What Is Vasospastic Angina?

Luohuoxi (Norvasc in English, amlodipine besylate tablets), a hypotensive drug developed by Pfizer. Since its introduction in 1990, Luohuoxi is one of the world's largest prescription drugs for the treatment of hypertension. Its use worldwide has exceeded 40 billion patient treatment days.

The indications are: 1. Hypertension: This product can be used alone or in combination with other antihypertensive drugs. For adults with hypertension, lowering blood pressure generally reduces the risk of cardiovascular events, mainly stroke and the risk of myocardial infarction. 2. Coronary heart disease (CAD): including chronic stable angina; vasospasm angina (Prinzmetal's or variant angina); coronary heart disease confirmed by angiography.

Whether prescription drugs: prescription
Drug Name: Network activity

Drug type: Essential medicines, medicines for health insurance workers
Use classification: Calcium antagonists

Lohhi ingredients

The main ingredient of this product is amlodipine besylate. Its chemical name is: 3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1 , 4-dihydro-6-methyl-3,5-pyridinedicarboxylate benzenesulfonate.
Chemical Structure:

Molecular formula: C ₂₀ H ₂₅ N ₂ O ₅ ClC ₆ H ₆ O ₃ S
Molecular weight: 567.1

Collocation

This product is a white tablet.

Luo Huo Xi indications

1. Hypertension This product is suitable for the treatment of hypertension. Can be used alone or in combination with other antihypertensive drugs.
2. Coronary heart disease (CAD)
Chronic stable angina pectoris This product is suitable for the symptomatic treatment of chronic stable angina pectoris. Can be used alone or in combination with other anti-angina drugs.
Vasospasm angina (Prinzmetal's or variant angina)
This product is suitable for the treatment of confirmed or suspected vasospasm angina pectoris. Can be used alone or in combination with other anti-angina drugs.
Coronary heart disease confirmed by angiography Coronary heart disease confirmed by angiography, but patients with an ejection fraction 40% and no heart failure can reduce the risk of hospitalization due to angina pectoris and the risk of coronary artery reconstruction.

Lohas Specifications

(1) 5mg; (2) 10mg.

Dosage and Administration

Adults: Usually the starting dose of this product for hypertension is 5mg once daily, and the maximum dose is 10mg once daily. Patients with small body, frailty, elderly, or with liver dysfunction, the initial dose is 2.5mg once daily; this dose can also be the dose of this product in combination with other antihypertensive drugs.
Dose adjustments should be based on individual patient response. General dose adjustment should begin after 7-14 days. If clinically needed, dose adjustments can be made more quickly when patients are closely monitored.
The recommended dose for chronic stable or vasospasm angina pectoris is 5-10 mg once daily. Older patients with liver dysfunction are advised to use lower doses. The effective dose for most patients is 10 mg once daily.
The recommended dose for coronary heart disease is 5-10 mg once daily. In clinical studies, most patients require a dose of 10 mg / day (see [Clinical Trials]).

Collateral

Adverse events in clinical trials <br Due to the very different conditions under which clinical trials are conducted, the incidence of adverse reactions observed in a clinical trial of one drug cannot be compared with the incidence of adverse reactions in another clinical trial of a drug Direct comparisons may not reflect the rates observed in clinical practice.
The safety of this product has been confirmed in clinical studies in the United States and other foreign countries, involving more than 11,000 patients. In general, patients are well tolerated by using this product in a daily dose range of 10 mg. The adverse reactions reported during the treatment of this product are mostly mild or moderate. In the clinical study of 10mg (N = 1730) of this product, which was directly compared with placebo (N = 1250), only 1.5% of the amlodipine group discontinued due to adverse reactions, compared with the placebo group (about 1%). Significant difference. The most common side effects are headache and edema. The incidence (%) of dose-related side effects is as follows:

The correlation of other adverse reactions with dose is uncertain, but the incidence of more than 1% in placebo-controlled studies includes:

Individual adverse reactions have been shown to be drug and dose related, and the incidence of adverse reactions of amlodipine in women is higher than that of men:

In clinically controlled studies, open studies, or post-marketing applications, the incidence of the following events in patients is 0.1%, and the relevance is uncertain. Here are listed to remind doctors to pay attention:
Cardiovascular system: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, hypotension, peripheral ischemia, syncope, tachycardia, orthostatic dizziness, orthostatic hypotension, vasculitis.
Central and peripheral nervous system: dull feeling, peripheral neuropathy, paresthesia, tremor, dizziness.
Gastrointestinal system: loss of appetite, constipation, indigestion **, difficulty swallowing, diarrhea, flatulence, pancreatitis, vomiting, hyperplasia of the gums.
Systemic: Allergic reactions, fatigue **, back pain, hot flushes, general malaise, pain, stiffness, weight gain, weight loss.
Musculoskeletal system: arthralgia, arthropathy, myalgia cramps **, myalgia.
Psychiatry: sexual dysfunction (male ** and female), insomnia, neuroticism, depression, abnormal dreaming, anxiety, personality disorder.
Respiratory system: dyspnea **, epistaxis.
Skin and appendages; angioedema, erythema polymorpha, pruritus **, rash **, erythema erythema, maculopapular rash.
** The incidence of these events was less than 1% in placebo-controlled studies, but these side effects occurred in 1% to 2% in all multi-dose studies.
Paresthesia: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus.
Urinary system: frequent urination, dysuria, nocturia.
Autonomic nervous system: dry mouth, hyperhidrosis.
Nutritional metabolism: high blood sugar, thirst.
Hematopoietic system: Leukopenia, purpura, thrombocytopenia.
The following events occurred <0.1%: heart failure, arrhythmia, premature beats, skin discoloration, urticaria, dry skin, hair loss, dermatitis, muscle weakness, twitching, ataxia, hypertonicity, migraine, skin hair Coldness, indifferent emotions, excitement, forgetfulness, gastritis, increased appetite, loose stools, cough, rhinitis, dysuria, polyuria, olfactory disorders, taste disorders, abnormal visual mediation, and dry eye.
Other occasional adverse reactions are difficult to distinguish from the effects of concomitant drugs or concomitant diseases, such as myocardial infarction or angina.
There was no clinically significant change in routine laboratory test data in the treatment of amlodipine. There were no clinically relevant changes in serum potassium, blood glucose, triglycerides, total cholesterol, high-density lipoprotein cholesterol, uric acid, urea nitrogen, or creatinine.
In the CAMELOT and PREVENT studies (see [Clinical Trials]), the adverse reactions were similar to those previously reported (see above). Peripheral edema is the most common adverse event.
Post-Market Reporting < br Because these reactions are reported voluntarily by a population of unknown sample size, it is not possible to reliably assess the frequency of occurrence or determine the causal relationship with drug exposure.
The following incidents in post-marketing applications are rarely reported, and their relevance to the drug has not been determined: male breast enlargement. In post-marketing applications, it has been reported that the use of amlodipine caused patients with jaundice and significantly increased transaminase (mostly consistent with the manifestations of biliary obstruction or hepatitis) and required hospitalization.
No other safety issues were found with the use of amlodipine besylate in the following patients: chronic obstructive pulmonary disease, well-compensated congestive heart failure, coronary heart disease, peripheral vascular disease, diabetes, and dyslipidemia.

Taboo

This product is contraindicated in patients allergic to amlodipine.

Precautions

1. Hypotension < br Symptomatic hypotension may occur, especially in patients with severe aortic stenosis. Because the vasodilator effect of this product is gradually produced, the occurrence of acute hypotension after taking this product is rarely reported.
2. Aggravated angina pectoris or myocardial infarction < br Very few patients, especially those with severe coronary obstructive disease, may experience worsening or acute angina pectoris when they start treatment with amlodipine besylate or increase their dose. Myocardial infarction.
3. Suspension of -blockers may be dangerous. Sudden discontinuation of -blockers may be dangerous. Because amlodipine is not a -blocker, it cannot be used for the risk of discontinuation of -blockers. Give effective protection; any beta-blocker should be discontinued gradually.
4. Use in patients with impaired liver function. <br /> Because this product is metabolized by the liver in large quantities, and the plasma clearance half-life (t1 / 2) of patients with liver dysfunction is 56 hours, this product is used in patients with severe liver dysfunction. Should increase slowly.

Medication for pregnant women and lactating women

Pregnancy Category C (FDA Classification)
Adequate and well-controlled studies have not been performed in pregnant women. Amlodipine should only be used during pregnancy if the potential benefits outweigh the potential risks to the fetus.
When pregnant rats and rabbits receive up to 10 mg amlodipine / kg / day orally during their main organ formation period (based on mg / m [sup] 2 [/ sup] basis conversion, the maximum recommended human doses are 10 mg 8 times and 23 times [calculated based on the patient's weight of 50 kg]) of amlodipine maleate, no teratogenicity or other embryo / fetal toxicity was found. However, a significant decrease in litter size (approximately 50%) was observed in rats treated with amlodipine maleate (dose equivalent to 10 mg amlodipine / kg / day) for 14 days before mating, throughout mating and conception. The number of deaths in the womb increased significantly (about 5 times). Studies have shown that amlodipine maleate at this dose can prolong the fertility and delivery periods in rats.
It is unknown whether this product can be secreted by breast milk. Breastfeeding women taking medication should discontinue breastfeeding.

Medication for children

The recommended dosage of this product for children with hypertension from 6 to 17 years is 2.5 mg to 5 mg once daily. There have been no studies in children with daily doses of more than 5 mg of this product (see the [Pharmacology and Toxicology] and [Pharmacokinetics] sections).
No data are available on the effect of this product on blood pressure in children under 6 years of age.

Luohuoxi elderly medicine

There is currently no clinical study of hyperthyroidism to determine whether elderly patients (over 65 years of age) and young patients respond differently to this product. In other clinical applications, no difference was found in response between elderly patients and young patients. In general, considering that the elderly may have reduced liver, kidney or heart function in most cases, and may be more complicated by other diseases or combined with other drugs, the dosage selection of elderly patients should be cautious, usually starting with a low dose range dose. The clearance rate of this product is reduced in elderly patients, resulting in an increase in the area under the curve (AUC) of about 40-60%, so it is advisable to start from a small dose (see [Usage and dosage]).

Luohuoxi Drug Interaction

1. In vitro data < br In vitro research data show that this product does not affect the binding of digoxin, phenytoin, warfarin, or indomethacin to plasma proteins.
2. Cimetidine < br The combination of cimetidine and cimetidine does not change the pharmacokinetics of amlodipine.
3. Grapefruit juice Twenty healthy volunteers took 240ml grapefruit juice and a single dose of 10mg amlodipine at the same time. No significant effect on the pharmacokinetics of amlodipine was observed.
4. Magnesium-aluminum hydroxide antacids < br Taking magnesium-aluminum hydroxide antacids and a single dose of amlodipine besylate at the same time did not have a significant effect on the pharmacokinetics of amlodipine.
5. Sildenafil < br A single dose of 100 mg sildenafil does not affect the pharmacokinetic parameters of amlodipine in patients with essential hypertension. Combination of two drugs, each drug can independently exert its antihypertensive effect.
6. Atorvastatin 10mg Repeated administration of this product combined with 80mg atorvastatin did not significantly change the steady-state pharmacokinetic parameters of atorvastatin.
7. Simvastatin 10mg amlodipine multiple administration combined with 80mg simvastatin, the exposure of simvastatin increased by 77% compared with simvastatin alone. Patients taking amlodipine should limit the simvastatin dose to less than 20 mg / day.
8. Digoxin <br /> The combination of digoxin and digoxin does not change the plasma digoxin level or kidney digoxin clearance rate in normal volunteers.
9. Ethanol (alcohol)
Single or multiple doses of 10 mg of this product have no significant effect on the pharmacokinetics of ethanol.
10. Warfarin < br The combination of this product with warfarin does not change the prothrombin reaction time of warfarin.
11. CYP3A4 inhibitor < br In elderly patients with hypertension, daily dose of 180 mg of diltiazem and 5 mg of this product will cause a 60% increase in systemic exposure of amlodipine. Taking this product with erythromycin in healthy volunteers did not significantly affect systemic exposure of amlodipine. However, strong inhibitors of CYP3A4 (such as ketoconazole, itraconazole, ritonavir) may increase amlodipine plasma concentrations more than diltiazem. Monitor hypotension and edema when taking amlodipine with a CYP3A4 inhibitor.
12. CYP3A4 inducer < br There is currently no data on the effect of CYP3A4 inducer on amlodipine. Blood pressure levels should be closely monitored when taking amlodipine with a CYP3A4 inducer.
13. Interactions with drugs / laboratory tests < br Unclear.

Luohuoxi drug overdose

Severe overdose may cause excessive dilation of peripheral blood vessels with significant hypotension and reflex tachycardia. In human studies, there is limited information on intentional overdose of this product.
A single oral dose of amlodipine maleate equivalent to 40 mg amlodipine / kg and 100 mg amlodipine / kg in mice and rats, respectively, could result in death. A single oral dose given to dogs equivalent to amlodipine 4 mg / kg amlodipine maleate (based on mg / m [sup] 2 [/ sup] conversion, at least 11 times the maximum recommended human dose) caused a significant Dilated blood vessels and hypotension.
Cardiopulmonary monitoring should be actively performed if there is an excessive amount of medication. Frequent blood pressure measurements are necessary. If hypotension occurs, supportive cardiovascular care should be provided, including raising the limbs and rehydration accurately. If these conservative treatments are applied and the hypotension is still not relieved, consider administering a vasoconstrictor (such as phenylephrine), paying attention to the amount of circulating fluid and urine. Due to the high binding rate of this product to plasma proteins, dialysis treatment is not beneficial.

Luohuoxi Clinical Trial

For Hypertensive Adults: The antihypertensive effect of amlodipine was confirmed in 15 double-blind, randomized, placebo-controlled studies, of which 800 were in the amlodipine group and 538 were in the placebo group. After placebo correction, patients with mild to moderate hypertension who received this product once a day had a statistically significant decrease in supine and orthostatic blood pressure 24 hours after administration. The mean orthostatic blood pressure decreased by 12 / 6mmHg, and the supine blood pressure decreased by 13 / 7mmHg. Antihypertensive effect of the drug was observed for 24 hours after administration at intervals of 24 hours (the effects of peak and trough depression were almost the same). Patients who had been on the drug for 1 year did not show tolerance to the drug. Three parallel, fixed-dose dose-response studies showed that within the recommended dose range, the reduction in supine and orthostatic blood pressure was dose-dependent. Drugs have similar effects on diastolic blood pressure in young and elderly patients. It has a greater effect on systolic blood pressure in elderly patients, which may be related to its higher baseline systolic blood pressure. The effect is similar for black and white races.
Pediatric patients; 268 hypertensive patients aged 6 to 17 years were first randomized to receive amlodipine 2.5 or 5 mg once daily for 4 weeks, and then again randomized to receive the same dose of amlodipine or placebo for 4 weeks. At the end of 8 weeks, blood pressure was lower in patients receiving 5 mg of amlodipine than in patients who were randomized again to placebo. It is difficult to quantify the antihypertensive strength of the drug, but the systolic blood pressure drop is less than 5mmHg at a dose of 5mg. Adverse events are similar to adults.
Effects on chronic stable angina:
The effect of amlodipine 5-10 mg / day on exercise-induced angina pectoris has been evaluated in 8 placebo-controlled, double-blind clinical studies with a duration of 6 weeks and a total of 1038 chronic stable angina pectoris Patients (684 amlodipine tablets and 354 placebo). In five of these studies, a 10 mg dose resulted in a significant increase in exercise (bicycle or activity plate) time. Amlodipine 10mg and 5mg, the average increase in symptom-restricted activity time was 12.8% (63 seconds) and 7.9% (38 seconds). In some studies, amlodipine 10 mg can also prolong the 1 mm ST segment deviation and reduce the frequency of angina pectoris. The long-lasting efficacy of amlodipine has been proven in long-term studies in patients with angina pectoris. The decrease in blood pressure (4/1 mmHg) and change in heart rate (+0.3 bpm) in patients with angina pectoris have no significant clinical significance.
Effects on vasospasm angina:
In a double-blind, placebo-controlled clinical study of 50 patients over 4 weeks, amlodipine treatment reduced approximately 4 angina pectoris episodes per week, and the placebo group reduced approximately 1 angina pectoris episode (p <0.01). ). The patients who withdrew from the study due to insufficient improvement in clinical symptoms were 2/23 in the Luohuoxi group and 7/27 in the placebo group.
For proven coronary heart disease:
The PREVENT study enrolled 825 patients with coronary heart disease confirmed by angiography, randomized to amlodipine (5-10 mg, once daily) or placebo and followed up for 3 years. Although this study did not find a significant change in the diameter of the coronary lumen through the main endpoint of coronary angiography, the data showed that the proportion of patients with coronary heart disease admitted to the hospital due to angina pectoris and the proportion of patients requiring coronary revascularization tended to decrease.
The CAMELOT study enrolled 1,318 patients who had recently been diagnosed with coronary heart disease by angiography. The left main branch of the coronary artery was disease-free, with no ejection fraction <40% or heart failure. Patients (76% male, 89% white, 93% American, 89% with a history of angina pectoris, 52% without PCI, 4% with PCI without stent placement, and 44% with stent placement) were randomized Assigned to the double-blind treatment group, in standard treatment (of which 89% received aspirin, 83% statins, 74% beta-blockers, 50% nitroglycerin, 40% anticoagulants, and 32% diuretics, but excluded Other calcium channel antagonists) received Luo Huo Xi 5-10 mg / day or placebo. The average follow-up time was 19 months. The primary end point was the time at which one of the following events occurred for the patient: angina pectoris admission; coronary artery reconstruction; myocardial infarction; cardiovascular death; heartbeat resuscitation; heart failure admission; stroke / TIA; or peripheral vascular disease. There were 110 (16.6%) and 151 (23.1%) first episodes in the amlodipine and placebo groups, respectively, with a hazard ratio of 0.691 (95% CI: 0.540-0.884, p = 0.003). A summary of the main endpoints is shown in Figure 1. The conclusions of this study mainly come from the preventive effect of drugs on hospitalization for angina pectoris and on coronary artery reconstruction (see Table 1). Figure 2 shows the effect of different subgroups.
In the CAMELOT study subgroup, coronary angiography (274 patients) compared with placebo, amlodipine did not reduce coronary plaque volume (intravascular ultrasound).
Figure 1: Kaplan-Meier analysis of composite clinical endpoints in the amlodipine and placebo groups

The clinical outcomes of the various major endpoints that are significant are summarized in Table 1 below. Other primary endpoints include cardiovascular death, cardiac resuscitation, myocardial infarction, admission to heart failure, stroke / TIA, or peripheral vascular disease, amlodipine There was no significant difference between the group and the placebo group.

Studies in Heart Failure Patients Amlodipine besylate was compared to placebo in four 8-12 week studies, including 697 patients with NYHA grade II / III heart failure. By measuring exercise tolerance, NYHA classification, clinical symptoms, or left ventricular ejection fraction, studies have confirmed that amlodipine besylate has no evidence of worsening heart failure. In a long-term (mean follow-up of at least 6 months, average 13.8 months), placebo-controlled, morbidity / mortality study of amlodipine besylate, 1153 NYHA class III (n = 931) or NYHA class IV ( n = 222) heart failure patients received a stable dose of diuretics, digoxin, and ACEI on the basis of 5 to 10 mg of amlodipine besylate, the main endpoint of the study for amlodipine besylate, There was no effect on NYHA classification or symptoms of heart failure. These composite endpoints are all-cause mortality and cardiovascular morbidity (particularly fatal arrhythmias, acute myocardial infarction, or hospital admission with increased heart failure). The total number of all-cause deaths and cardiovascular events in the amlodipine besylate and placebo groups were 222/571 (39%) and 246/583 (42%). Cardiovascular events accounted for approximately 25% of endpoint events.
In another randomized study (PRAISE-2), patients with heart failure in NYHA III (80%) or IV (20%) did not have clinical symptoms or clear ischemic disease, and received a stable dose of ACEI (99% ), Digitalis (99%) and diuretics (99%), received placebo (n = 827) or amlodipine (n = 827), followed for an average of 33 months, and died of all causes The primary endpoint of the rate was not significantly different between this product and the placebo group (95% confidence interval, the amlodipine group decreased from 8% to 29%). However, more pulmonary edema was reported in the amlodipine group.

Luo Huo Xi Pharmacology and Toxicology

Clinical pharmacological mechanism of action:
Amlodipine is a calcium dihydropyridine antagonist (also known as a calcium ion antagonist or a slow channel blocker). It inhibits the transmembrane of calcium ions into vascular smooth muscle and the heart muscle. Experimental data show that amlodipine can bind to both dihydropyridine and non-dihydropyridine. The contraction of myocardial and vascular smooth muscle relies on extracellular calcium ions entering the cell through ion channels to complete. Amlodipine can selectively inhibit calcium ion transmembrane transport, and its effect on vascular smooth muscle cells is stronger than that of cardiomyocytes. Negative inotropic effect of this drug can be observed in vitro, but this effect has not been observed in clinical animal doses. Amlodipine does not affect serum calcium concentrations. In the range of physiological pH, amlodipine is an ionized complex (pKa = 8.6), which gradually works by slowly binding / decomposing with calcium channel receptors at the binding site.
Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle, thereby reducing peripheral vascular resistance and blood pressure.
The specific mechanism by which amlodipine can relieve angina has not been fully determined, but the considerations are related to the following factors:
Overworked angina pectoris: Amlodipine reduces the heart rate-systolic blood pressure product by reducing peripheral vascular resistance (post-cardiac load), achieving a reduction in myocardial oxygen demand at different levels of exercise.
Vasospasm angina pectoris: Amlodipine has been proven in animal experiments and in vitro human coronary vascular experiments: it can inhibit vasospasm, restore coronary and arterial blood perfusion, and adapt to calcium, potassium adrenaline, serotonin, and thrombus. Of the A2 isomer. In vasospasm (Prinzmetal's or variant) angina pectoris, the effect of amlodipine mainly comes from its inhibition of coronary spasm.
Pharmacodynamics Hemodynamics: After taking a therapeutic dose of amlodipine in patients with hypertension, it can cause vasodilation and lower supine and standing blood pressure. With long-term administration, the decrease in blood pressure was not accompanied by significant changes in heart rate or plasma catecholamine concentration. Hemodynamic studies in patients with chronic stable angina pectoris found that rapid intravenous amlodipine can reduce arterial blood pressure and increase heart rate, but in clinical studies of patients with normal blood pressure angina pectoris, long-term oral amlodipine has a positive effect on heart rate or blood pressure. No significant effect.
Long-term oral amlodipine once a day, the effect on blood pressure control for at least 24 hours. The antihypertensive effect of young and elderly patients is related to plasma concentration. The extent of amlodipine blood pressure reduction is also related to the increase in blood pressure before treatment; therefore, the antihypertensive effect of patients with moderate hypertension (diastolic blood pressure 105-114mmHg) is better than mild hypertension (diastolic blood pressure 90-104mmHg). The patient is 50% stronger. There was no significant clinical change in blood pressure in normal blood pressure subjects (+ 1 / -2mmHg).
For patients with hypertension with normal renal function, the therapeutic dose of amlodipine can lead to a decrease in renal vascular resistance, an increase in glomerular filtration rate, and an increase in effective renal blood flow without affecting the filtration fraction and proteinuria.
Like other calcium channel antagonists, after amlodipine treatment in patients with normal cardiac function, hemodynamic tests of cardiac function show a small increase in cardiac index at rest and during exercise (or stepping), without Accompanied by dP / dt or changes in left ventricular end-diastolic pressure or volume. In the study of hemodynamics, amlodipine in the therapeutic dose range of animals or humans, even in combination with -blockers in humans, did not show negative inotropic effects. Similar findings were found in the use of other drugs with significant negative inotropic effects in normal healthy people and patients with well-compensated heart failure.
Electrophysiological effect: Amlodipine besylate does not affect sinus node or atrioventricular conduction function in live animal experiments and clinical experiments. In patients with chronic stable angina pectoris, 10 mg intravenously, AH, HV conduction, and sinus node recovery time after pacing did not change significantly. Similar results were observed in patients taking a beta-blocker in combination with amlodipine besylate. No adverse effects on ECG parameters have been observed in clinical studies of amlodipine combined with beta blockers in patients with hypertension or angina pectoris. In patients with angina pectoris only, the application of amlodipine did not change the conduction interval of the ECG, nor did it increase AV block.
Carcinogenicity, teratogenicity, and reproductive toxicity: Rats and mice were given amlodipine maleate 0.5, 1.25, and 2.5 mg / kg / day by food for two consecutive years without carcinogenic effects. The maximum dose for mice is equivalent to the maximum recommended human dose of 310 mg in mg / m [sup] 2 [/ sup]. The maximum dose for rats is converted to mg / m [sup] 2 [/ sup], which is twice the maximum recommended human dose of 310mg.
Teratogenicity studies of amlodipine maleate have shown no drug-related teratogenic effects, both at the gene and chromosome levels.
Rats (from 64 days before mating to male rats and from 14 days before mating to female rats) were given amlodipine maleate at a dose of 10 mg / kg / day (equivalent to mg / m2, 8 times that of humans) The maximum recommended dose 2) has no effect on fertility.

Colophysin pharmacokinetics

After the oral amlodipine treatment dose was given, the blood concentration reached a peak in 6 to 12 hours, and the absolute bioavailability was about 64 to 90%. The bioavailability of amlodipine was not affected by food intake.
Amlodipine is extensively (about 90%) metabolized by the liver into inactive metabolites, the other 10% is excreted as the original drug, and 60% of the metabolites are excreted in the urine. In vitro studies have shown that in patients with hypertension, plasma The protein binding rate is about 93%. The plasma clearance rate is biphasic, and the terminal elimination half-life is about 35-50 hours. After continuous daily administration for 7-8 days, the blood concentration of amlodipine reached a steady state.
The pharmacokinetics of amlodipine are not affected by impaired renal function. Therefore, patients with renal failure should still receive conventional initial doses.
In elderly patients and patients with liver function decline, amlodipine's drug clearance is slowed, resulting in an increase in the area under the curve (AUC) of about 40-60%, so a lower starting dose may be needed. A similar increase in AUC was also observed in patients with moderate to severe heart failure.
Pediatric patients: 1.25 mg to 20 mg of amlodipine was administered in 62 children with hypertension from 6 to 17 years of age. The weight-adjusted drug clearance and distribution volume were similar to those of adults.

Luohuoxi R & D History

In 1990, the first commercial amlodipine besylate (Norvasc) was launched in the United States;

In June 1994, Norvasc was successfully marketed in China under the name Luo Huo Xi. It has 20 years of clinical experience in China and is the most evidence-based CCB drug;
In 1994, a CAPE study showed that Norvasc significantly reduced symptomatic and asymptomatic myocardial ischemic attacks in patients with chronic stable angina pectoris, the effect can be maintained for more than 24 hours;
In 1996, a PRAISE study showed that Norvasc did not increase cardiovascular morbidity and mortality in patients with severe heart failure;
In 1997, a FERRUCCI study showed that Norvasc better reduced blood pressure in the morning;
In 2000, the PREVENT study showed that for CAD patients, Norvasc reduced hospitalization due to unstable angina and reduced the need for coronary revascularization;
In 2002, the ALLHAT study showed that Norvasc's better blood pressure control has significant advantages in reducing stroke and multiple cardiovascular diseases (peripheral artery disease, angina pectoris, etc.), and its safety has been fully verified;
In 2004, the VALUE study showed that Norvasc's early and sustained antihypertensive effect is better than ARB valsartan, and it can significantly reduce the incidence of myocardial infarction;
In 2004, the CAMELOT / NORMALISE study showed that Norvasc can significantly reduce cardiovascular events in patients with stable CAD. IVUS visually confirmed that Norvasc has a tendency to slow coronary atherosclerosis; comprehensive PREVENT, CAMELOT / NORMALISE research results, Norvasc obtained FDA approval New indications: coronary heart disease confirmed by coronary angiography;
2005, ASCOT-BPLA Study: ASCOT is the largest hypertension study in Europe. Based on Norvasc, when necessary, the combined treatment regimen is significantly better than the traditional drug antihypertensive regimen, which provides clinicians with concrete evidence-based evidence to choose the ideal antihypertensive combination therapy regimen. After VALUE and ALLHAT, Norvasc strengthens Norvasc's Basic medication status in antihypertensive therapy;
In 2008, a CASE J study showed that Norvasc-based therapy and candesartan-based therapy can provide similar clinical cardiac benefits;
In 2009, the SFDA approved a new indication for Norvasc: coronary heart disease confirmed by angiography, and Norvasc became a CCB with more coronary heart disease indications;
In January 2013, the US FDA updated its instructions: It is clear that Norvasc is used to lower blood pressure, which can reduce the risk of cardiovascular events;
In January 2014, the CFDA updated its instructions: Luo Huo Xi is suitable for the treatment of hypertension. For adults with hypertension, lowering blood pressure can reduce the risk of cardiovascular events, mainly stroke and the risk of myocardial infarction;
In June 2014, the 20th anniversary of Luohuo Xi's listing in China, which was fully verified in terms of efficacy and safety. Currently holds the number one market share in antihypertensive drugs.

Luo Huo Xi Storage

Shaded and sealed.

Lohovi packaging

Aluminum-plastic blister pack, 5mg: 7 tablets / box, 14 tablets / box, 28 tablets / box; 10mg: 30 tablets / box. Packed in polyethylene bottles, 10mg: 500 tablets / bottle.

Validity period

5mg: 60 months; 10mg: 24 months.

Lohas Execution Standard

WS1- (X-010) -2001Z

Luohuoxi Approval Number

5mg: National Medicine Standard H10950224;
10mg: National Medicine Standard H20093660.

Luohuoxi Production Enterprise

Pfizer Pharmaceutical Co., Ltd.

Lohus Approval Date

March 09, 2007

LOHAS Revised Date

June 26, 2009 December 9, 2009 March 25, 2010 June 7, 2010 May 23, 2011 April 9, 2012