Product name: Cozaia?
Common name: Losartan Potassium Tablets
English name: Losartan Potassium Tablets
Chinese Pinyin: Lushatanjia Pian
Specifications (1) 50mg, (2) 100mg
Packaging 50mg: aluminum-plastic plate packaging, 7 tablets/box
100mg: aluminum Plastic plate packaging, 7 pieces per box, 7 pieces × 2 plates/box, 7 pieces × 4 plates/box
Storage in a dark, sealed, dry place below 30°C.
Valid for 36 months
Executive standard 50mg JX20120137
100mg JX20120102
Imported drug registration certificate number
50mgH20130409
100mg H20130056
100mg H20130057
Manufacturer
Company name: Merck Sharp & Dohme (Australia) Pty. Ltd.< /p>
Address: 54-68 Ferndell Street, South Granville, New South Wales 2142, Australia
Ingredients
The main ingredients of this product are: losartan 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.
The structural formula is:
Molecular formula: C22H22ClKN6O
Molecular weight: 461.01
Properties 50mg: This product comes in a white oval film package Coated tablets. There is a score in the middle of one side of the tablet and 952 is printed on the other side. It will appear white after the coating is removed.
100mg: This product is a white teardrop-shaped film-coated tablet. One side of the tablet is engraved with 960, and the other side is unprinted. It appears white after the coating is removed.
This product can be used together with other antihypertensive drugs.
This product can be taken with or without food.
For most patients, the usual starting and maintenance dose is 50 mg once daily. The maximum antihypertensive effect can be achieved in 3 to 6 weeks of treatment. In some patients, increasing the dose to 100 mg once daily may produce further antihypertensive effects.
For patients with insufficient vascular volume (such as those treated with high-dose diuretics), a starting dose of 25 mg once daily may be considered (see Precautions).
For elderly patients or patients with renal impairment, including dialysis patients, there is no need to adjust the starting dose. Lower doses should be considered in patients with a history of hepatic impairment (see Precautions). Clinical trials have found that this product is well tolerated; adverse reactions are mild and short-lived, and treatment generally does not need to be terminated. The overall incidence of adverse reactions was similar to placebo.
In controlled clinical studies in essential hypertension, the only drug-related adverse reaction with an incidence of ≥1% and a higher incidence than placebo was dizziness. In addition, dose-related orthostatic hypotension occurred in less than 1% of patients. Although the incidence of rash was lower than placebo in controlled clinical trials, it has been reported sporadically.
In these clinical double-blind controlled studies of essential hypertension, the adverse reactions with an incidence rate of 1% or above after using this product, whether related to the drug or not, include: Losartan Potassium Tablets (n=2085) Blank tablets (n=535) General abdominal pain 1.7 1.7 Asthenia/fatigue 3.8 3.9 Chest pain 1.1 2.6 Edema/swelling 1.7 1.9 Cardiovascular system palpitations 1.0 0.4 Tachycardia 1.0 1.7 Digestive system diarrhea 1.9 1.9 Indigestion 1.1 1.5 Nausea 1.8 2.8 Musculoskeletal system back pain 1.6 1.1 Muscle spasm 1.0 1.1 Nervous/psychiatric system Dizziness 4.1 2.4 Headache 14.1 17.2 Insomnia 1.1 0.7 Respiratory system cough 3.1 2.6 Nasal congestion 1.3 1.1 Pharyngitis 1.5 2.6 Sinus disease 1.0 1.3 Upper respiratory tract infection 6.5 5.6 In addition to the above adverse effects In addition to the incident, at least two patients/subjects in clinical studies experienced potentially serious adverse events or other adverse events with an incidence rate of <1% after using losartan as follows. It cannot be determined whether these events are causally related to losartan:
General body: facial edema, fever, orthostatic hypotension, syncope;
Cardiovascular system: angina pectoris, second-degree atrioventricular block, cardiovascular accident, hypotension, myocardium Infarction, arrhythmias including atrial fibrillation, palpitations, sinus bradycardia, tachycardia, ventricular tachycardia, ventricular fibrillation;
Digestive system: loss of appetite, constipation, toothache, dry mouth, Flatulence, gastritis, vomiting;
Hematology: anemia;
Metabolism: gout;
Musculoskeletal system: arm pain, hip pain, joints Swelling, knee pain, musculoskeletal pain, shoulder pain, stiffness, joint pain, arthritis, fibromyalgia, muscle weakness;
Nervous/psychiatric system: anxiety, anxiety disorders, dystaxia, Confusion, depression, abnormal dreams, hypoesthesia, reduced libido, memory loss, migraine, nervousness, paresthesia, peripheral neuropathy, phobia, abnormal sleep, drowsiness, tremor, dizziness;
Respiratory system : Difficulty breathing, bronchitis, pharyngeal discomfort, epistaxis, rhinitis, respiratory congestion;
Skin: alopecia, dermatitis, dry skin, bruising, redness, flushing, photosensitivity, itching, rash , sweating, urticaria;
Special sensations: blurred vision, burning and stinging sensations in the eyes, conjunctivitis, taste disturbance, tinnitus, decreased visual acuity;
Urology Reproductive system: impotence, nocturia, frequent urination, urinary tract infection.
In a controlled clinical trial in patients with hypertension and left ventricular hypertrophy, this product was generally well tolerated. The most common drug-related adverse reactions were dizziness, fatigue/asthenia, and vertigo.
In the LIFE study, among patients who did not have diabetes at baseline, the incidence of new diabetes was lower in the losartan potassium group than in the atinolol group (242, respectively). bit ratio 320 bits, p<0.001). Because there was no placebo group in this study, it is unclear whether this result represents a benefit from losartan potassium or an adverse effect from atenolol.
In a controlled clinical trial in patients with type 2 diabetes and proteinuria, this product was generally well tolerated. The most common drug-related adverse reactions are asthenia/fatigue, dizziness, hypotension, and hyperkalemia (see Precautions, Hypotension and Electrolyte/Fluid Imbalance).
Other adverse reactions that have been reported since the launch of this product include:
Allergic reactions: angioedema (including swelling of the larynx and glottis leading to airway obstruction, and/or facial, Swelling of the lips, pharynx, and/or tongue) has been reported in rare patients treated with losartan. Some of these patients had previously developed angioedema from taking other medications, including ACE inhibitors. Vasculitis, including Henoch-Sch?nlein purpura, has been rarely reported.
Gastrointestinal reactions: hepatitis (rarely reported), abnormal liver function, vomiting.
General disorders and administration site conditions: Discomfort.
Hematological system: anemia, thrombocytopenia (rarely reported).
Musculoskeletal system: myalgia, joint pain.
Nervous/psychiatric system: migraine, grand mal epilepsy, taste disorder.
Reproductive system disorders: Erectile dysfunction/impotence.
Respiratory system: Cough.
Skin: urticaria, itching, erythroderma, photosensitivity.
Hyperkalemia and hyponatremia have been reported.
There was a spontaneous report of an unexplained drug-related death in the country.
Laboratory test results
In controlled clinical trials of essential hypertension, few patients treated with this product showed clinically important changes in laboratory parameters. . Hyperkalemia (serum potassium >5.5 mEq/L) occurred in 1.5% of patients. In a clinical study of patients with type 2 diabetes and proteinuria, hyperkalemia occurred in 9.9% of patients in the losartan group and 3.4% of patients in the placebo group (see Precautions, Hypotension and Electrolytes/ Fluid balance disorder). Elevations in ALT are rare and return 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 was observed in less than 0.1% of patients using this product alone.
Hemoglobin and hematocrit: Mild decreases in hemoglobin and hematocrit (average decreases of approximately 0.11% g and 0.09% by volume, respectively) frequently occur in patients treated with this product alone, but rarely Of clinical importance, no patient discontinued medication due to anemia.
Liver function tests: occasionally elevated liver enzymes and/or serum bilirubin. One patient (<0.1%) discontinued medication due to these laboratory adverse reactions in patients with essential hypertension treated with AZINOX? alone. Allergic reaction: angioedema. See Adverse Reactions
Hypotension and electrolyte/fluid balance imbalance
Symptomatic hypotension may occur in patients with insufficient vascular volume (such as those treated with large doses of diuretics). These conditions should be corrected before treatment with this product, or a lower starting dose should be used. (See Usage and Dosage).
It should be noted that electrolyte imbalance is common in patients with renal insufficiency, with or without diabetes. In clinical studies in patients with type 2 diabetes and proteinuria, the incidence of hyperkalemia was higher in the losartan potassium-treated group than in the placebo group; however, few patients discontinued treatment due to hyperkalemia (see Adverse Reactions and laboratory test results).
Liver function impairment
Pharmacokinetic data show that the plasma concentration of losartan is significantly increased in patients with liver cirrhosis. Therefore, patients with a history of liver function impairment should consider using lower doses. Dosage (see Dosage and Administration).
Renal function impairment
Due to inhibition of the renin-angiotensin system, changes in renal function, including renal failure, have been reported in sensitive individuals; after discontinuation of treatment , these changes in kidney function can be restored.
For patients whose renal function depends on the activity of the renin-angiotensin-aldosterone system (such as patients with severe congestive heart failure), treatment with angiotensin-converting enzyme inhibitors may cause oliguria and/or or progressive azotemia and (rarely) acute renal failure and/or death. Similar reports have been reported with losartan treatment.
For patients with bilateral renal artery stenosis or only one kidney with renal artery stenosis, other drugs that affect the renin-angiotensin system can increase their blood urea and serum creatinine levels. Similar reports have been reported using this product. These changes in kidney function can revert after stopping treatment.
Drugs for pregnant women and lactating women
Drug for pregnant women
When pregnant women take drugs in the second and third trimester of pregnancy, they directly act on the renin-angiotensin system. Drugs can cause damage to the developing fetus and even death. When pregnancy is discovered, this product should be stopped as soon as possible.
Although there is no experience with the use of this product in pregnant women, animal studies with losartan potassium have demonstrated fetal and neonatal injury and death. The mechanism is thought to be through drug-mediated effects on the kidneys. Caused by the action of hormone? Angiotensin system. Renal perfusion of the human fetus starting in the second trimester of pregnancy depends on the development of the renin-angiotensin system. Therefore, if this product is used in the second and third trimesters of pregnancy, the risk to the fetus will be increased.
Use in lactating women
It is not known whether losartan is excreted in human milk. Since many drugs can be excreted in human milk and have adverse effects on nursing infants, the decision to stop breastfeeding or drug use should be made based on the importance to the mother.
Pediatric use
The antihypertensive effect of this product has been established in hypertensive children aged >1 month to 16 years. Evidence from adequate controlled studies in children and adults and literature reporting its use in children supports the use of this product in these age groups.
Fifty hypertensive children, aged >1 month to <16 years old, were administered oral losartan once a day at a dose of about 0.54-0.77 mg/Kg (average dose). Pharmacokinetic studies. Losartan forms active metabolites in all age groups. Overall, the pharmacokinetics of losartan and its active metabolite were similar across the age groups studied and are consistent with existing adult pharmacokinetic data.
A clinical study participated in 177 hypertensive children aged 6-16 years old. Patients weighing ≥20Kg to <50Kg took 2.5, 25 or 50 mg of losartan every day, and patients weighing ≥ A patient weighing 50 kg takes 5, 50 or 100 mg of losartan daily. Once-daily administration reduces trough blood pressure in a dose-related manner. Dose-related effects on losartan were observed in all subgroups (e.g., age, Tanner stage, sex, race). However, the lowest doses studied, 2.5 mg and 5 mg, which correspond to an average dose of 0.7 mg/Kg per day, did not exhibit antihypertensive effects consistent with other doses.
In this study, this product was generally well tolerated.
For patients who can swallow tablets and weigh ≥20Kg to 50Kg, the starting dose is 50mg once a day. The maximum dose can be increased to 100 mg once daily.
For pediatric patients with insufficient vascular volume, these conditions should be corrected before taking this product.
The profile of adverse events in pediatric patients is similar to that already seen in adults.
This product is not recommended for use in children with glomerular filtration rate <30mL/min/1.73m2 or children with liver damage. As there are no data on use in neonates, its use is not recommended.
Geriatric use
In clinical studies, there is no age difference in the effectiveness and safety of this product.
Race
Based on the LIFE study, although both treatment groups were effective in reducing blood pressure in black patients, losartan was less effective in reducing cardiovascular disease compared with atenolol. Rate and mortality benefits did not apply to black patients with hypertension and left ventricular hypertrophy. Among all patients 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 atenolol (p=0.021). In the LIFE study, compared with atenolol, losartan reduced the risk of cardiovascular disease and death in non-black patients with hypertension and left ventricular hypertrophy (n=8660). The observed indicators were cardiovascular death and stroke. and the combined incidence of the primary clinical endpoint of 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 with the losartan group (p=0.03). In the subgroup of black patients (n = 533; 6% of patients in the LIFE study), 29 of 263 patients in the atenolol group (11%, 25.9 per 1000 patient-years) experienced the primary endpoint, This compared with 46 of 270 patients in the losartan group (17%, 41.8 per 1,000 patient-years). In clinical pharmacokinetic studies, it has been confirmed that there are no clinically significant drug interactions with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole and erythromycin. Rifampicin and fluconazole have been reported to reduce levels of active metabolites. The clinical consequences of these interactions have not been evaluated.
Like other drugs that inhibit angiotensin II and its effects, this product should be combined with potassium-sparing diuretics (such as spironolactone, triamterene, amiloride), potassium supplements, or potassium-containing diuretics. Potassium salt substitutes may increase serum potassium levels when used together.
As with other drugs that affect sodium excretion, lithium excretion may be decreased.
Therefore, serum lithium levels should be carefully monitored if lithium and angiotensin II receptor antagonists are coadministered.
Nonsteroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of diuretics and other antihypertensive drugs. Therefore, the antihypertensive effects of angiotensin II receptor antagonists or angiotensin-converting enzyme inhibitors may be attenuated by NSAIDs including COX-2 inhibitors.
For some patients with renal impairment (such as elderly or hypovolemic patients, including those who are receiving NSAIDs, including selective cyclooxygenase-2 inhibitors) (in patients treated with diuretics), concomitant use of angiotensin II receptor antagonists or angiotensin-converting enzyme inhibitors may result in further renal impairment, including the possible development of acute renal failure. These effects are usually reversible. Therefore, caution should be used when administering combination therapy to patients with renal insufficiency.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with angiotensin receptor blockers, ACE inhibitors, or aliskiren increases hypotension, Risk of fainting, hyperkalemia, and changes in renal function, including acute renal failure. Closely monitor blood pressure, renal function, and electrolytes in patients receiving losartan potassium tablets concomitantly with other drugs that affect the RAAS. Diabetic patients should not use Losartan Potassium Tablets and Aliskiren together. Patients with renal impairment (GFR<60ml/min) should avoid combined use of losartan potassium tablets and aliskiren. There is little data on overdose in humans. The most likely manifestations of overdose will be hypotension and tachycardia. Bradycardia can occur due to stimulation of the parasympathetic nerve (vagus nerve). If symptomatic hypotension occurs, supportive care should be given.
Losartan and its active metabolites cannot be removed by hemodialysis. Mechanism of action
Angiotensin II is the main active substance of the renin-angiotensin system. It is a powerful vasoconstrictor and plays a major role in the pathophysiological process of hypertension. Angiotensin II binds to AT1 receptors in multiple tissues (such as vascular smooth muscle, adrenal glands, kidneys, and heart), producing a variety of important biological effects including vasoconstriction and aldosterone release.
At the same time, it can also stimulate the proliferation of smooth muscle cells. Another angiotensin II receptor subtype has been confirmed to be AT2, but its role in the functional homeostasis of the cardiovascular system is unclear.
Losartan is a synthetic, potent orally active drug. Binding experiments and pharmacological bioassays have proven that it can selectively bind to the AT1 receptor. In vivo and in vitro studies have shown that Losartan and its pharmacologically active carboxylic acid metabolite (E?3174) can block the corresponding physiological effects of angiotensin II synthesized from any source or by any pathway. In contrast to other peptide angiotensin II antagonists, losartan has no agonistic effects.
Losartan selectively acts on AT1 receptors and does not affect the function of other hormone receptors or important ion channels in cardiovascular systems, nor does it inhibit angiotensin-converting enzyme that degrades bradykinin. (kininase II). Therefore, effects not directly related to AT1 receptor blockade such as bradykinin-mediated effects or edema (losartan 1.7%, placebo 1.9%) were not associated with losartan.
Toxicological studies
The LD50 of losartan potassium administered orally to male mice is 2248mg/Kg (6744mg/m) (1124 times the recommended maximum daily dose for adults). The significant minimum lethal doses of this product taken orally by mice and rats are 1000mg/Kg (3000mg/m) and 2000mg/Kg (11800mg/m) respectively, which are 500 times the maximum recommended daily dose for adults (calculated based on 50Kg body weight). and 1000 times.
The potential toxicity of losartan potassium was evaluated through a series of toxicity tests involving multiple oral administrations over three months in monkeys and one year in rats and dogs. Take medication on a level.
Losartan potassium was not found to have carcinogenic effects when rats and mice were given the maximum tolerated dose of this product and the observation time was 105 weeks and 92 weeks respectively.
In vitro alkali elution tests and chromosomal aberration tests show that the use of losartan potassium, which is equivalent to 1700 times the maximum plasma concentration that can be achieved at the recommended human therapeutic dose, has no direct mutagenic effect.
Losartan potassium 150 and 300mg/kg were administered orally to male and female rats respectively every day. No effect of this product on reproductive capacity was found.
Losartan potassium can cause adverse reactions in rat embryos and neonates, 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 was higher. Absorption: This product is well absorbed after oral administration and forms carboxylic acid-type active metabolites and other inactive metabolites after first-pass metabolism; the bioavailability is approximately 33%. The plasma concentrations of losartan and its active metabolite reach peak values ??at 1 hour and 3 to 4 hours respectively. There is no significant change in the plasma concentration of losartan when this product is taken with food.
Distribution: The plasma protein binding rate of losartan and its active metabolites is ≥99%, mainly binding to albumin. The volume of distribution of losartan is 34 liters. Studies 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 into active metabolites. After intravenous injection or oral administration of 14C-labeled losartan potassium, the radioactivity in circulating plasma mainly comes from losartan and its active metabolites. In the trial, only a small amount of losartan was converted into active metabolites in about 1% of individuals.
In addition to active metabolites, inactive metabolites are also produced, including two major metabolites produced by hydroxylation of butyl side chains and a small amount of N-2 glucuronide tetrazole.
Elimination: The plasma clearance rates of losartan and its active metabolite are 600 ml/min and 50 ml/min respectively. Renal clearance rates were 74 ml/min and 26 ml/min, respectively. When losartan potassium is taken orally, approximately 4% of the dose is excreted unchanged in the urine and 6% of the dose is excreted in the urine as an active metabolite. The pharmacokinetics of losartan and its active metabolite are linear up to 200 mg of oral losartan potassium.
After oral administration, the plasma concentrations of losartan and its active metabolites decrease exponentially in a multi-level manner, with terminal half-lives of 2 hours and 6-9 hours respectively. Losartan and its active metabolites show no significant accumulation in plasma when 100 mg is administered once daily.
Losartan and its metabolites are excreted in bile and urine. When humans take 14C-labeled losartan orally, 35% of the radioactivity appears in urine and 58% in feces. When 14C-labeled losartan was injected intravenously into humans, the radioactivity in urine and feces was 43% and 50% respectively.