan 50, 180, and 650 mg/kg/day from day 0 to day 20 of gestation at doses roughly equivalent to MRHD (300 mg/day, converted from body surface area); at 180 mg/kg/day and above, equivalent to 4 times MRHD (converted from body surface The embryonic subcutaneous edema was seen at 180 mg/kg/day and above, equivalent to 4 times the MRHD (based on body surface area conversion). No such adverse effects were observed in rats given Irbesartan 50, 150 and 450 mg/kg/day from day 6 to day 15 of gestation. In pregnant rabbits, oral administration of irbesartan 30 mg/kg/day at a dose equivalent to 1.5 times MRHD was associated with increased mortality and abortion rates in maternal animals, and increased early embryo uptake and decreased number of surviving embryos were seen in surviving animals. Irbesartan crosses the placental barrier in rats and rabbits. Irbesartan can be secreted into the milk of lactating rats after oral administration.
No effect on fertility was seen in mice and rats given hydrochlorothiazide 100 and 4 mg/kg by adulteration before mating and during gestation, respectively. No embryotoxicity was observed in pregnant mice and rats given hydrochlorothiazide at 3000 or 1000 mg/kg/day during organogenesis, equivalent to 600 or 400 times the MRHD, respectively.
Carcinogenicity
Irbesartan hydrochlorothiazide combination has not been studied for carcinogenicity.
No carcinogenicity was observed in mice given hydrochlorothiazide 600 mg/kg/day orally for 2 years and in rats given hydrochlorothiazide 100 mg/kg/day orally for 2 years, while an increased incidence of hepatocellular carcinoma was seen in males.
No carcinogenicity was seen in rats given oral irbesartan 500/1000 mg/kg/day for 2 years (males/females) and in mice given oral irbesartan 1000 mg/kg/day for 2 years. mean systemic exposure to irbesartan in male and female rats at the 500 mg/kg/day dose was approximately 3 and 11 times greater than exposure at MRHD (300 mg/day), respectively ( At 1000 mg/kg/day, the mean systemic exposure of irbesartan in female rats was approximately 21 times that of MRHD. At 1000 mg/kg/day, the exposure of irbesartan in male and female mice was 3 and 5 times that of MRHD, respectively.
Pharmacokinetics]
The combined use of Irbesartan and Hydrochlorothiazide has no effect on the pharmacokinetic properties of either drug.
Irbesartan and hydrochlorothiazide are orally effective drugs, and they do not require biotransformation for their activity. After oral administration of this product, its absolute bioavailability is 60-80% for Irbesartan and 50-80% for Hydrochlorothiazide. Eating does not affect the bioavailability of this product. The peak plasma concentrations after oral administration of Irbesartan and Hydrochlorothiazide were 1.5 to 2 hours and 1 to 2.5 hours, respectively.
The plasma protein binding rate of Irbesartan is about 96%, which is almost not bound to blood cells, and its distribution volume is 53-93 liters. Hydrochlorothiazide has a plasma protein binding rate of 68% and an apparent volume of distribution of 0.83 to 1.14 l/kg.
The pharmacokinetics of irbesartan were linear and dose-dependent in the range of 10 to 600 mg. When the oral dose is greater than 600 mg, its absorption is disproportionate to the dose; the mechanism is unclear. The total body clearance and renal clearance are 157-176 ml/min and 3.0-3.5 ml/min, respectively, and the terminal elimination half-life of irbesartan is 11-15 hours. Steady-state plasma concentrations were achieved within three days by once-daily dosing. Intra-plasma accumulation after repeated once-daily dosing was limited (<20%). Slightly higher concentrations of irbesartan were observed in women with hypertension in one study. However, there was no difference in half-life or accumulation. No drug dose adjustment was required in female patients. The peak concentration (Cmax) and area under the curve (AUC) values of irbesartan were slightly higher in older (³65 years) than in younger (18-40 years) individuals. However, the terminal half-life was not significantly altered. Dose adjustment was also not required in elderly patients.
The mean plasma half-life of hydrochlorothiazide is 5 to 15 hours.
After oral or intravenous administration of 14C-labeled irbesartan, 80-85% of the radioactivity in the circulation is derived from the prototype irbesartan. Irbesartan is metabolized in the liver by binding to glucuronide and oxidation. The major metabolite administered orally is glucuronide-bound irbesartan (approximately 6%). In vitro experiments have shown that irbesartan is mainly metabolized by the cytochrome P450 enzyme CYP2C9 by oxidation, with little effect of CYP3A4. Irbesartan and its metabolites are excreted by the biliary tract and the kidneys. After oral or intravenous administration of 14C irbesartan, approximately 20% of the radioactivity is recovered in the urine and the rest is excreted in the feces. Less than 2% of the dose is excreted in the urine as a prototype. Hydrochlorothiazide is not metabolized, but is rapidly excreted via the kidneys. At least 61% of the oral dose is excreted as a prototype within 24 hours. Hydrochlorothiazide crosses the placenta but does not cross the blood-brain barrier and can be secreted into breast milk.
Renal impairment: The pharmacokinetic parameters of irbesartan are not significantly altered in patients with renal impairment or those on hemodialysis. Irbesartan is not cleared by hemodialysis. The elimination half-life of hydrochlorothiazide has been reported to increase to 21 hours in patients with creatinine clearance <20 ml/min.
Hepatic impairment: In patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan were not significantly altered. No studies have been performed in patients with severe hepatic impairment.
Storage】Do not store above 30℃, store in original package.
Package】Polyamide/aluminum/polyvinyl chloride cold pressed solid pharmaceutical compound hard tablets and pharmaceutical aluminum foil, 6 tablets/plate/box.
Expiration date】24 months
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Approval number】
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Company Name: Anhui Global Pharmaceutical Co.
Address
Address: No. 3809 Huangshan Avenue, Bengbu City
Post
Postcode: 233050
Tel
Phone：0552-2153518
Web
Address: http://www.ahgp.com.cn
Manufacturer
Company name: Anhui Global Pharmaceutical Co.
Address: No. 3809 Huangshan Avenue, Bengbu City
Post
Zip code: 233050
Telephone
Phone：0552-2153518
Web
Address: http://www.ahgp.com.cn
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