Approval date: November 25, 2009
Modification date: December 04, 2014
Modification date: September 12, 2017
Modification date: 06/24/2019
Date of modification.
Year
Month
Date.
Clozaril Potassium Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drugs that act directly on the renin-angiotensin system can cause injury and death in the developing fetus.
When pregnancy is detected, this product should be discontinued as soon as possible.
Drug Name
Generic name: Losartan Potassium Tablets
English name: Losartan Potassium Tablets
Hanyu Pinyin: Lüshatanjia Pian
Ingredients
The main ingredient of this product is closartan potassium. Its chemical name is: 2-butyl-4-chloro-1-[[2′-(1H-tetrazol-5-yl)[1, 1′-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol monopotassium salt.
Its chemical structure formula is as follows
Molecular formula: C22H22ClKN6O
Molecular weight: 461.01
Properties
This product is white or off-white round convex film-coated tablets with indentations on one side, showing white or off-white after removing the coating.
Specification】50mg
Indications
Treatment of primary hypertension.
Dosage]
This product can be used together with other anti-hypertensive drugs.
This product may be taken with or without food.
For most patients, the usual starting and maintenance dose is 50 mg once daily, with maximum antihypertensive effect achieved after 3 to 6 weeks of treatment. In some patients, increasing the dose to 100 mg once daily (taken in the morning)
may produce further antihypertensive effects.
Crosartan can be combined with other antihypertensives, especially diuretics (e.g., hydrochlorothiazide) (see [Contraindications], [Precautions], and [Drug Interactions]).
In patients with hypovolemia (e.g., patients treated with high-dose diuretics), a starting dose of 25 mg once daily may be considered (see [Precautions]).
In elderly patients or patients with renal impairment including those on hemodialysis, no adjustment of the starting dose is necessary.
A lower dose should be considered for patients with a history of hepatic impairment (see [Precautions]).
Adverse Reactions
Clinical trials have found this product to be well tolerated; adverse reactions are mild and transient and generally do not require discontinuation of therapy. The overall incidence of adverse reactions with the use of this product was similar to that of placebo.
In a controlled clinical study of essential hypertension, the incidence was ≥1%, and the only adverse reaction related to the drug and occurring at a higher rate than placebo was dizziness. In addition, dose-related postural hypotension occurred in less than 1% of patients. Although rash had a lower incidence than placebo in controlled clinical trials, it has been reported on an individual basis.
In these clinical double-blind controlled studies of essential hypertension, adverse events occurring at an incidence of 1% and above after application of this product, whether or not related to the drug, were
Calsartan potassium tablets (n=2085)
(incidence, %) Placebo (n=535)
(incidence, %) generalized abdominal pain 1.71.7 weakness/fatigue 3.83.9 chest pain 1.12.6 edema/swelling 1.71.9 cardiovascular system palpitations 1.00.4 tachycardia 1.01.7 digestive system diarrhea 1.91.9 dyspepsia 1.11.5 nausea 1.82.8 musculoskeletal system back pain 1.61.1 muscle cramps 1.01.1 neurologic/psychiatric System dizziness4.12.4 headache14.117.2 insomnia1.10.7 respiratory system cough3.12.6 nasal congestion1.31.1 pharyngitis1.52.6 sinus disease1.01.3 upper respiratory tract infection6.55.6
In addition to the adverse events described above, other adverse events of potentially serious adverse events or incidence<1% occurred in at least two patients/subjects in clinical studies following the use of losartan and it could not be determined whether these events were causally related to losartan as follows.
Systemic: facial swelling, fever, postural hypotension, fainting.
Cardiovascular: angina pectoris, second-degree AV block, cardiovascular accident, hypotension, myocardial infarction, arrhythmia including atrial fibrillation, palpitations, sinus bradycardia, tachycardia, ventricular tachycardia, ventricular fibrillation.
Digestive system: loss of appetite, abdominal pain, constipation, toothache, dry mouth, flatulence, gastritis, vomiting.
Hematologic system: anemia.
Metabolic: gout.
Skeletal muscular system: arm pain, hip pain, joint swelling, knee pain, skeletal muscle pain, shoulder pain, stiffness, joint pain, arthritis, fibromyalgia, muscle weakness.
Neurological/psychiatric system: anxiety, anxiety disorders, ataxia, confusion, depression, abnormal dreams, dulled senses, decreased libido, memory loss, migraine, hypersensitivity, sensory abnormalities, peripheral neuropathy, phobias, sleep abnormalities, drowsiness, tremor, vertigo, cerebrovascular accidents.
Respiratory system: dyspnea, bronchitis, pharyngeal discomfort, rhinorrhea, rhinitis, respiratory congestion.
Skin: hair loss, dermatitis, dry skin, ecchymosis, erythema, flushing, photosensitivity, itching, rash, sweating, urticaria.
Special senses: blurred vision, burning and stinging sensation in the eyes, conjunctivitis, taste inversion, tinnitus, decreased visual acuity.
Genitourinary system: impotence, nocturia, urinary frequency, urinary tract infections.
In a controlled clinical trial conducted in patients with hypertension with left ventricular hypertrophy, this product was usually well tolerated. The most common drug-related adverse reactions were dizziness, malaise/fatigue, and vertigo.
In a controlled clinical trial in patients with type 2 diabetes mellitus with proteinuria, this product was usually well tolerated. The most common drug-related adverse reactions were malaise/fatigue, dizziness, hypotension, and hyperkalemia (see PRECAUTIONS, Hypotension and Electrolyte/Human Fluid Balance Imbalance).
In controlled clinical trials in heart failure, this product was usually well tolerated. The observed adverse events are typical of those expected to occur in this population. The most common drug-related adverse reactions were dizziness and hypotension.
Among patients receiving 150 mg of this product in the HEAAL (Heart Failure Endpoint Assessment with Angiotensin II Antagonist Cosartan) trial, the more frequent and clinically significant drug-related adverse reactions were hyperkalemia, renal impairment, renal failure, hypotension and elevated blood creatinine, elevated blood potassium, and elevated blood urea compared with patients receiving 50 mg of this product. These adverse reactions did not significantly affect discontinuation rates in patients in the losartan 150 mg group.
Other adverse reactions that have been reported since the introduction of this product include
Hypersensitivity reactions: Hypersensitivity reactions, angioedema (including swelling of the larynx and vocal cords leading to airway obstruction, and/or swelling of the face, lips, pharynx, and/or tongue) have been reported in a very small number of patients treated with colesartan. Some of these patients have previously experienced angioedema from other medications, including ACE inhibitors. Vasculitis, including Henoch-Schönlein (Hen-Schönlein II) purpura has been reported rarely.
Gastrointestinal reactions: hepatitis (rarely reported), abnormal liver function, vomiting.
General disorders and administration site conditions: discomfort.
Hematologic system: anemia, thrombocytopenia (rarely reported).
Musculoskeletal system: myalgia, arthralgia, rhabdomyolysis.
Neurological/psychiatric system: depression, migraine, grand mal seizures, taste disorders.
Reproductive system disorders: erectile dysfunction/impotence.
Respiratory system: cough.
Gastrointestinal system: diarrhea.
Hepatobiliary disorders: hepatitis, pancreatitis, liver function abnormalities.
Ear and vagus disorders: tinnitus.
Skin: urticaria, pruritus, erysipelas, photosensitivity.
Hyperkalemia and hyponatremia have been reported.
One spontaneous drug-related death of unknown origin has been reported in China.
Laboratory tests.
In controlled clinical trials of essential hypertension, few patients on this product showed clinically significant changes in laboratory parameters. hyperkalemia (serum potassium >5.5 mEq/L) was seen in 1.5% of patients. In a clinical study conducted in patients with type 2 diabetes mellitus with proteinuria, hyperkalemia was observed in 9.9% and 3.4% of patients in the cloxacin and placebo groups, respectively (see Caution, Hypotension and Electrolyte/Fluid Imbalance). elevations in ALT were rarer and returned to normal after discontinuation of the drug.
Creatinine, blood urea nitrogen: In patients with essential hypertension, a slight increase in blood urea nitrogen or serum creatinine has been observed in less than 0.1% of patients on this product alone.
Hemoglobin and erythropoietic pressure: Mild decreases in hemoglobin and erythropoietic pressure (mean decreases of approximately 0.11% g and 0.09% volume, respectively) were frequently observed in patients treated with this product alone, but were rarely clinically significant, and no patient discontinued the drug because of anemia.
Liver function tests: Occasional elevation of liver enzymes and/or serum bilirubin. In patients with essential hypertension treated with this product alone, one patient (<0.1%) discontinued the drug due to these laboratory adverse effects.
[Contraindications].
Contraindicated in patients with hypersensitivity to any of the components of this product.
Women in mid- and late-term pregnancy (during the middle and last trimester of pregnancy) (see [Precautions] and [Use in Pregnant and Lactating Women]).
Severe hepatic impairment.
Combination of this product with aliskiren-containing drugs is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see [Drug Interactions]).
[Precautions].
Embryotoxicity
The use of drugs that act on the renin-angiotensin system during mid- to late pregnancy can decrease fetal renal function and increase 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. (See [Medication for Pregnant and Lactating Women]).
Allergic reactions
Angioedema. Patients with a history of angioedema (swelling of the face, lips, throat, and/or tongue) should be monitored closely. (See [Adverse Reactions]).
Hypotension and electrolyte/fluid imbalance
Symptomatic hypotension can occur in patients with hypovolemia (e.g., patients treated with high-dose diuretics). These conditions should be corrected prior to treatment with this product or a lower starting dose should be used (see [Dosage]).
It should be noted that electrolyte balance imbalance is common in patients with renal insufficiency, with or without diabetes mellitus. In clinical studies in patients with type 2 diabetes mellitus with proteinuria, the incidence of hyperkalemia was higher in the closartan potassium treatment group than in the placebo group; however, few patients discontinued treatment due to hyperkalemia (see [Adverse Reactions] and Laboratory Findings).
Hyperkalemia may result when combined with other drugs that may increase blood potassium (see [Drug Interactions]).
Liver Function Impairment
Pharmacokinetic data indicate that plasma concentrations of cloxacin are significantly increased in patients with cirrhosis, so lower doses should be considered in patients with a history of hepatic impairment (see [DOSAGE]). There is no treatment experience with losartan in patients with severe hepatic impairment. Therefore, treatment with losartan is contraindicated in patients with severe hepatic impairment.
Renal impairment
Changes in renal function, including renal failure, have been reported in sensitive individuals due to inhibition of the renin-angiotensin system; changes in renal function can be restored in some patients after discontinuation of treatment.
In patients whose renal function is dependent on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin-converting enzyme inhibitors can cause oliguria and/or progressive azotemia and (rarely) acute renal failure and/or death. Similar reports have been reported for treatment with cloxacin.
Other drugs affecting the renin-angiotensin system can increase blood urea and serum creatinine levels in patients with bilateral renal artery stenosis or in those with only one kidney and renal artery stenosis. Similar reports have been made with the use of this product. Changes in renal function can be restored in some patients after discontinuation of treatment. Caution should be exercised in the use of cloxacin in patients with bilateral or solitary renal artery stenosis.
Renal Transplantation
There is no experience with the use of coxsartan in patients who have had a recently transplanted kidney.
Primary aldosteronism
In patients with primary aldosteronism, antihypertensive agents that act by inhibiting the renin-angiotensin system are usually ineffective. Therefore, the use of Crosartan is not recommended in these patients.
Coronary heart disease and cerebrovascular disease
As with all other antihypertensives, in patients with ischemic heart disease and cerebrovascular disease, an excessive drop in blood pressure may lead to myocardial infarction or stroke.
Heart Failure
In patients with heart failure with or without renal impairment, as with other drugs that act on the renin-angiotensin system, there is a risk of severe arterial hypotension with a risk of renal impairment (often acute).
There is no adequate experience with treatment with losartan in patients with heart failure combined with severe renal impairment, in patients with severe heart failure (NYHA class IV), and in patients with heart failure accompanied by symptomatic life-threatening arrhythmias. Therefore, caution should be exercised in the use of losartan in these patient populations. Caution should be exercised when colesartan is used in combination with b-blockers.
Aortic and mitral stenosis, obstructive hypertrophic cardiomyopathy
As with other vasodilators, special care should be taken in patients with aortic stenosis or mitral stenosis or obstructive hypertrophic cardiomyopathy.
Excipients
The drug contains lactose. It should not be taken in patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
Renin-angiotensin-aldosterone system (RAAS) dual blockade
There is evidence that the combination of ACE-inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of hypotension, hyperkalemia, and reduced renal function, including acute renal failure. Therefore, dual blockade of RAAS by combining ACE-inhibitors, angiotensin II receptor antagonists, or aliskiren is not recommended (see [Drug Interactions]). If dual blockade therapy is deemed truly necessary, it should only be performed under expert supervision and with frequent close monitoring of renal function, electrolytes, and blood pressure. ACE-inhibitors should not be used in combination with angiotensin II receptor antagonists in patients with diabetic nephropathy.
Other warnings and precautions.
As observed with angiotensin-converting enzyme inhibitors, colesartan and other angiotensin antagonists are significantly less effective in lowering blood pressure in blacks than in non-blacks, possibly because blacks are part of a low-renin population.
Pregnant and lactating women]
The use of Crosartan is not recommended during the first trimester of pregnancy. The use of Coxsartan is contraindicated during the fourth to ninth trimester of pregnancy.
For pregnant women
Drugs that act directly on the renin-angiotensin system can cause injury and death in the developing fetus. When pregnancy is detected, this product should be discontinued as soon as possible.
Although there is no experience with its use in pregnant women, animal studies with closartan potassium have demonstrated fetal and neonatal injury and death by a mechanism thought to be due to drug-mediated action on the renin-angiotensin system. Renal perfusion in the human fetus from mid-pregnancy is dependent on the development of the renin-angiotensin system, and therefore the risk to the fetus is increased if the product is applied in the middle and late stages of pregnancy.
In the middle and late stages of pregnancy, the use of drugs acting on the renin-angiotensin system decreases fetal renal function and increases the incidence of 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. Most of the epidemiological studies conducted on fetal abnormalities following the use of antihypertensive drugs in early pregnancy did not find differences between drugs affecting 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 there is no appropriate alternative therapy to 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.
Dosage for nursing women
It is not known whether cloxacin is secreted through human milk. Since many drugs can be secreted through human milk and have adverse effects on nursing infants, the decision to discontinue nursing or to discontinue the drug should be made in light of the importance to the mother.
Pediatric Dosage]
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.
Foreign trials have shown the anti-hypertensive effect of this product in hypertensive children aged > 6 to 16 years. There are no data on the effectiveness of its use in pediatric patients younger than 6 years of age or in those with a glomerular filtration rate <30 mL/min/1.73m2.
A pharmacokinetic study of cloxacin was conducted in 50 children with hypertension. Subjects ranged in age from >1 month to <16 years and received once-daily oral colesartan at a dose of approximately 0.54-0.77 mg/Kg (mean dose) (see [Pharmacokinetics]).
In a clinical study of 177 children aged 6-16 years with hypertension, patients weighing ≥ 20 Kg to <50 Kg were given 2.5, 25 or 50 mg of coxsartan daily, and patients weighing ≥ 50 Kg were given 5, 50 or 100 mg of coxsartan daily. Once-daily dosing reduced trough blood pressure in a dose-related manner. Dose correlations for losartan were observed in all subgroups of the population (e.g., age, Tanner stage, gender, race). However the lowest doses studied, 2.5 mg and 5 mg, corresponding to a mean dose of 0.7 mg/Kg per day, did not exhibit anti-hypertensive effects consistent with other doses. In this study, the product was generally well tolerated.
For patients who can swallow tablets and weigh ≥ 20 Kg to <50 Kg, the recommended dose is 25 mg once daily. the maximum dose can be increased to 50 mg once daily. for patients weighing >50 Kg, the starting dose is 50 mg once daily. the maximum dose can be increased to 100 mg once daily. in pediatric patients, doses >1.4 mg/kg (or more than 100 mg) have not been administered. kg (or more than 100 mg) has not been studied in pediatric patients.
In pediatric patients with hypovolemia, these conditions should be corrected prior to administration of this product.
The adverse event profile in pediatric patients is similar to that which has been found in adults.
The use of this product is not recommended in children with a glomerular filtration rate <30 ml/min/1.73 m2 with hepatic impairment.
[Geriatric Use].
There were no age differences in the efficacy or safety of this product in clinical studies.
Race
Based on the LIFE study, although both treatment groups were effective in lowering blood pressure in black patients, the benefit of colesartan in reducing cardiovascular morbidity and mortality compared to atenolol was not applicable to black patients with hypertension with left ventricular hypertrophy. Among all patients enrolled in the LIFE study (n=9193), the risk of the primary composite endpoint of cardiovascular death, stroke, and myocardial infarction was reduced by 13% in the losartan group compared with the atenolol group (p=0.021). In the LIFE study, compared with atenolol, losartan reduced the risk of cardiovascular morbidity and mortality in patients with hypertension with left ventricular hypertrophy (n=8660) outside of blacks, as observed by the combined incidence of the primary clinical endpoint of cardiovascular death, stroke and myocardial infarction (p=0.003).
However, in this study, black patients in the atenolol group had a lower risk of experiencing the primary composite endpoint compared to the crosartan group (p=0.03). In the subgroup of black patients (n=533; 6% of patients in the LIFE study), 29 of 263 patients (11%, 25.9 per 1000 patient-years) in the atenolol group had a primary endpoint compared with 46 of 270 patients (17%, 41.8 per 1000 patient-years) in the cloxacin group.
[Drug Interactions].
In clinical pharmacokinetic studies, no clinically significant drug interactions have been confirmed with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole, and erythromycin. Rifampicin and fluconazole have been reported to reduce levels of active metabolites. The clinical outcome of these interactions has not been evaluated.
As with other drugs that inhibit angiotensin II and its effects, this product can cause an increase in blood potassium when combined with potassium-preserving diuretics (e.g., spironolactone, aminopterin, amiloride), potassium supplements, salt substitutes containing potassium, or other drugs that may increase blood potassium (e.g., drugs containing methotrexate).
As with other drugs that affect sodium excretion, excretion of lithium may be reduced. Therefore, serum lithium levels should be carefully monitored if lithium salts and angiotensin II receptor antagonists are combined.
Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors), may reduce the effects of diuretics and other antihypertensives. Thus, the antihypertensive effects of angiotensin II receptor antagonists or angiotensin-converting enzyme inhibitors may be diminished by NSAIDs including COX-2 inhibitors.
In some patients with renal impairment (e.g., elderly or hypovolemic patients, including those receiving diuretics) who are being treated with NSAIDs including selective cyclooxygenase-2 inhibitors, concomitant administration of angiotensin II receptor antagonists or angiotensin-converting enzyme inhibitors may lead to further renal impairment, including the possibility of acute renal failure. These effects are usually reversible. Therefore, caution should be exercised when administering combination drug therapy to patients with renal insufficiency.
Clinical trial data indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) with the combination of two ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is associated with a higher frequency of adverse events, such as hypotension, hyperkalemia, and reduced renal function (including acute renal failure), than with monotherapy with RAAS-acting agents (see [Contraindications and [Precautions]).
Overdose]
Little information is available on overdose in humans. The most likely manifestations of overdose are hypotension and tachycardia. Bradycardia can occur due to parasympathetic (vagal) excitation. If symptomatic hypotension occurs, supportive therapy should be given.
Neither losartan nor its active metabolites can be cleared by hemodialysis.
Pharmacology and Toxicology
Pharmacological effects
Angiotensin II is the main active substance of the renin-angiotensin system and is a potent vasoconstrictor.
It plays a major role in the pathophysiological process of hypertension. Angiotensin II binds to AT1 receptors in a variety of tissues (e.g., vascular smooth muscle, adrenal glands, kidney, and heart) and produces a variety of important biological effects, including vasoconstriction and aldosterone release. It is also able to stimulate smooth muscle cell proliferation. Another angiotensin II receptor subtype, AT2, has been demonstrated, but its role in the functional homeostasis of the cardiovascular system is unclear.
Cloxacin is a synthetic, potent orally active drug. Binding tests and pharmacological bioassays have demonstrated its ability to bind selectively to the AT1 receptor. In vitro and in vivo studies have shown that losartan and its pharmacologically active carboxylic acid metabolite (E-3174) can block the corresponding physiological effects produced by angiotensin II synthesized from any source or by any route. In contrast to other peptide angiotensin II antagonists, losartan has no agonistic effect.
Cosartan selectively acts on AT1 receptors and does not affect the function of other hormone receptors or important ion channels in the cardiovascular system, nor does it inhibit the angiotensin-converting enzyme (kinase II) that degrades bradykinin. Therefore, effects not directly related to the blockade of AT1 receptors such as bradykinin-mediated effects or edema (1.7% for cloxacin and 1.9% for placebo) are not associated with cloxacin.
Toxicological studies
General Toxicology.
In repeated dosing toxicity tests, losartan induced a decrease in erythrocyte parameters (erythrocytes, hemoglobin, hematocrit), an increase in serum urea nitrogen and occasional increases in serum creatinine, a decrease in heart weight (no histological correlation seen) and gastrointestinal lesions (mucosal lesions, ulceration, erosion, hemorrhage).
Genotoxicity.
The microbial mutation test, V-79 mammalian cell mutation test, in vitro alkaline elution test and in vitro chromosomal aberration test results for closartan potassium were negative. The microbial mutation test, in vitro alkaline elution test and in vitro chromosomal aberration test for the active metabolites of closartan potassium were all negative.
Reproductive toxicity.
No significant effects on fertility were observed in male rats given oral doses of coxsartan potassium up to 150 mg/kg/day. In female rats given coxsartan potassium at doses of 200/300 mg/kg/day, a significant decrease (p < 0.05) in the number of corpus luteum, the number of implantations and the number of live fetuses in stage C was seen in the 200/300 mg/kg/day dose group, and a decrease in the number of corpus luteum was seen in the 100 mg/kg/day dose group; however, the relevance of the above findings to the drug is unclear, as no significant effects were seen in pregnant rats given coxsartan potassium orally at the above doses on the number of implantations, the rate of post-implantation loss, and the The above findings were not clearly correlated with the drug, as no significant effects were observed on the number of animals alive in the litter at parturition or on the rate of post-delivery loss. The systemic exposure (AUCs) of coxsartan and its active metabolites in rats given orally for 7 consecutive days at 125 mg/kg/day were approximately 66 and 26 times the maximum recommended human dose (100 mg/day), respectively.
Crosartan potassium was toxic to rat fetuses and neonatal rats, including decreased body weight, delayed physiological and behavioral development, death, and nephrotoxicity. Toxicity was observed at doses greater than 25 mg/kg/day (approximately three times the maximum recommended human dose based on body surface area), except for neonatal body weight gain, which could be affected at doses as low as 10 mg/kg/day. These toxicities were attributed to drug exposure during late gestation and lactation. Higher concentrations of cloxacin and its active metabolites were detected in the plasma of rat fetuses during late gestation as well as in breast milk.
Carcinogenicity.
No carcinogenicity was observed in mice or rats given the maximum tolerated dose of coxsartan potassium at doses up to 200 mg/kg/day for 92 weeks of continuous administration in mice and 270 mg/kg/day for 105 weeks of continuous administration 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.
[Pharmacokinetics].
Absorption: The product is well absorbed orally and forms carboxylic acid-type active metabolites and other inactive metabolites after first-pass metabolism, with a bioavailability of about 33%. The blood concentration of Crosartan and its active metabolites reach their peak at 1 hour and 3-4 hours respectively. Plasma concentrations of losartan did not change significantly when the product was taken with food.
Distribution: The plasma protein binding of losartan and its active metabolites is ≥99%, mainly to albumin. The volume of distribution of losartan was 34 liters. Studies conducted in rats have shown that losartan barely crosses the blood-brain barrier.
Metabolism: After intravenous or oral administration of losartan, approximately 14% of the dose is converted to active metabolites.
to active metabolites. The radioactivity in circulating plasma after intravenous or oral administration of 14C-labeled coxsartan potassium is primarily due to coxsartan and its active metabolites. In the trial, only a very small amount of coxsartan was converted to active metabolites in about 1% of individuals.
In addition to the active metabolites, inactive metabolites were also produced, including two major metabolites from hydroxylation of the butyl side chain and a small amount of N-2 glucosinolate tetrazolium.
Elimination: The plasma clearance of losartan and its active metabolite was 600 mL/min and 50 mL/min, respectively. Renal clearance was 74 mL/min and 26 mL/min, respectively. When closartan potassium is administered orally, approximately 4% of the dose is excreted in the urine in its original form and 6% is excreted in the urine as the active metabolite. The pharmacokinetics of coxsartan and its active metabolites are linear at oral doses of up to 200 mg of coxsartan potassium.
Following oral administration, the plasma concentrations of losartan and its active metabolites decreased exponentially in multiple steps with terminal half-lives of 2 hours and 6-9 hours, respectively. Neither losartan nor its active metabolites accumulated significantly in plasma when 100 mg was administered once daily.
Cloxacin and its metabolites were excreted via bile and urine. When 14C-labeled losartan was administered orally to humans, 35% of the radioactivity appeared in the urine and 58% in the feces. When 14C-labeled losartan was administered intravenously to humans, the radioactivity in urine and feces was 43 % and 50 %, respectively.
Special Populations.
Elderly
In elderly patients with hypertension, plasma concentrations of losartan and its active metabolites are not substantially different from those of younger hypertensive patients.
Gender
In female hypertensive patients, plasma levels of losartan were twice as high as in male hypertensive patients, while plasma levels of active metabolites did not differ between males and females.
Patients with alcoholic cirrhosis
In patients with mild and moderate cirrhosis due to alcohol, plasma concentrations of losartan and its active metabolites were 5 and 1.7 times higher after oral administration than in young male volunteers, respectively.
Renal insufficiency
In patients with creatinine clearance above 10 mL/min, plasma concentrations of losartan were unchanged. The AUC of losartan was approximately 2-fold higher in dialysis patients compared to patients with normal renal function.
Neither losartan nor its active metabolites are removed by hemodialysis.
Pediatric Patients
The pharmacokinetics of losartan have been studied in 50 hypertensive pediatric patients (age > 1 month to < 16 years) at daily oral doses of losartan ranging from 0.54 to 0.77 mg/kg losartan (mean dose).
Following oral administration of losartan, the pharmacokinetic parameters of losartan were approximately similar in infants, preschoolers, school-age children, and adolescents. The active metabolites of losartan were detected in all age groups. The pharmacokinetic parameters of the metabolites differed significantly between age groups, with statistically significant differences in preschoolers compared to adolescents.
Infants/young children were exposed to relatively high levels.
Storage】Store in a dry place under 30°C, protected from light and sealed.
Package】Polyamide/Aluminium/PVC cold pressed solid pharmaceutical laminated hard tablets and pharmaceutical aluminum foil, 7 tablets/box, 30 tablets/box and 60 tablets/box.
Expiration date】36 months
Executive Standard】Imported drug registration standard JX20190176
Approval number】Imported drug registration certificate number H20140913
【Manufacturing Company
Company Name: Sandoz GmbH
Company Address: Biochemiestra β e 10, 6250 Kundl, Austria
Production plant: Lek Pharmaceuticals d.d.
Production address: Verovskova 57,1526 Ljubljana, Slovenia
Tel: +386(0)15802111
Fax: +386(0)15683517
Domestic Tel: 0760-85319341
Domestic fax: 0760-85310695
Website: www.sandoz.com.cn