Torasemide Capsules
Torasemide Capsules

[Indications] Edema caused by congestive heart failure.

[Name of drug]
Generic name: Torasemide Capsules
Brand name: li zhi

Chinese Name: 托拉塞米胶囊

Chinese Pinyin: Tuolasaimi Jiaonang

 

[Ingredients]
Main ingredients: torasemide
Chemical name: N-{[(1- methyl ethyl) amino] carbonyl}-4-[(3- methyl phenyl) amino]-3- pyridine sulfonamide.
Chemical formula:

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Molecular formula: C16H20N4O3S
Molecular weight: 348.43

 

[Character] This product is hard capsule, the content is white or white particles and powder.
[Indications] Edema caused by congestive heart failure.
[Specification] 10mg/ granule
[Usage and Dosage] Take orally, the starting dose is 10mg (1 pills) per day, once a day, according to the condition, the dosage can be increased to 20mg (2 pills) once a day.

 

[Adverse Effects]
About 4000 patients were evaluated for the safety of the product: 800 cases were used for at least 6 months, and more than 380 cases for more than 1 years. Of these patients, 564 had clinical trials of this product in the United States, and 274 were blank controls. The side effects of this product are usually transient and have no relevance with age, sex, race, or course of treatment. The rate of discontinuation of treatment due to side effects was 3.5% (US), compared with 4.4% in the control group. In the United States and Europe, in patients with congestive heart failure due to side effects and discontinuation rate was 3 (38/1250), and furosemide was 3.4% (13/380) in patients with renal insufficiency; the discontinuation rate was 2% (8/409), and furosemide was 4.8% (11/230) in patients with liver cirrhosis; the discontinuation rate was 7.6% (11/ 170), furosemide was 0%. Disable the most common factors (according to the incidence rate from big to small program): dizziness, headache, nausea, weakness, vomiting, high blood sugar, excessive urination, hypokalemia, severe dry mouth, low blood volume, impotence, esophageal bleeding, indigestion. Because of these side effects, the withdrawal rate is between 0.1% and 0.5%. In the United States for the blank control study and drug possibly or probably related side effects are greater than 1% are: headache, dizziness, excessive urination, rhinitis, fatigue, diarrhea, cough, constipation, abnormal ECG, joint pain, nausea, indigestion, sore throat, muscle pain, chest pain, insomnia, edema, neuroticism.In these clinical trials, the daily dose range of this product ranged from 1.25mg to 20mg, and most patients were treated with 5mg ~ 10mg for a period of 1~52 days, with an average of 41 days. The only side effect of excessive urination incidence of torasemide group was higher than control group. In a controlled study of hypertension, excessive urination incidence rate of control group was 1%, 5mg/ of torasemide days was 4%, 10mg/ was 15% days. Excessive urination was not reported as an adverse event in patients with heart failure and hepatic and renal dysfunction receiving this treatment. The clinical study cannot exclude serious drug related adverse reaction: atrial fibrillation, chest pain, diarrhea, digitalis poisoning, gastrointestinal bleeding, high blood glucose, hyperuricemia, low blood potassium, low blood pressure, low blood volume, thrombosis, rash, rectal bleeding, tachycardia and syncope. A patient was reported to have angioedema after the use of the product and was found to be allergic to sulfa drugs. Clinical study of listed side effects and no drug therapy evaluation, arthritis and other nonspecific musculoskeletal problems of torasemide group than the control group, but control group than torasemide group gout. The incidence and severity of torasemide and dose related side effects of these. One patient received the drug discontinued because of myalgia, and one in the control group was discontinued because of gout. Hypokalemia: matters needing attention.

 

[Contraindicated]

1, Known hypersensitivity to torasemide or sulfonylurea drugs in patients with disabling this product.
2, No urine patients disable this product.

 

[Matters Needing Attention]

1, Because of sudden change in body fluid and electrolyte balance, may lead to liver coma, liver cirrhosis and ascites in patients with liver disease, caution with this product. It is better for such patients to start using this product (or any other diuretic) at the hospital. In order to prevent hypokalemia and metabolic alkalosis, it is better to share this product with aldosterone antagonists or a small amount of potassium excretion.

2, Ototoxicity: rapid intravenous injection with loop diuretics or other types of oral after the product had observed tinnitus and hearing loss (usually recovered), not sure these adverse reactions and the related products. In animal experiments, torasemide can be observed in the plasma concentration under high ototoxicity. Intravenous injection should be slow injection, the time is more than 2 minutes, the dose of a single dose of not more than 200mg.

3, Fluid volume and electrolyte depletion: the use of diuretics were observed in electrolyte imbalance, hypovolemia or prerenal azotemia, may cause one or more of the following symptoms: dry mouth, thirst, weakness, drowsiness, restlessness, nibbling sleep, muscle pain or cramps, fatigue, low blood pressure, oliguria, tachycardia, nausea and vomiting. Excessive diuresis may cause dehydration, reduced body fluids, and thrombosis or embolism (especially in elderly patients). Produced fluid and electrolyte imbalance, insufficient blood volume, prerenal azotemia patients, laboratory examination can increase the observed increase or decrease of blood sodium, blood, blood potassium chloride increased or decreased or decreased, pH level, blood urea nitrogen increased. If the above symptoms occur, stop using this product until the symptoms are recovered and re - use it at a low dose.

 

4. In a controlled trial in the United States, the average blood potassium dropped about 6 0.1mEq/L weeks after taking the product (5-10mg/ days). At any time during the treatment, the percentage of patients with potassium in the test group below 3.5mEq/L (1.5%) was similar to that in the placebo group (3%). After 1 years, the average blood potassium levels did not change further. In patients with congestive heart failure, cirrhosis or kidney disease, the dosage of this dose is higher than that in the US antihypertensive trial, and the rate of dose-dependent hypokalemia is higher. Patients with cardiovascular disease, especially the use of digitoxin in patients with hypokalemia induced by diuretics is a risk factor for cardiac arrhythmia. In patients with liver cirrhosis, diuretic and electrolyte in patients with rapid inadequate intake of patients, concomitant use of corticosteroids or adrenocorticotropic hormone drugs in patients with hypokalemia at greatest risk. The use of torasemide patients need regular monitoring of blood potassium and other electrolytes.

5. Other electrolytes:
(1) Calcium: The urinary calcium excretion in healthy volunteers increased after single use, but the serum calcium levels increased slightly in the 4-6 week trial of patients with hypertension. In a long-term trial of patients with congestive heart failure, serum calcium levels fell by an average of 1 years (0.02mmol/L) for 0.10mg/dL years. The use of this product in the treatment of 426 patients of 11 months, not as an adverse reaction reports of hypocalcemia
.

(2) Mg: The excretion of urinary magnesium increased after the single use of this product in healthy volunteers, but the blood magnesium levels increased only slightly in the 4-6 week trial of patients with hypertension. In the long-term test in the patients with hypertension, serum magnesium levels in patients with an average of 1 years, the increase of 0.03mg/dL (0.01mmol/L) is used for the treatment of 426 patients of 11 months, only 1 cases of hypomagnesemia (1.3mg/dL, equivalent to 0.53mmol/L), as one of the reports of adverse reactions. In a long-term study of patients with congestive heart failure in patients with an average of 1 years, estimated blood magnesium levels increased 0.2mg/dL (0.08mmol/L), but because many patients taking magnesium supplements, so these data are confused. In a 4 week trial, patients did not use magnesium supplements, 10mg group, 5mg of torasemide in serum magnesium level lower than that of 1.7mg/dI (0.70mmol/L) were 6% and 9% respectively.

6. Blood biochemistry:
(1) Blood urea nitrogen, creatinine and uric acid in the above parameters: torasemide dose dependently increased slightly. The blood urea nitrogen of the patients with elevated blood pressure was increased by 1.8mg/dL (0.6mmol/L), the serum creatinine increased by 0.05mg/dL (4mmol/L), and the serum uric acid increased by 1.2mg/dL (70mmol/L) on a daily basis for 6 weeks after the daily use of 10mg. After a long period of treatment, the above parameters can be slightly changed, but all can be recovered after withdrawal. Patients who use this product can develop symptomatic gout, but the incidence is similar to that in the placebo group.

(2) Blood sugar: Patients with high blood pressure took 10mg daily, and the average blood sugar level increased by 5.5mg/dL (0.3mmol/L) after 6 weeks, and the blood sugar level was further increased (0.1mmol/L) over the next 1 years (1.8mg/dL). In long-term trials of diabetics, there was no significant change in mean fasting blood glucose levels compared with baseline values. Cases with elevated blood sugar are reported, but not very common.
(3) Blood lipid: In the United States on patients with hypertension in short-term control test, 5mg, 10mg, 20mg taking torasemide every day, plasma total cholesterol levels were respectively increased by 4, 4 and 8mg/dL (0.10-0.20mmol/L), the symptoms disappeared after long-term medication.
(4) In one of the patients with hypertension short-term test, daily use of 5mg, 10mg, 20mg of torasemide, plasma triglyceride levels were respectively increased by an average of 16, 13, 71mg/dL (0.15-0.80mmol/L). In a long-term trial, patients were treated with this product 5-20mg daily. After 1 years of treatment, no significant clinical changes were observed in serum lipid levels compared with baseline values.

7 .In the long-term trials of hypertension patients, the hemoglobin, hematocrit and the number of erythrocytes in the experimental group decreased slightly, and the number of leukocytes, the number of platelets and alkaline phosphatase of serum increased slightly. Although there were significant statistical differences, these changes were not medically significant. In addition to alkaline phosphatase, no significant change was observed in the experiments on other anhydrides.

 

[Medication for Pregnant Women and Lactating Women]

1. Pregnant women: the product of rats dose to 5mg/kg/ days (with mg/kg and surface area, with dose were equivalent to 15 times the dose of 20mg and 10 times), the dosage to 1.6mg/kg/ days on rabbits (with mg/kg and surface area, with dose were equivalent to 5 times the dose of 20mg and 1.7 times) no embryotoxic or teratogenic effects, rabbit and rat dose was increased by 4 times and 5 times more, fetal and maternal toxicity including average weight loss, fetal absorption increased, fetal ossification delay. Because has not been fully controlled trials in pregnant women, and the reproductive toxicity test results of animal does not always indicate on the human body reaction, so pregnant women taking this product must be weighed.
2 . lactating women: it is not known whether this product can be secreted in human milk. Since many drugs can be secreted in human milk, lactating women should be careful with this product.
[Children Medication]

The efficacy and safety of this product have not been established, should be careful with this product. Preterm infants taking another diuretic, observed for patent ductus arteriosus and hyaline membrane disease caused by edema, occasionally with renal calcification, sometimes stones in X-ray almost invisible, but sometimes a staghorn filling in the renal pelvis. Some stones can disappear spontaneously, and the incidence of high urinary calcium decreases following coadministration with other loop diuretics. The risk of persistent patent ductus arteriosus increases following the use of another loop type diuretic in premature infants with hyaline membrane disease and may be associated with prostaglandin E mediated action. The use of this product has not been studied in such patients.

 

[Senile Medication]

In geriatric medicine clinical trials conducted in the United States, 24% of the patients over the age of 65, about 4% of the patients were under 75 years of age, the results showed that elderly patients taking the drug safety and efficacy showed no age-related differences compared with younger patients.

[Drug Interaction]
1. Patients with primary hypertension, put this product with beta blockers, ACE inhibitors and calcium channel blockers in patients with congestive heart failure, this product will be with digitoxin, ACE inhibitors and nitrates combined, no adverse reaction was found in addition to new or unexpected.
2.The product of the combination of glibenclamide, Hua Falin and plasma protein rate had no effect on phenprocoumon (coumarin derivatives related) had no effect on the anticoagulant effect, digoxin or carvedilol (vasodilators, beta blockers) pharmacokinetics has no effect. In healthy volunteers, this product was combined with spironolactone. The renal clearance rate of the latter decreased and the AUC value increased, but the clinical experience showed that there was no need to adjust the dosage of two drugs.
3. Because of salicylates and the product competition tubular secretion, so in combination with the product after salicylic acid can be observed in high dose group of salicylic acid toxicity, although not on the materials with non steroidal anti-inflammatory drug drug interactions studied, but these drugs combined with furosemide can lead to kidney dysfunction after occasionally.

4. Like many diuretics, indomethacin partially inhibits the urinary sodium excretion of this product. This phenomenon was observed in patients with limited sodium intake (50mEq/ days), but this phenomenon was not observed in patients with normal sodium intake (150mEq/ days).
5. Cimetidine and spironolactone on the pharmacokinetics and diuretic effect had no effect. Taking digoxin at the same time increases the AUC value of the product by 50%, but does not need to adjust the dosage.
6. No interaction between this product and the human drug has been studied. However, in animal testing, the absorption rate of oral products was decreased, and two drugs were not recommended.
7. While taking this product to probenecid excreted into the proximal tubule decreased and the diuretic effect of the product decreased.
8. It is known that other diuretics can reduce the renal clearance rate of lithium and increase the risk of lithium toxicity. Therefore, the combination of the two drugs must be considered carefully. The interaction between this product and lithium has not been studied.
9. Other potential ototoxicity of aminoglycoside antibiotics, diuretics increase and ethacrynic acid, especially in patients with renal function damage is more serious, no research on the interaction between the goods and the drug.

 

[Overdose]

There is no drug overdose overdose of this product is reported, but if an overdose of this product, is expected to have the symptoms of dehydration, hypovolemia, hypotension, hyponatremia, hypokalemia, hypochloremic alkalosis, blood concentration. Excessive use of the product should be followed by fluid infusion and electrolyte supplementation. Laboratory methods for determining serum concentrations of this product and its metabolites have not yet been widely applied. No data suggest that some physiological means, such as adjusting pH values in urine, can contribute to the elimination of this product and its metabolites. This product can not be removed by hemodialysis.

[Pharmacological and Toxicological]

Pharmacological action, this product is mainly used in the ascending branch of the medullary loop to block the Na+/K+/2Cl- translocation system. Clinical pharmacological studies have also confirmed that this is the site of this product in the human body and has no effect on other parts of the kidney. Therefore, the diuretic effect of this product is related to the rate of excretion of drugs in urine and is higher than that in the blood. Tora Sami Mike Zengana, chloride and water excretion in urine, but not significantly change glomerular filtration rate, renal blood flow and acid-base balance. Toxicological effects of carcinogenesis in rats and mice were given 9mg/kg/ days and 32mg/kg/ days of torasemide, no significant increase in the incidence of tumor, the dose equivalent to 27-96 times the dose of 20mg (mg/kg) or 5-8 (surface area) times. In the rat experiment, the rats in the high dose group were found to have renal tubular injury and renal interstitial inflammation. The incidence of renal adenoma and renal carcinoma increased significantly, but the incidence of the tumor was not higher than that of the historical control. In animal experiments, other non neoplastic renal damage such as diuretics, furosemide and hydrochlorothiazide were also found in the high dose group of similar.Mutagenic effect in vivo and vitro experiments, and the main body of the generation of torasemide in Xie Wujun mutagenicity. The above tests including Ames test (with or without S9), human lymphocyte chromosome aberration test and sister chromatid exchange test, hamster bone marrow micronucleus aberration test, mice and rats unscheduled DNA synthesis test. The reproductive toxicity of 25mg/kg/ days (given torasemide by mg/kg and body surface area, with dose were equivalent to 75 times the dose of 20mg and 13 times) had no effect on female and male rats reproductive ability. The rats were given 5mg/kg/ days of torasemide (mg/kg and surface area, dose were equivalent to 15 times for 20mg/ days and 10 times) and rabbit 1.6mg/kg/ days torasemide (mg/kg and surface area, dose were equivalent to 5 times for 20mg/kg/ days and 1.7 times) and no fetal toxicity teratogenicity. Fetal and maternal toxicity (mean weight loss, increased placental count, and delayed fetal ossification) were seen when rats were given 4 or 5 times greater doses of the rabbit.

 

[Pharmacokinetics]

Torasemide bioavailability is approximately 80%, individual difference is very small, the 90% confidence limit of 75%-89%. The absorption of drugs was very little affected by the first pass metabolism. The serum concentration reached peak (Cmax) within 1 hours after oral administration, and the dose was in the range of 2.5-200mg. The Cmax and AUC values of this product were proportional to the dose. While taking the medicine at the same time, the peak time of the blood serum was delayed for about 30 minutes, but the total bioavailability (AUC value) and the diuretic effect were not changed. The absorption of this product is basically not affected by liver and kidney dysfunction. The distribution of this product in healthy adults, mild to moderate renal failure and congestive heart failure is 12-15L, and the distribution volume of cirrhosis patients is about doubled. The half-life of this product in healthy volunteers is about 3.5 hours. In patients with normal renal function, liver metabolism rate and urinary excretion rate were about 80% and 20%, respectively. The main metabolite of this product in the human body is a carboxylic acid metabolite without pharmacological activity, and 2 minor metabolites may have some diuretic effects, but because of metabolic reasons, their diuretic effects can not be displayed. The plasma protein binding rate of torasemide is high (>99%), into the renal tubule by glomerular filtration is small, most of the main renal clearance by torasemide by proximal tubule actively secreted into the renal tubule.Decompensated congestive heart failure patients in the use of torasemide after liver and renal clearance rate were reduced, may be due to a decrease in hepatic congestion and renal plasma flow, the total removal rate of torasemide is roughly equivalent to 50% healthy volunteers. The plasma half-life and AUC value increase. Since the renal clearance rate is reduced, only a small amount of this product can enter the site of action in the spinal cord, so the effect of this product on sodium excretion in patients with congestive heart failure is lower than that in healthy volunteers. The renal clearance rate after renal failure in patients with renal failure was significantly decreased, but the total plasma clearance rate was not significantly changed. Only a small amount of this product can enter the site of action in the spinal cord, so the effect of sodium excretion is down. Patients with renal failure who receive high doses of this product still have diuretic effects. The total plasma clearance and elimination half-life remained normal in patients with impaired renal function after the elimination of hepatic metabolism. The distribution volume, plasma half-life and renal clearance increased after the use of this product, but the total clearance rate remained unchanged. In addition to the elderly patients with decreased renal function of renal clearance decreased (but the total plasma clearance and elimination half-life unchanged), torasemide subjects in pharmacokinetics and young subjects were similar in healthy elderly.

 

[Storage] Shading, sealed, placed in a dry place to save.
[Packing] Aluminium plastic packing, 10 tablets / plate ×1 plates / small box (or 2 plate / small box).
[Validity] Tentative 24 months.
[Performance Standards] YBH06002005
[Approval Number] SFDA approval number H20050526

 

[Production Enterprise]
Name of enterprise: Zhejiang Chengyi Pharmaceutical Co., Ltd

Production address: No. 118, Chemical Road, Dongtou District, Wenzhou city,Zhejiang province,China

Phone number: 86-577-6348-3979

Fax number: 86-577-6348-5135

URL:http://en.chengyipharma.com

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