100mg: aluminum-plastic plate packaging, 7 pieces in a box, 7 pieces× 2 pieces in a box, and 7 pieces× 4 pieces in a box.
Store away from light, sealed and stored in a dry place below 30℃.
The validity period is 36 months.
Implement the standard 50mg JX20 120 137.
100 mg JX20 120 102
Registration number of imported drugs
50 mg H20 130409
100 mg H20 130056
100 mg H20 130057
Production enterprise
Company name: Merck Sharp &; Dome (Australia) Limited. Limited (short for limited)
Address: 54-68 Fernandez Street, South glanville, New South Wales, Australia, 2 142.
Name of manufacturer: Merck Sharp &; Duomei co., ltd.
Address: Shortton Lane, Cranlington, Northumberland, NE 233, UK.
Name of packaging factory: Merck Sharp &; Dome (Australia) Limited. Limited (short for limited)
Address: 54-68 Fernandez Street, South glanville, New South Wales, Australia, 2 142.
composition
The main component of this product is losartan potassium. Its chemical name is: 2- butyl -4- chloro-1-[[2'-( 1H- tetrazole -5- yl)] [1, 1'? Biphenyl]? 4? Methyl]? 1H？ Imidazole? 5? Monopotassium salt of methanol.
Its structural formula is:
Molecular formula: C22H22ClKN6O
Molecular weight: 46 1.0 1
Description: 50mg: This product is a white oval film-coated tablet with a notch in the middle on one side and 952 printed on the other side. After the coating is removed, it is white.
100mg: This product is a white teardrop-shaped film-coated tablet. One side of the monument is engraved with 960, and the other side is not printed. After the coating is removed, it appears white. This product can be combined with other antihypertensive drugs.
This product can be taken with or without food.
For most patients, the initial and maintenance dose is usually 50 mg once a day. The maximum antihypertensive effect can be achieved after 3 ~ 6 weeks of treatment. In some patients, increasing the dose to 100mg once a day can further reduce blood pressure.
For patients with insufficient vascular capacity (such as patients who use large doses of diuretics), once a day with an initial dose of 25mg can be considered (see precautions).
For elderly patients or patients with renal damage, including hemodialysis patients, it is not necessary to adjust the initial dose. Patients with a history of liver injury should consider using a lower dose (see precautions). Clinical trials have found that this product is well tolerated; Adverse reactions are mild and short-lived, and there is generally no need to terminate treatment. The total incidence of adverse reactions was similar to that of placebo.
In the clinical controlled study of essential hypertension, dizziness is the only adverse reaction with the incidence ≥ 1%, which is related to drugs and the incidence is higher than that of placebo. In addition, less than 1% of patients have dose-related orthostatic hypotension. Although the incidence of rash in clinical controlled trials is lower than that in placebo, there are also individual reports.
In these clinical double-blind controlled studies of essential hypertension, the incidence of adverse reactions, whether drug-related or not, is 1% or above: losartan potassium tablets (n=2085) blank (n=535) general abdominal pain 1.7 1.7 fatigue /3.8 3.9 chest pain/kloc-. Kloc-0/. 1.8 2.8 Back pain in musculoskeletal system 1.6 1 Muscle spasm 1.0 1 Neurotic/Psychotic vertigo 4. 1.2.4 Headache/Kloc-0. .7 Respiratory Cough 3. 1.2.6 Nasal congestion 438+0.5 2.6 Sinus diseases1.0/.3 Upper respiratory tract infection 6.5 5.6 In addition to the above adverse events, at least two patients/subjects have potential serious adverse events or incidence in clinical research.
Whole body: facial edema, fever, postural hypotension, syncope;
Cardiovascular system: angina pectoris, second degree atrioventricular block, cardiovascular accident, hypotension, myocardial infarction, arrhythmia including atrial fibrillation, palpitation, sinus bradycardia, tachycardia, ventricular tachycardia and ventricular fibrillation;
Digestive system: anorexia, constipation, toothache, dry mouth, flatulence, gastritis, vomiting;
Blood system: anemia;
Metabolism: gout;
Musculoskeletal system: arm pain, hip pain, joint swelling, knee pain, musculoskeletal pain, shoulder pain, stiffness, joint pain, arthritis, fibromyalgia and myasthenia;
Nervous/mental system: anxiety, anxiety disorder, ataxia, confusion, depression, abnormal dreams, insensitivity, hyposexuality, memory loss, migraine, nervousness, paresthesia, peripheral neuropathy, phobia, abnormal sleep, lethargy, tremor and dizziness;
Respiratory system: dyspnea, bronchitis, pharyngeal discomfort, nosebleeds, rhinitis, respiratory congestion;
Skin: alopecia, dermatitis, dry skin, blood stasis, redness, flushing, light sensitivity, itching, rash, sweating, urticaria;
Special feelings: blurred vision, burning and tingling sensation in eyes, conjunctivitis, inverted taste, tinnitus and decreased vision;
Urogenital system: impotence, nocturia, frequent urination, urinary tract infection.
This product is generally well tolerated in controlled clinical trials of patients with hypertension and left ventricular hypertrophy. The most common drug-related adverse reactions are dizziness, fatigue/fatigue and dizziness.
In the LIFE study, among patients without diabetes at baseline, the incidence of new diabetes in losartan potassium group was higher than that in Artie group.
Lohr group was lower (242 and 320 respectively, P
In a controlled clinical trial for patients with type 2 diabetes and proteinuria, this product is generally well tolerated. The most common drug-related adverse reactions are fatigue/fatigue, dizziness, hypotension and hyperkalemia (see precautions, hypotension and electrolyte/body fluid imbalance).
Other adverse reactions reported since the product went on the market include:
Allergic reaction: Very few patients treated with losartan developed vascular edema (including swelling of larynx and glottis leading to airway obstruction, and/or swelling of face, lips, pharynx and/or tongue). Some of these patients had previously suffered from angioedema due to taking other drugs, including ACE inhibitors. Vasculitis, including Hennock? Schoenlein's purpura is rarely reported.
Gastrointestinal reactions: hepatitis (rarely reported), abnormal liver function, vomiting.
General symptoms and administration site status: discomfort.
Blood system: anemia, thrombocytopenia (rarely reported).
Musculoskeletal system: myalgia, joint pain.
Nervous/Mental System: Migraine, grand mal, Taste Disorder.
Reproductive system disorders: erectile dysfunction/impotence.
Respiratory system: cough.
Skin: urticaria, itching, erythroderma, photosensitivity.
Hyperkalemia and hyponatremia have been reported.
There are spontaneous reports of drug-related unexplained deaths in China.
Laboratory test results
In the clinical controlled trial of essential hypertension, the laboratory parameters of a few patients who used this product showed clinical significant changes. 1.5% patients developed hyperkalemia (serum potassium >: 5.5mEq/L). In a clinical study on proteinuria in type 2 diabetes mellitus, 9.9% patients in losartan group and 3.4% patients in placebo group developed hyperkalemia (see Precautions, hypotension and electrolyte/body fluid imbalance). ALT elevation is rare and returns to normal after drug withdrawal.
Creatinine and blood urea nitrogen: In patients with essential hypertension, less than 0. 1% of patients who used this product alone observed a slight increase in blood urea nitrogen or serum creatinine.
Hemoglobin and hematocrit: In patients treated with this product alone, hemoglobin and hematocrit often decrease slightly (the volume is about 0. 1 1%g and 0.09% respectively), but the clinical significance is not significant. No patient stopped taking the drug because of anemia.
Liver function test: occasionally liver enzymes and/or serum bilirubin increase. Among the patients with essential hypertension treated only with this product, one patient (
Allergic reaction: vascular edema. See Adverse Reactions
Hypotension and electrolyte/body fluid imbalance
Patients with insufficient vascular capacity (such as patients treated with high-dose diuretics) may have symptomatic hypotension. Before using this product for treatment, these conditions should be corrected or a lower initial dose should be used. (See usage and dosage).
It should be noted that electrolyte imbalance is very common in patients with renal insufficiency with or without diabetes. In the clinical study of type 2 diabetes with proteinuria, the incidence of hyperkalemia in losartan potassium treatment group was higher than that in placebo group. However, almost no patients stopped treatment because of hyperkalemia (see adverse reactions and laboratory results).
Liver function damage
Pharmacokinetic data show that the plasma concentration of losartan in patients with liver cirrhosis is significantly increased, and patients with a history of liver function damage should consider using a lower dose (see usage and dosage).
Renal insufficiency
Because of the inhibition of renin? Angiotensin system, there have been reports about renal function changes, including renal failure in sensitive individuals; These changes in renal function can be recovered after stopping treatment.
For patients whose renal function depends on the activity of renin-angiotensin-aldosterone system (such as patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors can lead to oliguria and/or progressive azotemia, and (rarely) acute renal failure and/or death. There are similar reports about the treatment of losartan.
What is the effect on renin in patients with bilateral renal artery stenosis or patients with unilateral renal artery stenosis? Other angiotensin system drugs can increase blood urea and serum creatinine. There are similar reports about the use of this product. These changes in renal function can be recovered after stopping treatment.
Medication for pregnant and lactating women
Medication for pregnant women
When pregnant women take drugs in the second and third trimester of pregnancy, they directly act on renin? Angiotensin system drugs can cause damage and even death to the developing fetus. When pregnant, you should stop using this product as soon as possible.
Although there is no experience of pregnant women using this product, animal studies using losartan potassium have proved that there are fetal and neonatal injuries and deaths, and its mechanism is considered to be the drug-mediated effect on renin? Caused by the action of the angiotensin system. Renal perfusion of human fetus depends on renin from the second trimester of pregnancy? The development of angiotensin system, therefore, if you use this product in the second and third trimester of pregnancy, the risk to the fetus will increase.
Medication for lactating women
It is not clear whether losartan is secreted by human milk. Because many drugs can be secreted by human milk, which has adverse effects on nursing babies, it is necessary to decide whether to stop breastfeeding or stop taking drugs from the consideration of maternal importance.
Children's medication
Years old > years old; To determine the antihypertensive effect of this product on hypertensive children aged 1 month to 16. Evidence from sufficient controlled studies of children and adults and literature reports on children's use of this product support the use of this product in these age groups.
50 children with hypertension, aged >: 1 month to.
A clinical study involving 177 hypertensive children aged 6- 16 and weighing ≥ 20kg.
In this study, this product is usually well tolerated.
For patients who can swallow tablets and weigh ≥20Kg to 50Kg, the initial dose is 50mg once a day. The maximum dose can be increased to 100mg once a day.
For children with insufficient vascular capacity, these conditions should be corrected before taking this product.
Adverse events in children patients are similar to those in adults.
Glomerular filtration rate is not recommended.
Medication for the elderly
race
Based on life research, although both treatment groups can effectively reduce the blood pressure of black patients, compared with atenolol, the benefits of losartan in reducing cardiovascular morbidity and mortality are not applicable to black patients with hypertension and left ventricular hypertrophy. Among all the patients who participated in the LIFE study (n=9 193), compared with the atenolol group, the main comprehensive end point risk of cardiovascular death, stroke and myocardial infarction in losartan group was reduced by 13%(p=0.02 1). In the LIFE study, compared with atenolol, losartan reduced the risk of cardiovascular disease and death in non-black hypertensive patients with left ventricular hypertrophy (n=8660), and the observation index was the comprehensive incidence of cardiovascular death, stroke and myocardial infarction (p=0.003). However, in this study, compared with the losartan group, the black patients in the atenolol group had a lower risk of experiencing the main comprehensive end point (p=0.03). In the subgroup of black patients (n = 53.36%), 29 of the 263 patients in the atenolol group (1 1%, 25.9/ 1000 patient-years) had the main end point, while 46 of the 270 patients in the losartan group (/. In clinical pharmacokinetic studies, it has been confirmed that there is no clinical drug interaction with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole and erythromycin. It is reported that rifampicin and fluconazole can reduce the level of active metabolites. The clinical results of these interactions have not been evaluated.
Like other drugs that inhibit angiotensin II and its effects, this product can lead to an increase in blood potassium when used with potassium-preserving diuretics (such as spironolactone, triamcinolone and amiloride), potassium supplements or potassium salt-containing substitutes.
Like other drugs that affect sodium excretion, lithium excretion may be reduced. Therefore, if lithium salt is used together with angiotensin II receptor antagonist, the serum lithium salt level should be carefully monitored.
Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase -2 inhibitors (COX-2 inhibitors), may reduce the effects of diuretics and other antihypertensive drugs. Therefore, the antihypertensive effect of angiotensin II receptor antagonists or angiotensin converting enzyme inhibitors may be weakened by NSAIDs including COX-2 inhibitors.
For some patients with renal impairment who are taking non-steroidal anti-inflammatory drugs including selective cyclooxygenase -2 inhibitors (such as elderly patients or hypovolemic patients, including those receiving diuretics), taking angiotensin II receptor antagonists or angiotensin converting enzyme inhibitors at the same time may lead to further renal impairment, including possible acute renal failure. These effects are usually reversible. Therefore, patients with renal insufficiency should be cautious when taking drugs together.
Compared with single therapy, dual blocking therapy of renin-angiotensin-aldosterone system (RAAS) and angiotensin receptor antagonist, ACE inhibitor or aliskiren will increase the risk of hypotension, syncope, hyperkalemia and renal function changes (including acute renal failure). Blood pressure, renal function and electrolytes of losartan potassium tablets patients who are combined with other drugs affecting RAAS should be closely monitored. Losartan potassium tablets and aliskiren should not be used in combination in diabetic patients. Patients with renal insufficiency (GFR)
Neither losartan nor its active metabolites can be eliminated by hemodialysis. Mechanism of action
Angiotensin Ⅱ is the main active substance of renin-angiotensin system and a powerful vasoconstrictor, which plays a major role in the pathophysiological process of hypertension. Angiotensin Ⅱ binds to AT 1 receptor in various tissues (such as vascular smooth muscle, adrenal gland, kidney and heart), which has many important biological effects, including vasoconstriction and aldosterone release.
It can also stimulate the proliferation of smooth muscle cells. It has been confirmed that another subtype of angiotensin II receptor is AT2, but its effect on the functional homeostasis of cardiovascular system is still unclear.
Losartan is a powerful synthetic oral active drug. Binding test and pharmacological and biological tests prove that it can selectively bind to AT 1 receptor. In vitro and in vivo studies have shown that losartan and its pharmacologically active carboxylic acid metabolites (such as? 3 174) can block the corresponding physiological effects produced by angiotensin ⅱ synthesized from any source or in any way. Compared with other peptide angiotensin II antagonists, losartan has no excitatory effect.
Losartan can selectively act on AT 1 receptor, without affecting the function of other hormone receptors or important ion channels in cardiovascular system, and without inhibiting angiotensin converting enzyme (kininase II) which degrades bradykinin. Therefore, effects that are not directly related to blocking AT 1 receptor, such as bradykinin-mediated effects or edema (losartan 1.7%, placebo 1.9%), have nothing to do with losartan.
Toxicological study
The LD50 of losartan potassium in male mice was 2248mg/Kg(6744mg/m2) (1 124 times the maximum recommended daily dose for adults). The significant minimum lethal dose of this product to mice and rats is 1000mg/Kg(3000mg/m2) and 2000mg/kg (11800mg/m2), which are 500 times of the maximum recommended daily dose for adults and/kloc respectively.
The potential toxicity of losartan potassium was evaluated by a series of three-month monkey toxicity tests and one-year rat and dog toxicity tests, and it was not found that it would hinder the administration of losartan potassium at the therapeutic dose level.
The maximum tolerated dose of this product was given to rats and mice, and the observation time was 105 and 92 weeks respectively. No carcinogenic effect of losartan potassium was found.
In vitro alkali elution test and chromosome aberration test show that the use of losartan potassium, which is equivalent to 1700 times of the maximum blood concentration that can be achieved by recommended therapeutic dose, has no direct mutagenic effect.
Male and female rats were given losartan potassium 150 and 300mg/kg orally every day, respectively, and no effect on reproductive capacity was found.
Losartan potassium has side effects on rat embryos and newborns, including weight loss, death and/or nephrotoxicity. In addition, the concentration of losartan potassium and its active metabolites in the milk of rats taking the drug is high. Absorption: this product is well absorbed by oral administration, and carboxylic acid active metabolites and other inactive metabolites are formed after the first metabolism; The bioavailability is about 33%. The plasma concentrations of losartan and its active metabolites were 65438 0 hours and 3? It peaked in 4 hours. When this product is taken with food at the same time, the plasma concentration of losartan has no obvious change.
Distribution: The plasma protein binding rate of losartan and its active metabolites is ≥99%, mainly binding with albumin. The distribution volume of losartan is 34 liters. Studies on rats show that losartan is difficult to cross the blood-brain barrier.
Metabolism: About 14% dose of losartan will be converted into active metabolites after intravenous injection or oral administration. After intravenous injection or oral administration of losartan potassium labeled with 14C, the radioactivity in circulating plasma mainly comes from losartan and its active metabolites. In the experiment, only a small amount of losartan was converted into active metabolites in about 65438 0% individuals.
In addition to active metabolites, there are inactive metabolites, including two main metabolites produced by hydroxylation of butyl side chain and a small amount of N-2 tetrazole glucoside.
Elimination: The plasma clearance rates of losartan and its active metabolites were 600 ml/min and 50 ml/min, respectively. The renal clearance rates were 74 ml/min and 26 ml/min respectively. When losartan potassium is taken orally, about 4% of the dose is excreted in urine in the original form, and 6% of the dose is excreted in urine in the form of active metabolites. When the oral dose of losartan potassium reached 200mg, the pharmacokinetics of losartan and its active metabolites were linear.
After oral administration, the plasma concentrations of losartan and its active metabolites decreased exponentially, and the terminal half-lives were 2 hours and 6-9 hours respectively. When 100mg is given once a day, losartan and its active metabolites have no obvious accumulation in plasma.
Losartan and its metabolites are excreted through bile and urine. When people take losartan labeled with 14C orally, 35% of the radioactivity appears in urine and 58% in feces. Losartan labeled with 14C was injected into human vein, and the radioactivity in urine and feces was 43% and 50% respectively.