Exforge 5/160 (amlodipine / valsartan) Oral Tablet
DRUG INTERACTIONS
No drug interaction studies have been conducted with Exforge and other drugs, although studies have been conducted with the individual amlodipine and valsartan components.
Studies with Amlodipine Simvastatin: Coadministration of simvastatin with amlodipine increases the systemic exposure of simvastatin.
Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.
CYP3A4 Inhibitors: Coadministration with CYP3A4 inhibitors (moderate and strong) result in increased systemic exposure to amlodipine warranting dose reduction.
Monitor for symptoms of hypotension and edema when amlodipine is coadministered with CYP3A4 inhibitors to determine the need for dose adjustment.
CYP3A4 Inducers: No information is available on the quantitative effects of CYP3A4 inducers on amlodipine.
Blood pressure should be monitored when amlodipine is coadministered with CYP3A4 inducers.
Studies with Valsartan No clinically significant pharmacokinetic interactions were observed when valsartan was coadministered 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: Coadministration of valsartan and warfarin did not change the pharmacokinetics of valsartan or the time-course of the anticoagulant properties of warfarin.
Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including valsartan, may result in deterioration of renal function, including possible acute renal failure.
These effects are usually reversible.
Monitor renal function periodically in patients receiving valsartan and NSAID therapy.
The antihypertensive effect of angiotensin II receptor antagonists, including valsartan may be attenuated by NSAIDs including selective COX-2 inhibitors.
Potassium: Concomitant use of valsartan with other agents that block the renin-angiotensin system, potassium sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium and in heart failure patients to increases in serum creatinine.
If co-medication is considered necessary, monitoring of serum potassium is advisable.
CYP 450 Interactions: In vitro metabolism studies indicate that CYP 450 mediated drug interactions between valsartan and coadministered drugs are unlikely because of low extent of metabolism [see Pharmacokinetics, Valsartan (12.3)].
Transporters: The results from an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2.
Coadministration of inhibitors of the uptake transporter (rifampin, cyclosporine) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.
Dual Blockade of the Renin-Angiotensin System (RAS): Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy.
Closely monitor blood pressure, renal function, and electrolytes in patients on Exforge and other agents that affect the RAS.
Do not coadminister aliskiren with Exforge in patients with diabetes.
Avoid use of aliskiren with Exforge in patients with renal impairment (GFR <60 mL/min).
OVERDOSAGE
Information on Amlodipine 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 2 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.
Marked and potentially prolonged systemic hypotension up to and including shock with fatal outcome have been reported.
If massive overdose should occur, initiate active cardiac and respiratory monitoring.
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, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output.
As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.
Administration of activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine has been shown to significantly decrease amlodipine absorption.
Information on Valsartan 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 (MRHD) on a mg/m 2 basis).
(Calculations assume an oral dose of 320 mg/day and a 60-kg patient.)
DESCRIPTION
Exforge is a fixed combination of amlodipine and valsartan.
Exforge 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 C 20 H 25 ClN 2 O 5 •C 6 H 6 O 3 S and its molecular weight is 567.1.
Valsartan is a nonpeptide, orally active, and specific angiotensin II antagonist acting on the AT 1 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 C 24 H 29 N 5 O 3 and its molecular weight is 435.5.
Exforge tablets are formulated in 4 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.
CLINICAL STUDIES
Exforge was studied in 2 placebo-controlled and 4 active-controlled trials in hypertensive patients.
In a double-blind, placebo-controlled study, a total of 1012 patients with mild-to-moderate hypertension received treatments of 3 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.
Table 1: Effect of Exforge on Sitting Diastolic Blood Pressure Amlodipine dosage Valsartan dosage 0 mg 80 mg 160 mg 320 mg Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted 0 mg -6.4 — -9.5 -3.1 -10.9 -4.5 -13.2 -6.7 5 mg -11.1 -4.7 -14.2 -7.8 -14.0 -7.6 -15.7 -9.3 *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.
Table 2: Effect of Exforge on Sitting Systolic Blood Pressure Amlodipine dosage Valsartan dosage 0 mg 80 mg 160 mg 320 mg Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted 0 mg -6.2 — -12.9 -6.8 -14.3 -8.2 -16.3 -10.1 5 mg -14.8 -8.6 -20.7 -14.5 -19.4 -13.2 -22.4 -16.2 *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 1246 patients with mild to moderate hypertension received treatments of 2 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.
Table 3: Effect of Exforge on Sitting Diastolic Blood Pressure Amlodipine dosage Valsartan dosage 0 mg 160 mg 320 mg Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted 0 mg -8.2 — -12.8 – 4.5 -12.8 -4.5 10 mg -15.0 -6.7 – 17.2 – 9.0 -18.1 -9.9 *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.
Table 4: Effect of Exforge on Sitting Systolic Blood Pressure Amlodipine dosage Valsartan dosage 0 mg 160 mg 320 mg Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted 0 mg -11.0 — -18.1 -7.0 -18.5 -7.5 10 mg -22.2 -11.2 -26.6 -15.5 -26.9 -15.9 *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 2 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.
Table 5: Effect of Exforge on Sitting Diastolic/Systolic Blood Pressure Treatment Group Diastolic BP Systolic BP Mean change* Treatment Difference** Mean change* Treatment Difference** Exforge 10/160 mg -11.4 -4.8 -13.9 -5.7 Exforge 5/160 mg -9.6 -3.1 -12.0 -3.9 Valsartan 160 mg -6.6 — -8.2 — *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 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.
Table 6: Effect of Exforge on Sitting Diastolic/Systolic Blood Pressure Treatment Group Diastolic BP Systolic BP Mean change* Treatment Difference** Mean change* Treatment Difference** Exforge 10/160 mg -11.8 -1.8 -12.7 -1.9 Amlodipine 10 mg -10.0 — -10.8 — *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 and the control group (Amlodipine 10 mg) Exforge 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.
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 group, 87.6% were Caucasian.
Black and Asian patients each represented approximately 4% of the population in the studied Exforge group.
Two additional double-blind, active-controlled studies were conducted in which Exforge was administered as initial therapy.
In 1 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 <200 mmHg) were randomized to receive either combination amlodipine/valsartan or amlodipine monotherapy for 8 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 the 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 the optional addition of HCTZ 12.5 mg for 4 weeks.
At the primary endpoint of 4 weeks, the treatment difference between amlodipine/valsartan and amlodipine was 6.6/3.9 mmHg.
There are no trials of the Exforge 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.
HOW SUPPLIED
Exforge 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 25 o C (77 o F); excursions permitted to 15-30 o C (59-86 o F).
[See USP Controlled Room Temperature.] Protect from moisture.
RECENT MAJOR CHANGES
Boxed Warning: Fetal Toxicity 01/2012 Indications and Usage: Benefits of lowering blood pressure ( 1 ) 12/2011 Contraindications: Known hypersensitivity ( 4 ) 09/2012 Contraindications: Dual RAS Blockade in Diabetics ( 4 ) 11/2012 Warnings and Precautions: Fetal Toxicity ( 5.1 ) 01/2012 Drug Interactions: Dual Blockade of the Renin-Angiotensin System ( 7 ) 11/2012
DOSAGE FORMS AND STRENGTHS
DOSAGE FORMS & 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
INDICATIONS AND USAGE
INDICATIONS & USAGE
BOXED WARNING
When pregnancy is detected, discontinue Exforge as soon as possible.
(5.1) Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.
(5.1)
WARNING AND CAUTIONS
WARNINGS AND PRECAUTIONS Hypotension: Correct volume depletion prior to initiation ( 5.2 ) Increased angina and/or myocardial infarction ( 5.3 ) Monitor renal function and potassium in susceptible patients ( 5.4 , 5.5 ) Pregnancy Category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.
Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.
Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.
When pregnancy is detected, discontinue Exforge as soon as possible [ see Use in Specific Populations (8.1) ].
Excessive hypotension was seen in 0.4% of patients with uncomplicated hypertension treated with Exforge 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.
Treatment with Exforge 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, 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.
Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine, particularly in patients with severe obstructive coronary artery disease.
Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics.
Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g.
patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on Exforge.
Monitor renal function periodically in these patients.
Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Exforge [see Drug Interactions (7)] .
Drugs that inhibit the renin-angiotensin system can cause hyperkalemia.
Monitor serum electrolytes periodically.
Some patients with heart failure have developed increases in potassium with valsartan therapy.
These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment.
Dosage reduction and/or discontinuation of Exforge may be required [ see Adverse Reactions (6.1) ].
INFORMATION FOR PATIENTS
Information for Patients Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to Exforge during pregnancy.
Discuss treatment options with women planning to become pregnant.
Patients should be asked to report pregnancies to their physicians as soon as possible.
T2012-215 November 2012
DOSAGE AND ADMINISTRATION
DOSAGE & ADMINISTRATION General Considerations: Majority of effect attained within 2 weeks ( 2.1 ) May be administered with other antihypertensive agents ( 2.1 ) Hypertension: May be used as add-on therapy for patients not controlled on monotherapy ( 2.2 ) Patients who experience dose-limiting adverse reactions on monotherapy may be switched to Exforge containing a lower dose of that component ( 2.2 ) May be substituted for titrated components ( 2.3 ) When used as initial therapy: Initiate with 5/160 mg, then titrate upwards as necessary to a maximum of 10/320 mg once daily ( 2.4 ) Dose once daily.
The dosage can be increased after 1 to 2 weeks of therapy to a maximum of one 10/320mg tablet once daily as needed to control blood pressure.
The majority of the antihypertensive effect is attained within 2 weeks after initiation of therapy or a change in dose.
Exforge may be administered with or without food.
Exforge may be administered with other antihypertensive agents.
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.
A patient who experiences dose-limiting adverse reactions on either component alone may be switched to Exforge containing a lower dose of that component in combination with the other to achieve similar blood pressure reductions.
The clinical response to Exforge 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.
For convenience, patients receiving amlodipine and valsartan from separate tablets may instead wish to receive tablets of Exforge containing the same component doses.
A patient may be initiated on Exforge if it is unlikely that control of blood pressure would be achieved with a single agent.
The usual starting dose is Exforge 5/160 mg once daily in patients who are not volume-depleted.