Hypertenipine-2.5

DESCRIPTION SECTION

DESCRIPTIONAmlodipine besylate, USP is a long-acting calcium channel blocker.Amlodipine besylate, USP is chemically described as 3-Ethyl-5-methyl (±)-2-[(2-aminoethoxy) methy l ] - 4 - ( 2 - c h l o r o p h e ny l ) - 1 , 4 - d i hydro-6-methy l - 3 , 5 - py r i d i n e d i c a r b ox y l a t e, monobenzenesulphonate. Its molecular formula is C20H25CIN2O5•C6H6O3S, and its structural formula is:Amlodipine besylate, USP is a white crystalline powder with a molecular weight of 567.1. It is slightly soluble in water and sparingly soluble in ethanol. 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, USP, each tablet contains the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate, and magnesium stearate.

CLINICAL PHARMACOLOGY SECTION

CLINICAL PHARMACOLOGYMechanism of ActionAmlodipine 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 cardiacmuscle. Experimental data suggest that amlodipine binds to both dihydropyridine andnondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smoothmuscle are dependent upon the movement of extracellular calcium ions into these cells throughspecific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, witha greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropiceffects can be detected in vitrobut such effects have not been seen in intact animals at therapeuticdoses. 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 channelreceptor is characterized by a gradual rate of association and dissociation with the receptor bindingsite, resulting in a gradual onset of effect.Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to causea reduction in peripheral vascular resistance and reduction in blood pressure.The precise mechanisms by which amlodipine relieves angina have not been fully delineated, butare thought to include the following:Exertional Angina: In patients with exertional angina, amlodipine besylate reduces the totalperipheral resistance (afterload) against which the heart works and reduces the rate pressureproduct, and thus myocardial oxygen demand, at any given level of exercise.Vasospastic Angina: Amlodipine besylate has been demonstrated to block constriction and restoreblood flow in coronary arteries and arterioles in response to calcium, potassium epinephrine,serotonin, and thromboxane A2 analog in experimental animal models and in human coronaryvessels in vitro. This inhibition of coronary spasm is responsible for the effectiveness of amlodipinebesylate in vasospastic (Prinzmetal’s or variant) angina.

PHARMACOKINETICS SECTION

Pharmacokinetics and MetabolismAfter oral administration of therapeutic doses of amlodipine besylate, absorption produces peakplasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to bebetween 64 and 90%. The bioavailability of amlodipine besylate is not altered by the presence offood.Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with10% of the parent compound and 60% of the metabolites excreted in the urine. Ex vivostudies haveshown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensivepatients. Elimination from the plasma is biphasic with a terminal elimination half-life of about 30-50hours. Steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutive dailydosing.The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patientswith renal failure may therefore receive the usual initial dose.Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine witha resulting increase in AUC of approximately 40-60%, and a lower initial dose may be required. Asimilar increase in AUC was observed in patients with moderate to severe heart failure.Pediatric PatientsSixty-two hypertensive patients aged 6 to 17 years received doses of amlodipine besylate between1.25 mg and 20 mg.Weight-adjusted clearance and volume of distribution were similar to values inadults.

PHARMACODYNAMICS SECTION

PharmacodynamicsHemodynamics Following administration of therapeutic doses to patients with hypertension,amlodipine besylate produces vasodilation resulting in a reduction of supine and standing bloodpressures. These decreases in blood pressure are not accompanied by a significant change in heartrate or plasma catecholamine levels with chronic dosing. Although the acute intravenousadministration of amlodipine decreases arterial blood pressure and increases heart rate inhemodynamic studies of patients with chronic stable angina, chronic oral administration ofamlodipine in clinical trials did not lead to clinically significant changes in heart rate or bloodpressures in normotensive patients with angina.With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least24 hours. Plasma concentrations correlate with effect in both young and elderly patients. Themagnitude of reduction in blood pressure with amlodipine besylate is also correlated with the heightof pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105-114mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure90-104 mmHg). Normotensive subjects experienced no clinically significant change in bloodpressures (+1/–2 mmHg).In hypertensive patients with normal renal function, therapeutic doses of amlodipine besylateresulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate andeffective renal plasma flow without change in filtration fraction or proteinuria.As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest andduring exercise (or pacing) in patients with normal ventricular function treated with amlodipinebesylate have generally demonstrated a small increase in cardiac index without significant influenceon dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipinebesylate has not been associated with a negative inotropic effect when administered in thetherapeutic dose range to intact animals and man, even when co-administered with beta-blockers toman. Similar findings, however, have been observed in normals or well-compensated patients withheart failure with agents possessing significant negative inotropic effects.Electrophysiologic Effects: Amlodipine besylate does not change sinoatrial nodal function oratrioventricular 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 sinusnode recovery time after pacing. Similar results were obtained in patients receiving amlodipinebesylate and concomitant beta blockers. In clinical studies in which amlodipine besylate wasadministered in combination with beta-blockers to patients with either hypertension or angina, noadverse effects on electrocardiographic parameters were observed. In clinical trials with anginapatients alone, amlodipine besylate therapy did not alter electrocardiographic intervals or producehigher degrees of AV blocks.

CLINICAL STUDIES SECTION

Clinical StudiesEffects in HypertensionAdult Patients: The antihypertensive efficacy of amlodipine besylate has been demonstrated in atotal of 15 double-blind, placebo-controlled, randomized studies involving 800 patients on amlodipinebesylate and 538 on placebo. Once daily administration produced statistically significant placebocorrectedreductions in supine and standing blood pressures at 24 hours postdose, averaging about12/6 mmHg in the standing position and 13/7 mmHg in the supine position in patients with mild tomoderate hypertension. Maintenance of the blood pressure effect over the 24-hour dosing intervalwas observed, with little difference in peak and trough effect. Tolerance was not demonstrated inpatients studied for up to 1 year. The 3 parallel, fixed dose, dose response studies showed that thereduction in supine and standing blood pressures was dose-related within the recommended dosingrange. Effects on diastolic pressure were similar in young and older patients. The effect on systolicpressure 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 wererandomized first to amlodipine besylate 2.5 or 5 mg once daily for 4 weeks and then randomizedagain to the same dose or to placebo for another 4 weeks. Patients receiving 5 mg at the end of 8weeks had lower blood pressure than those secondarily randomized to placebo. The magnitude ofthe treatment effect is difficult to interpret, but it is probably less than 5 mmHg systolic on the 5 mgdose. Adverse events were similar to those seen in adults.Effects in Chronic Stable Angina:The effectiveness of 5 to 10 mg/day of amlodipine besylate in exercise-induced angina has beenevaluated in 8 placebo-controlled, double-blind clinical trials of up to 6 weeks duration involving 1038patients (684 amlodipine besylate, 354 placebo) with chronic stable angina. In 5 of the 8 studiessignificant increases in exercise time (bicycle or treadmill) were seen with the 10 mg dose. Increasesin symptom-limited exercise time averaged 12.8% (63 sec) for amlodipine besylate 10 mg, andaveraged 7.9% (38 sec) for amlodipine besylate 5 mg. Amlodipine besylate 10 mg also increasedtime to 1 mm ST segment deviation in several studies and decreased angina attack rate. Thesustained efficacy of amlodipine besylate in angina patients has been demonstrated over long-termdosing. In patients with angina there were no clinically significant reductions in blood pressures (4/1mmHg) 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, amlodipinebesylate therapy decreased attacks by approximately 4/week compared with a placebo decrease ofapproximately 1/week (p less than 0.01). Two of 23 amlodipine besylate and 7 of 27 placebo patientsdiscontinued from the study due to lack of clinical improvement.Studies in Patients with Congestive Heart Failure:Amlodipine besylate has been compared to placebo in four 8-12 week studies of patients with NYHAclass II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence ofworsened 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 amlodipine besylate 5 to 10 mg in 1153 patients withNYHA classes III (n=93 1) or IV (n=222) heart failure on stable doses of diuretics, digoxin, and ACEinhibitors, amlodipine besylate had no effect on the primary endpoint of the study which was thecombined endpoint of all-cause mortality and cardiac morbidity (as defined by life-threateningarrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure), or on NYHAclassification, or symptoms of heart failure. Total combined all-cause mortality and cardiac morbidityevents were 222/571 (39%) for patients on amlodipine besylate and 246/583 (42%) for patients onplacebo; 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 failurewithout clinical symptoms or objective evidence of underlying ischemic disease, on stable doses ofACE inhibitor (99%), digitalis (99%) and diuretics (99%), to placebo (n=827) or amlodipine besylate(n=827) and followed them for a mean of 33 months. There was no statistically significant differencebetween amlodipine besylate and placebo in the primary endpoint of all cause mortality (95%confidence limits from 8% reduction to 29% increase on amlodipine besylate). With amlodipinebesylate there were more reports of pulmonary edema.

INDICATIONS & USAGE SECTION

INDICATIONS AND USAGE1. HypertensionAmlodipine besylate is indicated for the treatment of hypertension. It may be used alone or incombination with other antihypertensive agents.2. Coronary Artery DiseaseCronic Stable AnginaAmlodipine besylate is indicated for the symptomatic treatment of chronic stable angina.Amlodipine besylate may be used alone or in combination with other antianginal agents.Vasospastic Angina (Prinzmetal’s or Variant Angina)Amlodipine besylate is indicated for the treatment of confirmed or suspected vasospastic angina.Amlodipine besylate may be used as monotherapy or in combination with other antianginal drugs.

CONTRAINDICATIONS SECTION

CONTRAINDICATIONSAmlodipine besylate is contraindicated in patients with known sensitivity to amlodipine.

WARNINGS SECTION

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

PRECAUTIONS SECTION

PRECAUTIONSGeneral: Since the vasodilation induced by amlodipine besylate is gradual in onset, acutehypotension has rarely been reported after oral administration. Nonetheless, caution as with anyother peripheral vasodilator, should be exercised when administering amlodipine besylate,particularly in patients with severe aortic stenosis.Use in Patients with Congestive Heart Failure: In general, calcium channel blockers should beused with caution in patients with heart failure. Amlodipine besylate (5 to 10 mg per day) has beenstudied in a placebo-controlled trial of 1153 patients with NYHA Class III or IV heart failure (seeCLINICAL PHARMACOLOGY) on stable doses of ACE inhibitor, digoxin, and diuretics. Follow-upwas at least 6 months, with a mean of about 14 months. There was no overall adverse effect onsurvival or cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction,or hospitalization for worsened heart failure). Amlodipine besylate has been compared to placebo infour 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 exercisetolerance, NYHA classification, symptoms, or LVEF.Beta-Blocker Withdrawal: Amlodipine besylate is not a beta-blocker and therefore gives noprotection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be bygradual reduction of the dose of beta-blocker.Patients with Hepatic Failure: Since amlodipine besylate is extensively metabolized by the liverand the plasma elimination half-life (t 1/2) is 56 hours in patients with impaired hepatic function,caution should be exercised when administering amlodipine besylate to patients with severe hepaticimpairment.

DRUG INTERACTIONS SECTION

Drug Interactions: In vitro data indicate that amlodipine besylate has no effect on the humanplasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.Effect of other agents on Amlodipine besylate.CIMETIDINE: Co-administration of amlodipine besylate with cimetidine did not alter thepharmacokinetics of amlodipine besylate.GRAPEFRUIT JUICE: Co-administration of 240 mL of grapefruit juice with a single oral dose ofamlodipine 10 mg in 20 healthy volunteers had no significant effect on the C6H6O3Spharmacokinetics of amlodipine.MAALOX (antacid): Co-administration of the antacid Maalox with a single dose of amlodipinebesylate had no significant effect on the pharmacokinetics of amlodipine besylate.SILDENAFIL: A single 100 mg dose of sildenafil (Viagra®) in subjects with essential hypertensionhad no effect on the pharmacokinetic parameters of amlodipine besylate. When amlodipine besylateand sildenafil were used in combination, each agent independently exerted its own blood pressurelowering effect.Effect of Amlodipine besylate on other agents.ATORVASTATIN: Co-administration of multiple 10 mg doses of amlodipine besylate with 80 mg ofatorvastatin resulted in no significant change in the steady state pharmacokinetic parameters ofatorvastatin.DIGOXIN: Co-administration of amlodipine besylate with digoxin did not change serum digoxin levelsor digoxin renal clearance in normal volunteers.ETHANOL (alcohol): Single and multiple 10 mg doses of amlodipine besylate had no significanteffect on the pharmacokinetics of ethanol.WARFARIN: Co-administration of amlodipine besylate with warfarin did not change the warfarinprothrombin response time.In clinical trials, amlodipine besylate has been safely administered with thiazide diuretics, betablockers,angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin,digoxin, warfarin, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.

DRUG & OR LABORATORY TEST INTERACTIONS SECTION

Drug/Laboratory Test Interactions: None known.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION

Carcinogenesis, Mutagenesis, Impairment of Fertility: Rats and mice treated with amlodipinemaleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of0.5, 1.25, and 2.5 amlodipine mg/kg/day showed no evidence of a carcinogenic effect of the drug.For the mouse, the highest dose was, on a mg/m2 basis, similar to the maximum recommendedhuman dose of 10 mg amlodipine/day*). For the rat, the highest dose, was on a mg/m2 basis, abouttwice the maximum recommended human dose*.Mutagenicity studies conducted with amlodipine maleate revealed no drug related effects at eitherthe gene or chromosome level.There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 daysand females for 14 days prior to mating) at doses up to 10 mg amlodipine/kg/day (8 times* themaximum recommended human dose of 10 mg/day on a mg/m2 basis).

PREGNANCY SECTION

Pregnancy Category C: No evidence of teratogenicity or other embryo/fetal toxicity was found whenpregnant rats and rabbits were treated orally with amlodipine maleate at doses up to 10 mgamlodipine/kg/day (respectively 8 times* and 23 times* the maximum recommended human dose of10 mg on a mg/m2 basis) during their respective periods of major organogenesis. However, litter sizewas significantly decreased (by about 50%) and the number of intrauterine deaths was significantlyincreased (about 5-fold) in rats receiving amlodipine maleate at a dose equivalent to 10 mgamlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipinemaleate has been shown to prolong both the gestation period and the duration of labor in rats at thisdose. There are no adequate and well-controlled studies in pregnant women. Amlodipine should beused during pregnancy only if the potential benefit justifies the potential risk to the fetus.*Based on patient weight of 50 kg.

NURSING MOTHERS SECTION

Nursing Mothers: It is not known whether amlodipine is excreted in human milk. In the absence ofthis information, it is recommended that nursing be discontinued while amlodipine besylate isadministered.

PEDIATRIC USE SECTION

Pediatric Use: The effect of amlodipine besylate on blood pressure in patients less than 6 years ofage is not known.

GERIATRIC USE SECTION

Geriatric Use: Clinical studies of amlodipine besylate did not include sufficient numbers of subjectsaged 65 and over to determine whether they respond differently from younger subjects. Otherreported clinical experience has not identified differences in responses between the elderly andyounger patients. In general, dose selection for an elderly patient should be cautious, usually startingat the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, orcardiac function, and of concomitant disease or other drug therapy. Elderly patients have decreasedclearance of amlodipine with a resulting increase of AUC of approximately 40-60%, and a lowerinitial dose may be required (see DOSAGE AND ADMINISTRATION).

ADVERSE REACTIONS SECTION

ADVERSE REACTIONSAmlodipine besylate has been evaluated for safety in more than 11,000 patients in U.S. and foreignclinical trials. In general, treatment with amlodipine besylate was well-tolerated at doses up to 10 mgdaily. Most adverse reactions reported during therapy with amlodipine besylate were of mild ormoderate severity. In controlled clinical trials directly comparing amlodipine besylate (N=1730) indoses up to 10 mg to placebo (N=1250), discontinuation of amlodipine besylate due to adversereactions 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 sideeffects which occurred in a dose related manner are as follows:

OVERDOSAGE SECTION

OVERDOSAGESingle oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mgamlodipine/kg in mice and rats, respectively, caused deaths. Single oral amlodipine maleate dosesequivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the maximumrecommended human dose on a mg/m2 basis) caused a marked peripheral vasodilation andhypotension.Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotensionand possibly a reflex tachycardia. In humans, experience with intentional overdosage of amlodipinebesylate is limited. Reports of intentional overdosage include a patient who ingested 250 mg andwas asymptomatic and was not hospitalized; another (120 mg) was hospitalized, underwent gastriclavage and remained normotensive; the third (105 mg) was hospitalized and had hypotension (90/50mmHg) which normalized following plasma expansion. A case of accidental drug overdose has beendocumented in a 19-month-old male who ingested 30 mg amlodipine (about 2 mg/kg). During theemergency room presentation, vital signs were stable with no evidence of hypotension, but a heartrate 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, cardiovascularsupport including elevation of the extremities and the judicious administration of fluids should beinitiated. If hypotension remains unresponsive to these conservative measures, administration ofvasopressors (such as phenylephrine) should be considered with attention to circulating volume andurine output.Intravenous calcium gluconate may help to reverse the effects of calcium entry blockade. Asamlodipine besylate is highly protein bound, hemodialysis is not likely to be of benefit.

DOSAGE & ADMINISTRATION SECTION

DOSAGE AND ADMINISTRATIONAdults: The usual initial antihypertensive oral dose of amlodipine besylate is 5 mg once daily witha maximum dose of 10 mg once daily. Small, fragile, or elderly individuals, or patients with hepaticinsufficiency may be started on 2.5 mg once daily and this dose may be used when addingamlodipine besylate to other antihypertensive therapy.Dosage should be adjusted according to each patient’s need. In general, titration should proceedover 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 assessedfrequently.The recommended dose for chronic stable or vasospastic angina is 5 to 10 mg, with the lower dosesuggested in the elderly and in patients with hepatic insufficiency. Most patients will require 10 mgfor adequate effect. See ADVERSE REACTIONS section for information related to dosage and sideeffects.The recommended dose range for patients with coronary artery disease is 5 to 10 mg once daily. Inclinical studies the majority of patients required 10 mg (see CLINICAL PHARMACOLOGY, Clinicalstudies).Children: The effective antihypertensive oral dose in pediatric patients ages 6-17 years is 2.5 mg to5 mg once daily. Doses in excess of 5 mg daily have not been studied in pediatric patients. SeeCLINICAL PHARMACOLOGY.Co-administration with Other Antihypertensive and/or Antianginal Drugs: Amlodipine besylatehas been safely administered with thiazides, ACE inhibitors, beta-blockers, long-acting nitrates,and/or sublingual nitroglycerin.

HOW SUPPLIED SECTION

HOW SUPPLIEDAmlodipine besylate 2.5 mg Tablets (amlodipine besylate, USP equivalent to 2.5 mg of amlodipineper tablet) are supplied as white, round, flat-faced, beveled edged tablets debossed with IG on oneside and 237 on the other and supplied as follows:NDC 31722-237-90 Bottle of 90NDC 31722-237-10 Bottle of 1000Amlodipine besylate 5 mg Tablets (amlodipine besylate, USP equivalent to 5 mg of amlodipine pertablet) are supplied as white, round, flat-faced, beveled edged tablets debossed with IG on one sideand 238 on the other and supplied as follows:NDC 31722-238-90 Bottle of 90NDC 31722-238-10 Bottle of 1000Amlodipine besylate 10 mg Tablets (amlodipine besylate, USP equivalent to 10 mg of amlodipine pertablet) are supplied as white, round, flat-faced, beveled edged tablets debossed with IG on one sideand 239 on the other and supplied as follows:NDC 31722-239-90 Bottle of 90NDC 31722-239-10 Bottle of 1000Manufactured by:InvaGen Pharmaceuticals, IncHauppauge, NY 11788Manufactured for:Camber Pharmaceuticals, Inc.Piscataway, NJ 08854Rev : 09/07

STORAGE AND HANDLING SECTION

Store at 20°-25°C (68°-77°F). [See USP Controlled Room Temperature].

SPL UNCLASSIFIED SECTION

DESCRIPTION SECTION

PRODUCT DESCRIPTION  Primary Ingredients Hypertensa consists of a proprietary blend of amino acids, cocoa, cinnamon and flavonoids in specific proportions. These ingredients fall into the category of Generally Regarded as Safe” (GRAS) as defined by the Food and Drug Administration (FDA) (Sections 201(s) and 409 of the Federal Food, Drug, and Cosmetic Act). A GRAS substance is distinguished from a food additive on the basis of the common knowledge about the safety of the substance for its intended use. The standard for an ingredient to achieve GRAS status requires not only technical demonstration of non-toxicity and safety, but also general recognition of safety through widespread usage and agreement of that safety by experts in the field. Many ingredients have been determined by the U.S. Food and Drug Administration (FDA) to be GRAS, and are listed as such by regulation, in Volume 21 Code of Federal Regulations (CFR) Sections 182, 184, and 186.  Amino Acids  Amino Acids are the building blocks of proteins. All amino acids are GRAS listed as they have been ingested by humans for thousands of years. The doses of the amino acids in Hypertensa are equivalent to those found in the usual human diet. Patients with hypertension may require an increased amount of certain amino acids that cannot be obtained from normal diet alone. Arginine, for example, is a conditional amino acid. The body can make arginine in the liver, but the liver produced arginine can only be used in the liver itself. Arginine is needed to produce nitric oxide (NO). NO is required to dilate the constricted blood vessels that are the cause of high blood pressure. Patients with hypertension have an increase in the enzyme, arginase that degrades arginine before it can be used to produce NO. Some patients with hypertension have a resistance to the use of arginine that is similar to the mechanism found in insulin resistance that is genetically determined. Patients with hypertension cannot acquire sufficient arginine from the diet without ingesting a prohibitively large amount of calories, particularly calories from protein. .  Flavonoids  Flavonoids are a group of phytochemical compounds found in all vascular plants including fruits and vegetables. They are a part of a larger class of compounds known as polyphenols. Many of the therapeutic or health benefits of colored fruits and vegetables, cocoa, red wine, and green tea are directly related to their flavonoid content. The specially formulated flavonoids found in Hypertensa cannot be obtained from conventional foods in the necessary proportions to elicit a therapeutic response. Other Ingredients Hypertensa contains the following “inactive” or other ingredients, as fillers, excipients, and colorings: magnesium stearate, microcrystalline cellulose, Maltodextrin NF, gelatin (as the capsule material),  Physical Description  Hypertensa is a yellow to light brown powder. Hypertensa contains L-Glutamine, L-Histadine, L-Arginine, L-Leucine, L-Cysteine, Whey Protein Hydrolysate, Choline Bitartrate, Cinnamon, Caffeine, Cocoa, Ginseng, and Grape Extract.

CLINICAL PHARMACOLOGY SECTION

CLINICAL PHARMACOLOGY  Mechanism of Action Hypertensa acts by restoring and maintaining the balance of NO in patients with hypertension.  Metabolism The amino acids in Hypertensa are primarily absorbed by the stomach and small intestines. All cells metabolize the amino acids in Hypertensa. Circulating arginine and choline blood levels determine the production of NO and acetylcholine.  Excretion Hypertensa is not an inhibitor of cytochrome P450 1A2, 2C9, 2C19, 2D6, or 3A4. These isoenzymes are principally responsible for 95% of all detoxification of drugs, with CYP3A4 being responsible for detoxification of roughly 50% of drugs. Amino acids do not appear to have an effect on drug metabolizing enzymes.

INDICATIONS & USAGE SECTION

INDICATIONS FOR USE  Hypertensa is intended for the clinical dietary management of the metabolic processes in patients with hypertension.

CLINICAL STUDIES SECTION

CLINICAL EXPERIENCE  Administration of Hypertensa has demonstrated significant functional improvements in blood pressure when used for the dietary management of the metabolic processes associated with hypertension. Administration of Hypertensa results in the reduction of blood pressure in hypertensive patients. Hypertensa has no effect on normal blood pressure.

CONTRAINDICATIONS SECTION

PRECAUTIONS AND CONTRAINDICATIONS  Hypertensa is contraindicated in an extremely small number of patients with hypersensitivity to any of the nutritional components of Hypertensa.

ADVERSE REACTIONS SECTION

ADVERSE REACTIONS   Oral supplementation with L-arginine at high doses up to 15 grams daily is generally well tolerated. The most commonly reported adverse reactions at higher doses — from 15 to 30 grams daily — are nausea, abdominal cramps, and diarrhea. Some patients may experience these symptoms at lower doses. The total combined amount of amino acids in each Hypertensa capsule does not exceed 400 mg.

DRUG INTERACTIONS SECTION

DRUG INTERACTIONS  Hypertensa does not directly influence the pharmacokinetics of prescription drugs. Clinical experience has shown that administration of Hypertensa may allow for lowering the dose of co-administered drugs under physician supervision.  POST-MARKETING SURVEILLANCE Post-marketing surveillance has shown no serious adverse reactions. Reported cases of mild rash and itching may have been associated with allergies to Hypertensa flavonoid ingredients, including cocoa and chocolate. The reactions were transient in nature and subsided within 24 hours.

OVERDOSAGE SECTION

OVERDOSE  There is a negligible risk of overdose with Hypertensa as the total dosage of amino acids in a one month supply (90 capsules) is less than 36 grams. Overdose symptoms may include diarrhea, weakness, and nausea.

DOSAGE & ADMINISTRATION SECTION

DOSAGE AND ADMINISTRATION   Recommended Administration For the dietary management of the metabolic processes associated with hypertension. Take (2) capsules once or twice daily, as directed by physician. As with most amino acid formulations Hypertensa should be taken without food to increase the absorption of key ingredients.

HOW SUPPLIED SECTION

How Supplied  Hypertensa is supplied in green and white, size 0 capsules in bottles of 60 and 90 capsules.  Physician Supervision Hypertensa is a Medical Food product available by prescription only, and must be used while the patient is under ongoing physician supervision.   U.S. patent pending. Manufactured by Arizona Nutritional Supplements, Inc. Chandler AZ 85225 Distributed by Physician Therapeutics LLC, Los Angeles, CA 90077. www.ptlcentral.com © Copyright 2003-2006, Physician Therapeutics LLC, all rights reserved NDC: 68405-1007-02 NDC: 68405-1007-03

STORAGE AND HANDLING SECTION

Storage Store at room temperature, 59-86OF (15-30OC) Protect from light and moisture. Hypertensa is supplied to physicians in a recyclable plastic bottle with a child-resistant cap.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PHYSICIAN THERAPEUTICS  HYPERTENSA  Medical Food  Rx only  90 Capsules  Directions for use:  Must be administered under physician supervision.  For adults only.  As a Medical Food, take two (2) capsules four times daily in between meals or as directed by physician.   For the dietary management of hypertension.  Contains no added sugar, starch, wheat, yeast, preservatives, artifical flavor.  Storage:  Keep tightly closed in a cool dry place 8-320 C (45-900F), relative humidity, below 50%.  Warning: Keep this product out of the reach of children.  NDC# 68405-1007-03  Ingredients:  Each serving (per 2 capsules) contains:  Proprietary Amino Acid Blend L-Glutamine  L-Histadine, L-Arginine, L-Leucine, L-Cysteine, Whey Protein Hydrolysate, Choline Bitatarate, Cinnamon (bark), Caffeine, Cocoa(6% Theobromine) (fruit), Ginseng, Grape Extract (20% Polyphenol) (seed) other indgredients: Tricalcium phosphate, gelatin, silicon dioxide, vegetable magnesium stearate, microcrystalline cellulose, chlorophyllin copper complex, titanium dioxide.   Distributed exclusive by:  A  Division of Targeted Medical Pharma, Inc  Los Angeles, CA 90077  www.ptlcentral.com Patent Pending.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

For the Dietary Management of Hypertension.  Two capsules twice daily or as directed by physician. See product label and insert.  Hypertensa Medical Food  PHYSICIAN THERAPEUTICS  Hypertensa      +      Amlodipine 2.5 mg  A Convenience Packed Medical Food and Drug  Hypertenipine-2.5  PHYSICIAN THERAPEUTICS  > Hypertensa 90 Capsuled  > Amlodipine 2.5 mg 30 Tablets  No Refills Without   Physician Authorization  Rx Only  NDC# 68405-037-36  of this co-pack  As prescribed by physician. See product label and product information insert.  Amlodipine 2.5 mg  Rx Drug

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL