Exforge Information
Exforge (Amlodipine) Warning: Avoid Use In Pregnancy
Exforge (Amlodipine) indications And Usage
Exforge (Amlodipine) (amlodipine and valsartan) is indicated for the treatment of hypertension.
Exforge (Amlodipine) may be used in patients whose blood pressure is not adequately controlled on either monotherapy.
Exforge (Amlodipine) may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals.
The choice of Exforge (Amlodipine) as initial therapy for hypertension should be based on an assessment of potential benefits and risks including whether the patient is likely to tolerate the lowest dose of Exforge (Amlodipine) .
Patients with stage 2 hypertension (moderate or severe) are at a relatively higher risk for cardiovascular events (such as strokes, heart attacks, and heart failure), kidney failure and vision problems, so prompt treatment is clinically relevant. The decision to use a combination as initial therapy should be individualized and should be shaped by considerations such as baseline blood pressure, the target goal and the incremental likelihood of achieving goal with a combination compared to monotherapy. Individual blood pressure goals may vary based upon the patient’s risk.
Data from the high-dose multifactorial study [ ] provide estimates of the probability of reaching a blood pressure goal with Exforge (Amlodipine) compared to amlodipine or valsartan monotherapy. The figures below provide estimates of the likelihood of achieving systolic or diastolic blood pressure control with Exforge (Amlodipine) 10/320 mg, based upon baseline systolic or diastolic blood pressure. The curve of each treatment group was estimated by logistic regression modeling. The estimated likelihood at the right tail of each curve is less reliable due to small numbers of subjects with high baseline blood pressures.
For example, a patient with a baseline blood pressure of 160/100 mmHg has about a 67% likelihood of achieving a goal of
Exforge (Amlodipine) dosage And Administration
Amlodipine is an effective treatment of hypertension in once daily doses of 2.5 mg to 10 mg while valsartan is effective in doses of 80 mg to 320 mg. In clinical trials with once daily Exforge (Amlodipine) (amlodipine and valsartan) using amlodipine doses of 5 mg to 10 mg and valsartan doses of 160 mg to 320 mg, the antihypertensive effects increased with increasing doses.
The hazards [ ] of valsartan are generally independent of dose; those of amlodipine are a mixture of dose-dependent phenomena (primarily peripheral edema) and dose-independent phenomena, the former much more common than the latter [ ].
The majority of the antihypertensive effect is attained within 2 weeks after initiation of therapy or a change in dose. The dosage can be increased after 1 to 2 weeks of therapy to a maximum of one 10/320 mg tablet once daily as needed to control blood pressure [ ].
Exforge (Amlodipine) may be administered with or without food.
Exforge (Amlodipine) may be administered with other antihypertensive agents.
Elderly patients
Renal Impairment
Hepatic Impairment
A patient whose blood pressure is not adequately controlled with amlodipine (or another dihydropyridine calcium-channel blocker) alone or with valsartan (or another angiotensin II receptor blocker) alone may be switched to combination therapy with Exforge (Amlodipine) .
A patient who experiences dose-limiting adverse reactions on either component alone may be switched to Exforge (Amlodipine) containing a lower dose of that component in combination with the other to achieve similar blood pressure reductions. The clinical response to Exforge (Amlodipine) should be subsequently evaluated and if blood pressure remains uncontrolled after 3 to 4 weeks of therapy, the dose may be titrated up to a maximum of 10/320 mg.
Exforge (Amlodipine) dosage Forms And Strengths
5/160 mg tablets, debossed with NVR/ECE (side 1/side 2)
10/160 mg tablets, debossed with NVR/UIC
5/320 mg tablets, debossed with NVR/CSF
10/320 mg tablets, debossed with NVR/LUF
Exforge (Amlodipine) Arraycontraindications
Exforge (Amlodipine) warnings And Precautions
Exforge (Amlodipine) can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus
Drugs that act on the renin angiotensin system can cause fetal and neonatal morbidity and mortality when used in pregnancy. In several dozen published cases, ACE inhibitor use during the second and third trimesters of pregnancy was associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death [ ]
Excessive hypotension was seen in 0.4% of patients with uncomplicated hypertension treated with Exforge (Amlodipine) in placebo-controlled studies. In patients with an activated renin-angiotensin system, such as volume-and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur in patients receiving angiotensin receptor blockers. Volume depletion should be corrected prior to administration of Exforge (Amlodipine) . Treatment with Exforge (Amlodipine) should start under close medical supervision.
Initiate therapy cautiously in patients with heart failure or recent myocardial infarction and in patients undergoing surgery or dialysis. Patients with heart failure or post-myocardial infarction patients given valsartan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. In controlled trials in heart failure patients, the incidence of hypotension in valsartan-treated patients was 5.5% compared to 1.8% in placebo-treated patients. In the Valsartan in Acute Myocardial Infarction Trial (VALIANT), hypotension in post-myocardial infarction patients led to permanent discontinuation of therapy in 1.4% of valsartan-treated patients and 0.8% of captopril-treated patients.
Since the vasodilation induced by amlodipine is gradual in onset, acute hypotension has rarely been reported after oral administration. Nonetheless, caution, as with any other peripheral vasodilator, should be exercised when administering amlodipine, particularly in patients with severe aortic stenosis.
If excessive hypotension occurs with Exforge (Amlodipine) , the patient should be placed in a supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.
In studies of ACE inhibitors in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen have been reported. In a 4-day trial of valsartan in 12 hypertensive patients with unilateral renal artery stenosis, no significant increases in serum creatinine or blood urea nitrogen were observed. There has been no long-term use of valsartan in patients with unilateral or bilateral renal artery stenosis, but an effect similar to that seen with ACE inhibitors should be anticipated.
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may occur particularly in volume depleted patients. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar outcomes have been reported with valsartan.
Exforge (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. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
Exforge (Amlodipine) has been evaluated for safety in over 2,600 patients with hypertension; over 1,440 of these patients were treated for at least 6 months and over 540 of these patients were treated for at least one year. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy.
The overall frequency of adverse reactions was neither dose-related nor related to gender, age, or race. In placebo-controlled clinical trials, discontinuation due to side effects occurred in 1.8% of patients in the Exforge (Amlodipine) -treated patients and 2.1% in the placebo-treated group. The most common reasons for discontinuation of therapy with Exforge (Amlodipine) were peripheral edema (0.4%), and vertigo (0.2%).
The adverse reactions that occurred in placebo-controlled clinical trials in at least 2% of patients treated with Exforge (Amlodipine) but at a higher incidence in amlodipine/valsartan patients (n=1,437) than placebo (n=337) included peripheral edema (5.4% vs. 3.0%), nasopharyngitis (4.3% vs. 1.8%), upper respiratory tract infection (2.9% vs 2.1%) and dizziness (2.1% vs 0.9%).
Orthostatic events (orthostatic hypotension and postural dizziness) were seen in less than 1% of patients.
Other adverse reactions that occurred in placebo-controlled clinical trials with Exforge (Amlodipine) (≥ 0.2%) are listed below. It cannot be determined whether these events were causally related to Exforge (Amlodipine) .
Blood and Lymphatic System Disorders:
Cardiac Disorders:
Ear and Labyrinth Disorders:
Gastrointestinal Disorders:
General Disorders and Administration Site Conditions:
Immune System Disorders:
Infections and Infestations:
Metabolism and Nutrition Disorders:
Musculoskeletal and Connective Tissue Disorders:
Nervous System Disorders:
Psychiatric Disorders:
Renal and Urinary Disorders:
Reproductive System and Breast Disorders:
Respiratory, Thoracic and Mediastinal Disorders:
Skin and Subcutaneous Tissue Disorders:
Vascular Disorders:
Isolated cases of the following clinically notable adverse reactions were also observed in clinical trials: exanthema, syncope, visual disturbance, hypersensitivity, tinnitus, and hypotension.
Studies with Amlodipine:
Norvasc has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. Other adverse events that have been reported 0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain were:
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:
Other events reported with amlodipine at a frequency of ≤0.1% of patients include: 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, 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.
Adverse reactions reported for amlodipine for indications other than hypertension may be found in the prescribing information for Norvasc.
Studies with Valsartan:
Diovan has been evaluated for safety in more than 4,000 hypertensive patients in clinical trials. In trials in which valsartan was compared to an ACE inhibitor with or without placebo, the incidence of dry cough was significantly greater in the ACE inhibitor group (7.9%) than in the groups who received valsartan (2.6%) or placebo (1.5%). In a 129 patient trial limited to patients who had had dry cough when they had previously received ACE inhibitors, the incidences of cough in patients who received valsartan, HCTZ, or lisinopril were 20%, 19%, and 69% respectively (p
Other adverse reactions, not listed above, occurring in >0.2% of patients in controlled clinical trials with valsartan are:
Body as a Whole:
Musculoskeletal:
Neurologic and Psychiatric:
Urogenital:
Other reported events seen less frequently in clinical trials were: angioedema.
Adverse reactions reported for valsartan for indications other than hypertension may be found in the prescribing information for Diovan.
Amlodipine:
Valsartan:
Blood and Lymphatic:
Hypersensitivity:
Digestive:
Renal:
Clinical Laboratory Tests:
Dermatologic:
Vascular:
Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
Exforge (Amlodipine) drug Interactions
No drug interaction studies have been conducted with Exforge (Amlodipine) and other drugs, although studies have been conducted with the individual amlodipine and valsartan components, as described below:
Studies with Amlodipine
In clinical trials, amlodipine 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.
Cimetidine:
Grapefruit juice:
Sildenafil:
®
Atorvastatin:
Digoxin:
Warfarin:
Simvastatin:
Studies with Valsartan
No clinically significant pharmacokinetic interactions were observed when valsartan was co-administered with amlodipine, atenolol, cimetidine, digoxin, furosemide, glyburide, hydrochlorothiazide, or indomethacin. The valsartan-atenolol combination was more antihypertensive than either component, but it did not lower the heart rate more than atenolol alone.
Warfarin:
The antihypertensive effect of angiotensin II receptor antagonists, including valsartan may be attenuated by NSAIDs including selective COX-2 inhibitors.
In vitro
Pharmacokinetics, Valsartan
Neutropenia:
Exforge (Amlodipine) use In Specific Populations
Pregnancy Category D [see ]
Exforge (Amlodipine) , like other drugs that act on the renin angiotensin system, can cause fetal and neonatal morbidity and death when used during the second or third trimester of pregnancy. Exforge (Amlodipine) can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Angiotensin II receptor antagonists, like valsartan, and angiotensin converting enzyme (ACE) inhibitors exert similar effects on the renin-angiotensin system. In several dozen published cases, ACE inhibitor use during the second and third trimesters of pregnancy was associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios was also reported, presumably from decreased fetal renal function. In this setting, oligohydramnios was associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus were also reported, although it is not clear whether these occurrences were due to exposure to the drug. In a retrospective study, first trimester use of ACE inhibitors, a specific class of drugs acting on the renin angiotensin system, was associated with a potential risk of birth defects.
When pregnancy occurs in a patient using Exforge (Amlodipine) , the physician should discontinue Exforge (Amlodipine) treatment as soon as possible. The physician should inform the patient about potential risks to the fetus based on the time of gestational exposure to Exforge (Amlodipine) (first trimester only or later). If exposure occurs beyond the first trimester, an ultrasound examination should be done.
In rare cases when another antihypertensive agent cannot be used to treat the pregnant patient, serial ultrasound examinations should be performed to assess the intraamniotic environment. Routine fetal testing with non-stress tests, biophysical profiles, and/or contraction stress tests may be appropriate based on gestational age and standards of care in the community. If oligohydramnios occurs in these situations, individualized decisions about continuing or discontinuing Exforge (Amlodipine) treatment and about pregnancy management should be made by the patient, her physician, and experts in the management of high risk pregnancy. Patients and physicians should be aware that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Infants with histories of exposure to Exforge (Amlodipine) should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, these infants may require blood pressure and renal perfusion support. Exchange transfusion or dialysis may be required to reverse hypotension and/or support decreased renal function.
Healthcare professionals who prescribe drugs acting directly on the renin angiotensin system should counsel women of childbearing potential about the risks of these agents during pregnancy [see ]
It is not known whether amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while amlodipine is administered.
It is not known whether valsartan is excreted in human milk. Valsartan was excreted into the milk of lactating rats; however, animal breast milk drug levels may not accurately reflect human breast milk levels. Because many drugs are excreted into human milk and because of the potential for adverse reactions in nursing infants from Exforge (Amlodipine) , a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
In controlled clinical trials, 323 (22.5%) hypertensive patients treated with Exforge (Amlodipine) were ≥65 years and 79 (5.5%) were ≥75 years. No overall differences in the efficacy or safety of Exforge (Amlodipine) was observed in this patient population, but greater sensitivity of some older individuals cannot be ruled out.
Valsartan:
Exforge (Amlodipine) overdosage
Single oral doses of amlodipine maleate equivalent to 40 mg/kg and 100 mg/kg amlodipine in mice and rats, respectively, caused deaths. Single oral doses equivalent to 4 or more mg/kg amlodipine in dogs (11 or more times the maximum recommended human dose on a mg/m basis) caused a marked peripheral vasodilation and hypotension.
Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension. In humans, experience with intentional overdosage of amlodipine is limited. Reports of intentional overdosage include a patient who ingested 250 mg and was asymptomatic and was not hospitalized; another (120 mg) who 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 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 was 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 amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.
Limited data are available related to overdosage in humans. The most likely effect of overdose with valsartan would be peripheral vasodilation, hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. Depressed level of consciousness, circulatory collapse and shock have been reported. If symptomatic hypotension should occur, supportive treatment should be instituted.
Valsartan is not removed from the plasma by hemodialysis.
Valsartan was without grossly observable adverse effects at single oral doses up to 2000 mg/kg in rats and up to 1000 mg/kg in marmosets, except for the salivation and diarrhea in the rat and vomiting in the marmoset at the highest dose (60 and 37 times, respectively, the maximum recommended human dose on a mg/m basis). (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.)
Exforge (Amlodipine) description
Exforge (Amlodipine) is a fixed combination of amlodipine and valsartan.
Exforge (Amlodipine) contains the besylate salt of amlodipine, a dihydropyridine calcium-channel blocker (CCB). Amlodipine besylate is a white to pale yellow crystalline powder, slightly soluble in water and sparingly soluble in ethanol. Amlodipine besylate’s chemical name is 3-Ethyl-5-methyl(4RS)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate benzenesulphonate; its structural formula is
Its empirical formula is CHClNO•CHOS and its molecular weight is 567.1.
Valsartan is a nonpeptide, orally active, and specific angiotensin II antagonist acting on the AT receptor subtype. Valsartan is a white to practically white fine powder, soluble in ethanol and methanol and slightly soluble in water. Valsartan’s chemical name is N-(1-oxopentyl)-N-[[2’-(1H-tetrazol-5-yl) [1,1’-biphenyl]-4-yl]methyl]-L-valine; its structural formula is
Its empirical formula is CHNO and its molecular weight is 435.5.
Exforge (Amlodipine) tablets are formulated in four strengths for oral administration with a combination of amlodipine besylate, equivalent to 5 mg or 10 mg of amlodipine free-base, with 160 mg, or 320 mg of valsartan providing for the following available combinations: 5/160 mg, 10/160 mg, 5/320 mg, and 10/320 mg.
The inactive ingredients for all strengths of the tablets are colloidal silicon dioxide, crospovidone, magnesium stearate and microcrystalline cellulose. Additionally the 5/320 mg and 10/320 mg strengths contain iron oxide yellow and sodium starch glycolate. The film coating contains hypromellose, iron oxides, polyethylene glycol, talc and titanium dioxide.
Exforge (Amlodipine) clinical Pharmacology
Amlodipine
Amlodipine is a dihydropyridine calcium 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.
Valsartan
Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Valsartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis.
There is also an AT receptor found in many tissues, but AT is not known to be associated with cardiovascular homeostasis. Valsartan has much greater affinity (about 20,000-fold) for the AT receptor than for the AT receptor. The increased plasma levels of angiotensin following AT receptor blockade with valsartan may stimulate the unblocked AT receptor. The primary metabolite of valsartan is essentially inactive with an affinity for the AT receptor about one-200 that of valsartan itself.
Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because valsartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of valsartan on blood pressure.
Amlodipine
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 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 pressure (+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 normals or well-compensated patients with heart failure with agents possessing significant negative inotropic 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 of 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.
Amlodipine has indications other than hypertension which can be found in the Norvasc* package insert.
Valsartan
Valsartan inhibits the pressor effect of angiotensin II infusions. An oral dose of 80 mg inhibits the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours. No information on the effect of larger doses is available.
Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin and consequent rise in angiotensin II plasma concentration in hypertensive patients. Minimal decreases in plasma aldosterone were observed after administration of valsartan; very little effect on serum potassium was observed.
In multiple dose studies in hypertensive patients with stable renal insufficiency and patients with renovascular hypertension, valsartan had no clinically significant effects on glomerular filtration rate, filtration fraction, creatinine clearance, or renal plasma flow.
Administration of valsartan to patients with essential hypertension results in a significant reduction of sitting, supine, and standing systolic blood pressure, usually with little or no orthostatic change. Valsartan has indications other than hypertension which can be found in the Diovan package insert.
Exforge (Amlodipine)
Exforge (Amlodipine) has been shown to be effective in lowering blood pressure. Both amlodipine and valsartan lower blood pressure by reducing peripheral resistance, but calcium influx blockade and reduction of angiotensin II vasoconstriction are complementary mechanisms.
Amlodipine
Peak plasma concentrations of amlodipine are reached 6-12 hours after administration of amlodipine alone. Absolute bioavailability has been estimated to be between 64% and 90%. The bioavailability of amlodipine is not altered by the presence of food.
The apparent volume of distribution of amlodipine is 21 L/kg. Approximately 93% of circulating amlodipine is bound to plasma proteins in hypertensive patients.
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.
Elimination of amlodipine 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 7-8 days of consecutive daily dosing.
Valsartan
Following oral administration of valsartan alone peak plasma concentrations of valsartan are reached in 2-4 hours. Absolute bioavailability is about 25% (range 10%-35%). Food decreases the exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (C) by about 50%.
The steady state volume of distribution of valsartan after intravenous administration is 17 L indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (95%), mainly serum albumin.
Valsartan shows bi-exponential decay kinetics following intravenous administration with an average elimination half-life of about 6 hours. The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and co-administered drugs are unlikely because of the low extent of metabolism.
Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). Following intravenous administration, plasma clearance of valsartan is about 2 L/h and its renal clearance is 0.62 L/h (about 30% of total clearance).
Exforge (Amlodipine)
Following oral administration of Exforge (Amlodipine) in normal healthy adults, peak plasma concentrations of valsartan and amlodipine are reached in 3 and 6-8 hours, respectively. The rate and extent of absorption of valsartan and amlodipine from Exforge (Amlodipine) are the same as when administered as individual tablets. The bioavailabilities of amlodipine and valsartan are not altered by the co-administration of food.
Special Populations
Geriatric
Gender
Studies with Valsartan:
Renal Insufficiency
Studies with Amlodipine:
Studies with Valsartan:
Hepatic Insufficiency
Studies with Amlodipine:
Studies with Valsartan:
Exforge (Amlodipine) nonclinical Toxicology
Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg amlodipine/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on mg/m basis, similar to the maximum recommended human dose [MRHD] of 10 mg amlodipine/day. For the rat, the highest dose was, on a mg/m basis, about two and a half times the MRHD. (Calculations based on a 60 kg patient.)
Mutagenicity studies conducted with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level.
There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of up to 10 mg amlodipine/kg/day (about 10 times the MRHD of 10 mg/day on a mg/m basis).
There was no evidence of carcinogenicity when valsartan was administered in the diet to mice and rats for up to 2 years at concentrations calculated to provide doses of up to 160 and 200 mg/kg/day, respectively. These doses in mice and rats are about 2.4 and 6 times, respectively, the MRHD of 320 mg/day on a mg/m basis. (Calculations based on a 60 kg patient.)
Mutagenicity assays did not reveal any valsartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella and E. coli, a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with Chinese hamster ovary cells, and a rat micronucleus test.
Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses of up to 200 mg/kg/day. This dose is about 6 times the maximum recommended human dose on a mg/m basis.
No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses of up to 10 mg amlodipine/kg/day (respectively, about 10 and 20 times the maximum recommended human dose [MRHD] of 10 mg amlodipine on a mg/m basis) during their respective periods of major organogenesis. (Calculations based on a patient weight of 60 kg.) However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) for 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. 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.
No teratogenic effects were observed when valsartan was administered to pregnant mice and rats at oral doses of up to 600 mg/kg/day and to pregnant rabbits at oral doses of up to 10 mg/kg/day. However, significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones were observed in studies in which parental rats were treated with valsartan at oral, maternally toxic (reduction in body weight gain and food consumption) doses of 600 mg/kg/day during organogenesis or late gestation and lactation. In rabbits, fetotoxicity (i.e., resorptions, litter loss, abortions, and low body weight) associated with maternal toxicity (mortality) was observed at doses of 5 and 10 mg/kg/day. The no observed adverse effect doses of 600, 200 and 2 mg/kg/day in mice, rats and rabbits, respectively, are about 9, 6 and 0.1 times the MRHD of 320 mg/day on a mg/m basis. (Calculations based on a patient weight of 60 kg.)
In the oral embryo-fetal development study in rats using amlodipine besylate plus valsartan at doses equivalent to 5 mg/kg/day amlodipine plus 80 mg/kg/day valsartan, 10 mg/kg/day amlodipine plus 160 mg/kg/day valsartan, and 20 mg/kg/day amlodipine plus 320 mg/kg/day valsartan, treatment-related maternal and fetal effects (developmental delays and alterations noted in the presence of significant maternal toxicity) were noted with the high dose combination. The no-observed-adverse-effect level (NOAEL) for embryo-fetal effects was 10 mg/kg/day amlodipine plus 160 mg/kg/day valsartan. On a systemic exposure [AUC] basis, these doses are, respectively, 4.3 and 2.7 times the systemic exposure [AUC] in humans receiving the MRHD (10/320 mg/60 kg).
Exforge (Amlodipine) clinical Studies
Exforge (Amlodipine) was studied in 2 placebo-controlled and 4 active-controlled trials in hypertensive patients. In a double-blind, placebo controlled study, a total of 1,012 patients with mild-to-moderate hypertension received treatments of three combinations of amlodipine and valsartan (5/80, 5/160, 5/320 mg) or amlodipine alone (5 mg), valsartan alone (80, 160, or 320 mg) or placebo. All doses with the exception of the 5/320 mg dose were initiated at the randomized dose. The high dose was titrated to that dose after a week at a dose of 5/160 mg. At week 8, the combination treatments were statistically significantly superior to their monotherapy components in reduction of diastolic and systolic blood pressures.
*Mean Change and Placebo-Subtracted Mean Change from Baseline (mmHg) at Week 8 in Sitting Diastolic Blood Pressure. Mean baseline diastolic BP was 99.3 mmHg.
*Mean Change and Placebo-Subtracted Mean Change from Baseline (mmHg) at Week 8 in Sitting Systolic Blood Pressure. Mean baseline systolic BP was 152.8 mmHg.
In a double-blind, placebo controlled study, a total of 1,246 patients with mild to moderate hypertension received treatments of two combinations of amlodipine and valsartan (10/160, 10/320 mg) or amlodipine alone (10 mg), valsartan alone (160 or 320 mg) or placebo. With the exception of the 10/320 mg dose, treatment was initiated at the randomized dose. The high dose was initiated at a dose of 5/160 mg and titrated to the randomized dose after 1 week. At week 8, the combination treatments were statistically significantly superior to their monotherapy components in reduction of diastolic and systolic blood pressures.
*Mean Change and Placebo-Subtracted Mean Change from Baseline (mmHg) at Week 8 in Sitting Diastolic Blood Pressure. Mean baseline diastolic BP was 99.1 mmHg.
*Mean Change and Placebo-Subtracted Mean Change from Baseline (mmHg) at Week 8 in Sitting Systolic Blood Pressure. Mean baseline systolic BP was 156.7 mmHg.
In a double-blind, active-controlled study, a total of 947 patients with mild to moderate hypertension who were not adequately controlled on valsartan 160 mg received treatments of two combinations of amlodipine and valsartan (10/160, 5/160 mg), or valsartan alone (160 mg). At week 8, the combination treatments were statistically significantly superior to the monotherapy component in reduction of diastolic and systolic blood pressures.
*Mean Change from Baseline at Week 8 in Sitting Diastolic/Systolic Blood Pressure. Mean baseline BP was 149.5/96.5 (systolic/diastolic) mmHg
**Treatment Difference = difference in mean BP reduction between Exforge (Amlodipine) and the control group (Valsartan 160 mg)
In a double-blind, active-controlled study, a total of 944 patients with mild to moderate hypertension who were not adequately controlled on amlodipine 10 mg received a combination of amlodipine and valsartan (10/160 mg), or amlodipine alone (10 mg). At week 8, the combination treatment was statistically significantly superior to the monotherapy component in reduction of diastolic and systolic blood pressures.
*Mean Change from Baseline at Week 8 in Sitting Diastolic/Systolic Blood Pressure. Mean baseline BP was 147.0/95.1 (systolic/diastolic) mmHg
**Treatment Difference = difference in mean BP reduction between Exforge (Amlodipine) and the control group (Amlodipine 10 mg)
Exforge (Amlodipine) was also evaluated for safety in a 6-week, double-blind, active-controlled trial of 130 hypertensive patients with severe hypertension (mean baseline BP of 171/113 mmHg). Adverse events were similar in patients with severe hypertension and mild/moderate hypertension treated with Exforge (Amlodipine) .
A wide age range of the adult population, including the elderly was studied (range 19-92 years, mean 54.7 years). Women comprised almost half of the studied population (47.3%). Of the patients in the studied Exforge (Amlodipine) group, 87.6% were Caucasian. Black and Asian patients each represented approximately 4% of the population in the studied Exforge (Amlodipine) group.
Two additional double-blind, active-controlled studies were conducted in which Exforge (Amlodipine) was administered as initial therapy. In one study, a total of 572 Black patients with moderate to severe hypertension were randomized to receive either combination amlodipine/valsartan or amlodipine monotherapy for 12 weeks. The initial dose of amlodipine/valsartan was 5/160 mg for 2 weeks with forced titration to 10/160 mg for 2 weeks, followed by optional titration to 10/320 mg for 4 weeks and optional addition of HCTZ 12.5 mg for 4 weeks. The initial dose of amlodipine was 5 mg for 2 weeks with forced titration to 10 mg for 2 weeks, followed by optional titration to 10 mg for 4 weeks and optional addition of HCTZ 12.5 mg for 4 weeks. At the primary endpoint of 8 weeks, the treatment difference between amlodipine/valsartan and amlodipine was 6.7/2.8 mmHg.
In the other study of similar design, a total of 646 patients with moderate to severe hypertension (MSSBP of ≥ 160 mmHg and
There are no trials of the Exforge (Amlodipine) combination tablet demonstrating reductions in cardiovascular risk in patients with hypertension, but the amlodipine component and several ARBs, which are the same pharmacological class as the valsartan component, have demonstrated such benefits.
Exforge (Amlodipine) how Supplied/storage And Handling
Exforge (Amlodipine) is available as non-scored tablets containing amlodipine besylate equivalent to 5 mg, or 10 mg of amlodipine free-base with valsartan 160 mg or 320 mg, providing for the following available combinations: 5/160 mg, 10/160 mg, 5/320 mg and 10/320 mg.
All strengths are packaged in bottles of 30 and 90 count.
5/160 mg Tablets - dark yellow, ovaloid shaped, film coated tablet with beveled edge, debossed with “NVR” on one side and “ECE” on the other side.
Bottles of 30 NDC # 0078-0488-15
Bottles of 90 NDC # 0078-0488-34
10/160 mg Tablets - light yellow, ovaloid shaped, film coated tablet with beveled edge, debossed with “NVR” on one side and “UIC” on the other side.
Bottles of 30 NDC # 0078-0489-15
Bottles of 90 NDC # 0078-0489-34
5/320 mg Tablets - very dark yellow, ovaloid shaped, film coated tablet with beveled edge, debossed with “NVR” on one side and “CSF” on the other side.
Bottles of 30 NDC # 0078-0490-15
Bottles of 90 NDC # 0078-0490-34
10/320 mg Tablets - dark yellow, ovaloid shaped, film coated tablet with beveled edge, debossed with “NVR” on one side and “LUF” on the other side.
Bottles of 30 NDC # 0078-0491-15
Bottles of 90 NDC # 0078-0491-34
Store at 25C (77F); excursions permitted to 15-30C (59-86F). [See USP Controlled Room Temperature.] Protect from moisture.
Exforge (Amlodipine)
Exforge (Amlodipine)
Exforge (Amlodipine)
Exforge (Amlodipine)
Exforge (Amlodipine)
