Approval date: November 15, 2007
Modification date: December 05, 2007
October 21, 2008
July 13, 2016
December 19, 2016
June 21, 2019
December 01, 2019
June 15, 2020
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Cloxacin Potassium Hydrochlorothiazide Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug name]
Generic name: Losartan Potassium and Hydrochlorothiazide Tablets
English name: Losartan Potassium and Hydrochlorothiazide Tablets
Hanyu Pinyin: Lüshatanjia Qinglüsaiqin Pian
Ingredients
This product is a compound preparation, the composition of which is: each tablet contains chloroxatan potassium 50mg and hydrochlorothiazide 12.5mg.
The chemical name of potassium cloxartan is: 2-butyl-4-chloro-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol monopotassium salt.
The chemical name of hydrochlorothiazide is: 6-chloro-3,4-dihydro-2H-1,2,4-benzothiazine-7-sulfonamide-1,1-dioxide.
Chemical structure formula.
Cloxacin potassium.
Hydrochlorothiazide: Molecular formula: Potassium Closartan: C22H22ClKN6O; Hydrochlorothiazide: C7H8ClN3O4S2
Molecular weight: Chlorsartan potassium: 461.01; Hydrochlorothiazide: 297.74
Properties
This product is a film-coated tablet, which appears white or off-white after removing the coating.
Indications
This product is used for the treatment of hypertension, and is suitable for patients treated with combined medication.
Specification
Each tablet contains Coxsartan Potassium 50mg, Hydrochlorothiazide 12.5mg.
Dosage
The usual starting and maintenance dose of this product is one tablet of coxsartan potassium hydrochlorothiazide (50mg+12.5mg) once daily. In patients with inadequate response, the dose may be increased to two cloxacin potassium hydrochlorothiazide tablets (50mg+12.5mg) once daily, and this dose is the maximum daily dose. Usually, the anti-hypertensive effect is obtained within 3 weeks of starting treatment.
This product should not be used in patients with insufficient blood volume (e.g. patients treated with high doses of diuretics).
It is not recommended for patients with severe renal insufficiency (creatinine clearance ≤ 30 mL/min) or hepatic insufficiency.
In elderly patients with hypertension, no adjustment of the starting dose is required, but Cloxacin Potassium Hydrochlorothiazide Tablets (100mg+25mg) should not be used as starting therapy in elderly patients.
This product can be taken in combination with other anti-hypertensive drugs.
This product can be taken with food or alone.
[Adverse Reactions].
In clinical trials of cloxacin potassium-hydrochlorothiazide, no specific adverse reactions have been observed with this combination formulation. It was limited to previously reported adverse reactions to coxsartan potassium and/or hydrochlorothiazide. The overall incidence of adverse reactions with this combination was similar to that of placebo. The percentage of treatment interruptions was also similar to that of placebo.
In general, coxsartan potassium-hydrochlorothiazide was well tolerated. The vast majority of adverse reactions were mild and transient and did not require interruption of therapy.
Dizziness was the only adverse effect reported in controlled clinical trials of chloroxantan potassium-hydrochlorothiazide for essential hypertension that was drug-related and occurred at an incidence greater than 1% or more and higher than placebo.
In controlled clinical trials in hypertensive patients with left ventricular hypertrophy, losartan (usually in combination with hydrochlorothiazide) was well tolerated. The most common drug-related adverse reactions were dizziness, weakness/fatigue, and vertigo.
Other adverse reactions identified with post-marketing use of this product, and/or with the use of Crosartan and hydrochlorothiazide alone in clinical trials or post-marketing, are as follows.
Benign, malignant and tumors of unknown nature (including cystic and polypoid): non-melanoma skin cancer (basal cell carcinoma, squamous cell carcinoma)
Hematologic and lymphatic system disorders: thrombocytopenia, anemia, aplastic anemia, hemolytic anemia, leukopenia, granulocyte deficiency.
Immune system disorders: angioedema (including laryngeal and vocal edema leading to airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue) has rarely been reported in patients treated with losartan; some of these patients have had angioedema from other medications (e.g., ACE inhibitors).
Metabolic and nutritional disorders: anorexia, hyperglycemia, hyperuricemia, electrolyte imbalances including hyponatremia and hypokalemia.
Psychiatric disorders: insomnia, restlessness.
Neurological disorders: taste disorders, headaches, migraines, sensory abnormalities.
Eye disorders: yellow vision, transient blurred vision.
Cardiac disorders: palpitations, tachycardia.
Vascular diseases: dose-related postural hypotension, necrotizing vasculitis (vasculitis) (cutaneous vasculitis).
Gastrointestinal disorders: dyspepsia, abdominal pain, irritation of the digestive tract, cramps, diarrhea, constipation, nausea, vomiting, pancreatitis, salpingitis.
Respiratory, thoracic and mediastinal diseases: cough, nasal congestion, pharyngitis, sinus disorders, upper respiratory tract infections, respiratory distress (including pneumonia and pulmonary edema)
Hepatobiliary diseases: hepatitis, jaundice (intrahepatic bile accumulation jaundice)
Skin and subcutaneous tissue disorders: rash, pruritus, purpura (including Henoch-Schönlein purpura), toxic epidermolysis bullosa, urticaria, erythroderma, photosensitivity, cutaneous lupus erythematosus.
Musculoskeletal and connective tissue disorders: back pain, painful muscle spasms, muscle cramps, myalgia, arthralgia.
Renal and urological disorders: diabetes, renal dysfunction, interstitial nephritis, renal failure.
Reproductive and breast disorders: erectile dysfunction/impotence.
Systemic discomfort and administration site abnormalities: chest pain, swelling/swelling, malaise, fever, weakness.
Studies: abnormal liver function.
Description of selected adverse reactions
Non-melanoma skin cancer (basal cell carcinoma, squamous cell carcinoma)
Based on available data from epidemiological studies, a cumulative dose-dependent relationship was found between hydrochlorothiazide and non-melanoma skin cancers (BCC and SCC).
The largest study included 71,533 people with basal cell carcinoma (BCC) and 8,629 people with squamous cell carcinoma (SCC), which were matched to 1,430,833 and 172,462 population controls, respectively. For the basal cell carcinoma (BCC) population, the adjusted ratio (OR) was 1.29 (95% Cl: 1.23-1.35) for high cumulative doses of hydrochlorothiazide (≥50,000 mg) and for the squamous cell carcinoma (SCC) population, the adjusted ratio (OR) was 3.98 (95% Cl: 3.98) for high cumulative doses of hydrochlorothiazide (≥50,000 mg). 3.98 (95% Cl: 3.68-4.31). Cumulative dose-response relationships were observed in both the basal cell carcinoma (BCC) population and the squamous cell carcinoma (SCC) population. Another study that included 633 lip cancers with 63,067 population controls evaluated the relationship between lip cancer (SCC) and hydrochlorothiazide exposure. There was a cumulative dose-response relationship between lip cancer (SCC) and hydrochlorothiazide exposure: the adjusted ratio (OR) was 2.1 (95% Cl: 1.7-2.6) for former users of hydrochlorothiazide; for high-dose users (≥25,000 mg), the OR increased to 3.9 (95% Cl: 3.0-4.9): for the highest cumulative dose (≥ 100,000 mg), the ratio (OR) increased to 7.7 (95% Cl: 5.7-10.5).
LABORATORY FINDINGS: In controlled clinical trials, clinically important changes in clinically important standard laboratory indicators were rarely associated with the application of this product. Hyperkalemia (blood potassium >5.5 mEq/L) occurred in 0.7% of patients, but in these trials, discontinuation of this product was not required. Elevated ALT rarely occurs and is usually restored after discontinuation of this product.
Contraindications
-Patients who are hypersensitive to any of the ingredients of this product.
-Patients with anuria.
-Patients who are allergic to other sulfonamides.
-This product should not be used in combination with aliskiren in diabetic patients (see [Drug Interactions]).
Precautions]
Cloxacin-hydrochlorothiazide
Embryotoxicity
The use of drugs that act on the renin-angiotensin system in mid to late pregnancy can decrease fetal renal function and increase fetal and neonatal morbidity and mortality. The resulting hypohydramnios may 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 possible when pregnancy is detected. See [Use in Pregnant and Lactating Women].
Allergic reactions: angioedema. (See [Adverse Reactions])
Hepatic and renal impairment
This product is not recommended for patients with hepatic insufficiency or severe renal insufficiency (creatinine clearance ≤ 30 mL/min) (see [DOSAGE AND ADMINISTRATION]).
Cloxacin
Renal insufficiency
Inhibition of the renin-angiotensin system can lead to changes in renal function, and individual sensitive patients have been reported to develop
Renal failure (especially in conditions where renal function is dependent on the renin-angiotensin-aldosterone system, such as with
severe cardiac insufficiency or patients with abnormal renal function). In some patients, changes in renal function can be reversed after cessation of therapy.
The occurrence of anemia has been reported in some patients with severe renal disease or who received a renal transplant while treated with cloxacin potassium.
In patients with bilateral or unilateral renal artery stenosis or renal artery stenosis in the sole kidney, the use of other drugs that affect the renin-angiotensin system can cause an increase in plasma urea and creatinine; similar effects have been reported with coxsartan. These changes in renal function can be reversed by discontinuation of the drug.
Elevated serum potassium
May cause hyperkalemia when combined with other drugs that may increase blood potassium (see [Drug Interactions)].
Hydrochlorothiazide
Hypotension and electrolyte imbalance
As with all other antihypertensive treatments, symptomatic hypotension may occur in some patients. In cases of concomitant diarrhea or vomiting, patients should be observed for clinical signs of water or electrolyte imbalance, such as hypovolemia, hyponatremia, hypochloremic alkalosis, hypomagnesemia, or hypokalemia. Blood electrolyte tests should be performed regularly.
Effects on metabolism and endocrine
Thiazide therapy decreases glucose tolerance. Dose adjustment of glucose-lowering drugs, including insulin, may be required (see [Drug Interactions]).
Thiazides may reduce urinary calcium excretion and cause intermittent mild elevation of blood calcium. Significant hypercalcemia may be a manifestation of occult hyperparathyroidism. Therefore, thiazides should be discontinued before parathyroid function measurements are performed.
Elevated cholesterol and triglycerides may be associated with thiazide diuretic therapy.
Thiazide therapy may promote hyperuricemia and/or gout in some patients. Because coxsartan lowers uric acid, the combination of coxsartan potassium and hydrochlorothiazide may reduce diuretic-induced hyperuricemia.
Non-melanoma skin cancer
In epidemiological studies, the risk of non-melanoma skin cancer (basal cell carcinoma [BCC] and squamous cell carcinoma [SCC]) was found to increase with increasing cumulative doses of hydrochlorothiazide. The photosensitizing effect of hydrochlorothiazide may be the causative mechanism for non-melanoma skin cancer.
Patients taking hydrochlorothiazide should be informed of the risk of non-melanoma skin cancer and advised to take precautions to reduce sunlight and artificial UV exposure. Patients should be regularly examined for new skin lesions and suspicious skin lesions should be reported to the physician for evaluation. The use of hydrochlorothiazide may need to be reconsidered in patients with prior non-melanoma skin cancer (see [Adverse Reactions]).
Other
Allergic reactions may occur with thiazide administration regardless of the patient’s history of allergy or bronchial asthma. Cases of exacerbation or provocation of systemic lupus erythematosus have been reported with thiazides.
Anti-doping tests.
This product contains hydrochlorothiazide, which can cause a positive anti-doping test result.
Use with caution in athletes.
Pregnant women and nursing mothers
The use of drugs that act directly on the renin-angiotensin system can lead to damage and death of the developing embryo. Therefore, this product should be discontinued as soon as possible after pregnancy is detected.
Although there is no experience with the use of this product in pregnant women, animal studies have confirmed that coxsartan potassium is injurious and lethal to the fetus and newborn, and the mechanism is thought to be mediated by the drug’s effect on the renin-angiotensin system. In humans, fetal renal perfusion begins in mid-gestation, and renal perfusion is dependent on the development of the renin-angiotensin system. Therefore, there is an increased risk to the fetus if this product is administered in the middle or late stages of pregnancy.
The use of drugs acting on the renin-angiotensin system during mid- and late pregnancy decreases fetal renal function and increases fetal and neonatal morbidity and mortality. The resulting low amniotic fluid may 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 possible when pregnancy is discovered.
These adverse outcomes are usually associated with the use of these drugs in mid- to late-pregnancy. Epidemiologic studies have examined fetal abnormalities following the use of antihypertensive drugs in pre-pregnancy, and most studies do not distinguish between drugs that affect the renin-angiotensin system and other antihypertensive drugs. Appropriate management of maternal hypertension during pregnancy is more important to optimize maternal and fetal outcomes.
In exceptional cases, the mother needs to be informed of the potential risk to the fetus in particular patients for whom no appropriate alternative therapy is available to replace drugs acting on the renin-angiotensin system. Serial ultrasonography is performed to assess the intra-amniotic environment. If low amniotic fluid is observed, discontinue the drug unless it is believed to be life-saving for the mother. Depending on the number of weeks of pregnancy, fetal testing may be appropriate. However, patients and physicians should be aware that hypoamniotic fluid may occur only after sustained irreversible fetal damage has occurred. Closely monitor for hypotension, oliguria, and hyperkalemia in infants who have been exposed to this product in utero.
Thiazides can cross the placental barrier and appear in the cord blood. Pregnant women with hypertension and no other medical conditions are advised not to use diuretics routinely to avoid exposing the mother and fetus to unnecessary hazards such as fetal or neonatal jaundice, thrombocytopenia, and other adverse effects that may occur in adults. Diuretics do not prevent the development of toxemia in pregnancy and there is no satisfactory evidence of its efficacy in toxemia.
It is not clear whether cloxacin can be excreted through breast milk, but thiazides can appear in human breast milk. Because of its potential adverse effects on the nursing infant, the importance of the drug to the mother should be weighed against the decision to discontinue lactation or discontinue the drug.
Pediatric use]
Safety and efficacy in children have not been established.
Infants who have been exposed to this product in utero.
If oliguria or hypotension occurs, direct attention to support of blood pressure and renal perfusion. Exchange transfusion or renal perfusion may be required as a means of reversing hypotension and/or replacing abnormal renal function.
[Geriatric Use].
In clinical studies, there were no clinically significant differences in the efficacy and safety of this product in elderly (≥65 years) and younger (<65 years) patients.
Drug Interactions
Cloxacin
In clinical pharmacokinetic trials, no clinically significant drug interactions have been identified with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital (see Hydrochlorothiazide: Alcohol, Barbiturates or Narcotics below), ketoconazole, and erythromycin. Rifampicin and fluconazole have been reported to reduce levels of active metabolites. The clinical significance of these interactions has not been evaluated.
As with other drugs that block angiotensin II and its effects, closartan potassium may cause an increase in blood potassium when combined with potassium-preserving diuretics (e.g., ambrisentin, aminopterin, amiloride), potassium supplements, salt substitutes containing potassium, or other drugs that may increase blood potassium (e.g., drugs containing meperidine).
Lithium excretion may be reduced when used concomitantly with other medications that affect sodium excretion. Therefore, monitor serum lithium levels carefully if lithium salts will be used in combination with angiotensin II receptor antagonists.
Nonsteroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors)
(NSAIDs) may reduce the effectiveness of diuretics or other antihypertensive drugs. Thus, the effects of angiotensin II receptor antagonists or angiotensin-converting enzyme inhibitors may also be diminished by NSAIDs, including selective COX-2 inhibitors.
In some patients with renal insufficiency taking NSAIDs including selective COX-2 inhibitors (e.g., elderly patients or volume-deficient patients, including those on diuretic therapy), concomitant administration of angiotensin II receptor antagonists or angiotensin-converting enzyme inhibitors may result in further deterioration of renal function, including the possibility of acute renal failure, and this effect is usually reversible. Therefore, caution should be exercised when administering combination therapy to patients with renal insufficiency.
Dual blockade therapy with the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors (including angiotensin receptor antagonists, ACE inhibitors, or aliskiren) increases the risk of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes in patients on combined use of closartan potassium hydrochlorothiazide tablets and other medications that affect the RAAS. Do not combine chloroxantine potassium hydrochlorothiazide tablets and aliskiren in patients with diabetes. Avoid the combination of chlorasartan potassium hydrochlorothiazide tablets and aliskiren in patients with impaired renal function (GFR < 60 mL/min).
Hydrochlorothiazide
When used concomitantly, 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 adjustment of the dose of glucose-lowering drugs.
Other antihypertensives – additive effects.
Cholestyramine and colestipol resins
– The presence of anion-exchange resin hinders the absorption of hydrochlorothiazide
. Single dose administration of cholestyramine or colestipol resin binds to hydrochlorothiazide and reduces the absorption of thiazides from the gastrointestinal tract by up to 85% and 43%, respectively.
Corticosteroids, ACTH or glycyrrhetinic acid (present in licorice) – exacerbate electrolyte loss, especially leading to hypokalemia.
Pressor amines (e.g., epinephrine) – May reduce response to pressor amines, but not enough to prevent their use.
Skeletal muscle relaxants, non-depolarizing (e.g., barrel-arrow venomine) – may enhance response to muscle relaxants.
Lithium- Diuretics reduce the renal clearance of lithium, highly increase the risk of lithium toxicity, and are not recommended for concomitant use. Refer to the instructions for lithium preparations prior to use.
NSAIDs, including selective COX-2 inhibitors – The use of NSAIDs, including selective COX-2 inhibitors, decreases the diuretic, natriuretic, and antihypertensive effects of diuretics.
In some patients with renal insufficiency taking NSAIDs including selective COX-2 inhibitors (e.g., elderly patients or volume-deficient patients, including those on diuretic therapy), concomitant administration of angiotensin II receptor antagonists or angiotensin-converting enzyme inhibitors may result in further deterioration of renal function, including the possibility of acute renal failure, an effect that is usually reversible. Therefore, caution should be exercised when administering combination drug therapy to patients with renal insufficiency.
Drug/laboratory assay interactions
Due to their effect on calcium metabolism, thiazides interfere with parathyroid function assay tests (see [Precautions]).
Drug overdose]
There is no specific information on the treatment of overdose of this product; symptomatic and supportive therapy may be used. Discontinue the product and monitor the patient closely. Recommended measures include inducing vomiting (if an overdose has just occurred) and correcting dehydration, electrolyte imbalance, hepatic coma, and hypotension with appropriate steps.
Clozaril
Information on human overdose is limited. The most obvious signs of overdose are hypotension and tachycardia; bradycardia may be due to parasympathetic (vagal) excitation. If symptomatic hypotension occurs, supportive therapy should be administered.
Neither cloxacin potassium nor its active metabolite is cleared by hemodialysis.
Hydrochlorothiazide
Signs and symptoms are most commonly caused by electrolyte loss (hypokalemia, hypochlorhydria, hyponatremia), and dehydration due to excessive diuresis. Hypokalemia may exacerbate cardiac arrhythmias if digitalis is used concomitantly.
The extent to which hydrochlorothiazide is cleared by hemodialysis is still not known.
Pharmacology and Toxicology
Pharmacological effects
The two components of losartan-hydrochlorothiazide have additive effects in lowering blood pressure, and the magnitude of blood pressure lowering is greater with losartan-hydrochlorothiazide than with either component alone. Moreover, as a result of diuretic effects, hydrochlorothiazide increases plasma renin activity, increases aldosterone secretion, lowers blood potassium, and increases angiotensin II levels. Administration of Crosartan blocks all physiological effects related to angiotensin II and reduces potassium loss associated with diuretics by inhibiting aldosterone.
Crosartan has a mild and transient pro-uricosuric effect. Hydrochlorothiazide can cause moderate elevation of uric acid, and the combination of losartan and hydrochlorothiazide may reduce diuretic-induced hyperuricemia.
Cosartan is an orally administered angiotensin II receptor (AT1 receptor) antagonist. The mechanism of action of thiazides against hypertension is not known.
Toxicological studies
Genotoxicity.
The results of Ames test for cloxacin potassium-hydrochlorothiazide (4:1 by weight) and V-79 Chinese hamster lung cell mutation test were negative. The results of the in vitro alkali elution test in rat hepatocytes and the in vitro chromosome aberration test in Chinese hamster ovary cells were all negative.
Reproductive toxicity.
No significant effects on fertility or mating behavior were observed in male rats given a combined dose of 135 mg/kg/day of coxsartan and 33.75 mg/kg/day of hydrochlorothiazide, and the in vivo exposure (AUCs) of coxsartan, its active metabolites, and hydrochlorothiazide were approximately 60-fold, 60-fold, and 30-fold higher than those of humans given a combined dose of 100 mg of coxsartan and 25 mg of hydrochlorothiazide, respectively. times higher. A slight but statistically significant decrease in fertility and fertility index was seen in female rats given a combination of doses as low as 10 mg/kg/day of coxsartan and 2.5 mg/kg/day of hydrochlorothiazide; in rats given 50 mg/kg/day of coxsartan and 12.5 mg/kg/day of hydrochlorothiazide, the exposure (AUCs) of coxsartan and its active metabolites, hydrochlorothiazide, were approximately 6-fold, 2-fold, and 2-fold higher than the exposure of human coadministered coxsartan 100 mg with hydrochlorothiazide 25 mg, respectively.
No teratogenicity was observed in rats or rabbits given coxsartan potassium at a maximum dose of 10 mg/kg/day and hydrochlorothiazide at 2.5 mg/kg/day; the exposure (AUCs) of coxsartan, its active metabolites, and hydrochlorothiazide in rabbits was 5, 1.5, and 1 times higher than that of human given coxsartan 100 mg and hydrochlorothiazide 25 mg, respectively. A slight increase in the incidence of embryonic polyribbing was seen in female rats given coxsartan 10 mg/kg/day in combination with hydrochlorothiazide 2.5 mg/kg/day before and during gestation. In rats given coxsartan 50 mg/kg/day in combination with hydrochlorothiazide 12.5 mg/kg/day during late gestation and/or lactation, similar toxicity, including weight loss, nephrotoxicity and mortality, was observed in fetuses and newborns as in rats given coxsartan alone, and the exposure (AUCs) of coxsartan and its active metabolites, hydrochlorothiazide, in vivo were approximately 0.5 mg/kg/day higher than those in humans given coxsartan 100 mg/kg/day and hydrochlorothiazide 25 mg/day, respectively. and hydrochlorothiazide 25 mg, respectively, were 35-fold, 10-fold, and 10-fold higher. No embryotoxicity was observed in pregnant mice or pregnant rats given hydrochlorothiazide alone at doses up to 3000 and 1000 mg/kg/day during the major organogenesis period, respectively.
Cloxacin and its active metabolites were secreted at high levels in the milk of rats.
Carcinogenicity.
No carcinogenicity studies have been conducted with the co-administration of closartan potassium and hydrochlorothiazide.
Closartan potassium: No carcinogenicity was observed in mice or rats given the maximum tolerated dose of closartan potassium at doses up to 200 mg/kg/day for 92 weeks in mice and 270 mg/kg/day for 105 weeks in rats, respectively. The incidence of adenocarcinoma of the pancreatic alveoli was slightly increased in female rats given coxsartan potassium at 270 mg/kg/day. Systemic exposure to coxsartan and active metabolites in mice and rats at the highest dose was approximately 30 and 15 times (mice) and 160 and 90 times (rats) the exposure to 100 mg/day in adults at 50 kg body weight, respectively.
Hydrochlorothiazide: In mice and rats given orally up to doses of 600 mg/kg/day and 100 mg/kg/day, respectively, for 2 years, no carcinogenicity was observed in male and female rats and female mice, and suspected hepatocarcinogenic effects were seen in male mice.
Pharmacokinetics
Absorption
Cloxacin
After oral administration, losartan is well absorbed and undergoes first-pass metabolism to form an active hydroxy acid metabolite and other inactive metabolites. The in vivo bioavailability of losartan tablets is about 33%. The mean peak concentrations of losartan and its active metabolites are reached within 1 hour and 3-4 hours, respectively. The simultaneous consumption of a standard meal has no clinically significant effect on the plasma concentration of losartan.
Distribution
Cosartan
The binding of losartan and its active metabolites to plasma proteins, mainly albumin, exceeds 99%. The volume of distribution of losartan is 34 liters. Studies in rats suggest that losartan barely crosses the blood-brain barrier.
Hydrochlorothiazide
Hydrochlorothiazide crosses the placental barrier but not the blood-brain barrier and can be secreted from breast milk.
Metabolism
Clozaril
After intravenous use or oral administration, 14% of cloxacin is converted to its active metabolite. Following oral or intravenous administration of 14C-labeled closartan potassium, the main source of radioactivity in circulating plasma is cloxacin and its active metabolites. In approximately 1% of the individuals studied, only a very small amount of coxsartan was converted to the active metabolite.
In addition to the active metabolites, inactive metabolites were also formed, including two major metabolites formed by hydroxylation of the butyl side chain and a minor metabolite, N-2 tetrazolium glucosinolate.
Elimination
Cosartan
The plasma clearance of losartan and its active metabolite is approximately 600 mL/min and 50 mL/min, respectively. the renal clearance of losartan and its active metabolite is approximately 74 mL/min and 26 mL/min, respectively. when losartan is administered orally, approximately 4% is excreted in its original form in the urine and approximately 6% is excreted as the active metabolite in the urine. The pharmacokinetic properties of losartan and its active metabolites are linear over the range of oral dosages of up to 200 mg of losartan potassium.
After oral administration, the plasma concentrations of losartan and its active metabolites decreased in a multi-exponential manner, and their terminal half-lives were approximately 2 hours and 6-9 hours, respectively. Neither losartan nor its active metabolites accumulate significantly in plasma at a dose of 100 mg once daily. The clearance of both losartan and its active metabolite is mainly via biliary and urinary secretion. In humans, after oral administration of 14C-labeled closartan potassium, approximately 35% of the radioactivity appears in the urine and 58% in the feces. In humans, after intravenous administration of 14C-labeled closartan, approximately 43% of the radioactivity was in the urine and 50% in the feces.
Hydrochlorothiazide
Hydrochlorothiazide is not metabolized, but it is rapidly cleared by the kidneys. 24-hour plasma concentration monitoring reveals plasma half-lives varying between 5.6 and 14.8 hours. At least 61% of the oral dose is cleared in its original form within 24 hours.
Special Populations
Cosartan-hydrochlorothiazide
Plasma concentrations of losartan and its active metabolites, as well as the absorption of hydrochlorothiazide, do not differ significantly between elderly and young hypertensive patients.
Cosartan
Age
Plasma concentrations of losartan and its active metabolites did not differ significantly between elderly patients with hypertension and younger patients with hypertension.
Females
Plasma concentrations of losartan were 2-fold higher in female hypertensive patients compared to male hypertensive patients. There were no differences in concentrations of active metabolites between females and males. It was not possible to determine that these apparent pharmacokinetic differences were clinically significant.
Hepatic insufficiency
Plasma concentrations of losartan potassium and its active metabolites were 5-fold and 1.7-fold higher, respectively, in patients with mild and moderate alcoholic cirrhosis after oral administration than in young male volunteers.
Renal insufficiency
In patients with creatinine clearance greater than 10 mL/min, plasma concentrations of losartan were not altered. The AUC of coxsartan was approximately 2-fold higher in patients on hemodialysis than in patients with normal renal function. Plasma concentrations of the active metabolites were not altered in patients with renal insufficiency or hemodialysis.
Both the potassium losartan and its active metabolites cannot be removed by hemodialysis.
Storage】Sealed and stored.
Package】Polyvinyl chloride solid pharmaceutical hard tablets and pharmaceutical aluminum foil, with polyester/aluminum/polyethylene pharmaceutical composite film and bag. 7 tablets per board, 1 board per box; 10 tablets per board, 1 board per box; 7 tablets per board, 2 boards per box; 7 tablets per board, 4 boards per box.
【Validity】24 months
【Execution standard
【Approval number】.
State Drug Administration H20074021
[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; 010-59603945; 010-61508688
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; 010-59603945; 010-61508688
Web
Address: www.winsunny.com.cn