Approval date: 01/01/2007
Modification date: July 16, 2010
January 04, 2013
October 18, 2015
December 20, 2016
Amlodipine benzoate tablets instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: amlodipine besylate tablets
Trade name: Amlodipine Besilate Tablets
English name: Amlodipine Besilate Tablets
Hanyu Pinyin: Benhuangsuan Anlüdiping Pian
Ingredients
The main ingredient is Amlodipine Besilate.
Chemical name: (±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid-5-methyl ester, 3-ethylbenzenesulfonate.
The chemical structure formula is
Molecular formula: C20H25ClN2O5-C6H6O3S
Molecular weight: 567.05
[Properties] This product is white or off-white octagonal tablets, one side of which has an engraved mark and one side has 5mg printed.
Indications
1. Hypertension
This product is suitable for the treatment of hypertension. It can be applied alone or in combination with other anti-hypertensive drugs.
The control of hypertension is part of comprehensive management of cardiovascular risk. Comprehensive management measures may need to include: lipid control, diabetes management, antithrombotic therapy, smoking cessation, physical activity and sodium intake restriction.
Elevated systolic or diastolic blood pressure both increase cardiovascular risk. At higher levels of basal blood pressure, the absolute increase in risk per mm Hg of blood pressure elevation is higher. The relative degree of risk reduction obtained by lowering blood pressure is similar in people with different absolute cardiovascular risks. In patients with severe hypertension, a slight reduction in blood pressure provides a greater clinical benefit.
In adults with hypertension, in general, lowering blood pressure reduces the risk of cardiovascular events, primarily stroke, and myocardial infarction.
2.Coronary heart disease
Chronic stable angina pectoris
This product is indicated for the symptomatic treatment of chronic stable angina pectoris. It can be applied alone or in combination with other anti-anginal drugs.
Vasospastic angina (Prinzmetal’s or variant angina)
This product is indicated for the treatment of confirmed or suspected angina pectoris with vasospasm. It can be used alone or in combination with other anti-anginal drugs.
Angiographically confirmed coronary artery disease
In patients with angiographically confirmed coronary artery disease but with an ejection fraction ≥ 40% and without heart failure, this product may reduce the risk of hospitalization for angina pectoris as well as reduce the risk of coronary artery reconstruction.
Specification】 5 mg (based on C20H25ClN2O5)
Dosage and Administration
Adults
The usual starting dose for hypertension is 5 mg once daily and the maximum dose is 10 mg once daily.
For patients who are small, frail, elderly, or with hepatic insufficiency, the starting dose is 2.5 mg once daily; this dose can also be used in combination with other antihypertensive drugs.
Dose adjustments should be made based on individual patient response and target blood pressure. Generally, a wait of 7 to 14 days should be allowed before the adjustment step. If clinically indicated, dose adjustments may also be made rapidly with close monitoring of the patient.
The recommended dose for the treatment of chronic stable or vasospastic angina is 5 to 10 mg once daily, with lower doses recommended for elderly and hepatic insufficiency patients, with an effective dose of 10 mg once daily in most patients.
The recommended dose for the treatment of coronary artery disease is 5 to 10 mg once daily. In clinical studies, most patients required a dose of 10 mg/day.
[Adverse Reactions].
Experience from clinical trials
The incidence of adverse reactions observed in clinical trials for one drug cannot be directly compared with the incidence of adverse reactions in clinical trials for another drug, and may not reflect the incidence observed in clinical practice due to the widely varying conditions under which clinical trials are conducted.
More complete data on the safety of this product are available from clinical studies in the United States and other foreign countries involving more than 11,000 patients. Overall, patients have tolerated the use of this product up to a daily dose of 10 mg well. The adverse reactions reported during treatment were mostly mild or moderate. In clinical studies in which this product was administered at 10 mg (N=1730) in direct control with placebo (N=1250), only 1.5% of the amlodipine group discontinued due to adverse reactions, which was not significantly different from the placebo group (approximately 1%). The most frequently reported adverse reactions that were more frequent than placebo are reflected in the table below. The incidence of dose-related adverse reactions (%) was as follows.
Amlodipine Placebo 2.5 mg
N=275 5 mg
N=296 10 mg
N=268 N=520 Edema 1.8 3.0 10.8 0.6 Dizziness 1.1 3.4 3.4 1.5 Flushing 0.7 1.4 2.6 0.0 Palpitations 0.7 1.4 4.5 0.6
The correlation of other adverse reactions with dose was uncertain, but those with an incidence of more than 1% in placebo-controlled studies included
Amlodipine benzoate (%)
(N=1730) Placebo (%)
(N=1250) Fatigue 4.5 2.8 Nausea 2.9 1.9 Abdominal pain 1.6 0.3 Drowsiness 1.4 0.6 Individual adverse reactions shown to be drug and dose related and to occur more frequently in women than in men with amlodipine showed the following.
Amlodipine benzoate Placebo Male %
(N=1218) Female %
(N=512) Male %
(N=914) Female %
(N=336) Edema 5.6 14.6 1.4 5.1 Flushing 1.5 4.5 0.3 0.9 Palpitations 1.4 3.3 0.9 0.9 Drowsiness 1.3 1.6 0.8 0.3
The incidence <1%, but >0.1%, of the following events in patients in controlled clinical studies, open studies, or postmarketing applications, the relevance of which is uncertain, are listed here to alert physicians to.
Cardiovascular system: arrhythmias (including ventricular tachycardia as well as atrial fibrillation), bradycardia, chest pain, peripheral local ischemia, syncope, tachycardia, and vasculitis.
Central and peripheral nervous system: hyperalgesia, peripheral neuropathy, sensory abnormalities, tremor, vertigo.
Gastrointestinal system: loss of appetite, constipation, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.
Systemic: anaphylactic reactions, malaise1, back pain, hot flashes, general discomfort, pain, stiffness, weight gain, weight loss.
Musculoskeletal system: arthralgia, arthropathy, painful muscle spasms1, myalgia.
Psychiatric: sexual dysfunction (male1 and female), insomnia, neuroticism, depression, dream abnormalities, anxiety, personality disorders.
Respiratory: dyspnea1, epistaxis.
Skin and appendages: angioedema, erythema multiforme, pruritus1, rash1, erythematous rash, maculopapular rash.
Special senses: visual abnormalities, conjunctivitis, diplopia, ocular pain, tinnitus.
Urinary system: frequent urination, abnormal urination, nocturia.
Autonomic nervous system: dry mouth, excessive sweating.
Nutritional metabolism: hyperglycemia, thirst.
Hematopoietic system: leukopenia, purpura, thrombocytopenia.
1 In placebo-controlled studies, the incidence of these events was less than 1%, but in all multi-dose studies, the incidence of these side effects ranged from 1% to 2%.
Routine laboratory test data did not change clinically significantly with this treatment. There were no clinically relevant changes in blood potassium, blood glucose, triglycerides, total cholesterol, HDL cholesterol, uric acid, urea nitrogen, or creatinine.
In the CAMELOT and PREVENT studies (see [Clinical Trials]), the adverse effects were similar to those reported previously (see above). Peripheral edema was the most common adverse event.
Post-marketing reports
Because these reactions were voluntarily reported by an unknown sample size of the population, it was not possible to reliably evaluate the frequency of occurrence or to determine causality with drug exposure.
The following events occurring in postmarketing applications have been reported rarely and their relevance to the drug has not been determined: gynecomastia. In postmarketing applications, patients have developed jaundice with markedly elevated transaminases (mostly consistent with manifestations of biliary obstruction or hepatitis) requiring hospitalization, which may be associated with amlodipine.
Post-marketing reports suggest that extrapyramidal disease may be associated with the use of amlodipine besylate.
No other safety concerns have been identified with amlodipine besylate in patients with: chronic obstructive pulmonary disease, well compensated congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes mellitus, and dyslipidemia.
Contraindications]
Amlodipine is contraindicated in patients with hypersensitivity to amlodipine and any of the components of this product.
Precautions】
Hypotension
Symptomatic hypotension may occur, especially in patients with severe aortic stenosis. Because the vasodilating effect of this product is gradual, acute hypotension after taking this product has rarely been reported.
Exacerbation of angina pectoris or myocardial infarction
Very few patients, especially those with severe coronary artery obstructive disease, may experience worsening angina or acute myocardial infarction when treatment with amlodipine besylate is initiated or the dose is increased.
Use in patients with impaired hepatic function
Because this product is heavily metabolized by the liver and has a plasma clearance half-life (t1/2) of 56 hours in patients with hepatic insufficiency, it should be used in slowly increasing doses in patients with severe hepatic insufficiency.
Pregnant women and nursing mothers
Pregnancy
Risk Summary
The limited data available in post-marketing reports on the use of Loxodren in pregnant women are insufficient to determine the drug-related risks of major birth defects and miscarriage. There is a risk of poorly controlled hypertension in pregnancy and fetus [see “Disease Related Maternal and/or Embryonic/Fetal Risk”]. In animal reproduction studies, no evidence of adverse developmental effects was observed when amlodipine maleate was administered orally to pregnant rats and rabbits during organogenesis at approximately 10 and 20 times the maximum recommended human dose (MRHD), respectively. However, the number of litters in rats was significantly reduced (by approximately 50%) and the number of intrauterine stillbirths was significantly increased (by approximately 5-fold). Studies have demonstrated that amlodipine at this dose prolongs gestation and parturition in rats [see “Animal Data”].
The expected background risk of major birth defects and miscarriage in the indicated population is not known. All pregnancies are at background risk for birth defects, miscarriage, or other adverse outcomes. In the general U.S. population, the predicted background risks for major birth defects and miscarriage in clinically confirmed pregnancies are 2% – 4% and 15% 20%, respectively.
Disease Related Maternal and/or Embryonic/Fetal Risks
Hypertension during pregnancy increases the risk of preeclampsia, gestational diabetes, preterm labor and delivery complications (e.g., need for cesarean delivery and postpartum hemorrhage) in pregnant women. Hypertension increases the risk of intrauterine growth restriction and intrauterine stillbirth. Pregnant women with hypertension should be carefully monitored and managed accordingly.
Animal data
No teratogenicity or other embryonic/fetal toxicity was observed when pregnant rats and rabbits received up to 10 mg amlodipine maleate/kg/day (10 and 20 times MRHD, respectively, based on body surface area) orally during their respective major organogenesis periods. However, in rats treated with amlodipine maleate (at a dose equivalent to 10 mg amlodipine/kg/day) for 14 days before mating, throughout mating and during conception, a significant reduction in litter size (approximately 50%) and a significant increase in the number of in utero deaths (approximately 5-fold) were observed. Studies have demonstrated that amlodipine maleate at this dose can prolong the period of conception and delivery in rats.
Lactation
Risk Summary
Based on the limited data from published clinical lactation studies, the presence of amlodipine in human milk has been estimated at a median relative infant dose of 4.2%. Adverse effects of amlodipine in breastfed infants have not been observed. There are no available data on the effect of amlodipine on lactation.
Pediatric Dosage]
Clinical data suggest that this product (2.5 mg to 5 mg/day) is effective in pediatric patients 6 to 17 years of age (see [Clinical Trials]). The recommended dose of this product in pediatric hypertensive patients 6 to 17 years of age is 2.5 mg to 5 mg once daily. There are no studies in pediatric patients with doses above 5 mg of this product daily (see [Clinical Trials]).
There is no information on the effect of this product on blood pressure in pediatric patients under 6 years of age.
Geriatric Use]
There are no adequate clinical studies to determine whether elderly patients (65 years of age or older) respond differently to this product than younger patients. No other clinical applications have found differences in response between elderly patients and younger patients. In general, given that in most cases the elderly have reduced hepatic, renal or cardiac function and are more likely to have other co-morbidities or to be co-administered with other drugs, dose selection in elderly patients should be cautious and it is usually advisable to start with a low dose in the dose range. The clearance of this product is reduced in elderly patients, resulting in an increase in the area under the curve (AUC) of approximately 40-60%, so it is advisable to start with a small dose (see [Dosage]).
Drug Interactions]
Amlodipine besylate is a weak inhibitor of CYP3A and may increase CYP3A substrate concentrations.
Effects of other drugs on amlodipine (see [Pharmacokinetics])
CYP3A inhibitors
Combination with moderate and strong CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may result in increased systemic exposure to amlodipine and may require dose reduction. When amlodipine is co-administered with CYP3A inhibitors, hypotension and edema symptoms should be monitored to determine if dose adjustment is required.
CYP3A Inducers
Blood levels of amlodipine are highly variable when combined with known CYP3A4 inducers. Close monitoring of blood pressure is required both during and after drug combination, and dose adjustments should be made if necessary. This is especially true when using strong CYP3A4 inducers (rifampicin, Kanye extract, etc.).
Sildenafil
When sildenafil and amlodipine are combined, each drug exerts its own antihypertensive effect independently, so hypotensive conditions should be monitored.
Effects of amlodipine on other drugs (see [Pharmacokinetics])
Simvastatin
The combination of simvastatin and amlodipine increases the exposure to simvastatin. Patients taking amlodipine should limit the dose of simvastatin to less than 20 mg/day.
Immunosuppressants
When combined, amlodipine may increase systemic exposure to cyclosporine or tacrolimus. Frequent monitoring of blood trough concentrations of cyclosporine and tacrolimus is recommended, and dose adjustments should be made when appropriate.
[Drug Overdose].
Severe overdose may result in excessive peripheral vasodilation with significant hypotension and reflex tachycardia. There is limited information on intentional overdose in human studies.
Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg were administered to mice and rats, respectively, and resulted in death. Administration of a single oral dose of amlodipine maleate equivalent to amlodipine 4 mg/kg (at least 11 times the maximum recommended human dose based on mg/m2 conversion) to dogs caused significant peripheral vasodilation and hypotension.
If there is an overdose, active cardiopulmonary monitoring should be performed. Frequent blood pressure measurements are essential. If hypotension occurs, cardiovascular support therapy should be provided, including elevation of the extremities as well as accurate fluid replacement. If hypotension does not resolve with the application of these conservative treatments, consider administration of vasoconstrictors (e.g., phenylephrine) and attention to circulating fluid volume and urine output. Dialysis treatment is not beneficial because of the high binding of this product to plasma proteins. Intravenous calcium gluconate may be beneficial to reverse the effects of calcium channel blockade. Gastric lavage may be necessary in some cases. In healthy volunteers, the absorption of amlodipine decreased when activated charcoal was administered 2 hours after amlodipine 10 mg was given.
Pharmacology and Toxicology]
Pharmacological effects
Amlodipine is a dihydropyridine calcium antagonist (also known as a calcium antagonist or slow channel blocker) that inhibits calcium ions from entering vascular smooth muscle and cardiac muscle across the membrane. Experimental data show that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. The contraction of cardiac and vascular smooth muscle is dependent on the entry of extracellular calcium ions into the cell through ion channels. Amlodipine selectively inhibits calcium transport across the membrane and has a stronger effect on vascular smooth muscle cells than on cardiac cells. A negative inotropic effect can be observed in in vitro experiments, but this effect has not been observed in in vivo animal studies with clinical therapeutic doses. Amlodipine does not affect serum calcium concentrations. In the physiological pH range, amlodipine is an ionized complex (pKa=8.6) that achieves its gradual onset of action by slow binding/disintegration 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 exact mechanism by which amlodipine is able to relieve angina is not fully established, but is considered to be related to the following factors.
Exertional angina: Amlodipine reduces the heart rate-systolic blood pressure product by decreasing peripheral vascular resistance (cardiac afterload), achieving a decrease in myocardial oxygen demand at different exercise levels.
Vasospastic angina: In vivo animal studies and in vitro human coronary vascular studies have shown that amlodipine inhibits vasospasm and restores perfusion in coronary arteries as well as small arteries, thereby accommodating changes in calcium, potassium epinephrine, serotonin and thromboxane A2 isomers. In vasospastic (Prinzmetal’s or variant) angina, the effect of amlodipine is mainly derived from its inhibition of coronary artery spasm.
Pharmacodynamics
Hemodynamics: The administration of therapeutic doses of amlodipine besylate to hypertensive patients induces vasodilation resulting in a decrease in supine and standing blood pressure. The decrease in blood pressure was not accompanied by significant changes in heart rate or plasma catecholamine concentrations with long-term administration. In hemodynamic studies in patients with chronic stable angina, rapid intravenous administration of amlodipine besylate was found to decrease arterial blood pressure and increase heart rate, but long-term oral administration of amlodipine in clinical studies in angina patients with normal blood pressure did not have a significant effect on heart rate or blood pressure.
The blood pressure control effect of long-term oral amlodipine besylate once daily was maintained for at least 24 hours. The antihypertensive effect was correlated with plasma concentration in both young and elderly patients. The degree of blood pressure reduction with amlodipine also correlated with the degree of pre-treatment blood pressure elevation; thus, the antihypertensive effect was 50% stronger in patients with moderate hypertension (diastolic blood pressure 105-114 mmHg) than in patients with mild hypertension (diastolic blood pressure 90-104 mmHg). There was no clinically significant change in blood pressure in normotensive subjects (+1/-2 mmHg).
In hypertensive patients with normal renal function, therapeutic doses of amlodipine besylate resulted in decreased renal vascular resistance, increased glomerular filtration rate, and increased effective renal blood flow, without affecting filtration fraction or proteinuria.
As with other calcium channel antagonists, hemodynamic testing of cardiac function at rest and during exercise (or stepping) in patients with normal cardiac function treated with amlodipine besylate showed a small increase in cardiac index and was not accompanied by changes in dP/dt or left ventricular end-diastolic pressure or volume. In hemodynamic studies, no negative inotropic effects were observed in animals or humans applying amlodipine besylate in the therapeutic dose range, even in combination with beta-blockers in humans. Similar findings have been observed with other drugs with significant negative inotropic effects in normal healthy subjects and in well compensated patients with heart failure.
Electrophysiological effects: Amlodipine besylate did not affect sinus node or atrioventricular conduction function in in vivo animal studies and clinical trials. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction or the time to recovery of the sinus node after pacing. similar results were observed in patients with beta-blockers in combination with amlodipine besylate. No adverse effects on ECG parameters have been observed in clinical studies combining amlodipine and beta-blockers in patients with hypertension or angina pectoris. In patients with angina pectoris only, amlodipine did not alter ECG conduction intervals or increase AV conduction block.
Toxicological studies
Genotoxicity.
Genotoxicity tests with amlodipine maleate at the genetic or chromosomal level were negative.
Reproductive toxicity.
No significant effects on fertility were observed in rats (male rats from 64 days prior to mating and female rats from 14 days prior to mating) given amlodipine maleate orally at doses up to 10 mg/kg/day (equivalent to 8 times the maximum recommended human dose of 10 mg for a body weight of 50 kg in terms of amlodipine, converted to body surface area). Oral administration of amlodipine maleate to pregnant rats and rabbits at doses up to 10 mg/kg/day (approximately 10 and 20 times the maximum recommended human dose, respectively) during the respective periods of major organogenesis did not show any significant effects on embryonic fetal growth and development. However, amlodipine maleate given orally at 10 mg/kg/day for 14 days before mating, throughout mating and conception in rats showed a significant reduction in litter size (approximately 50%) and a significant increase in the number of intrauterine stillbirths (approximately 5-fold), and showed that amlodipine maleate at this dose level prolonged the period of conception and delivery in rats.
Carcinogenicity.
Amlodipine maleate 0.5, 1.25 and 2.5 mg/kg/day was administered orally for 2 years in mice and rats by adulteration, and no carcinogenic effect was observed. The high dose in mice was approximately equivalent to the maximum recommended human dose, and the high dose in rats was approximately twice the maximum recommended human dose.
Pharmacokinetics]
Amlodipine besylate is administered orally at therapeutic doses, and the blood concentration reaches its peak in 6-12 hours.
Amlodipine is extensively (about 90%) metabolized to inactive metabolites by the liver, the other 10% is excreted as prodrug, and 60% of the metabolites are excreted in the urine. In vitro studies have shown that plasma protein binding is about 93% in hypertensive patients. Its plasma clearance is biphasic, with a terminal elimination half-life of approximately 30-50 hours. The blood concentration of amlodipine reaches steady state after 7 to 8 days of continuous daily administration.
The pharmacokinetics of amlodipine are not affected by renal impairment. Therefore, patients with renal failure should still receive the usual initial dose.
In elderly patients and in patients with hepatic insufficiency, the drug clearance of amlodipine is slowed, resulting in an increase in the area under the curve (AUC) of approximately 40-60% and therefore a lower starting dose may be indicated. A similar increase in AUC was observed in patients with moderate to severe heart failure.
Pediatric patients: In 62 pediatric hypertensive patients aged 6 to 17 years who were treated with 1.25 mg to 20 mg amlodipine besylate, weight-corrected drug clearance and volume of distribution were similar to those in adults.
Drug Interactions
In vitro data show that amlodipine does not affect the binding of digoxin, phenytoin, warfarin, or indomethacin to human plasma proteins.
Effects of other drugs on amlodipine
Combination with cimetidine, magnesium and aluminum hydroxide antacids, sildenafil, and grapefruit juice had no effect on amlodipine exposure.
CYP3A inhibitors
Daily doses of 180 mg diltiazem with 5 mg amlodipine in elderly patients with hypertension resulted in a 60% increase in systemic amlodipine exposure. Coadministration with erythromycin did not significantly affect systemic exposure to amlodipine in healthy volunteers. However, strong inhibitors of CYP3A4 (e.g., ketoconazole, clarithromycin) may substantially increase amlodipine blood levels (see [Drug Interactions]).
Effects of Amlodipine on Other Drugs
The combination of amlodipine does not alter exposure to atorvastatin, digoxin, ethanol (alcohol), or the prothrombin response time to warfarin.
Simvastatin: When multiple doses of 10 mg amlodipine were combined with 80 mg simvastatin, exposure to simvastatin was increased by 77% compared with simvastatin alone (see [Drug Interactions]).
Cyclosporine: A prospective study in renal transplant patients (N=11) showed a mean 40% increase in cyclosporine trough concentration levels when co-administered with amlodipine (see [Drug Interactions]).
Tacrolimus: A prospective study in CYP3A5-expressing healthy Chinese volunteers (N = 9) demonstrated a 2.5- to 4-fold increase in tacrolimus exposure in combination with amlodipine compared to tacrolimus alone. This finding was not observed in CYP3A5 non-expressors (N = 6). However, a 3-fold increase in tacrolimus plasma exposure resulting in a reduction in the required tacrolimus dose has been reported in a renal transplant recipient (CYP3A5 non-expressor) for the initiation of amlodipine in post-transplant hypertension. The possibility of these drug interactions cannot be ruled out regardless of CYP3A5 genotype status (see [Drug Interactions]).
Storage]
Store under shade and seal.
Packaging
Aluminum-plastic packaging, 7 tablets per plate, one plate per box.
Aluminum-plastic package, 7 tablets per plate, 2 plates per box.
Aluminum-plastic packaging, 14 tablets per plate, one plate per box.
Aluminum-plastic packaging, 20 tablets per plate, one plate per box.
[Expiration date
36 months
【Execution standard
Approval number
State Drug Certificate H20010700
Manufacturer
Company Name: China Resources Saike Pharmaceutical Co.
Address: No. 3 Jinghai 7 Road, Zhongguancun Science and Technology Park, Tongzhou District, Beijing
Postal Code: 101111
Telephone number: 400-810-8780
Fax number: 010-67793887
Web
Address: www.saike.com.cn