Approval Date: September 29, 2006
Revision date: June 02, 2011
Revision Date: 02/01/2015
Revision date: December 01, 2015
Revised on.
Erbesartan Tablets Instructions
Please read the instruction manual carefully and use under the guidance of your physician
[Drug Name]Generic Name: Irbesartan TabletsTrade Name: Jiga®English Name: Irbesartan TabletsHanyu Pinyin: Ebeishatan Pian
[Ingredients
The main ingredient of this product is Irbesartan, whose chemical name is: 2-butyl-3-[4-[ 2-(2-(1H-tetrazol-5-yl)phenyl]phenylmethyl]-1,3-diazaspiro[4,4]non-1-en-4-one.
The chemical structure formula is.
Molecular formula: C25H28N6O
Molecular weight: 428.54[Properties] This product is a film-coated tablet, which appears white or off-white after removing the coating .
[Indications]
Treatment of essential hypertension.
Combined hypertension in 2type 2 diabetic nephropathy Treatment.
[Specifications]
0.15g
[dosage]
The usual recommended initial and maintenance dose is150 mg daily, and diet has no effect on dosing. In general, Irbesartan150mgonce daily is more effective than75 mg can better control blood pressure for 24 hours. However, in some special patients, especially those undergoing hemodialysis and those older than 75 years, the initial dose may be considered with “font-family:Arial”>75 mg.
The use of Irbesartan150 mg once daily is not effective in controlling Patients whose blood pressure is not effectively controlled may increase the dose of this product to 300 mg, or add other antihypertensive drugs. In particular, the addition of diuretics such as hydrochlorothiazide has been shown to have additive effects.
In hypertensive patients with 2type 2 diabetes mellitus The initial dose of treatment should be 150mgonce daily and increased to 300 mgonce daily as a better maintenance dose for the treatment of renal disease. Clinical studies have demonstrated renal benefit of irbesartan in patients with hypertension2type 2 diabetes mellitus. In the study, irbesartan was added to other antihypertensive drugs when necessary to lower patients’ blood pressure and achieve target values.
Renal impairment: No dose adjustment of this product is required in patients with renal impairment, but for patients on hemodialysis, a low initial dose may be considered (75mg).
Low blood volume: blood volume and/or sodium deficiency should be corrected prior to the use of this product.
Hepatic impairment: No dose adjustment of this product is required in patients with mild to moderate hepatic impairment. There is no clinical experience with patients with severe hepatic impairment.
Elderly patients: Although75years of age or older may be considered from75 mgas a starting dose, no dose adjustment is usually required in elderly patients.
Children: The safety and efficacy of irbesartan in children have not been established.
[Adverse Reactions]
The following definitions were used for the incidence of adverse reactions listed below:
Very common (³1/10); common (³1/100); occasional (³1/1000,<1/100); rare (³1/10,000,<1/1000); very rare (<1/10,000).
For hypertension: In a placebo-controlled trial in hypertensive patients, the overall incidence of adverse events in the irbesartan group (56.2%) versus the placebo group (56.5%) did not differ between The incidence of treatment discontinuation due to clinical or laboratory adverse events was less in the irbesartan treatment group (3.3%) than in the placebo group (4.5%) than the placebo group (). Adverse events occurred independent of dose (within the recommended dose range), sex, age, race, or treatment period.
In placebo-controlled trials, there were1965 Patients received Irbesartan and the following adverse drug reactions were reported:
Neurological abnormalities:
Common: Dizziness
Occasional: postural dizziness
Cardiac abnormalities:
Sometimes: tachycardia, edema
Vascular abnormalities:
Sometimes: flushing
Abnormalities of breathing, chest, and diaphragm:
Sometimes: cough
Gastrointestinal abnormalities:
Common: nausea, vomiting
Occasional: diarrhea, indigestion, heartburn
Reproductive system and breast abnormalities:
Occasional: sexual dysfunction
Systemic abnormalities and circumstances at the site of administration:
Common: Fatigue
Occasional: chest pain
Check:
Common: A significant increase in plasma creatine kinase levels was commonly observed in the group receiving irbesartan (1.7%). However, none of the increases were associated with clinically identifiable skeletal muscle events.
for hypertension with renal disease and2type 1 diabetes: In addition to the adverse drug reactions mentioned under hypertension, in diabetic hypertensive patients with microalbuminuria and normal renal function, there were reported 0.5%of patients (i.e., occasionally) developed postural dizziness and postural hypotension, exceeding the placebo group.
In diabetic hypertensive patients with chronic renal insufficiency and significant proteinuria, there were reports of>2% of patients experienced the following adverse reactions and exceeded the placebo group.
Neurological abnormalities:
Very common: Dizziness
Common: postural dizziness
Vascular abnormalities:
Common: upright hypotension
Skeletal muscle, connective tissue and bone abnormalities:
Common: skeletal muscle pain
Check:
The incidence of hyperkalemia was higher in the irbesartan-treated diabetic patients than in the placebo group. In diabetic hypertensive patients with microalbuminuria and normal renal function, those in the 300 mggroup on irbesartan had29.4% (are very common))present with hyperkalemia (³5.5 mEq/L), whereas the incidence of hyperkalemia in the placebo group was 22%. In diabetic hypertensive patients with chronic renal insufficiency and significant proteinuria, the application of irbesartan300 mg in the group with46.3% (are very common)) “font-family:equivocal”>present with hyperkalemia (³5.5 mEq/L), whereas the incidence of hyperkalemia in the placebo group was 26.3%. In hypertensive patients with progressive diabetic nephropathy treated with irbesartan, hemoglobin reduction was seen in 1.7% of patients (which is common), but was not clinically significant.
In addition, the following adverse reactions have been reported since the introduction of irbesartan:
Immune system abnormalities:
Very rare: like other angiotensin-IIAs with receptor antagonists, hypersensitivity reactions such as rash, urticaria, and angioneurotic edema have occurred in a small number of cases.
Metabolic and nutritional abnormalities:
Hyperkalemia
Nervous system abnormalities:
Headache, vertigo
Ear and vagal abnormalities:
Tinnitus
Gastrointestinal abnormalities:
Lack of taste
Hepatobiliary abnormalities:
Elevated liver enzymes, hepatitis, jaundice, abnormal liver function
Skeletal muscle, connective tissue and bone abnormalities:
myalgia (associated with elevated plasma creatine kinase levels in some cases), arthralgia, and painful muscle spasms
Renal and urinary tract abnormalities:
Renal impairment, including individual cases of renal failure in patients at risk
Systemic abnormalities:
Weakness
Diseases of the blood and lymphatic system
Thrombocytopenia
Dermal and subcutaneous tissue disorders:
Leukocyte rupture vasculitis
[Contraindicated]
Known hypersensitivity to the ingredients of this product.
During the first4to9months.
Lactation.
Diabetes or moderate to severe renal impairment (GFRless than60 ml/min/1.73 m2) patients cannot use this product in combination with aliskiren.
This product should not be used in combination with angiotensin-converting enzyme inhibitors (ACEIs) in patients with diabetic nephropathy.
[Precautions]
Renin-angiotensin-aldosterone system ( RAAS)Dual blockade: Compared to single agents,RAASdual blockade increases the risk of hypotension, hyperkalemia, and abnormal renal function, so it is not recommended with angiotensin-converting enzyme inhibitors (ACEI) or aliskiren concomitantly. Patients with diabetes mellitus or moderate to severe renal impairment (GFR less than60 ml/min/1.73 m2Concomitant use of this product with aliskiren is contraindicated in patients with .
Patients with diabetic nephropathy should not combine this product with angiotensin-converting enzyme inhibitors (ACEIs) in combination.
General considerations: For those whose vascular tone and renal function are largely dependent on renin- angiotensin-aldosterone system activity (e.g., patients with severe congestive heart failure or in patients with renal disease including renal artery stenosis), treatment with angiotensin-converting enzyme inhibitors or angiotensinIIreceptor antagonists that affect this system is associated with the development of acute hypotension, azotemia, oliguria, or, rarely, acute renal failure. As with any antihypertensive drug, excessive blood pressure lowering in patients with ischemic cardiomyopathy or ischemic cardiovascular disease may lead to myocardial infarction or stroke.
Fetal/Newborn Morbidity and mortality:
Although there is no experience with the use of this product in pregnant women, in utero exposure to ACE in mid to late gestation has been reported span>inhibitors may lead to developmental fetal injury and death. Therefore, in contrast to any direct action of renin-angiotensin -Similar to drugs of the 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.
Low blood pressure-Patients with hypovolemia: In hypertensive patients without other comorbidities, this product rarely causes hypotension. Similar to ACE inhibitors, in sodium-deficient/in patients with hypovolemia, such as those receiving heavy diuretics and/ or salt restriction Symptomatic hypotension may occur in patients on treatment or hemodialysis. Before starting irbesartan therapy, it is important to correct hypovolemia and/ or sodium deficiency or consider a lower starting dose.
Renal vascular hypertension: Patients with bilateral renal artery stenosis or stenosis occurring in the arteries of a single functioning kidney on a dose that affects renin-angiotensin-aldosterone system In the presence of an increased risk of severe hypotension and renal insufficiency, increased serum creatinine and/ or urea nitrogen levels have been reported. Although there is no experience with this product in patients with unilateral or bilateral renal artery stenosis, similar effects of angiotensinIIreceptor antagonists should be considered.
Renal Impairment and Renal Transplantation: Regular monitoring of serum potassium and creatinine is recommended when this product is used in patients with renal impairment. There is no experience with the use of this product in patients who have recently undergone renal transplantation.
Combined with2Type Hypertensive patients with diabetes mellitus and renal disease: In all subgroups, analysis of the results of studies in patients with advanced renal disease showed inconsistent effects of irbesartan on renal and cardiovascular events. In particular, the product appears to be of less benefit to women and non-white populations.
Hyperkalemia: as with other conditions affecting renin– =”font-family:equivocal”>Angiotensin-aldosterone system, hyperkalemia may occur during the use of this product, especially in the presence of renal impairment, due to diabetic renal impairment, or in the presence of a diabetic kidney. impairment, significant proteinuria due to diabetic renal impairment and/ or heart failure. Close monitoring of serum potassium levels in these patients is recommended.
Lithium: It is not recommended to combine this product with lithium.
Primary aldosteronism: Patients with primary aldosteronism are usually more susceptible to drugs that inhibit renin by -antihypertensive drugs that do not respond to the angiotensin system. Therefore, this product is not recommended for these patients.
Race: As observed with angiotensin-converting enzyme inhibitors, irbesartan and other angiotensin antagonists are significantly less effective in lowering blood pressure in blacks than in non-blacks, possibly because of the higher proportion of hypertensive patients with low renin levels.
Effect on the ability to drive and operate machinery: The effect of irbesartan on the ability to drive and operate machinery has not been studied, but based on its pharmacodynamic properties, irbesartan may not have an effect on such ability. When driving or operating machinery, one should consider that occasional dizziness or fatigue can occur during hypertension treatment.
[For pregnant and lactating women]
Pregnancy:
Direct action on renin– drugs that act on the angiotensin system may cause damage or even death in the developing embryo. Therefore, unlike any drugs that act directly on renin- Similar to angiotensin- aldosterone system drugs, this product should not be used during pregnancy. If pregnancy occurs during treatment, treatment with this product must be discontinued as soon as possible. As a safety precaution, it is best not to use this product during the first trimester of pregnancy. Switch to an appropriate alternative treatment before planning a pregnancy. During the first4months to9months of pregnancy span style=”font-family:isoline”>months, substances that act directly on the renin-angiotensin system can cause fetal and neonatal renal failure, fetal cephalic dysplasia and fetal death; therefore, it is contraindicated from 4months tomonths of gestation. family:Arial”>9months pregnant women. If pregnancy is detected, the product should be discontinued as soon as possible and cranial and renal function should be ultrasounded if treated for a longer period of time due to neglect.
Lactation: This product is contraindicated during lactation. It is not known whether irbesartan is secreted into human breast milk. Irbesartan can be secreted into rat milk.
[Pediatric use]
The safety and efficacy of this product in children have not been established.
[Geriatric use]
Although75 years Older adults above 75 mg may be considered as a starting dose, but no dose adjustment is usually required for older patients. See [Pharmacokinetics]
[Drug Interactions]
Diuretics and other antihypertensive drugs: When this product is combined with other blood pressure lowering drugs, the hypotensive effect may be enhanced. However, it can be safely combined with other blood pressure-lowering drugs such as long-acting calcium channel blockers,breceptor blockers, and thiazide diuretics. When the first use of this product has been preceded by a high-dose diuretic may result in risk of volume depletion and hypotension.
Potassium-supplementing drugs and potassium-preserving diuretics: based on other drugs that can affect renin-Clinical experience with drugs of the angiotensin system suggests that the combination of potassium-preserving diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs that increase serum potassium levels (e.g., heparin sodium) may result in increased, sometimes severe, serum potassium levels, and close monitoring of potassium levels is required in such patients and is therefore not recommended.
Lithium: Reversible increases in serum lithium and toxic effects have been reported when lithium and angiotensin-converting enzyme inhibitors are combined.
Therefore, the combination of this product with lithium is not recommended. If this product needs to be combined with lithium, careful monitoring of serum lithium concentrations is recommended.
Non-steroidal anti-inflammatory drugs (NSAIDs): the antihypertensive effects of angiotensin II receptor antagonists (including irbesartan), which can be NSAIDs (including selectiveCOX-2inhibitors) are diminished. The combination of angiotensinIIreceptor antagonists (including irbesartan) in patients with reduced blood volume (including those treated with diuretics), elderly, or pre-existing renal impairment with NSAIDs (including selectiveCOX-2inhibitors) therapy may lead to deterioration of renal function, including possible acute renal failure, which is usually reversible. Combinations should be administered with caution and renal function should be monitored regularly.
RAS(renin-Angiotensin-Dual blockade of the aldosterone) system: compared with monotherapy, concomitant use of angiotensin receptor blockers, ACEinhibitors , or aliskiren, causing a double blockade of the RASsystem, which can elevate the risk of hypotension, hyperkalemia, and abnormal renal function, including acute renal failure. Blood pressure, renal function, and electrolytes should be closely monitored. Diabetes or moderate to severe renal impairment (GFRless than60 ml/min /m2) is contraindicated in patients with concomitant use of this product with aliskiren-containing drugs, and is not recommended in other patients.
Angiotensin-converting enzyme inhibitors (ACEIs = “font-family:equivocal”>): This product is not recommended for use in combination with ACEIs.
This product is compatible withACEIis contraindicated in patients with diabetic nephropathy and is not recommended for use in other patients.
Additional Information About Drug Interactions: In healthy male subjects, when combined with irbesartan150 mg, the pharmacokinetics of digoxin were not altered when combined with irbesartan. Irbesartan pharmacokinetics were not affected when combined with hydrochlorothiazide. Irbesartan is primarily metabolized by CYP2C9 and to a lesser extent by glucuronidation. Inhibition of the glucuronosyltransferase pathway does not lead to clinically meaningful interactions. In in vitro assays, it was observed that irbesartan and warfarin, toluenesulfonylurea (CYP2C9substrate) and nifedipine (CYP2C9inhibitor). However, in healthy male subjects, no meaningful pharmacokinetic or pharmacodynamic interactions were observed when irbesartan and warfarin were combined. When combined with nifedipine, the pharmacokinetics of irbesartan were not affected. The effect of CYP2C9inducing agents such as rifampin on the pharmacokinetics of irbesartan has not been studied. Based on in vitro test data, and those whose metabolism relies on cytochromeP450isozymesCYP1A1,CYP1A2, the CYP2A6, CYP2B6,CYP2D6,CYP2E1orCYP3A4drugs do not interact.
[Drug overdose]
Adults on this product at doses up to 900 mg/day for continuous8weeks of dosing showed no toxicity. Irbesartan overdose most likely manifests as hypotension and tachycardia; bradycardia also occurs. There is no specific information related to the treatment of overdose with this product. Patients should be monitored closely and treatment should be symptomatic and supportive. Recommended measures include emetic and/ or gastric lavage. Activated charcoal is useful for drug overdose treatment. Hemodialysis does not clear irbesartan.
[Pharmacology and Toxicology]
Erbesartan is a potent, orally active selective angiotensin-IIreceptor (AT1subtype) antagonists.
Regardless of the source or synthetic pathway of angiotensin-II,
it should block all angiotensin mediated by AT1receptors -II action. Its effect on angiotensin-II receptors (AT1) selective antagonism leads to increased plasma renin and angiotensin-II Elevated levels and decreased plasma aldosterone levels. Serum potassium is not significantly affected when the recommended dose of irbesartan alone is administered to patients without electrolyte disturbances. Irbesartan does not inhibit angiotensin-converting enzyme (ACEkinaseII), which in the presence of this enzyme produces angiotensin-II, which also degrades bradykinin to inactive metabolites. The activity of irbesartan does not require metabolic activation.
In healthy subjects, a single oral dose of 300 mg of irbesartan was associated with an elevated effect of inhibition of angiotensin-II. Dose-related. 150 mg or 300 mg oral doses produced a complete suppressive effect (100%) 4 hours after dosing, with partial suppression remaining for up to 24 hours (60% and 40% at 300 mg and 150 mg, respectively).
In patients with hypertension, inhibition of angiotensin-II receptors after long-term administration of irbesartan caused angiotensin-II plasma concentrations 1.5-2-fold and plasma renin levels 2-3-fold. Aldosterone levels usually decreased after irbesartan administration, but potassium levels were not significantly affected at the recommended dose.
In patients with hypertension, long-term oral administration of irbesartan (up to 300 mg) had no effect on glomerular filtration rate, renal plasma flow, or filtration fraction. In a multi-dose dosing study in hypertensive patients, irbesartan had no clinically meaningful effect on fasting triglycerides, total cholesterol, HDL-cholesterol, or fasting glucose concentrations. Irbesartan had no effect on serum uric acid and no pro-uric acid excretion during long-term oral administration.
There was no evidence of abnormal organismal or target organ toxic effects at clinically relevant doses. In preclinical safety studies, high doses (murine doses of³250 mg/kg/day; the dose for rhesus monkeys is³100mg/kg/100mg/kg/ =”font-family:equine”>day) of irbesartan resulted in a decrease in erythrocyte parameters (erythrocyte count, hemoglobin, hematocrit). At very high doses (³500 mg/kg/day ), Irbesartan induces renal degenerative effects (e.g., interstitial nephritis, tubular swelling, elevated plasma urea nitrogen and creatinine concentrations) in rats and rhesus monkeys, which are thought to be secondary to the hypotensive effects of the drug, the latter of which may lead to inadequate renal perfusion. Moreover, irbesartan induces hyperplasia/hypertrophy of the glomerular parametrium (when used in rats at doses of³90mg/kg/day; for rhesus monkeys the dose is³10 mg/kg/day). All these changes are thought to be due to the pharmacological effects of Irbesartan. For the therapeutic doses of irbesartan used in humans, the hyperplasia/ of glomerular parietal cells was not associated with it.
There is no evidence that this drug is mutagenic, mitogenic, or carcinogenic.
Animal studies of irbesartan have shown transient toxic effects in murine embryos (increased renal pelvis formation and ureteral or subcutaneous edema) that resolved after birth. In rabbit experiments, abortion or early absorption was observed at doses that significantly induced toxic effects in females. No teratogenic effects were observed in murine and rabbit experiments.
[Pharmacokinetics]
After oral administration, irbesartan is well absorbed: its absolute bioavailability is approximately 60%to80%. Ingestion does not significantly affect its bioavailability.
The binding rate of Irbesartan plasma protein is about 96%, which is almost not and blood cells, with a distribution volume of 53 to 93 L.
given orally or intravenously14C-after irbesartan, the blood circulation is 80%to85% of the radioactivity comes from the prototype irbesartan. Irbesartan is metabolized in the liver by oxidation in combination with glucuronide. The major circulating metabolite is glucuronide-binding irbesartan (approximately 6%). In vitro experiments have shown that irbesartan is mainly produced by cytochromeP450enzymeCYP2C9 oxidative metabolism, isoenzyme CYP3A4 had almost no effect.
The pharmacokinetics of irbesartan are between10 to600mgrange showing linearity and dose correlation. A failure to increase proportionally is observed at oral doses greater than600 mg (twice the maximum recommended dose); the mechanism is unclear. After oral administration approximately1.5 to2hours to reach peak plasma concentration. Total body clearance and renal clearance were 157~ respectively 176and3.0～3.5 ml/min, the terminal clearance half-life of irbesartan is11to15 hours. Steady-state plasma concentrations were achieved over three days with once-daily dosing. Limited intra-plasma accumulation after repeated once-daily dosing (<20%). Higher concentrations of irbesartan were observed in female hypertensive patients in one study. However, there was no difference in its half-life and accumulation. No drug dose adjustment was required in female patients. The Cmax and AUCvalues in older subjects (³65years) than those younger subjects (18~40years) high. However the terminal half-life was not significantly altered. Dose adjustment was also not required in elderly patients. See [Geriatric Use]
Erbesartan and its metabolites are excreted by the biliary tract and kidneys. After oral or intravenous administration of14C- irbesartan, approximately family:Arial”>20% of the radioactivity can be recovered in the urine and the rest excreted in the feces. Less than2% of the dose is excreted in the urine as a prototype.
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.
Hepatic Impairment: In patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan were not significantly altered. No pharmacokinetic studies were performed in patients with severe hepatic impairment.
[Storage] 30C below dry place. .
[Package] PVC solid pharmaceutical hard tablets/aluminum foil for pharmaceutical packaging, 7 tablets/plate/box.
[Expiration date] 24 months
[Executive Standard
[Approval number] 国药准字H20000513
[Manufacturer
Company name: Jiangsu Hengrui Pharmaceutical Co.
Production Address: No. 38, Huanghe Road, Lianyungang Economic and Technological Development Zone
Postal code: 222047
Phone number: 800-8283900 400-8283900
Fax number: 0518-85463261
Website:http://www.hrs.com.cn