Date of approval.
Date of revision.
Olmesartanate Tablets Instructions
Please read the instructions carefully and use under the guidance of your physician
Discontinue use of this product as soon as pregnancy is detected. Drugs that act directly on the renin-angiotensin system that
Can cause damage and death in the developing fetus
Drug Name
Generic Name: Olmesartan Tablets
English name: Olmesartan Medoxomil Tablets
Hanyu Pinyin: Aomeishatanzhi Pian
Ingredients
The main ingredient of this product is Olmesartan ester.
Chemical name: 2,3-dihydroxy-2-butenyl-4-(1-hydroxy-1-methylethyl)-2-propyl-1-[p-(o-1H-tetrazol-5-phenyl)benzyl]imidazole-5-carboxylate, cyclic 2,3-carbonate
Chemical structure formula.
Molecular formula: C29H30N6O6
Molecular weight: 558.59
Properties
Appearance] This product is white or off-white film-coated tablets, which appear white or off-white after removing the coating.
Indications
This product is indicated for the treatment of hypertension.
Control of hypertension is part of comprehensive management of cardiovascular risk. Comprehensive management measures may need to include: lipid control, diabetes management, antithrombotic therapy, smoking cessation, physical activity, and sodium intake restriction.
Elevated systolic or diastolic blood pressure both increase cardiovascular risk. At higher levels of basal blood pressure, the absolute increase in risk per mm Hg of blood pressure elevation is higher. The relative degree of risk reduction obtained by lowering blood pressure is similar in people with different absolute cardiovascular risks. In patients with severe hypertension, a slight reduction in blood pressure provides a greater clinical benefit.
In adults with hypertension, in general, lowering blood pressure reduces the risk of cardiovascular events, primarily stroke, and myocardial infarction.
However, there is no evidence from controlled clinical trials of this product to reduce cardiovascular risk.
Specification】20mg
Dosage]
The dose should be individualized. In patients with normal blood volume, the recommended starting dose as monotherapy is usually 20mg once daily. The dose may be increased to 40mg for patients who require further blood pressure reduction after 2 weeks of treatment.
Doses greater than 40 mg have not shown greater blood pressure lowering effects. When the daily dose was the same, twice daily dosing did not show superiority compared to once daily dosing.
This product can be taken with or without food. It can be used in combination with other diuretics or in combination with other antihypertensive drugs.
No dose adjustment is necessary for the administration of this product to elderly patients with moderate to significant hepatic or renal impairment (creatinine clearance <40mL/min) (see [Pharmacokinetics] for special populations).
Olmesartanate must be administered under close medical supervision in patients with possible hypovolemia (e.g., patients treated with diuretics, especially those with renal impairment), and a lower starting dose may be considered.
[Adverse Reactions].
1. Clinical trial experience
The safety of olmesartanate was evaluated in controlled clinical trials in up to 3,275 patients, of whom approximately 900 were treated for at least 6 months and more than 525 were treated for at least 1 year. The results showed that olmesartanate was well tolerated, with an adverse event rate similar to that of the placebo group. Adverse events were usually mild and transient and were independent of differences in dose, gender, age and race.
In the placebo-controlled clinical trial, the only adverse event with an incidence greater than 1% in patients treated with olmesartanate and higher than in the placebo-treated group was dizziness (3% vs. 1%).
Adverse events with an incidence lower than or similar to the placebo group and greater than 1% were: back pain, bronchitis, elevated creatine phosphokinase, diarrhea, headache, hematuria, hyperglycemia, hypertriglyceridemia, flu-like symptoms, pharyngitis, rhinitis, and sinusitis.
The incidence of cough was similar in patients in the placebo group (0.7%) and in the olmesartanate group (0.9%).
Adverse events with an incidence similar to the placebo group and less than 1% greater than 0.5% were: chest pain, malaise, pain, peripheral edema, dizziness, abdominal pain, dyspepsia, gastroenteritis, nausea, tachycardia, hypercholesterolemia, hyperlipidemia, hyperuricemia, joint pain, arthritis, muscle pain, bone pain, rash and facial edema. It is not clear whether the above adverse events are related to the administration of this product.
Laboratory findings: Changes in clinically significant laboratory parameters rarely correlated with olmesartanate in controlled clinical trials.
Hemoglobin and hematocrit: Occasionally, a slight decrease in hemoglobin and hematocrit was seen (an average decrease of approximately 0.3 g/dL and 0.3 volume percent, respectively).
Liver function tests: Occasionally, elevated liver enzymes and/or elevated blood bilirubin were seen, but returned to normal on their own.
2. Post-marketing experience
The following are post-marketing reported adverse reactions. Because these adverse reactions were spontaneously reported from an indeterminate number of patients, their incidence and causal relationship to the drug cannot usually be assessed with certainty.
Systemic: malaise, angioedema, anaphylactic reactions.
Gastrointestinal: vomiting, stomatitis diarrhea-like enteropathy.
Metabolic and nutritional system: hyperkalemia.
Musculoskeletal system: rhabdomyolysis.
Genitourinary system: acute renal failure, elevated blood creatinine.
Skin and appendages: alopecia, pruritus, urticaria.
Data from a controlled trial and epidemiologic study suggest that high-dose olmesartan administration may increase cardiovascular (CV) risk in patients with diabetes, but overall data are inconclusive. A randomized, placebo-controlled, double-blind ROADMAP study (Randomized Trial of Olmesartan and Diabetic Microalbuminuria Prevention, n=4447) evaluated olmesartan 40 mg/day vs. placebo in patients with type 2 diabetes, normoalbuminuria, and at least 1 other risk factor for CV disease (with or without hypertension). The study achieved its primary endpoint of delaying the onset of microalbuminuria, but olmesartan had no benefit in terms of reducing glomerular filtration rate (GFR). The results showed that CV mortality (specifically sudden cardiac death, fatal myocardial infarction, fatal stroke, and hemodynamic reconstruction death) was higher in the olmesartan group than in the placebo group (15 cases in the olmesartan group vs. 3 cases in the placebo group, HR 4.9, 95% confidence interval [CI] 1.4, 17), but the risk of nonfatal myocardial infarction was lower in the olmesartan group (HR 0.64, 95% CI 0.35, 1.18).
The epidemiological study included patients aged 65 years and older with a total exposure > 300,000 patient-years. The subgroup of diabetic patients who received high-dose olmesartan (40 mg/d) for up to > 6 months had a higher risk of death than diabetic patients receiving other angiotensin receptor blockers (HR 2.0, 95% CI 1.1, 3.8). In contrast, the risk of death was lower in the high-dose olmesartan group of nondiabetic patients than in nondiabetic patients receiving other angiotensin receptor blockers (HR 0.46, 95% CI 0.24, 0.86). No differences were seen between patients in the low-dose olmesartan group and those receiving other angiotensin receptor blockers or receiving treatment for <6 months.
In conclusion, the above data raise concern that the use of high-dose olmesartan in patients with diabetes may lead to an elevated CV risk. Of concern, however, is the reliability of the results for elevated CV risk. It should be noted that observations from large epidemiological studies regarding survival benefit in non-diabetic patients are similar to the adverse outcomes in diabetic patients.
Contraindications]
This product is contraindicated in patients with hypersensitivity to the ingredients contained in this product.
This product should not be used in combination with aliskiren in patients with diabetes mellitus.
Precautions]
Fetal toxicity
In mid to late pregnancy, the use of drugs that act directly on the renin-angiotensin system can decrease fetal renal function and increase fetal and neonatal morbidity and mortality. The resulting hypohydramnios can be associated with fetal pulmonary insufficiency and skeletal deformities. Potential neonatal adverse effects include craniosynostosis, anuria, hypotension, renal failure, and death. The use of this product should be discontinued as soon as pregnancy is detected (see [Use in Pregnant and Lactating Women]).
Neonatal morbidity
This product should not be used for the treatment of hypertension in children under 1 year of age. Drugs that act directly on the renin-angiotensin system can affect the development of the immature kidney.
Hypotension in patients with hypovolemia or hyponatremia
Symptomatic hypotension may occur after the first dose of this product in patients with hypovolemia or low sodium (e.g., those treated with high-dose diuretics) and must be treated with this drug under careful medical supervision. If hypotension occurs, the patient should lie on his or her back and receive intravenous saline if necessary. Once the blood pressure is stable, treatment with this drug may be continued.
Renal impairment
The use of ACE inhibitors and angiotensin receptor antagonists in those patients whose renal function is dependent on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure) has been associated with oliguria and/or progressive azotemia, acute renal failure, and/or death (rare). Treatment with olmesartan in such patients may be expected to produce similar results.
Renal insufficiency
Olmesartan blood concentrations are elevated in patients with renal insufficiency compared to patients with normal renal function. After multiple doses, the AUC in patients with severe renal impairment (creatinine clearance <20 mL/min) was approximately three times the normal value. No pharmacokinetic studies of olmesartan have been performed in patients receiving hemodialysis. No starting dose adjustment is required in patients with moderate to significant renal insufficiency (creatinine clearance<40mL/min).
Hepatic insufficiency
Increased AUC0®¥ and maximum blood concentration (Cmax) were observed in patients with moderate hepatic impairment compared to controls, with an approximately 60% increase in AUC. No adjustment of the starting dose is required in patients with moderate to significant hepatic insufficiency.
Renal artery stenosis
It has been reported that ACE inhibitors may increase blood creatinine or blood urea nitrogen (BUN) in patients with unilateral or bilateral renal artery stenosis. There is no experience with long-term use of olmesartanate in such patients, but similar results may occur.
Stomatitis diarrhea-like enteropathy
Severe chronic diarrhea with significant weight loss has been reported in patients taking olmesartan for several months to several years. Intestinal biopsies of patients often show signs of villi atrophy. If a patient develops these symptoms while taking olmesartan, other etiologies should be ruled out. In the absence of other etiologies, consider discontinuing this product.
Black patients
As with other ACE inhibitors, beta-blockers, and other angiotensin receptor blockers, this product is less effective in lowering blood pressure in black patients (usually those with low renin).
Pregnant and lactating women]
In the middle and late stages of pregnancy, the use of drugs that act directly on the renin-angiotensin system can reduce fetal renal function and increase fetal and neonatal morbidity and mortality. The resulting hypohydramnios can be associated with fetal lung hypoplasia and skeletal deformities. Potential neonatal adverse effects include craniosynostosis, anuria, hypotension, renal failure, and death. The product should be discontinued as soon as pregnancy is detected. These adverse outcomes are usually associated with the use of these drugs in the middle and late stages of pregnancy. Most epidemiological studies addressing fetal abnormalities following early gestational exposure to antihypertensives do not distinguish between drugs acting on the renin-angiotensin system and other antihypertensive drugs. Proper control of maternal blood pressure during pregnancy is important to optimize both maternal and fetal outcomes.
In the rare cases where an appropriate alternative drug acting on the renin-angiotensin system cannot be found, the pregnant woman should be informed of the potential risks of the drug to the fetus and a series of ultrasounds should be performed to assess the intra-amniotic condition. When low amniotic fluid is found, the drug should be discontinued unless it is necessary to save the life of the pregnant woman. Perform fetal testing based on gestational weeks. However, patients and physicians should be aware that in the presence of low amniotic fluid, the fetus may have sustained, irreversible damage. Infants who have been exposed to this product in utero should be closely monitored for hypotension, oliguria, and hyperkalemia (see [Pediatric Dosage]).
There is no clinical experience with the use of this product in pregnant women.
It is not known whether olmesartan can be secreted via breast milk, but small amounts are secreted in the milk of nursing rats. Because of potential adverse effects on nursing neonates, the importance of the drug to the mother must be considered in deciding to discontinue nursing or discontinue the drug.
Pediatric Dosage]
Neonates who have been exposed to this drug in utero: If oliguria or hypotension occurs, treat with blood pressure maintenance and renal perfusion. Blood exchange therapy or dialysis may be used to reverse hypotension and/or as an alternative therapy for renal dysfunction.
The anti-hypertensive effect of this product was evaluated by a randomized, double-blind clinical trial conducted abroad in pediatric patients aged 1 to 16 years. The pharmacokinetics of this product were evaluated in pediatric patients aged 1 to 16 years. The product was usually well tolerated in pediatric patients, and the incidence of adverse effects was similar to that of adult patients.
It has not been shown to be effective in pediatric patients less than 6 years of age.
This product should not be used for the treatment of hypertension in children under 1 year of age. The renin-angiotensin-aldosterone system (RAAS) plays a key role in kidney development. In very young mice, RAAS inhibitors cause abnormal kidney development. Drugs that act directly on the renin-angiotensin-aldosterone system (RAAS) can affect the normal development of the kidney.
[Geriatric Use].
In clinical trials, no overall differences in efficacy or safety were observed between elderly patients and younger patients, and no dose adjustment was required for elderly patients. However, the possibility of higher sensitivity in some older individual patients cannot be ruled out.
Drug Interactions]
Olmesartanate is not metabolized by the hepatic cytochrome P450 system and has no effect on P450 enzymes. Therefore, drug interactions related to the inhibition, induction or metabolism of these enzymes are not expected.
There were no significant drug interactions with the combined application of digoxin or warfarin in healthy subjects, nor did the combined application of antacids [Al(OH)3/Mg(OH)2] significantly alter the bioavailability of olmesartan.
Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors).
Co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including olmesartanate, in elderly patients, patients with hypovolemia (including those receiving diuretics), or patients with impaired renal function may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Regular monitoring of renal function should be performed in patients receiving olmesartanate and NSAID therapy.
NSAIDs (including selective COX-2 inhibitors) may reduce the antihypertensive effects of angiotensin II receptor antagonists (including olmesartanate).
Dual inhibition of the renin-angiotensin system (RAS).
The application of dual inhibition of the RAS with a combination of angiotensin receptor inhibitors, ACE inhibitors, or aliskiren increases the risk of hypotension, hyperkalemia, and altered renal function, including acute renal failure, compared with monotherapy. Most patients who use a combination of two RAS inhibitors do not achieve additional efficacy compared to the use of a single agent. In general, avoid the combination of RAS inhibitors. Blood pressure, renal function and electrolytes should be closely monitored in patients taking this and other drugs that affect the RAS.
This product should not be used in combination with aliskiren in patients with diabetes mellitus. Avoid combining this product with aliskiren in patients with renal impairment (glomerular filtration rate <60mL/min).
In combination with colesevelam hydrochloride.
Concomitant administration with the bile acid chelator colevelam hydrochloride decreases systemic exposure and peak blood levels of olmesartan. Olmesartan esters taken at least 4 hours earlier than colevelam may reduce drug interactions. Consider taking olmesartan at least 4 hours prior to the administration of colevelam hydrochloride.
Lithium
Increased serum lithium concentrations and reversible toxicity have been reported when lithium preparations are combined with angiotensin II receptor antagonists (including this product). Monitor serum lithium concentrations during co-administration.
Drug overdose]
Data on drug overdose in humans are limited. The most likely manifestations of overdose are hypotension and tachycardia. Bradycardia may occur if the parasympathetic nervous system (vagus nerve) is excited. If symptomatic hypotension occurs, appropriate treatment and supportive therapy should be given. Whether olmesartan can be cleared by hemodialysis is not known.
Pharmacology and Toxicology]
Pharmacological effects
Angiotensin I (Ang I) is converted to angiotensin II (Ang II) by angiotensin converting enzyme (ACE, kinase II). Angiotensin II is the main pressure-raising factor of the renin-angiotensin system, and its effects include constriction of blood vessels, promotion of aldosterone synthesis and release, stimulation of the heart, and promotion of sodium reabsorption by the kidney.
Olmesartan ester is a precursor drug that is absorbed and hydrolyzed by the gastrointestinal tract to olmesartan. Olmesartan is a selective angiotensin II type 1 receptor (AT1) antagonist that blocks the vasoconstrictive effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in vascular smooth muscle, and therefore acts independently of the Ang II synthesis pathway. Olmesartan has an affinity for AT1 that is more than 12,500-fold greater than that for AT2.
Blocking the renin-angiotensin system (RAS) using ACE inhibitors is a mechanism used by many drugs for hypertension, but ACE inhibitors also inhibit the degradation of bradykinin, whereas olmesartan ester does not inhibit ACE, so it does not affect bradykinin, and whether this difference is clinically relevant is unclear.
Blockade of angiotensin II receptors inhibits the negative feedback mechanism of angiotensin II regulation of renin secretion. However, the resulting increase in plasma renin activity and rise in circulating angiotensin II concentrations did not affect the antihypertensive effect of olmesartan.
Toxicological studies
Genotoxicity.
The in vitro Syrian hamster embryonic cell conversion assay and Ames assay for olmesartan and olmesartan ester showed no evidence of genotoxicity. Olmesartan and olmesartanate both caused chromosome breakage in cultured Chinese hamster lung cells in vitro; olmesartanate was positive in an in vitro mouse lymphoma thymidine kinase mutation test (this test was not performed with olmesartan).
Reproductive toxicity.
No reproductive toxicity was observed in female and male rats given olmesartan ester starting 2 and 9 weeks prior to mating at doses up to 1000 mg/kg/day (approximately 120 times the maximum recommended daily dose of MRHD in humans), respectively.
Carcinogenicity.
No carcinogenicity was seen in rats given orally olmesartanate for 2 years at a maximum dose of 2000 mg/kg/day, which is approximately 480 times the maximum recommended human dose (MRHD) of 40 mg/day based on body surface area. Two 6-month carcinogenicity studies were conducted in mice: p53 knockout mice were administered orally and Hras2 transgenic mice were administered orally by adulteration at a maximum dose of 1000 mg/kg/day (approximately 120 times the MRHD), and no carcinogenicity was observed.
Pharmacokinetics]
Olmesartan has a linear pharmacokinetic profile whether administered orally as a single dose (up to 320 mg) or as multiple doses (up to 80 mg/dose). Steady-state blood concentrations are achieved within 3-5 days, with no accumulation in plasma with once-daily dosing.
[Absorption]
Olmesartan ester is absorbed orally through the gastrointestinal tract and is rapidly and completely de-esterified and hydrolyzed to olmesartan, with an absolute bioavailability of approximately 26%. Peak blood concentration is reached after 1 to 2 hours of oral administration. Eating does not affect the bioavailability of olmesartan.
[Distribution]
Olmesartan has a plasma protein binding rate of 99%, does not penetrate red blood cells, and has a steady-state volume of distribution of approximately 17 liters.
In rats, Olmesartan does not easily cross the blood-brain barrier, but it can cross the placental barrier and be distributed to fetal rats, and to a small extent to rat milk.
[Metabolism and excretion]
Olmesartan esters are rapidly and completely converted to olmesartan and then not further metabolized. Olmesartan is eliminated in a biphasic manner, with a final elimination half-life of approximately 13 hours and a total plasma clearance of 1.3 L/hour and a renal clearance of 0.6 L/hour. Approximately 35% to 50% of the absorbed drug is excreted in the urine and the remainder is excreted in the feces via the bile.
[Pharmacokinetics in Special Populations]
Children: Studies of olmesartan pharmacokinetics in pediatric hypertensive patients aged 1 to 16 years, taking weight into account, have shown that clearance of olmesartan in pediatric patients is similar to that in adults. Pharmacokinetics in pediatric patients younger than 1 year of age have not been studied.
Elderly: The maximum plasma concentrations of olmesartan were similar in young adults and elderly (≥ 65 years). Mild accumulation of olmesartan was observed in older adults on multiple doses; the mean steady-state area under the drug curve (AUCss) was 33% higher in older adults, with a corresponding 30% reduction in renal clearance (CLR).
Hepatic insufficiency: AUC0®¥ and maximum blood concentration (Cmax) were increased in patients with moderate hepatic impairment, with an approximately 60% increase in AUC.
Renal insufficiency: The area under the drug-time curve (AUC) in patients with severe renal impairment (creatinine clearance less than 20 ml/min) after multiple doses was approximately three times greater than in those with normal renal function. No studies have been conducted in patients receiving hemodialysis.
[Drug Interactions]
Bile acid sequestrant cauleveram hydrochloride.
Concomitant administration of olmesartanate 40 mg with colevelam hydrochloride 3750 mg in healthy subjects resulted in a 28% reduction in Cmax and 39% reduction in AUC of olmesartan. When olmesartanate was taken 4 hours earlier than colavilan, it produced a smaller effect, with a 4% and 15% reduction in Cmax and AUC, respectively.
Storage】Store under 25℃ under shade and seal.
Package】Polyvinyl chloride solid pharmaceutical hard tablets and aluminum foil for pharmaceutical packaging, 7 tablets/plate, 14 tablets/box.
Expiration date】36 months
Execution Standard
Approval number】
【Marketing license holder
Company Name: Shenzhen Xinlitai Pharmaceutical Co.
Address: 37/F, Main Building, Chegongmiao Greenview Plaza, No. 6009 Shennan Avenue, Futian District, Shenzhen
Postal Code: 518040
Telephone number: 0755-83867888
Fax number: 0755-83867338
Website： http//:www.salubris.com
Manufacturer
Company name: Shenzhen Xinlitai Pharmaceutical Co.
Address: No. 38, Fenghuanggang Road, Xixiang Town, Baoan District, Shenzhen
Postal Code: 518102
Telephone number: 0755-83867888
Fax number: 0755-83867338
Website: http//:www.salubris.cn