Norvasc Information
Norvasc (Amlodipine) Dosage And Administration
The usual initial antihypertensive oral dose of Norvasc (Amlodipine) is 5 mg once daily with a maximum dose of 10 mg once daily.
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 Norvasc (Amlodipine) to other antihypertensive therapy.
Adjust dosage according to each patient's need. In general, titration should proceed over 7 to 14 days so that the physician can fully assess the patient's response to each dose level. Titration may proceed more rapidly, however, if clinically warranted, provided the patient is assessed frequently.
The recommended dose for chronic stable or vasospastic angina is 5–10 mg, with the lower dose suggested in the elderly and in patients with hepatic insufficiency. Most patients will require 10 mg for adequate effect
The recommended dose range for patients with coronary artery disease is 5–10 mg once daily. In clinical studies, the majority of patients required 10 mg .
Norvasc (Amlodipine) Dosage Forms And Strengths
2.5, 5, and 10 mg Tablets
Norvasc (Amlodipine) Contraindications
Norvasc (Amlodipine) is contraindicated in patients with known sensitivity to amlodipine.
Norvasc (Amlodipine) Adverse Reactions
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.
Norvasc (Amlodipine) has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. In general, treatment with Norvasc (Amlodipine) was well-tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with Norvasc (Amlodipine) were of mild or moderate severity. In controlled clinical trials directly comparing Norvasc (Amlodipine) (N=1730) at doses up to 10 mg to placebo (N=1250), discontinuation of Norvasc (Amlodipine) due to adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). The most common side effects are headache and edema. The incidence (%) of side effects that occurred in a dose related manner are as follows:
Other adverse experiences that were not clearly dose related but were reported with an incidence greater than 1.0% in placebo-controlled clinical trials include the following:
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:
The following events occurred in 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:
Central and Peripheral Nervous System:
Gastrointestinal:
General:
Musculoskeletal System:
Psychiatric:
Respiratory System:
Skin and Appendages:
Special Senses:
Urinary System:
Autonomic Nervous System:
Metabolic and Nutritional:
Hemopoietic:
The following events occurred in
Other reactions occurred sporadically and cannot be distinguished from medications or concurrent disease states such as myocardial infarction and angina.
Norvasc (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 , the adverse event profile was similar to that reported previously (see above), with the most common adverse event being peripheral edema.
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.
Norvasc (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.
Norvasc (Amlodipine) Overdosage
Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of Norvasc (Amlodipine) is limited.
Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. 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 basis) caused a marked peripheral vasodilation and hypotension.
If massive overdose should occur, initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential. Should hypotension occur, provide cardiovascular support including elevation of the extremities and the judicious administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output. As Norvasc (Amlodipine) is highly protein bound, hemodialysis is not likely to be of benefit.
Norvasc (Amlodipine) Description
Norvasc (Amlodipine) is the besylate salt of amlodipine, a long-acting calcium channel blocker.
Amlodipine besylate is chemically described as 3-Ethyl-5-methyl (±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate. Its empirical formula is CHClNO•CHOS, and its structural formula is:
Amlodipine besylate is a white crystalline powder with a molecular weight of 567.1. It is slightly soluble in water and sparingly soluble in ethanol. Norvasc (Amlodipine) (amlodipine besylate) Tablets are formulated as white tablets equivalent to 2.5, 5, and 10 mg of amlodipine for oral administration. In addition to the active ingredient, amlodipine besylate, each tablet contains the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate, and magnesium stearate.
Norvasc (Amlodipine) Clinical Pharmacology
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. 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. Negative inotropic effects can be detected but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. 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.
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.
The precise mechanisms by which amlodipine relieves angina have not been fully delineated, but are thought to include the following:
After oral administration of therapeutic doses of Norvasc (Amlodipine) , absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of Norvasc (Amlodipine) is not altered by the presence of food.
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. studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. 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.
The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.
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.
Norvasc (Amlodipine) Clinical Studies
In PREVENT, 825 patients with angiographically documented coronary artery disease were randomized to Norvasc (Amlodipine) (5–10 mg once daily) or placebo and followed for 3 years. Although the study did not show significance on the primary objective of change in coronary luminal diameter as assessed by quantitative coronary angiography, the data suggested a favorable outcome with respect to fewer hospitalizations for angina and revascularization procedures in patients with CAD.
CAMELOT enrolled 1318 patients with CAD recently documented by angiography, without left main coronary disease and without heart failure or an ejection fraction
In an angiographic substudy (n=274) conducted within CAMELOT, there was no significant difference between amlodipine and placebo on the change of atheroma volume in the coronary artery as assessed by intravascular ultrasound.
Figure 1 - Kaplan-Meier Analysis of Composite Clinical Outcomes for Norvasc (Amlodipine) versus Placebo
Figure 2 – Effects on Primary Endpoint of Norvasc (Amlodipine) versus Placebo across Sub-Groups
Table 1 below summarizes the significant composite endpoint and clinical outcomes from the composites of the primary endpoint. The other components of the primary endpoint including cardiovascular death, resuscitated cardiac arrest, myocardial infarction, hospitalization for heart failure, stroke/TIA, or peripheral vascular disease did not demonstrate a significant difference between Norvasc (Amlodipine) and placebo.
Norvasc (Amlodipine) has been compared to placebo in four 8–12 week studies of patients with NYHA Class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsened heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or left ventricular ejection fraction. In a long-term (follow-up at least 6 months, mean 13.8 months) placebo-controlled mortality/morbidity study of Norvasc (Amlodipine) 5–10 mg in 1153 patients with NYHA Classes III (n=931) or IV (n=222) heart failure on stable doses of diuretics, digoxin, and ACE inhibitors, Norvasc (Amlodipine) had no effect on the primary endpoint of the study which was the combined endpoint of all-cause mortality and cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure), or on NYHA classification, or symptoms of heart failure. Total combined all-cause mortality and cardiac morbidity events were 222/571 (39%) for patients on Norvasc (Amlodipine) and 246/583 (42%) for patients on placebo; the cardiac morbid events represented about 25% of the endpoints in the study.
Another study (PRAISE-2) randomized patients with NYHA Class III (80%) or IV (20%) heart failure without clinical symptoms or objective evidence of underlying ischemic disease, on stable doses of ACE inhibitors (99%), digitalis (99%), and diuretics (99%), to placebo (n=827) or Norvasc (Amlodipine) (n=827) and followed them for a mean of 33 months. There was no statistically significant difference between Norvasc (Amlodipine) and placebo in the primary endpoint of all-cause mortality (95% confidence limits from 8% reduction to 29% increase on Norvasc (Amlodipine) ). With Norvasc (Amlodipine) there were more reports of pulmonary edema.
Norvasc (Amlodipine) How Supplied/storage And Handling
Norvasc (Amlodipine) – 5 mg Tablets (amlodipine besylate equivalent to 5 mg of amlodipine per tablet) are white, elongated octagon, flat-faced, beveled edged engraved with both "Norvasc (Amlodipine) " and "5" on one side and plain on the other side and supplied as follows:
NDC 21695-151-15 Bottle of 15
Norvasc (Amlodipine)
Norvasc (Amlodipine)
Norvasc (Amlodipine) Principal Display Panel - Mg Tablets
