ipine to 20 mg daily [see clinical pharmacology (12.3) ] . immunosuppressants amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered. frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate [see clinical pharmacology (12.3) ] .

mited sodium intake. many patients will require more than one drug to achieve blood pressure goals. for specific advice on goals and management, see published guidelines, such as those of the national high blood pressure education program's joint national committee on prevention, detection, evaluation, and treatment of high blood pressure (jnc). numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. the largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmhg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). these considerations may guide selection of therapy. levamlodipine may be used alone or in combination with other antihypertensive agents.

nts with impaired hepatic function, titrate slowly when administering amlodipine to patients with severe hepatic impairment.

nsive oral dose in pediatric patients ages 6–17 years is 1.25 mg to 2.5 mg once daily. doses in excess of 2.5 mg daily have not been studied in pediatric patients [see clinical pharmacology (12.4) , clinical studies (14.1) ] .

rials directly comparing amlodipine besylate (n = 1730) at doses up to 10 mg to placebo (n = 1250), discontinuation of amlodipine besylate because of adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). the most commonly reported side effects more frequent than placebo are reflected in the table below. the incidence (%) of side effects that occurred in a dose related manner are as follows: amlodipine placebo 2.5mg 5mg 10mg n=275 n=296 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 palpitation 0.7 1.4 4.5 0.6 other adverse reactions that were not clearly dose related but were reported with an incidence greater than 1.0% in placebo-controlled clinical trials include the following: amlodipine (%) (n=1730) placebo (%) (n=1250) fatigue 4.5 2.8 nausea 2.9 1.9 abdominal pain 1.6 0.3 somnolence 1.4 0.6 for several adverse experiences that appear to be drug and dose related, there was a greater incidence in women than men associated with amlodipine treatment as shown in the following table: amlodipine (%) 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 somnolence 1.3 1.6 0.8 0.3 the following events occurred in <1% but >0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship: cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, tachycardia, vasculitis. central and peripheral nervous system: hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo. gastrointestinal: anorexia, constipation, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia. general: allergic reaction, asthenia, these events occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies. back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease. musculoskeletal system: arthralgia, arthrosis, muscle cramps, myalgia. psychiatric: sexual dysfunction (male and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization. respiratory system: dyspnea, epistaxis. skin and appendages: angioedema, erythema multiforme, pruritus, rash, rash erythematous, rash maculopapular. special senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus. urinary system: micturition frequency, micturition disorder, nocturia. autonomic nervous system: dry mouth, sweating increased. metabolic and nutritional: hyperglycemia, thirst. hemopoietic: leukopenia, purpura, thrombocytopenia. amlodipine therapy has not been associated with clinically significant changes in routine laboratory tests. no clinically relevant changes were noted in serum potassium, serum glucose, total triglycerides, total cholesterol, hdl cholesterol, uric acid, blood urea nitrogen, or creatinine. in the camelot and prevent studies of amlodipine in coronary artery disease, the adverse event profile was similar to that reported previously (see above), with the most common adverse event being peripheral edema. 6.2 postmarketing experience because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. the following postmarketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia. in postmarketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine. postmarketing reporting has also revealed a possible association between extrapyramidal disorder and amlodipine. amlodipine has been used safely in patients with chronic obstructive pulmonary disease, well-compensated congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles.

ipine to 20 mg daily [see clinical pharmacology (12.3) ] . immunosuppressants amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered. frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate [see clinical pharmacology (12.3) ] .

on period and the duration of labor in rats at this dose [see data ]. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage). hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. pregnant women with hypertension should be carefully monitored and managed accordingly. data animal data no evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine at doses up to 10 mg amlodipine/kg/day (approximately 10 and 20 times the mrhd based on body surface area, respectively) during their respective periods of major organogenesis. however for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving amlodipine at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose. 8.2 lactation risk summary limited available data from a published clinical lactation study reports that amlodipine is present in human milk at an estimated median relative infant dose of 4.2%. no adverse effects of amlodipine on the breastfed infant have been observed. there is no available information on the effects of amlodipine on milk production. 8.4 pediatric use levamlodipine (1.25 to 2.5 mg daily) is effective in lowering blood pressure in patients 6 to 17 years [see clinical studies (14.1) ] . effect of levamlodipine on blood pressure in patients less than 6 years of age is not known. 8.5 geriatric use clinical studies of amlodipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. other reported clinical experience has not identified differences in responses between the elderly and younger patients. in general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. elderly patients have decreased clearance of amlodipine with a resulting increase of auc of approximately 40–60%, and a lower initial dose may be required [see dosage and administration (2.1) ] .

unknown. all pregnancies have a background risk of birth defect, loss or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage). hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. pregnant women with hypertension should be carefully monitored and managed accordingly. data animal data no evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine at doses up to 10 mg amlodipine/kg/day (approximately 10 and 20 times the mrhd based on body surface area, respectively) during their respective periods of major organogenesis. however for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving amlodipine at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose.

the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect. amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure. amlodipine is a 1:1 racemic mixture of levamlodipine and dextro amlodipine, it has been demonstrated that levamlodipine is the pharmacologically active, anti-hypertensive isomer. 12.2 pharmacodynamics hemodynamics: following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. these decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina. with chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. plasma concentrations correlate with effect in both young and elderly patients. the magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105–114 mmhg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90–104 mmhg). normotensive subjects experienced no clinically significant change in blood pressures (+1/–2 mmhg). in hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria. as with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dp/dt or on left ventricular end diastolic pressure or volume. in hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects. electrophysiologic effects: amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. in patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter a-h and h-v conduction and sinus node recovery time after pacing. similar results were obtained in patients receiving amlodipine and concomitant beta-blockers. in clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. in clinical trials with angina patients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of av blocks. drug interactions sildenafil : when amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect [see drug interactions (7.1) ] . 12.3 pharmacokinetics the exposure (c max and auc) of levamlodipine is similar between levamlodipine tablets 5 mg and norvasc ® (amlodipine besylate) 10 mg under fasting condition. absorption after oral administration of levamlodipine tablets, absorption produces peak plasma concentrations between 6 and 12 hours. absolute bioavailability has been estimated to be between 64 and 90%. the bioavailability of levamlodipine tablets is not altered by the presence of food. distribution ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. metabolism amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. excretion elimination from the plasma is biphasic with a terminal elimination half-life of about 30–50 hours. steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing. specific populations renal impairment the pharmacokinetics of amlodipine are not significantly influenced by renal impairment. patients with renal failure may therefore receive the usual initial dose. hepatic impairment elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in auc of approximately 40–60%, and a lower initial dose may be required. a similar increase in auc was observed in patients with moderate to severe heart failure. 12.4 pediatric patients sixty-two hypertensive patients aged 6 to 17 years received doses of amlodipine between 1.25 mg and 20 mg. weight-adjusted clearance and volume of distribution were similar to values in adults. drug interactions in vitro data indicate that amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin. impact of other drugs on amlodipine co-administered cimetidine, magnesium-and aluminum hydroxide antacids, sildenafil, and grapefruit juice have no impact on the exposure to amlodipine. cyp3a inhibitors : co-administration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. erythromycin co-administration in healthy volunteers did not significantly change amlodipine systemic exposure. however, strong inhibitors of cyp3a (e.g., itraconazole, clarithromycin) may increase the plasma concentrations of amlodipine to a greater extent [see drug interactions (7.1) ] . impact of amlodipine on other drugs amlodipine is a weak inhibitor of cyp3a and may increase exposure to cyp3a substrates. co-administered amlodipine does not affect the exposure to atorvastatin, digoxin, ethanol and the warfarin prothrombin response time. simvastatin : co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone [see drug interactions (7.2) ] . cyclosporine : a prospective study in renal transplant patients (n=11) showed on an average of 40% increase in trough cyclosporine levels when concomitantly treated with amlodipine [see drug interactions (7.2) ] . tacrolimus : a prospective study in healthy chinese volunteers (n=9) with cyp3a5 expressers showed a 2.5- to 4-fold increase in tacrolimus exposure when concomitantly administered with amlodipine compared to tacrolimus alone. this finding was not observed in cyp3a5 non-expressers (n= 6). however, a 3-fold increase in plasma exposure to tacrolimus in a renal transplant patient (cyp3a5 non-expresser) upon initiation of amlodipine for the treatment of post-transplant hypertension resulting in reduction of tacrolimus dose has been reported. irrespective of the cyp3a5 genotype status, the possibility of an interaction cannot be excluded with these drugs [see drug interactions (7.2) ] .

ve daily dosing. specific populations renal impairment the pharmacokinetics of amlodipine are not significantly influenced by renal impairment. patients with renal failure may therefore receive the usual initial dose. hepatic impairment elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in auc of approximately 40–60%, and a lower initial dose may be required. a similar increase in auc was observed in patients with moderate to severe heart failure.

ct on systolic pressure was greater in older patients, perhaps because of greater baseline systolic pressure. effects were similar in black patients and in white patients. pediatric patients two hundred sixty-eight hypertensive patients aged 6 to 17 years were randomized first to amlodipine 2.5 or 5 mg once daily for 4 weeks and then randomized again to the same dose or to placebo for another 4 weeks. patients receiving 2.5 mg or 5 mg at the end of 8 weeks had significantly lower systolic blood pressure than those secondarily randomized to placebo. the magnitude of the treatment effect is difficult to interpret, but it is probably less than 5 mmhg systolic on the 5 mg dose and 3.3 mmhg systolic on the 2.5 mg dose. adverse events were similar to those seen in adults.

rn baby. tell your healthcare provider if you become pregnant during treatment with levamlodipine tablets. are breastfeeding or plan to breastfeed. levamlodipine tablets can pass into your breast milk. talk to your healthcare provider about the best way to feed your baby during treatment with levamlodipine tablets. tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. how should i take levamlodipine tablets? take levamlodipine tablets exactly as your healthcare provider tell you to. take levamlodipine tablets 1 time a day. if you take too much levamlodipine tablets, contact your local poison control center or go to the nearest hospital emergency room right away. what are the possible side effects of levamlodipine tablets? levamlodipine tablets may cause serious side effects, including : low blood pressure (hypotension). levamlodipine tablets may cause low blood pressure, especially in people that have a condition called severe aortic stenosis. tell your healthcare provider if you feel faint or lightheaded. worsening chest pain (angina) or heart attack. levamlodipine tablets may cause worsening chest pain or heart attack after starting or increasing your dose, especially in people with a condition called severe obstructive coronary artery disease. if that happens, call your healthcare provider right away or go directly to a hospital emergency room. the most common side effects of levamlodipine tablets include: swelling of your legs or ankles tiredness nausea stomach pain sleepiness dizziness flushing (hot or warm feeling in your face) heart palpitations (very fast heartbeat) these are not all of the possible side effects of levamlodipine tablets. call your doctor for medical advice about side effects. you may report side effects to fda at 1-800-fda-1088. how should i store levamlodipine tablets? store levamlodipine tablets at 68°f to 77°f (20°c to 25°c). keep levamlodipine tablets out of the light. keep levamlodipine tablets and all medicines out of the reach of children. general information about the safe and effective use of levamlodipine tablets. medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. do not use levamlodipine tablets for a condition for which it was not prescribed. do not give levamlodipine tablets to other people, even if they have the same symptoms that you have. it may harm them. you can ask your pharmacist or healthcare provider for information about levamlodipine tablets that is written for health professionals. what are the ingredients in levamlodipine tablets? active ingredient: levamlodipine maleate inactive ingredients: betadex, colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, and pregelatinized starch manufactured by: cspc ouyi pharmaceutical co., ltd. distributed by: xspire pharma llc ridgeland, ms 39157 for more information, call toll free number 1-888-252-3901