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Amlodipine - FDA prescribing information, side effects and uses



Salvanets.bizAmlodipine 5 mg side effects


6/17/2014
01:55 | Author: Kate Thompson

Amlodipine 5 mg side effects
Amlodipine - FDA prescribing information, side effects and uses

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The usual initial antihypertensive oral dose of Amlodipine besylate tablet, USP is 5 mg once daily, and the maximum dose is 10 mg once daily.

Effect of Amlodipine on blood pressure in patients less than 6 years of age is not known.

Metabolic and Nutritional: hyperglycemia, thirst.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. 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). Many patients will require more than one drug to achieve blood pressure goals.

No clinically relevant changes were noted in serum potassium, serum glucose, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine. Amlodipine therapy has not been associated with clinically significant changes in routine laboratory tests.

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.

Limit the dose of simvastatin in patients on Amlodipine to 20 mg daily. Coadministration 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.

Central and Peripheral Nervous System: hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo.

When Amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect. A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of Amlodipine.

Respiratory System: dyspnea, 1 epistaxis.

Amlodipine besylate is the besylate salt of Amlodipine, a long-acting calcium channel blocker.

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:

None known. Pregnancy Category C. 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.

Urinary System: micturition frequency, micturition disorder, nocturia.

Vasospastic Angina: Amlodipine has been demonstrated to block constriction and restore blood flow in coronary arteries and arterioles in response to calcium, potassium epinephrine, serotonin, and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro. This inhibition of coronary spasm is responsible for the effectiveness of Amlodipine in vasospastic (Prinzmetal's or variant) angina.

Exertional Angina: In patients with exertional angina, Amlodipine reduces the total peripheral resistance (after load) against which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand, at any given level of exercise.

Coadministration of Amlodipine with warfarin did not change the warfarin prothrombin response time.

Clinical studies of Amlodipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Elderly patients have decreased clearance of Amlodipine with a resulting increase of AUC of approximay 40–60%, and a lower initial dose may be required. 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. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Amlodipine besylate tablet, USP is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including Amlodipine besylate tablet, USP.

Coronary artery disease: The recommended dose range for patients with coronary artery disease is 5 to 10 mg once daily. In clinical studies, the majority of patients required 10 mg.

Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of Amlodipine is limited.

Psychiatric: sexual dysfunction (male 1 and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization.

Amlodipine besylate tablet, USP is indicated for the symptomatic treatment of chronic stable angina. Amlodipine besylate tablet, USP may be used alone or in combination with other antianginal agents.

Amlodipine besylate tablet, USP is contraindicated in patients with known sensitivity to Amlodipine.

Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely.

Its molecular formula is C 20 H 25 CIN 2 O 5 •C S, and its structural formula is:. Amlodipine besylate is chemically described as 3-Ethyl-5-methyl (±)-2--4-(2-chlorophenyl)-1, 4-dihydro-6-methyl-3, 5-pyridinedicarboxylate, monobenzenesulphonate.

Because Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t 1/2 ) is 56 hours in patients with impaired hepatic function, titrate slowly when administering Amlodipine to patients with severe hepatic impairment.

General: allergic reaction, asthenia, 1 back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease.

In vitro data indicate that Amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.

Coadministration of Amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.

These considerations may guide selection of therapy. 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).

In addition to the active ingredient, Amlodipine besylate, each tablet contains the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate dihydrate, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate. Amlodipine besylate tablets, USP are formulated as white to off white tablets equivalent to 2.5, 5, and 10 mg of Amlodipine for oral administration. It is slightly soluble in water and sparingly soluble in ethanol. Amlodipine besylate is a white or almost white powder with a molecular weight of 567.1.

In patients with recently documented CAD by angiography and without heart failure or an ejection fraction <40%, Amlodipine besylate tablet, USP is indicated to reduce the risk of hospitalization for angina and to reduce the risk of a coronary revascularization procedure.

Doses in excess of 5 mg daily have not been studied in pediatric patients [see Clinical Pharmacology ( 12.4 ), Clinical Studies ( 14.1 )]. The effective antihypertensive oral dose in pediatric patients ages 6–17 years is 2.5 mg to 5 mg once daily.

Musculoskeletal System: arthralgia, arthrosis, muscle cramps, 1 myalgia.

Coadministration of a magnesium and aluminum hydroxide antacid with a single dose of Amlodipine had no significant effect on the pharmacokinetics of Amlodipine.

Coadministration of Amlodipine with cimetidine did not alter the pharmacokinetics of Amlodipine.

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.

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:

Adjust dosage according to blood pressure goals. Titrate more rapidly, however, if clinically warranted, provided the patient is assessed frequently. In general, wait 7 to 14 days between titration steps.

Angiographically Documented CAD. Amlodipine besylate tablet, USP may be used as monotherapy or in combination with other antianginal agents. Amlodipine besylate tablet, USP is indicated for the treatment of confirmed or suspected vasospastic angina.

Skin and Appendages: angioedema, erythema multiforme, pruritus, 1 rash, 1 rash erythematous, rash maculopapular.

Gastrointestinal: anorexia, constipation, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.

Coadministration of multiple 10 mg doses of Amlodipine with 80 mg of atorvastatin resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.

Coadministration 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 coadministration in healthy volunteers did not significantly change Amlodipine systemic exposure. Monitor for symptoms of hypotension and edema when Amlodipine is coadministered with CYP3A4 inhibitors. However, strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of Amlodipine to a greater extent.

Amlodipine (2.5 to 5 mg daily) is effective in lowering blood pressure in patients 6 to 17 years.

Hemopoietic: leukopenia, purpura, thrombocytopenia.

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.

Autonomic Nervous System: dry mouth, sweating increased.

Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. The most commonly reported side effects more frequent than placebo are reflected in the table below. In general, treatment with Amlodipine was well-tolerated at doses up to 10 mg daily. In controlled clinical trials directly comparing Amlodipine (N=1730) at doses up to 10 mg to placebo (N=1250), discontinuation of Amlodipine because of adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). Most adverse reactions reported during therapy with Amlodipine were of mild or moderate severity. The incidence (%) of side effects that occurred in a dose related manner are as follows:. and foreign clinical trials.

Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of Amlodipine, particularly in patients with severe obstructive coronary artery disease.

Blood pressure should be closely monitored when Amlodipine is coadministered with CYP3A4 inducers. No information is available on the quantitative effects of CYP3A4 inducers on Amlodipine.

Most patients will require 10 mg for adequate effect. Angina: The recommended dose for chronic stable or vasospastic angina is 5 to 10 mg, with the lower dose suggested in the elderly and in patients with hepatic insufficiency.

Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, tachycardia, vasculitis.

Amlodipine besylate tablet, USP may be used alone or in combination with other antihypertensive agents. Chronic Stable Angina.

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. 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.

Vasospastic Angina (Prinzmetal's or Variant Angina).

Single oral Amlodipine maleate doses equivalent to 4 or more mg Amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m 2 basis) caused a marked peripheral vasodilation and hypotension. Single oral doses of Amlodipine maleate equivalent to 40 mg Amlodipine/kg and 100 mg Amlodipine/kg in mice and rats, respectively, caused deaths.

The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Within the physiologic pH range, Amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with 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. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by Amlodipine. Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that Amlodipine binds to both dihydropyridine and nondihydropyridine binding sites.

Generic Name: Amlodipine besylate Dosage Form: tablet.

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:

Frequent blood pressure measurements are essential. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output. Should hypotension occur, provide cardiovascular support including elevation of the extremities and the judicious administration of fluids. If massive overdose should occur, initiate active cardiac and respiratory monitoring. As Amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.

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.

2 Based on patient weight of 50 kg.

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.

Single and multiple 10 mg doses of Amlodipine had no significant effect on the pharmacokinetics of ethanol.

In the CAMELOT and PREVENT studies, the adverse event profile was similar to that reported previously (see above), with the most common adverse event being peripheral edema.

2.5, 5, and 10 mg Tablets.

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. Hemodynamics: Following administration of therapeutic doses to patients with hypertension, Amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures.

Plasma concentrations correlate with effect in both young and elderly patients. Normotensive subjects experienced no clinically significant change in blood pressures (+1/–2 mmHg). With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. 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).

However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving Amlodipine maleate at a dose equivalent to 10 mg Amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose. No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with Amlodipine maleate at doses up to 10 mg Amlodipine/kg/day (respectively, 8 times 2 and 23 times 2 the maximum recommended human dose of 10 mg on a mg/m 2 basis) during their respective periods of major organogenesis.

In the absence of this information, it is recommended that nursing be discontinued while Amlodipine is administered. It is not known whether Amlodipine is excreted in human milk.

1 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.

The precise mechanisms by which Amlodipine relieves angina have not been fully delineated, but are thought to include the following:

Coadministration of 240 mL of grapefruit juice with a single oral dose of Amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of Amlodipine.

Small, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 2.5 mg once daily and this dose may be used when adding Amlodipine besylate tablet, USP to other antihypertensive therapy.

There are no adequate and well-controlled studies in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the risk to the fetus.

Special Senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus.


Amlodipine 5 mg side effects