Norvasc 10 mg / Amlopres 10 mg

NORVASC® is the besylate salt of amlodipine, a long-acting calcium channel blocker.
NORVASC® is chemically described as (R.S.) 3-ethyl-5-methyl-2- (2-aminoethoxymethyl)-4-(2-chlorophenyl) 1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate benzenesulphonate. Its empirical formula is C₂0H₂₅CIN₂0₅·C ₆H₆0₃S. 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 besylate) tablets are formulated as white tablets equivalent to 2.5, 5 and 10 mg of arnlodipine 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.

Mechanism of Action: NORVASC is a dihydropyridine calcium antagonist (calcium ion antagonist or slow channel blocker) that inhibits the transmenibrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that NORVASC 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. NORVASC 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 in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by NORVASC. Within the physiologic pH range, NORVASC 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.
NORVASC 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 NORVASC relieves angina have not been fully delineated, but are thought to include the following:

Exertional Angina: In patients with exertional angina, NORVASC 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.

Vasospastic Angina: NORVASC 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 NORVASC in vasospastic (Prinzmetal's or variant) angina.

Pharmacokinetics and Metabolism: After oral administration of therapeutic doses of NORVASC, 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 is not altered by the presence of food.
NORVASC 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. Ex vivo 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 NORVASC are reached after 7 to 8 days of consecutive daily dosing.
The pharmacokinetics of NORVASC 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.

Pharmacodynamics: Hemodynamics Following administration of therapeutic doses to patients with hypertension, NORVASC 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 administration of oral 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 NORVASC 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).
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 NORVASC 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, NORVASC has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when coadministered with beta-blockers to man. Similar findings, however, have been observed in normals or well compensated patients with heart failure with agents possessing significant negative inotropic effects.
In a double-blind, placebo-controlled clinical trial involving 118 patients with well compensated heart failure (NYHA Class II and Class III), treatment with NORVASC did not lead to worsened heart failure, based on measures of exercise tolerance, left ventricular ejection fraction and clinical symptomatology. Studies in patients with NYHA Class IV heart failure have not been performed and, in general, all calcium channel blockers should be used with caution in any patient with heart failure.
In hypertensive patients with normal renal function, therapeutic doses of NORVASC 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.

Electrophysiologic Effects: NORVASC 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 NORVASC and concomitant beta blockers. In clinical studies in which NORVASC 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, NORVASC therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.

Effects in Hypertension: The antihypertensive efficacy of NORVASC has been demonstrated in a total of 15 double-blind, placebo-controlled, randomized studies involving 800 patients on NORVASC and 538 on placebo. Once daily administration produced statistically significant placebo-corrected reductions in supine and standing blood pressures at 24 hours postdose, averaging about 12/6 mmHg in the standing position and 13/7 mmHg in the supine position in patients with mild to moderate hypertension. Maintenance of the blood pressure effect over the 24 hour dosing interval was observed, with little difference in peak and trough effect. Tolerance was not demonstrated in patients studied for up to 1 year. The 3 parallel, fixed dose, dose response studies showed that the reduction in supine and standing blood pressures was dose-related within the recommended dosing range. Effects on diastolic pressure were similar in young and older patients. The effect on systolic pressure was greater in older patients, perhaps because of greater baseline systolic pressure. Effects were similar in black and white patients.

Effects in Chronic Stable Angina: The effectiveness of 5-10 mg/day of NORVASC in exercise-induced angina has been evaluated in 8 placebo-controlled, double-blind clinical trials of up to 6 weeks duration involving 1038 patients (684 NORVASC, 354 placebo) with chronic stable angina. In 5 of the 8 studies significant increases in exercise time (bicycle or treadmill) were seen with the 10 mg dose. Increases in symptom-limited exercise time averaged 12.8% (63 sec) for NOR VASC 10 mg, and averaged 7.9% (38 sec) for NORVASC 5 mg. NORVASC 10 mg also increased time to 1 mm ST segment deviation in several studies and decreased angina attack rate. The sustained efficacy of NORVASC in angina patients has been demonstrated over long-term dosing. In patients with angina there were no clinically significant reductions in blood pressures (4/1 mmHg) or changes in heart rate (+0.3 bpm).

Effects in Vasospastic Angina: In a double-blind, placebo-controlled clinical trial of 4 weeks duration in 50 patients, NORVASC therapy decreased attacks by approximately 4/week compared with a placebo decrease of approximately 1/week (p<0.01). Two of 23 NORVASC and 7 of 27 placebo patients discontinued from the study due to lack of clinical improvement.

2. Chronic Stable Angina
NORVASC is indicated for the treatment of chronic stable angina. NORVASC may be used alone or in combination with other antianginal agents.

3. Vasospastic Angina (Prinzmetal's or Variant Angina) NORVASC is indicated for the treatment of confirmed or suspected vasospastic angina. NORVASC may be used as monotherapy or in combination with other antianginal drugs.

Increased Angina and/or Myocardial Infarction: Rarely, patients, particularly those with severe obstructive coronary artery disease, have developed documented increased frequency, duration and/or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.

General: Since the vasodilation induced by NORVASC is gradual in onset, acute hypotension has rarely been reported after oral administration of NORVASC. Nonetheless, caution should be exercised when administering NORVASC as with any other peripheral vasodilator particularly in patients with severe aortic stenosis.

Use in Patients with Congestive Heart Failure: Although hemodynamic studies and a controlled trial in NYHA Class II-III heart failure patients have shown that NORVASC did not lead to clinical deterioration as measured by exercise tolerance, left ventricular ejection fraction, and clinical symptomatology, studies have not been performed in patients with NYHA Class IV heart failure. In general, all calcium channel blockers should be used with caution in patients with heart failure.

Beta-Blocker Withdrawal: NORVASC is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be by gradual reduction of the dose of beta-blocker

Patients with Hepatic Failure: Since NORVASC is extensively metabolized by the liver and the plasma elimination half-life (t 1/2) is 56 hours in patients with impaired hepatic function, caution should be exercised when administering NORVASC to patients with severe hepatic impairment.

Drug Interactions: In vitro data in human plasma indicate that NORVASC has no effect on the protein binding of drugs tested (digoxin, phenytoin, warfarin, and indomethacin). Special studies have indicated that the co- administration of NORVASC with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers; that co-administration with cimetidine did not alter the pharmacokinetics of amlodipine; and that co-administration with warfarin did not change the warfarin prothrombin response time.
In clinical trials, NORVASC has been safely administered with thiazide diuretics, beta-blockers, angiotensin converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, non-steroidal anti- inflammatory drugs, antibiotics, and oral hypoglycemic drugs.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to provide daily dosage levels of 0.5,11.25, and 2.5 mg/kg/day showed no evidence of carcinogenicity The highest dose (for mice, similar to, and for rats twice^* the maximum recommended clinical -dose of 10 mg on a Mg/M² basis), was close to the maximum tolerated dose for mice but not for rats.
Mutagenicity studies revealed no drug related effects at either the gene or chromosome levels.
There was no effect on the fertility of rats treated with amloclipine (males for 64 days and females 14 days prior to mating) at doses up to 10 mg/kg/day (8 times^* the maximum recommended human dose of 10 mg on a Mg/M² basis).

Pregnancy Category C: No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats or rabbits were treated orally with up to 10 mg/kg amlodipine (respectively 8 times^* and 23 times^* the maximum recommended human dose of 10 mg on a Mg/M² basis) during their respective periods of major organogenesis. However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats administered 10 mg/kg amloclipine 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. There are no adequate and well-controlled studies in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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

Pediatric Use: Safety and effectiveness of NORVASC in children have not been established.

NORVASC has been evaluated for safety in more than 11,000 patients in U.S, and foreign clinical trials. In general, treatment with NORVASC was well-tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with NORVASC were of mild or moderate severity In controlled clinical trials directly comparing NORVASC (N=1730) in doses up to 10 mg to placebo (N=1250), discontinuation of NORVASC 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 which occurred in a dose related manner are as follows:

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:

			NORVASC                  PLACEBO
	ADR	  	M=%	 F=%	  	 M=%	  F=%
		     (N=1218)  (N=512)  	(N=914)  (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, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension.

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

Gastrointestinal: anorexia, constipation, dyspepsia" dysphagia. diarrhea, flatteries vomiting. gingival hyperplasia.

General: asthenia,^** back pain, hot flushes, malaise, pain, rigors, weight gain.

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

Skin and Appendages: pruritus,^** rash,^** rash erythematous, rash maculopapular.

^**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 following events occurred in <= 0.1% of patients:
cardiac failure, pulse irregularity, extrasystoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, coughing, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia.
Other reactions occurred sporadically and cannot be distinguished from medications or concurrent disease states such as myocardial infarction and angina.
NORVASC 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 postmarketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis) in some cases severe enough to require hospitalization have been reported in association with use of amlodipine.
NORVASC has been used safely in patients with chronic obstructive pulmonary disease, well compensated congestive heart failure, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles.

Single oral doses of 40 mg/kg and 100 mg/kg in mice and rats, respectively, caused deaths. A single oral dose of 4 mg/kg or higher in dogs caused a marked peripheral vasodilation and hypotension.

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 is limited. Reports of intentional overdosage include a patient who ingested 250 mg and was asymptomatic and was not hospitalized; another (120 mg) was hospitalized, underwent gastric lavage and remained normotensive; the third (105 mg) was hospitalized and had hypotension (90/50 mmHg) which normalized following plasma expansion. A patient who took 70 mg amlodipine and an unknown quantity of benzodiazepine in a suicide attempt, developed shock which was refractory to treatment and died the following day with abnormally high benzodiazepine plasma concentration. A case of accidental drug overdose has been documented in a 19 month old male who ingested 30 mg amlodipine (about 2 mg/kg). During the emergency room presentation, vital signs were stable with no evidence of hypotension, but a heart rate of 180 bpm. Ipecac was administered 3.5 hours after ingestion and on subsequent observation (overnight) no sequelae were noted.
If massive overdose should occur, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements are essential. Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine), should be considered with attention to circulating volume and urine output. Intravenous calcium gluconate may help to reverse the effects of calcium entry blockade. As NORVASC is highly protein bound, hemodialysis is not likely to be of benefit.

NORVASC® -2.5 mg Tablets (arnlodipine besylate equivalent to 2.5 mg of amlodipine per tablet) are supplied as white, diamond, flat-faced, beveled edged engraved with "NORVASC" oil one side and "2.5" on the other side and supplied as follows:

NDC 0069-1520-66 Bottle of 100

NORVASC®-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" and "5" on one side and plain on the other side and supplied as follows:

NDC 0069-1530-66 Bottle of 100
NDC 0069-1530-41 Unit Dose package of 100
NDC 0069-1530-72 Bottle of 300

NORVASC®-10 mg Tablets (amlodipine besylate equivalent to 10 mg of amlodipine per tablet) are white, round, flat-faced, beveled edged engraved with both "NORVASC" and "10" on one side and plain on the other side and supplied as follows:

NDC 0069-1540-66 Bottle of 100
NDC 0069-1540-41 Unit Dose package of 100

Store bottles at controlled room temperature, 59º to 86ºF (15ºC to 30ºC) and dispense in tight, light-resistant containers (USP).