FUREN Amlodipine Besylate Tablets For Hypertension 5mg*21

[Drug Name]
Generic Name: Amlodipine Besylate Tablets
Trade Name: Furen Amlodipine Besylate Tablets 5mg x 21 Tablets
Pinyin Code: FuRen BenHuangSuanAnLvDiPingPian

[Main Ingredient]
The main ingredient of this product is amlodipine besylate. Chemical Name: 3-Ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate benzenesulfonate. Molecular Formula: C20H25N2O5CI·C6H6O3S. Molecular Weight: 567.1

[Properties]
This product is white tablets.

[Indications/Main Functions]
1. Hypertension: This product is indicated for the treatment of hypertension. It can be used alone or in combination with other antihypertensive drugs. Hypertension control is part of comprehensive cardiovascular risk management, which may include lipid control, diabetes management, antithrombotic therapy, smoking cessation, physical exercise, and sodium restriction. Increases in either systolic or diastolic blood pressure increase cardiovascular risk. The absolute risk increase per mmHg increase is greater at higher baseline blood pressure levels. The relative magnitude of risk reduction achieved by lowering blood pressure is similar among individuals with varying absolute cardiovascular risk. In patients with severe hypertension, even a small reduction in blood pressure can provide significant clinical benefit. In adults with hypertension, lowering blood pressure generally reduces the risk of cardiovascular events, primarily stroke and myocardial infarction. 2. Coronary Artery Disease (CAD) - Chronic Stable Angina: This product is indicated for the symptomatic treatment of chronic stable angina. It can be used alone or in combination with other antianginal medications. Vasospastic Angina (Prinzmetal's or variant angina): This product is indicated for the treatment of confirmed or suspected vasospastic angina. It can be used alone or in combination with other antianginal medications. For patients with angiographically confirmed coronary artery disease (CAD), an ejection fraction ≥40%, and no heart failure, this medication can reduce the risk of hospitalization for angina and the need for coronary revascularization.

[Specifications]
5mg*21 tablets

[Dosage and Administration]
Adults: The typical starting dose for hypertension is 5 mg once daily, with a maximum dose of 10 mg once daily. For patients who are small, frail, elderly, or have hepatic insufficiency, the starting dose is 2.5 mg once daily; this dose can also be used in combination with other antihypertensive medications. Dose adjustments should be made based on individual patient response. Generally, dose adjustments should be initiated after 7-14 days. If clinically indicated, dose adjustments may be made more quickly under close monitoring. The recommended dose for the treatment of chronic stable or vasospastic angina is 5-10 mg once daily. Lower doses are recommended for elderly patients and those with hepatic insufficiency. The effective dose for most patients is 10 mg once daily. The recommended dose for the treatment of coronary artery disease is 5-10 mg once daily. In clinical studies, most patients required a dose of 10 mg/day (see [Clinical Trials]). Combination with other antihypertensive and/or antianginal medications: Amlodipine is safe for use with thiazide diuretics, ACE inhibitors, beta-blockers, long-acting nitrates, and/or sublingual nitroglycerin.

[Adverse Reactions]
The safety of this product has been demonstrated in clinical studies in the United States and other countries involving over 11,000 patients. Overall, patients tolerated the product well at doses up to 10 mg daily. Adverse reactions reported during treatment with this product were mostly mild to moderate. In a clinical study comparing 10 mg of this product (N=1730) directly with placebo (N=1250), only 1.5% of patients in the amlodipine group discontinued treatment due to adverse reactions, which was not significantly different from the placebo group (approximately 1%). The most common side effects were headache and edema. The incidence of dose-related side effects (%) is shown in Table 1: Adverse events 2.5mgN=275 5.0mgN=296 10.0mgN=268 PlaceboN=520 Edema 1.8 3.0 10.8 0.6 Dizziness 0.7 3.4 3.4 1.5 Flushing 0.7 1.4 2.6 0.0 Palpitations 0.7 1.4 4.5 0.6 Other adverse reactions are uncertainly related to dose, but those with an incidence of more than 1% in placebo-controlled studies include Table 2: Placebo-controlled studies Amlodipine (%) (N=1703) Placebo (%) (N=1250) Headache 7.3 7.8 Fatigue 4.5 2.8 Nausea 2.9 1.9 Abdominal pain 1.6 0.3 Somnolence 1.4 0.6 Some adverse reactions that appear to be drug- and dose-related and occur more frequently in women than in men are shown in Table 3: Amlodipine Placebo Adverse Events Male % (N=1218) Female % (N=512) Male % (N=914) Female % (N=336) Edema 5.6 14.6 1.4 5.1 Hot flashes 1.5 4.5 0.3 0.9 Palpitations 1.4 3.3 0.9 0.9 Somnolence 1.3 1.6 0.8 0.3 In controlled clinical studies, open-label studies, or post-marketing use, the following events occurred in <1% but >0.1% of patients. Their relevance is uncertain and is listed here to alert physicians: Cardiovascular System: Arrhythmias (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension. Vasculitis. Central and Peripheral Nervous System: Dysesthesia, peripheral neuropathy, paresthesia, tremor, dizziness. Gastrointestinal: Anorexia, constipation, dyspepsia, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia. Systemic: Allergic reaction, fatigue, back pain, hot flashes, malaise, pain, stiffness, weight gain, weight loss. Musculoskeletal: Arthralgia, arthritis, muscle cramps, myalgia. Psychiatric: Sexual dysfunction (male and female), insomnia, nervousness, depression, abnormal dreams, anxiety, personality disorder. Respiratory: Dyspnea, rhinitis. Skin and Appendages: Angioedema, erythema multiforme, pruritus, rash, erythematous rash, maculopapular rash. These events occurred in less than 1% of patients in placebo-controlled studies, but in all multiple-dose studies, the incidence of these side effects ranged from 1% to 2%. Sensory: Visual disturbances, conjunctivitis, diplopia, eye pain, tinnitus. Urinary: Frequent urination, dysuria, nocturia. Autonomic Nervous System: Dry mouth, hyperhidrosis. Nutritional Metabolism: Hyperglycemia, thirst. Hematopoietic System: Leukopenia, purpura, thrombocytopenia. The following events occurred in <0.1% of patients: heart failure, arrhythmia, premature beats, skin discoloration, urticaria, dry skin, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cool skin, apathy, excitement, amnesia, gastritis, increased appetite, loose stools, cough, rhinitis, dysuria, polyuria, olfactory disturbances, dysgeusia, visual accommodation disturbances, and dry eyes. Other occasional adverse reactions were difficult to distinguish from the effects of concomitant medications or concomitant diseases, such as myocardial infarction or angina. There were no clinically significant changes in routine laboratory test values with amlodipine treatment. There were no clinically relevant changes in serum potassium, blood glucose, triglycerides, total cholesterol, high-density lipoprotein cholesterol, uric acid, blood urea nitrogen, or creatinine. In the CAMELOT and PREVENT studies (see [Clinical Trials]), adverse reactions were similar to those reported previously (see above). Peripheral edema is the most common adverse event. The following events have been reported rarely in postmarketing use, and their relationship to the drug has not been established: male breast enlargement. In postmarketing use, there have been reports of jaundice and marked elevations in transaminases (often consistent with biliary obstruction or hepatitis) requiring hospitalization in patients treated with amlodipine. Amlodipine is safe in the following patients: chronic obstructive pulmonary emphysema, well-compensated congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes mellitus, and dyslipidemia.

[Contraindications]
This product is contraindicated in patients with hypersensitivity to dihydropyridines or any of its components.

[Drug Interactions]
In vitro data indicate that amlodipine does not affect the plasma protein binding of digoxin, phenytoin, warfarin, or indomethacin. Effects of Other Drugs on Amlodipine: Cimetidine: Coadministration with cimetidine does not alter the pharmacokinetics of amlodipine. Grapefruit juice: Concomitant administration of 240 mg of grapefruit juice and a single 10 mg dose of amlodipine in 20 healthy volunteers did not significantly affect the pharmacokinetics of amlodipine. Aluminum/magnesium (antacids): Concomitant administration of aluminum/magnesium antacids and a single dose of amlodipine did not significantly affect the pharmacokinetics of amlodipine. Sildenafil: A single 100 mg dose of sildenafil (Viagra) did not affect the pharmacokinetics of amlodipine in patients with essential hypertension. Each drug can independently exert its antihypertensive effect when taken together. Effects of this product on other drugs: Atorvastatin: Multiple doses of 10 mg of this product combined with 80 mg of atorvastatin did not significantly alter the steady-state pharmacokinetic parameters of atorvastatin. Digoxin: Concomitant administration of amlodipine and digoxin did not alter plasma digoxin concentrations or renal clearance in normal volunteers. Ethanol: Single or multiple doses of 10 mg of this product did not significantly affect the pharmacokinetics of ethanol. Warfarin: Coadministration of this product with warfarin does not alter the prothrombin reaction time of warfarin. Clinical studies have demonstrated the safety of this product in combination with thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, nonsteroidal anti-inflammatory drugs, antidepressants, and oral hypoglycemic agents. Interactions with drugs/laboratory tests: Unknown.

[Precautions]
1. Warning: A very small number of patients, particularly those with severe coronary artery obstructive disease, may experience increased frequency, prolonged duration, and/or worsening of angina pectoris, or acute myocardial infarction, when initiating calcium channel blocker therapy or increasing the dose. The mechanism of action is currently unknown. 2. Because the vasodilatory effect of this drug is gradual, rare cases of acute hypotension have been reported following administration of this drug. However, caution should be exercised when using this drug in combination with other peripheral vasodilators in patients with severe aortic stenosis. 3. Use in Patients with Heart Failure: Calcium channel blockers should be used with caution in patients with congestive heart failure. In a long-term, placebo-controlled study (PRAISE-2) in patients with non-ischemic heart failure (NYHAI class IV), although the incidence of exacerbations of heart failure was not significantly different from placebo, there was an increase in reports of amlodipine-related pulmonary edema. 4. Use in Patients with Impaired Hepatic Function: As with all other calcium channel blockers, the half-life of this drug is prolonged in patients with impaired hepatic function, but a recommended dose for this drug in such patients has not yet been established. Therefore, caution should be exercised in such patients. 5. Use in Patients with Renal Failure: Changes in amlodipine blood concentrations are not correlated with the degree of renal impairment; therefore, a normal dose can be used. This product cannot be dialyzed. 6. Discontinuation of Beta-Blockers: Amlodipine is not a beta-blocker and, therefore, does not provide protection against the risks associated with abrupt discontinuation of beta-blockers; any beta-blocker should be discontinued gradually.

[Pediatric Use]
The recommended dose of this drug for hypertensive children aged 6 to 17 years is 2.5 mg to 5 mg once daily. There are no studies using doses exceeding 5 mg daily in pediatric patients. There are no data on the effect of this drug on blood pressure in children under 6 years of age.

[Use in Elderly Patients]
There are currently no adequate clinical studies to determine whether elderly patients (over 65 years of age) respond differently to this drug than younger patients. Other clinical studies have not demonstrated differences in responses between elderly and younger patients. Generally, given that elderly patients are more likely to have decreased hepatic, renal, or cardiac function, concurrent diseases, or concomitant medications, dose selection for elderly patients should be cautious, and a lower dose should generally be used to initiate the treatment. Elderly patients have decreased clearance of this drug, resulting in an approximately 40-60% increase in the area under the curve (AUC), so a lower dose should be used initially (see [Dosage and Administration]).

[Overdose]
Single oral doses of amlodipine at 40 mg/kg and 100 mg/kg can cause lethality in mice and rats, respectively. Single oral doses of amlodipine exceeding 4 mg/kg can cause significant peripheral vasodilation and hypotension in dogs (on a mg/m² basis, this is 11 times the maximum recommended human dose). Severe overdose may result in excessive peripheral vasodilation with marked hypotension and reflex tachycardia. Data on intentional overdose with amlodipine are limited in humans. Reports of intentional overdose include one patient who ingested 250 mg of amlodipine and remained asymptomatic and not hospitalized. Another patient (120 mg) was admitted to the hospital, underwent gastric lavage, and remained normotensive. A third patient (105 mg) was admitted with hypotension (90/50 mmHg), which resolved after plasma volume expansion. There is a documented accidental overdose in a 19-month-old male infant who ingested 30 mg of amlodipine (approximately 2 mg/kg). Upon presentation to the emergency department, vital signs were stable, with no hypotension, but a heart rate of 180 beats/minute. Ipecac was administered 3.5 hours after the ingestion, and no sequelae were noted during subsequent observation (overnight). If a large dose is ingested, active cardiopulmonary monitoring should be performed. Frequent blood pressure monitoring is essential. If hypotension occurs, cardiovascular support should be initiated, including limb elevation and adequate fluid administration. If hypotension persists despite these conservative treatments, vasoconstrictors (such as phenylephrine) may be considered, while monitoring circulating fluid and urine output. Intravenous calcium gluconate may also be helpful in reversing the effects of calcium antagonists. Due to its high plasma protein binding, dialysis is not beneficial.

[Pharmacology and Toxicology]
Clinical Pharmacology: Mechanism of Action: Amlodipine is a dihydropyridine calcium antagonist (also known as a calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane entry of calcium ions into vascular smooth muscle and myocardium. Experimental data indicate that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. Cardiac and vascular smooth muscle contraction relies on the entry of extracellular calcium ions into the cell through ion channels. Amlodipine selectively inhibits transmembrane calcium ion transport, with a stronger effect on vascular smooth muscle cells than on myocardial cells. Negative inotropic effects have been observed in vitro, but these effects have not been observed in live animals at therapeutic doses. Amlodipine does not affect serum calcium concentrations. Within the physiological pH range, amlodipine is an ionized complex (pKa = 8.6) that achieves its gradual onset of action by slowly binding and dissociating from the binding site of calcium channel receptors. 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 relieves angina pectoris is not fully elucidated, but is believed to be related to the following factors: Exertional angina: Amlodipine reduces peripheral vascular resistance (cardiac afterload), thereby lowering the heart rate-systolic blood pressure product and reducing myocardial oxygen demand at various levels of exercise. Vasospastic angina: Amlodipine has been demonstrated in animal studies and in vitro human coronary studies to inhibit vasospasm and restore blood flow in coronary arteries and arterioles, thereby adapting to changes in calcium, epinephrine potassium, serotonin, and thromboxane A2 isomers. In vasospastic (Prinzmetal's or variant) angina, the effect of amlodipine is primarily due to its inhibition of coronary artery spasm. Pharmacodynamics and Hemodynamics: In hypertensive patients, therapeutic doses of amlodipine cause vasodilation, resulting in a decrease in supine and standing blood pressure. With long-term administration, this decrease in blood pressure is not accompanied by significant changes in heart rate or plasma catecholamine concentrations. In hemodynamic studies in patients with chronic stable angina, rapid intravenous administration of amlodipine has been shown to lower arterial blood pressure and increase heart rate. However, in clinical studies of normotensive patients with angina, long-term oral administration of amlodipine has no significant effect on heart rate or blood pressure. Long-term oral administration of amlodipine once daily maintains blood pressure control for at least 24 hours. The antihypertensive effect in both young and elderly patients is correlated with plasma concentrations. The extent of blood pressure reduction with amlodipine is also related to the degree of pre-treatment blood pressure elevation; thus, the blood pressure-lowering effect is 50% greater in patients with moderate hypertension (diastolic blood pressure 105-114 mmHg) than in those with mild hypertension (diastolic blood pressure 90-104 mmHg). Normotensive subjects experience no clinically significant changes in blood pressure (+1/-2 mmHg). In hypertensive patients with normal renal function, therapeutic doses of amlodipine result in a decrease in renal vascular resistance, an increase in glomerular filtration rate, and an increase in effective renal blood flow, without affecting filtration fraction or proteinuria. As with other calcium channel blockers, hemodynamic assessments of cardiac function in patients with normal cardiac function after treatment with amlodipine demonstrate a small increase in cardiac index at rest and during exercise (or stepping), without changes in dP/dt or left ventricular end-diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with negative inotropic effects in animals or humans, even when used in combination with beta-blockers in humans, at doses within the therapeutic range. Similar findings have been observed with other drugs with significant negative inotropic effects in healthy individuals and patients with well-compensated heart failure. Electrophysiological Effects: In both animal models and clinical trials, Norvasc did not affect sinoatrial (SA) node or atrioventricular (AV) conduction function. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction, nor did it alter SA node recovery time after pacing. Similar findings were observed in patients receiving Norvasc in combination with beta-blockers. Clinical studies of the combined use of amlodipine and beta-blockers in patients with hypertension or angina pectoris did not observe adverse effects on electrocardiographic (ECG) parameters. In patients with angina pectoris alone, amlodipine administration did not alter ECG conduction intervals or increase AV block. Carcinogenicity, Teratogenicity, and Reproductive Toxicity: No carcinogenic effects were observed in rats and mice administered amlodipine at 0.5, 1.25, and 2.5 mg/kg/day, administered by diet, for two years. The maximum dose used in mice is equivalent to the maximum recommended human dose (MRHD) of 10 mg (mg/m²). The maximum dose used in rats is twice the MRHD of 10 mg (mg/m²). Teratogenicity studies with amlodipine have shown no drug-related teratogenic effects at either the genetic or chromosomal level. Administration of amlodipine to rats (male rats starting 64 days before mating and female rats starting 14 days before mating) at doses of up to 10 mg/kg/day (8 times the MRHD* in mg/m²) did not affect fertility. [Pharmacokinetics] Following oral administration of therapeutic amlodipine doses, peak plasma concentrations are reached 6 to 12 hours later, with an absolute bioavailability of approximately 64 to 90%. Amlodipine's bioavailability is not affected by food intake. Amlodipine is extensively metabolized (approximately 90%) by the liver to inactive metabolites, with the remaining 10% excreted as parent drug. 60% of these metabolites are excreted in the urine. In vitro studies have shown that plasma protein binding is approximately 93% in hypertensive patients. Its plasma clearance is biphasic, with a terminal elimination half-life of approximately 35 to 50 hours. Steady-state amlodipine plasma concentrations are achieved after 7 to 8 days of daily dosing. The pharmacokinetics of amlodipine are not affected by renal impairment. Therefore, patients with renal failure should still receive the usual initial dose. Elderly patients and those with impaired liver function experience slower clearance of amlodipine, resulting in an approximately 40-60% increase in the area under the curve (AUC), necessitating the use of a lower starting dose. Similar increases in AUC have been observed in patients with moderate to severe heart failure. Pediatric patients: In 62 pediatric hypertensive patients aged 6 to 17 years, treatment with 1.25 mg to 20 mg of amoxidipine was conducted, and the weight-adjusted drug clearance and volume of distribution were similar to those in adults.