Date of approval.
Date of revision.
Olmesartanate Hydrochlorothiazide Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
【Warning】 Once pregnancy is detected, stop using this product as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death in the developing fetus. See [Precautions] for more information on fetal toxicity.
Drug Name]
Generic name: Olmesartan ester hydrochlorothiazide tablets
English name: Olmesartan Medoxomil and Hydrochlorothiazide Tablets
Hanyu Pinyin: Aomeishatanzhi Qinglüsaiqin Pian
Ingredients
This product is a compound preparation, its composition is: each tablet contains Olmesartan 20mg and Hydrochlorothiazide 12.5mg.
Chemical Name.
Olmesartan ester: 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
Hydrochlorothiazide: 6-chloro-3, 4-dihydro-2H-1, 2, 4-benzothiadiazine-7-sulfonamide-1, 1-dioxide
Chemical structure formula.
Olmesartan ester hydrochlorothiazide Molecular Formula: Olmesartan ester (C29H30N6O6); Hydrochlorothiazide (C7H8ClN3O4S2)
Molecular weight: Olmesartan ester (558.59); hydrochlorothiazide (297.74)
Characteristic】
This product should be film-coated tablets, appearing white or off-white after removing the coating.
Indications
This product is suitable for the treatment of hypertension. It is suitable for patients whose blood pressure is not adequately controlled by olmesartanate or hydrochlorothiazide alone.
This product is a fixed-dose compound and is not indicated for the initial treatment of hypertension.
It may be used alone or in combination with other antihypertensive agents.
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 basal blood pressure levels, 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 on the reduction of cardiovascular risk with olmesartanate hydrochlorothiazide tablets.
Specification
Each tablet contains olmesartanate 20mg and hydrochlorothiazide 12.5mg.
Dosage]
Olmesartanate, as monotherapy in patients with normal blood volume, is usually recommended at a starting dose of 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 40mg 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.
No adjustment of the starting dose is necessary in elderly patients, patients with moderate to significant renal impairment (creatinine clearance <40mL/min), or patients with moderate to significant hepatic impairment (see [Pharmacokinetics] for special populations). In patients with possible hypovolemia (e.g., patients treated with diuretics, especially those with renal impairment), treatment with this product must be initiated under careful medical supervision and a lower starting dose may be considered (see [Precautions] for hypovolemia or hypotension in patients with low sodium).
The effective dose of hydrochlorothiazide is 12.5 mg to 50 mg once daily.
Compound therapy is usually initiated after satisfactory results have not been achieved with single component therapy with olmesartanate or hydrochlorothiazide.
This product is administered orally as one tablet once daily. This product can be taken with or without food.
The dose of this product should be individualized. The dose may be adjusted at intervals of 2 to 4 weeks based on the antihypertensive effect. In the dose range of 10mg/12.5mg to 40mg/25mg, the anti-hypertensive effect of this product is correlated with the dose administered.
The antihypertensive effect of olmesartanate hydrochlorothiazide tablets starts within one week and reaches the maximum antihypertensive effect at four weeks.
This product can be used in combination with other antihypertensive drugs.
If a patient has a creatinine clearance >30 mL/min.
can be treated with the regular dose of this product. In patients with more severe renal impairment, a medullary diuretic would be preferable to a thiazide diuretic, so this product is not recommended.
Dose adjustment is not required in patients with hepatic impairment (see [Pharmacokinetics] for special populations).
Adverse reactions]
Clinical trial experience
Olmesartan esters-hydrochlorothiazide
The safety of olmesartan esters-hydrochlorothiazide was evaluated in 1243 patients with hypertension. Olmesartan esters hydrochlorothiazide tablets were well tolerated, with an incidence of adverse events similar to that of placebo and a similar rate of clinical trial withdrawals due to adverse events. Adverse reactions were generally mild and transient and were not associated with differences in dose, sex, age, or race.
In a placebo-controlled clinical trial, adverse reactions with an incidence greater than 2% and higher than the placebo group included: nausea, hyperuricemia, dizziness, and upper respiratory tract infection.
Adverse reactions with an incidence greater than 2% but similar to or lower than the placebo group included: headache and urinary tract infections.
Other adverse events with an incidence greater than 1.0% reported in more than 1,200 hypertensive patients treated with olmesartane-hydrochlorothiazide in controlled or open trials, whether or not attributable to treatment, included: chest pain, back pain, peripheral edema, dizziness, abdominal pain, dyspepsia, gastroenteritis, diarrhea, elevated serum glutamate transaminase, elevated gamma-glutamyl transferase, elevated serum glutamate transaminase , elevated creatine phosphokinase, arthritis, arthralgia, myalgia, cough, rash, and hematuria.
Two cases of facial edema were reported in 1243 patients treated with olmesartane-hydrochlorothiazide. Angioedema has been reported with angiotensin II receptor antagonists.
Olmesartanate
Other adverse events with an incidence greater than 0.5% reported in over 3100 hypertensive patients receiving olmesartanate monotherapy in controlled or open trials, whether or not associated with drug therapy, include tachycardia and hypercholesterolemia.
Hydrochlorothiazide
Adverse reactions to hydrochlorothiazide are as follows: weakness, pancreatitis, jaundice (intrahepatic cholestatic jaundice), salpingitis, abdominal cramps, gastric irritation, aplastic anemia, granulocytic deficiency, leukopenia, hemolytic anemia, thrombocytopenia, purpura, photosensitivity, urticaria, necrotizing vasculitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonia and pulmonary edema, allergic reactions , muscle cramps, agitation, renal failure, renal dysfunction, interstitial nephritis, erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermolysis bullosa, transient blurred vision and xanthopsia.
Laboratory findings
Olmesartane-hydrochlorothiazide.
In controlled clinical trials, changes in clinically significant laboratory parameters showed little correlation with treatment with olmesartan esters-hydrochlorothiazide.
Creatinine, blood urea nitrogen: Elevated blood urea nitrogen and blood creatinine were observed in 1.3% of patients>50%. No patients in the olmesartane-hydrochlorothiazide clinical trial withdrew from the clinical trial due to elevated creatinine or blood urea nitrogen. Mean uric acid values: small elevation.
Hemoglobin and hematocrit: The percentage of patients treated with olmesartanate-hydrochlorothiazide who had a decrease in hemoglobin and hematocrit of more than 20% was 0.0% and 0.4% (1 case), respectively, compared with 0.0% and 0.0%, respectively, in the placebo-treated group. No patient discontinued the drug due to anemia.
Hydrochlorothiazide.
Hyperglycemia, glycosuria, hyperuricemia, electrolyte imbalances (including hyponatremia and hypokalemia), elevated cholesterol and triglycerides.
Post-marketing experience
The following post-marketing adverse reactions have been reported with olmesartanate hydrochlorothiazide tablets.
Systemic: malaise
Gastrointestinal.
Vomiting
Metabolic and nutritional disorders: hyperkalemia
Musculoskeletal.
Rhabdomyolysis
Skin and adnexa: alopecia, pruritus
Adverse reactions reported after the marketing of olmesartanate: peripheral edema, headache, cough, abdominal pain, nausea, vomiting, diarrhea, stomatitis diarrhea-like enteropathy, allergic reactions, rash, pruritus, angioedema, acute renal failure, elevated liver enzymes, elevated blood creatinine, hyperkalemia, myalgia and states of weakness such as malaise, fatigue, sleepiness, malaise.
A controlled trial suggested 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 delayed 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).
[Contraindication].
Contraindicated in patients with hypersensitivity to the ingredients contained in this product.
Due to the presence of hydrochlorothiazide, it is contraindicated in patients with anuria or hypersensitivity to other sulfonamides.
This product should not be used in combination with aliskiren in patients with diabetes mellitus.
Precautions] 1.
1. Fetal toxicity
In mid and 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 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 for a particular patient, the pregnant woman should be informed of the potential hazards of this product to the fetus and a series of ultrasounds should be performed to assess the intra-amniotic condition. When low amniotic fluid is detected, the product should be discontinued unless it is necessary to save the life of the pregnant woman. Fetal testing may be performed as appropriate, but this is based on the gestational week to determine if it should be performed. However, patients and physicians should be aware that it is possible that persistent and irreversible damage to the fetus may occur without hypohydramnios. Infants who have been exposed to this product in utero should be monitored closely for hypotension, oliguria, and hyperkalemia.
There is no clinical experience with the use of this product in pregnant women. No teratogenic reactions were observed when the 1.6:1 combination of olmesartanate and hydrochlorothiazide was given orally to pregnant mice at doses up to 1625 mg/kg/day (122 times the maximum recommended human dose on a mg/m2 basis) or to pregnant rats at doses up to 1625 mg/kg/day (280 times the maximum recommended human dose on a mg/m2 basis). In rat tests, fetal rat body weights were significantly lower than controls at doses of 1625 mg/kg/day (a toxic and sometimes lethal dose for the mother rat). The developmentally nontoxic dose in rats was 162.5 mg/kg/day, which is 28 times the maximum recommended human dose (40 mg olmesartanate/25 mg hydrochlorothiazide/day) on a mg/m2 basis.
Thiazides are able to cross the placental barrier and appear in the umbilical cord blood. There is a risk of the following in fetuses and newborns: jaundice, thrombocytopenia and other adverse reactions that may occur in adults.
2. Hypotension in patients with hypovolemia or low sodium
Patients with activated renin-angiotensin system, such as those with hypovolemia or hyponatremia (e.g., those treated with high-dose diuretics), as with any other angiotensin receptor antagonist, may experience symptomatic hypotension after the first dose of this drug and must be treated with this drug under close 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. A transient hypotensive reaction is not a contraindication to further treatment.
3. Patients with hepatic impairment
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, as minor changes in fluid and electrolyte balance can trigger hepatic coma.
4. Impaired renal function
Oliguria and/or progressive azotemia, acute renal failure and/or death (rare) may occur with the use of angiotensin-converting enzyme (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). Similar results may be expected with olmesartanate treatment in such patients.
It has been reported that ACE inhibitors may elevate blood creatinine or blood urea nitrogen (BUN) in patients with unilateral or bilateral renal artery stenosis, but there is no experience with long-term use of olmesartanate in such patients, but similar results may occur.
If progressive renal impairment becomes apparent, consider discontinuing diuretic therapy.
Thiazides should be used with caution in patients with severe renal disease. Thiazides can promote azotemia in patients with renal disease. In patients with renal impairment, accumulation effects of thiazides may occur.
5.
Hypotension
Symptomatic hypotension: Patients should be aware of the possibility of dizziness while taking this product, especially during the first few days of treatment, and should report this to the prescribing physician. Patients should be advised that if syncope occurs, the product should be discontinued until a physician is consulted.
All patients should be aware that inadequate fluid intake, profuse sweating, diarrhea, or vomiting can cause an excessive drop in blood pressure, which may also lead to dizziness and syncope.
6.
Electrolyte Imbalance
Olmesartane-hydrochlorothiazide
This product contains hydrochlorothiazide, which can cause hypokalemia and hyponatremia, and olmesartan, which can inhibit the renin-angiotensin system (RAS) and cause hyperkalemia. Serum electrolytes should be monitored regularly.
In a double-blind clinical trial of multiple doses of olmesartan ester and hydrochlorothiazide, the incidence of hypokalemia (serum potassium<3.4 mEq/L) in hypertensive patients was 2.1%; the incidence of hyperkalemia (serum potassium>5.7 mEq/L) was 0.4%. In this trial, no patient discontinued treatment due to changes in serum potassium.
Hydrochlorothiazide
Serum electrolytes should be measured periodically at appropriate intervals to detect possible electrolyte imbalances. All patients receiving thiazide therapy should be observed for clinical indications of fluid and electrolyte imbalances, such as hyponatremia, hypochloremic alkalosis, and hypokalemia. It is important to monitor serum and urine electrolytes when patients experience severe vomiting or when parenteral fluids are administered. Warning signs and symptoms of fluid and electrolyte imbalance, regardless of the cause, include dry mouth, thirst, weakness, sluggishness, drowsiness, restlessness, confusion, seizures, muscle pain or cramps, muscle fatigue, hypotension, hypuria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.
Hypokalemia may develop when severe cirrhosis is present or after prolonged treatment, especially when accompanied by active polyuria.
Inadequate oral administration of electrolytes can also produce hypokalemia. Hypokalemia can cause cardiac arrhythmias and may also increase the heart’s toxic side effects to digitalis or make such responses more sensitive (e.g., increased ventricular excitability).
Although the effects of any chloride deficiency are usually mild and do not require specific treatment except in specific cases (e.g., liver disease or renal disease), chloride supplementation may be required to treat metabolic alkalosis.
Dilutional hyponatremia can occur in patients with swelling in hot weather, and except in rare cases (where hyponatremia is life-threatening), the appropriate treatment is to restrict water intake rather than salt supplementation. In cases of actual hyponatremia, appropriate salt supplementation is an optional treatment option.
Thiazides increase the excretion of urinary magnesium and this can cause hypomagnesemia.
7. Effects on metabolism and endocrine
The dose of insulin or oral hypoglycemic drugs should be adjusted appropriately in diabetic patients. Hyperglycemia occurs with thiazide diuretics, so underlying diabetes mellitus may appear as a significant clinical manifestation during thiazide therapy.
Thiazides may reduce urinary calcium excretion. When no known disorder of calcium metabolism is present, thiazides may cause intermittent mild elevations of blood calcium. Significant hypercalcemia may be a manifestation of occult hyperparathyroidism. Therefore, thiazides should be discontinued before parathyroid function tests are performed.
Elevated cholesterol and triglycerides may be associated with thiazide diuretic therapy.
Thiazides may promote hyperuricemia or gout in some patients.
8. 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 villi atrophy. If a patient develops these conditions while taking olmesartan, other etiologies should be ruled out. In the absence of other etiologies, consider discontinuing this product.
9. Acute myopia and secondary angle-closure glaucoma
Hydrochlorothiazide contains a sulfonamide group that causes an idiosyncratic response, causing acute transient myopia and acute angle-closure glaucoma. Symptoms include acute loss of visual acuity and eye pain, which usually occur within hours to weeks after the first dose. Acute closed-angle glaucoma may result in permanent vision loss if not treated promptly. Hydrochlorothiazide should first be discontinued as soon as possible, and if intraocular pressure remains uncontrolled, immediate drug or surgical treatment should be considered. Risk factors for acute closed-angle glaucoma may include a history of allergy to sulfonamide-based drugs or penicillin.
10. Other
Hypersensitivity reactions may occur with the administration of thiazides, especially in patients with a history of allergy or bronchial asthma.
Cases of systemic lupus erythematosus exacerbated or provoked by thiazide diuretics have been reported.
Sympathectomy patients may increase the anti-hypertensive effect of this product.
11.
Use with caution in athletes
This product contains hydrochlorothiazide, a diuretic, and should be used with caution by athletes.
Pregnant women and nursing mothers
When pregnant women use the drug in the middle and late stages of pregnancy, the direct action of the drug on the RAS may cause damage to the developing fetus or even death. Once pregnancy is detected, the use of this product should be stopped as soon as possible. (See [Precautions] for fetal toxicity)
It is not known whether olmesartan can be secreted through 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.
Thiazides can cross the placental barrier and appear in the umbilical cord blood, and can also be secreted through breast milk. Because of the potential adverse effects on nursing newborns, the importance of the drug to the mother must be considered in order to discontinue nursing or discontinue the drug.
Pediatric Dosage]
Newborns 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.
Data on the safety and efficacy of the drug in children have not been established.
[Geriatric Use].
The sample size of elderly (³65 years) subjects in clinical trials of olmesartanate hydrochlorothiazide tablets was not sufficient to determine whether they responded differently to the drug than younger adult patients. Some relevant clinical trials also did not determine differences between older and younger adult patients. Given the greater likelihood of hepatic, renal or cardiac decline and concomitant disease or other medications in the elderly, dose selection for elderly patients should generally be cautious, generally starting at a low dose.
Olmesartan and hydrochlorothiazide are mainly excreted by the kidneys, and patients with impaired renal function are at an increased risk of toxic side effects to this product.
[Drug Interactions].
Olmesartan ester-hydrochlorothiazide
Agents that increase serum potassium
The combination of this product with other drugs that increase blood potassium levels may lead to hyperkalemia, and care should be taken to monitor blood potassium.
Olmesartanate
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 do not occur.
There were no significant drug interactions with the combined application of hydrochlorothiazide, 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.
Lithium
Serum lithium concentrations and toxicity have been reported to be increased when lithium preparations are combined with angiotensin II receptor antagonists, including olmesartan. Serum lithium concentrations should be monitored during co-administration.
Dual inhibition of the renin-angiotensin system (RAS).
Dual inhibition of the RAS by application 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 using a combination of two RAS inhibitors did 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 impaired renal function (glomerular filtration rate <60mL/min). This is because this combination therapy is associated with an increased risk of hypotension, hyperkalemia, and altered renal function (including acute renal failure) compared with monotherapy.
Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors).
The concomitant use of NSAIDs and ARBs may act synergistically and thereby reduce glomerular filtration rate. 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. Renal function should be monitored regularly 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).
In combination with colesevelam hydrochloride.
Concomitant administration with the bile acid sequestrant colevelam hydrochloride decreases the systemic drug 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 before taking colevelam hydrochloride.
Hydrochlorothiazide
Concomitant administration of the following drugs may interact with thiazide diuretics.
Alcohol, barbiturates, or narcotics – may contribute to the development of upright hypotension.
Glucose-lowering drugs (oral preparations and insulin) – may require dose adjustment of glucose-lowering drugs
Other antihypertensive drugs – additive or synergistic effects.
Cauleenamide and cauletipox resin – the presence of an anion exchange resin hinders the absorption of hydrochlorothiazide. Single dose administration of koleenamine or koletipol resin binds to hydrochlorothiazide and reduces the absorption of thiazides from the gastrointestinal tract by 85% and 43%, respectively.
Corticosteroids, ACTH – exacerbate electrolyte loss, especially leading to hypokalemia.
Ascending amines (e.g., norepinephrine) – may reduce the response to ascending amines, but not enough to prevent their use.
Non-depolarizing skeletal muscle relaxants (e.g., barrel-arrow toxin) – may enhance the response to myorelaxants.
Lithium – usually not administered concomitantly with diuretics. Diuretics reduce the renal clearance of lithium and highly increase the risk of lithium toxicity. The instructions for lithium preparations should be consulted before using the olmesartane-hydrochlorothiazide combination.
NSAIDs – The use of NSAIDs in some patients decreases the diuretic, pro-urinary sodium excretion, and anti-hypertensive effects of medullary collaterals diuretics, potassium-protective diuretics, and thiazide diuretics. Therefore, when olmesartanate-hydrochlorothiazide tablets and NSAIDs are used together, patients should pay close attention to monitor whether the diuretics achieve the desired effect.
[Drug overdose].
Olmesartanate
Information on drug overdose in humans is 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.
Hydrochlorothiazide
Human drug overdose is most commonly associated with signs and symptoms caused by electrolyte loss (hypokalemia, hypochlorhydria, hyponatremia) and dehydration due to excessive diuresis. The most common signs and symptoms of drug overdose are nausea and drowsiness. Hypokalemia may exacerbate cardiac arrhythmias if digitalis is used concomitantly. The extent to which hydrochlorothiazide can be eliminated by hemodialysis remains unknown.
Pharmacology and Toxicology
Pharmacological effects
Olmesartan ester is the precursor drug of olmesartan. Olmesartan is a selective angiotensin II type 1 receptor (AT1) antagonist, which blocks the vasoconstrictive effect of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor of vascular smooth muscle, so its effect is independent of the angiotensin II synthesis pathway. Olmesartan has an affinity for AT1 that is more than 12,500-fold greater than that for AT2. AT2 receptors have been found in many tissues, but this receptor has not been found to be associated with cardiovascular self-stabilization. The blockade of angiotensin II receptors by olmesartan inhibits the negative feedback mechanism of angiotensin II on renin secretion. However, the resulting increase in plasma renin activity and the rise in circulating angiotensin II concentration do not affect the antihypertensive effect of olmesartan.
Hydrochlorothiazide is a thiazide diuretic. Thiazides can affect the mechanism of electrolyte reabsorption by the renal tubules, leading directly to a near-equal increase in sodium and chloride excretion. The diuretic effect of hydrochlorothiazide indirectly reduces plasma volume, correspondingly increasing plasma renin activity, increasing aldosterone secretion, increasing urinary potassium loss, and decreasing serum potassium. The renin-angiotensin-aldosterone system is regulated by angiotensin II, so the combination of hydrochlorothiazide with angiotensin II receptor antagonists reverses the potassium loss associated with diuretics. The mechanism of action of thiazides against hypertension is not fully understood.
Hydrochlorothiazide produces diuretic effects within 2 hours of oral administration, peaking at approximately 4 hours and lasting 6-12 hours.
Toxicological studies
Genotoxicity.
Olmesartanate-hydrochlorothiazide (ratio 20:12.5) bacterial reversion mutation (Ames) test results were negative. Olmesartanate-hydrochlorothiazide (40:12.5, 20:12.5, 10:12.5) showed positive results in the in vitro chromosomal aberration test in Chinese hamster lung cells, and positive results were also seen for any ratio of olmesartanate and hydrochlorothiazide alone, with no synergistic effect in chromosomal aberration. Oral administration of olmesartane-hydrochlorothiazide (20:12.5 ratio) to mice at doses up to 3144 mg/kg resulted in a negative bone marrow micronucleus test.
Reproductive toxicity.
There is no clinical experience with the use of this product in pregnant women. Oral administration of olmesartanate with hydrochlorothiazide (20:12.5) to pregnant mice and rats at doses up to 1625 mg/kg/day (122 and 280 times the maximum recommended human dose, respectively, based on body surface area) did not show teratogenic reactions; 1625 mg/kg/day (a toxic and sometimes lethal dose for females) showed a reduction in embryo weight in rats. No developmental toxicity was observed in rats at 162.5 mg/kg/day (28 times the maximum recommended dose for humans based on body surface area).
Carcinogenicity.
Olmesartan ester hydrochlorothiazide: The carcinogenic potential of olmesartan ester-hydrochlorothiazide was not examined because there was no evidence of a relevant carcinogenic effect of the two single ingredients under conditions relevant to clinical use.
Olmesartanate: Olmesartanate was administered orally to rats at doses up to 2000 mg/kg/day (480 times the maximum recommended human dose based on body surface area) for two years without carcinogenicity. p53 knockout mice and Hras2 transgenic mice were administered orally at doses up to 1000 mg/kg/day (120 times the maximum recommended human dose based on body surface area), respectively. 120 times the maximum recommended human dose) for 6 months, and no carcinogenicity was observed.
Hydrochlorothiazide: Hydrochlorothiazide was administered to mice and rats at doses up to 600 mg/kg/day and 100 mg/kg/day by oral adulteration method for 2 years.
Pharmacokinetics]
Olmesartan showed linear pharmacokinetic properties regardless of single oral administration of olmesartan ester (maximum dose up to 320mg) or multiple oral administration (maximum dose up to 80mg/dose). Steady-state blood levels are achieved within 3-5 days, with no accumulation in plasma from once-daily dosing.
In healthy subjects, co-administration of olmesartanate with hydrochlorothiazide had no clinically relevant effect on the pharmacokinetics of each component.
[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 ester
Olmesartan has a plasma protein binding rate of 99% and does not penetrate red blood cells, with a steady-state volume of distribution of approximately 17 liters. Protein binding remained constant when olmesartan plasma concentrations were well above the concentration range obtained with the recommended dose.
In rats, olmesartan does not easily cross the blood-brain barrier, but can cross the placental barrier and be distributed to fetal rats, and to a lesser extent to rat milk.
Hydrochlorothiazide
The median time to peak concentration of hydrochlorothiazide after oral administration of olmesartan ester and hydrochlorothiazide is 1.5-2 hours after administration. The plasma protein binding of hydrochlorothiazide is 68% and the apparent volume of distribution is 0.83 to 1.14 L/kg.
Hydrochlorothiazide can cross the placental barrier and can be secreted into breast milk, but it cannot cross the blood-brain barrier.
[Metabolism and excretion]
Olmesartanate
Olmesartan esters are rapidly and completely converted to olmesartan without further metabolism. 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.
Hydrochlorothiazide
Hydrochlorothiazide is not metabolized, but it is rapidly eliminated by the kidneys. At least 61% of the oral dose is eliminated in its native form within 24 h. Plasma half-lives have been observed to fluctuate in the range of 5.6 to 14.8 h in 24 h plasma concentration assays.
[Pharmacokinetics in Special Populations]
Olmesartanate.
Children: The pharmacokinetics of olmesartan was studied in hypertensive patients aged 1 to 16 years. The clearance of olmesartan in pediatric patients was similar to that in adults when weight was taken into account. Olmesartan pharmacokinetics were not studied in pediatric patients younger than 1 year of age.
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; renal clearance (CLR) was 30% lower in older adults, and correspondingly the mean steady-state area under the drug curve (AUCss) was 33% higher in older adults.
Gender: There were slight differences in the pharmacokinetics of olmesartanate between women and men. The area under the drug-time curve (AUC) and peak blood concentration (Cmax) are 10-15% higher in women than in men.
Hepatic insufficiency: Patients with moderate hepatic impairment had increased AUC0®¥ and maximum blood concentrations (Cmax), and the area under the drug-time curve (AUC) was increased by approximately 60%.
Renal insufficiency: Olmesartan serum concentrations were elevated in patients with renal insufficiency compared to patients with normal renal function. The area under the drug-time curve (AUC) after multiple dosing in patients with severe renal impairment (creatinine clearance <20 ml/min) was approximately three times greater than in those with normal renal function. Not studied in patients receiving hemodialysis.
Hydrochlorothiazide
Renal insufficiency: In a study of patients with renal insufficiency, the mean elimination half-life of hydrochlorothiazide was twice as long in patients with mild/moderate renal insufficiency (30 < CrCl < 90 mL/min) compared to patients with normal renal function (CrCl > 90 mL/min), and in patients with severe renal insufficiency (≤ 30 mL/min) The mean elimination half-life of hydrochlorothiazide is 3 times longer in patients with severe renal insufficiency (≤ 30 mL/min).
Drug Interaction]
The bile acid sequestrant coleviram hydrochloride.
Concomitant administration of olmesartanate 40 mg with colevelam hydrochloride 3750 mg in healthy subjects resulted in a 28% decrease in Cmax and 39% decrease in AUC of olmesartan. When olmesartanate was taken 4 hours earlier than colevelam, it produced a smaller effect, with a 4% and 15% reduction in Cmax and AUC, respectively.
Storage】Store under shade and seal.
Package】Aluminum-plastic package with composite film bag. 7 tablets per plate, 1 plate per box; 10 tablets per plate, 1 plate per box; 10 tablets per plate, 2 plates per box.
【Validity】18 months
【Execution standard
【Approval number】
[Drug Marketing License Holder
Name
Name: Beijing Fuyuan Pharmaceutical Co.
Registered address: No. 8 Guangyuan East Street, Tongzhou Industrial Development Zone, Tongzhou District, Beijing
Postal Code: 101113
Telephone and fax numbers: 400 600 2626; 010-61508688; 010-59603945
Web
Address: www.winsunny.com.cn
【Manufacturer】
Company name: Beijing Fuyuan Pharmaceutical Co.
Address: No. 8 Guangyuan East Street, Tongzhou Industrial Development Zone, Tongzhou District, Beijing
Postal Code: 101113
Telephone and fax numbers: 400 600 2626; 010-61508688; 010-59603945
Web
Address: www.winsunny.com.cn